I checked 6 multidisciplinary journals on Sunday, March 29, 2026 using the Crossref API. For the period March 22 to March 28, I found 13 new paper(s) in 5 journal(s).

Nature

GPT-4o mini: Non-social science research article
Androgen activity in the male embryonic hindbrain drives lethal PFA ependymoma
Jiao Zhang, Winnie Ong, Alexandra Rasnitsyn, Ricardo Daniel Gonzalez, Rodrigo Lopez Gutierrez, Polina Balin, Amr Saadeldin, Xiaochong Wu, Maria C. Vladoiu, Vicente Santa-Maria Lopez, Fernando Gonzalez-Salinas, Navneesh Yadav, Dinesh Mohanakrishnan, Kannan Boosi Narayana Rao, Raja Gopal Reddy Mooli, Hinda Najem, Sebastian Pacheco, Kaitlin Kharas, Cory Richman, David Przelicki, Evan Y. Wang, Haipeng Su, Rachel Naomi Curry, Runze Yang, Michelle Masayo Kameda-Smith, Bryn Livingston, David Scott, Zaili Luo, Mingyang Xia, Namal Abeysundara, Anders W. Erickson, Ncedile Mankahla, Lucas ZhongMing Hu, Chu Pan, Raul Suarez, Ning Huang, Yihao Wu, Hao Wang, Tajana Douglas, Jonelle Pallota, Steven HĂ©bert, Karen Ng, Krystin Mantione, Heather Whetstone, Hassaan Maan, Hussein Lakkis, Juyeun Lee, Sadeesh K. Ramakrishnan, Yanxin Pei, Yujie Tang, Frank Y. Lin, Guillermo Aldave, Marco Gallo, Robert M. Friedlander, Faiyaz Notta, Laura K. Donovan, Murali Chintagumpala, Bo Wang, Yun Li, Daniel D. De Carvalho, Zhaolei Zhang, Ying Mao, Wei Hua, Charles Eberhart, Calixto-Hope G. Lucas, Sriram Venneti, Poul H. Sorensen, Alberto Delaidelli, Hao Li, Wenhao Zhou, Jason Kirk, Dean G. Tang, Tao Jiang, Hailong Liu, Justin D. Lathia, Hiromichi Suzuki, Jeremy N. Rich, Lincoln D. Stein, Nada Jabado, Vijay Ramaswamy, Q. Richard Lu, Amy B. Heimberger, Craig Daniels, Kulandaimanuvel Antony Michealraj, Claudia L. Kleinman, Michael D. Taylor
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Posterior fossa type A (PFA) ependymoma is an unusual infantile brain tumour with few known somatic mutations, thought to be driven by epigenetic mechanisms1. PFA ependymoma has a markedly higher incidence and worse prognosis in male children than in female children2. The mechanisms that underlie these sex differences are at present unknown. Here we show that the cellular hierarchy of PFA ependymoma is less differentiated in male individuals than it is in female individuals. In the normal developing mouse hindbrain, male gliogenic progenitors are less differentiated than matched female sibling controls. To further parse the effects of chromosomal versus gonadal contributions in the male hindbrain, we used the four-core genotype mouse model3, which showed that androgen signalling, rather than sex chromosomes, prolongs hindbrain differentiation in male mice. Androgen supplementation promotes the growth of PFA ependymoma, but not that of other brain tumours. Conversely, androgen blockade diminishes both the stem-like potential and the proliferation of PFA ependymoma. We conclude that androgen signalling in both the normal developing hindbrain and PFA ependymoma is sufficient to promote growth and delay differentiation. Anti-androgen therapies represent a potential clinical avenue to target this currently untreatable childhood cancer.
GPT-4o mini: Non-social science research article
Retraction Note: Multisensory learning binds neurons into a cross-modal memory engram
Zeynep Okray, Pedro F. Jacob, Ciara Stern, Kieran Desmond, Nils Otto, Clifford B. Talbot, Paola Vargas-Gutierrez, Scott Waddell
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GPT-4o mini: Non-social science research article
Rapid concerted switching of the neural code in the inferotemporal cortex
Yuelin Shi, Dasheng Bi, Janis K. Hesse, Frank F. Lanfranchi, Shi Chen, Doris Y. Tsao
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A fundamental paradigm in neuroscience is that neurons represent the world through fixed tuning functions, with stable mappings from stimulus features to firing rates 1 . Here, we report that tuning can instead shift rapidly and coherently across a neural population, enabling a dynamic transition from detecting a broad category to discriminating individual exemplars. We set out to address a longstanding debate in visual neuroscience about whether the inferotemporal cortex uses a specialized code for specific object categories or a general-purpose code that applies to all objects. We found that face-selective cells in macaque inferotemporal cortex initially adopted a general code optimized for face detection. However, after a rapid concerted population event lasting less than 20 ms, the neural code transformed into a face-specific one, with two striking features: response gradients to principal detection-related dimensions reversed direction, and new tuning emerged for multiple higher-dimensional features that support fine face discrimination. These dynamics in face patches were specific to face stimuli and did not occur in response to non-face objects. Thus, for faces, face cells transition from detection to discrimination by switching from an object-general code to a face-specific one. More broadly, our findings indicate that there is a previously unknown mechanism for neural representation: concerted stimulus-dependent switching of the neural code used by a cortical area.
GPT-4o mini: Non-social science research article
Moderate global warming does not rule out extreme global climate outcomes
Emanuele Bevacqua, Erich Fischer, Jana Sillmann, Jakob Zscheischler
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Effectively communicating worst-case projections of global future climate—hereinafter referred to as worst-case climate outcomes—is essential for risk assessment and developing robust adaptation strategies to global warming 1–7 . Yet, current approaches for identifying spatially consistent climate outcomes are limited, with worst-case global climates typically communicated via the average of climate model projections at high global warming levels, such as 3 °C or 4 °C above the preindustrial era 8,9 . Here we show that extreme global climate outcomes may occur even under moderate 2 °C warming for several sectors. For droughts in global key breadbasket regions, precipitation extremes over highly populated areas and fire weather extremes across forests, global climatic impact-drivers at 2 °C of global warming may turn out to be much more extreme than model-averaged projections at 3 °C or 4 °C warming. We derive these results by identifying sector-specific, spatially consistent potential high- and low-impact global climate outcomes through spatially averaging projected sector-relevant climatic impact-drivers across key global regions. Our approach can easily be adapted to a wide range of sectors to support the improvement of sector-specific climate risk assessment and to inform climate policy. As global warming approaches 1.5 °C (ref. 10 ), these findings underscore the urgency of rapid mitigation to limit warming well below 2 °C, as even a 2 °C world may entail severe impacts.
GPT-4o mini: Non-social science research article
Decadal-scale droughts disrupted the African Humid Period in the Sahara
Florence Sylvestre, Martin Melles, Volker Wennrich, MichĂšle Dinies, Françoise ChaliĂ©, Didier Swingedouw, Anne Dallmeyer, Xiaoxu Shi, Martin Claussen, Andrea Jaeschke, Christine Cocquyt, Jens Karls, Jan Kuper, Baba Mallaye, Jean-Charles Mazur, Christine PaillĂšs, Remadji Rirongarti, Janet Rethemeyer, Benedikt Ritter-Prinz, Enno Schefuß, Finn Viehberg, Bernd Wagner, Martin Werner, Abdallah N. Yacoub, Stefan Kröpelin
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During the early and mid-Holocene, the Sahara and Sahel experienced a humid phase, the so-called African Humid Period (AHP)1. The AHP started around 14.8 thousand years before present (kyr bp), peaked between 9.0 kyr bp and 6.0 kyr bp and experienced short-lived droughts of as yet poorly constrained age and duration2,3. Here we show that the AHP was punctuated by two droughts of decadal-scale duration, at about 9.3 kyr bp and 8.2 kyr bp, and another more tentatively identified drought at 6.3 kyr bp. Our findings arise from a multiproxy time series from the annually layered (varved) sedimentary archive of Lake Yoa in Chad, which covers the past 10.25 kyr continuously. During the more prominent drought at 8.2 kyr bp, pollen and diatom data, along with leaf-wax isotopes and geochemical source area indicators, imply that a reduction in local precipitation and fluvial supply to Lake Yoa caused a lake-level drop accompanied by an expansion of reed belts along the shore. The proxy data, together with our climate simulations, suggest that the 8.2 kyr bp drought event was a direct and rapid response to a potential weakening of the Atlantic Meridional Overturning Circulation (AMOC) owing to sudden freshwater input into the North Atlantic. The results underline the need for improved decadal predictions4 to better anticipate such drought risks in the future.
GPT-4o mini: Non-social science research article
Quantifying climate loss and damage consistent with a social cost of carbon
Marshall Burke, Mustafa Zahid, Noah S. Diffenbaugh, Solomon Hsiang
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Climate change is causing measurable harm globally1,2. Political and legal efforts seek to link these damages with specific emissions, including in discussions of loss and damage (L&D)3,4; however, no quantitative definition of L&D exists5,6, nor is there a framework to link past and future emissions from specific sources to monetized, location-specific damages. Here we develop such a framework, which is integrated with recent efforts to estimate the social cost of carbon7. Using empirical estimates of the non-linear relationship between temperature and aggregate economic output, we show that future damages from past emissions—one component of L&D—are at least an order of magnitude larger than historical damages from the same emissions. For instance, one tonne of CO2 emitted in 1990 caused US$180 in discounted global damages by 2020 ($40–530) and will cause an additional $1,840 through 2100 ($500–5,700). Thus, settling debts for past damages will not settle debts for past emissions. In other illustrative estimates, a single long-haul flight per year over the past decade leads to about $25k ($6,000–77,000) in future damages by 2100, and US emissions since 1990 caused $500 billion ($180–1,300 billion) of damage in India and $330 billion ($110–820 billion) in Brazil. Carbon removal offers an alternative to transfer payments for settling L&D, but is increasingly ineffective in limiting damages as the delay between emission and recapture increases.
GPT-4o mini: Non-social science research article
Exposed phosphatidylserine is an inhibitory molecule in T cell exhaustion
Christopher B. Medina, Ewelina Sobierajska, Minghao Gong, Daniel T. McManus, Maheshwor Thapa, Judong Lee, Se Jin Im, Jason E. Toombs, Joshua M. Mitchell, Yating Wang, Jennifer W. Carlisle, Gordon J. Freeman, Viraj A. Master, Suresh S. Ramalingam, Haydn T. Kissick, Shuzhao Li, Rolf A. Brekken, Rafi Ahmed
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In cancer and chronic infection, CD8 T cell exhaustion is hallmarked by expression of inhibitory receptors such as PD1, TIM3, LAG3 and others1,2,3. Thus, inhibitory molecule focus has been limited to cell-surface proteins. Here we evaluate the surface lipid metabolite phosphatidylserine (PS) as a regulator of exhaustion. PS primarily localizes to the inner plasma membrane of live cells but is well known to be externalized to the outer membrane during cell death. The role of exposed PS on live immune cells is less clear. We show that viable, antigen-specific CD8 T cells externalize PS during lymphocytic choriomeningitis virus (LCMV) infection. T cell activation induced initial PS exposure, and chronic antigen stimulation sustained externalization. Transcriptomic and lipidomic analyses also identified PS accumulation in exhausted CD8 T cells. To evaluate a role for exposed PS in exhaustion, we treated LCMV chronically infected mice with a PS-targeting antibody (mch1N11)4 and found that it expanded LCMV-specific CD8 responses. PD1+TCF1+ stem-like CD8 T cells downregulated quiescence-associated gene modules and increased proliferation after antibody treatment, highlighting an inhibitory role for PS. Mechanistically, exposed PS on T cells functioned extrinsically to suppress dendritic cell immunostimulatory phenotypes, in turn limiting CD8 T cell responses. PS-targeting antibody with anti-PDL1 synergized to increase CD8 responses and improve viral control. Finally, we show that PD1+ CD8 T cells from human tumours can also expose PS. In summary, we detail CD8 T cell PS biology and provide insight into a mechanism by which exposed PS functions as a ‘non-classical’ extrinsic inhibitory molecule in exhaustion.
GPT-4o mini: Non-social science research article
Disequilibrium response to tapping crustal magma reveals storage conditions
Janine Birnbaum, Fabian B. Wadsworth, Jackie E. Kendrick, Ben Kennedy, Paul A. Wallace, Marize Muniz da Silva, Kai-Uwe Hess, Yan Lavallée
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The conditions under which magma accumulates and is stored are fundamental to unravelling the processes of crust formation, planetary differentiation, geothermal heat recharge and volcanic eruptions. Storage pressure, temperature and volatile saturation are typically inferred from erupted volcanic products. However, changes during kilometres of magma ascent induce disequilibrium crystallization and vesiculation, and inverting back to storage conditions comes with unresolvable uncertainties. Here we explore opportunities arising from magma drilling at Krafla volcano, Iceland, to reconstruct real, in situ magmatic conditions. The findings show that, over the approximately 5 min in which the magma is quenched, vapour bubbles consisting of H 2 O and CO 2 exsolve, grow and resorb, but the changes can be accounted for by multiparametric inversion (for chemistry, vesicularity and vitrification), and that the magma was stored under volatile-saturated lithostatic conditions, unlike previous assertions of lower vapour pressures based on classic methods 1 . These new disequilibrium simulations reconcile the glass chemistry with conceptual models of magma storage and provide us with the unique pairing of precisely measured depth and volatile pressure on a single magma body and thus a robust method to improve our understanding of magma storage conditions and evolution.
GPT-4o mini: Non-social science research article
Functional hierarchy of the human neocortex across the lifespan
Hoyt Patrick Taylor, Khoi Minh Huynh, Kim-Han Thung, Guoye Lin, Wenjiao Lyu, Weili Lin, Sahar Ahmad, Pew-Thian Yap
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Large-scale gradients of functional connectivity between brain areas organize the human neocortex, linking brain topography to the texture of cognition 1,2 . In adults, three dominant axes—sensory–association, visual–somatosensory and modulation–representation—run, respectively, from primary sensory to transmodal association areas, from visual to body-centred systems and from control and attention networks to default mode and sensory areas 1–4 . These gradients provide a compact description of large-scale cortical hierarchies that underlie distinct modes of information processing. However, how these gradients and their multiscale biological and cognitive correlates evolve across the lifespan is unknown. Here we establish a continuous normative reference of functional organization from birth to 100 years of age, revealing complex, nonlinear developmental trajectories. Gradient architecture is anchored by primary sensory systems in infancy, differentiates along association and control axes during childhood and adolescence and gradually dedifferentiates during ageing. The importance of this functional architecture is corroborated by biology and behaviour: gradient metrics predict cognitive performance across development; structure–function coupling varies by axis and age; and distinct transcriptomic signatures are strongest early in life and weaken with age, consistent with a transient genetic scaffold for gradient architecture. Our lifespan gradients unify diverse research into developmental brain connectivity and provide a shared multimodal reference for future studies.
GPT-4o mini: Non-social science research article
The DNA virome varies with human genes and environments
Nolan Kamitaki, David Tang, Steven A. McCarroll, Po-Ru Loh
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Many viruses have adapted to persist in infected humans for life 1,2 . Variable host control of their ongoing abundance (viral load) can lead to clearance or disease 3–5 . Here we analysed the viral DNA load of 31 common viruses in human blood and saliva using whole-genome sequencing data from UK Biobank ( n = 490,401), All of Us ( n = 414,817) and Simons Foundation Powering Autism Research for Knowledge (SPARK; n = 12,519). Viral DNA load varied markedly with age, time of day and season; most viruses were also present at greater abundance in men than in women. Human genetic variation at dozens of loci associated with DNA load of seven viruses: Epstein–Barr virus (EBV, 45 loci), human herpesvirus (HHV)-7 (37 loci), HHV-6B, Merkel cell polyomavirus and three anelloviruses. Variation at the major histocompatibility complex (MHC) locus generated the strongest associations ( P  = 5.8 × 10 –9 to 2.5 × 10 –1459 ), which were specific to each virus. The HLA-B*08:01 allele also exhibited a host–virus genetic interaction with EBV subtype ( P  = 7.4 × 10 –70 ). Other human genetic effects implicated genes encoding proteins that process peptides for antigen presentation, such as ERAP1 (HHV-7, P = 2.7 × 10 –78 ) and ERAP2 (EBV, P = 4.6 × 10 –111 ). Mendelian randomization analyses supported a strong causal effect of EBV DNA load on increased risk of Hodgkin’s lymphoma ( P  = 1.8 × 10 –3 ), but not multiple sclerosis ( P = 0.52). This suggests that higher chronic EBV load increases lymphoma risk, whereas associations of EBV infection with autoimmune conditions reflect host immune responses to particular viral epitopes.
GPT-4o mini: Non-social science research article
Parasites trigger epithelial cell crosstalk to drive gut–brain signalling
Kouki K. Touhara, Jinhao Xu, Joel Castro, Hong-Erh Liang, Guochuan Li, Mariana Brizuela, Andrea M. Harrington, Sonia Garcia-Caraballo, Tracey O’Donnell, Daniel Neumann, Nathan D. Rossen, Fei Deng, Gudrun Schober, Yulong Li, Richard M. Locksley, Stuart M. Brierley, David Julius
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Parasitic infections modulate both immune and sensory responses, but how these systems collaborate to elicit protective behaviours remains incompletely understood. The gut epithelium contains specialized sensory cells that detect pathogens and irritants. These include cholinergic tuft cells, which sense parasites and initiate type 2 immune responses 1–3 , as well as serotonergic enterochromaffin (EC) cells, which detect irritants and communicate with afferent nerve fibres to transmit nociceptive signals 4–6 . Here we show that paracrine signalling between these cells constitutes a mechanism for neuro–immune interaction and gut–brain communication. We find that tuft cells use two distinct mechanisms of acetylcholine (ACh) release despite lacking synaptic vesicles and excitable membranes. These include acute release in response to parasite-derived metabolites, followed by constitutive ‘leak-like’ release, which occurs with type 2 inflammation. Although both mechanisms can activate muscarinic receptors on crypt-residing EC cells, only the sustained mode of ACh release elicits levels of serotonin sufficient to stimulate vagal afferent neurons that suppress food intake. This two-phase paracrine signalling mechanism explains how parasitic infection progresses from an initial asymptomatic phase to symptomatic established disease, in which type 2 immune and sensory signalling pathways within the gut–brain axis collaborate to evoke protective behaviours.
GPT-4o mini: Non-social science research article
Genomic history of early dogs in Europe
Anders Bergström, Anja FurtwĂ€ngler, Sarah Johnston, Erika Rosengren, Abagail Breidenstein, Thomas Booth, Jesse B. McCabe, Jessica Peto, Mia Williams, Monica Kelly, Frankie Tait, Chris Baumann, Rita Radzeviciute, Christopher Barrington, Kyriaki Anastasiadou, Alexandre Gilardet, Isabelle Glocke, Mattias Sherman, Anastasia Brativnyk, Alexander Herbig, Kay PrĂŒfer, Saskia Pfrengle, Joscha Gretzinger, Tatiana R. Feuerborn, Ella Reiter, Anna Linderholm, Sophy Charlton, Fernando Racimo, Lea Mikkola, Hugo Anderson-Whymark, Douglas Baird, Anne Birgitte Gotfredsen, HervĂ© Bocherens, Anne Bridault, Rainer Brocke, DorothĂ©e G. Drucker, Andrew S. Fairbairn, Laurent Frantz, Boris Gasparyan, Liane Giemsch, Mietje GermonprĂ©, Luc Janssens, Andrew W. Kandel, Kurt KjĂŠr, Martina LĂĄzničkovĂĄ-GaletovĂĄ, Daniel Loponte, Ola Magnell, Louise Martin, Susanne C. MĂŒnzel, Gökhan Mustafaoğlu, BjĂžrnar MĂ„ge, Angela Perri, Franziska Pfenninger, Martina RoblíčkovĂĄ, Annelise Roman-Binois, Özlem SarıtaƟ, Katharina SchĂ€ppi, J. Alison Sheridan, Karl-Göran Sjögren, Jan StorĂ„, Lasse Vilien SĂžrensen, Yvonne Tafelmaier, Florian Ter-Nedden, Olaf Thalmann, Greger Larson, Verena J. Schuenemann, Johannes Krause, Pontus Skoglund
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The earliest morphologically identifiable dogs are from Europe and date to at least 14,000 years ago 1–5 , although early remains are also found in other regions. The origin of early dogs in Europe, and their relationships to other dogs, has remained elusive in the absence of genome-wide data. Similarly, although dogs were the only domestic animal to predate agriculture, little is known about how the arrival of Neolithic farmers from Southwest Asia affected the dogs living with European Mesolithic hunter-gatherers. Here we analysed 216 canid remains, including 181 from Palaeolithic and Mesolithic Europe. We developed a genome-wide capture approach that enriched endogenous DNA by 10–100-fold and could distinguish dog from wolf ancestry for 141 of 216 remains. The oldest dog data that we recovered are from a 14,200-year-old dog from the Kesslerloch site in Switzerland, and we find that it shares ancestry with later worldwide dogs—inconsistent with the hypothesis that European Upper Palaeolithic dogs derived wholly from a separate domestication process. The Kesslerloch dog already displays more affinity to Mesolithic, Neolithic and present-day European dogs than to Asian dogs, demonstrating that dog genetic diversification had started well before 14,200 years ago. We find a Neolithic influx of Southwest Asian ancestry into Europe, but this seems to have been of smaller magnitude than in humans, suggesting that Mesolithic dogs contributed substantially to Neolithic, and, ultimately, probably also modern, European dogs.
GPT-4o mini: Non-social science research article
CO2 subsurface mineral storage by its co-injection with recirculating water
Eric H. Oelkers, Serguey Arkadakskiy, Zeyad Ahmed, Noushad Kunnummal, Jakub Fedorik, Massimo Marchesi, Mouadh Addassi, Abdirizak Omar, Niccolo Menegoni, Sigurdur R. Gislason, Grimur Bjornsson, Davide Berno, Thomas Finkbeiner, Abdulkader Afifi, Hussein Hoteit
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Carbon capture and storage (CCS) has the potential to help nations meet their Paris Agreement CO 2 reduction commitments 1,2 . The ability to capture CO 2 within mafic and ultramafic rocks through mineralization of carbon is an example of such a CCS technology 3,4 , but large-scale deployment has yet to be achieved 5,6 . Each geologic environment in the Earth’s crust requires a distinct carbon storage solution. Whereas some regions of the subsurface contain saline aquifers and sedimentary traps suitable for traditional carbon storage through the injection of high-pressure, dense CO 2 below impermeable caprocks, other regions may lack caprocks 5–9 . In these regions, carbon storage is possible through the mineralization of injected water-dissolved CO 2 forming stable carbonate minerals through its reactions with reactive silicate rocks and minerals 6,10,11 . A notable challenge to applying this process at scale is that it can require 20–50 times or more water than the mass of CO 2 stored 12 . Here we report on an industrial-scale pilot project designed to find a carbon disposal solution for western Saudi Arabia. This arid region has large point-source CO 2 emitters, including petroleum refining and desalination facilities, but lacks saline aquifers and sedimentary traps 13–17 . We find that a CO 2 injection approach based on the recirculation of subsurface fluids can eliminate the need for external water. Our results demonstrate the feasibility of carbon mineral storage in regions in which access to water resources may be limited.
GPT-4o mini: Non-social science research article
Inactivating SnRK1ÎČ1A promotes broad-spectrum disease resistance in rice
Guixin Yuan, Xunli Lu, Xingbin Wang, Mengfei Li, Shiwei Wang, Zhaoxiang Huang, Zhigang Li, Fengrui Zhang, Xin Zhang, Jun Yang, Hailong Guo, Vijai Bhadauria, Wang-Sheng Zhu, Wensheng Zhao, Meng Yuan, Jian-Min Zhou, You-Liang Peng
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Rice is a staple crop for more than half of the world’s population, and its sustainable production is vital to ensure global food security. However, rice is susceptible to several devastating fungal diseases1, including blast disease caused by Magnaporthe oryzae, sheath blight by Rhizoctonia solani, false smut by Ustilaginoidea virens, brown spot by Bipolaris oryzae, bakanae by Fusarium fujikuroi and head blight by Fusarium graminearum. The mechanisms underlying the susceptibility to these fungal diseases remain unclear. Here we report that the ÎČ subunit of SnRK1, SnRK1ÎČ1A, confers broad-spectrum susceptibility to these fungal diseases. Our findings show that diverse rice fungal pathogens have convergently evolved an effector-like protein, Gas2, which interacts with SnRK1ÎČ1A to prevent its ubiquitination-mediated degradation and promotes its nuclear translocation. SnRK1ÎČ1A is markedly induced on fungal infection, promoting susceptibility by inhibiting SnRK1α1, an α subunit of SnRK1 known to positively regulate broad-spectrum resistance in rice2. Notably, rice lines with disrupted SnRK1ÎČ1A are resistant to several fungal diseases without compromising growth and yield in the field under normal farming conditions. This study demonstrates that broad-spectrum disease resistance in crops can be achieved by disrupting inducible susceptibility genes whose encoded proteins are targeted by effectors conserved across several pathogens.
GPT-4o mini: Non-social science research article
Dogs were widely distributed across western Eurasia during the Palaeolithic
William A. Marsh, Lachie Scarsbrook, Eren YĂŒncĂŒ, Lizzie Hodgson, Audrey T. Lin, Maria De Iorio, Olaf Thalmann, Mark G. Thomas, Mahaut Goor, Anders Bergström, Angela Noseda, Sarieh Amiri, Fereidoun Biglari, DuĆĄan Borić, Katia Bougiouri, Alberto Carmagnini, Maddalena GiannĂŹ, Tom Higham, Ophelie Lebrasseur, Anna Linderholm, Marcello A. Mannino, Caroline Middleton, Gökhan Mustafaoğlu, Angela Perri, Joris Peters, Mike Richards, Özlem SarıtaƟ, Pontus Skoglund, Rhiannon E. Stevens, Chris Stringer, Kristina Tabbada, Helen M. Talbot, Laura G. Van der Sluis, Silvia M. Bello, Vesna Dimitrijevic, Louise Martin, Marjan Mashkour, Simon A. Parfitt, Sonja Vukovic, Selina Brace, Oliver E. Craig, Douglas Baird, Sophy Charlton, Greger Larson, Ian Barnes, Laurent A. F. Frantz
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Archaeological evidence suggests that dogs diverged from wolves during the Palaeolithic, more than 15,000 years ago 1–7 . The earliest unequivocal genetic evidence, however, is associated with dog remains from Mesolithic archaeological contexts approximately 10,900 years ago 8,9 . Here we generate both nuclear and mitochondrial genomes from canid remains at PınarbaĆŸÄ± in TĂŒrkiye (15,800 years ago) 10 and Gough’s Cave in the UK (14,300 years ago) 11 , as well as from dogs excavated from two Mesolithic sites in Serbia (Padina between 11,500–7,900 years ago and Vlasac 8,900 years ago) 12,13 . Our analyses indicate that a genetically homogeneous dog population was already widely distributed across Europe and Anatolia during the Late Upper Palaeolithic (by at least 14,300 years ago). This finding suggests that dogs were exchanged among genetically and culturally distinct western Eurasian Late Palaeolithic human populations, namely the Magdalenian, Epigravettian and Anatolian hunter-gatherers 10,14–16 . Last, we identify a major influx of eastern Eurasian dog ancestry during the Mesolithic, concomitant with the movement of eastern hunter-gatherer populations into Europe 14 , which led to the establishment of the primary ancestry characteristics that define European dog populations today.
GPT-4o mini: Non-social science research article
Structural energetics of cold sensitivity
Kevin Y. Choi, Xiaoxuan Lin, Yifan Cheng, David Julius
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Thermosensitive transient receptor potential (TRP) ion channels enable somatosensory nerve fibres to detect changes in our thermal environment over a wide physiologic range 1–3 . In mammals, the menthol receptor, TRPM8, is activated by temperatures below approximately 26 °C and is essential for the perception of cold or chemical cooling agents 4–6 . A fascinating, yet still unachieved goal is to elucidate mechanisms, both structural and thermodynamic, whereby TRPM8 or other thermosensitive channels are gated by changes in ambient temperature. Recent studies using cryogenic electron microscopy have attempted to address this challenging question but are limited by difficulties in visualizing temperature-evoked conformational sub-states or assessing the energetic landscape governing gating transitions 7,8 . Here we close this gap by combining cryogenic electron microscopy with hydrogen–deuterium exchange mass spectrometry to elucidate a mechanism for cold-evoked activation of TRPM8. First, we visualize TRPM8 channels in cellular membranes, where bona fide menthol- and cold-evoked open states are captured. We also identify a new ‘semi-swapped’ architecture in which interdigitation of channel sub-units is rearranged substantially following repositioning of the S6 transmembrane helix and elements of the pore region. We then use hydrogen–deuterium exchange mass spectrometry to pinpoint the pore and TRP helices as the regions exhibiting the greatest stimulus-evoked energetic changes that drive channel gating. Specifically, cold-evoked stabilization of the outer pore region repositions the pore lining S6 transmembrane helix while enabling binding of a regulatory lipid to stabilize the open channel. Structural mechanisms associated with activation are validated by comparison of human TRPM8 with the menthol-sensitive but relatively cold-insensitive avian orthologue. We propose a free energy landscape and conformational pathway whereby cold or cooling agents activate this thermosensory receptor.
GPT-4o mini: Non-social science research article
Author Correction: 7-Dehydrocholesterol is an endogenous suppressor of ferroptosis
Florencio Porto Freitas, Hamed Alborzinia, Ancély Ferreira dos Santos, Palina Nepachalovich, Lohans Pedrera, Omkar Zilka, Alex Inague, Corinna Klein, Nesrine Aroua, Kamini Kaushal, Bettina Kast, Svenja M. Lorenz, Viktoria Kunz, Helene Nehring, Thamara N. Xavier da Silva, Zhiyi Chen, Sena Atici, Sebastian G. Doll, Emily L. Schaefer, Ifedapo Ekpo, Werner Schmitz, Aline Horling, Peter Imming, Sayuri Miyamoto, Ann M. Wehman, Thiago C. Genaro-Mattos, Karoly Mirnics, Lokender Kumar, Judith Klein-Seetharaman, Svenja Meierjohann, Isabel Weigand, Matthias Kroiss, Georg W. Bornkamm, Fernando Gomes, Luis Eduardo Soares Netto, Manjima B. Sathian, David B. Konrad, Douglas F. Covey, Bernhard Michalke, Kurt Bommert, Ralf C. Bargou, Ana Garcia-Saez, Derek A. Pratt, Maria Fedorova, Andreas Trumpp, Marcus Conrad, José Pedro Friedmann Angeli
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GPT-4o mini: Non-social science research article
Ectopic NMDAR expression in cancer unmasks germline-encoded autoimmunity
Sam O. Kleeman, Kevin Michalski, Xiang Zhao, Ruben Steigerwald, Miriam Ferrer, Llewelyn Levett, Ethan Ertel, Austin Schultz, Noriko Simorowski, Pamela Moody, Tse-Luen Wee, Cristina Valente, Sharon Fox, Mateusz Makuch, Selina Thomsen, Ruby Harrison, Claire Regan, Jonathan Preall, Qing Gao, Dennis Thomas, Jill Habel, Rachel Rubino, Sarosh Irani, Hiro Furukawa, Tobias Janowitz
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Autoimmunity and anti-cancer immunity lie on the same biological continuum1,2, but their link remains obscure. The paraneoplastic neurological syndrome ANRE (anti-NMDA receptor (NMDAR) encephalitis) is a paradigm for their connectivity3, given that intratumoural NMDAR expression is correlated with the generation of anti-NMDAR antibodies4,5. Here we verify ectopic expression of GluN1 and GluN2B NMDAR subunits in triple-negative breast cancer (TNBC)6 and model this using orthotopic TNBC tumours with inducible expression of GluN1–GluN2B NMDARs. We show that NMDAR expression is sufficient to induce the recruitment of B cells and their affinity maturation, consistent with an integrated adaptive immune response. Reconstruction of extended intratumoural B cell phylogenies and cryogenic electron microscopy structural analyses demonstrate that affinity-matured hypermutated and class-switched antibodies emerged from pre-existing germline-configuration lower-affinity anti-NMDAR antibodies. Distinct matured antibodies targeted specific epitopes and induced conformational rearrangements within the NMDAR amino-terminal domain, predictive of their functional effects, ranging from inhibition to potentiation. Passive transfer of an NMDAR-potentiating antibody caused autonomic dysregulation and lowered the seizure threshold in healthy female mice, recapitulating key diagnostic criteria of ANRE4,5. We further identify a correlation between intratumoural NMDAR expression and anti-NMDAR antibody titres in patients with TNBC. Taken together, our data establish a direct connection between intratumoural NMDAR expression, antibody maturation and the onset of autoimmunity. These findings suggest that germline-encoded anti-NMDAR antibodies contribute to immune surveillance but can also trigger autoimmune disease after maturation, revealing a mechanistic trade-off between cancer immunity and neurotoxicity.
GPT-4o mini: Non-social science research article
Structural basis of supercoiling-induced CRISPR–Cas9 off-target activity
Quentin M. Smith, Sylvia Whittle, Ricardo J. Aramayo, Daniel E. Rollins, Adam S. B. Jalal, Deborah I. Egharevba, Kyle L. Morris, Alice L. B. Pyne, David S. Rueda
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CRISPR–Cas9 is a powerful genome-editing tool 1 , but genome-wide off-target activity can hinder therapeutic applications. Negative supercoiling ((−)SC) has been implicated in off-target activity, but a molecular-level understanding is lacking. Here, using (−)SC DNA minicircles, we observe supercoiling-driven structural defects in the DNA that are resolved by Cas9 binding. Cryo-electron microscopy structures of Cas9 bound in both the on-target and off-target configurations highlight that the Cas9 HNH domain is poised in a more catalytically competent conformation. New DNA–RNA mismatch geometries are accommodated across the protospacer and structural plasticity in the protospacer adjacent motif distal region of the protospacer is topology dependent. Together, our study reveals the molecular basis for (−)SC-induced Cas9 targeting and provides a framework for the design of next-generation high-fidelity CRISPR effectors with topological context.
GPT-4o mini: Non-social science research article
Superluminal correlations in ensembles of optical phase singularities
T. Bucher, A. Gorlach, A. Niedermayr, Q. Yan, H. Nahari, K. Wang, R. Ruimy, Y. Adiv, M. Yannai, T. L. Abudi, E. Janzen, C. Spaegele, C. Roques-Carmes, J. H. Edgar, F. H. L. Koppens, G. M. Vanacore, H. H. Sheinfux, S. Tsesses, I. Kaminer
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Phase singularities—points carrying quantized topological charge—are universal features found across diverse wave systems from superfluids and superconductors to acoustic and optical fields1,2,3,4. Ensembles of these singularities exhibit distance correlations resembling particles in liquids5,6,7,8, extensively studied for their role in exotic material phases9,10,11. By contrast, the full correlations in phase space that govern the system evolution have remained unexplored and experimentally inaccessible. Here we directly measure the ultrafast dynamics of optical singularity ensembles, capturing their full phase-space correlations, presenting the joint distance–velocity distribution. Our observations show a breakdown of the particle-singularity analogy12: phase singularities accelerate towards formally divergent velocities in the moment before annihilation7,13,14, indicated by measurements of velocities exceeding the speed of light. These apparent superluminal velocities are paradoxically amplified by the slow group velocity of hyperbolic phonon polaritons in our material platform, hexagonal boron nitride membranes15,16,17,18,19. We demonstrate these phenomena using combined hardware and algorithmic advances in ultrafast electron microscopy18,20,21,22,23,24,25, achieving spatial and temporal resolutions, each an order of magnitude below the polaritonic wavelength and cycle period. Our findings deepen our understanding of phase singularities and their universality, enabling to probe topological defect dynamics at previously unattainable timescales.
GPT-4o mini: Non-social science research article
Aversive learning hijacks a brain sugar sensor to consolidate memory
Raquel Francés, Typhaine Comyn, Coraline Desnous, Francesca Bettoni, Alice Pavlowsky, Thomas Preat, Pierre-Yves Plaçais
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The formation of food-related memories involves post-ingestion nutrient sensing signals1,2,3,4,5. Whether nutrient sensors act beyond feeding-relevant behaviour is less well understood. Here we show that an internal sugar sensor in the Drosophila brain6 is involved in memory consolidation, both in fasted flies subjected to an appetitive learning task involving a sucrose reward and in flies fed ad libitum subjected to an aversive learning task independent of food cues7,8. In the latter, spaced repetition of learning sessions, a prerequisite to induce long-term memory, lures brain fructose-sensing neurons into a fasted state through a disinhibition mechanism that transiently restores their sensing ability despite satiation9. Post-learning sugar ingestion activates disinhibited fructose-sensing neurons, which triggers memory consolidation through the release of the glycoprotein hormone thyrostimulin10,11, as in appetitive learning. The reset of fructose-sensing neurons by spaced training also results in a fasted state-like feeding behaviour, manifesting in a strong increase in sucrose preference and intake. By revealing a mechanism of non-homeostatic hunger and its critical relevance for memory consolidation, our results provide a neural circuit basis, and a cognitive value, to a behaviour akin to emotional eating.
GPT-4o mini: Non-social science research article
Topological soliton frequency comb in nanophotonic lithium niobate
Nicolas Englebert, Robert M. Gray, Luis Ledezma, Ryoto Sekine, Thomas Zacharias, Rithvik Ramesh, Benjamin K. Gutierrez, Pedro Parra-Rivas, Alireza Marandi
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Frequency combs have revolutionized metrology, ranging and optical clocks1, motivating substantial efforts on the development of chip-scale comb sources2,3. Some on-chip comb sources exist and have been implemented through electro-optic modulation4,5, mode-locked lasers6,7, quantum cascade lasers8,9,10 or soliton formation by Kerr nonlinearity11,12. However, widespread deployment of on-chip comb sources has remained elusive, as they still require radiofrequency sources, high-Q (high-quality factor) resonators or complex stabilization schemes while facing efficiency challenges. Here, we demonstrate an on-chip frequency comb source based on the integration of a lithium niobate nanophotonic circuit with a semiconductor laser that can alleviate these challenges. We show the formation of temporal topological solitons in an on-chip nanophotonic parametric oscillator with quadratic nonlinearity and low finesse. These solitons, independent of the dispersion regime, consist of phase defects separating two π-out-of-phase continuous wave solutions at the signal frequency, which is half the input pump frequency13,14. We use on-chip cross-correlation for temporal measurements and confirm formation of topological solitons as short as 60 fs around 2 Όm, in agreement with a generalized parametrically forced Ginzburg–Landau theory15,16,17. Moreover, we demonstrate a proof-of-concept turn-key operation of a hybrid-integrated source of topological frequency comb. Topological solitons are potential candidates for the development of integrated comb sources, which are dispersion-sign agnostic and do not require high-Q resonators or high-speed modulators, and can provide access to hard-to-reach spectral regions, including mid-infrared regions18.
GPT-4o mini: Non-social science research article
A fast starburst wind consumes most of the energy from supernovae
character(0), Marc Audard, Hisamitsu Awaki, Ralf Ballhausen, Aya Bamba, Ehud Behar, Rozenn Boissay-Malaquin, Laura Brenneman, Gregory V. Brown, Lia Corrales, Elisa Costantini, Renata Cumbee, MarĂ­a DĂ­az Trigo, Chris Done, Tadayasu Dotani, Ken Ebisawa, Megan E. Eckart, Dominique Eckert, Satoshi Eguchi, Teruaki Enoto, Yuichiro Ezoe, Adam Foster, Ryuichi Fujimoto, Yutaka Fujita, Yasushi Fukazawa, Kotaro Fukushima, Akihiro Furuzawa, Luigi Gallo, Javier A. GarcĂ­a, Liyi Gu, Matteo Guainazzi, Kouichi Hagino, Kenji Hamaguchi, Isamu Hatsukade, Katsuhiro Hayashi, Takayuki Hayashi, Natalie Hell, Edmund Hodges-Kluck, Ann Hornschemeier, Yuto Ichinohe, Daiki Ishi, Manabu Ishida, Kumi Ishikawa, Yoshitaka Ishisaki, Jelle Kaastra, Timothy Kallman, Erin Kara, Satoru Katsuda, Yoshiaki Kanemaru, Richard Kelley, Caroline Kilbourne, Shunji Kitamoto, Shogo Kobayashi, Takayoshi Kohmura, Aya Kubota, Maurice Leutenegger, Michael Loewenstein, Yoshitomo Maeda, Maxim Markevitch, Hironori Matsumoto, Kyoko Matsushita, Dan McCammon, Brian McNamara, François Mernier, Eric D. Miller, Jon M. Miller, Ikuyuki Mitsuishi, Misaki Mizumoto, Tsunefumi Mizuno, Koji Mori, Koji Mukai, Hiroshi Murakami, Richard Mushotzky, Hiroshi Nakajima, Kazuhiro Nakazawa, Jan-Uwe Ness, Kumiko Nobukawa, Masayoshi Nobukawa, Hirofumi Noda, Hirokazu Odaka, Shoji Ogawa, Anna Ogorzalek, Takashi Okajima, Naomi Ota, Stephane Paltani, Robert Petre, Paul Plucinsky, Frederick S. Porter, Katja Pottschmidt, Kosuke Sato, Toshiki Sato, Makoto Sawada, Hiromi Seta, Megumi Shidatsu, Aurora Simionescu, Randall Smith, Hiromasa Suzuki, Andrew Szymkowiak, Hiromitsu Takahashi, Mai Takeo, Toru Tamagawa, Keisuke Tamura, Takaaki Tanaka, Atsushi Tanimoto, Makoto Tashiro, Yukikatsu Terada, Yuichi Terashima, Yohko Tsuboi, Masahiro Tsujimoto, Hiroshi Tsunemi, Takeshi Tsuru, AyƟegĂŒl TĂŒmer, Hiroyuki Uchida, Nagomi Uchida, Yuusuke Uchida, Hideki Uchiyama, Yoshihiro Ueda, Shinichiro Uno, Jacco Vink, Shin Watanabe, Brian J. Williams, Satoshi Yamada, Shinya Yamada, Hiroya Yamaguchi, Kazutaka Yamaoka, Noriko Yamasaki, Makoto Yamauchi, Shigeo Yamauchi, Tahir Yaqoob, Tomokage Yoneyama, Tessei Yoshida, Mihoko Yukita, Irina Zhuravleva, Kazuki Ampuku, Erin Boettcher, Skylar Grayson, Gabriel Grell, Peter Kosec, Seiya Sasamata, Evan Scannapieco
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Starburst galaxies often host multiphase, galaxy-scale winds thought to enrich the circumgalactic medium and limit further star formation by disrupting interstellar gas clouds1,2,3. These winds are primarily powered by supernovae4,5,6, but it remains unclear how supernova energy forms an organized flow. Here we use the Resolve spectrometer on the X-ray Imaging and Spectroscopy Mission to show that the hot (T = 2 × 107 K) gas in the nucleus of the starburst galaxy M82 is moving quickly, with a line-of-sight velocity dispersion \(\sigma =59{5}_{-128}^{+464}\,\mathrm{km}\,{{\rm{s}}}^{-1}\). This is consistent with a hot, nuclear wind generated by thermal pressure. We show that a free-wind model reproduces the measured temperature but underpredicts the velocity. The inferred mass and energy outflow rates from the nucleus, about 7 M⊙ yr−1 and 4 × 1042 erg s−1, require that most supernova energy is thermalized. These outflow rates provide enough energy to power the ≳30 M⊙ yr−1 cool outflow and still transport up to 3 M⊙ yr−1 to the intergalactic medium, suggesting that thermal gas pressure is sufficient to power the multiphase wind without additional support from cosmic rays7. We also show that the nuclear gas is hotter and faster than the plasma seen on larger scales (\(kT\,=\,{0.72}_{-0.08}^{+0.10}\,\mathrm{keV}\), \(\sigma =17{5}_{-73}^{+86}\,\mathrm{km}\,{{\rm{s}}}^{-1}\)), suggesting a distinct origin for the latter.
GPT-4o mini: Non-social science research article
Precipitation observing network gaps limit climate change impact assessment
Jiajia Su, Chiyuan Miao, Francis Zwiers, Hylke Beck, Phil Jones, Qiaohong Sun, Louise J. Slater, Wouter R. Berghuijs, Yoshihide Wada, Daniel Rosenfeld, Jiaojiao Gou, Yi Wu, Paolo Tarolli, Pasquale Borrelli, Panos Panagos, Lisa V. Alexander, Qi Zhang, Jinlong Hu, Seung-Ki Min, Luis Samaniego, Qingyun Duan, Georgia Destouni, Jose A. Marengo, Reza Modarres, Soroosh Sorooshian
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Reliable future climate projections and water deficiency assessments require precipitation observations that are both spatially comprehensive and temporally complete, yet many global regions still suffer from observation sparsity1,2. Here we evaluate the distribution of 221,483 internationally exchanged precipitation gauges worldwide, with records across 1900–2022, and further explore where new gauges are most needed under different scenarios. We find that at present only 13.4% of the global land surface meets the World Meteorological Organization requirements for annual precipitation monitoring, indicating widespread scarcity that has serious socioeconomic implications. Europe has the highest continental gauge density (2.4 gauges per 1,000 km2), with Germany leading among countries over 50,000 km2 (22.4 gauges per 1,000 km2). Globally, 25% of land surface already requires urgent expansion of gauge networks because of climate variability, including northern South America, northern North America, Central Africa and southern Asia. Considering projected precipitation changes and socioeconomic conditions under a high-emission scenario further identifies high-need regions in India, Greenland, Bolivia and China because of climate sensitivity and socioeconomic vulnerabilities, increasing this share to 32.1% of global land. Our findings highlight important gaps in global precipitation monitoring that require strategic investments in new gauges and underscore the need for open data access.
GPT-4o mini: Non-social science research article
Epigenetic memory of colitis promotes tumour growth
Surya Nagaraja, Lety Ojeda-Miron, Ruochi Zhang, Ena Oreskovic, Conrad Hock, Yan Hu, Daniel Zeve, Karina Sharma, Roni R. Hyman, Qiming Zhang, Andrew Castillo, David T. Breault, Ömer H. Yilmaz, Jason D. Buenrostro
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Chronic inflammation is a well-established risk factor for cancer, but the underlying molecular mechanisms remain unclear1,2. Using a mouse model of colitis, we demonstrate that colonic stem cells retain an epigenetic memory of inflammation following disease resolution that persists for more than 100 days. Here we find that memory of colitis is characterized by a cumulative gain of activator protein 1 (AP-1) transcription factor activity, with durable changes to chromatin accessibility. Further, we develop SHARE-TRACE, a method that enables simultaneous profiling of gene expression, chromatin accessibility and clonal history in single cells, enabling high-resolution tracking of epigenomic memory. This approach reveals that memory of colitis is propagated cell-intrinsically and inherited through stem cell divisions, with some clones demonstrating stronger memory than others. Finally, we show that colitis primes stem cells for increased expression of an AP-1-regulated gene program following oncogenic mutation that accelerates tumour growth, a phenotype dependent on AP-1 activity. Together, our findings provide a mechanistic link between chronic inflammation and malignancy, revealing how long-lived epigenetic alterations in regenerative tissues may contribute to disease susceptibility and suggesting potential diagnostic and therapeutic strategies to mitigate cancer risk in patients with chronic inflammatory conditions.
GPT-4o mini: Non-social science research article
Electrochemical corrosion accompanies dendrite growth in solid electrolytes
Cole D. Fincher, Colin Gilgenbach, Christian Roach, Rachel Osmundsen, Aubrey Penn, Michael D. Thouless, W. Craig Carter, Brian W. Sheldon, James M. LeBeau, Yet-Ming Chiang
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Charging rates, cycling performance and safety of solid-state batteries using metal negative electrodes are often limited by dendrites1,2,3, the growth of which depends on coupling between electrochemical and mechanical driving forces. Previously, it has been assumed that dendrites propagate when plating-induced stresses reach the fracture stress of the solid electrolyte. Here we show that dendrites can propagate at far lower stresses. Using operando birefringence microscopy4, we directly measure stresses around growing dendrites in garnet Li6.6La3Zr1.6Ta0.4O12, a highly stable solid electrolyte5,6,7. Plating-induced stresses are present throughout growth and approach the mechanical fracture stress for the slowest-growing dendrites. As current densities and dendrite velocities increase, the stresses accompanying dendrite growth surprisingly decrease, with dendrite propagation occurring at stresses up to 75% lower than under mechanical load alone. Cryogenic scanning transmission electron microscopy (STEM) of dendrites propagated at high current reveals electrolyte decomposition to new phases, associated with which is a net molar volume contraction. The electrochemically induced mode of embrittlement may be mitigated through understanding and control of the nature of phase transitions accompanying instability.
GPT-4o mini: Non-social science research article
Oxygen supply through the tracheolar–muscle system does not constrain insect gigantism
Edward P. Snelling, Antonia V. Lensink, Susana Clusella-Trullas, Chris Weldon, Philipp Lehmann, John S. Terblanche, Nicholas L. Payne, Jon F. Harrison, Anthony J. R. Hickey, Ashleigh Donaldson, Christian M. Deschodt, Roger S. Seymour
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The idea that atmospheric oxygen has dictated the maximum body size of insects across their evolutionary history is ingrained in popular and scientific literature1,2,3. In Nature 30 years ago, the hypothesis was put forward that a limitation on oxygen diffusion at the level of the tracheoles constrains the maximum body size of insects and that increased atmospheric oxygen concentration in the late Palaeozoic permitted insect gigantism4. Here we contest this hypothesis by showing that the relative space occupied by tracheoles in the flight muscle of insects (1) increases by only 1.8-fold over a 10,000-fold body mass range (1,320 micrographs, 44 species, 10 orders), (2) is typically 1% or less in most species, and (3) that this observation holds when we extend our relationship to the long-extinct gigantic dragonfly-like Meganeuropsis permiana (approximately 100 g). The small space requirement and the lack of a strong increase in tracheolar investment with body size, despite clear evolutionary potential to do so, provide convincing evidence that diffusive oxygen transport through the tracheolar–muscle system does not constrain the maximum body size of extant or gigantic prehistoric insects.
GPT-4o mini: Non-social science research article
Dominant clones leverage developmental epigenomic states to drive ependymoma
Alisha S. Kardian, Hua Sun, Siri Ippagunta, Nicholas Laboe, Srinidhi Varadharajan, Kwanha Yu, Hsiao-Chi Chen, Erik Emanus, Tuyu Zheng, Riley M. Deneen, Jon P. Connelly, Yong-Dong Wang, Jiangshan Zhan, Hengxi Liu, Kimberley Lowe, Taylor Bugbee, Rakesh Pathak, Amanda Bland, Sanya Mehta, Sophie Cochiolo, Amir Arabzade, Blake Holcomb, Kaitlin M. Budd, Gabriele Kembuan, Tristen Wright, Emma Caesar, Maxwell Park, Amelia Hancock, David Gee, Joel Murdoch, Yi Xiao, Samuel K. McBrayer, Thomas E. Merchant, Jun Qi, Adam D. Durbin, Lindsay A. Schwarz, Li Wang, Andrew M. Donson, Nicholas K. Foreman, Sameer Agnihotri, Alfonso Lavado, Suzanne J. Baker, David W. Ellison, Hyun Kyoung Lee, Shondra M. Pruett-Miller, Kelsey C. Bertrand, Benjamin Deneen, Stephen C. Mack
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ZFTA–RELA is the most recurrent genetic alteration seen in paediatric supratentorial ependymoma (EPN) and is sufficient to initiate tumours in mice1. Despite its oncogenic potential, ZFTA–RELA (ZR) is observed nearly exclusively in childhood EPN, with tumours located distinctly in the supratentorial brain of the central nervous system1. We proposed that specific chromatin modules accessible during brain development would render distinct cell lineage programs at direct risk of transformation by ZR. To test this hypothesis, we performed combined single-nucleus assay for transposase-accessible chromatin and RNA (snMultiome) sequencing of the developing mouse forebrain compared with ZR-driven mouse and human EPN. We demonstrated that specific developmental lineage programs present in transient progenitor cells and regulated by PLAG/L family transcription factors were at risk of neoplastic transformation. Binding of this chromatin network by ZR or other PLAG/L family motifs targeting fusion oncoproteins led to persistent chromatin accessibility at oncogenic loci and oncogene expression. Cross-species analysis of mouse and human ZR EPN revealed significant cell type heterogeneity indicating incomplete neurogenic and gliogenic differentiation, with a small percentage of cycling progenitor-like or radial glial-like cells that established a putative tumour cell hierarchy. In vivo lineage tracing studies identified neoplastic clones that aggressively dominated tumour growth and established the entire EPN cellular hierarchy. These findings identify developmental epigenomic states that are critical for fusion-oncoprotein-driven transformation and show how these states continue to shape tumour progression.
GPT-4o mini: Non-social science research article
Towards end-to-end automation of AI research
Chris Lu, Cong Lu, Robert Tjarko Lange, Yutaro Yamada, Shengran Hu, Jakob Foerster, David Ha, Jeff Clune
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The automation of science is a long-standing ambition in artificial intelligence (AI) research 1,2 . Although the community has made substantial progress in automating individual components of the scientific process, a system that autonomously navigates the entire research life cycle—from conception to publication—has remained out of reach. Here we present a pipeline for automating the entire scientific process end to end. We present The AI Scientist, which creates research ideas, writes code, runs experiments, plots and analyses data, writes the entire scientific manuscript, and performs its own peer review. Its ideas, execution and presentation are of sufficient quality that the manuscript generated by this AI system passed the first round of peer review for a workshop of a top-tier machine learning conference. The workshop had an acceptance rate of 70%. Our system leverages modern foundation models 3–5 within a complex agentic system. We evaluate The AI Scientist in two settings: a focused mode using human-provided code templates as an initial scaffold for conducting research on a specific topic and a template-free, open-ended mode that leverages agentic search for wider scientific exploration 6,7 . Both settings produce diverse ideas and automatically test, report on and evaluate them. This achievement demonstrates the growing capacity of AI for making scientific contributions and signifies a potential paradigm shift in how research is conducted. As with any impactful new technology, there could be important risks, including taxing overwhelmed review systems and adding noise to the scientific literature. However, if developed responsibly, such autonomous systems could greatly accelerate scientific discovery.
GPT-4o mini: Non-social science research article
Towards intelligent and miniaturized drug delivery devices
Xinwei Wei, John B. Buse, Hongming Chen, Tejal A. Desai, Molly M. Stevens, Giovanni Traverso, Robert Langer, Zhen Gu
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Advances at the intersection of biotechnology, artificial intelligence, electronics and materials science are reshaping how drugs can be delivered inside the body. Intelligent and miniaturized drug delivery devices (IMDDDs) leverage these technologies to achieve precise pharmacokinetics, targeted distribution and programmable release while minimizing toxicity and improving patient adherence. Unlike conventional approaches, IMDDDs can incorporate real-time sensing and adaptive control, enabling drug administration that is more precise and more responsive to dynamic physiological conditions. In this Review, we outline key categories and design principles, highlight artificial intelligence technologies for augmenting performance, discuss potential clinical applications across cancer, diabetes, cardiovascular disease, vaccination and beyond, and examine translation challenges and opportunities. By uniting engineering innovation with medical need, IMDDDs exemplify the next generation of drug delivery technologies.
Nature DOI suffix ≠ "/s...": Not a research article
How the war in Iran is reshaping the energy landscape
Aisha Al-Sarihi
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Nature DOI suffix ≠ "/s...": Not a research article
Dogs have deep genetic roots in ice-age Europe
Lauren M. Hennelly, Mikkel-Holger S. Sinding
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Nature DOI suffix ≠ "/s...": Not a research article
How DNA in dirt is shaking up the study of human origins
Dyani Lewis
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Nature DOI suffix ≠ "/s...": Not a research article
Scientists should join collaborative online editing communities for biodiversity
Heidi M. Meudt, Siobhan Leachman, Tiago Lubiana, Sabine von Mering
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Nature DOI suffix ≠ "/s...": Not a research article
Sock. Something. Um.
Daniel Roop
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Nature DOI suffix ≠ "/s...": Not a research article
Chats with sycophantic AI make you less kind to others
Matthew Hutson
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Nature DOI suffix ≠ "/s...": Not a research article
Why labs need a napping room to help you work, rest and play
Holly Newson
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Nature DOI suffix ≠ "/s...": Not a research article
How to measure a good life – tips for moving beyond GDP
Richard Heys, Himanshi Bhardwaj, Cliodhna Taylor
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Nature DOI suffix ≠ "/s...": Not a research article
First atlas of brain organization shows development over a lifetime
Gemma Conroy
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Nature DOI suffix ≠ "/s...": Not a research article
Why AI hasn’t caused a job apocalypse — so far
Martha Gimbel
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Nature DOI suffix ≠ "/s...": Not a research article
Trump’s new science advisers include 12 technology chiefs — and one academic
Dan Garisto
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Nature DOI suffix ≠ "/s...": Not a research article
Antimatter has been transported for the first time ever — in the back of CERN’s truck
Elizabeth Gibney
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Nature DOI suffix ≠ "/s...": Not a research article
Long-distance quantum link generates entanglement faster than it is lost
Ronald Hanson, Tracy Northup
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Nature DOI suffix ≠ "/s...": Not a research article
Giants of the deep and the wonder of space: Books in Brief
Andrew Robinson
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Nature DOI suffix ≠ "/s...": Not a research article
‘Zombie cells’ return from the dead — after a genome transplant
Ewen Callaway
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Nature DOI suffix ≠ "/s...": Not a research article
The intelligence illusion: why AI isn’t as smart as it is made out to be
David Adam
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Nature DOI suffix ≠ "/s...": Not a research article
Testosterone promotes growth of a type of brain tumour in young boys
Najla Kfoury-Beaumont
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Nature DOI suffix ≠ "/s...": Not a research article
Forty-five years of progress after a key paper about the evolution of cooperation
Sarah Mathew, Robert Boyd
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Nature DOI suffix ≠ "/s...": Not a research article
The pros and cons of China’s health role in Africa
Sarah Wild
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Nature DOI suffix ≠ "/s...": Not a research article
These medical X-rays are all deepfakes — and they fool even radiologists
Jenna Ahart
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Nature DOI suffix ≠ "/s...": Not a research article
The surprising science behind red-light therapy — and how it really works
Lynne Peeples
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Nature DOI suffix ≠ "/s...": Not a research article
Why insects aren't huge: a new challenge to a decades-old idea
Nick Petrić Howe, Maren Hunsberger
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Nature DOI suffix ≠ "/s...": Not a research article
Daily briefing: Why stress causes eczema to flare up in mice
Flora Graham
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Nature DOI suffix ≠ "/s...": Not a research article
‘Grade inflation’ hits PhD students. What’s behind the increase?
Mariana Lenharo
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Nature DOI suffix ≠ "/s...": Not a research article
Pilot project paves way to storing CO2 underground as minerals in arid countries
Juliane Weber
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Nature DOI suffix ≠ "/s...": Not a research article
Daily briefing: The surprising science behind red-light therapy
Flora Graham
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Nature DOI suffix ≠ "/s...": Not a research article
Motherhood derails women’s academic careers — these data reveal how and why
Diana Kwon
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Nature DOI suffix ≠ "/s...": Not a research article
Major conference catches illicit AI use — and rejects hundreds of papers
Elizabeth Gibney
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Nature DOI suffix ≠ "/s...": Not a research article
Salt lakes are shrinking and expanding, causing havoc in conservation
Egor Zadereev
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Nature DOI suffix ≠ "/s...": Not a research article
Briefing Chat: ‘Zombie cells’ resurrected with new genes
Shamini Bundell, Nick Petrić Howe
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Nature DOI suffix ≠ "/s...": Not a research article
How the idea of human superiority over nature was invented
Brock Bastian
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Nature DOI suffix ≠ "/s...": Not a research article
UK scraps airborne lab that tracks climate, pollution and weather systems
Euan G. Nisbet, Maria R. Russo
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Nature DOI suffix ≠ "/s...": Not a research article
Daily briefing: Tiny bones from Neanderthal fetus point to downfall of the species
Flora Graham
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Nature DOI suffix ≠ "/s...": Not a research article
Daily briefing: We’ve just had the 11 hottest years on record
Flora Graham
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Nature DOI suffix ≠ "/s...": Not a research article
Remembrance of inflammations past
Chengxiang Qiu, Jay Shendure
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Nature DOI suffix ≠ "/s...": Not a research article
Geopolitical tensions are leading China to rethink research collaboration
Futao Huang
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Nature DOI suffix ≠ "/s...": Not a research article
Can a mouse be cloned indefinitely? Decades-long experiment has answers
Heidi Ledford
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Can China keep up its extraordinary research growth?
Simon Baker
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Nature DOI suffix ≠ "/s...": Not a research article
Daily briefing: Earliest known dog genome pushes genetic record back 5,000 years
Jacob Smith
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Nature DOI suffix ≠ "/s...": Not a research article
Eye drops made from pig semen deliver cancer treatment to mice
Rachel Fieldhouse
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Nature DOI suffix ≠ "/s...": Not a research article
Why China’s philanthropists are digging deep for research
Ben Deighton
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Marine life is a silent casualty of armed conflicts
Seithikurippu R. Pandi-Perumal, Konda Mani Saravanan
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Nature DOI suffix ≠ "/s...": Not a research article
‘Continuity over novelty’: why environmental science needs to rethink its focus
Michael Paul Nelson
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Extreme climate outcomes could still occur with just 2 °C of global warming
Rachel Warren
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Nature DOI suffix ≠ "/s...": Not a research article
Who let the wolves in? Genetic record for domestic dogs pushed back by 5,000 years
Ewen Callaway
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Nature DOI suffix ≠ "/s...": Not a research article
Drowning in data sets? Here’s how to cut them down to size
Sarah Wild
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Nature DOI suffix ≠ "/s...": Not a research article
The world just lived through the 11 hottest years on record — what now?
Rachel Fieldhouse, Mohana Basu
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Nature DOI suffix ≠ "/s...": Not a research article
How I squeeze fresh science from public data
Rhys H. Parry
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Nature DOI suffix ≠ "/s...": Not a research article
How to build an AI scientist: first peer-reviewed paper spills the secrets
Davide Castelvecchi
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Nature Human Behaviour

GPT-4o mini: Non-social science research article
Sustainable neuroscience through open science
Lara M. C. Puhlmann, Alina Koppold, Gordon B. Feld, Tina B. Lonsdorf, Kirsten Hilger, Susanne Vogel, Çağatay GĂŒrsoy, Alexandros Kastrinogiannis, Louisa Kulke, Alexander Lischke, Anett MĂŒller-Alcazar, Julian Packheiser, Matthias F. J. Sperl, Yu-Fang Yang, Laura Bechtold, Sebastian Ocklenburg, Helena Hartmann
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The effect of praise from peers on empathy and political inclusion towards racial or ethnic outgroups
Adeline Lo, Jonathan Renshon, Lotem Bassan-Nygate
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Outgroup bias is well documented and pernicious, manifesting in negative attitudes and behaviour towards outgroups. Addressing it is a first-order priority for Diversity, Equity and Inclusion programmes, as well as society more generally. Empathy—taking the perspective and understanding the experiences of others—holds promise for attenuating outgroup bias, but existing methods are expensive. Through seven pilots, we develop a low-cost, easily scalable ‘peer praise’ intervention that encourages empathy. In this report, we experimentally test (N = 5,303) whether our intervention promotes empathy and inclusive behaviour/attitudes among White US respondents towards Black and Latino/a Americans, a context where outgroup bias is particularly durable. We measure costly choices to engage in empathy, test whether peer praise promotes political (an index of letter writing and donations) and attitudinal (an index of social distance and thermometer ratings) inclusion, and, in a separate experiment (N = 4,404), test whether praise specifically from co-partisans can also promote inclusion. We find that peer praise for empathy neither motivates White participants to engage in empathy for racial outgroups, nor changes their attitudes or self-reported empathy towards outgroups. However, peer praise for empathy does encourage politically inclusive behaviour towards racial outgroups in the form of writing letters on behalf of racial equality to the government. Other registered analyses show that peer praise for empathy can change attitudes both in the short term (Wave 1) and over time (in our longitudinal Wave 2) but only for certain subgroups. Overall, this study provides an examination of a treatment to promote outgroup empathy. That treatment is demonstrated to be effective for behavioural outcomes related to political inclusion across all respondents and can even change attitudes, although only for some demographics. Broadly, our study suggests the importance of targeting empathy-promoting interventions towards receptive groups as well as the difficulty in promoting outgroup empathy, particularly when group identity is highlighted.
The overlooked threat of democratic neutrality in the USA
Matthew E. K. Hall, B. Tyler Leigh, Brittany C. Solomon
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Despite increasing concerns about American democracy, recent studies find little public support for undemocratic practices. However, these studies ignore democratic neutrality—that is, expressing neither agreement nor disagreement with undemocratic practices. Here, integrating research on uncertainty, indifference, ambivalence, conditionality and socially desirable responding, we argue that democratic neutrality poses an overlooked threat to democracy. Reanalysing prominent survey data (N = 45,095) and conducting two original surveys (N = 3,039; including a candidate-choice experiment), we document democratic neutrality as (a) prevalent (half of Americans express neutrality towards one or more undemocratic practices), (b) reflecting substantively meaningful attitudes (versus inattention), (c) correlated with theoretically related constructs, (d) distinct from opposition to undemocratic practices, and (e) as consequential as outright support for undemocratic practices in shaping preferences for anti-democratic candidates. Our findings challenge optimistic empirical accounts of Americans’ attitudes towards democracy. Democratic neutrality may help explain, and be targeted to ameliorate, democratic backsliding.

Proceedings of the National Academy of Sciences

GPT-4o mini: Non-social science research article
The m5C orchestrator NSUN7 drives SPARC/HMGB1 axis–mediated inflammation to exacerbate kidney injury
Yu-hang Dong, Shuai-shuai Xie, Shuai Sun, Yu Ren, Qin Yang, Jie Wei, Rui Hou, Xiang-yu Li, Jing-wen Wu, Wen-xian Ma, Ju-tao Yu, Meng-ting He, Chao Li, Jia-nan Wang, Ming-lu Ji, Zi-yi Liu, Ze-hui Dong, Xiao-yu Shen, Xin-yu Chen, Xiao-guo Suo, Wei Dong, Juan Jin, Jie Wang, Wen-bin Wang, Xiao-ming Meng
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Growing evidence indicates that kidney inflammation is a major contributor to the pathogenesis of various renal diseases, including acute kidney injury (AKI). Although RNA modifications have been implicated in regulating kidney inflammation, their precise roles remain largely unknown. Here, we show that kidney inflammation and injury were associated with elevated RNA 5-methylcytosine (m5C) modifications, primarily driven by the NOP2/Sun RNA methyltransferase family member 7 (NSUN7). Both global and kidney-specific deletion of Nsun7 in mice reduced m5C abundance, attenuated inflammatory responses, and decreased macrophage infiltration, underscoring its proinflammatory role in the kidney. Mechanistically, we identified secreted protein acidic and cysteine-rich (SPARC) as a major downstream effector of NSUN7. SPARC upregulation amplified inflammatory responses in renal tubular epithelial cells by interacting with high mobility group box 1 and further promoted proinflammatory macrophage infiltration via tubular-macrophage crosstalk. Notably, therapeutic silencing of Nsun7 using a kidney-specific DNA tetrahedral molecular carrier developed for this study effectively alleviated inflammation and improved renal outcomes in AKI models. Collectively, our findings identify NSUN7 as a key driver of renal inflammation via SPARC regulation and underscore its potential as a therapeutic target in inflammatory kidney diseases.
GPT-4o mini: Non-social science research article
Life-like behavior emerging in active and flexible microstructures
Mengshi Wei, Daniela J. Kraft
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Many organisms leverage an interplay between shape and activity to generate motion and adapt to their environment. Embedding such mechanical feedback into synthetic micrometer-sized robots could eliminate the need for sensors, software, and actuators. Current active micrometer-scale systems, however, do not possess a flexible body with which they can autonomously sense and react to their environment. Here, we experimentally realize active and flexible structures by concatenating anisotropic micrometer-sized units using 3D microprinting and activating them using AC fields. We demonstrate that this minimal design integrates mechanical feedback between activity and shape, resulting in a rich array of modes of motion—including railway and undulatory locomotion, rotation, and beating. It furthermore gives rise to emergent sense-response abilities, which enable autonomous reorientation, navigation, and collision avoidance. Our approach offers a versatile platform for designing biomimetic model systems and autonomously operating microrobots with embodied intelligence.
GPT-4o mini: Non-social science research article
General and selective nickel-electrocatalyzed cross-electrophile C*( sp 2 )–C( sp 2 ) coupling
Wenbin Xie, Zhe Song, Qinqin Shi, Panping Sheng, Gu Xu, Kaikai Wen, Lutang Zhao, Tobin J. Marks, Zhi-Xiang Wang, Hui Huang
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Transition metal-catalyzed cross-coupling of two similar electrophiles (XEC) to construct C( sp 2 )–C( sp 2 ) bonds is a powerful emerging synthetic methodology. However, efficient and selective XEC to create heterocoupled C*( sp 2 )–C( sp 2 ) linkages from equimolar reagents while suppressing competing homocoupling, presents a synthetic challenge. Here, we describe a promising approach to address this challenge via electrocatalytic synthesis. This approach utilizes renewable and readily available electricity to replace traditional redox reagents, minimizing chemical use and chemical waste generation, while controlling the reaction pathway by the applied potential. This highly selective and general electrocatalytic eXEC process to construct C*( sp 2 )–C( sp 2 ) bonds is enabled by sequential and controllable eXEC oxidative addition processes, and supported mechanistically by experiment and DFT computation. Generality and efficacy are demonstrated by more than 80 examples, including important biaryl, fluorophore, and pharmaceutical products. Notably, the stoichiometric precision of eXEC enables the first synthesis of solution-processable low polydispersity conjugated opto-electronic polymers. Therefore, this report provides a conceptually attractive method to selectively create diverse and useful C*( sp 2 )–C( sp 2 ) coupled molecules and macromolecules.
GPT-4o mini: Non-social science research article
Unprecedented Amazonian rainforests damage during the 2023–2024 droughts
Hao Bai, Xiangzhuo Liu, Hui Yang, Jerome Chave, Philippe Ciais, Jean-Pierre Wigneron, Sassan Saatchi, Jingfeng Xiao, Thuy Le Toan, Xiaomei Hu, Ziyan Yang, Lijun Wang, Lei Fan, Yitong Yao, Xiuzhi Chen, Yanxu Liu, Baolin Xue, Qinghua Guo, Zhiyao Tang, Hongyan Liu, Jingyun Fang, Shengli Tao
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Between 2023 and 2024, Amazonian rainforests experienced two consecutive, record-breaking droughts—each more intense than any previously observed—yet their impacts remain largely unquantified. Using newly developed monthly radar satellite observations (1992 to 2025) that track forest moisture and biomass dynamics, we analyzed the long-term responses of intact Amazonian rainforests to past major droughts—particularly the 2023–2024 event—and projected their post-drought recovery. We found a biome-wide sharp decline in radar signal during 2023–2024, marking the lowest level observed since 1992. Spatially, 26.8% of the forests reached their three-decade minima during this period, primarily in eastern Amazonia. This ratio is more than double that recorded during the 2005 drought, when 11.0% of the forests reached such minima. Moreover, projections based on both historical and future CMIP6 precipitation scenarios consistently indicated that, even 7 y after the 2023–2024 droughts, less than 50% of the affected areas are expected to recover to predrought conditions, and these forests are associated with lower soil cation concentrations, higher soil sand content, and lower canopy height—characteristics that lessen the risk of hydraulic failure. Given that severe droughts have occurred approximately every 7 y over the past three decades, Amazonian rainforests may face another drought before fully recovering from the 2023–2024 event. Our results therefore highlight the growing vulnerability of the Amazonian rainforests to intensifying climate extremes driven by El Niño events and ongoing anthropogenic climate change, providing evidence that these forests are approaching the limits of their preindustrial operating space.
GPT-4o mini: Non-social science research article
Recurrent SARS-CoV-2 Omicron broadly neutralizing humanized antibodies in different single human V H 1-2-rearranging mouse models
Himanshu Batra, Sai Luo, Kevin O. Saunders, Jaclyn S. Higgins, Fanchong Jian, Jun Zhang, Md Golam Kibria, G. M. Jonaid, Qingchen J. Zhou, Amanda Eaton, Kenneth Cronin, Michael L. Mallory, Melissa Mattocks, Robert J. Edwards, Robert Parks, Esther M. Lee, Adam Yongxin Ye, Aimee Chapdelaine Williams, Geeyoun Jung, Katayoun Mansouri, S. Munir Alam, David C. Montefiori, Ming Tian, Ralph S. Baric, Yunlong Cao, Barton F. Haynes, Bing Chen, Frederick W. Alt
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During V(D)J recombination, antibody diversity is enhanced by nontemplated junctional modifications that generate immensely diverse heavy chain (HC) and light chain (LC) complementarity-determining 3 antigen-contact regions (CDR3s). We previously developed a mouse model that generates diverse antibody repertoires by rearranging a single human V H 1-2 and VÎș1-33, associated with highly diverse CDR3s generated by V(D)J recombination with mouse Ds and/or Js. Immunization of this model with SARS-CoV-2 D614G spike elicited an antibody that potently neutralized SARS-CoV-2 variants through Omicron BA.2.754. Here, we report a related mouse model in which a single V H 1-2 rearranges to human D3-3 and J H 6, generating diverse HC-CDR3s much longer on average than those of our prior model. Omicron BA.4/.5 spike-ferritin nanoparticle-immunization of the new model elicited four highly related humanized antibodies that potently neutralize downstream Omicron subvariants. All four antibodies had 12 AA HC-CDR3s with two aromatic amino acids that engage an epitope comprising a hydrophobic patch opened-up by early Omicron lineage mutations and conserved in subsequent variants. Immunization of our prior, shorter CDR3-based model, elicited slightly less potent neutralizing antibodies that bound the same Omicron epitope, and were similar in all other aspects to those from the long, fully human CDR3 model. One tested antibody from each set reduced lung viral titers in a mouse-adapted BQ1.1 challenge. The antibodies we describe are related in their epitope recognition to recently described antibodies from Omicron-infected humans. These studies validate the utility of single human V H - and VÎș-rearranging mice for discovering humanized antibodies that neutralize emerging pathogens.
GPT-4o mini: Non-social science research article
Dynamic translocation of Inside-Out proteins to the cell surface underlies cellular adaptation to cancer-induced stress
Tomasz Slezak, Kelly M. O’Leary, Tanya Guevara Avella, Natalia Musial, Jinyang Li, Anna Andrzejczak, Elizabeth F. Scott, Duc Anh Le, Anthony A. Kossiakoff
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Inside-Out (I-O) protein display, the noncanonical surface localization of intracellular proteins, represents an underexplored feature of tumor cell biology. Here, we map the molecular landscape and trafficking mechanisms that control the presentation of I-O proteins on cancer cell membranes. Employing APEX2-mediated proximity biotinylation and a custom antibody generation and validation platform, we identified approximately 140 high-confidence I-O proteins, primarily ribosomal, proteasomal, chaperone, and translation factors, notably enriched in protein families associated with stress-response pathways. Validation of 500 antibodies encompassing 40 I-O targets across seven tumor cell lines confirmed selective and robust surface localization, while in vivo imaging in mouse xenografts demonstrated pronounced and tumor-specific antibody accumulation. I-O proteins were absent on peripheral blood mononuclear cells (PBMCs) and in normal tissues, indicating cancer cell selectivity. Functional analyses revealed that I-O protein tethering to the membrane is dependent on heparan sulfate interactions; enzymatic removal of these glycans led to the clearance of I-O proteins from the cell surface. Notably, the removed proteins returned to baseline levels within 6 h, indicating a dynamic balance related to Endoplasmic Reticulum (ER)-Golgi trafficking and cellular stress. Nearly half of these I-O proteins overlapped with known stress granule (SG) components; however, stress elements that promote SG formation do not similarly affect surface display of I-O proteins. Furthermore, I-O proteins are present on standard cancer cell lines under lower stress levels needed to induce SG formation, suggesting parallel yet mechanistically distinct aspects of the stress response. These findings position I-O display as a paradigm in protein trafficking, different from traditional secretion pathways and closely linked to stress response.
GPT-4o mini: Non-social science research article
Physics-constrained neural ordinary differential equation models to discover and predict microbial community dynamics
Jaron Thompson, Bryce M. Connors, Victor M. Zavala, Ophelia S. Venturelli
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Microbial communities play essential roles in shaping ecosystem functions and predictive modeling frameworks are crucial for understanding, controlling, and harnessing their properties. Competition and cross-feeding of metabolites drives microbiome dynamics and functions. Existing mechanistic models that capture metabolite-mediated interactions in microbial communities have limited flexibility due to rigid assumptions. While machine learning models provide flexibility, they require large datasets, are challenging to interpret, and can overfit to experimental noise. To overcome these limitations, we develop a physics-constrained machine learning model, which we call the neural species mediator (NSM), that combines a mechanistic model of metabolite dynamics with a machine learning component. The NSM outperforms mechanistic or machine learning components on in vitro experimental datasets and provides insights into direct biological interactions. In summary, carefully embedding a neural network into a mechanistic model of microbial community dynamics improves prediction performance and interpretability compared to its constituent mechanistic or machine learning components.
GPT-4o mini: Non-social science research article
Monoclonal antibodies from COVID-19 convalescent patients target cryptic epitopes for broad SARS-CoV-2 neutralization
Aakanksha Harit, Michael Mor, Ron Yefet, Lee S. Izhaki-Tavor, Meital Gal-Tanamy, Natalia T. Freund, Moshe Dessau
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The COVID-19 pandemic, which has resulted in over seven million global fatalities, poses a substantial threat to public health and precipitated a global economic crisis. Emerging variants of concern (VOCs) with enhanced transmissibility and improved immune evasion may compromise the efficacy of current antiviral and immunotherapies, necessitating comprehensive investigations into the immune response to SARS-CoV-2. The conformational dynamics of the receptor binding domain in SARS-CoV-2 spike and the presentation of neutralizing antibody epitopes influence viral transmission and infection rates. In this study, we have identified highly conserved non-receptor-binding motif epitopes for two potent monoclonal antibodies (mAbs), TAU-1109 and TAU-2310, isolated from convalescent human patients, which contribute to the broad neutralizing activity of these mAbs against all the circulating VOCs, including the recently emerged Omicron subvariants. We employed high-resolution structural data in conjunction with systematic biochemical investigation to elucidate the neutralization mechanism of TAU-1109 and TAU-2310. The mechanism involves antibody-mediated destabilization of the spike trimer, resulting in the premature shedding of the S1 subunit and rendering the spike incapable of mediating host cell entry. The identification of conserved cryptic epitopes in our study advances the mechanistic understanding of immune response against SARS-CoV-2, providing alternative avenues for the development of universal therapeutic antibodies and vaccines to combat COVID-19.
GPT-4o mini: Non-social science research article
Chromatin accessibility regulates age-dependent nuclear mechanotransduction
Yawen Liao, Luezhen Yuan, Trinadha Rao Sornapudi, Max Land, Rajshikhar Gupta, G. V. Shivashankar
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The integration of environmental cues into cellular programs is crucial for cell function. Yet, how this integration is modulated due to cellular aging remains unclear. We propose that the 3D chromatin organization filters these signals and investigated how age-related chromatin changes in human dermal fibroblasts affect responses to mechanical tension and TGF-ÎČ. Young fibroblasts exhibited synergistic gene expression enhancement in response to combined stimuli, a response that was markedly blunted or divergent in aged cells. These distinct outcomes correlated with significant age-related differences in chromatin accessibility. We identified the AP-1 complex and other transcription factors with age-specific activity as pivotal in remodeling chromatin and orchestrating these divergent mechanochemical responses during cellular aging. We validated that disrupting AP-1 activity inhibits fibroblast activation by preventing JUNB recruitment to the transcription machinery. Our findings establish chromatin as a key integrator of mechanochemical signals and characterize the age-related alterations to this integration that modify the cellular responsiveness of aged cells, highlighting AP-1 and its network as potential therapeutic targets against age-related decline.
GPT-4o mini: Non-social science research article
Archaeogenetic insights into the demographic history of Late Neanderthals
Charoula M. Fotiadou, Jesper Borre Pedersen, HĂ©lĂšne Rougier, Mirjana Roksandic, Maria A. Spyrou, Kathrin NĂ€gele, Ella Reiter, HervĂ© Bocherens, Andrew W. Kandel, Miriam N. Haidle, Timo P. Streicher, Nicholas J. Conard, Flora Schilt, Ricardo Miguel Godinho, Thorsten Uthmeier, Luc Doyon, Patrick Semal, Johannes Krause, Alvise Barbieri, DuĆĄan Mihailović, Isabelle Crevecoeur, Cosimo Posth
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The demographic history of Neanderthals is only partially understood. In Europe, some degree of genetic continuity has been shown from 120 thousand years ago (ka) onward despite the occurrence of multiple subsequent diversification events. While it has been proposed that a population turnover preceded the emergence of Late Neanderthals in Europe, the extent, timing, and geographic location of this event are currently unknown. Here, we report ten mitochondrial DNA sequences (mtDNAs) of Neanderthal individuals from six archaeological sites in Belgium, France, Germany and Serbia, and analyze them alongside 49 published mtDNAs. The integration of phylogenetic and molecular dating analyses with an extensive archaeological dataset enabled us to reconstruct temporal and spatial patterns in Neanderthal distribution. Remarkably, nearly all Late Neanderthal individuals across Europe belong to a single mtDNA lineage that diversified recently, confirming a large-scale genetic replacement. Our analyses date this diversification event to approximately 65 ka and suggest that it likely originated from a population refugium in southwestern France from which Neanderthals appear to have undergone a major range dispersal across Europe. In addition, we detect a sharp decline in the Neanderthal mtDNA effective population size beginning ~45 ka and reaching a minimum ~42 ka, shortly before their extinction. This study demonstrates that integrating molecular and archaeological datasets provides a more detailed understanding of the Late Neanderthal population’s history, and highlights the critical role of climate-driven refugia and subsequent range expansions in shaping the genetic landscape of Neanderthals through time.
GPT-4o mini: Non-social science research article
A high-coverage Neandertal genome from the Altai Mountains reveals population structure among Neandertals
Diyendo Massilani, StĂ©phane PeyrĂ©gne, Leonardo N. M. Iasi, Cesare de Filippo, Fabrizio Mafessoni, Alba Bossoms Mesa, Arev P. SĂŒmer, Yaniv Swiel, Divyaratan Popli, Shahar Silverman, Michael James Boyle, Maxim B. Kozlikin, Michael V. Shunkov, Anatoly P. Derevianko, Tom Higham, Katerina Douka, Matthias Meyer, Hugo Zeberg, Janet Kelso, Svante PÀÀbo
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We present a genome sequenced to ~37-fold genomic coverage from an approximately 110,000-y-old male Neandertal from Denisova Cave in the Altai Mountains and analyze it together with previously published Neandertal genomes of high quality. We show that he belonged to a population more closely related to a ~120,000-y-old Neandertal from Denisova Cave than to Neandertals in Europe or to a ~80,000-y-old Neandertal from Chagyrskaya Cave in the Altai Mountains. Both Neandertals from Denisova Cave show evidence of gene flow from Denisovans, a pattern not seen in later Neandertals from the Altai region or from Western Europe. The extent of chromosomal regions of homozygosity in Neandertals from the Altai region between 120,000 and 80,000 y ago indicates that they lived in smaller and more isolated groups than later Neandertals in Europe (54,000 to 40,000 y ago). We estimate the extent of allele frequency differentiation among Neandertal populations and find that the older Eastern Neandertals in the Altai region and younger Western Neandertals in Europe were as differentiated as the most differentiated present-day human populations worldwide.
GPT-4o mini: Non-social science research article
Ultrasensitive measurement of brain penetration mechanics and blood vessel rupture with microscale probes
Abdulmalik Obaid, Mina-Elraheb Hanna, Song-Wen Huang, Yu-Ting Hu, Omar JĂĄidar, William Nix, Jun B. Ding, Nicholas A. Melosh, Yu-Wei Wu
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Microscale electrodes, on the order of 10 to 100 ”m, are rapidly becoming critical tools for neuroscience and brain–machine interfaces for their high channel counts and spatial resolution, yet the mechanical details of how probes at this scale insert into brain tissue are largely unknown. Here, we performed quantitative measurements of the force and compression mechanics together with real-time microscopy for in vivo insertion of a systematic series of microelectrode probes as a function of diameter (7.5 to 100 ”m and rectangular Neuropixels) and tip geometry (flat, angled, and electrochemically sharpened). These results elucidated the role of tip geometry, surface forces, and mechanical scaling with diameter. Surprisingly, the insertion force postpia penetration was constant with distance and did not depend on tip shape. Real-time microscopy revealed that at small enough lengthscales (<25 ”m), blood vessel rupture and bleeding during implantation could be entirely avoided. This appears to occur via vessel displacement, avoiding capture on the probe surface which led to elongation and tearing for larger probes. We propose a three-zone model to account for the probe size dependence of bleeding, and provide mechanistic guidance for probe design.
GPT-4o mini: Non-social science research article
Inorganic phosphate and the rapid mobilization of metabolic energy in neurons
Paul C. Rosen, Shivang Sullere, Panhui Fu, Juan R. Martínez-François, Daniel J. Brooks, Erica Kim, Chenghua Gu, Gary Yellen
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Neurons experience brief, intense periods of energy demand when they are excited, but how they rapidly coordinate energy expenditure with production is incompletely understood. Part of the difficulty has been measuring the levels of molecules involved in this metabolic response with spatiotemporal precision in single live cells. Here, we engineered a quantitative fluorescent biosensor to monitor cytosolic inorganic phosphate (P i ), a fundamental component of energy metabolism that has a classically proposed but largely neglected role in activating glycolysis. Using two-photon fluorescence lifetime imaging, we observed millimolar increases in P i within seconds of stimulating mouse neurons both ex vivo and in vivo. Drawing on results from metabolic modeling, biosensor imaging, and enzymology, we argue that P i is a sensitive reporter of energy usage that potently links metabolic energy supply with demand in neurons. Quantitative live-cell imaging of P i should be a valuable approach for studying bioenergetics more generally.
GPT-4o mini: Non-social science research article
Unique structural and ligand-binding properties of the Staphylococcus aureus serine hydrolase FphE
Jeyun Jo, Tulsi Upadhyay, Xiangyan You, John M. Bennett, Hyunbin Lee, Matthew Bogyo, Matthias Fellner
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Staphylococcus aureus is a human pathogen capable of forming biofilms that complicate treatment and facilitate chronic infections. A family of S. aureus serine hydrolases are important regulators of virulence and biofilm formation. Among these, FphE is highly specific to S. aureus and therefore a viable target for both imaging and therapy. Here, we present bioinformatic and structural evidence that FphE may be involved in aromatic compound metabolism. In addition, 12 distinct crystal forms reveal that FphE exists as a highly unusual but stable and flexible, cross-subunit homodimer, unique to the large alpha/beta hydrolase superfamily. Substrate engagement favors retention of the dimeric state, which is a more catalytically active form of the enzyme, and small-angle X-ray scattering confirms that the dimeric architecture occurs in solution. High-resolution cocrystal structures of FphE covalently bound to two chemically distinct ligands reveal different modes of active site engagement, supporting an atypical structural plasticity of the dimer interface. Together, these findings establish FphE as a structurally unique alpha/beta hydrolase and provide a foundation for structure-guided development of S. aureus –specific inhibitors and imaging probes.
GPT-4o mini: Non-social science research article
NLRP1B is an integrated decoy that subverts Shigella flexneri E3 ligase activity to promote effector-triggered immunity
Siwon Chung, Hannah Hudson, Kaitlin A. Stromberg, Andrew Sandstrom
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Inflammasomes are cytosolic immune complexes that recognize pathogen-associated stimuli to initiate a potent inflammatory response. While some inflammasomes directly recognize pathogen-associated molecules, others, such as the NLRP1B inflammasome, respond to pathogen-associated activities. Specifically, the NLRP1B inflammasome senses the enzymatic activity of pathogen-secreted proteases and E3 ligases through a mechanism of “functional degradation”—effectors that promote the proteasomal degradation of NLRP1B induce activation of this inflammasome. However, why pathogens would target NLRP1B for degradation when doing so promotes a robust inflammatory response is unclear. We propose that NLRP1 acts as an integrated decoy receptor by mimicking other host proteins targeted for degradation by pathogens. Specifically, we hypothesize that NLRP1B encodes sequences and features such that these pathogen effectors are unable to distinguish between NLRP1B and their other targets. To test this hypothesis, we determine how the Shigella flexneri E3 ligase IpaH7.8 is recognized by NLRP1B and whether these interactions are equivalent to those between IpaH7.8 and its other substrates, the Gasdermin (GSDM) family of proteins. Here, we show that IpaH7.8 recognizes both the GSDMs and NLRP1B through a single shared interface and that NLRP1B presents a surface similar to that recognized by IpaH7.8 on the GSDMs. In this way, NLRP1B acts as a decoy for the GSDMs to subvert the activity of IpaH7.8 to promote inflammasome activation. These data demonstrate that NLRP1B acts as an integrated decoy receptor and establish the use of integrated decoy receptors by the vertebrate immune system.
GPT-4o mini: Non-social science research article
Convergent motifs of early olfactory processing are recapitulated by layer-wise efficient coding
Juan Carlos FernĂĄndez del Castillo, Farhad Pashakhanloo, Venkatesh N. Murthy, Jacob A. Zavatone-Veth
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The architecture of early olfactory processing is a striking example of convergent evolution. Typically, a panel of broadly tuned receptors is selectively expressed in sensory neurons (each neuron expressing only one receptor), and each glomerulus receives projections from just one neuron type. Taken together, these three motifs—broad receptors, selective expression, and glomerular convergence—constitute “canonical olfaction,” since a number of model organisms including mice and flies exhibit these features. The emergence of this distinctive architecture across evolutionary lineages suggests that it may be optimized for information processing, an idea known as efficient coding. In this work, we show that by maximizing mutual information one layer at a time, efficient coding recovers several features of canonical olfactory processing under realistic biophysical assumptions. We also explore the settings in which noncanonical olfaction may be advantageous. Along the way, we make several predictions relating olfactory circuits to features of receptor families and the olfactory environment.
GPT-4o mini: Non-social science research article
Uncovering the embodied dimension of the wandering mind
Leah Banellis, Niia Nikolova, Malthe BrĂŠndholdt, Melina VejlĂž, Ignacio Rebollo, Nicolas Legrand, Francesca Fardo, Jonathan Smallwood, Micah G. Allen
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When at rest, the mind becomes preoccupied with self-generated thoughts, commonly known as mind-wandering. While the social, autobiographical, and temporal features of these thoughts have been extensively studied, little is known about how frequently the wandering mind turns toward the interoceptive and somatic body. To map this underexplored component of “body-wandering,” we conducted a large-scale neuroimaging study in 536 healthy participants, expanding a retrospective multidimensional experience sampling approach to include probes targeting visceral and somatomotor thoughts. Our findings reveal a robust interindividual dimension of body-wandering characterized by negative affect, high autonomic arousal, and a reduction in socially oriented thoughts. Despite this negative tone, individual differences in the propensity for body-wandering thoughts were associated with lower self-reported symptoms of ADHD and depression. Multivariate functional connectivity analyses further revealed that affective, body-oriented thoughts are related to a pattern of thalamocortical connectivity interlinking somatomotor and interoceptive-allostatic cortical networks. Collectively, these results demonstrate that self-generated thoughts exhibit core embodied features which are linked to the ongoing physical and emotional milieu of the visceral body.
GPT-4o mini: Non-social science research article
Receptor sequence divergence, gain, loss, duplication, and neofunctionalization drive olfactory adaptation in Drosophila suzukii
Qi Xue, Hany K. M. Dweck
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Shifts in ecological niches are often driven by evolutionary changes in the olfactory system, yet the underlying mechanisms remain poorly understood. To investigate this, we used Drosophila suzukii , an invasive fruit pest, as a model. Unlike most Drosophila species, which prefer overripe fruit, D. suzukii strongly prefers laying eggs in ripe fruit. We found that this shift is accompanied by pronounced changes in the odorant tuning of only a few olfactory receptor neurons (ORNs) compared to Drosophila melanogaster . Some changes are shared with its relative Drosophila biarmipes , whereas others are unique to D. suzukii . These shifts resulted not only from receptor sequence divergence but also from additional mechanisms. In one ORN, a second odorant receptor ( Or ), distinct from the ancestral Or , mediates detection of a leaf-derived odorant, while a single amino acid substitution—likely acting with additional changes—in the ancestral Or fine-tunes sensitivity to fruit-ripening esters. In two additional ORNs, four gene duplicates derived from an ancestral Or mediate tuning shifts: Two duplicates maintain responses similar to the original ORN, while two tandem duplicates confer responses in a preexisting ORN that has lost its ancestral Or . This neofunctionalization is unique to D. suzukii . Finally, we show that two of the receptors underlying these innovations are required for attraction to ripe fruit but are dispensable for egg-laying preference. Our findings reveal how receptor sequence divergence, coexpression, loss, duplication, and neofunctionalization drive sensory adaptation and ecological specialization and provide a foundation for identifying additional attractants and repellents to control D. suzukii .
GPT-4o mini: Non-social science research article
Phages drive the dissemination of antibiotic resistance genes by facilitating host adaptation to heavy metal stress
Luo-Qin Shen, Lu Wang, Zhiyuan Yao, Da Lin, Yu-Qiu Ye, Wan-rong Zhang, Mao Ye, Ming-Ming Sun, Shuai Du, Di Wu, Patrick O’Connor, Dong Zhu
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Heavy metals are increasingly recognized as major drivers of antibiotic resistance gene (ARG) dissemination in soil ecosystems. However, the role of phages in heavy metal–driven ARG dissemination and the underlying mechanisms remain poorly understood. Here, through integrative metagenomic, viromics, and metabolomic analyses of paddy soils across China, we reveal that soil phages promote ARG dissemination under heavy metal stress, likely through two potential mechanisms. First, phage-encoded auxiliary metabolic genes (AMGs) reprogram host metabolism to enhance bacterial survival and adaptation, thereby facilitating the cotransfer of adjacent ARGs and indirectly promoting horizontal dissemination. Second, phage-encoded heavy metal detoxification genes (HDGs) directly mediate metal detoxification, driving the cotransfer of neighboring ARG fragments and inducing lipid peroxidation–associated increases in membrane permeability, which collectively enhance ARG mobilization. We further identify a significant enrichment of lysogenic phages coharboring ARGs with AMGs or HDGs (AMG–ARG and HDG–ARG fragments), underscoring their contribution to ARG dissemination. Phage transplantation experiments confirm that elevated heavy metal stress triggers lysogenic phage-mediated ARG transduction to bacterial hosts. Cumulatively, our experiments highlight the pivotal role of phages in mediating ARG transfer under heavy metal pressure and underscore the necessity of incorporating phage dynamics into ARG risk assessments.
GPT-4o mini: Non-social science research article
Cell type diversification and phenotype convergence underlying white fin-ornamentation of cyprinid fishes
Delai Huang, Tiffany Liu, August A. Carr, Pietro H. de Mello, Yipeng Liang, Leah P. Shriver, François Chauvigné, Stephen L. Johnson, Joan Cerdà, Gary J. Patti, David M. Parichy
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Neural crest–derived cells offer valuable opportunities to dissect mechanisms of cell fate specification and differentiation and the underpinnings of cell type diversification over evolutionary time. Particularly useful for such analyses are pigment cells of ectothermic vertebrates that arise from neural crest cells or via latent neural crest–derived stem cells. Among these are white cells, leucophores, present in a variety of species that contribute to patterns on the body or ornamentation on the fins. To better understand developmental and evolutionary origins of these cells, we examined leucophores harboring deposits of yellow/orange carotenoids—xantholeucophores—of zebrafish and leucophores of white cloud minnow. We show that white phenotypes of both cell types require sepiapterin reductase and an accumulation of pale and colorless pteridines. We further demonstrate that xantholeucophores of zebrafish develop from yellow, sepiapterin-rich xanthophore-like cells and that this transition requires both gap junctional communication and the aquaglyceroporin/peroxiporin channel Aquaporin 3, revealing similarities and differences in differentiation and patterning compared to pigment cells on the body. These findings identify xantholeucophores of zebrafish and leucophores of white cloud minnow as distinct developmentally, genetically, and biochemically from other white cells of zebrafish—melanoleucophores—that develop directly from melanophores and depend on guanine crystals, as well as white cells of medaka fish and anemonefish. Our results highlight remarkable convergences and parallelisms in the acquisition of white cell phenotypes within and between phylogenetic lineages and identify this as a rich system for enquiries into the evolutionary individuation of novel cell types.
GPT-4o mini: Non-social science research article
Immune cell profiling reveals expanded stem cell–like memory T cells in anti-GAD65-associated neurological syndromes
Sumanta Barman, Saskia RĂ€uber, Katharina Eisenhut, Daniela Esser, Martijn van Duijn, Madeleine Scharf, Marisol Herrera-Rivero, Paul Disse, Lara-Maria Preuth, Valeria Gulyaeva, Ilja Schwan, Eliza vom Stein, Marius Jonas, Duygu Pul, Michael Heming, Louisa MĂŒller-Miny, Manuela Paunovic, Christine Strippel, Ebru Haholu, Jan Bartosch, Elisabeth Kaufmann, Justina Dargvainiene, Sabine Kahl, Marius Ringelstein, Eric Bindels, Heinz Wiendl, Nikolas H. Stoecklein, Johannes Fischer, Norbert Goebels, Lars Komorowski, Michael Roden, Andrea Rossi, Monika Stoll, Albert J. Becker, Motaz Hamed, Christian G. Bien, Romana Höftberger, Jan Bauer, Sven G. Meuth, Maarten J. Titulaer, Frank Leypoldt, Gerd Meyer zu Hörste, Franziska Thaler, Nico Melzer, character(0), character(0), Juna M. de Vries, Mariska M. P. Nagtzaam, Suzanne C. Franken, Yvette S. Crijnen, Juliette Brenner, Robin W. van Steenhoven, Jeroen Kerstens, Marienke A. A. M. de Bruijn, Anna E. M. Bastiaansen, Remco M. Hoogenboezem, Sharon Veenbergen, Peter A. E. Sillevis Smitt, Marwa Al-Dubai, Luise Appeltshauser, Ilya Ayzenberg, Carolin Baade-BĂŒttner, Andreas van Baalen, Sebastian Baatz, Oliver BĂ€hr, Bettina Balint, Iason Bartzokis, Sebastian Bauer, Annette Baumgartner, Tobias Baumgartner, Antonios Bayas, Stefanie Becker, Sonka Benesch, Robert Berger, Birgit Berger, Martin Berghoff, Sarah Bernsen, Achim Berthele, Christian Bien, Corinna Bien, Julia Bierwith, Andreas Binder, Stefan Bittner, Daniel Bittner, Franz Blaes, Astrid Blaschek, Amelie Bohn, Moritz Böhringer, Marie Braun, Sergio Castro-Gomez, Justina Dargvainiene, Timo Deba, Julia Maren Decker, Johanna-Maria Dietmaier, Andre Dik, Julian Dominik, Kathrin Doppler, Mona Dreesmann, Lena Edelhoff, Laura Ehrhardt, Sven Ehrlich, Katharina Eisenhut, Alexander Emmer, Dominique Endres, Marina Entscheva-Storr, Daniela Esser, Thorleif Etgen, JĂŒrgen Hartmut Faiss, Kim Kristin Falk, Timo Faustmann, Walid Fazeli, Alexander Finke, Carsten Finke, Felix Fischbach, Dirk Fitzner, Marina Flotats-Bastardas, Mathias Fousse, Tobias Freilinger, Manuel Friese, Hannah Fuhrer, Armin Johannes Gaebler, Marco Gallus, Marcel Gebhard, Christian Geis, Clemens Gödel, Anna Gorsler, Armin Grau, Oliver Grauer, Britta Greshake, Catharina roß, Thomas GrĂŒter, Aiden Haghikia, Robert Handreka, Iris Hannibal, Niels Hansen, Sandra Hansmann, Jens Harmel, Antonia Harms, Yetzenia Dubraska Haro Alizo, Alkomiet Hasan, Martin HĂ€usler, Ida Sybille Haussleiter, Joachim Havla, Chung Ha-Yeun, Wolfgang Heide, Valentin Held, Kerstin Hellwig, Marina Herwerth, Philip Hillebrand, Frank Hoffmann, Christian Hofmann, Ulrich Hofstadt-van Oy, Dominica Hudasch (ehem. Ratuszny), Yannik HĂŒlsmann, Martinv HĂŒmmert, Peter Huppke, Hagen Huttner, Fatme Seval Ismail, Martina Jansen, Mareike Jansen, Marius Jonas, Aleksandra Juranek, Daniel Kamp, Michael Karenfort, Annika Kather, Max Kaufmann, Christoph Kellinghaus, Constanze Kerin (geb. Mönig), Ruth Kerkhoff, Rolf Kern, Jaqueline Klausewitz, Michael Kluge, Susanne Knake, Benjamin Knier, Ellen Knierim, Frank Kohlert, Inga Koneczny, Felix Konen, Peter KörtvĂ©lyessy, Stjepana Kovac, Andrea Kraft, Markus KrĂ€mer, Verena Kraus, Christos Krogias, Gregor KuhlenbĂ€umer, Olga Kukhlenko, Tania KĂŒmpfel, Albrecht Kunze, Hanna Lapp, Christoph Lehrich, Martin Lesser, Jan Lewerenz, Frank Leypoldt, Andreas Linsa, Daniel LĂŒdecke, Jan LĂŒnemann, Marie Madlener, Michael Malter, Nils Margraf, Carlos Martinez Quesada, Monika Meister, Nico Melzer, Kristin Stefanie Melzer, Til Menge, Sven Meuth, Gerd Meyer zu Hörste, Fabian Möller, Marie-Luise Mono, Sigrid Mues, Hiltrud Muhle, Anna-Katharina Mundorf, Marc Nikolaus, Jost Obrocki, Friedemann Paul, Loana Penner, Lena Kristina Pfeffer, Thomas Pfefferkorn, Steffen Pfeuffer, Alexandra Philipsen, Johannes Piepgras, Julika Pitsch, Felix von Podewils, Mosche Pompsch, Josef Priller, Anne-Katrin Pröbstel, Harald PrĂŒĂŸ, Duygu Pul, Daniel Rapp, Johanna Maria Helena Rau, Saskia RĂ€uber, Markus Rauchenzauner, Robert Rehmann, Ina Reichen, Gernot Reimann, Momsen Reincke, Raphael Reinecke, Jonathan Repple, Nele Retzlaff, Sigrid Reuter, Marius Ringelstein, Henrik Rohner, Felix Rosenow, Kevin RostĂĄsy, Theodor RĂŒber, Stephan RĂŒegg, Yannic Saathoff, Jens Schaumberg, Hanna Schellhorn, Ruth Schilling, Jens Schmidt, Melissa Schmitz, Ina-Isabelle SchmĂŒtz, Hauke Schneider, Patrick Schramm, Stephan Schreiber, Stefanie Schreiber, Gesa Schreyer, Ina Schröder, Simon Schuster, Philip Schwenkenbecher, GĂŒnter Seidel, Frank Seifert, Thomas Seifert-Held, Makbule Senel, Kai Siebenbrodt, Olga Simova, Claudia Sommer, Juliane Spiegler, Oliver Stammel, Slobodan Stankovic, Andreas Steinbrecher, Johann Steiner, Henning Stolze, Muriel Stoppe, Karin Storm van’s Gravesande, Christine Strippel, Dietrich Sturm, Klarissa Hanja StĂŒrner, Kurt-Wolfram SĂŒhs, Steffen Syrbe, Simone Taube, Franziska Thaler, Florian Then Bergh, Katrin Thies, Anja Tietz, Corinna Trebst, George Trendelenburg, Regina Trollmann, Thanos Tsaktanis, Hayrettin Tumani, Mehtap TĂŒredi, Christian Urbanek, Rem Vaizian, Niklas Vogel, Max Vogtmann, Matthias von Mering, Katharina von Zedtwitz, Judith Wagner, Jan Wagner, Elias Wagner, Barbara Wagner, Klaus-Peter Wandinger, Mirko Wegschneider, Judith Weiser, Robert Weissert, Njiku Melchior Wellmer, Brigitte Wildemann, Jonathan Wickel, Karsten Witt, Katharina Wurdack, Yavor Yalachkov, Lara Zieger
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The immunopathogenesis of autoimmune neurological syndromes (AINS) with antibodies against the 65 kDa isoform of glutamic acid decarboxylase (anti-GAD65 AINS) remains poorly understood. To elucidate underlying disease mechanisms and identify relevant cell populations, we performed single-cell RNA and immune repertoire sequencing of cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMCs) of eight anti-GAD65 AINS individuals compared to eight noninflammatory controls. In addition, PBMCs from 19 anti-GAD65 AINS individuals and 20 healthy controls were analyzed by multidimensional flow cytometry, and brain tissue specimens from four anti-GAD65 AINS individuals were examined histologically. We detected higher frequencies of stem cell–like memory T cells (TSCM) within the PBMCs and a marked enrichment and clonal expansion of activated CD4 + TSCM in the CSF of anti-GAD65 AINS individuals. Expanded T cells exhibited increased expression of proinflammatory genes. Histological analyses confirmed intraparenchymal CD8 + TSCM in three of four anti-GAD65 AINS individuals and rare meningeal/intraparenchymal CD4 + TSCM in one person. Although CSF B cell receptors (BCRs) displayed little to no clonal expansion, recombinant expression of 40 CSF BCRs revealed that 25% were GAD65-reactive with increased somatic hypermutations compared to non-GAD65-reactive BCRs. These findings further support the concept of an antigen-specific intrathecal immune response. In summary, we characterize the immune landscape of anti-GAD65 AINS at single-cell resolution and identify clonally expanded TSCM with cytotoxic properties as a hallmark of this disease.
GPT-4o mini: Non-social science research article
Identifying a cancer therapeutic target: Cell-SELEX identifies a membrane protein for aptamer-mediated growth suppression
Wei Cui, Hang Xiao, Xiaohong Wen, Chen Li, Suxia Bao, Jiahao Zeng, Yangbing Li, Yan Qiao, Kemin Wang, Honghui Wang, Jin Huang, Qiuping Guo
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The identification of functional ligand-membrane protein interactions under native conditions remains a major challenge in cancer biology. Using cell-systematic evolution of ligands by exponential enrichment, we identified a high-affinity DNA aptamer, CW06, against breast cancer cells. To precisely identify its native membrane target, we developed Aptamer-mediated Metabolic Glycan-labeling Proximity Hybridization (Apt-MGPH), which revealed the mitochondrial solute carrier SLC25A24 as the specific target. Unexpectedly, CW06 treatment upregulated SLC25A24 expression, disrupting methionine metabolism, depleting cytosolic SAM, and inducing G1 cell cycle arrest and senescence via the p21–HMGA1 axis. In mouse xenograft models, CW06 significantly inhibited tumor growth without affecting healthy tissues. Targeted degradation of SLC25A24 reverses these effects, confirming its regulatory role in the metabolism–senescence axis. Our study establishes Apt-MGPH as a robust tool for membrane target identification and highlights aptamer-induced target overexpression as a strategy for cancer therapy.
GPT-4o mini: Non-social science research article
Biologically grounded on-chip model identifies selective topographic reorganization within hyperexcitable corticostriatal networks
Maxime Poinsot, Marine Dos Santos, Baptiste Marthy, Ana Borges-Correia, Eduardo Gascon, Benoit Charlot, Maxime Cazorla
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The mammalian cerebral cortex projects to the striatum in a precise, hierarchical topography, forming parallel loops that underlie sensorimotor, associative, and limbic processing. Despite the striatum’s lack of clear anatomical boundaries, these projections remain functionally segregated, suggesting the existence of intrinsic organizing principles. Disruptions in corticostriatal connectivity and excitability are common in neurodevelopmental disorders, but it remains unclear whether such abnormalities are a cause or a consequence of circuit dysfunction. Here, we hypothesized that the excitability state of cortical neurons plays a direct role in shaping the topographic organization of their striatal projections. To test this, we engineered a biologically faithful in vitro platform inspired by the Tesla valve, enabling adjacent corticostriatal territories to be modeled under controlled excitability regimes. We found that cortical hyperexcitability disrupted the normal developmental transition from axonal growth to stabilization, leading to premature invasion of neighboring territories and the formation of ectopic convergence zones. As a result, the segregation between parallel pathways was lost, while local connectivity patterns remained unaffected. These findings reveal that intrinsic, activity-sensitive mechanisms constrain long-range axonal growth to shape the wiring diagram of the corticostriatal projectome. They also highlight the power of biologically grounded on-chip models to uncover how early circuit vulnerabilities can lead to connectivity defects characteristic of disorders such as autism spectrum disorder, schizophrenia, epilepsy, and obsessive-compulsive disorder.
GPT-4o mini: Non-social science research article
Microstrain-engineered platinum nanoclathrins for fuel cells
Zhiyong Yu, Qing Yao, Chen Sun, Liangqun Zhao, Yonggang Feng, Rui Qin, Fei Xue, Xueli Yan, Zhiwei Hu, Wei-Hsiang Huang, Chih-Wen Pao, Lili Han, Nanjun Chen, Xiaoqing Huang
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Proton exchange membrane fuel cells (PEMFCs) hold great promise for clean energy conversion, yet their performance is limited by insufficient mass transport bottlenecks within the catalyst layer. Addressing this fundamental issue demands innovative catalyst nanostructuring. Inspired by the evolutionarily optimized channel systems in cellular transport mechanisms, we design clathrin-mimetic noble metal nanostructures featuring nanoporous shells and internal cavities via a selenium-induced self-assembly method. The creation of such nanoclathrin relies on the in situ formed Se, where the amorphous structure induces the disordered growth of noble metals on the surface, ultimately establishing the nanoclathrin architecture. This strategy can be extended to create diverse nanoclathrins with controlled hollow size, shell thickness, as well as composition. Furthermore, precise microstrain engineering enables performance fine-tuning of platinum nanoclathrins (Pt NCLs) for half reactions in PEMFCs. Benefiting from enhanced mass transfer and optimized microstrain, Pt NCLs can serve as both efficient cathode and anode catalysts in practical fuel cells, achieving rated power densities of 1.25 W cm −2 in H 2 /O 2 and 0.83 W cm −2 in H 2 /Air, which positions Pt NCLs among the best-performing pure-Pt catalysts and even rivals many state-of-the-art Pt-alloy catalysts. The clathrin-like structures also exhibit excellent stability, retaining 95.7% of their initial activity after 30,000 accelerated stress test cycles. This work highlights the significance of designing clathrin-like architecture with promoted mass transfer for practical devices and beyond in sustainable energy applications.
GPT-4o mini: Non-social science research article
Cnpy1 is a candidate endoplasmic reticulum chaperone of vomeronasal type 2 GPCRs
G. V. S. Devakinandan, Abdul Rishad, Nandana Nanda, Syed Dastagir Hussain, Sishir Subedi, Adish Dani
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Mouse vomeronasal sensory neurons are continuously generated from stem cells and differentiate to express either V1R or V2R G protein–coupled receptors (GPCRs), along with their respective Gαi2 or Gαo G-protein subunits. We previously reported that Gαo-type neurons exhibit elevated expression of endoplasmic reticulum (ER) chaperones and a distinctive hypertrophic, gyroid ER architecture, suggesting specialized proteostatic demands. Here, we identify a transcript for the mouse Canopy1 ( Cnpy1) gene that yields full-length Cnpy1 protein selectively expressed in and localized to the ER of Gαo neurons. Immunoprecipitation coupled with mass spectrometry revealed that Cnpy1 associates specifically with V2R GPCRs and multiple ER chaperones. Cnpy1 deletion resulted in mice that were deficient in Gαo neuronal activation upon exposure to vomeronasal stimuli and a marked reduction in male–male aggressive behavior. In the absence of Cnpy1, Gαo neurons develop normally till birth but undergo selective, progressive apoptosis during postnatal development. Unexpectedly, Cnpy1-null vomeronasal neurons displayed neither an obvious unfolded protein response nor defects in V2R GPCR traffic to dendritic tips, indicating that Cnpy1 is required for V2R assembly or functional maturation but dispensable for their ER export. Together, these findings identify Cnpy1 as a component of an ER chaperone complex that is essential for Gαo neuron signaling and survival.
GPT-4o mini: Non-social science research article
Genomic epidemiology of Salmonella and Campylobacter in poultry production: Quantifying the contribution of primary breeders
David J. Lipman
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The US broiler production system processes over 9.3 billion chickens annually through a highly integrated pyramid structure where two primary breeding companies supply genetic stock to approximately 40 major integrators operating nationwide. To provide a quantitative, system-wide estimate of contamination origins, I analyzed whole-genome sequences from Salmonella and Campylobacter isolates collected from over 800 processing facilities as part of the United States Department of Agriculture’s Food Safety Inspection Service verification sampling (2019-2025). Single-linkage clustering identified isolates sharing common origins (≀2, 4, or 8 SNPs genome-wide), which were categorized by processing complex, company, and geographical distributions to infer contamination sources. Among the isolates analyzed, 78% of Campylobacter , 77% of non-Enteritidis Salmonella , and 96% of Salmonella Enteritidis belonged to clusters spanning multiple companies and geographic regions—a pattern consistent with primary breeder origin. The geographic spread of Enteritidis isolates within clusters matched a random model, and cluster populations showed temporal turnover yet spatial synchrony—patterns explicable only by contamination from the apex of the breeding pyramid. Campylobacter showed regional clustering implying sources at lower levels of the breeding pyramid. Cluster persistence exceeded multiple production cycles (median >4 y for Campylobacter , >4.5 y for 75% of Enteritidis isolates), indicating stable contamination reservoirs upstream of processing. These results demonstrate that the primary breeders are a major source of broiler contamination and suggest that upstream interventions targeting breeding stock, in particular for Enteritidis, may represent an efficient strategy for further reducing clinical cases of foodborne illness.
GPT-4o mini: Non-social science research article
Fibro-adipogenic progenitor cells from murine SMA muscles are intrinsically adipogenic
Yangyi E. Luo, Zoe Abe-Teh, Tarek Alsaghir, Katie D. Heiden, Kari B. Basso, Elisabeth R. Barton
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Spinal muscular atrophy (SMA) is a neurodegenerative disorder caused by mutations in the SMN1 gene. Although classically viewed as a neurogenic disease, SMA patients exhibit poor skeletal muscle regeneration and increased fatty-fibrotic infiltration. Fibro-adipogenic progenitors (FAPs) are mesenchymal precursor cells that contribute to muscle remodeling and underlie fat and fibrosis formation. Because FAPs transiently express Smn1 during regeneration, FAPs were examined in muscles from adult C/C SMA and control mice to determine if reduced Smn activity altered their properties. We performed a nonbiased screen of FAPs following BaCl 2 -induced injury using an in situ cell surface proteomic strategy that probed the cellular membrane and environment of FAPs in early regeneration. Proteomic profiling revealed early adipogenic priming in SMA tissues, with increased levels of perilipin-4 and adipocyte lipid-binding proteins. Significantly more adipocytes accumulated in C/C SMA muscles after glycerol injection versus controls. Further, SMA FAPs produced more fat than control FAPs when transplanted into glycerol injured muscles lacking FAPs. RNA sequencing of FAPs isolated after BaCl 2 or glycerol injury identified transcriptional enrichment of lipid biosynthesis and dysregulated lipid metabolism in SMA FAPs. Primary FAPs isolated from C/C SMA muscles mirrored heightened adipocyte formation, which was normalized by increasing Smn activity with Risdiplam. Conversely, adipogenesis of primary FAPs from control muscles was enhanced when subjected to siRNA Smn1 knockdown. Together, these findings demonstrate that reduced Smn activity potentiates intrinsic adipogenic bias in FAPs that may contribute to pathological fat deposition in SMA muscle.
GPT-4o mini: Non-social science research article
Ecological speciation in allopatry is rooted in older divergence
Andrew D. C. MacColl
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GPT-4o mini: Non-social science research article
Versatile artificial muscles by decoupling anisotropy
Eric Weissman, Rohan Khatavkar, Jiefeng Sun
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Artificial muscles offer unique advantages for robotics, but their inability to adapt to diverse scenarios significantly limits their widespread application. We present the helical anisotropically reinforced polymer actuator (HARP)—a versatile class of artificial muscles. The HARP not only exhibits state-of-the-art performance (contraction ratios up to 75%, power densities of 1.93 kW/kg, and energy efficiencies of 29%) but also possesses a broad and decoupled design space, i.e., the anisotropy source, tube, and core can be independently and freely selected. This decoupled design space enables the selection of numerous useful properties (e.g., abrasion resistance, high specific work, etc.). Using this, we demonstrate that the HARP can satisfy the requirements of diverse applications by tuning the selection of parameters. This is especially important for applications necessitating multiple requirements simultaneously, like a maneuverable continuum robot or an untethered musculoskeletal quadruped. Unifying high performance with versatility within a single artificial muscle framework, the HARP offers a practical path toward deploying artificial muscles across a wide spectrum of robotic systems.
GPT-4o mini: Non-social science research article
The low-density lipoprotein receptor LDLR mediates cellular entry of nonenveloped hepatitis A virus
Tomoyuki Shiota, Yuguang Zhao, Itoe Shiota, Helen M. E. Duyvesteyn, Manami Yamaoka, Anshuman Das, Maryna Kapustina, Pranav Shah, Masamichi Muramatsu, Xiangxi Wang, Elizabeth E. Fry, David I. Stuart, Stanley M. Lemon
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Hepatitis A virus (HAV) is an unusual picornavirus with two types of extracellular virions: nonenveloped particles (nHAV) shed in feces and quasi-enveloped particles (eHAV) circulating in blood. Both enter cells by clathrin-dependent endocytic pathways merging in late endolysosomes with capsid binding to ganglioside receptors. Phosphatidylserine receptors facilitate eHAV endocytosis, but no protein receptor has been identified for nHAV. Here, we show low-density lipoprotein receptor (LDLR) is such a receptor. LDLR knockout did not alter viral attachment to cells, but restricted cellular uptake of nHAV (not eHAV). Soluble LDLR ectodomain blocked nHAV entry, as did antibody to LDLR. Recombinant LDLR-related protein-associated protein 1, a pan-LDLR family chaperone, also inhibited nHAV entry, including residual entry into knockout cells, suggesting other LDLR family members may similarly facilitate endocytosis. Reconstituting full-length LDLR expression restored nHAV entry in knockout cells, whereas LDLR mutants lacking LA repeats 4 to 7 or the EGF-like/propeller domain did not. ELISAs confirmed LDLR binds nHAV, optimally above pH7, without destabilizing the capsid. A 1.7Å resolution cryoelectron microscopy (cryo-EM) structure revealed LDLR interacts with VP1 at the fivefold vertex of the capsid. Extreme blurring of the LDLR density prevented detailed identification of LDLR interactions, and suggested binding does not follow particle symmetry, being either flexible or to multiple LDLR regions. Additional cryo-EM studies show ganglioside GD1a binds to a similar region of the capsid. Collectively, these data reveal the LDLR to be an important entry factor, shuttling nHAV from the extracellular environment to endolysosomes where it is likely released at low pH to bind gangliosides.
GPT-4o mini: Non-social science research article
Mineral-facilitated aqueous synthesis of hydrogen cyanide from prebiotically abundant amino acids for chemical evolution
Zening Yang, Yamei Li, Norio Kitadai, Masahiro Yamamoto, Yuichiro Ueno, Yanjing Lu, Ailong Li, Kiyohiro Adachi, Akira Yamaguchi, Daisuke Hashizume, Ryuhei Nakamura
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Recent advances in prebiotic chemistry suggest that hydrogen cyanide (HCN) serves as a fundamental precursor for nearly all essential biomolecules and protometabolic processes for life’s emergence. Although prevailing models of endogenous cyanide production rely on atmospheric methane, the availability of methane remains uncertain. Unlike methane, amino acids were likely prebiotically abundant, forming through multiple synthetic pathways under a methane-free, nonreducing atmosphere. Here, we demonstrate that HCN can form from proteinogenic amino acids in anaerobic aqueous solutions facilitated by geochemically available minerals, offering a route to overcome HCN scarcity under a nonreducing atmosphere. On manganese dioxide, the glycine-to-cyanide conversion proceeded across a broad range of pHs (2.0 to 12.6) and substrate concentrations (1 ÎŒM to 100 mM), achieving a maximum selectivity of 57%. The reaction involves α-proton abstraction in amino acids, which is distinct from conventional chemical decarboxylation processes of amino acids, highlighting the unique role of MnO 2 in activating the α-C-H bond to form HCN. HCN generation was observed for nearly all proteinogenic amino acids and short peptides. Because amino acids can be synthesized from HCN-independent pathways from abundant carbon sources such as CO 2 and CO, amino acid-derived HCN alleviates the requirement on atmospheric methane and can sustain continued chemical evolution in ambient aqueous environments.
GPT-4o mini: Non-social science research article
Adipose Dicer-1 modulates systemic insulin signaling and longevity via a miR-8–Aop–Dilp6 axis
María C. Ingaramo, Francisco Ramello, Silvano J. Santander, Yemina Abelendo, Andrés Dekanty
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Interorgan communication is essential for metabolic homeostasis and healthy aging, with adipose tissue acting as a central hub that coordinates systemic metabolism, stress responses, and longevity. Here, we show that the miRNA-processing enzyme Dicer-1 (Dcr-1) acts in the fat body (FB) to regulate Dilp2 secretion from brain insulin-producing cells (IPCs), thereby modulating systemic insulin signaling and lifespan in Drosophila . Dcr-1 expression is reduced in multiple long-lived conditions, and its partial downregulation enhances oxidative stress resistance, alters lipid metabolism, and extends lifespan even under dietary restriction. Proteomic profiling of FBs from Dcr-1 heterozygous flies revealed widespread metabolic reprogramming and stress adaptation consistent with attenuated insulin/IGF signaling (IIS). Mechanistically, reduced Dcr-1 lowers miR-8 levels in the FB, which indirectly upregulates Drosophila insulin-like peptide 6 (Dilp6). Dilp6 acts nonautonomously to suppress Dilp2 secretion from IPCs, reducing systemic IIS and promoting longevity. We further show that Dcr-1 reduction activates the ETS-family repressor Aop/ETV6 downstream of Ras-Erk signaling, which is required for Dilp6 induction and the lifespan extension observed upon miR-8 depletion. Collectively, these findings reveal a miRNA-dependent regulatory axis that couples adipose-derived endocrine signals to systemic insulin regulation and aging, positioning Dcr-1 as a central node in the control of metabolic homeostasis and lifespan.
GPT-4o mini: Non-social science research article
Ultrasound-responsive liposomes: A mechanistic framework to decode the effects of acoustic parameters
Ignasi Simon, Rebecca F. A. van den Elshout, Gandhika K. Wardhana, Masoumeh Aqamolaei, Isabella S. T. de Jonge, Remco Hartkamp, Riccardo Alessandri, Tiago L. Costa, Alina Y. Rwei
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Ultrasound offers a noninvasive, clinically relevant means to achieve precise spatiotemporal control of cargo release from ultrasound-responsive drug delivery systems within deep tissues. This approach enables targeted delivery of therapeutic agents, enhancing efficacy while minimizing systemic toxicity. While previous studies show that release from ultrasound-responsive liposomes depends on acoustic parameters, the underlying mechanisms remain unclear. A deeper mechanistic understanding is essential to achieve precision over release and maximize therapeutic outcomes. To address this, we propose a sonoporation-based framework to describe release dynamics across varying frequencies, pressures, duty cycles, and pulse repetition frequencies for ultrasound-responsive poly(ethylene glycol)-functionalized liposomes. Using computational simulations validated by empirical results, our framework identifies a critical pressure threshold for release onset and demonstrates how the time spent above this threshold, modulated by acoustic parameters, governs release efficiency. To elucidate these effects, custom-built ultrasound transducers with different resonance frequencies were fabricated and characterized to ensure precise sample alignment, minimize acoustic distortion, and maintain a controlled focal-volume-to-sample-volume ratio across different frequencies. COMSOL simulations indicated that oscillatory acoustic pressure plays a more dominant role than acoustic radiation force, while coarse-grained molecular dynamics simulations captured pressure-dependent pore formation dynamics within the lipid bilayer. Together, our experiments and simulations highlight mechanical effects—particularly oscillatory acoustic pressure—as the primary driver of sonoporation-facilitated release. Finally, we discuss how optimizing acoustic parameters through this mechanistic framework could facilitate safe and effective clinical translation by considering tissue safety and ultrasound transducer design.
GPT-4o mini: Non-social science research article
Tyrosine phosphoproteome profiling identifies cell-intrinsic signals limiting the efficacy of tyrosine kinase inhibitor therapies
Cameron T. Flower, Forest M. White
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Tyrosine kinases (TKs) are frequently mutated or overexpressed in cancer, and TK inhibitors (TKIs) are an important therapeutic modality against TK-driven cancers, but many patients show an underwhelming response to TKIs prescribed on the basis of tumor genotype. To find cell-intrinsic TK signaling patterns which might be predictive of poor response to TKI therapies, we used high-sensitivity multiplexed mass spectrometry to quantify endogenous levels of 1,222 phosphotyrosine (pY) sites across the proteomes of TK-driven human cancer cell lines with variable response to genotype-matched TKIs. In direct comparisons between TKI-tolerant and TKI-sensitive lines with a common driver TK, we found that TKI treatment was equally effective at blocking driver TK signaling, and higher basal activity of the driver TK did not always predict higher sensitivity to TKI. All tolerant lines showed a dampened proteome-wide pY response to TKI exposure compared to sensitive lines, suggesting that tumor cells with more robust TK signaling are less vulnerable to driver TK blockade. We found that each tolerant line depends on a unique set of compensatory TKs and signaling axes but are unified by hyperactivity of at least one of the SRC family kinases (SFKs) or the related ABL1/2 kinases, both at rest and under TKI treatment, despite the absence of SFK or ABL genetic mutations. In time- and dose-resolved drug combination experiments, SFK/ABL inhibitors were potently synergistic with all TKIs tested, demonstrating that elevated SFK/ABL signaling is a conserved bottleneck for maximal TKI efficacy which could be exploited therapeutically.
GPT-4o mini: Non-social science research article
Global stability of ecological and evolutionary dynamics via equivalence
Stefano Allesina
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The replicator and the Generalized Lotka–Volterra equations are closely related, foundational models in evolutionary game theory and community ecology, respectively. The concept of evolutionary stability and its relationship with dynamic stability has received significant attention: In the replicator equation, an evolutionarily stable strategy is also dynamically globally stable—i.e., will be reached by any trajectory originating from positive conditions. Intriguingly, the converse is not true: There are replicator equations yielding dynamically stable strategies that are not evolutionarily stable. Here, we consider two classes of equivalence (i.e., transformations that do not alter the qualitative dynamics) for the replicator equation, to determine whether a globally stable, but not evolutionarily stable strategy maps into an equivalent state that is evolutionarily stable—and show that this is the case for the examples that have been put forward so far. We derive the same two classes of equivalence for the Generalized Lotka–Volterra model, obtaining the same conditions for stability as for the replicator equation, and show that in this way we can characterize stability when other methods fail. By unifying the approach to proving stability for the replicator equation and Lotka–Volterra models, we bring these foundational equations even closer together.
GPT-4o mini: Non-social science research article
PHGDH phosphorylation mediated by WNK1 serves as a dual marker of metabolic vulnerability and responsiveness to oxaliplatin treatment
Shaobo Fang, Guoguo Jin, Mingyang Yan, Yanming Song, Simin Zhao, Chengjuan Zhang, Yang Shao, Kexin Zhao, Meng Liu, Zhenwei Wang, Xinyang Jia, Qinxin Guo, Manman Guo, Meiyun Wang, Zhiping Guo, Zigang Dong
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Metabolic reprogramming is a fundamental hallmark of cancer progression. However, the oncogenic mechanisms underlying serine metabolism and its impact on chemotherapeutic sensitivity in gastric cancer (GC) remain poorly defined. Here, through integrated metabolomics and 13 C-labeled metabolic flux analysis, we identify marked dysregulation of serine metabolism in GC, primarily driven by increased expression of phosphoglycerate dehydrogenase (PHGDH). Mechanistically, we show that with no lysine kinase 1 (WNK1) phosphorylates PHGDH at Ser349 and Ser371, enhancing its enzymatic activity and protein stability by preventing ubiquitin-mediated degradation. In vivo, WNK1 knockout mice exhibit significantly reduced gastric tumor burden, accompanied by decreased serine levels and disrupted redox balance, supporting the protumorigenic role of the WNK1–PHGDH axis. Clinically, enhanced PHGDH activity, elevated serine levels, and increased glutathione abundance are strongly associated with poor oxaliplatin response in GC patient cohorts, suggesting PHGDH as a potential predictive biomarker for chemotherapy resistance. Together, these findings delineate a WNK1–PHGDH–driven serine metabolic reprogramming axis that promotes redox adaptation and chemoresistance in GC, highlighting its dual value as a mechanistic driver and a therapeutic vulnerability in cancer treatment.
GPT-4o mini: Non-social science research article
Probing charge-transfer processes in Pt/TiO 2 photocatalysts by amperometric/potentiometric photo-SECM
Tianyu Bo, Haoqing Su, Ziyuan Wang, Je Hyun Bae, Gaukhar Askarova, Shu Hu, Michael V. Mirkin
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Electrocatalysts in combination with photoelectrodes can provide higher activity and/or lower overpotential for a broad range of photoelectrochemical processes. Although cocatalyst nanoparticles (NPs) on semiconductor surfaces have been extensively studied, spatially resolved kinetic measurements of charge-transfer processes in such systems remain challenging. Here, we introduce a unique approach based on a single setup employing contact amperometric/potentiometric photo-scanning electrochemical microscopy for quantitative, high-resolution measurements of photoelectrochemical processes in nanostructured photocatalysts. Amperometric SECM experiments are coupled with nanoscale local potential measurements made using the same nanotip, which is brought within the tunneling distance from the sample surface. Pt NPs electrodeposited on the surface of Nb-doped TiO 2 rutile (110) single crystals are used as a model experimental system to demonstrate the capabilities of the developed technique for probing local rates of photogenerated hole/electron transfers, such as overall water splitting (OWS) with coevolved H 2 and O 2 , as well as the oxidation/reduction of a reversible redox mediator (e.g., ferro/ferricyanide). This methodology resolves spatial variations in photocatalytic reactivity of nanoscale cocatalysts supported on semiconductors with a spatial resolution on the order of 10 nm. In the Pt/Nb:TiO2 system, this method identifies distinct cathodic and anodic sites separated by ~150 nm, with local surface potentials of approximately −0.53 V and +0.58 V vs. Ag/AgCl, respectively. Complementary structural/compositional and spectroscopic analyses reveal the coexistence of metallic Pt and oxidized Pt species under OWS conditions, establishing asymmetric surface energetics consistent with a ~1.5 eV difference in local band-edge position and thereby driving directional carrier separation within Nb:TiO 2 .
GPT-4o mini: Non-social science research article
KLF2 overrides the resident memory CD8 T cell differentiation program, in opposition to KLF3
Taylor A. DePauw, Kexin Gai, Jian Shen, Nicholas J. Maurice, Ka Hyun Rhee, William J. Valente, Christine H. O’Connor, Weiguo Cui, Changwei Peng, Stephen C. Jameson
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Numerous transcriptional regulators have been associated with the differentiation pathways that lead to recirculating vs. tissue-resident memory T cells. However, it is unclear whether independent, coordinated expression of these regulators is required to determine residency vs. recirculation or whether there is a hierarchy, with some factors playing a dominant role in controlling T cell trafficking. We report that ablation of the gene encoding Kruppel-like factor 2 (KLF2) during CD8 + T cell activation leads to rapid transcriptional reprogramming, such that effector T cells fail to recirculate and prematurely acquire canonical phenotypic and transcriptional characteristics of resident memory cells (T RM ). Klf2 -deficient memory CD8 + T cells retained the capacity to undergo recall responses, including in vivo pathogen control. These data suggest that KLF2 diverts CD8 + T cells from the T RM differentiation program. In contrast, ablation of another member of the KLF family, KLF3, enhanced differentiation of some recirculating T cell subsets and limited production of T RM in lymphoid tissues. However, both KLF2 and KLF3 were required for differentiation of long-lived effector cells, suggesting cooperation between these factors in some situations. These findings indicate that KLFs occupy a central nexus in coordinating activated CD8 + T cell differentiation and trafficking.
GPT-4o mini: Non-social science research article
Convergent evolution increases boron transport through SNPs and tandem duplications at BOR1 and BOR2 in Arabidopsis thaliana
Emmanuel Tergemina, CĂ©lia Neto, Md Mamunur Rashid, Herculano Dinis, David E. Salt, Angela M. Hancock
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Boron (B) is a crucial micronutrient, particularly in volcanic soils where its deficiency hampers agriculture. Here, we investigate the genetic basis of leaf B accumulation in natural populations of Arabidopsis thaliana that colonized volcanic islands in Cape Verde. Using a combination of genome-wide association studies (GWAS) and mapping in a recombinant intercross population, we identified a case of convergent phenotypic evolution in which multiple variants in the two principal B transporter genes, BOR1 and BOR2 , increase leaf B accumulation in parallel. These include multiple tandem duplications at BOR1 that arose independently in different populations. Overall, this study reveals a remarkable case of convergent evolution occurring within a relatively short time scale, where different types of de novo mutations at B efflux transporter genes achieve similar phenotypic outcomes. Further, our findings show that integrating recombinant populations with GWAS in natural populations can improve power to overcome allelic heterogeneity.
GPT-4o mini: Non-social science research article
Tau catalyzes amyloid-ÎČ aggregation and toxicity in a polymorph-dependent manner
Michele Mosconi, Chiara Leonardi, Zev Armour-Garb, Beatrice Rocutto, Marten Beeg, Georg Meisl, Lei Ortigosa-Pascual, Luca Broggini, Mario Salmona, Stefano Ricagno, Tuomas P. J. Knowles, Luisa Diomede
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Interactions between amyloidogenic proteins are emerging as critical drivers of neurodegenerative diseases. Among others, in Alzheimer’s disease (AD) and severe forms of chronic traumatic encephalopathy (CTE), codeposition of tau and amyloid-ÎČ (AÎČ) leads to worsening of clinical outcomes and disease progression. Despite the importance of such heterotypic interactions, the underlying molecular mechanisms have proven challenging to be established. Here, we investigated the direct interaction between AÎČ and tau, combining in vitro reconstruction, and in vivo models. We find that characteristic AD paired helical filament (PHF) and CTE folds catalyze the primary nucleation of AÎČ42 in a fold-specific manner with enzyme-like kinetics. In particular, CTE fibrils exhibit the highest catalytic activity and constrain AÎČ42 polymorphism, suggesting templating effects. Moreover, PHF and CTE tau fibrils increase AÎČ42 toxicity in SH-SY5Y neuroblastoma cells and transgenic Caenorhabditis elegans, preserving fold-dependent reactivities. Our findings shed light on the molecular mechanisms of heterotypic interaction between amyloidogenic proteins in disease-relevant conditions, highlighting the role of amyloid structure and recognition mechanisms as key determinants. These results offer insights into the pathological mechanisms of multiple proteinopathies. The mechanisms described here might be used as a blueprint for structure-based design of new therapeutic agents targeting specific amyloidogenic interactions.
GPT-4o mini: Non-social science research article
Unveiling the developmental and tumor-suppressive roles of the p53 variant p53psi
Chiara Gorrini, Soode Jafari, Gordon Duncan, Bryan Snow, Liam Hendrikse, Louis McLoughlin, Jillian Haight, Andrew Wakeham, Chantal Tobin, Andrew Elia, Paramesh Ramachandran, Rhoda Law, Bevan Gang, Tsai-Ling Lu, Isabel Morgado-Palacin, Annick You-Ten, Thorsten Berger, Raffaella Sordella, Tak W. Mak
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Through alternative splicing, the TP53 gene can generate multiple protein isoforms with distinct biochemical properties. The p53psi isoform has been identified as a shorter variant than full-length p53 as it lacks nuclear localization, oligomerization, and part of the DNA binding domains due to the use of an alternative 3’ splice site in intron 6. Several TP53-truncating mutations, including those producing p53psi, have been detected in a significant proportion of human tumors. However, the mechanistic roles of these truncated p53 proteins remain poorly understood. Here, we describe the generation and analysis of a genetically engineered mouse model that expresses the p53psi protein in place of the full-length p53 protein. In the C57/BL6J genetic background, mice heterozygous for the targeted p53psi allele (p53 KI/+ ) appear phenotypically normal, survive to adulthood, and reproduce. However, heterozygote matings fail to yield viable p53psi homozygote knock-in (p53 KI/KI ) pups, indicating that forced p53psi expression disrupts embryogenesis. Timed matings revealed that homozygous p53psi expression is embryonically lethal on day E16.5. E14.5-16.5 embryos were pale, reduced in size, and exhibited exencephaly, a defect typically associated with neural tube closure failure. Mouse embryonic fibroblasts (MEFs) derived from p53psi embryos and transformed with the E1A and H-RasV12 oncogenes formed tumors with a decreased growth rate compared to their p53 null counterparts, suggesting that p53psi retains at least some tumor-suppressive functions. Our mechanistic studies suggest that p53psi modulates tumorigenesis by triggering senescence. These findings provide insights into the role of the p53psi variant, paving the way for a better interpretation of TP53 mutational patterns in human cancers.
GPT-4o mini: Non-social science research article
Dynamical modeling of individual sensory reactivity and habituation learning
Marina Boon, Matthew Smart, Anton V. Persikov, Boyd van Reijmersdal, Mehrdad Maghbouli, Robert A. Marmion, Bob Carpenter, Stanislav Y. Shvartsman, Annette Schenck
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Empirical research on sensory processing often focuses on group averages to uncover how sensory input translates into behavior. While this population-level approach has revealed important general principles of genetic and environmental control of behavior, it masks the rich and potentially meaningful variation observed at the level of individuals. Key features of sensory processing are reactivity, the degree to which a stimulus elicits a response, and habituation, a fundamental learning process that serves as a cognitive filter by reducing the response to repeated, irrelevant stimuli. We developed a model-based approach to quantify individual sensory processing dynamics, using a visual escape paradigm in Drosophila . We collected light-off jump responses in more than two hundred flies and quantified them individually via Bayesian inference of a dynamical model’s parameters. Considering both reactivity and habituation, we found that quantitative properties of individual responses vary greatly even in an isogenic population raised under identical environmental conditions. By moving from population averages to individual-based analyses, we uncover and quantify pronounced stochasticity in individual responses. Furthermore, we found that individual reactivity and habituation parameters display substantial temporal stability over a two-week interval, indicating that these behaviors are stable, intrinsic properties of an individual. The presented framework enables robust stratification of individual behavioral phenotypes and provides a quantitative platform for modeling interindividual differences in sensory processing, including frequently observed atypical responses in neurogenetic diseases.
GPT-4o mini: Non-social science research article
VIBES: A multiscale modeling approach integrating within-host and between-hosts dynamics in epidemics
Paulo Cesar Ventura, Yong Dam Jeong, Maria Litvinova, Allisandra G. Kummer, Shingo Iwami, Hongjie Yu, Stefano Merler, Alessandro Vespignani, Keisuke Ejima, Marco Ajelli
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Infectious disease spread is a multiscale process composed of within-host (biological) and between-host (social) drivers and disentangling them from each other is a central challenge in epidemiology. Here, we introduce VIBES, a multiscale modeling framework that explicitly integrates viral dynamics based on patient-level data with population-level transmission on a data-driven network of social contacts. Using SARS-CoV-2 as a case study, we analyze three emergent epidemic properties, namely the generation time, serial interval, and presymptomatic transmission. First, we established a purely biological baseline, thus independent of the reproduction number ( R ), from the within-host model, estimating a generation time of 6.3 d for symptomatic individuals and 43.1% presymptomatic transmission. Then, using the full model incorporating social contacts, we found a shorter generation time (5.4 d at R = 3.0) and an increase in presymptomatic transmission (52.8% at R = 3.0), disentangling the impact of social drivers from a purely biological baseline. We further show that as pathogen transmissibility increases ( R from 1.3 to 6), competition among infectious individuals shortens the generation time and serial interval by up to 21% and 13%, respectively. Conversely, a social intervention, like isolation, increases the proportion of presymptomatic transmission by about 30%. Our framework also estimates metrics that are challenging to obtain empirically, such as the generation time for asymptomatic individuals (5.6 d; 95%CI: 5.1 to 6.0 at R = 1.3). Our findings establish multiscale modeling as a powerful tool for mechanistically quantifying how pathogen biology and human social behavior shape epidemic dynamics as well as for assessing public health interventions.
GPT-4o mini: Non-social science research article
Small-molecule CBLB inhibitor abolishes EGFR ubiquitination, reduces receptor endocytosis, and diminishes cell motility signaling
Itziar Pinilla-Macua, Ratul Mukerji, Frederick Cohen, Alexander Sorkin
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Endocytosis of the epidermal growth factor receptor (EGFR) is considered a key regulator of the receptor signaling activity. However, the molecular mechanisms underlying EGFR endocytosis are incompletely understood. Although ligand-induced ubiquitination of EGFR is known to promote its endocytic trafficking, the importance of EGFR ubiquitination in clathrin-mediated endocytosis, the primary physiological route of EGFR internalization, remains debated, and the relative contributions of ubiquitination-dependent and -independent mechanisms are not defined. Hence, we used NX-1013, a small-molecule inhibitor of the Casitas B-lineage lymphoma-b (CBLB) E3 ubiquitin ligase, to dissect the role of EGFR ubiquitination in its endocytic trafficking and signaling. Strikingly, brief treatment with NX-1013 completely abolished EGF-induced EGFR ubiquitination, demonstrating that this process is exclusively mediated by the closely related CBLB and CBL ligases. NX-1013 inhibited clathrin-mediated internalization of activated EGFR by 60 to 70%. The remaining, ubiquitination-independent internalization required EGFR kinase activity, was highly clathrin-dependent, and was significantly impaired by depletion of the AP-2 clathrin adaptor complex. Interestingly, inhibition of CBLs and EGFR endocytosis by NX-1013 did not affect major downstream signaling pathways in human oral squamous cell carcinoma cells, with the exception of Rac1 activation and EGFR-dependent cell migration, both of which were suppressed.
GPT-4o mini: Non-social science research article
Recent extremes in Antarctic sea ice extent modulated by ocean heat ventilation
Earle A. Wilson, Lexi Arlen, Ethan C. Campbell
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Antarctic sea ice extent (SIE) has experienced unprecedented variability in recent decades, with record expansion through 2015, followed by an abrupt transition to sustained decline. Using over two decades of under-ice Argo float observations, we show that changes in ocean heat ventilation have modulated these extreme sea ice variations on interannual timescales. Between 2007 and 2015, the ocean thermocline warmed and shoaled within the Weddell Sea and off East Antarctica, with the former accounting for most of the interannual variability in Antarctic SIE. After 2016, as Antarctic SIE declined, surface salinity increased, enhancing exchange between the sharpened thermocline and surface waters. Idealized modeling of the Weddell Sea indicates that these upper ocean trends were due to concurrent variations in wind-driven Ekman upwelling and precipitation. During the sea ice expansion phase, increased precipitation enhanced ocean stratification, suppressing the upward flux of subsurface heat while promoting sea ice growth. However, between 2014 and 2016, a nearly three-fold increase in upwelling rates weakened the upper ocean stratification, releasing the accumulated subsurface heat. Though a similar sequence of events occurred along the East Antarctic margin, distinct upper-ocean trends and surface forcing in the Pacific sector of the Southern Ocean imply alternative drivers of recent sea ice loss in that region. Nevertheless, these results suggest that future multiyear Antarctic SIE variability will depend on the competing influences of wind-driven upwelling and surface freshwater fluxes.
GPT-4o mini: Non-social science research article
Maternal KrĂŒppel-like factor 2 (KLF2)+ CD4 T cells promote fertility and fetal tolerance
Ngan N. M. Nguyen, Alexander E. Brady, Abigail Russi, Giang Pham, Bo Li, Lucien H. Turner, Michael Kotliar, Artem Barski, Xiaofei Sun, Sing Sing Way
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Pregnancy requires expanded maternal tolerance to semiallogeneic fetal-expressed antigens to protect against fetal loss and other pregnancy complications. Our understanding of how this biological imperative works remains uncertain. Here we show pregnancy primes expansion of antigen-experienced KrĂŒppel-like factor 2 (KLF2)+ CD4 T cells with fetal specificity, and that these maternal cells play an essential role in optimal fertility and protecting against fetal resorption. Antigen-experienced KLF2+ CD4 cells purified from pregnant dams are poised for IL10 production and suppress responder T cell proliferation in coculture. Mice with conditional loss of KLF2 in T cells become pregnant less efficiently after allogeneic mating with genetically discordant males, but not after syngeneic mating with genetically identical males. Impaired fertility is associated with diminished and variable early pregnancy progesterone levels, whereas progression from mating to pregnancy is restored with exogenous progesterone. To bypass fertility defects, complementary experiments show that initiating induced KLF2 deletion in CD4 T cells midgestation causes fetal resorption associated with expansion of activated fetal-specific CD8 effector T cells across maternal tissues, particularly in the uterine draining lymph node and at the maternal–fetal interface. Reciprocally, these phenotypes are overturned with CD8 T cell depletion or in mice reconstituted with CD4 cells from wild-type donors which upregulate KLF2 expression in pregnant recipients. These findings demonstrate that maternal KLF2+ CD4 T cells promote fetal tolerance and fertility, particularly during allogeneic pregnancy.
GPT-4o mini: Non-social science research article
Polypharmacology of S-1117, an Fc-fused IgG-selective degrading enzyme, for chronic treatment of autoantibody-mediated diseases
Liliana M. Sanmarco, Alex Pellerin, Tobias Green, Agustin Plasencia, Jordan M. Anderson, Nam Le, Andita Newton, Jiyun Chen, Maria Cecilia Ramello, Ryan Peckner, Julia Manasson, Yi Xing, Heather Vital, Nathan Higginson-Scott, John S. Sundy, Kevin L. Otipoby, Ivan D. Mascanfroni
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Antigen-specific immunoglobulin-G (IgG) antibodies cause or contribute to the pathogenesis of a wide spectrum of human diseases and conditions. Multiple therapeutic approaches have been developed, yet they are limited by variable safety and efficacy, patient inconvenience, and cost. IdeS, a cysteine protease derived from S. pyogenes , specifically cleaves IgG antibodies, representing a unique opportunity for the treatment of IgG-mediated diseases. However, clinical utilization of IdeS is limited by the immunogenic nature of bacterial proteases and short half-life. Using Seismic’s IMPACT platform, we engineered S-1117, an IgG cleaving enzyme fused to a human effectorless IgG1 Fc domain for an extended half-life. S-1117 is being developed to address the limitations of existing therapies in IgG-mediated diseases. In vitro and in vivo pharmacology studies demonstrate that S-1117 exhibits reduced B and T cell immunogenicity, a superior pharmacokinetic profile, and manufacturability and developability properties resembling those of monoclonal antibodies. S-1117 cleavage of IgG reduces circulating levels of IgG, including pathogenic IgG autoantibodies and IgG immune-complexes, and reduces IgG antibody effector functions, such as complement fixation, antibody-dependent cellular cytotoxicity, and antibody-dependent cell phagocytosis. The polypharmacology of S-1117 further extends to cleaving the antigen receptor on IgG-positive memory B cells, thereby modulating activation of memory B cells.
GPT-4o mini: Non-social science research article
Small molecule–constrained paratope mimetic bicyclic peptides as potent inhibitors of group 1 and 2 influenza A virus hemagglutinins
Rameshwar U. Kadam, Jarek Juraszek, Boerries Brandenburg, Divita Garg, Xueyong Zhu, Mandy Jongeneelen, Chan Tang, Wim B. G. Schepens, Christophe Buyck, Bart Stoops, Jan Vermond, Ronald Vogels, Robert H. E. Friesen, Maria J. P. van Dongen, Ian A. Wilson
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Influenza continues to be a major threat to global health and a substantial economic burden. Innovative strategies are needed to tackle the growing resistance to established influenza therapeutics and to develop new therapeutics with novel mechanisms of action. Previous peptide and small molecule designs have been successful only against influenza group 1 hemagglutinin (HA). Here, we report on a CLIPS (Chemical Linkage of Peptides onto Scaffolds)-based approach to design potent peptidic inhibitors of influenza A viruses that now extend to both group 1 and group 2 HAs. This approach merges features of antibodies and small molecules to design constrained bicyclic peptides that engage the highly conserved HA stem. The heavy-chain complementarity-determining region 3 (HCDR3) of human broadly neutralizing antibody FI6v3 was grafted onto functionalized small molecule scaffolds. The designed peptides exhibited in vitro heterosubtypic cross-reactivity in binding to group 1 (H1 and H5) and group 2 (H3 and H7) HAs and in neutralization of H1N1, H5N1, and H7N3 viruses. A crystal structure of the bicyclic peptide with HA from H1N1 A/Puerto Rico/8/1934 (H1/PR8) at 2.35 Å resolution revealed that the designed peptide faithfully mimics the binding mode and functionality of the parent antibody FI6v3 to the highly conserved stem epitope. These structural and functional data illustrate how both group 1 and group 2 influenza A viruses can now be targeted by constrained peptidic ligands that should aid in development of pan-influenza therapeutics.
GPT-4o mini: Non-social science research article
Structural insights into SetA-mediated Rab1 glucosylation and PI3P-guided localization during early Legionella infection
Ha Na Im, Yeon Lee, Yunju Song, Hyunggu Hahn, Hyerry Jeon, Donghyuk Shin, Sangho Lee, Kyung-Hee Kim, Kyung-Tae Kim, Se Won Suh, Dong Man Jang, Hyoun Sook Kim
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The bacterial pathogen Legionella pneumophila secretes effector proteins that remodel host endomembranes to establish a replication-permissive niche known as the Legionella -containing vacuole (LCV). Among these, SetA disrupts vesicle trafficking by glucosylating the small GTPase Rab1, essential for ER-to-Golgi transport. Here, we report comprehensive structural and mechanistic insights into SetA-mediated Rab1 glucosylation and its PI3P-dependent membrane targeting. Crystal structures of its N-terminal glycosyltransferase and C-terminal lipid-binding domains, captured in multiple ligand-bound states, reveal how SetA specifically recognizes GDP-bound Rab1 and the head group of phosphatidylinositol 3-phosphate (PI3P), which is enriched on early LCV membranes. SAXS-based full-length modeling, biochemical assays, and cellular imaging analyses demonstrate that SetA integrates Rab1 modification with membrane localization, thereby perturbing Golgi integrity and ER morphology. Together, these findings define the dual structural mechanisms underlying SetA’s coordination of substrate glucosylation and membrane association, providing a spatiotemporal framework for understanding Legionella ’s early infection strategy.
GPT-4o mini: Non-social science research article
A conserved ethylene-triggered cell death mechanism may underlie hollow stem formation across plant species
Mengxiao Yan, Weijuan Fan, Yinghui Meng, Jiamin Zhao, Wei Yang, Ziyin Xu, Yusen Gao, Haiyan Zhuang, Wuyu Zhou, Yuqin Wang, Qingjun Huang, Ling Yuan, Hongxia Wang, Jun Yang
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Hollow stems have independently evolved multiple times across the plant kingdom and play crucial roles in plant development and various environmental adaptations. However, the mechanisms underlying stem hollowness remain poorly understood. Water spinach ( Ipomoea aquatica ) is one of the few hollow-stemmed plants in the Convolvulaceae family (eudicot: asterid), and its hollow stems are essential for thriving in aquatic environments. Using histochemical staining and transcriptome analysis, we found that programmed cell death (PCD) is involved in cavity formation at water spinach shoot tips. Single-cell and spatial transcriptome analyses further revealed that ethylene and reactive oxygen species (ROS) likely drive and regulate this process by activating transcription factors IaNAC074 , IaNAC087 , IaNAC029 , IaNTL9 , and IaTGA9 , which likely initiate PCD, senescence, and autophagy, collectively leading to pith cell death. These findings were validated through treatments with ethylene and ROS reagents in water spinach, as well as transient expression assays in tobacco. Additionally, transcriptomic data suggest that these mechanisms may also play a role in hollow stem formation in horsetail (fern), moso bamboo (monocot), and broad bean (eudicot: rosid), highlighting the conservation of PCD regulatory mechanisms in hollow stem formation. This study not only fills a major knowledge gap in the adaptive mechanisms of hollow stem formation but also opens broad avenues for agricultural and ecological applications, offering strategies to enhance crop tolerance to flooding and accelerate crop growth.
GPT-4o mini: Non-social science research article
Neural signatures of human psychological resilience driven by acute stress
Noriya Watanabe, Shinichi Yoshida, Ruedeerat Keerativittayayut, Masaki Takeda
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Neurophysiological mechanisms underlying psychological resilience—the ability to overcome adversity—have been extensively studied in animals. However, compared to that in animals, human resilience is unique in that it is underpinned by higher-order cognitive functions, such as self-confidence, tenacity, and a positive attitude to challenges. Given these discrepancies, the neurophysiological mechanisms underlying human-specific resilience remain unclear. To address this issue, we aimed to record multimodal responses after acute stress exposure over 1.5 h using functional brain imaging and peripheral physiological measurements. We showed that the degree of individual resilience is indexed by multiple changes in neural dynamics 1 h after acute stress. Functional magnetic resonance imaging and electroencephalography show that activity in the cortical salience network and power in high-beta and gamma oscillations increase in less resilient individuals. Contrastingly, activity in the cortical default mode network and spontaneous activity in the posterior hippocampus increase in more resilient individuals. Machine learning analysis confirmed that, 1 h after stress exposure, the functional connectivity in the salience network was the most influential, followed by that in the default mode network, gamma power, high-beta power, and hippocampal activity. The neurophysiological dynamics for resilience do not occur as previously thought, but rather in a time-lagged manner against stress exposure. Our findings shed light on an approach to recovery from stress-induced deficits such as delayed neuromodulation after a stressful event.
GPT-4o mini: Non-social science research article
The phospholipid profile of T cells shapes ACSL4 dependency and ferroptosis sensitivity of naive, effector, and memory T cells
Gariné Magarditchian, Ivan Berest, Aikaterini Ziogou, Mai Matsushita, Michelle Reid, Alaa Othman, Manfred Kopf
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Iron-dependent phospholipid (PL) peroxidation, which is reduced by glutathione peroxidase 4, is recognized as the hallmark of cells undergoing ferroptosis. Although studies have attempted to elucidate the molecular mechanisms underlying ferroptosis in cancer cells, the regulation of ferroptosis in effector and memory T cells remains largely unknown. Here, using genome-wide CRISPR-Cas9 knockout screens, we demonstrate that acyl-CoA synthetase long-chain family member 4 (ACSL4) is the predominant ferroptosis inducer in primary T cells cultured in vitro, while other identified iron- and lipid metabolism–related genes only slightly modulate their sensitivity to ferroptosis. However, ACSL4 dependency relies on the PL composition of the cells. In vitro cultured T cells treated with polyunsaturated fatty acids (PUFAs), as well as effector CD8 + T cells that are enriched in PUFA-containing PLs (PUFA-PLs), undergo ferroptosis in the absence of ACSL4. In contrast to effector T cells, naive and memory T cells share a similar PL profile, characterized by a scarcity of PUFA-PLs, and are resistant to ferroptosis. Overall, the PL composition is a central feature and determines the differential susceptibility of effector and memory T cells to ferroptosis and its molecular mechanism.
GPT-4o mini: Non-social science research article
Oseltamivir aziridines are potent influenza neuraminidase inhibitors and imaging agents
Merijn B. L. Vriends, Elisha Moran, Martín Calvelo, Thomas Hansen, Isabelle B. Pickles, Xincheng Xin, Marieke Biezeno, Zachary W. B. Armstrong, Maria J. Ferraz, Lei Li, Alice Lilley, Ruth Harvey, Dmitri V. Filippov, Qinghua Liao, Sybrin P. Schröder, Gijsbert A. van der Marel, Marta Artola, Johannes M. F. G. Aerts, James N. Blaza, Jeroen D. C. Codée, Carme Rovira, Herman S. Overkleeft, Gideon J. Davies
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Influenza neuraminidase (NA) is a critical target for seasonal and pandemic antivirals, including the strains of current concern. Current treatments, such as Zanamivir and Oseltamivir, are limited by noncovalent binding and emerging resistance. We hypothesized that Oseltamivir aziridines would unite transition-state mimicry for tight binding, with aziridine-enabled covalent capture of the catalytic tyrosine, thereby supporting both therapy and activity-based quantification. Here, we present oseltamivir-based aziridines, inspired by cyclophellitol chemistry, that act as covalent inhibitors and activity-based probes via an N -acylaziridine warhead. Free-energy calculations, and NMR observations, indicate a 4 H 5 half-chair preference consistent with the NA transition state, and selected analogues inhibit multiple NA subtypes with low nanomolar binding constants. Diverse evidence establishes covalency: time-dependent inactivation, inhibitor washout, intact-mass shifts, MS/MS identification of a tyrosine adduct, and QM/MM reaction profiles, while cryoEM of N1 aligns with the proposed binding mode, revealing an elimination product. The inhibitors demonstrate formidable activity against diverse viral neuraminidases, including H5N1, and further enable imaging and quantification of active NA. With their dual therapeutic and diagnostic potential, these first-in-class inhibitors indeed benefit from transition state mimicry and covalency, and thus offer a powerful platform for antiviral development and neuraminidase imaging, addressing urgent global health needs in influenza treatment and prevention.
GPT-4o mini: Non-social science research article
Targeting the ANGPTL4/NRP1/ABL1/RAD51 axis reverses cisplatin resistance by impairing DNA damage repair in head and neck cancer
Emmanuel B. Asiedu, Ajay Kumar, Alexander Choi, Derek Osorio Luciano, Kevin Lo, Deepti Sharma, Tao Ma, Feyruz Rassool, Akrit Sodhi, Silvia Montaner
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Drug chemoresistance remains a major reason of treatment failure in cancer patients. In head and neck squamous cell carcinoma (HNSCC), the seventh most common cancer worldwide, cisplatin chemotherapy remains the gold standard for advanced tumors but often faces loss of responsiveness and the drawback of relapse. We previously showed that the metabolic and angiogenic factor angiopoietin-like 4 (ANGPTL4) is a molecular biomarker of oral dysplasia and HNSCC. We also found that through interaction with Neuropilin 1 (NRP1), ANGPTL4 activates proliferative and migratory pathways that contribute to HNSCC development. Using HNSCC xenografts, patient tumor-derived organoids, tumor spheroids, and HNSCC cell lines, CAL27, HN13, and HN4, here we provide evidence of the role of ANGPTL4 in the development of platinum-based chemoresistance in HNSCC through the promotion of DNA damage response (DDR) and homologous recombination (HR). ANGPTL4 enhanced these mechanisms by promoting phosphorylation of RAD51 recombinase in Tyr 315/54 through an NRP1/ABL1-dependent mechanism. Pharmacologic inhibition of NRP1 or ABL1 reversed ANGPTL4-mediated DDR and HR, and increased HNSCC cell death in combination with cisplatin, in vitro and in vivo. Our results reveal a role for ANGPTL4 in RAD51-dependent DNA repair and suggest that ANGPTL4/NRP1/ABL1/RAD51 may serve as an alternative therapeutic target for HNSCC.
GPT-4o mini: Non-social science research article
Self-regulated dual-mode solar energy harvesting
Raphael Kay, Rafiq Omair, Joanna Aizenberg
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Traditional solar energy harvesters are single-mode—typically designed to convert available sunlight either into heat or electricity. However, neither energy form is continuously useful, and an optimal variant should instead be capable of autonomously toggling relative thermal and electrical yield based on need. Here, we introduce passive, dual-mode indoor solar energy harvesting by using a fluid layer trapped above a Fresnel lens as a phase-changing switch within a solar waveguide. When warm out and electricity is desired, the fluid is in its vapor phase, causing a refractive index difference with the microstructured lens beneath it to concentrate sunlight toward a solar cell. When cold out and heat is instead desired, the fluid condenses atop the Fresnel structure to reduce refractive index differences, causing sunlight to refract past the solar cell and convert to heat when absorbed indoors. Using water as a phase-changing switch, we built an exemplary system that self-regulates indoor temperature and solar cell light exposure over ambient heating and cooling cycles. Our approach is general across everyday materials and manufacturing methods and may be deployed on the surfaces of vehicles, greenhouses, and residential or commercial buildings.
GPT-4o mini: Non-social science research article
Amplifying toughness in silica-reinforced natural rubber by preserving long chains
Matthew Wei Ming Tan, Guodong Nian, Zheqi Chen, Xianyang Bao, Yakov Kutsovsky, Zhigang Suo
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Natural rubber outperforms synthetic rubbers because of its long chains and strain-induced crystallization (SIC). However, these advantages are largely lost when the natural rubber chains are masticated during processing, and silica particles are added for reinforcement. Mastication eases mixing but shortens chains and lowers performance. Silica particles require covalent interlinks with rubber chains, but these interlinks restrict chain stretch and alignment, reducing SIC. Here, we show that the performance of silica-reinforced natural rubber can be markedly enhanced by preserving long natural rubber chains. We use a solvent to dissolve natural rubber latex into individual rubber chains and use the solution to uniformly disperse silica particles. After drying, the uncured compound can be stored and molded prior to curing. The long rubber chains are then sparsely crosslinked with one another and interlinked with the silica particles. The long strands readily align under stretch and increase SIC. Preserving long chains elevates toughness by an order of magnitude, from ~2 to 44 kJ m –2 . High toughness arises from energy dissipation across multiple length scales, over long rubber strands, silica particles, and a zone of SIC. High modulus of ~19 MPa arises from two interpenetrating networks: the network of densely entangled rubber chains and the network of percolated silica particles. The resulting material achieves high toughness while maintaining high modulus, a combination uncommon in silica-reinforced synthetic and natural rubbers.
GPT-4o mini: Non-social science research article
DIRAS2 modulates MAPK pathway–mediated ferroptosis to regulate excitation/inhibition balance and seizure susceptibility
Chenlu Zhang, Liqin Hu, Hui Zhang, Min Yang, Yuansong Zhang, Ningning Zhang, Yuanhang Xu, Yuping Zhao, Lingxin Ren, Haokun Guo, Wei Li, Xuefeng Wang, Yong Yang, Xin Tian
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Epilepsy is a common neurological disorder that is widely believed to be associated with an imbalance between neuronal excitation and inhibition (E/I). DIRAS2, a Ras-related GTPase, has not been well understood regarding its role and function within the nervous system. In this study, we found that DIRAS2 is downregulated in the hippocampus during the epileptogenesis phase in a kainic acid-induced epilepsy model, while it is upregulated during the chronic phase in this epilepsy model and in patients with temporal lobe epilepsy. Overexpression of DIRAS2 alleviates epileptic seizure susceptibility and activity, whereas knockdown of DIRAS2 has an opposite effect. Whole-cell patch-clamp recordings reveal that DIRAS2 reduces the neuronal E/I ratio and alleviates neuronal hyperexcitability. Mechanistically, quantitative proteomic analysis reveals that ferroptosis is involved in mediating the effects of DIRAS2. Knockdown of DIRAS2 can exacerbate ferroptosis, while overexpression protects against ferroptosis in both in vivo and in vitro studies. Ferrostatin-1, a ferroptosis inhibitor, can rescue the E/I imbalance and epileptic behavioral changes induced by DIRAS2 knockdown. Finally, we found that DIRAS2 regulates ferroptosis by inhibiting the extracellular signal-regulated kinase/p38 mitogen-activated protein kinase pathway in epileptic mice. In summary, our study demonstrates the role of DIRAS2 in epilepsy and provides a potential target for epilepsy treatment.
GPT-4o mini: Non-social science research article
A modular platform for Sterically Masked Activated Cytokines (SMACks)
Travis J. Morgenstern, Naruhisa Ota, Zhonghua Lin, Laura M. Lechermann, Herman Gill, Annie Ogasawara, Simon Williams, Kevin A. Marroquin, Alexis Scherl, Christopher W. Davies, James R. Byrnes, Dhaya Seshasayee, James T. Koerber
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Cytokines are critical signaling molecules, but their therapeutic potential remains unrealized due to pleiotropic effects across cell types. Current strategies to develop conditionally active cytokines involve complex engineering and production, limiting their application to a select few cytokines and receptors. Here, we describe a simple, highly modular format called Sterically Masked Activated Cytokine (SMACk) via facile assembly of a targeting Fab/VHH, cytokine, and Fc. We first develop an interleukin-22 (IL-22) SMACk selective for intestinal epithelial cells, wherein the Fab/VHH serves a dual masking and targeting role. Detailed analysis revealed a cis signaling mechanism via a reduced on-rate and identified tunable format parameters. In mice, the IL-22-SMACk showed selective activity in the colon and efficacy in a colitis model. Finally, we highlight the versatility of SMACks by selectively directing interferon-α, IL-2, IL-4, or IL-7 to CD8 + T cells, underscoring the potential of this platform to advance cytokine research and therapies.
GPT-4o mini: Non-social science research article
Data-driven Mori–Zwanzig modeling of Lagrangian particle dynamics in turbulent flows
Xander M. de Wit, Alessandro Gabbana, Michael Woodward, Yen Ting Lin, Federico Toschi, Daniel Livescu
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The dynamics of Lagrangian particles in turbulence play a crucial role in mixing, transport, and dispersion in complex flows. Their trajectories exhibit highly nontrivial statistical behavior, motivating the development of surrogate models that can reproduce these trajectories without incurring the high computational cost of direct numerical simulations of the full Eulerian field. This task is particularly challenging because reduced-order models typically lack access to the full set of interactions with the underlying turbulent field. Novel data-driven machine learning techniques can be powerful in capturing and reproducing complex statistics of the reduced-order/surrogate dynamics. In this work, we show how one can learn a surrogate dynamical system that is able to evolve a turbulent Lagrangian trajectory in a way that is point-wise accurate for short-time predictions (with respect to Kolmogorov time) and stable and statistically accurate at long times. This approach is based on the Mori–Zwanzig formalism, which prescribes a mathematical decomposition of the full dynamical system into resolved dynamics that depend on the current state and the past history of a reduced set of observables, and the unresolved orthogonal dynamics due to unresolved degrees of freedom of the initial state. We show how by training this reduced order model on a point-wise error metric on short time-prediction, we are able to correctly learn the dynamics of Lagrangian turbulence, such that also the long-time statistical behavior is stably recovered at test time. This opens up a range of applications, for example, for the control of active Lagrangian agents in turbulence.
GPT-4o mini: Non-social science research article
VAMP8 function reveals tight linkage between endocytic recycling and endocytosis
Ailing Liu, Yueping Li, Zheng Huang, Wen Chen, Peiliu Xu, Xiangying Wei, Guosheng Hu, Shuangquan Liu, Xiaoxia Liu, Yaohui He, Danling Wang, Sandra L. Schmid, Zhiming Chen
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Clathrin-mediated endocytosis (CME) is a multistage process that involves the initiation and stabilization of clathrin-coated pits (CCPs) that invaginate and finally detach from the plasma membrane to form clathrin-coated vesicles (CCVs). Given that Soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins are essential for downstream vesicle targeting and fusion events, their recruitment into nascent CCVs has been suggested to be a prerequisite for CME progression. However, which and how SNARE proteins regulate CME remains to be explored. Here, we showed that siRNA-mediated knockdown of the R-SNARE, vesicle-associated membrane protein 8 (VAMP8) impairs CCP initiation, stabilization, and invagination and strongly inhibits CME. Mechanistically, recruitment of VAMP8 to CCVs is not required for CME. Instead, depletion of VAMP8 inhibits recycling of endocytic cargoes and as exemplified here by transferrin receptor, skews their trafficking toward lysosomal degradation. VAMP8 depletion therefore indirectly impairs CCV formation and inhibits CME by depleting endocytic cargo. Overall, our study provides insights into the crosstalk between endocytosis and endocytic recycling of CME cargo and demonstrates the critical role for cargo recruitment in stabilizing nascent CCPs to regulate CME.
GPT-4o mini: Non-social science research article
Large future genetic diversity losses are predicted from conservation indicators even with habitat protection
Kristy S. Mualim, Jeffrey P. Spence, Clemens Weiß, Oliver Selmoni, Meixi Lin, Moises Exposito-Alonso
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Genetic diversity within species underpins evolutionary adaptation and has recently been included as a target for protection in the United Nations’ Global Biodiversity Framework (GBF). Yet, we lack mathematical tools to estimate past genetic diversity loss across species—or predict future losses—based on demographic proxies used in conversation policy. To fill this gap, we developed a spatiotemporal framework to predict the dynamics of genetic diversity under realistic habitat change scenarios, calibrated with population-scale genomic data from 29 plant and animal species. To estimate how much genetic diversity has already been lost, we analyzed habitat area and population size losses for 4,611 species from the last five decades, using data from the Living Planet Index, the Red List, and new GBF indicators. We estimate that species have already lost 1 to 13% of π genetic diversity. Furthermore, we predict that genetic diversity losses lag behind population and habitat area declines, such that an average of 6 to 45% of genetic diversity will be lost under different scenarios even if population sizes or habitats do not decline further. Our results highlight that safeguarding existing habitats is insufficient to maintain the genetic health of species, and that genetic monitoring from proxy indicators will only detect major genetic diversity losses after it is already too late.
GPT-4o mini: Non-social science research article
Structural insight of a photosystem I-CpcL-phycobilisome supercomplex from a cyanobacterium Anabaena sp. PCC 7120
Zhiyuan Mao, Zhenhua Li, Xingyue Li, Liangliang Shen, Tingyun Kuang, Wenda Wang, Jian-Ren Shen, Guangye Han
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Phycobilisomes (PBSs) are supramolecular pigment–protein complexes composed of phycobiliproteins and linker proteins, serving as the major light-harvesting complexes that capture and transfer light energy to photosystem II (PSII) and photosystem I (PSI) in cyanobacteria and eukaryotic red algae. In cyanobacteria, a rod-type PBS that does not have a core is specifically connected to PSI by a linker protein CpcL to form a PSI-CpcL-PBS supercomplex. However, the mechanism of CpcL-PBS association to PSI remains unclear. Here, we report the cryoelectron microscopic structures of PSI-CpcL-PBS at 2.98 Å and CpcL-PBS at 2.93 Å resolution from a cyanobacterium Anabaena sp. PCC 7120, respectively. CpcL-PBS is located on the stromal side of a PSI tetramer and exhibits a structure of three-layered PBS consisting of four linkers (CpcL, CpcC1, CpcC2, PecC) and 18 pairs of phycocyanin αÎČ monomers. The C-terminal transmembrane helix of CpcL inserts to the membrane and interacts with PsaA, PsaB, and PsaM of PSI at an interface I between two PSI monomers, enabling the formation of the PSI-CpcL-PBS supercomplex. The exact structure of protein subunits and arrangement of bilin and chlorophyll pigments are revealed, which provide a structural basis for the assembly of PSI-CpcL-PBS and possible excitation energy transfer pathways from antennas to PSI within this supercomplex, shedding light on the organization and attachment of CpcL-PBS in cyanobacterial thylakoids.
GPT-4o mini: Non-social science research article
DNA methylation site loss for plasticity-led novel trait genetic fixation
Takafumi Katsumura, Suguru Sato, Kana Yamashita, Shoji Oda, Takashi Gakuhari, Shodai Tanaka, Kazuko Fujitani, Toshiyuki Nishimaki, Tadashi Imai, Yasutoshi Yoshiura, Hirohiko Takeshima, Yasuyuki Hashiguchi, Yoichi Sekita, Hiroshi Mitani, Motoyuki Ogawa, Hideaki Takeuchi, Hiroki Oota
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Phenotypic plasticity allows organisms to adapt traits in response to environmental changes, yet the molecular basis by which such plastic traits become genetically fixed remains unclear. Here, we investigated gut-length plasticity in medaka fish ( Oryzias latipes ) through genome-wide methylation profiling, CRISPR/Cas9-mediated deletion, and population genomic analyses. We found that seasonal methylation of CpG sites upstream of the Plxnb3 is correlated with gut-length plasticity, and deletion of this region abolishes plasticity. Additionally, standing variation in Ppp3r1 is associated with genetically fixed longer gut length in populations lacking plasticity. These results suggest that loss of epigenetic regulation via CpG site reduction triggers the genetic fixation of novel traits. Our findings provide molecular evidence linking epigenetic plasticity and genetic assimilation, advancing understanding of plasticity-led evolution in natural populations.
GPT-4o mini: Non-social science research article
Using wavelet decomposition to determine the dimension of structures from projected images
Svitlana Mayboroda, David N. Spergel
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Mesoscale structures in turbulent media can often be described as fractional dimensional across a wide range of scales. The goal of this paper is to determine the structure’s dimension from a projected image. Our method exploits the laws of scaling of wavelet power spectra under projection and does not carry any restrictions on the embedding and projected dimensions. We show that the wavelet power spectrum of a projected Îł dimensional measure is P j = 2 − j Îł , where j is the wavelet scale. We contrast the wavelet method with the popular box-counting approach. For projected images, the use of box-counting at fixed thresholds often leads to erroneous results. We apply the method to James Webb Space Telescope (JWST) infrared and Chandra X-ray observations of the supernova remnant Cassiopeia A. We find that the emissions can be represented by projections of mesoscale substructures with fractal dimensions varying from Îł = 1.69 ± 0.02 for the warm CO layer observed by JWST, up to Îł = 2.49 ± 0.03 for the hot X-ray emitting gas layer in the supernova remnant.
GPT-4o mini: Non-social science research article
CD47 stabilizes ROBO2 to regulate glioblastoma progression by preventing ITCH-mediated ubiquitination
Ruhi Polara, Briony L. Gliddon, Raja Ganesan, Lorena T. Davies, John Toubia, Sakthi Lenin, Ghizal Siddiqui, Olivia Morris-Hanon, Melinda N. Tea, Paul A. B. Moretti, Dung A. Nguyen, Chung Hoow Kok, Chloe Shard, Alexander H. Staudacher, Michael P. Brown, Darren J. Creek, Guillermo A. Gomez, Daniel Thomas, Stuart M. Pitson, Nirmal Robinson
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CD47 is an innate immune checkpoint that inhibits phagocytosis by myeloid cells, contributing to immune evasion by cancer cells. CD47-blocking antibodies have limited efficacy in glioblastoma (GBM), and the cell-intrinsic role of CD47 is poorly understood. In this study, we show that CD47 is highly expressed at the invasive edge of GBM tumors, and its elevated expression correlates with poor patient survival. We demonstrate that CD47 loss impairs GBM cell proliferation, migration, and invasion, independent of immune activity, and leads to reduced tumor burden and prolonged survival in vivo. Our study identifies ROBO2 signaling as a key downstream effector of CD47 and demonstrates that loss of ROBO2 similarly reduces GBM cell proliferation and migration. Importantly, we have uncovered that CD47 stabilizes ROBO2 by sequestering the E3 ubiquitin ligase ITCH, thereby blocking ubiquitination and proteasomal degradation of ROBO2. These findings establish CD47 as a key regulator of GBM cell plasticity and highlight the therapeutic potential of targeting CD47 – ROBO2 signaling in GBM.
GPT-4o mini: Non-social science research article
Mechanism of 30S subunit recognition and modification by the conserved bacterial ribosomal RNA methyltransferase RsmI
Mohamed I. Barmada, Erin N. McGinity, Suparno Nandi, Debayan Dey, Natalia Zelinskaya, George M. Harris, Lindsay R. Comstock, Christine M. Dunham, Graeme L. Conn
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Ribosomal RNA (rRNA) modifications are important for ribosome function and can influence bacterial susceptibility to ribosome-targeting antibiotics. The universally conserved 16S rRNA nucleotide C1402, for example, is the only 2’- O -methylated nucleotide in the bacterial small (30S) ribosomal subunit and this modification fine-tunes the shape and structure of the peptidyl tRNA binding site. The Cm1402 modification is incorporated by the conserved bacterial 16S rRNA methyltransferase RsmI, but it is unclear how RsmI recognizes its 30S substrate and specifically modify its buried target nucleotide. We determined a 2.42 Å resolution cryo-EM structure of the RsmI–30S complex and, with accompanying functional analyses, show that RsmI anchors itself to the 30S subunit through multiple contacts with a conserved 16S rRNA surface previously only seen in the assembled subunit. This positions RsmI to bind a h44 conformation that is substantially reorganized compared to its structure in the mature 30S subunit allowing access to C1402. These analyses also reveal an essential contribution to 30S subunit interaction made by the previously structurally uncharacterized RsmI C-terminal domain, RsmI-induced RNA–RNA interactions with C1402, and an unappreciated dependence on a divalent metal ion for activity that suggests RsmI may be a member of a distinct class of metal- and SAM-dependent RNA O -methyltransferases. This study significantly expands our mechanistic understanding of how intrinsic bacterial methyltransferases like RsmI modify their rRNA targets. Further, recognition of distant ribosome features and reorganization of a critical rRNA functional center point to a potential role in accurate 30S subunit biogenesis.
GPT-4o mini: Non-social science research article
Controlled propagation of soliton bullets in an engineered strain field
Alexis de la Cotte, Xingzhou Tang, Chuqiao Chen, S. J. Kole, Noe Atzin, Juan J. de Pablo, Nicholas L. Abbott
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Predicting and controlling the propagation of nonlinear responses in materials is critical to a range of fields, from the manipulation of single electrons in quantum optics to the understanding of crack propagation and failure of quasi-brittle materials. Solitons, which are highly localized strain patterns that propagate and persist due to nonlinear feedback mechanisms, can be produced in liquid crystal (LC) films under high-frequency AC electric fields. In previous work using uniformly oriented films of LC, soliton bullets propagated in one preset direction perpendicular to the far-field orientation of the LC director. Here, we show that confinement of the LC between asymmetric surfaces and the introduction of strain can provide a versatile mechanism to modulate the propagation direction of solitons. Specifically, we find that soliton bullets propagate along two oblique axes, where the angle can be dynamically modulated with the electric field frequency. The origins of this behavior are understood through theory and simulations, where the forces driving soliton motion are analyzed. Importantly, asymmetric flexoelectric torques lead to frequency-dependent oblique trajectories in the presence of hybrid LC anchoring, with numerical simulations predicting asynchronous out-of-plane fluctuations that are verified in experiments. Overall, our results highlight the interplay between the nonlinear action of external fields and the far-field strain on soliton propagation. They also show that confinement can be used to control the direction of propagation of nonlinear signals and demonstrate how LCs can be used as model systems to test and predict the effects of nonlinear excitations in new material designs.
GPT-4o mini: Non-social science research article
CALHM5 deficiency alleviates aortic aneurysm by regulating smooth muscle calcium homeostasis
Bo Yang, Ting Xu, Qianqian Yang, Liangzhu Mo, Jianyi Huo, Taiyang Mu, Yating Zhi, Yun Du, Haojie Wang, Lingchuan Guo, Zhen Zhu, Yulong Feng, Yu Rui, Li Zhu, William A. Coetzee, Qinqin Gao, Hua-Qian Yang
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Ion channels are the second most common clinical drug target besides G protein–coupled receptors. Aneurysmal diseases pose a significant threat to human life. Novel drug targets for its treatment remain to be explored. We investigated the role of an ion channel, calcium homeostasis modulators 5 (CALHM5), on the development of aortic aneurysms. We characterized CALHM5 as a plasma membrane ion channel abundant in smooth muscle cells of both humans and mice, playing a pivotal role in regulating calcium homeostasis. Notably, CALHM5 deficiency suppressed the transcription of the L-type calcium channel (LTCC) pore-forming subunit by downregulating cAMP-response element binding proteins. This in turn diminished blood vessel contractility and decreased blood flow. Intriguingly, CALHM5 expression is downregulated in smooth muscle tissues of aortic aneurysm patients. Furthermore, CALHM5 deficiency was observed to ameliorate the development of abdominal aortic aneurysms in mice, partly by stimulating smooth muscle cell proliferation. CALHM5 emerges as an ion channel prominently expressed in arterial smooth muscles, serving as a physiological regulator of smooth muscle contraction and presenting itself as a promising therapeutic target for aortic aneurysms.
GPT-4o mini: Non-social science research article
Status of the sunken nuclear submarine Komsomolets in the Norwegian Sea
Justin P. Gwynn, Hilde Elise Heldal, Hans-Christian Teien, Andrey Volynkin, Simon M. Jerome, Ole Christian Lind
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The study documents in detail the extent of damage to the exterior of the sunken nuclear submarine Komsomolets and that previous remedial action carried out by Russia was still in place. No evidence was found of any plutonium in the near environment around the damaged forward section of the submarine from the nuclear warheads that were reported to be part of Komsomolets armament in the torpedo compartment. It was confirmed that releases from the reactor were still occurring, but not continuously, with maximum activity concentrations of 90 Sr and 137 Cs that were 400,000 and 800,000 times higher, respectively, than typical levels of these radionuclides in the Norwegian Sea. Elevated levels of 239 Pu, 240 Pu, and 236 U were also detected in the releases from the reactor, with atom ratios of 240 Pu/ 239 Pu and 236 U/ 239 Pu that indicate that the nuclear fuel in the reactor is corroding. Despite that releases from the reactor have occurred for over 30 y, there is little evidence of any accumulation of radionuclides in the near environment around the submarine as the released radionuclides appear to be rapidly diluted in the surrounding seawater. Releases from the reactor in Komsomolets can be expected to continue, so further investigations should be carried out to determine the mechanisms behind the observed releases, the corrosion processes that are occurring within the reactor and the implications of these for further releases and the fate of the remaining nuclear material in the reactor.
GPT-4o mini: Non-social science research article
Germline-targeted baboon apolipoprotein L-1 protects mice against African trypanosomes
Sara Fresard, Sarah J. Pangburn, Kayla Leiss, Daphne Boodwa-Ko, Daniella Kovacsics, Chris J. Schoenherr, Jeremy S. Rabinowitz, Aris N. Economides, Li Li, Weigang Qiu, Bernardo Gonzalez-Baradat, Alessandro Rosa, Russell Thomson, Jayne Raper, Joseph Verdi
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Some primates are immune to infection by most African trypanosome parasites due to apolipoprotein L-1 (APOL1), a primate-specific ion channel-forming protein. Our long-term objective has been to reduce African trypanosomiasis in livestock by genetic bioengineering of cattle with primate APOL1 . To select which primate APOL1 , we analyzed Papio ssp. APOL1 proteins and found that Papio hamadryas APOL1 was a strong candidate for transgenic animal production based on its trypanosome-killing capacity, ion channel properties, and stability. We generated seven transgenic murine lines based on the P. hamadryas APOL1 sequence and used these mice to investigate the level of APOL1 expression required for trypanosome immunity in vivo. We challenged the murine lines with three human and four livestock trypanosome isolates. P. hamadryas APOL1 provided protection against all of the human and three of the livestock trypanosome isolates, though not against Trypanosoma vivax despite the logical hypothesis that APOL1 plays a role in primate immunity to that parasite. Occasionally, lower APOL1 expression in heterozygote mice selected for the emergence of APOL1 resistant parasites in several trypanosome spp. Alarmingly, these resistant parasites were also resistant to high levels of APOL1 in homozygous mice, indicating an increase in virulence. A more-highly expressed chimeric APOL1 transgene encoding Homo sapiens APOL1 with the P. hamadryas APOL1 C-terminus was more effectively protective in heterozygote mice; however, we could not produce homozygous mice, suggesting endogenous toxicity to the mice. Together, these data bear relevance to our long-term objective to generate transgenic APOL1 cattle, the feasibility of which is discussed.
GPT-4o mini: Non-social science research article
Inhibition of coronaviral exoribonuclease activity by TRIM-mediated SUMOylation
Kannan Balakrishnan, Surajit Chakraborty, Cindy Chiang, Caleb M. Stratton, Shanti Pandey, Anna A. Tumanova, Shaun K. Olsen, Michaela U. Gack
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Members of the TRIM E3 ligase family are effectors of the host innate or intrinsic defense against various viruses; however, how specific TRIM proteins antagonize coronavirus infection is still largely elusive. Through an RNAi screen targeting 71 human TRIM genes, we identified multiple TRIM proteins with antiviral or proviral activity against SARS-CoV-2. TRIM32 potently restricted SARS-CoV-2 replication in a RING E3 ligase-dependent but interferon-independent manner. Mechanistically, TRIM32 binds to and SUMOylates the 3â€Č‐to‐5â€Č exoribonuclease (ExoN) of Nsp14, an enzyme essential for SARS-CoV-2 replication. TRIM32-mediated Nsp14 SUMOylation at K9 and K200 inhibits RNA binding and Nsp10 cofactor recruitment, respectively, ultimately suppressing ExoN activity. Our study further revealed that Nsp14 SUMOylation by TRIM32 and its antiviral activity are broadly conserved for coronaviruses. These results identify the coronaviral Nsp14 protein as a direct target of host restriction via SUMOylation, which may uncover ways to therapeutically inhibit coronavirus infections in humans.
GPT-4o mini: Non-social science research article
Spinning carbon and sinking phosphorus: Misaligned cycles in the sea
Matthew J. Church, Katie N. Coates
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GPT-4o mini: Non-social science research article
Giant photorefractive and photoexpansion effects in a van der Waals semiconductor
Anton A. Minnekhanov, Georgy A. Ermolaev, Alexey P. Tsapenko, Ilia M. Fradkin, Gleb I. Tselikov, Adilet N. Toksumakov, Aleksandr S. Slavich, Arslan B. Mazitov, Sergey A. Smirnov, Nikita D. Orekhov, Ivan A. Kruglov, Sergei A. Ivanov, Ilya P. Radko, Andrey A. Vyshnevyy, Aleksey V. Arsenin, Kostya S. Novoselov, Valentyn S. Volkov
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Nanophotonics relies on precise nanoscale structuring, yet conventional fabrication techniques remain complex and costly. Layered van der Waals (vdW) materials, with their intrinsic anisotropy and high refractive indices, offer a promising route toward simplified nanostructuring and tunable optical functionality. However, no vdW material has previously been shown to exhibit a strong photorefractive effect—a key requirement for light-based modulation. Here, we report a giant photorefractive response (Δ n up to 0.3) in crystalline arsenic trisulfide (As 2 S 3 ), observed at low optical intensities. In addition to refractive-index modulation, light exposure enables controlled thickness tuning of As 2 S 3 . The material exhibits a giant photoexpansion of up to 7%, depending on the illumination intensity, which may originate from light-induced generation of point defects, consistent with molecular-dynamics modeling. Building on this photoexpansion effect, we introduce a maskless nanopatterning technique based on continuous-wave laser writing, achieving ~500 nm pitch (~50,000 dpi) without the need for ultrafast lasers. The combination of high photosensitivity, anisotropy, ease of exfoliation and transfer, and optical transparency positions vdW As 2 S 3 as a practical platform for integrated photonics, adaptive optics, reconfigurable photonic elements, and dense optical encoding.
GPT-4o mini: Non-social science research article
GFAP + FOXF2 + ependymal cells promote blood–brain barrier repair via DLL4–NOTCH signaling after neural injury
Qi Xie, Hui Lu, Xiaoman Wang, Siya Wu, Qian He, Mengqi Yuan, Shuang Zhang, Linlin Hu, Changxiong Gong, Xiaofeng Cheng, Yiliang Fang, Zhaoyou Meng, Yilong Wang, Sen Lin, Qingwu Yang
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Ependymal cells in the adult ventricular-subventricular zone are increasingly recognized for functions extending beyond cerebrospinal fluid dynamics; however, their identity and functional specialization remain incompletely understood. While ependymal cells (EP) have been implicated in interactions with the stem cell niche and the vasculature, their role in repair processes following neural injury remains elusive. In this study, we employed region-specific single-cell transcriptomics of the subventricular zone (SVZ) and ipsilesional peri-infarct territory in mice to identify a distinct subpopulation of GFAP + FOXF2 + EP that selectively expand within the SVZ after neural injury. Notably, these cells were absent from other brain regions. Immunohistochemical validation revealed characteristic ependymal features, including typical pinwheel architecture and expression of Foxj1 and ÎČ-catenin. Furthermore, the absence of the proliferation marker Ki67 and the resistance of this subpopulation to Ara-C-mediated ablation indicate that these cells do not possess proliferative properties. Conditional deletion of Foxf2 in GFAP + cells led to impaired endothelial junction integrity and increased blood–brain barrier (BBB) permeability. In contrast, overexpression of Foxf2 via GFAP promoter-driven adeno-associated virus delivery enhanced vascular repair and facilitated functional recovery. Mechanistically, these GFAP + FOXF2 + EP secrete exosomal DLL4, which was associated with enhanced NOTCH pathway activity and restoration of BBB function. While the mechanism linking this limited cell population to the broad reparative effect, particularly the complete signaling amplification cascade, remains to be fully elucidated, these findings identify a subset of EP that contributes to BBB repair.
GPT-4o mini: Non-social science research article
The audience shapes the information content of the honey bee waggle dance
Tao Lin, Shihao Dong, Gaoying Gu, Fu Zhang, Xiuchuan Ye, Tianyi Wang, Ziqi Wang, Jianjun Li, James C. Nieh, Lars Chittka, Ken Tan
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The honey bee waggle dance, which encodes food location, is often thought to involve only one-way information transfer from dancers to signal receivers. Here, we show that the information content of the dance is influenced by the presence of followers and the number of appropriately aged potential followers in the hive, rather than the total number of bees on the dance floor. Dancers reduced the precision of directional and distance communication when they had fewer actual and potential followers. Even when the dance floor was crowded with young bees that do not follow dances, dancers showed the same declines in precision. These declines appear to arise as a byproduct of audience seeking during the return run, when dancers with fewer followers spent more time moving and covered greater distances across the dance floor. Although their mean waggle run duration and the distance covered per waggle run remained unchanged, both measures became markedly more variable when followers were scarce. Dancers likely use quorum sensing of tactile contacts and, potentially, age-specific odors to sense audience size. These results reveal that waggle dancing is a socially responsive process shaped by feedback from followers, demonstrating bidirectional information flow within this communication system.
GPT-4o mini: Non-social science research article
Alternative splicing rewires banana aroma biosynthesis
Adam Jozwiak
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GPT-4o mini: Non-social science research article
Endogenous ATP–powered nanomotors directing neural stem cell differentiation for Parkinson’s disease treatment
Miaomiao Ding, Bin Chen, Jing Xiao, Jinghui Rong, Ye Feng, Chao Gao, Dailing Du, Yingfeng Tu, Fei Peng
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Transplantation-free neuron regeneration remains attractive yet unsolved for reversing Parkinson’s disease (PD). Here, we present enzyme-driven mesoporous gold nanomotors (Apyrase@Au) that leverage endogenous biochemical energy for spatiotemporally controlled promotion of neural stem cell (NSC) differentiation, without exogenous stem cell transplantation. By catalyzing endogenous adenosine triphosphate (ATP) hydrolysis, Apyrase@Au nanomotors simultaneously generate directional propulsion and localized signaling messenger protons. These protons induce calcium influx and activate quiescent NSCs within the ventricular-subventricular zone of PD mice, directing their differentiation into functional neurons and alleviating moving dysfunction. The bioenergy-converting system imparts dual functionality to active matter, propelling while concurrently yielding bioactive products. This work demonstrates the potential of ATP-powered nanomachines as a self-sustaining and targeted biointerface, offering a promising strategy for promoting NSC differentiation and alleviating moving dysfunction in degenerative diseases.
GPT-4o mini: Non-social science research article
Correspondence of large-scale functional brain network decline across aging mice and humans
Ezra Winter-Nelson, Eyal Bergmann, Micaela Y. Chan, Gabriella Vill, Liang Han, Ziwei Zhang, Alexandra Kavushansky, Irit Dolgopyat, Jad Asleh, Jennifer D. Whitesell, Itamar Kahn, Gagan S. Wig
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Human aging is marked by progressive reorganization of large-scale functional brain networks; these brain network changes have been linked to cognitive decline and disease vulnerability. Conversely, while mice have served as powerful models for understanding the molecular and cellular changes that occur over the lifespan, an absence of precise characterization of age-related changes in large-scale functional brain network organization has limited cross-species translational insights. Here, using densely sampled resting-state functional MRI data acquired cross-sectionally and longitudinally in awake mice over a broad range of adulthood (n = 82; 3 to 20 mo), we describe organizational features and age-related alterations of the mouse’s functional connectome. Mouse resting-state functional connectivity recapitulates known functional circuits, demonstrating the organizational validity of these signals. Graph theoretic analysis applied to functional connectivity reveals that mice exhibit modular architectures of functional brain network organization and that increasing age is associated with decreasing system segregation, indicative of network dedifferentiation analogous to observations in humans. Notably, mouse resting-state brain networks are more segregated than those of humans [determined using data from the Human Connectome Project and its developmental- and aging-counterparts (n = 1,179; 18 to 90 y)], attributable to mice exhibiting a diminished contribution of long-range functional relationships that integrate distributed systems. Mice also exhibit slower rates of age-related decline in brain network organization relative to humans, highlighting important species differences in functional brain network organization and trajectories of brain network aging. These findings establish a model of large-scale functional brain network aging in mice and provide a translational bridge across species and spatial scales of analysis.
GPT-4o mini: Non-social science research article
HairTime: A noninvasive assay for estimating circadian phase from a single hair sample
Bert Maier, Luísa K. Pilz, Selin Özcakir, Ali Rahjouei, Ashraf N. Abdo, Jan de Zeeuw, Dieter Kunz, Achim Kramer
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Circadian clocks govern daily physiological and behavioral processes and are crucial for health; disruptions can lead to various diseases. The circadian phase of entrainment—the phase of the internal circadian clock in relation to external environmental cycles—is influenced by both genetic and environmental factors, varies between individuals, and is reflected in daily behaviors such as sleep–wake patterns, cognitive performance, and physical activity. While circadian phase may also fluctuate within individuals, the dynamics and extent of such variation in daily life remain largely unexplored. The gold standard for circadian phase assessment, dim-light melatonin onset (DLMO), is impractical for large-scale studies, and blood-based molecular biomarkers, while promising, are limited in feasibility. To address these challenges, we developed HairTime, a noninvasive assay that estimates circadian phase from a single daytime hair sample. Developed and evaluated in two steps—a training and a validation study—HairTime demonstrated strong predictive power compared to DLMO. Suitable for large-scale studies, it was assessed using over 4,000 samples. Circadian phase estimations showed a normal distribution and were associated with age, sex, and notably, work schedules, with earlier timing on workdays, suggesting that societal factors can modulate internal rhythms. Together, these findings establish HairTime as a promising tool for assessing circadian phase in research and lay the foundation for future applications in personalized chronotherapy.
GPT-4o mini: Non-social science research article
Depth of nutrient uptake by deep-rooted plants is regulated by water availability
Langlang Li, John N. Christensen, Markus Bill, Wenming Dong, Yuxin Wu, Curtis Beutler, Matthias Sprenger, Brian W. Gulick, Sharon E. Bone, Boris Faybishenko, John Sanders, Chunwei Chou, Amanda Henderson, Nicholas J. Bouskill, Kenneth H. Williams, Benjamin Gilbert
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The capacity of some plants to access water and nutrients at depths greater than one meter is a critical functional trait that confers resistance to drought and impacts both belowground and shallow soil processes. Here, we report water and strontium isotopic data from an alpine meadow transect showing the correlation between water and nutrient acquisition depths. The isotopic compositions of Sr ( 87 Sr/ 86 Sr ratio) and water in rock and soil, and in plant leaf tissues, reveal that deeper-rooted plants acquire a higher proportion of water, Sr, and cation nutrients that are derived from the saprolite, a zone of silicate weathering, than shallow-rooted grass. A three-decade dendrochemical record reveals that reductions of wet precipitation drive deep-rooted plants to acquire cation nutrients from deeper saprolite or bedrock regions. Thus, the depth of cation nutrient acquisition by deep-rooted plant species at this site is tightly coupled with, and likely determined by, water availability in soil, saprolite, and bedrock. The enhanced uptake of cations as well as water from deeper saprolite zones could impact the rate of bedrock weathering and watershed chemistry during drought.
GPT-4o mini: Non-social science research article
Reply to MacColl: Repeated evolution from standing genetic variation
Marius Roesti, Jeffrey S. Groh, Felicity C. Jones, Catherine L. Peichel, Dolph Schluter
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GPT-4o mini: Non-social science research article
A mitochondrial–neuroinflammation–D-serine connection in epilepsy
Herman Wolosker, Daniel J. Liebl
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GPT-4o mini: Non-social science research article
Specialization of independently acquired flagellar FliC proteins in plant-associated Sphingomonas balances swimming and immunogenicity
Dor Russ, Chinmay Saha, Karnelia Paul, Zhiyu Zheng, Theresa F. Law, Manuel Anguita-Maeso, Derek S. Lundberg, Connor R. Fitzpatrick, Jeffery L. Dangl
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Plants monitor their environment for microbial invaders using pattern-recognition receptors that detect microbe-associated molecular patterns (MAMPs). Flagellin, the main component of bacterial flagellum, contains the flg22 epitope recognized by the plant immune receptor FLS2. Immune recognition can create an evolutionary conflict, requiring bacteria to balance flagellar function and immune evasion. Here, we show that plant-associated Sphingomonas resolve this constraint by partitioning two flagellar functions, motility and colonization, across two divergent and independently acquired flagellin genes. Comparative genomics revealed widespread coexistence of FliC proteins expressing either an immunogenic variant (FliC-H) or a nonimmunogenic variant (FliC-L). The nonimmunogenic FliC-L is necessary and sufficient for full directional swimming, whereas FliC-H is dispensable for swimming, but sufficient for full attachment and colonization. Flagellin expression patterns mirror these functions. Thus, FLS2 recognizes the flagellar variant required for colonization rather than motility, potentially restricting colonizing bacteria from entering internal leaf and root tissues.
GPT-4o mini: Non-social science research article
Energy landscape statistics and thermodynamics of a machine-learned model of water
Ryan J. Szukalo, Andreas Neophytou, Axel Gomez, Nicolas Giovambattista, Francesco Sciortino, Pablo G. Debenedetti
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Water’s anomalous thermodynamic behavior arises from the presence of intricate hydrogen-bond networks that are highly sensitive to many-body interactions, challenging molecular modeling for decades. The ongoing machine learning revolution has opened the possibility of performing quantum-accurate liquid-structure calculations at affordable computational cost. Beyond reproducing water’s thermodynamic properties with high fidelity, such simulations provide a stringent benchmark for theoretical models and a route to deeper physical understanding. We use the recently developed machine-learned Deep Potential Many-Body Polarizable water model to show that the free energy of supercooled water can be accurately modeled with the potential energy landscape formalism. The resulting equation of state predicts the presence of a liquid–liquid critical point in excellent agreement with recent estimates. Together with previous studies based on empirical classical water potentials, it confirms that the potential energy landscape of water is Gaussian, providing a unifying framework for extracting thermodynamic behavior across model complexity, from empirical force fields to quantum-trained neural network models.
GPT-4o mini: Non-social science research article
Fab–Fc and Fab–Fab interactions of variable strength and valency contribute to the high concentration viscosity of IgG 1 antibodies
Joel Heisler, Jennifer L. Hofmann, Zhenyu Tan, Jonathan Zarzar, Saeed Izadi, Paul J. Carter
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The variable domains in Fab regions are well-established contributors to high concentration viscosity of IgG, primarily through charge and hydrophobic interactions. In contrast, the roles of the Fc and the number of self-interacting sites (valency) are less well understood. Here, we investigate the relative contributions of Fab–Fab and Fab–Fc interactions to high concentration viscosity for a diverse panel of 20 IgG 1 antibodies, by rheometry, coarse-grained simulations, and molecular surface property analysis. Strikingly, fragmentation of IgG 1 into F(abâ€Č) 2 plus Fc reduced viscosity (−11 to −93%) for all antibodies tested, demonstrating prevalent contributions of Fc to viscosity. Coarse-grained simulations with one site per Fab and two sites per Fc qualitatively tracked trends in experimental rheometry data for 20 parental antibodies and their fragments. In these simulations Fab–Fab and Fab–Fc interaction strengths were independently varied to capture possible interaction differences arising from parental sequences or any mutations. These coarse-grained simulations suggest that Fab–Fc attractions generate branched IgG 1 networks and disproportionately larger clusters relative to Fab–Fab interactions of comparable strength. This study suggests that a four-site self-interaction model, previously proposed for a single antibody (omalizumab), is broadly applicable to diverse IgG 1 . Beyond well-established variable domain engineering, this self-interaction model predicts that Fc engineering may reduce IgG 1 viscosity, a much sought after goal to enable subcutaneous delivery. Clinically validated Fc mutations are demonstrated here to substantially reduce the viscosity for multiple IgG 1 (−33 to −91% reduction, n = 6), supporting this emerging antibody design concept.
One test, many tongues: Surveying language proficiency across the globe
Pol van Rijn, Yue Sun, Harin Lee, Raja Marjieh, Ilia Sucholutsky, Francesca Lanzarini, Elisabeth André, Nori Jacoby
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Language influences our thinking and affects many aspects of cognition, from how we perceive the world to how we interact socially. Thus, objectively characterizing linguistic background is crucial for research in many areas, including second language acquisition, psycho-linguistics, and cognitive science. Traditional language proficiency tests, however, are manually composed by experts, limiting their scope for both lab and online settings. Here, we propose a pipeline that automatically derives a language proficiency test from a corpus of text and applies it to create new tests for 1,939 languages. Using this approach, we conducted a large-scale survey examining L1 and L2 proficiency across 34 countries, with participants tested on all 34 languages. Drawing from human ratings from 4,137 participants, our results validate that our test can effectively distinguish native speakers, second-language speakers, and nonspeakers within one minute, making it an effective tool for evaluating linguistic proficiency. We show that participants’ linguistic and demographic backgrounds systematically influence both their language proficiency and their self-reported skills, and we map the prevalence of global languages, such as English and Spanish, among online participants. Moreover, we show that our vocabulary tests are strongly correlated with other linguistic competences—such as listening and writing—in a set of typologically varied languages, demonstrating our test is an efficient instrument to assess language proficiency. More broadly, our work offers a significant resource for investigating global variation in language skills and contributes to reducing the overreliance on the English language in the cognitive and social sciences.
How the 2025 NIH grant terminations varied by researchers’ demographic groups
Diego F. M. Oliveira, Qian Huang, Teresa K. Woodruff, Brian Uzzi
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In early 2025, the NIH unexpectedly terminated 2,291 active research grants, withdrawing $2.45 billion and disrupting thousands of projects. While the economic magnitude of these cuts is known, less is understood about how they differed across researchers’ demographic groups. Using an original dataset of publicly available records, we documented how cancelations varied by gender and career stage. Although cuts occurred across all regions and institution types, statistical patterns show that early-career investigators—assistant professors, postdoctoral scholars, trainees, and graduate students—were disproportionately affected, as were women. Women’s projects were smaller on average, had a larger share of unspent funds at cancelation, and were more concentrated in training and transition awards. Although available data cannot determine downstream causal effects, NIH economic multipliers suggest a potentially large unrealized loss to the US research enterprise. These patterns highlight the vulnerability of early-career researchers and women to abrupt funding instability and underscore the need for sustained investment to protect the future scientific workforce.
Cross-cultural evidence that shame is a defense against reputational damage
Yiftach Argaman, Daniel Sznycer, Jan Crusius, Florian van Leeuwen, Yohsuke Ohtsubo, Hitomi Ishihara, Jin-Ying Zhuang, Qi-Jun Zhou, Thomas Castelain, FĂ©lix Neto, Joana Neto, Assaf Kron
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Because shame leads to evasions, aggression, and other behaviors that victims and third parties find undesirable, a prominent theory regards this emotion as maladaptive. By contrast, an alternative, adaptationist theory asks whether shame might benefit the actor. Indications that an individual now offers fewer benefits or imposes greater costs on others, if they reach others’ minds, lead the individual to be socially devalued: Others become less inclined to help and more inclined to harm her. Thus, an adaptationist theory views shame as a neurocognitive adaptation designed to minimize the leakage of reputation-damaging information and the cost of being devalued. Here, we report tests of two predictions derived from the adaptationist theory across six countries—the United States, the Netherlands, Portugal, Spain, Japan, and China—and two cultural regions within the United States—Southern states (honor) and Northern states (nonhonor). First, failures that indicate reductions in abilities more highly valued by others will elicit more intense shame. Second, failures will trigger greater shame when they occur in public rather than in private. The data supported both predictions in all six countries and in both US cultural regions. The improbable fit between the severity of the devaluative threat and the intensity of shame suggests that this emotion is an adaptation. Further, the replication of these findings across regions that vary widely along the individualism–collectivism and honor–nonhonor dimensions suggests that shame is part of human nature rather than a cultural construction.
The psychology of offensive and defensive intergroup violence: Preregistered insights from 58 countries
Jonas R. Kunst, Tomasz Besta, MichaƂ Jaƛkiewicz, Anna Natalia Gajda, Markus Sanden, Mina Marie FlatebĂž, Sulaiman Olanrewaju Adebayo, Marios Adonis, Collins Badu Agyemang, Raymond Agyenim Boateng, Serap Arslan Akfirat, Samir Al-adawi, Chiara Ambrosio, Gulnaz Anjum, John Jamir Benzon R. Aruta, Ivars Austers, Oumar Barry, Brock Bastian, Maja Becker, Michael Bender, Nora Cornelia Glerud Benningstad, Islam Borinca, Göksu Celikkol, Jiƙí Čeněk, Trawin Chaleeraktrakoon, Phatthanakit Chobthamkit, Hoon-Seok Choi, Suyeong Choi, Patricia Ciordas, Ann-Cathrin Coenen, Aleksandra Cupta, Piyanjali de Zoysa, Sandesh Dhakal, Lauren E. Duncan, Tuğçenaz Elcil, Barkan Eskiili, Edgardo Etchezahar, Renata Franc, Silvia Galdi, Magdalena Garvanova, Paul Gill, Augusto Gnisci, Angel GĂłmez, TalĂ­a GĂłmez Yepes, Igor Grossmann, Emily A. Haines, Fatjona Haka, Boaz Hameiri, Imaduddin Hamzah, Mai Helmy, Roland Imhoff, Shanmukh Kamble, Fiona Kazarovytska, Anna Kende, Narine Khachatryan, Sasha Y. Kimel, Jack W. Klein, Adam Komisarof, David Lacko, Timo Juhani Lajunen, Barbara LĂĄĆĄticovĂĄ, Claudio LĂłpez-Calle, Wilson LĂłpez-LĂłpez, Barbara Kalebić Maglica, Romualdas Malinauskas, Sona Manusyan, Khatuna Martskvishvili, Gustave Adolphe Messanga, Marta Miklikowska, Jelena Minic, Tamara Mohorić, Francesca Mottola, Silvana Mula, Pasquale Musso, Dieynaba Gabrielle Ndiaye, FĂ©lix Neto, Joana Neto, Laina Ngom Dieng, Ihuoma Faith Obioma, Tosin Tunrayo Olonisakin, Simon Ozer, Penny Panagiotopoulou, Beata Pastwa-Wojciechowska, Vassilis Pavlopoulos, Tomislav Pavlović, Inha Petrovska, Andrzej Piotrowski, Xenia Daniela Poslon, Lotte Pummerer, Mahima Raina, Jano Ramos-Diaz, Vilja Robertsson, Bettina Rottweiler, David L. Sam, Rosa Scardigno, Marion K. Schulmeyer, Anna Stefaniak, Anna Studzinska, Mark J. M. Sullman, Marcin Szulc, Willy Taffo NembouĂ©, Ergyul Tair, Nicole Tausch, Narendra Singh Thagunna, Emma F. Thomas, JoaquĂ­n Ungaretti, Colette Van Laar, Ćœermēna Vazne, Alexandra VĂĄzquez, Jose Villanueva-Alvarado, Anna Wlodarczyk, Kumar Yogeeswaran, Milan Obaidi
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Evolutionary theory and historical evidence suggest humans possess distinct psychological tendencies for defensive and offensive violence, which have insufficiently been considered in research. In a large-scale preregistered study across 58 countries ( N = 18,128), we demonstrate that violent extremist intentions manifest along two distinct psychological phenomena: defensive extremism, motivated by protecting one’s group from (perceived) threats, and offensive extremism, driven by establishing group dominance. We show that these dimensions a) can be reliably differentiated across diverse cultural contexts, b) are distinctively associated with psychological dispositions, and c) systematically differentiate countries varying in macrolevel sociopolitical functioning and violence. Across nations, a two-factorial structure was observed that was invariant at the scalar level. Defensive extremist intentions were consistently higher than offensive extremism in 56 out of 58 countries, suggesting greater moral acceptance of protective violence. While psychopathy was positively related to both types of violent extremist intentions, those high in Machiavellianism and narcissism demonstrated particularly higher levels of defensive extremist intentions. By contrast, those scoring high on religious fundamentalism and social dominance orientation demonstrated particularly higher levels of offensive extremist intentions. Unexpectedly, liberal political group identification was associated with higher offensive but lower defensive extremist intentions. Crucially, offensive (but not defensive) intentions were associated with macrolevel societal dysfunction, including political terror and internal conflict. These findings establish that defensive and offensive violent extremist intentions represent two conceptually different forms of extremism across a large and diverse range of countries, with consequences for research and practice.
Rethinking same-sex sexual behavior: From sensory error to social function
Viraj R. Torsekar
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How to revive science in America
Harvey V. Fineberg
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Multigenerational and gender-symmetric transmission of migration behaviors in historical Quebec
Marielle CÎté-Gendreau
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Migration decisions are embedded in social and family trajectories that escape traditional data sources, which tend to observe individuals in isolation. Genealogical microdata now make it possible to trace these dynamics over long time horizons. This paper documents how prior generations’ migration histories shape future internal migration behavior, leveraging rich historical microdata spanning over two centuries and multiple generations at the scale of an entire population (Quebec, Canada; 1621–1861). As the cultural norm preserved women’s maiden names throughout the life course, genealogies could be assembled as exhaustively for women as for men. Using residential trajectories reconstructed from these linked vital data, the study shows that the mobility of married couples depends on both spouses’ parents’ and grandparents’ migration histories. Descendants of migratory people are substantially more likely than their peers from sedentary families to migrate themselves, the effect of the grandparental generation being about half that of the parental generation. These effects compound such that couples with multiple migratory ascendants are even more likely to migrate. Moreover, husbands’ and wives’ migration backgrounds are equally predictive of their joint mobility decisions, suggesting a substantial role of women in shaping couples’ mobility and challenging the conventional assumption that migration decisions were historically made by men. These results reveal deep family history as an underexplored axis of migrant selection. The long-lasting influence of family should be integrated in migration theories.
Gender gaps in reading increase during unplanned and planned school closures
Emil Smith, Ea H. BlaabĂŠk, David Reimer, Mads M. JĂŠger
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Why do girls outperform boys in education? One contributing factor might be that girls read more than boys, which fosters competencies relevant in education. Moreover, boys might rely more heavily on schools to support and encourage reading, meaning that unplanned and planned school closures disproportionally affect boys. We map the gender gap in reading in the period 2020 to 2022 using two large-scale datasets from Denmark, one measuring students’ weekly reading in school via a popular reading app and the other measuring students’ borrowing of library books. Our data document a clear gender gap in reading that increased during unplanned school closures due to the COVID-19 pandemic and planned closures due to vacations. Our findings underscore the role of schools in mitigating gender differences in reading.
The power of leadership in changing social norms in heterogeneous societies
Fabio Galeotti, Jona Krutaj, Marie Claire Villeval
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Abandoning detrimental social norms is complex due to the strong pressure to conform. We examine how leaders can guide norm change in heterogeneous societies where individual preferences evolve at different rates. Inspired by the model and experimental design of [J. Andreoni, N. Nikiforakis, and S. Siegenthaler, Proc. Natl. Acad. Sci. U.S.A. 118 , e2014893118 (2021)], we conduct a large-scale laboratory experiment in which we manipulate the speed at which preferences change within a society and introduce leaders with different, evolving preferences. Without leaders, a minority of citizens with rapidly changing preferences cannot overturn an existing norm in a society where most individuals have slow-changing preferences. When fast-changing citizens form the majority, norm change occurs in most groups, but at high welfare costs. In contrast, exogenously selected leaders are highly effective at coordinating expectations and shifting heterogeneous societies toward a more efficient norm—at lower welfare costs and regardless of the underlying distribution of preference evolution across individuals. However, the timing of norm change depends on whether leaders prioritize their preferences (autocratic leadership) or those of the majority (democratic leadership). A follow-up experiment shows that peer-to-peer communication encourages leaders to adopt a more democratic leadership style. These results highlight the pivotal role of leadership in driving norm change and the importance of public voice in shaping leaders’ behavior.

Science

GPT-4o mini: Non-social science research article
Scientists can save nuclear arms control
Rose Gottemoeller
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February 2026 saw the end of the New Strategic Arms Reduction Treaty, known as New START, the last nuclear arms control agreement between the United States and Russia. Without limitations on nuclear weapons, what comes next? Can scientists step in, as they did in years past, to help stop the risk of nuclear war?
GPT-4o mini: Non-social science research article
High-dimensional topological photonic entanglement
M. Javad Zakeri, Armando Perez-Leija, Andrea Blanco-Redondo
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The generation and manipulation of high-dimensional quantum states lies at the heart of modern quantum computation. The use of topology to resiliently encode and transport quantum information has been widely investigated in condensed matter and has recently penetrated quantum photonics. However, a route to scale up to a large number of entangled topological photonic modes has been missing. In this work, we demonstrate a method to generate high-dimensional topological photonic entanglement. Our platform relies on designed silicon photonic waveguide topological superlattices, which support nonlinear generation of energy-time–entangled photon pairs on a superposition of multiple topological modes. We show strong signatures of entanglement of up to five topological modes with resilience to nanofabrication imperfections, providing a route toward scalable, fault-tolerant quantum photonic states.
GPT-4o mini: Non-social science research article
Distinctive DNA sequence features define epigenetic longevity of inflammatory memory
Christopher J. Cowley, Sairaj M. Sajjath, Luis F. Soto-Ugaldi, Mara Steiger, Samantha B. Larsen, Thomas Carroll, Douglas Barrows, Alexandra Mattei, Kevin A. U. Gonzales, Wei Wang, Kevin Li, Alexander Meissner, Helene Kretzmer, Dana Pe’er, Elaine Fuchs
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Tissues harbor memories of inflammation, which heighten sensitivity to diverse future assaults. Whether and how these adaptations are sustained through time and cell division remain poorly understood. We show that in mice, epidermal stem cells store lifelong, functional epigenetic records of psoriasis-like skin flares. Applying deep learning to investigate these chromatin dynamics, we unearth CpG dinucleotide density as a major driver of memory persistence. Although unnecessary for inflammation-induced transcription factors to open and establish memories, CpG-enriched sequences thereafter become essential, reinforcing accessibility across cellular generations by integrating DNA demethylation, methylation-sensitive transcription factors, sequence-intrinsic nucleosome disaffinity, and the nucleosome-destabilizing histone variant H2A.Z. Thus, once activated by inflammation-induced transcription factors, DNA sequences orchestrate persistent poise, imparting long-lasting memory to stress-sensitive genes and profoundly affecting tissue fitness upon recall.
GPT-4o mini: Non-social science research article
Family single-cell atlases reveal pig pregnancy and fetal growth restriction critical cell types
Liping Cai, Qing Zhang, Tianxiong Yao, Xiaoxiao Zou, Lei Xie, Siyu Yang, Yanyuan Xiao, Fei Huang, Zhiwei Peng, Jiawen Yang, Jianzhen Huang, Qiqi Jing, Ziqi Ling, Min Zheng, Chuanmin Qiao, Jinyuan Wu, Jiaqi Chen, Tao Jiang, Qin Liu, Min Liu, Zhe Chen, Jingquan Li, Hui Jiang, Haoyun Jiang, Zuoquan Chen, Yaya Liao, Yizhong Huang, Longyun Li, Yunyan Zhou, Zhou Zhang, Chao Yin, Yu Ye, Hui Yang, Biao Chen, Zhong Wang, Huanfa Gong, Dong Chen, Cong Huang, Xinkai Tong, Zhimin Zhou, Hao Fu, Yingchun Sun, Xiao Sun, Min Yan, Lin Wu, Shuqi Xiong, Yaxiang Wang, Xinke Xie, Mengqing Zhou, Xiaodong Liu, Xianhua Xie, Fusheng Wu, Zifeng Liu, Mei Ge, Sanya Xiong, Chenyu Li, Tao Shen, Yuxin Liu, Xi Tang, Xiaolong Chang, Siyi Liu, Chuangang Yu, Naixiang Yu, Zikang Hu, Dengshuai Cui, Jiahong Zhong, Sha Liu, Jianchao Hu, Yang Wen, Weiwei Zhou, Guanyue Wei, Shiyao Lin, Yiwen Xiahou, Liqing Chen, Jianjun Li, Ruirong Liu, Xiaoyun Chen, Yujie Shu, Feng Chen, Chao Wei, Xiaofen Hu, Yong Li, Yong Hou, Qingjie Zeng, Jun Gao, Ying Su, Jing Li, Junwu Ma, Yuanmei Guo, Congying Chen, Shijun Xiao, Huashui Ai, Zhiyan Zhang, Weiwei Liu, Qiang Yang, Yuyun Xing, Lin Rao, Bin Yang, Lusheng Huang
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Although massive cell atlases are already available, it is still a challenge to obtain an atlas of all tissues within a single body, especially in fetuses and pregnant mothers. We present a transcriptomic atlas of 2.56 million single cells covering 115 and 119 tissues from one fetal pig and its pregnant mother, respectively. We found that a cluster of heart capillary endothelial cells with enhanced fatty acid transit capability was enriched for pregnancy but restored after gestation. We also deciphered that l -leucine transport insufficiency in the trophoblast causes fetal growth restriction by reducing a muscle type II myofiber subcluster. Our “all-from-one” strategy enabled the identification of tissue cell type–specific transcription factors and provided insights into pregnancy heart adaptation and fetal growth restriction.
GPT-4o mini: Non-social science research article
Population genomics of Anopheles darlingi , the principal South American malaria vector mosquito
Jacob A. Tennessen, Raphael Brosula, Estelle Chabanol, Sara Bickersmith, Angela M. Early, Margaret Laws, Katrina A. Kelley, Maria Eugenia Grillet, Dionicia Gamboa, Eric R. Lucas, Jean-Bernard Duchemin, Martha L. Quiñones, Maria Anice Mureb Sallum, Eduardo S. Bergo, Jorge E. Moreno, Sanjay Nagi, Nicholas J. Arisco, Mohini Sooklall, Reza Niles-Robin, Marcia C. Castro, Horace Cox, Mathilde Gendrin, Jan E. Conn, Daniel E. Neafsey
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Malaria in South America remains a serious public health problem. Anopheles ( Nyssorhynchus ) darlingi is the most important malaria vector across tropical Latin America. Vector-targeted disease control efforts require a thorough understanding of mosquito demographic and evolutionary patterns. We present and analyze whole genomes of 1094 An. darlingi (median depth 18x) from six South American countries. We observe deep geographic population structure, high genetic diversity including 13 putative segregating inversions, and no evidence for sympatric cryptic taxa despite high interpopulation divergence. Strong signals of selection are plausibly driven by insecticides, especially on cytochrome P450 genes. Our results will facilitate effective mosquito surveillance and control while highlighting ongoing challenges that a diverse vector poses for malaria elimination in the Western hemisphere.
GPT-4o mini: Non-social science research article
Cooperation by non-kin during birth underpins sperm whale social complexity
Alaa Maalouf, Joseph DelPreto, Maxime Lucas, Simone Poetto, Jacob Andreas, Antonio Torralba, Shane Gero, Giovanni Petri, Daniela Rus, David F. Gruber
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We quantitatively document a sperm whale birth event, revealing collective support behaviors across kinship lines. Using high-resolution drone footage, computer vision, and multiscale network analysis, we studied the interactions within a Caribbean sperm whale unit comprising two matrilines. Our results suggest that a female family member led birth assistance and that after delivery, all individuals oriented toward and helped lift the newborn, taking turns in a coordinated, cross-kin effort. Despite historically observed foraging segregation, kinship barriers dissolved as all unit members contributed. These analyses provide evidence of birth attendance, or assistance, in a nonprimate species, a behavior long considered characteristic only of humans and their close relatives.
GPT-4o mini: Non-social science research article
SWOT detects dispersive tsunami tied to a near-trench source in the 2025 Kamchatka earthquake
Ignacio SepĂșlveda, Bjarke Nilsson, Yao Yu, MatĂ­as Carvajal, Matthew Brandin, Alice-Agnes Gabriel, David Sandwell
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Tsunamis from large subduction earthquakes pose severe coastal hazards, yet their genesis near the trench remains poorly constrained by land-based seismic geodetic data and distant deep-water sensors. Following the 29 July 2025 magnitude 8.8 Kamchatka earthquake, the NASA/CNES Surface Water and Ocean Topography (SWOT) satellite captured a distinct train of short-wavelength tsunami waves, which we link to near-trench tsunamigenesis. Sensitivity analyses of earthquake slip indicated tsunamigenesis within 10 kilometers of the trench, an inference not attainable from land seismology and geodesy or sparse deep-water seafloor pressure records alone. These results provide the first high-resolution, two-dimensional spaceborne observation directly linking the measured dispersive tsunami wavefield to near-trench tsunamigenesis, extending earlier model- and gauge-based inferences. They establish SWOT as a constraint on source processes, with implications for tsunami hazard science and subduction-zone geodynamics.
GPT-4o mini: Non-social science research article
Cryo–electron microscopy structure of the budding yeast telomerase holoenzyme
Hongmiao Hu, Hannah Neumann, Gabriela M. Teplitz, Elsa Franco-EchevarrĂ­a, Pascal Chartrand, Raymund J. Wellinger, Thi Hoang Duong Nguyen
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Telomerase is a reverse transcriptase that synthesizes telomeric repeats at chromosome ends, safeguarding genome integrity. We present the cryo–electron microscopy structure of the budding yeast telomerase, which exhibits substantial divergence from its ciliate and vertebrate counterparts. The structure reveals a stable core formed by telomerase RNA TLC1; the three ever shorter telomere (Est) proteins, Est1, Est2 and Est3; and the Pop1/Pop6/Pop7 complex (Pop1/6/7). TLC1, Est3, and Pop1/6/7 serve critical roles in complex assembly. We identified a zinc finger (ZnF) motif in the telomerase reverse transcriptase (TERT) subunit Est2 that is crucial for telomerase function. Structure prediction suggests the presence of ZnFs in TERT from diverse species. These findings offer insights into the functional organization of yeast telomerase and underscore the evolutionary diversity of telomerase holoenzymes.
GPT-4o mini: Non-social science research article
Thalamic activation of the visual cortex at the single-synapse level
Yang Chen, Marinus Kloos, Zsuzsanna Varga, Yonghai Zhang, Inken Piro, Tatsuo K. Sato, Bert Sakmann, Israel Nelken, Arthur Konnerth
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Deciphering thalamocortical (TC) activation at the level of individual synapses is essential to understanding how the cortex processes sensory information. In this work, we studied TC computation underlying the emergence of orientation selectivity in the mammalian primary visual cortex (V1). Using two-photon glutamate imaging and optogenetic cortical silencing in vivo, we identified and characterized TC synapses onto mouse V1 layer 4 neurons. We found that TC- but not corticocortical-recipient spines lacked postsynaptic Ca 2+ signals. Our results directly validate the core predictions of Hubel and Wiesel’s feedforward model and reveal distinctive synaptic properties that are critical for cortical computation and plasticity.
GPT-4o mini: Non-social science research article
Experimental evidence of a liquid-liquid critical point in supercooled water
Seonju You, Marjorie Ladd-Parada, Kyeongmin Nam, Aigerim Karina, Seoyoung Lee, Myeongsik Shin, Cheolhee Yang, Yeseul Han, Sangmin Jeong, Kichan Park, Kyeongwon Kim, Minjeong Ki, Robin Tyburski, Iason Andronis, Keely Ralf, Jae Hyuk Lee, Intae Eom, Minseok Kim, Rory Ma, Dogeun Jang, Fivos Perakis, Peter H. Poole, Katrin Amann-Winkel, Kyung Hwan Kim, Anders Nilsson
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The search for the liquid-liquid critical point in supercooled water is challenging owing to rapid crystallization. We studied supercooled water at timescales before ice formation by heating high- and low-density amorphous ices using infrared ultrafast laser pulses, followed by x-ray scattering. By varying the pump laser fluence, we accessed liquid states straddling the predicted critical point. We observed a crossover from a discontinuous to a continuous transition at which broad and slow structural variations occurred, consistent with critical fluctuations and slowing down. We also observed a rapid increase in the heat capacity indicating a critical divergence at 210 ± 8 K coincident with enhanced density fluctuations. These results suggest that our experiments have directly probed the vicinity of a critical point in supercooled water.
GPT-4o mini: Non-social science research article
An Early Miocene ape from the biogeographic crossroads of African and Eurasian Hominoidea
Shorouq F. Al-Ashqar, Erik R. Seiffert, Sanaa El-Sayed, Belal S. Salem, Abdullah S. Gohar, Hossam El-Saka, Mohamed Amin, Hesham M. Sallam
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The Early Miocene fossil record documenting hominoid evolution has long been restricted primarily to sites in East Africa, whereas contemporaneous North African sites have only yielded remains of cercopithecoid monkeys. Here, we describe a fossil ape from North Africa, a new genus ( Masripithecus ) from the Early Miocene (~17 million to 18 million years) of northern Egypt, on the basis of mandibular remains. A combined molecular-morphological Bayesian tip-dating analysis positions Masripithecus closer to crown hominoids than coeval fossil apes from East Africa, thereby filling a phylogenetic and biogeographic gap in the evolution of stem hominoids. This evidence suggests that crown Hominoidea might have originated during the Early Miocene in the underexplored northeastern part of Afro-Arabia, rather than in eastern Africa or Eurasia.
GPT-4o mini: Non-social science research article
Systems-level organization of extracellular proteostasis
ClĂĄudio M. Gomes, Michele Vendruscolo
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One defining feature of complex organisms is the ability to maintain protein homeostasis beyond cellular boundaries. We review how extracellular proteostasis is organized as a hierarchical network spanning pericellular, tissue, and systemic tiers. At each tier, secreted chaperones, proteases, vesicles, receptors, immune sentinels, and clearance organs cooperate to recognize, buffer, and eliminate misfolded proteins. Feedback through immune signaling, stress-induced protein secretion, and glymphatic and lymphatic transport adjusts capacity to proteotoxic load. We illustrate how failures in this stratified defense underlie neurodegenerative disorders and systemic amyloidoses, and we highlight strategies that stabilize extracellular proteins, augment clearance pathways, or enhance fluid transport. Viewing extracellular proteostasis as an integrated systems-level network reveals opportunities for combinatorial and preventive therapies.
GPT-4o mini: Non-social science research article
High-temperature memristors enabled by interfacial engineering
Jian Zhao, Cameron S. Jorgensen, Krishnamurthy Mahalingam, Cynthia Bowers, Wataru Sugimoto, Kai Ito, Seung Ju Kim, Ruoyu Zhao, Yichun Xu, Han-Ting Liao, Rajiv K. Kalia, Aiichiro Nakano, Kohei Shimamura, Fuyuki Shimojo, Priya Vashishta, Ajit K. Roy, Ning Ge, Miao Hu, R. Stanley Williams, Qiangfei Xia, Sabyasachi Ganguli, J. Joshua Yang
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Non-volatile memories (NVM) that operate reliably at high temperature are essential for electronics in extreme environments. Here, we reported graphene (Gra)/HfO x /tungsten (W) memristors that operated reliably up to 700 °C with an ON/OFF current ratio >10 3 , data retention >50 hours and endurance >10 9 switching cycles. Transmission electron microscopy (TEM) revealed significant W diffusion into the inert platinum (Pt) electrode of conventional Pt/HfO x /W memristors after high-temperature annealing, which was an effect responsible for the thermal failure of conventional devices but not observed in Gra/HfO X /W devices. First-principles calculations attributed the enhanced thermal stability to weaker W adsorption and higher surface diffusion barriers on graphene than metals like Pt. These results underscore the critical role of interfacial engineering and potential of 2D materials in enabling reliable high-temperature NVM technologies.
GPT-4o mini: Non-social science research article
Rapid adaptation and extinction in synchronized outdoor evolution experiments of Arabidopsis
Xing Wu, Tatiana Bellagio, Yunru Peng, Lucas Czech, Meixi Lin, Patricia Lang, Ruth Epstein, Mohamed Abdelaziz, Jake Alexander, Carlos Alonso-Blanco, Heidi Lie Andersen, Modesto Berbel, Joy Bergelson, Oliver Bossdorf, Liana Burghardt, Mireille Caton-Darby, Robert Colautti, Carolin Delker, Panayiotis G. Dimitrakopoulos, Kathleen Donohue, Walter Durka, Gema Escribano-Avila, Steven J. Franks, Felix B. Fritschi, Alexandros Galanidis, Alfredo Garcia-FernĂĄndez, Ana GarcĂ­a-Muñoz, Elena Hamann, Allison Hutt, JosĂ© M. Iriondo, Thomas E. Juenger, Stephen R. Keller, Karin Koehl, Arthur Korte, Pamela Korte, Alexander Kutschera, Carlos Lara-Romero, Laura Leventhal, Daniel Maag, Arnald Marcer, MartĂ­ March-Salas, Juliette de Meaux, BelĂ©n MĂ©ndez-Vigo, Javier Morente-LĂłpez, Timothy C. Morton, Zuzana MĂŒnzbergova, Anne Muola, Hanna Akiko Nomoto, Meelis PĂ€rtel, F. Xavier PicĂł, Brandie Quarles-Chidyagwai, Marcel Quint, Niklas Reichelt, Agnieszka Rudak, Johanna Schmitt, Gregor Schmitz, Merav Seifan, Basten L. Snoek, Remco Stam, Marc Stift, John R. Stinchcombe, Mark A. Taylor, Peter Tiffin, IrĂšne Till-Bottraud, Anna Traveset, Jean-Gabriel Valay, Martijn Van Zanten, Vigdis Vandvik, Cyrille Violle, Detlef Weigel, Maciej WĂłdkiewicz, François Vasseur, J. F. Scheepens, Moises Exposito-Alonso
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Climate change forces species to adapt rapidly to avoid extinction. To directly observe rapid adaptation and extinction, we conducted synchronized evolution experiments with Arabidopsis thaliana in 30 locations across Western Europe, the Mediterranean, the Levant, and North America. Whole-genome pooled sequencing of ~70,000 surviving plants revealed repeatable allele frequency shifts in similar climates but divergent shifts across contrasting ones, indicating evolutionary adaptation. We identified genetic variants linked to climate adaptation, including genes involved in processes ranging from thermal-stress sensing to spring-flowering timing. Evolutionary trends were often predictable, but variable, across environments. In warmer climates, evolutionary predictability correlated with population survival over 5 years, whereas erratic changes preceded extinction. These results show that rapid climate adaptation is possible, but understanding its limits will be crucial for biodiversity forecasting.
GPT-4o mini: Non-social science research article
Structure and organization of AMPA receptor-TARP complexes in the mammalian cerebellum
Alexander M. Scrutton, Nayanika Sengupta, Josip Ivica, Imogen Stockwell, Sew Peak-Chew, Bishal Singh, Kunimichi Suzuki, Veronica T. Chang, Stephen H. McLaughlin, James M. Krieger, A. Radu Aricescu, Ingo H. Greger
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AMPA receptors (AMPARs) are multimodal transducers of glutamatergic signals throughout the brain. Their diversity is exemplified in the cerebellum: At afferent synapses, AMPARs mediate high-frequency excitation, whereas in Bergmann glia (BG) they support calcium transients that modulate synaptic transmission. This spectrum arises from different combinations of core subunits (GluA1-4), auxiliary proteins, and posttranscriptional modifications. Using mass spectrometry, cryo–electron microscopy, and electrophysiology, we characterize major cerebellar AMPARs in pigs: calcium-impermeable GluA2/A4 heteromers with four transmembrane AMPAR regulatory protein (TARP) subunits, mainly neuronal in origin, and BG-specific, calcium-permeable GluA1/A4 heteromers containing two type II TARPs. We also showed that GluA4 receptors frequently exhibit compact N-terminal domains that promote their synaptic delivery. Our study defines the organizational principles of mammalian cerebellar AMPAR complexes and reveals how different receptor subtypes support cell type–specific functions.
GPT-4o mini: Non-social science research article
A genetically encoded device for transcriptome storage in mammalian cells
Yu-Kai Chao, Michelle Wu, Qiyu Gong, Fei Chen
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Understanding how cells make decisions over time requires the ability to link past molecular states to future phenotypic outcomes. We present TimeVault, a genetically encoded system that records and stores transcriptomes within living mammalian cells for future readout. TimeVault leverages engineered vault particles that capture messenger RNA through polyadenosine [poly (A)]–binding protein. We demonstrate that the transcriptome stored by TimeVaults is stable in living cells for more than 7 days. TimeVault enables high-fidelity transcriptome-wide recording with minimal cellular perturbation, capturing transient stress responses and revealing gene expression changes underlying drug-naïve persister states in lung cancer cells that evade epidermal growth factor receptor (EGFR) inhibition. By linking past and present cellular states, TimeVault provides a powerful tool for decoding how cells respond to stress, make fate decisions, and resist therapy.
GPT-4o mini: Non-social science research article
Chromatin buffers torsional stress during transcription
Jin Qian, Lucyna Lubkowska, Shuming Zhang, Chuang Tan, Yifeng Hong, Xiaomeng Jia, Robert M. Fulbright, James T. Inman, Taryn M. Kay, Joshua Jeong, Glenn Hauk, Deanna Gotte, James M. Berger, Mikhail Kashlev, Michelle D. Wang
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During eukaryotic transcription, RNA polymerase II (Pol II) must overcome nucleosome obstacles and, because of DNA’s helical structure, must also rotate relative to DNA, which generates torsional stress. However, there is limited understanding of how Pol II transcribes through nucleosomes while supercoiling DNA. In this work, we determined that Pol II generates a torque of 9 piconewton-nanometers (pN·nm) alone and 13 pN·nm with transcription factor IIS (TFIIS), making it a powerful rotary motor. When Pol II encounters a nucleosome, passage becomes more efficient on a chromatin substrate compared with on a single-nucleosome substrate, which demonstrates that chromatin substantially buffers torsional stress during transcription. Furthermore, topoisomerase supercoiling relaxation allows Pol II to transcribe through multiple nucleosomes. Our results reveal a role of chromatin beyond the more conventional view of it being just a roadblock to transcription.
Science abstract < 200 char.: Not a research article
Cascading impacts of natural disasters in a connected world
Laurie S. Huning, Manuela I. Brunner
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Multifaceted effects of extreme climate-related events are essential for risk models and management
Science abstract < 200 char.: Not a research article
An out of this world buddy movie Project Hail Mary Phil Lord and Christopher Miller, directors Amazon MGM Studios, 2026. 156 minutes.
Jackie Faherty
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An astronaut and an alien engineer team up against an existential threat in a new film
Science abstract < 200 char.: Not a research article
A village injury, a lifelong mission
Renqi Luo
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Science abstract < 200 char.: Not a research article
‘Morning sickness hormone’ may help reduce alcohol intake
Catherine Offord
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GDF15, thought to contribute to nausea during pregnancy, also acts as a brake on drinking, researchers argue
Science abstract < 200 char.: Not a research article
Beyond the US-China biotech scoreboard
Y. Tony Yang
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Science abstract < 200 char.: Not a research article
Coal-to-gas transition strains equity in China
Bing Zhang, Jingyan Han, Yong Zhao, Jianbo Liu, Huanyu Chang
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Science abstract < 200 char.: Not a research article
The dawn of modern apes
David M. Alba, JĂșlia Arias-Martorell
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An Egyptian fossil places the origin of modern apes in northeastern Afro-Arabia
Science abstract < 200 char.: Not a research article
Neanderthals lived on a knife’s edge for 350,000 years
Andrew Curry
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A pair of studies illuminates these humans’ long, hardscrabble existence
Science abstract < 200 char.: Not a research article
The Mpemba effect goes quantum
Zack Savitsky
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Quirk of freezing water found on atomic scales, hinting at technological applications
Science abstract < 200 char.: Not a research article
Pioneering preprint server goes solo
Jeffrey Brainard
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ArXiv splits from Cornell, aiming to raise funds to cope with rapid growth
Science abstract < 200 char.: Not a research article
A global methane observation system to track climate feedbacks for verifiable climate impact
Jennifer D. Watts, Elsa Ordway, Sparkle L. Malone, Qing Zhu, Paul I. Palmer, Dhruv Patel-Tupper, Philippe Ciais, Fa Li, Danielle R. Monteverde, Kyle A. Arndt, Lori Bruhwiler, Brian Buma, Hinsby Cadillo-Quiroz, Eugenie Euskirchen, Alison M. Hoyt, Meredith Holgerson, Gustaf Hugelius, Robert B. Jackson, Daniel Jacob, McKenzie Kuhn, Susan M. Natali, Shushi Peng, Clarice R. Perryman, Benjamin Poulter, Camilo Rey-SĂĄnchez, Le Bienfaiteur Sagang, Edward A. G. Schuur, Ruth K. Varner, Rodrigo Vargas
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Methane measurements, particularly of natural sources, need to be expanded considerably
Science abstract < 200 char.: Not a research article
Playing dead
Martin Enserink
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Resurrection plants can wither to nothing in a drought, then spring back to life. Jill Farrant thinks the feat holds lessons for crops
Science abstract < 200 char.: Not a research article
AI ‘agents’ go rogue in realistic simulations
Jeffrey Brainard
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Algorithms that autonomously control other software and files can become “agents of chaos,” violating privacy, security
Science abstract < 200 char.: Not a research article
Is astronomy a luxury?
Andy Lawrence
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Science abstract < 200 char.: Not a research article
First science from private Moon lander challenges picture of lunar volcanism
Paul Voosen
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Blue Ghost data suggest NASA’s growing commercial Moon program can deliver results
Science abstract < 200 char.: Not a research article
Catching water’s hidden transition
Francesco Paesani
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Rapid measurements capture structural transition in a short-lived liquid state of supercooled water
Science abstract < 200 char.: Not a research article
In Other Journals
Sacha Vignieri, Mattia Maroso, Sarah H. Ross, Melissa McCartney, Jack Huang, Ian S. Osborne, Stella M. Hurtley
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Editors’ selections from the current scientific literature
Science abstract < 200 char.: Not a research article
Iran war rains collateral damage on heritage sites
Kristin Romey
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Internet blackouts and academic isolation cloud efforts to track cultural toll of U.S.-Israeli strikes
Science abstract < 200 char.: Not a research article
When disease resists diagnosis The Elusive Body Alexandra Sifferlin Viking, 2026. 320 pp.
Lucy Tu
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Structural constraints stymie patients and physicians when symptoms cannot be easily explained
Science abstract < 200 char.: Not a research article
World’s oldest dog identified at ancient hunter-gatherer site
David Grimm
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15,800-year-old puppy pushes confirmed origin of our canine companions back nearly 5000 years
Science abstract < 200 char.: Not a research article
Designed to remember
Guillaume Blot, Przemyslaw Sapieha
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Specific DNA sequence features encode the persistence of epigenetic memory of inflammation
Science abstract < 200 char.: Not a research article
My lesson in teaching
Ravirajsinh Jadeja
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Science abstract < 200 char.: Not a research article
In defense of social friction
Anat Perry
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Sycophantic AI distorts social judgments and behaviors
Science abstract < 200 char.: Not a research article
In Science Journals
Di Jiang, Sacha Vignieri, Angela Hessler, Corinne Simonti, Claire Olingy, Allison Williams, Yevgeniya Nusinovich, Ian S. Osborne, Stella M. Hurtley, Mattia Maroso, Peter Stern, Sarah H. Ross, Ekeoma Uzogara, Yury Suleymanov, John Foley
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Highlights from the Science family of journals
Sycophantic AI decreases prosocial intentions and promotes dependence
Myra Cheng, Cinoo Lee, Pranav Khadpe, Sunny Yu, Dyllan Han, Dan Jurafsky
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Despite rising concerns about sycophancy—excessive agreement or flattery from artificial intelligence (AI) systems—little is known about its prevalence or consequences. We show that sycophancy is widespread and harmful. Across 11 state-of-the-art models, AI affirmed users’ actions 49% more often than humans, even when queries involved deception, illegality, or other harms. In three preregistered experiments ( N = 2405), even a single interaction with sycophantic AI reduced participants’ willingness to take responsibility and repair interpersonal conflicts, while increasing their conviction that they were right. Despite distorting judgment, sycophantic models were trusted and preferred. This creates perverse incentives for sycophancy to persist: The very feature that causes harm also drives engagement. Our findings underscore the need for design, evaluation, and accountability mechanisms to protect user well-being.

Science Advances

GPT-4o mini: Non-social science research article
Characterizing many-body dynamics with projected ensembles on a superconducting quantum processor
Zhiguang Yan, Zi-Yong Ge, Rui Li, Yu-Ran Zhang, Franco Nori, Yasunobu Nakamura
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Quantum simulators allow the experimental exploration of nonequilibrium quantum many-body dynamics, which have traditionally been characterized through expectation values or entanglement measures, based on density matrices of the system. Recently, a more general framework for studying quantum many-body systems based on projected ensembles has been introduced, revealing quantum phenomena, such as deep thermalization in chaotic systems. Here, we experimentally investigate a chaotic quantum many-body system using projected ensembles on a three-dimensional–integrated frequency-tunable superconducting processor, enabling both high-fidelity control and scalable architecture. Our results provide direct evidence of deep thermalization by observing a Haar-distributed projected ensemble for the steady states within a charge-conserved sector. Moreover, by introducing an ensemble-averaged entropy as a metric, we establish a benchmark for many-body information leakage from the system to its environment. Our work paves the way for studying quantum many-body dynamics using projected ensembles, and the scalability of our benchmark method represents a notable advance toward quantum computation and simulation.
GPT-4o mini: Non-social science research article
One-component ionizable amphiphilic Janus dendrimers as a delivery platform for efficient mRNA vaccine development
Nathan A. Ona, Dapeng Zhang, Lisa C. Lindesmith, Wook-Jin Park, Jaclynn A. Meshanni, Sydni Berkihiser, Jessica A. Vasserman, Sepideh Toshtzar, Nathanael C. Moore, Blair Williams, Benjamin Nakagawa, Ishana Baboo, Liuyan Pan, Wanting Cheng, Xiomara Mercado-LĂłpez, Wendy Bonilla-Acosta, Paul D. Brewer-Jensen, Mark R. Zweigart, Yaoska I. Reyes, Michael L. Mallory, Samantha R. May, Yongfeng Zhou, Virgil Percec, Ralph S. Baric, Yongsheng Li, Drew Weissman, Elena N. Atochina-Vasserman
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There have been rapid advances in nucleoside-modified messenger RNA–based vaccines, particularly during the SARS-CoV-2 pandemic, demonstrating a rapid and cost-effective approach for addressing infectious diseases. A major challenge remains in developing a delivery system that protects mRNA from degradation and facilitates its passage through tissue and cellular barriers. Current four-component lipid nanoparticles enable efficient endosomal escape and are a pivotal technology for the delivery of mRNA vaccines. However, challenges such as stability, availability, durability, and adverse effects persist. We have developed a self-assembling one-component ionizable amphiphilic Janus dendrimers (IAJD) delivery system with naturally occurring amino heads, capable of efficiently delivering mRNA to the spleen and lymph nodes. This single-component system simplifies synthesis, reduces development complexity, and enables rapid global distribution of mRNA vaccines during pandemics. As a proof of concept, one-component IAJD97, formulated with mRNA encoding norovirus mRNA capsid protein, demonstrates the potential of IAJDs as efficient delivery platform for mRNA vaccines, advancing their effectiveness and expanding applications to improve public health outcomes.
GPT-4o mini: Non-social science research article
Amygdala transcranial ultrasound stimulation disrupts threat acquisition and extinction learning
Gregory A. Fonzo, Kevin S. LaBar
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Transcranial ultrasound stimulation applied to the human amygdala selectively impacts the initial phases of both threat learning and its subsequent extinction.
GPT-4o mini: Non-social science research article
Seismic rhythms: Earthquake response to tectonic, hydrological, and tidal forcing in California
Krittanon Sirorattanakul, Jean-Philippe Avouac
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Seismicity is primarily driven by tectonics, but stress variations of natural or human-made origin can induce detectable modulations, offering insights into earthquake physics. Here, we identify regions in California exhibiting significant seasonal modulations of seismicity rate linked to hydrological surface loading but no significant semidiurnal tidal modulation. The peak seismicity rate lags behind the peak stressing rate by half a month. Assuming instantaneous nucleation substantially overpredicts the response, whereas time-dependent nucleation governed by rate-and-state friction accurately captures both the amplitude and the time delay with friction-stress parameter a σ ~ 1 to 10 kilopascals (kPa) and characteristic relaxation time t a ~ 0.05 to 1 year. The seismicity response to tidal and seasonal stress perturbations allows us to probe fault mechanical properties, providing a way to improve seismic hazard assessment.
GPT-4o mini: Non-social science research article
Scalable Ising machine composed entirely of Si transistors
Seong-Yun Yun, Joon Pyo Kim, Jaeyong Jeong, Sang-Won Lee, Ye-Seong Chung, Sanghyeon Kim, Yang-Kyu Choi
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We introduce a complementary metal-oxide semiconductor (CMOS) Ising machine (CIM) composed entirely of silicon-based metal-oxide semiconductor field-effect transistors (MOSFETs). Instead of adhering to the conventional functions of MOSFETs as switches or amplifiers, CIM adopts an unprecedented approach that uses the dual characteristics of MOSFETs to function as both oscillators and couplers, enabling the coupling strength between oscillators to be tuned through gate biasing. These dual behaviors facilitate effective synchronization within the CIM, while the use of MOSFETs ensures full compatibility with standard CMOS fabrication technology and provides a pathway toward scalable hardware implementation. We also address the challenge of frequency variability, a critical issue in a large-scale CIM, by finely tuning the gate voltage of the oscillating transistors. This strategy notably enhances the stability and reliability of the CIM, achieving a level of control that is difficult to attain in other Ising machines using heterotypic device architectures. This CIM was applied to solve a MaxCUT problem. The demonstrated advantages of our CIM, including its compact cell size, high scalability, and robust operation, represent a promising direction for the advancement of future large-scale and energy-efficient Ising machines.
GPT-4o mini: Non-social science research article
Wheat fiber mitigates colitis via non-SCFA microbial metabolite-trained intestinal macrophages
Seong-eun G. Kim, Rachael Ott, Alexis Bretin, Hirohito Abo, Yanling Wang, Yadong Wang, Shawn Winer, Daniel A. Winer, Lavanya Reddivari, Stacey L. Heaver, Ruth E. Ley, Michael Pellizzon, Vu L. Ngo, Andrew T. Gewirtz
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The advent of highly refined wheat products has reduced fiber consumption, which is associated with increased risk for inflammatory bowel disease (IBD). We found that enriching diets with wheat fiber (WF) protected mice against colitis, especially relative to a low-fiber diet, as assessed by clinical, histopathologic, morphologic, and immunologic parameters. WF’s protection against colitis was independent of short-chain fatty acids (SCFAs) yet associated with preservation of microbiota diversity, including maintenance of Bacteroides thetaiotaomicron ( B. theta ), which was necessary and sufficient for WF’s colitis protection. B. theta ’s presence in gnotobiotic mice resulted in WF-induced fecal metabolites that reprogrammed macrophages toward an M2-like phenotype. Metabolic and phenotypic reprogramming of macrophages ex vivo via WF-induced metabolites, followed by their transplantation into mice, recapitulated WF’s protection against colitis. Thus, microbiota-mediated metabolism of WF promotes macrophages that reduce proneness to intestinal inflammation, suggesting a mechanism by which WF consumption may curb development of IBD.
GPT-4o mini: Non-social science research article
Artificial embryonic node elucidates the role of flow in left-right symmetry breaking in vertebrates
Tanveer ul Islam, Ishu Aggarwal, Yves Bellouard, Patrick R. Onck, Jaap M. J. den Toonder
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During the embryonic development of vertebrates, initially, symmetric embryos develop asymmetrically arranged organs. The asymmetry initiates with the formation of a small fluid-filled cavity on the embryo called the embryonic node, which contains motile cilia that generate specific flow patterns. The mechanism by which this nodal flow is sensed and causes asymmetry development has remained elusive despite major experimental and computational efforts. Existing hypotheses focus on either mechanical or chemical signaling processes. We report an experimental artificial embryonic node that, combined with numerical simulations, enables in-depth investigation of nodal flow and its role in left-right asymmetry development. Dissimilar fluid velocity profiles develop around primary cilia on the left and right nodal sides, producing distinct cilium bending. Also, the distribution of signaling particles with specific diffusivities exhibits spatial and temporal asymmetry. Together, our results support both mechanical and chemical sensing hypotheses and suggest a potential synergy between the two sensing mechanisms for the enhanced robustness of left-right asymmetry development.
GPT-4o mini: Non-social science research article
Enhanced two-dimensional ferromagnetism in van der Waals ÎČ-UTe 3 monolayers
Sean M. Thomas, Andres E. Llacsahuanga Allcca, Wolfgang Simeth, Caitlin S. Kengle, Zachary W. Riedel, Fabio Orlandi, Dmitry Khalyavin, Pascal Manuel, Filip Ronning, Eric D. Bauer, Joe D. Thompson, Jian-Xin Zhu, Allen O. Scheie, Yong P. Chen, Priscila F. S. Rosa
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The discovery of local-moment magnetism in van der Waals (vdW) semiconductors down to the single-layer limit has led to a paradigm shift in the understanding of two-dimensional (2D) magnets. The incorporation of strong electronic and magnetic correlations in 2D vdW metals remains a sought-after platform to enable control of emergent quantum phases and to achieve more theoretically tractable microscopic models of complex materials. To date, however, there is limited success in the discovery of such metallic vdW platforms, and f-electron monolayers remain out of reach. Here, we demonstrate that strongly correlated ÎČ–uranium tritelluride (ÎČ-UTe 3 ) can be exfoliated to the monolayer limit. Unexpectedly, ÎČ-UTe 3 remains ferromagnetic in this limit with an enhanced ordering temperature of 35 kelvin, a factor of two larger than its bulk counterpart. Our work establishes ÎČ-UTe 3 as a materials platform for investigating and modeling correlated behavior in the monolayer limit and opens numerous avenues for quantum control with, e.g., strain engineering.
GPT-4o mini: Non-social science research article
Fast sampling of protein conformational dynamics
Michael A. Sauer, Souvik Mondal, Brandon Neff, Sthitadhi Maiti, Matthias Heyden
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Protein function often depends on dynamic transitions between conformations rather than just static structures. However, our current ability to characterize or predict such dynamics lags behind recent advances in protein structure prediction. Enhanced sampling methods can speed up molecular dynamics simulations to study protein conformational transitions but require prior knowledge of key collective motions involved. Here, we demonstrate for a series of proteins of varying complexity that the required information is encoded in anharmonic low-frequency vibrations. Using recently developed methods, we show that this information can be easily extracted from short dynamics simulations without requiring prior knowledge. Combined with enhanced sampling, we correctly predict conformational transitions in all test proteins and generate highly reproducible free energy landscapes. This allows for the rapid generation of accurate protein conformational ensembles, which is critical to unravel the complex relationship between protein sequence, structure, and dynamics.
GPT-4o mini: Non-social science research article
EnvZ/OmpR-driven cooperative behavior promotes cefiderocol resistance in a hanging-droplet evolution system
Bowen Li, Kaiwen Song, Qi Wang, Xu Gao, Ruobing Wang, Shitao Shen, Wei Wang, Hui Wang
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Understanding how bacteria rapidly adapt to recently introduced antibiotics increasingly demands experimental models that move beyond classical evolution systems. We developed a microbial evolution hanging-droplet system (MEHS) that uses gravity-driven flow to sustain continuous exponential growth, doubling daily reproduction rate. Using this MEHS, Klebsiella pneumoniae rapidly adapted to fluctuating cefiderocol (CFDC) exposure. However, resistant clones comprised only a minor fraction of the evolved populations. Many mutations overlapped with variants previously observed in clinical practice, including alterations in EnvZ/OmpR two-component system that reprogrammed siderophore biosynthesis. These changes promoted cross-protection of susceptible subpopulations, alleviating the fitness costs typically associated with resistance and facilitating population-level adaptation. Moreover, the detection of similar variants in clinical isolates collected before CFDC use highlights their latent potential to evolve under selective pressure. Our findings establish MEHS as a powerful platform for resolving clinically relevant resistance trajectories and point to regulatory nodes as potential targets for disrupting cooperative behaviors that undermine antibiotic efficacy.
GPT-4o mini: Non-social science research article
Mechanism of ribosome stalling by the AMD1 C-terminal tail arrest peptide
Emir Maldosevic, Fabio S. Boiocchi, Michal I. Swirski, Kyle A. Meiklejohn, Martina M. Yordanova, Pavel V. Baranov, Ahmad Jomaa
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AMD1 encodes adenosylmethionine decarboxylase 1 (AMD1), a key enzyme in polyamine biosynthesis. A subset of ribosomes translating the AMD1 coding sequence read through the stop codon and pause at a second in-frame stop 384 nucleotides downstream, producing a conserved C-terminal extension (C-tail). Despite growing evidence that such cis-acting elements regulate translation of their genes, the molecular mechanism by which the C-tail mediates ribosome stalling remains unclear. Here, we determined the structure of the ribosome nascent chain complex paused by the AMD1 C-tail which traps eukaryotic release factor 1 (eRF1) with the ATP-binding cassette subfamily E member 1 (ABCE1). The nascent chain forms a molecular clamp that positions an arginine hook in the peptidyl-transferase center, occluding the accommodation of the eRF1 GGQ motif thereby hampering translation termination. Analysis of aggregated ribosome profiling data revealed several genes with a pattern of stop codon readthrough followed by ribosome stalling at a specific location, suggesting that regulatory readthrough-stall mechanisms may not be limited to AMD1 .
GPT-4o mini: Non-social science research article
Engineering low-symmetry colloidal crystals with optical anisotropies
Haixin Lin, Sangmin Lee, Yinsheng Guo, Vahagn Mkhitaryan, Diego M. Solís, Víctor F. Martín, José M. Taboada, Ana Sånchez-Iglesias, Jinghan Zhu, Marek Grzelczak, Lin Sun, Byeongdu Lee, Shunzhi Wang, Wenjie Zhou, Jinsong Wu, Richard P. Van Duyne, Fernando Obelleiro, Luis M. Liz-Marzån, F. Javier García de Abajo, Sharon C. Glotzer, Chad A. Mirkin
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Engineered low-symmetry colloidal crystals are emerging as promising performance-enhancing alternatives to natural materials for optical devices. However, current synthesis methods cannot precisely control structural features such as the orientation of the optical axes in these crystals. Here, DNA-modified nanorods and nanopentabipyramids were used as programmable atom equivalents to synthesize low-symmetry colloidal crystals. These crystals display three different lattice symmetries and crystal habits, aligning their optical axes in perpendicular, parallel, and oblique configurations relative to the crystal surface. The low lattice symmetries of the colloidal crystals define their optical anisotropies. Specifically, the rhombohedral colloidal crystals exhibit substantial polarization-dependent transmission and scattering characteristics. Optical measurements supported by simulations suggest that these colloidal crystals exhibit large optical anisotropy. This work expands the potential of programmable matter by developing a class of optically anisotropic materials engineered from DNA upon conjugation with relatively simple and readily available nanoparticle building blocks.
GPT-4o mini: Non-social science research article
Harnessing cooperative sorbate-sorbent adaptation in a flexible metal-organic framework for switchable hydrocarbon separation
Han Fang, Meagan Mulcair, Jia-Peng Han, Bo Zhang, Brian Space, Shi-Qiang Wang, Mei-Hui Yu, Ze Chang, Xian-He Bu
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The pursuit of selective adsorption for separating molecules with similar shapes and interactions remains a formidable challenge. This work harnesses a powerful, previously unrecognized mechanism in a flexible metal-organic framework (Flex-Cd-MOF-3) to achieve switchable adsorption selectivity. Specifically, Flex-Cd-MOF-3, a descendant of Flex-Cd-MOF-2 with increased linker rigidity and functionalization, exhibits both local rearrangements and reversible framework expansion or shrinkage, showing phase-dependent propylene/propane selectivity. Considering propane, mutually beneficial conformational changes in the material and sorbate co-occur that are not possible with rigid propylene, reshaping the energy landscapes. These distinct interaction mechanisms, for otherwise very similar molecules, directly lead to pore swelling and shrinking at different pressures and phase switchable selectivity. An innovative modeling approach was developed that describes the full desorption pathway, explaining the relative binding energies and the sorbate-dependent mechanism of pore shrinkage. This work establishes cooperative sorbate-sorbent adaptation as a generalizable adsorption mechanism for achieving precise separation of similar molecules through distinct intermolecular interactions.
GPT-4o mini: Non-social science research article
Stage-specific epigenetic priming amplifies gene activation during lineage commitment
Arion Foertsch, Naama Hirsch, Janine Seyfferth, Ward Deboutte, Herbert Holz, Maria Shvedunova, Remzi Karayol, Thomas Stehle, Laura Arrigoni, Niyazi Umut Erdogdu, Asifa Akhtar
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Neural progenitor cells exhibit developmental plasticity as they can commit to distinct developmental trajectories. The male-specific lethal complex (MSLc) is linked to multiple developmental disorders, suggesting a role in neural fate commitment. To dissect MSLc function, we used a multipronged approach combining chronic and acute depletion models. Knockout of the MSLc scaffolding component MSL1 caused embryonic lethality by E10.5 (embryonic day 10.5), and single-cell multiomics revealed altered cell population composition across multiple germ layer–derived lineages, including neuroectoderm. Two-dimensional directed differentiation models showed that the MSLc facilitates accessibility at regulatory elements during early stages of neurogenesis. Neurodevelopmental genes displayed reduced enhancer-promoter contacts and failed to reach appropriate expression levels when the MSLc was absent early in neural differentiation. In contrast, MSLc loss at later stages did not recapitulate this phenotype, indicating that MSLc-mediated gene priming is a key mechanism enabling timely activation of lineage-specifying transcriptional programs.
GPT-4o mini: Non-social science research article
Microtubules guide Aurora B substrate geometries for accurate chromosome segregation
Yiming Niu, Keith F. DeLuca, Randall H. Owen, Hide A. Konishi, Rui Gong, Gregory M. Alushin, Jennifer G. DeLuca, Hironori Funabiki
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Accurate chromosome segregation requires differential regulation of microtubule-binding substrates by Aurora B, the kinase subunit of the chromosomal passenger complex (CPC). How microtubules simultaneously up- and down-regulate Aurora B phosphorylation remains unclear. Devising a new cryo–electron microscopy workflow, we determined microtubule-bound structures of the CPC and key Aurora B substrates that resolve their phosphorylation sites, finding that microtubules can promote or restrict Aurora B–mediated phosphorylation depending upon binding geometry. The kinetochore Ndc80 complex oligomerizes on microtubules through multivalent interactions including its kinase recognition sites, sterically restricting kinase access to counteract phosphorylation-induced detachment. Attenuating this oligomerization compromised stable kinetochore-microtubule attachments and causes chromosome mis-segregation. Conversely, Aurora B recognition sites of the microtubule-depolymerase mitotic centromere–associated kinesin (MCAK) remain accessible on microtubules, explaining how microtubule-bound CPC can promote MCAK phosphorylation and inactivation. We propose that microtubule-guided substrate remodeling can serve as a general mechanism for controlling Aurora B–mediated phosphorylation during mitosis, which can coordinate diverse processes underlying faithful chromosome segregation.
GPT-4o mini: Non-social science research article
Toward ultimate NMR resolution with deep learning
Amir Jahangiri, Tatiana Agback, Ulrika Brath, Vladislav Orekhov
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Resolution in NMR is defined as the ability to distinguish and accurately determine signal positions while mitigating overlap. In the pursuit of ultimate resolution, we introduce peak probability presentations ( P 3 ), a statistical spectral representation that assigns a probability to each spectral point, indicating the likelihood that a peak maximum occurs at that location. The mapping between the traditional spectrum and P 3 is achieved using MR-Ai, a physics-inspired and computationally efficient deep-learning neural network. P 3 is validated on 60 database proteins and showcased on the challenging Tau and MATL1 proteins. Using synthetic spectra, we show that the achieved peak-localization precision closely approaches the theoretical limits set by the Cramér-Rao lower bound and Bayesian Monte Carlo estimates. Furthermore, MR-Ai enables the coprocessing of multiple spectra, facilitating direct information exchange between datasets to enhance spectral quality, particularly in cases of highly sparse sampling.
GPT-4o mini: Non-social science research article
Synergy of liberated anions and intense electric field in frustrated ion pairs for enhancing CO 2 cycloaddition
Decun Luo, Han-Xuan Liu, Zheng-Qing Huang, Xi-Yang Yu, Lei Chen, Riguang Zhang, Zhun Hu, Chun-Ran Chang
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Frustrated Lewis pairs (FLPs) have emerged as a transformative strategy in small-molecule activation, leveraging steric inhibition to sustain highly reactive Lewis acid–base pairs capable of heterolyzing nonpolar molecules such as H 2 and CO 2 through electric field (EF)–induced polarization. Despite their promise, FLPs exhibit inherent limitations in activating highly stable, kinetically inert substrates, owing to insufficient field strength and limited polarization efficacy. The systems with intensified charge separation, termed frustrated ion pairs (FIPs), can transcend these constraints by combining extreme ionic reactivity with persistent frustration. Here, we propose a geometrically controlled FIPs system that systematically modulates interionic distance and interaction via cation size engineering, ensuring sustained frustration and remarkable catalytic enhancement. The relationship between the interaction strength of anions and cations in the FIPs and their performance in CO 2 cycloaddition exhibits a volcanic curve trend. FIPs catalysts with optimal distance (4.11 Å) and interaction strength (−78 kJ·mol −1 ·Å −1 ) between its cation and anion exhibit optimal catalytic performance ( TOF  = 184 hour −1 ). The frustrated configuration liberates Br − from electrostatic confinement, achieving unprecedented nucleophilic activity by reducing the ring-opening energy barrier by 48.7 kJ·mol −1 compared to conventional ionic pairs. Optimal ion-pair distance in FIPs generates an intense asymmetric electric field that strongly polarizes CO 2 , yielding an induced dipole moment of ∆Ό = 0.132 D. Moreover, the FIPs structure is extended to heterogeneous systems and exhibits a similar trend with homogeneous ones, showing its application potential.
GPT-4o mini: Non-social science research article
Structural basis of odorant recognition by a mammalian class II odorant receptor
Minsu Gil, Chulwon Choi, Minseok Kim, Minsik Bae, Hajin Lee, Intae Choi, Wonpil Im, Hee-Jung Choi
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Mammalian odorant receptors (ORs) sense diverse environmental chemicals, yet structural insights into odorant recognition by mammalian class II ORs remain limited. Here, we present the cryo-EM structure of a native mammalian class II OR, mouse Olfr412, a human OR1D2 ortholog, bound to the odorant methyl- trans -cinnamate and the G s protein. The odorant-binding pocket of Olfr412 is located deeper within the transmembrane domain than that of the class I OR OR51E2 and is largely composed of poorly conserved hydrophobic residues, providing a structural basis for broad odorant recognition in class II ORs. Structural and molecular dynamics analyses suggest that the conserved Y 6x55 plays a key role in odorant recognition and activation, functionally paralleling R 6x59 in class I ORs and is further stabilized by intramolecular interaction with the conserved ECL2 residue E 45x51 . Together, our findings uncover structural mechanisms underlying odorant recognition and activation in class II ORs.
GPT-4o mini: Non-social science research article
Boosting photocatalytic hydrogen production in complex environments by confining trace MoBT x MBene
Binfen Wang, Hongwei Wang, Wenyu Xu, Zelin Chang, Jialin Li, Yutong Gong, Fei Huang, Junjie Wang, Xinliang Li
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Charge carrier recombination represents a fundamental constraint in semiconductor photocatalysis. Combining heterostructure design with deliberate defect engineering to facilitate hydrogen intermediate (*H) adsorption is a viable strategy for boosting photocatalytic hydrogen evolution reaction (HER). Herein, we design defective MBene via controlled etching and perform in situ hydrothermal assembly to develop a tailored MoBT x /CdS heterostructure. Incorporating a mere 0.5 wt % two-dimensional MoBT x MBene leads to a fourfold enhancement in HER activity over bare CdS. The established MoBT x /CdS catalyst achieves a remarkable HER of 10.2 millimoles per gram per hour under ambient conditions with 23.2% apparent quantum yield and sustains 90.2% activity after 24 hours of continued operation. Outstanding environmental adaptability is demonstrated through a consistent HER value of 7.1 millimoles per gram per hour in tap water and 5.7 millimoles per gram per hour in seawater. The temperature-dependent performance demonstrates notable robustness, reaching 11.1 millimoles per gram per hour at 35°C while preserving 40% functionality at harsh 5°C. Integrated photoelectrochemical and computational analyses elucidate that Mo vacancies create band alignment–optimizing electron traps and reduced *H adsorption barriers, enhancing fast carrier separation. Concurrently, interfacial covalent Mo─S bonds establish atomic-level charge-transfer pathways and enable rapid electron migration. This work establishes a previously unidentified paradigm for advanced photocatalyst design through concerted defect-interface modulation.
GPT-4o mini: Non-social science research article
Blood feeding triggers the terminal differentiation of precursor cells in tick salivary glands
Sazzad Mahmood, Stephen Lu, Ana Beatriz Barletta Ferreira, Markus Berger, Oladele A. Oluwayiose, Christine A. Schneider, Jacqueline M. Leung, Melina Garcia Guizzo, Yixiang Zhang, Randall Johnson, Kevin W. Cormier, Motoshi Suzuki, Nathan T. Brandes, Gwendolyn Cooper, Joshua Gold, Benjamin Schwarz, Lisa R. Olano, Justin Lack, Carolina Barillas-Mury, José M. Ribeiro, Lucas Tirloni
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Ticks transmit a wide range of pathogens to humans. During blood feeding, they inject salivary proteins that suppress host immune responses, enabling prolonged feeding and pathogen transmission. A hallmark of this process is the dynamic reprogramming of salivary gene expression, known as the sialome switch. Here, we describe a previously unrecognized cellular mechanism underlying this phenomenon in two medically important tick species. Using integrated multi-omics and imaging approaches, we identified a conserved population of undifferentiated salivary gland precursor cells in unfed ticks. Upon host attachment, these precursors undergo terminal differentiation into specialized secretory subtypes through a conserved transcriptional and signaling framework that drives salivary gland activation and maturation. Unlike other blood-feeding arthropods, tick salivary glands dynamically remodel in response to host contact, producing saliva with a shifting composition. This study suggests the cellular basis of adult female tick salivary gland maturation and offers targets to disrupt feeding and pathogen transmission.
GPT-4o mini: Non-social science research article
Pixelated electrically reconfigurable metasurfaces for intelligent thermal emission control
Xiu Liu, Hyeonggyun Kim, Zexiao Wang, Xinyi Fang, Yibai Zhong, Tianyi Huang, Muchuan Chen, Gianluca Piazza, Sheng Sheng
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The era of intelligent machines demands advanced hardware capable of high-density data collection and processing within compact platforms. Thermal-infrared emission, with its dual functionalities of heat and light, enables promising applications in optical data acquisition and information processing. However, the inherent stochastic nature and slow thermal response speed of thermal emission limit practical applications. In this work, we demonstrate electrically programmable, pixelated metasurfaces based on GeTe phase-change materials that enable dynamic and localized control of thermal-infrared emission. By integrating GeTe into hybrid plasmonic meta-atoms with strong field confinement, we achieve fast, nonvolatile switching with large optical contrast using minimal active material. This approach allows multidimensional tunability, establishing a versatile platform for reconfigurable photonic systems with high integration density, adaptive functionality, and embedded intelligence.
GPT-4o mini: Non-social science research article
A galactic cosmic ray cavity in Earth-Moon space
Wensai Shang, Ji Liu, Zigong Xu, Chao Yue, Ruilong Guo, Chao Xiao, Quanqi Shi, Robert F. Wimmer-Schweingruber, Jingnan Guo, Alexander W. Degeling, Robert Rankin, Anmin Tian, Qiu-Gang Zong, Chenyao Han, Jong-Sun Park, Huizi Wang, Wenlong Liu, Suiyan Fu, L. M. Zhai, D. Chen, Sulan Ni, T. L. Chen
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In regions of the Solar System distant from planetary magnetic fields, galactic cosmic rays (GCRs) have generally been assumed to be uniformly distributed over the Earth-Moon distance. However, our analysis of data from the LND (Lunar Lander Neutron and Dosimetry) experiment onboard the Chang’E-4 lander revealed a region of reduced GCR flux in the prenoon sector of the lunar orbit. Further investigation suggests the presence of an energetic particle cavity, formed by Earth’s magnetic field acting as an obstacle to GCR propagation. This cavity indicates that the influence of Earth’s magnetic field within the space environment extends unexpectedly up to and far beyond the lunar orbit. This finding offers the potential to avoid high radiation levels during future lunar exploration and deep-space missions.
GPT-4o mini: Non-social science research article
Noise-tolerant correlated coincidence imaging based on supercorrelated light at 1550 nm
Yu Yan, Jiamin Li, Ruikang Li, Yanqiang Guo, Jiang Qiu, Shuangping Han, Zihua Liu, Jianyong Hu, Chengbing Qin, Liantuan Xiao
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Single photon–level imaging at 1550 nanometers is a key driver for crucial advancements in the next-generation laser detection technology. This cutting-edge approach plays a vital role in space ranging, target recognition, and three-dimensional remote sensing. However, it has faced severe challenges such as insufficient noise-tolerant performance. Here, we introduced noise-tolerant correlated coincidence imaging (CCI) based on supercorrelated light (SCL). The light source, generated through nonlinear interaction between a pulsed laser and a photonic crystal fiber, exhibits a broader power-law photon number probability distribution and extremely strong photon correlation [with second-order correlation function g (2) (0) up to 18,166]. Our noise-tolerant CCI can resist random environmental noise up to 100,000 times stronger than the echo signal photons. SCL offers an exceptionally strong noise tolerance for single photon–level imaging in extreme environments with intense noise, paving the way for the future development of extremely sensitive light detection.
GPT-4o mini: Non-social science research article
Mechanistic insights into the therapeutic properties of delta opioid receptor
Sarah M. Bernhard, Susovan Roy Chowdhury, Tsuyoshi Murata, Erin L. Reinl, Nokomis Ramos-Gonzalez, Elizabeth Denn, Kevin Appourchaux, Asuka Inoue, Sarah K. England, Jonathan F. Fay, Susruta Majumdar, Baron Chanda, Tao Che
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The delta opioid receptor (DOR) is a promising target for treating pain, anxiety, and depression, yet no DOR-based drugs have reached the clinic. Here, we examine how ligands with varying therapeutic properties modulate DOR function. While full agonists rapidly internalize the receptor, partial agonists show a slower rate of internalization, and antagonists increase cell-surface DOR levels. High-resolution structures of ligand-bound DOR-G i1 complexes, including those with antagonists engaged, reveal key interactions that account for DOR ligand selectivity, potency, and efficacy. Single-molecule fluorescence resonance energy transfer studies show that DOR dynamically samples three distinct states (active, obligate preactive, and inactive), and transition rates are tuned by both ligand efficacy and G protein coupling. The endogenous agonist, met-enkephalin, not only stabilizes the active-state conformation but also catalyzes transitions between the active and inactive states. These results reveal how ligand-specific interactions and receptor dynamics can govern pharmacological profiles and provide a framework for developing DOR-targeted therapeutics.
GPT-4o mini: Non-social science research article
Layer-by-layer decoding of contemporary and historic painting composition using MALDI mass spectrometry imaging and machine learning
VĂĄclav Krupička, Florent GrĂ©lard, Landry Blanc, Aleksandra Popowich, JosĂ© Luis Lazarte Luna, Nicolas Desbenoit, Julie Arslanoglu, Caroline Tokarski
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Layer-by-layer characterization of modern and historic paintings is essential for understanding how an artwork was created and how it has changed over time. This information can reveal historical or societal insights, inform attribution and classification, and support preservation efforts. The determination of the identity, structure, and composition of art material remains challenging due to the complex, multilayered nature of paintings. These structures often contain mixtures of organic and inorganic components, with unknown in situ chemical interactions, that create cross-linked and chemically modified molecular networks and assemblies. In this work, we have developed a method with high chemical specificity to identify and map organic and inorganic components in modern and historic multilayered paint systems. Our approach achieves an unprecedented level of molecular detail using a single technique. In addition, we have designed the method for automated composition assignment of individual layer through high-resolution matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) and a dedicated composition prediction model.
GPT-4o mini: Non-social science research article
Light-driven toluene ammoxidation via mixture photocatalyst of halide perovskite Cs 3 Bi 2 Br 9 and TiO 2
Tong Xia, Qi Wang, K. M. Liew, Flemming Besenbacher, Yi-Tao Dai
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Benzonitrile is vital for the production of rubbers, pharmaceuticals, and dyes. Traditional benzonitrile synthesis via toluene ammoxidation requires high temperatures (≄350°C), leading to high energy consumption. Here, we demonstrate a photocatalytic route for benzonitrile synthesis under milder conditions (100° to 120°C, 1 to 4 bar, blue light irradiation). Using ammonia, dioxygen, and toluene as precursors, gram-scale benzonitrile (1.751 grams) was produced over a mixture photocatalyst [lead-free halide perovskite cesium bismuth bromide (Cs 3 Bi 2 Br 9 ) + titanium dioxide], demonstrating satisfactory selectivity (85 to 90%) and a linear yield rate of 600 ÎŒmol hour −1 . The photocatalyst exhibited excellent quantum efficiencies (up to 40%) and maintained stability over a 30-hour test period. Mechanism studies revealed that, in the presence of an interfacial effect, the perovskite phase primarily activated benzyl carbon (sp 3 )–hydrogen bonds, while titanium dioxide facilitated the oxidation of alcohol intermediate to aldehydes. These benzaldehydes were subsequently converted to benzonitriles via ammoxidation, predominantly catalyzed by Cs 3 Bi 2 Br 9 through aldimines (RCH═NH).
GPT-4o mini: Non-social science research article
High-voltage Na 3 V 2 (PO 4 ) 2 F 3 cathodes enabled by low-valence metal cations
Yutian Chen, Deyan Luan, Hao Zhao, Siyang Meng, Jianwei Li, Zhiming Liu, Xiong Wen (David) Lou
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Na 3 V 2 (PO 4 ) 2 F 3 (NVPF) is regarded as a highly promising cathode material for sodium-ion batteries. Here, we propose a general strategy for modulating the local electronic structure of vanadium (V) by introducing low-valence metal ions, such as Cu 2+ , Cd 2+ , and Ag + . This approach microscopically shortens the length of the suspended V─F2 bonds within the NVPF framework, effectively mitigating the loss of fluorine and the formation of undesirable Na 3 V 2 (PO 4 ) 3 (NVP). Consequently, this intervention indirectly enhances the overall working voltage and energy density of the battery. Density functional theory (DFT) is used to verify and deeply investigate the intrinsic mechanism of fluorine stabilization in the NVPF system. The experimental results show that NVPF with 2.5% of doped Cu exhibits a higher mid-working voltage (3.69 volts), higher energy density (447.7 watt-hours per kilogram), and excellent cycling stability (83.3% capacity retention at 20 C after 10,000 cycles).
GPT-4o mini: Non-social science research article
Harnessing semen-derived exosomes for noninvasive fundus drug delivery: A paradigm for exosome-based ocular fundus therapeutics
Jiansong Zhao, Tian Yin, Yaxin Deng, Hongbing Liu, Mingli Wei, Chenxiao Chu, Xinxin Liang, Xiaoshuang Bi, Haibing He, Jingxin Gou, Xing Tang, Yu Zhang
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Exosomes, despite their promise as drug carriers for crossing biological barriers, remain underexplored for noninvasive posterior ocular delivery. Here, we demonstrate that semen-derived exosomes (SEVs) penetrate ocular barriers effectively, owing to their epidermal growth factor expression, which mediates reversible tight-junction disruption. SEVs reach the posterior segment via dual corneal and conjunctival routes. Using this, we engineered FA-SEVs@CMG eye drops, where SEVs are modified with folic acid (FA) and loaded with a nanozyme system (CMG) composed of carbon dots, manganese dioxide, and glucose oxidase. This eye drop leverages SEVs’ excellent penetration ability and FA’s targeting effect to enhance drug delivery to retinoblastoma (RB) cells. Internalized CMG induces intense oxidative stress, disrupts the autophagy-apoptosis balance, and triggers RB cell self-destruction. In vivo, FA-SEVs@CMG effectively inhibits RB growth while preserving retinal function. This work establishes the first SEV-based platform for noninvasive posterior segment delivery, offering a transformative strategy for treating posterior ocular diseases.
GPT-4o mini: Non-social science research article
The human amygdala in threat learning and extinction
Sjoerd Meijer, Eleonora Carpino, Benjamin R. Kop, Jesse Lam, Lycia D. de Voogd, Karin Roelofs, Lennart Verhagen
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Here, we resolve the long-standing but unconfirmed hypothesis that the human amygdala is essential for rapidly acquiring cued-conditioned threat responses. We provide causal evidence for the amygdala’s contribution to forming threat memories that are resistant to extinction. Using transcranial ultrasound stimulation (TUS), a noninvasive technique that modulates deep brain structures with high spatial and temporal precision, we targeted the bilateral amygdala during Pavlovian threat conditioning in healthy adults. Linear mixed-effects models and computational modeling of trial-level skin conductance responses revealed that amygdala-TUS (experiment I, n  = 25), but not hippocampus-TUS (experiment II, n  = 25), selectively slowed initial threat acquisition, augmented subsequent extinction, and modulated declarative memory of retrospective threat probability. These findings demonstrate that the human amygdala drives an emotional learning state—learning fast, forgetting slow. Our study shows the potential of TUS for targeted neuromodulation of human deep brain structures implicated in conditions such as posttraumatic stress disorder, where pathological threat memories persist despite therapy.
GPT-4o mini: Non-social science research article
Clinically relevant stereochemistry reprograms amyloid proteome for aggregation cross-talk–conferred neuroprotection
Jiaxin Zhou, Juan Liu, Xilin Liu, Lixia Ren, Zhilin Yu, Zhen Zheng, Gongyu Li
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The stereochemical diversity of AÎČ42 in the brains of patients with Alzheimer’s disease (AD) is a clinically recognized but poorly understood phenomenon. A critical gap in our knowledge is how the complex mixture of these stereoisomers collectively influences the aggregation pathway and neurotoxicity of AÎČ42 at the molecular level. Drawing from stereoproteome data from AD patient brain tissues and previous studies, we engineered a panel of stereoisomers to more simply simulate the stereochemical diversity of the AD marker AÎČ42. We found that the coexistence of L-AÎČ42 with specific D-isomers initiates a potent antagonistic effect, suppressing the formation of toxic fibrils. This stereochemically driven antagonism conferred notable neuroprotection, suggesting an endogenous protective mechanism. This proof-of-concept work elucidates at the molecular level that by regulating the stereochemical composition of AÎČ, its inherent cellular protective antagonistic effect can be activated, providing unprecedented molecular basis for understanding the disease mechanism and subsequent possible clinical research.
GPT-4o mini: Non-social science research article
A small-molecule stabilizer of the calpastatin–calpain-2 complex restores mitochondrial function and mitigates neurodegeneration
Di Hu, Xiaoyan Sun, Yutong Shang, Kathleen Lundberg, Drew J. Adams, Xin Qi
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Mitochondrial dysfunction and dysregulated proteolysis drive Huntington’s disease (HD), tauopathy, and related neurodegenerative disorders. Calpain-2, a Ca 2+ -activated protease restrained by calpastatin (CAST), is pathologically overactivated, yet no therapies directly target this axis. We identify A36, a brain-penetrant small molecule derived from CHIR99021 that selectively stabilizes the CAST–calpain-2 complex without inhibiting GSK3. A36 acts as a protein-protein interaction stabilizer, enhancing CAST–calpain-2 binding, preventing CAST degradation, and thereby limiting calpain-2 activation and mitochondrial damage. In patients with HD induced pluripotent stem cell–derived neurons and mutant mouse striatal neurons, A36 normalized mitochondrial morphology and membrane potential, reduced oxidative stress, and improved survival. In vivo, A36 displayed favorable pharmacokinetics and central nervous system exposure; treatment reduced striatal neurodegeneration, mutant huntingtin aggregation, and motor deficits in HD R6/2 mice, and lowered phosphorylated tau, neuroinflammation, and cognitive decline in tauopathy PS19 mice. These findings establish pharmacological stabilization of CAST–calpain-2 as a therapeutic strategy and position A36 as a mechanism-selective modulator with broad neurodegenerative disease potential.
GPT-4o mini: Non-social science research article
Quantifying urban and landfill methane emissions in the United States using TROPOMI satellite data
Xiaolin Wang, Daniel J. Jacob, Hannah Nesser, Nicholas Balasus, Lucas A. Estrada, Melissa P. Sulprizio, Daniel H. Cusworth, Tia R. Scarpelli, Zichong Chen, James D. East, Daniel J. Varon
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Urban areas are major sources of population-driven methane with high potential for mitigation, but emission quantification and sectoral attribution remain uncertain. Using satellite observations and a high-resolution (12 kilometers by 12 kilometers) atmospheric inversion framework, we find that emissions from 12 major US urban areas are 80% higher than the US Environmental Protection Agency Greenhouse Gas Inventory (EPA GHGI), with up to four times higher emissions in Houston but 32 to 37% lower emissions in Los Angeles and Cincinnati. Landfills are the principal cause of inventory underestimates, with city-level management practices driving large variations in per capita emissions. Examination of individual landfills with gas collection systems shows gas collection efficiencies averaging 38% (range: 5 to 90%), much lower than their reported average of 70% (range: 40 to 87%). An exception is Los Angeles, where we find landfill gas collection averaging 85%, suggesting large urban methane mitigation potential through improved landfill management.
GPT-4o mini: Non-social science research article
Unraveling branch point–driven SR45a splicing dynamics in heat stress for plant adaptation
Wei-Bo Xu, Meng Wang, Xue-Han Zhang, Qian-Huan Guo, Peng Liu, Chang-Ai Wu, Guo-Dong Yang, Jin-Guang Huang, Shi-Zhong Zhang, Cheng-Chao Zheng, Kang Yan
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Heat stress impairs plant development by disrupting essential molecular processes. Alternative splicing (AS) is emerging as a key regulatory mechanism in heat responses, yet how stress-responsive AS is fine-tuned within core splicing regulators remains underexplored. Here, we uncover a heat-activated, autoregulatory splicing switch in the serine/arginine-rich factor SR45a, critically dependent on intron 4. Using an intron 4–based luciferase reporter, we show that heat enhances intron removal, promoting the full-length isoform over truncated variants. This switch relies on branch point (BP) recognition, with SR45a and cap-binding protein 20 (CBP20) coordinating BP-dependent splicing under stress. Overexpression of either protein enhances thermotolerance by stabilizing AS dynamics. HSFA2 directly activates SR45a transcription, linking transcriptional and splicing control. Notably, intron 4–mediated splicing is conserved in both maize and wheat, suggesting its potential as a portable regulatory module in crops. Our study establishes a stress-inducible SR45a-CBP20-BP axis and introduces an intron-based strategy for engineering thermotolerance via precision splicing control.
GPT-4o mini: Non-social science research article
MUTE drives asymmetric divisions to form stomatal subsidiary cells in Crassulaceae succulents
Xin Cheng, Heike Lindner, Lidia Hoffmann, Antonio Aristides Pereira Gomes Filho, Paola Ruiz Duarte, Susanna F. Boxall, Yiğit Berkay GĂŒndoğmuƟ, Jessica H. Pritchard, Sam Haldenby, Matthew Gemmell, Alistair Darby, Miro LĂ€derach, James Hartwell, Michael T. Raissig
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Among the evolutionary innovations of many succulents is a photosynthetic lifestyle, where stomatal gas exchange is decoupled from light-dependent carbon fixation. Many Crassulaceae leaf succulents form a stomatal morphotype consisting of kidney-shaped guard cells surrounded by three anisocytic subsidiary cells (SCs), whose function and development remained unknown. Here, we established KalanchoĂ« laxiflora as a developmental model. Potassium staining suggested SCs to shuttle osmolytes and support turgor-driven stomatal movements. Gene editing, reporter lines, protein overexpression, and RNA sequencing implicated the stomatal transcription factor MUTE in facilitating the additional rounds of asymmetric divisions required to form SCs in succulents. This is opposite to the role of MUTE in Arabidopsis thaliana , where it stops rather than induces asymmetric divisions but reminiscent of MUTE ’s subsidiary cell–related function in grasses. Our work firmly establishes K. laxiflora as a model for succulent development and deciphers an intricate genetic mechanism that generates innovative stomatal morphology in Crassulaceae succulents.
GPT-4o mini: Non-social science research article
A radio oval above Earth’s auroral oval
Siyuan Wu, Daniel K. Whiter, Laurent Lamy, Ulrich Taubenschuss, Philippe Zarka, Brieuc Collet, Xiangyu Wang, Georg Fischer, Hao Ning, Yao Chen, Mengmeng Wang, Shengyi Ye, Zhonghua Yao, William S. Kurth, Xiaoli Luan
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Auroral kilometric radiation (AKR), Earth’s strongest radio emission, has long been associated with discrete auroras and electrons near a few kilo–electron volt (keV) range. However, auroras also occur in diffuse forms with broader electron energies, raising the question of why AKR has not been observed above diffuse auroras or linked to electrons outside the kilo–electron volt population. Comprehensive AKR source distributions have remained elusive because of observational limitations, and their local-time coverage remains largely unknown. Using spacecraft measurements, we identify a “radio oval” above the optical auroral oval, spanning the full local-time range, where AKR is emitted over both discrete and diffuse auroras. The AKR source electrons display diverse precipitation features, including monoenergetic (peak flux at 3.82 kilo–electron volts), broadband (1.34 kilo–electron volts), low-energy (0.47 kilo–electron volts), and diffuse types (>1 kilo–electron volt). These results reveal that the cyclotron maser instability—the mechanism driving AKR—can arise in diverse plasma environments, broadening our understanding of both AKR generation and auroral complexity.
GPT-4o mini: Non-social science research article
Human NLRP3 inflammasome activation leads to formation of condensate at the microtubule organizing center
Jue Wang, Man Wu, Le Xiao, Gang Du, Muyuan Chen, Venkat G. Magupalli, Peter D. Dahlberg, Hao Wu, Grant J. Jensen
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The NLRP3 inflammasome is a multiprotein molecular machine that drives inflammatory responses in innate immunity. Although its dysregulation is implicated in numerous human diseases, its structural organization in cells remains poorly understood. Here, we used precise fluorescence-guided cryo–focused ion beam (cryo-FIB) milling and cryo–electron tomography (cryo-ET) to visualize NLRP3 inflammasomes in situ within human macrophages at various stages of activation. After priming and activation, we observed expansion and dispersion of Golgi cisternae, along with the emergence of 50-nanometer NLRP3-associated vesicles, which likely transport NLRP3 to the MTOC. Dense NLRP3-containing condensates then formed in and around the MTOC. In later stages, the condensates solidified, coincident with widespread mitochondrial damage, autophagy, and pyroptotic cell death.
GPT-4o mini: Non-social science research article
PRISM: A unified platform for phage isolation and characterization from single-droplet microenvironments
Han Zhang, Justin Boeckman, Rohit Gupte, Ashlee Prejean, Jonathan Miller, Alexandra Rodier, Paul de Figueiredo, Mei Liu, Jason Gill, Arum Han
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The exploration of bacteriophage diversity remains constrained by reliance on conventional plaque assays, which bias discovery toward phages that form visible plaques. We present PRISM (Phage Recovery and Investigation in Single-droplet Microenvironments), a droplet microfluidics–based, plating-independent platform for high-throughput isolation, quantification, and characterization of bacteriophages. By encapsulating phage-host interactions in water-in-oil microdroplets at single-phage resolution and coupling them with fluorescence-based detection and sorting, we demonstrate PRISM’s capabilities across several key applications: (i) recovery of both “plaquing” and “nonplaquing” Salmonella phages from environmental samples, where nonplaquing phages were missed by conventional approaches; (ii) accurate titering of poor-plaquing phages, such as Rhodococcus phage ReqiDocB7; and (iii) plating-independent determination of phage resistance and lysogeny frequency, with results closely matching conventional estimates. This highlights PRISM’s enhanced resolution and accuracy, as well as its ability to detect nonplaquing or slow-replicating phages, underscoring the platform’s power to access viral populations overlooked using conventional methods.
GPT-4o mini: Non-social science research article
Altered morphology and diffusivity of water confined in MXenes: Machine learning–accelerated computations combined with experiments
Jiawei Tang, Weiwei Sun, Chaofan Chen, Lars Bannenberg, Xuehang Wang, Tingwei Zhu, Litao Sun, Jinlan Wang, Guobing Ying, Yu Xie, Naresh C. Osti, Alexander I. Kolesnikov, Eugene Mamontov, Madhusudan Tyagi, Jingsong Huang, Paul R. C. Kent
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Nanoconfined water exhibits unique properties compared to bulk water due to limited quantities, frustrated hydrogen bonding, and surface interactions, which are fundamental for energy storage and transport applications. We integrate machine learning–accelerated ab initio molecular dynamics with x-ray diffraction (XRD) and inelastic neutron scattering (INS) to systematically analyze the thermodynamic and dynamic behavior of water confined between functionalized (-F, -O, and -OH) two-dimensional (2D) Ti 3 C 2 T x MXene layers. As water intercalates between layers, the interlayer spacing exhibits layer-dependent staging characteristics. The water polarization can be flipped by the count and morphology of intercalated molecules interacting with MXene surface groups, resulting in varying electrostatic potential profiles. On the basis of interfacial electrostatic potential, hydrogen bond lifetime, and molecular orientation, we establish a linear combination of exponential model describing water diffusivity. These computational insights align well with experimental x-ray and neutron measurements, suggesting strategies for tuning water morphology and transport by tailoring MXene surface chemistry and water content for electrochemical energy storage and nanofluidic applications.
GPT-4o mini: Non-social science research article
Nanoscale coherent chemical fluctuations driving superior thermoelectric performance in vacancy-tailored ductile AgCu(S,Se,Te)
Yuxiang Zhan, Kunpeng Zhao, Hexige Wuliji, Yifan Yuan, Xiang Liu, Tian-Ran Wei, Ting Zhang, Min Zhu, Xun Shi
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(Ag,Cu) 2 (S,Se,Te) alloys, as rare examples of p-type inorganic ductile semiconductors, have emerged as promising candidates for wearable electronics because of their mechanical flexibility and favorable processability. However, the multicomponent nature of this system introduces diverse microstructures and intricate defect landscapes that complicate the optimization of thermoelectric performance. Here, we reveal the presence of compositionally inhomogeneous yet structurally coherent nanoscale chemical fluctuations within this alloy system. These fluctuations, together with abundant dislocations and twin boundaries, serve as efficient phonon scattering centers to suppress the lattice thermal conductivity to approach glass-like levels. Concurrently, tuning the cation ratios and vacancies allows for precise control over the carrier concentration and thereby leads to enhanced power factors. Last, a peak zT of 0.98 at 360 kelvins is achieved, marking a record for Ag-based ductile thermoelectrics. This study highlights the essential role of chemical fluctuations in modulating phonon and charge transports and offers valuable insight into the microstructure-defect–property interplay in ductile materials.
GPT-4o mini: Non-social science research article
Sequential formation of Drosophila circuit asymmetry via prolonged structural plasticity
Johann W. Markovitsch, Daniel Mitić, Alisa del Pilar JimĂ©nez GarcĂ­a, Zane Alsberga, Sarah Kainz, Rashmit Kaur, Thomas Hummel
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Structural and functional differences between brain hemispheres are a common feature of animal nervous systems with reduced bilateral asymmetry often linked to impaired cognitive performance. How neuronal left-right asymmetry is initiated and integrated into a bilaterally symmetrical ground pattern is poorly understood. Here, we show that the directional asymmetry of a Drosophila central brain circuit originates from axonal interactions of two types of bilateral pioneer neurons. Subsequent recruitment of neighboring neurons into the asymmetric neuropil primordium results in hemisphere-specific microcircuits. Circuit lateralization requires dynamic expression of the cell adhesion molecule Fasciclin 2 to maintain structural plasticity in axonal remodeling. Reduced circuit asymmetry following cell type–specific Fasciclin 2 manipulation affects adult brain function. These results reveal an unexpected degree of developmental plasticity of late-born Drosophila neurons in the formation of a circuit node via the lateralized recruitment of symmetric circuit components.
GPT-4o mini: Non-social science research article
Comparative proteomic profiling of receptor kinase signaling reveals key trafficking components enforcing plant stomatal development
Pengfei Bai, Minh Huy Vu, Chiaki Komatsu, Ophelia Papoulas, Kazuo Ebine, Akira Nozawa, Tatsuya Sawasaki, Takashi Ueda, Edward M. Marcotte, Keiko U. Torii
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Receptor kinases are pivotal for growth, development, and environmental response of plants. Yet, their regulatory mechanisms and spatial dynamics remain underexplored. The ERECTA-family receptor kinases coordinate diverse developmental processes, including stomatal development. To understand the proteomic landscape of the ERECTA-mediated signaling pathways, we report comparative analyses of the ERECTA interactome and proximitome by epitope-tagged affinity-purification (ET-AP) and TurboID-based proximity labeling (TbID-PL) mass spectrometry, respectively. While ET-AP recovered receptor complex components (e.g., TOO MANY MOUTHS), TbID-PL effectively captured transient associations with the components of endosomal trafficking, i.e., clathrin-mediated endocytosis machinery. We further identify that specific subfamily members of phosphatidylinositol-binding clathrin assembly proteins (PICALMs) interact with and synergistically regulate ERECTA internalization. Mutations in PICALMs impair ERECTA endocytosis and lead to excessive stomatal clustering by dampening the downstream signaling output. Together, we provide a proteomic atlas of the ERECTA signaling network and demonstrate that timely removal of receptor kinase by the endocytosis machinery is essential for active signal transduction enforcing stomatal patterning.
GPT-4o mini: Non-social science research article
Primary human intestinal organoids model enteric infection of monkeypox virus and enable scalable drug discovery
Pengfei Li, Xin Wang, Jiangrong Zhou, Yang Yao, Yining Wang, Guige Xu, Rick Schraauwen, Ana Maria Gonçalves da Silva, Charlotte de Henau, Roberto Incitti, Dewy Mae Offermans, Annemarie C. de Vries, Denis E. Kainov, Intikhab Alam, Karine Raymond, Amaro Nunes Duarte-Neto, Marcel J. C. Bijvelds, Qiuwei Pan
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Monkeypox virus (MPXV) infection-associated intestinal manifestations, including diarrhea and proctitis, have been frequently reported during mpox outbreaks. Here, we present clinical evidence that MPXV can directly infect the human intestine and induce lesions. Intriguingly, primary organoids cultured from human ileum and rectum support productive infections by MPXV strains from clade IIb, Ia, and Ib, which are responsible for the 2022–2023 global outbreak and concurrent outbreaks in Africa. Given that primary intestinal organoids can be rapidly expanded at large scale, we were able to screen a broad-spectrum antiviral drug library. We identified 12 leading candidates of safe-in-human agents, including clinically used drugs such as clofarabine. We extensively validated the anti-MPXV activity of clofarabine in human intestinal and skin organoids, consistently demonstrating potent antiviral activity against clade Ia, Ib, and IIb strains. These findings are important for better understanding the clinical manifestations of mpox. Primary intestinal organoid-based infection models and the established antiviral drug discovery pipeline bear major implications for responding to the current mpox global health emergency and sustaining epidemic poxvirus preparedness.
GPT-4o mini: Non-social science research article
The GAPLESS-OsCASP complex mediates Casparian strip formation for proper localization and abundance of endodermal proteins in rice
Baolei Zhang, Xiaoqian Sun, Chunmei Meng, Huawei Zheng, Jinge Liu, Ruiting Liu, Tianyi Tan, Boning Xin, Xingxiang Chen, Jixing Xia
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Casparian strip (CS) seals the extracellular space between neighboring endodermal cells and helps plants maintain nutrient homeostasis. However, little is known about CS formation and function in rice. Here, we demonstrate that GAPLESS1/2/3, along with OsCASP1/2/3/5, redundantly regulate endodermal CS formation by forming an interdependent complex in rice. Triple knockout of GAPLESSs or quadruple knockout of OsCASPs resulted in delayed CS initiation, disrupted CS-CSD adhesion, and disordered CS at the endodermis. In these mutants, GAPLESS1, OsCASP1, and SCHENGEN3a (OsSGN3a) uniformly localized to the plasma membrane or cytoplasm in root tips, with lower abundance in endodermal cells. Furthermore, CS defects in these mutants triggered strong suberization on endodermal cells via OsSGN3a/b-mediated signaling, thereby restricting and reducing the accumulation of the Si transporter Lsi1 exclusively to nonsuberized cells. Like Oscasp1 , the triple gapless mutant exhibited large ionomic changes in shoots. Therefore, the GAPLESS-OsCASP complex functions in CS formation, with its roles in regulating ion homeostasis and protein localization and abundance.
GPT-4o mini: Non-social science research article
Chiral nonlinear polaritonics with van der Waals metasurfaces
Connor Heimig, Alexander A. Antonov, Dmytro Gryb, Thomas Possmayer, Thomas Weber, Michael Hirler, Jonas Biechteler, Luca Sortino, Leonardo de S. Menezes, Stefan A. Maier, Maxim V. Gorkunov, Yuri Kivshar, Andreas Tittl
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Chiral optical cavities are crucial for the development of nonequilibrium quantum materials by discriminating and selectively coupling to light of a specific circular polarization, but fundamentally cannot be realized with conventional mirror cavities. Here, we demonstrate this unique functionality by developing a monolithic transition metal dichalcogenide (TMDC) metasurface with broken out-of-plane symmetry, allowing for the selective formation of self-hybridized chiral exciton-polaritons. Our metasurface maintains maximal chirality for oblique incidence up to 20°, thereby outperforming all previously known designs. Moreover, we study the chiral strong-coupling regime in nonlinear experiments and reveal polaritonic signatures in chiral third-harmonic generation. Our results position maximally chiral van der Waals (vdW) metasurfaces as a versatile platform for tunable chiral polaritonics with applications in nonreciprocal photonic devices and valleytronics.
GPT-4o mini: Non-social science research article
Role of Atlantic multidecadal variability in modulating Arctic sea ice loss and wetting
Ziyi Cai, Qinglong You, James A. Screen, Hans W. Chen, Ruonan Zhang, Zhiyan Zuo, Deliang Chen, Judah Cohen, Shichang Kang, Weiming Ma, Sergey K. Gulev, G. W. K. Moore, Renhe Zhang
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Arctic precipitation has increased in recent decades (hereafter, Arctic wetting), but the drivers remain uncertain. Using observations, reanalyses, and single-model initial-condition large ensembles (SMILEs), we show that enhanced evaporation due to sea ice loss has been the primary driver of Arctic wetting during 1979–2024, especially in the Atlantic sector. However, the externally forced component in most SMILEs explains only ~69% of sea ice loss and 75% of wetting in the observations and reanalyses. Further analysis reveals that the observed transition of one of the Northern Hemisphere’s interdecadal internal variability—Atlantic multidecadal variability (AMV)—from a negative to a positive phase substantially enhanced Arctic sea ice loss, thereby accelerating wetting by about 31%. Under SSP3-7.0, if the AMV switches phase in the near future from the current +1 to a −1 standard deviation anomaly, then the rates of Arctic sea ice loss and wetting would slow by nearly 29 and 33%, respectively, relative to the externally forced response alone. These results underscore the pivotal role of AMV in modulating Arctic sea ice loss and wetting and highlight the need to account for AMV phase changes in near-term Arctic climate projections.
GPT-4o mini: Non-social science research article
Functional and structural basis of a hypermorphic TRPC3 variant
Briar Bell, Angela M. Jaramillo-Granada, Luis O. Romero, Irene A. Gutierrez, Venkata K.P.S. Mallampalli, Guizhen Fan, Sameer Varma, Matthew L. Baker, Irina I. Serysheva, Valeria VĂĄsquez, Julio F. Cordero-Morales
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Cerebellar ataxias are characterized by impaired motor coordination resulting from neuronal dysfunction within the cerebellum. The mechanisms underlying this pathology and its cerebellar-specific neurodegeneration remain unknown. We uncover how a gain-of-function canonical transient receptor potential member 3 (TRPC3) mutation, coupled with a cerebellum-specific isoform, stabilizes the channel’s open state, resists the leading inhibitor Pyr3, and drives calcium-dependent cell death. Restoring calcium homeostasis by expressing a Purkinje cell calcium pump improves cell viability. Transgenic expression of the TRPC3 hypermorphic variant in Caenorhabditis elegans induces neurodegeneration, confirming its pathogenicity across species. Cryo–electron microscopy and molecular simulations reveal the structural basis for the stabilization of the cerebellar-specific TRPC3 variant in its open state and uncover a druggable allosteric inhibitory binding site. These findings provide an explanation for the vulnerability of cerebellar neurons in TRPC3-associated ataxias and highlight a site for therapeutic intervention.
GPT-4o mini: Non-social science research article
Targeted intracellular oral RNA delivery through tea polyphenol nanovesicle to outer membrane vesicle transfer for colitis treatment
Taisong Fang, Songbai Liu
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Efficient oral delivery of RNA to the target site is a long-standing issue for nucleic acid–based therapy. Herein, we adopted a vesicle-to-vesicle transfer strategy and established an efficient approach to encapsulate and stabilize RNA for targeted oral delivery. The amphiphilic specifically acylated epigallocatechin directly performed encapsulation of RNA and generated nanovesicles in high efficiency without assistance of additional materials. The RNA encapsulated in the nanovesicles was efficiently transferred to outer membrane vesicles (OMVs) derived from Escherichia coli Nissle 1917 probiotic through membrane fusion with simple operation. The derived hybrid vesicles (HVs) were further anchored with bilirubin and Lys-Asp-Glu-Leu grafted hyaluronic acid (HA-BR-KDEL) ligand for sequential cellular and intracellular targeting to the endoplasmic reticulum of inflammatory cells in inflamed intestinal tract. Oral delivery of HVs@HA-BR-KDEL notably alleviated colitis symptoms in mice and contributed to the restoration of intestinal homeostasis. The tea polyphenol hybrid OMV strategy holds great promise for oral gene-mediated treatment.
GPT-4o mini: Non-social science research article
CLOCK-catalyzed histone H3K37 glutarylation suppresses H3K36 trimethylation pathways in glioblastoma
Yu Wang, Runxin Zhou, Xiao Zeng, Dingyuan Guo, Nan Li, Shuangli Li, Xu Zhang, Mingxuan Shi, Li Jiang, Mingzhu Fan, Shan Feng, Lili He, Anbing Shi, Ke Liu, Yusong R. Guo, Lichun He, Mingchang Li, Yugang Wang
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Circadian CLOCK (circadian locomotor output cycles kaput) can mediate chromatin remodeling events implicated in gene transcription. The acetyltransferase roles of CLOCK are well studied, but CLOCK-mediated chromatin remodeling events are not well understood. We report that CLOCK can use glutaryl–coenzyme A to catalyze glutarylation at histone H3 Lys 37 (H3K37glut). H3K37glut is undocumented. The glutaryl moiety of H3K37glut can be pulled by its neighboring H3H39 and H3R40 residues via electrostatic interactions and bent over the pyrrolidine ring of the neighboring H3P38 residue, forming a conformation to block SETD2 binding to the N-terminal tail of histone H3. It reduces SETD2-catalyzed H3K36 trimethylation (H3K36me3) and the H3K36me3-regulated downstream pathways in cells. In glioblastoma, both CLOCK protein and CLOCK-mediated H3K37glut are abnormally up-regulated. H3K37glut significantly correlates with suppressed H3K36me3 level in human glioblastoma tissues, tumor progression, and survival of patients with glioblastoma. This study expands the repertoire of histone modification and diversifies the mechanisms underlying CLOCK-implicated chromatin dynamics. It also unearths an undocumented mechanistic link between dysregulated circadian CLOCK and decreased H3K36me3 pathways in glioblastoma.
GPT-4o mini: Non-social science research article
A synergistic interaction between PRMT5 and LSD1 inhibitors in AML
Nesteene Joy Param, Elisa Arceci, Francesco Fiorentino, Luca Pignata, Denis Torre, Nayeli Gutiérrez-Trejo, Jia Yi Fong, Pierre-Alexis Goy, Brenda Y. Han, Chiara Lambona, Elisabetta Di Bello, Carola Castiello, Marco Barone, Megan Schwarz, Cheryl Arrowsmith, Koichi Ito, Peggy Scherle, Dave Keng Boon Wee, Steven Ndoye, Tommaso Tabaglio, Anand D. Jeyasekharan, Manikandan Lakshmanan, Roberto Cirilli, Hansjörg Habisch, Tobias Madl, Andrea Mattevi, Sergio Valente, Antonello Mai, Ernesto Guccione
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Acute myeloid leukemia (AML) is a hematopoietic malignancy caused by abnormal proliferation and differentiation of blasts. PRMT5, a methyltransferase that catalyzes symmetric dimethylation of arginine (SDMA) residues, has been implicated in cancer stem cell homeostasis and shown to be a potential therapeutic target in AML. However, given the toxicity of complete PRMT5 inhibition, there is a need to identify effective synergistic therapies. Through a targeted screen of compounds that inhibit key nodes of PRMT5-regulated pathways, we identified a synthetic lethality between inhibition of PRMT5 and LSD1, a lysine demethylase known to affect AML blast differentiation. The two inhibitors broadly reshape the transcriptome of targeted cells and synergize to promote AML differentiation and eventually growth inhibition and apoptosis, in a p53-dependent manner. To leverage this synthetic lethal interaction, we generated new dual compounds to inhibit both enzymes and recapitulated the effects of the drug combination. Our results uncover an unexpected convergence of PRMT5- and LSD1-regulated targets, paving the way for new therapeutic opportunities.
GPT-4o mini: Non-social science research article
Reversible aggregation-redispersion of Cu sites in Cu/CeO 2 catalysts with unlocked hydrogenation activity
Yu Zhang, Ningqiang Zhang, Yiwei Liu, Haofan Lei, Tao Zhou, Wenlong Wu, Wei-Wei Wang, Han Yan, Chao Ma, Ken-ichi Shimizu, Chun-Jiang Jia, Jie Zeng
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For oxide-supported metal catalysts, metal-support interaction (MSI) facilitates metal dispersion at the expense of the metallic character, resulting in a trade-off between active site utilization and intrinsic activity. Here, we used a thermal aging strategy to modulate the MSI in Cu/CeO 2 catalysts, facilitating the formation of metallic Cu sites upon H 2 reduction while maintaining metal dispersion. Systematic experiments confirmed that thermal aging at 800°C lowered the reduction temperature and increased the reduction degree of Cu sites. Microscopy evidenced few-atom-layered Cu nanoclusters before and after H 2 reduction, whereas in situ spectroscopy revealed metallic Cu nanoparticles under H 2 atmosphere. This discrepancy indicated a reversible structural evolution from aggregation to redispersion in thermally aged Cu/CeO 2 . The catalytic activity for acetylene semihydrogenation was unlocked on metallic Cu sites, compared to nearly inactive Cu sites in conventional Cu/CeO 2 counterparts. Our work developed an effective strategy for rational modulation of MSI, offering the feasibility to tailor-make active sites for specific reactions.
GPT-4o mini: Non-social science research article
Pathogenic GM-CSF drives functional diversification of inflammatory macrophages in autoimmune arthritis
Hiroki Mukoyama, Yusuke Takeuchi, Daiya Ohara, Yoonha Lee, Hitomi Watanabe, Hiroki Kato, Gen Kondoh, Akio Morinobu, Keiji Hirota
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Autoimmune T cells orchestrate joint inflammation and pain in concert with synovial macrophages; however, the mechanisms governing the development and functional diversification of these macrophages remain unclear. Using a model of T helper 17 cell (T H 17 cell)–mediated autoimmune arthritis, we show that joint-infiltrating Ly6C hi monocytes in response to autoimmune T H 17 cells, rather than resident synovial macrophages, are the primary mediators of disease pathogenesis. Granulocyte-macrophage colony-stimulating factor (GM-CSF), a critical component of the pathogenic circuit driven by arthritogenic T H 17 cells, does not contribute to monocyte recruitment to the synovium but facilitates their subsequent differentiation into functionally distinct synovial macrophage subsets, thereby amplifying joint inflammation. Single-cell RNA sequencing identified two GM-CSF–dependent subpopulations of pathogenic synovial macrophages—Arginase-1 + and epithelial cell adhesion molecule (EpCAM) + clusters—both expressing proinflammatory cytokines and matrix metalloproteinases. Notably, EpCAM + macrophages uniquely express Ccl17 , a pronociceptive mediator implicated in arthritic pain. Collectively, these findings delineate a GM-CSF–driven program of macrophage diversification that underpins both joint inflammation and pain, implicating this axis in the chronic activation of inflammatory and nociceptive pathways in autoimmune arthritis.
GPT-4o mini: Non-social science research article
GraFT: A robust network-based spatiotemporal analysis of filamentous structures
Isabella Østerlund, Arne Neumann, Zhiming Ma, Yansong Miao, Staffan Persson, Zoran Nikoloski
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The actin cytoskeleton forms a dynamic network composed of filaments that remain flexible when bundled up, leading to complex filamentous structures in plant cells. Understanding the properties of these filamentous structures under different conditions and in different cell types can provide insight into their function. Yet, despite developments in the study of the plant actin cytoskeleton, it remains challenging to segment and identify actin filamentous structures, preventing quantification of their spatiotemporal properties. To address this problem, we devised a network-based approach termed Graph of Filaments over Time (GraFT) to trace and track filamentous structures in cytoskeleton networks extracted from two-dimensional time series imaging data. Our comparative analyses using both synthetic test cases and real-world actin cytoskeleton networks of Arabidopsis thaliana hypocotyls exposed to different treatments demonstrated that GraFT accurately traces and tracks actin filamentous structures. Moreover, GraFT facilitates automated quantification of properties for filamentous structures, providing fine-grained insights of effects of different treatments on the level of individual structures. Therefore, GraFT offers a substantial step toward an automated framework facilitating robust spatiotemporal studies of the plant actin cytoskeleton.
GPT-4o mini: Non-social science research article
Cold atmospheric plasma–engineered nanovaccine with spatiotemporal sequential immunization reprograms antitumor immunity
Shuo Li, Peiyu Wang, Zhenyu Wu, Qianwen Mu, Renwu Zhou, Nina Liu, Yue Xi, Xiaoyu An, Yan Li, Di Sun, Hao Liang, Chenhao Zhang, Qihang Huang, Ziqi Zhuang, Xiaojun Wang, Liqian Zhao, Dingwei Gan, Xiaoyong Wang, Xue Liu, Gang Liu, Chao Liu
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Cancer immunotherapy remains limited by insufficient antigen presentation and immunosuppressive tumor microenvironment. Here, we present a vaccine strategy based on cold atmospheric plasma (CAP)–engineered tumor cell–derived immune reprogramming nanovesicles (CAPTURE) that integrates spatiotemporal sequential immunization to potentiate antitumor immunity. CAPTURE is engineered from tumor cells pretreated with CAP, which up-regulates major histocompatibility complex class I expression via p62-mediated autophagy to promote full-spectrum epitope antigen presentation, and surface-functionalized anti-CD28 (αCD28) on CAPTURE provides costimulatory signals to directly activate T cells through αCD28-CD28, bypassing B7-CTLA-4–mediated T cell inhibition. Under spatiotemporal sequential immunity, CAPTURE exhibits homologous tumor targeting and lymph node accumulation, enhancing antigen presentation for CD8 + T cell activation and tumor immunogenic remodeling. In mouse models, CAPTURE achieved near-complete tumor suppression, driven by amplified cytotoxic T cell responses, increased T cell clonal diversity, and CXCR3-mediated tumor infiltration. This study presents a universal biomimetic nanovaccine strategy that can reshape both T cells’ immunity and tumor cells’ immunogenicity, induce broad-spectrum immune responses to overcome immune evasion, and offer unique insights and innovative technologies for precision cancer immunotherapy.
GPT-4o mini: Non-social science research article
Machine learning–directed massively parallel programmable nucleic acid amplification
Zhi Weng, Wenle Huang, Yi Wu, Xuehao Xiu, Hui Lv, Fei Wang, Xiaolei Zuo, Chunhai Fan, Ping Song
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Dynamic regulation of amplification efficiency is pivotal yet challenging in molecular diagnostics and DNA data storage. Here, we develop a thermodynamics-based approach to achieve continuous and precise modulation of nucleic acid amplification efficiency. By decoupling sequence specificity from hybridization energy regulation via a primer-tag compensation strategy, we demonstrate programmed amplification with high resolution (33 versus 81%). Leveraging 2483 experimental data, we constructed a machine learning model that improved prediction accuracy from R 2 = 0.62 to = 0.86. In DNA data storage, this amplification strategy increases the density for information preview by nearly one order of magnitude and robust file steganography via differential amplification. In clinical validation, our method outperformed uniform amplification in cervical cancer RNA variant analysis, detecting rare RNA fusions and improving detection sensitivity by 100-fold under 10 4 simulated sequencing depth. This programmable technique is anticipated to extend to single-cell sequencing and spatial transcriptomics, offering a powerful tool for molecular diagnostics and synthetic biology.
GPT-4o mini: Non-social science research article
A conserved glycan motif induces broadly reactive functional antibodies against the zoonotic pathogen Streptococcus suis
Yao Shi, Göran Widmalm, Charlotte Sorieul, Thomas J. Roodsant, Jeffrey S. Rush, Natalia Korotkova, Manouk Vrieling, Antonius A. C. Jacobs, Mirlin Spaninks, Ries Grommen, C. Coral Domínguez-Medina, Irene M. Schimmel, Nicole N. van der Wel, Cameron W. Kenner, Christian Heiss, Parastoo Azadi, Li Tan, Jeroen D. C. Codée, Arjan Stegeman, Constance Schultsz, Lindert Benedictus, Nina M. van Sorge
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Streptococcus suis is a largely neglected but emerging bacterial zoonotic pathogen of global concern for animal welfare, antibiotic resistance development, and human health. No effective vaccines are now available. Here, we identified and characterized the function and structure of two cell wall polysaccharide variants in pathogenic S. suis strains using genetic deletion and (heterologous) complementation, lectin staining, glycan composition analysis, and specialized NMR spectroscopy. Both glycan variants were anionic polymers that differed in the presence of glucose in the side chain as a result of allelic variation in a glycosyltransferase gene. Deletion of this variable glycosyltransferase revealed an identical glycan “core” and affected S. suis morphology and lysozyme resistance. Immunization of pigs with this core domain elicited antibodies that recognized antigenically diverse pathogenic S. suis strains and induced complement deposition on encapsulated pathogenic S. suis strains. This study provides valuable insights for developing next-generation glycoconjugate vaccines, whereby a single-glycan target could protect against the emerging zoonotic pathogen S. suis .
Public opinion on police misconduct: Discrimination and information resistance
Kristine Eck, Christoph V. Steinert
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High-profile cases of police violence have given rise to contentious debates, yet scholars know little about why individuals interpret violent police encounters differently. We fielded a survey experiment in Germany designed to probe whether the victim’s identity matters to public opinion ( N = 15,941). Our design approximates the way news events unfold sequentially over time, allowing us to measure whether eventual discriminatory beliefs persist even in the face of mounting evidence. We show that respondents are less likely to consider the actions of the police to constitute misconduct when the victim has an immigrant name compared to a traditionally German name. Discriminatory beliefs remain even when respondents are informed about evidence confirming that misconduct occurred. Our analysis shows that these results are driven by right-wing respondents, with both moderates and extremists exhibiting discriminatory beliefs and a resistance to updating. These findings help illuminate why debates over policing are so intractable.