I checked 6 multidisciplinary journals on Friday, January 23, 2026 using the Crossref API. For the period January 16 to January 22, I found 4 new paper(s) in 4 journal(s).

Nature

GPT-4o mini: Non-social science research article
Predatory aggression evolved through adaptations to noradrenergic circuits
GĂŒniz Göze Eren, Leonard Böger, Marianne Roca, Fumie Hiramatsu, Jun Liu, Luis Alvarez, Desiree L. Goetting, Lewis A. Cockram, Nurit Zorn, Ziduan Han, Misako Okumura, Monika Scholz, James W. Lightfoot
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Behaviours are adaptive traits evolving through natural selection. Crucially, the genetic, molecular and neural modifications that shape behavioural innovations are poorly understood 1 . Here, we identify specialized adaptations linked to the evolution of invertebrate aggression 2 . Using the predatory nematode Pristionchus pacificus , we developed a machine learning model from behavioural tracking data and identified robust behavioural states associated with aggressive episodes. Strikingly, predatory aggression coincides with a rewiring of key circuits across nematode evolution. We find modifications to the noradrenergic pathway, with octopamine promoting aggressive predatory bouts whereas tyramine antagonistically induces passive states. Modulation occurs through the octopamine receptors Ppa-ser-3 and Ppa-ser-6 , and tyramine receptor Ppa-lgc-55 . These localize to sensory neurons whose inhibition diminishes aggressive events. Crucially, this octopaminergic innovation emerged within this predatory lineage, consistent with an ancient divergence in function. Thus, evolutionary adaptations in noradrenergic circuits facilitated the emergence of aggressive behavioural states associated with complex predatory traits.
GPT-4o mini: Non-social science research article
Pyramidal neurons proportionately alter cortical interneuron subtypes
Sherry Jingjing Wu, Min Dai, Shang-Po Yang, Cai McCann, Yanjie Qiu, Vipin Kumar, Giovanni J. Marrero, Jeremiah Tsyporin, Shuhan Huang, David Shin, Jeffrey A. Stogsdill, Daniela J. Di Bella, Qing Xu, Bin Chen, Samouil L. Farhi, Evan Z. Macosko, Fei Chen, Gord Fishell
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The mammalian cerebral cortex comprises a complex neuronal network that maintains a precise balance between excitatory pyramidal neurons and inhibitory interneurons. Accumulating evidence indicates that specific interneuron subtypes form stereotyped microcircuits with distinct pyramidal neuron classes1,2,3. Here we show that pyramidal neurons have an active role in this process by promoting the survival and terminal differentiation of their associated interneuron subtypes. In the wild-type cortex, interneuron subtype abundance mirrors the prevalence of their pyramidal neuron partners. In Fezf2 mutants, which lack L5b pyramidal neurons and are expanded in L6 intratelencephalic neurons, corresponding subtype-specific shifts occur through two distinct mechanisms: somatostatin interneurons adjust their programmed cell death, whereas parvalbumin interneurons switch their subtype identity. Silencing neuronal activity or blocking vesicular release in L5b pyramidal neurons revealed that their communication with interneurons does not require voltage-gated synaptic activity but engages both tetanus toxin-sensitive and tetanus toxin-insensitive pathways. Moreover, a targeted bioinformatic screen for ligand–receptor pairs displaying subtype-specific expression and reduced expression of pyramidal neuron-derived ligand in Fezf2 mutants identified candidate secreted factors and adhesion molecules. These findings reveal distinct, pyramidal neuron-driven mechanisms for sculpting interneuron diversity and integrating them into local cortical circuits.
GPT-4o mini: Non-social science research article
Biological insights into schizophrenia from ancestrally diverse populations
Tim B. Bigdeli, Chris Chatzinakos, Jaroslav Bendl, Peter B. Barr, Sanan Venkatesh, Bryan R. Gorman, Tereza Clarence, Giulio Genovese, Conrad O. Iyegbe, Roseann E. Peterson, Sergios-Orestis Kolokotronis, David Burstein, Jacquelyn L. Meyers, Yuli Li, Sundar Natarajan, Michael O. Francis, Nallakkandi Rajeevan, Kei-Hoi Cheung, character(0), character(0), character(0), Lynn E. DeLisi, Thomas R. Kosten, Hongyu Zhao, Eric Achtyes, Peter F. Buckley, Dolores Malaspina, Douglas Lehrer, Mark H. Rapaport, David L. Braff, Michele T. Pato, Ayman H. Fanous, Carlos N. Pato, character(0), character(0), character(0), Grant D. Huang, Sumitra Muralidhar, J. Michael Gaziano, Saiju Pyarajan, Kiran Girdhar, Donghoon Lee, Gabriel E. Hoffman, Mihaela Aslan, John F. Fullard, Georgios Voloudakis, Philip D. Harvey, Panos Roussos
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Schizophrenia and related psychoses occur in all human populations, with the highest rates of diagnosis among Black individuals and those of mainly African ancestry1. Decades of research have established a highly heritable and polygenic basis for schizophrenia, which is mostly shared across populations2,3,4. However, a recruitment bias towards European cohorts5 has led to discoveries that are poorly generalizable to African populations. This exclusion of the world’s most genetically diverse populations narrows our understanding of disease biology and risks exacerbating health disparities. Here we show that electronic health records linked with genomic data from the Million Veteran Program (MVP)6—a national research programme that looks at the effects of genes, lifestyle, military experiences and exposures on the health and wellness of veterans—enable a comprehensive assessment of schizophrenia genetics in populations of African ancestry in the USA. We identify ancestry-independent associations in African populations and expand the catalogue of implicated regions by more than 100 loci. Through statistical fine-mapping and integrative transcriptomic analyses, we refine disease-associated signals to consensus genes with convergent neurobiological functions. These findings provide a much-needed view of schizophrenia’s genetic architecture in populations of African ancestry, and offer biological insights that both extend previous work and broaden its global relevance.
GPT-4o mini: Non-social science research article
Author Correction: Anthropogenic influences on major tropical cyclone events
Christina M. Patricola-DiRosario, Michael F. Wehner
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GPT-4o mini: Non-social science research article
Ageing promotes microglial accumulation of slow-degrading synaptic proteins
Ian H. Guldner, Viktoria P. Wagner, Patricia Moran-Losada, Sophia M. Shi, Sophia W. Golub, Johannes F. Hevler, Kelly Chen, Barbara T. Meese, Ali Ghoochani, Ernst Pulido, Hamilton Se-Hwee Oh, Yann Le Guen, Nannan Lu, Pui Shuen Wong, Ning-Sum To, Dylan Garceau, Zimin Guo, Jian Luo, Carolyn R. Bertozzi, Emma Lundberg, Monther Abu-Remaileh, Michael Sasner, Andreas Keller, Andrew C. Yang, Tom H. Cheung, Tony Wyss-Coray
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Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with ageing1,2. Here we engineered bioorthogonal tools3 that enabled us to tag the nascent neuronal proteome and study its turnover with ageing, its propensity to aggregate and its interaction with microglia. We show that neuronal protein half-life approximately doubles on average between 4-month-old and 24-month-old mice, with the stability of individual proteins differing among brain regions. Furthermore, we describe the aged neuronal ‘aggregome’, which encompasses 1,726 proteins, nearly half of which show reduced degradation with age. The aggregome includes well-known proteins linked to diseases and numerous proteins previously not associated with neurodegeneration. Notably, we demonstrate that neuronal proteins accumulate in aged microglia, with 54% also displaying reduced degradation and/or aggregation with age. Among these proteins, synaptic proteins are highly enriched, which suggests that there is a cascade of events that emerge from impaired synaptic protein turnover and aggregation to the disposal of these proteins, possibly through microglial engulfment of synapses. These findings reveal the substantial loss of neuronal proteome maintenance with ageing, which could be causal for age-related synapse loss and cognitive decline.
GPT-4o mini: Non-social science research article
Afar fossil shows broad distribution and versatility of Paranthropus
Zeresenay Alemseged, Fred Spoor, Denné Reed, W. Andrew Barr, Denis Geraads, René Bobe, Jonathan G. Wynn
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The Afar depression in northeastern Ethiopia contains a rich palaeontological and archaeological record, which documents 6 million years of human evolution. Abundant faunal evidence links evolutionary patterns with palaeoenvironmental change as a principal underlying force1. Many of the earlier hominin taxa recognized today are found in the Afar, but Paranthropus has been conspicuously absent from the region. Here we report on the discovery, in the Mille-Logya research area, of a partial mandible that we attribute to Paranthropus, dated to between 2.5 and 2.9 million years ago and found in a well-understood chronological and faunal context. The find is among the oldest fossils attributable to Paranthropus and indicates that this genus, from its earliest known appearance, had a greater geographic distribution than previously documented2. Often seen as a dietary specialist feeding on tough food, the range of diverse habitats with which eastern African Paranthropus can now be associated shows that this suggested adaptive niche did not restrict its ability to disperse as widely as species of Australopithecus and early Homo. The discovery of Paranthropus in the Afar emphasizes how little is known about hominin evolution in eastern Africa during the crucial period between 3 and 2.5 million years ago, when this genus and the Homo lineage presumably emerged.
GPT-4o mini: Non-social science research article
Accretion bursts crystallize silicates in a planet-forming disk
Jeong-Eun Lee, Chul-Hwan Kim, Jaeyeong Kim, Seokho Lee, Young-Jun Kim, Seonjae Lee, Giseon Baek, Joel D. Green, Gregory J. Herczeg, Doug Johnstone, Klaus M. Pontoppidan, Yuri Aikawa, Yao-Lun Yang, Logan Francis, Mihwa Jin, Hyerin Jang
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Crystalline silicates form at high temperatures (>900 K) (refs. 1,2). Their presence in comets3,4,5,6 suggests that high-temperature dust processing occurred in the early Solar System and was subsequently transported outwards to comet-forming regions. However, direct evidence for this crystallization and redistribution in Sun-like protostars has remained unknown. By comparing James Webb Space Telescope mid-infrared spectra of the periodically bursting protostar EC 53 (ref. 7), we detect crystalline silicate (forsterite and enstatite) emission features that appear only during the burst. The emergence of these features indicates active crystal formation by thermal annealing in the hot inner disk during the accretion burst. We also detect a nested outflow—a collimated atomic jet enclosed by slower molecular outflows, consistent with magnetohydrodynamic wind models8. This configuration provides a mechanism for the outward transport of freshly crystallized silicates9. To our knowledge, our results provide the first direct observational evidence of in situ silicate crystallization during episodic accretion bursts in a very young star still embedded in its dense envelope. Although we do not directly detect grains transported to the outer disk, the observed trends are consistent with outward redistribution, indicating that both dust processing and transport occur during the earliest and most dynamic stages of star formation.
GPT-4o mini: Non-social science research article
Fibre integrated circuits by a multilayered spiral architecture
Zhen Wang, Ke Chen, Xiang Shi, Qinhao Du, Yulu Ai, Pengzhou Li, Li Yong, Xiao Sun, Ning Wang, Xuemeng Hu, Chen Lu, Chengqiang Tang, Liyuan Wang, Yuanyuan Zheng, Yichi Zhang, Hongyu Guo, Zhaofangzhou Pu, Xiaokun Wang, Yanan Zhang, Haibo Jiang, Yue Liu, Zhihang Tang, Lingsen You, Jue Deng, Renchao Che, Yue Gao, Songlin Zhang, Bingjie Wang, Xuemei Sun, Jiajun Qin, Ya Huang, Li Shen, Junbo Ge, Xiaoyang Zeng, Lin Chen, Peining Chen, Huisheng Peng
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Fibre electronic devices are transforming traditional fibres and garments into new-generation wearables that can actively interact with human bodies and the environment to shape future life1,2,3,4,5. Fibre electronic devices have achieved almost all of the desired functions, such as powering6,7, sensing8,9 and display10,11 functions. However, viable information-processing fibres, which lie at the heart of building intelligent interactive fibre systems similar to any electronic product, remain the missing piece of the puzzle12,13,14,15. Here we fill this gap by creating a fibre integrated circuit (FIC) with unprecedented microdevice density and multimodal processing capacity. The integration density reaches 100,000 transistors per centimetre, which effectively satisfies the requirements for interactive fibre systems. The FICs can not only process digital and analogue signals similar to typical commercial arithmetic chips but also achieve high-recognition-accuracy neural computing similar to that of the state-of-the-art in-memory image processors. The FICs are stable under harsh service conditions that bulky and planar counterparts have difficulty withstanding, such as repeated bending and abrasion for 10,000 cycles, stretching to 30%, twisting at an angle of 180° cm−1 and even crushing by a container truck weighing 15.6 tons. The realization of FICs enables closed-loop systems in a single fibre, without the need for any external rigid and bulky information processors. We demonstrate that this fully flexible fibre system paves the way for the interaction pattern desired in many cutting-edge applications, for example, brain–computer interfaces, smart textiles and virtual-reality wearables. This work presents new insights that can promote the development of fibre devices towards intelligent systems.
GPT-4o mini: Non-social science research article
Editorial Expression of Concern: En passant neurotrophic action of an intermediate axonal target in the developing mammalian CNS
Hao Wang, Marc Tessier-Lavigne
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GPT-4o mini: Non-social science research article
Quantum spin resonance in engineered proteins for multimodal sensing
Gabriel Abrahams, Ana Ć tuhec, Vincent Spreng, Robin Henry, Idris Kempf, Jessica James, Kirill Sechkar, Scott Stacey, Vicente Trelles-Fernandez, Lewis M. Antill, Christiane R. Timmel, Jack J. Miller, Maria Ingaramo, Andrew G. York, Jean-Philippe Tetienne, Harrison Steel
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Sensing technologies that exploit quantum phenomena for measurement are finding increasing applications across materials, physical and biological sciences 1–7 . Until recently, biological candidates for quantum sensors were limited to in vitro systems, had poor sensitivity and were prone to light-induced degradation. These limitations impeded practical biotechnological applications, and high-throughput study that would facilitate their engineering and optimization. We recently developed a class of magneto-sensitive fluorescent proteins including MagLOV, which overcomes many of these challenges 8 . Here we show that through directed evolution, it is possible to engineer these proteins to alter the properties of their response to magnetic fields and radio frequencies. We find that MagLOV exhibits optically detected magnetic resonance in living bacterial cells at room temperature, at sufficiently high signal-to-noise for single-cell detection. These effects are explained through the radical-pair mechanism, which involves the protein backbone and a bound flavin cofactor. Using optically detected magnetic resonance and fluorescence magnetic-field effects, we explore a range of applications, including spatial localization of fluorescence signals using gradient fields (that is, magnetic resonance imaging using a genetically encoded probe), sensing of the molecular microenvironment, multiplexing of bio-imaging and lock-in detection, mitigating typical biological imaging challenges such as light scattering and autofluorescence. Taken together, our results represent a suite of sensing modalities for engineered biological systems, based on and designed around understanding the quantum-mechanical properties of magneto-sensitive fluorescent proteins.
GPT-4o mini: Non-social science research article
Critical role for a high-plasticity cell state in lung cancer
Jason E. Chan, Chun-Hao Pan, Jonathan Rub, Gary Guzman, Klavdija Krause, Emma Brown, Zeda Zhang, Hannah Styers, Griffin Hartmann, Zhuxuan Li, Xueqian Zhuang, Scott W. Lowe, Doron Betel, Yan Yan, Tuomas Tammela
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Plasticity—the ability of cells to undergo phenotypic transitions—drives cancer progression and therapy resistance1,2,3. Recent studies have suggested that plasticity in solid tumours is concentrated in a minority subset of cancer cells4,5,6, yet functional studies examining this high-plasticity cell state (HPCS) in situ are lacking. Here we develop mouse models enabling the detection, longitudinal lineage tracing and ablation of the HPCS in autochthonous lung tumours in vivo. Lineage tracing reveals that the HPCS cells possess a high capacity for cell state transitions, giving rise to both early neoplastic (differentiated) and progressed lung cancer cell states in situ. Longitudinal lineage tracing using secreted luciferases reveals that HPCS-derived cells have a high capacity for growth compared with bulk cancer cells or another cancer cell state with features of differentiated lung epithelium. Ablation of HPCS cells in early neoplasias abrogates benign-to-malignant transition, whereas ablation in established tumours by suicide gene or chimeric antigen receptor (CAR) T cells robustly reduces tumour burden. We further demonstrate that the HPCS gives rise to therapy-resistant cell states, whereas HPCS ablation suppresses resistance to chemotherapy and oncoprotein-targeted therapy. Notably, an HPCS-like state is ubiquitous in regenerating epithelia and in carcinomas of multiple other tissues, revealing a convergence of plasticity programs. Our work establishes the HPCS as a critical hub enabling reciprocal transitions between cancer cell states. Targeting the HPCS in lung cancer and in other carcinomas may suppress cancer progression and eradicate treatment resistance.
GPT-4o mini: Non-social science research article
Editorial Expression of Concern: The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM
J. Sayos, C. Wu, M. Morra, N. Wang, X. Zhang, D. Allen, S. van Schaik, L. Notarangelo, R. Geha, M. G. Roncarolo, H. Oettgen, J. E. De Vries, G. Aversa, C. Terhorst
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GPT-4o mini: Non-social science research article
The transition from monocyte to tissue-resident macrophage requires DHPS
Gustavo E. Carrizo, Pianpian Lin, Seung Hyun Lee, Kevin Shenderov, Camille Blériot, Minsun Cha, Lena Schimmelpfennig, Zhen Shen, Nikki van Teijlingen Bakker, Katarzyna M. Grzes, Beth Kelly, Niloufar Safinia, Kate L. Schole, Yaarub Musa, Gerhard Mittler, Yoh Zen, Edward J. Pearce, Florent Ginhoux, David E. Sanin, Daniel J. Puleston, Erika L. Pearce
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Tissue-resident macrophages (RTMs) form during embryogenesis, self-renew locally, and regulate tissue homeostasis by clearing dead cells and debris 1–6 . During tissue damage, however, bone-marrow-derived monocytes enter tissues and differentiate into RTMs, repairing the tissue and replenishing macrophages in the niche 1 . The universal cell-intrinsic mechanisms that control the monocyte-to-RTM transition and the maintenance of mature RTMs across tissues remain elusive 3 . Here we show that deoxyhypusine synthase (DHPS), an enzyme that mediates spermidine-dependent hypusine modification of translation factor eIF5A 5,7 , is required for RTM differentiation and maintenance. Mice with myeloid cell lack of DHPS ( Dhps -ΔM mice) had a global defect in RTMs across tissues, resulting in persistent but ultimately futile monocyte influx. Transcriptional analyses of DHPS-deficient macrophages indicated a block in their ability to differentiate into mature RTMs, whereas proteomics revealed defects in cell adhesion and signalling pathways. Sequencing of ribosome-engaged transcripts identified a subset of mRNAs involved in cell adhesion and signalling that rely on DHPS for efficient translation. Imaging of DHPS-deficient macrophages in tissues showed differences in morphology and tissue interactions, which were correlated with their failed RTM differentiation. DHPS-deficient macrophages were also defective in critical homeostatic RTM functions including efferocytosis and tissue maintenance. Together, our results demonstrate a cell-intrinsic, tissue-agnostic pathway that drives differentiation of monocyte-derived macrophages into RTMs.
GPT-4o mini: Non-social science research article
Author Correction: An autonomous laboratory for the accelerated synthesis of inorganic materials
Nathan J. Szymanski, Bernardus Rendy, Yuxing Fei, Rishi E. Kumar, Tanjin He, David Milsted, Matthew J. McDermott, Max Gallant, Ekin Dogus Cubuk, Amil Merchant, Haegyeom Kim, Anubhav Jain, Christopher J. Bartel, Kristin Persson, Yan Zeng, Gerbrand Ceder
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GPT-4o mini: Non-social science research article
LetA defines a structurally distinct transporter family
Cristina C. Santarossa, Yupeng Li, Sara Yousef, Hale S. Hasdemir, Carlos C. Rodriguez, Max A. B. Haase, Minkyung Baek, Nicolas Coudray, John G. Pavek, Kimber N. Focke, Annika L. Silverberg, Carmelita Bautista, Johannes T.-H. Yeh, Michael T. Marty, David Baker, Emad Tajkhorshid, Damian C. Ekiert, Gira Bhabha
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Membrane transport proteins translocate diverse cargos, ranging from small sugars to entire proteins, across cellular membranes1,2,3. A few structurally distinct protein families have been described that account for most of the known membrane transport processes4,5,6. However, many membrane proteins with predicted transporter functions remain uncharacterized. Here we determined the structure of Escherichia coli LetAB, a phospholipid transporter involved in outer membrane integrity, and found that LetA adopts a distinct architecture that is structurally and evolutionarily unrelated to known transporter families. LetA localizes to the inner membrane, where it is poised to load lipids into its binding partner, LetB, a mammalian cell entry (MCE) protein that forms an approximately 225 Å long tunnel for lipid transport across the cell envelope. Unexpectedly, the LetA transmembrane domains adopt a fold that is evolutionarily related to the eukaryotic tetraspanin family of membrane proteins, including transmembrane AMPA receptor regulatory proteins (TARPs) and claudins. Through a combination of deep mutational scanning, molecular dynamics simulations, AlphaFold-predicted alternative states and functional studies, we present a model for how the LetA-like family of membrane transporters facilitates the transport of lipids across the bacterial cell envelope.
GPT-4o mini: Non-social science research article
Relatively warm deep-water formation persisted in the Last Glacial Maximum
Jack H. Wharton, Emilia Kozikowska, Lloyd D. Keigwin, Thomas M. Marchitto, Mark A. Maslin, Martin Ziegler, David J. R. Thornalley
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The Last Glacial Maximum (19–23 thousand years ago) was characterized by low greenhouse gas concentrations and continental ice sheets that covered large parts of North America and Europe 1 . Glacial climate was therefore very different, with colder global mean temperatures and an increased Equator-to-pole temperature gradient, probably resulting in stronger westerlies 2 . However, the state of the deep North Atlantic Ocean under these glacial climate forcings remains uncertain 3–6 , particularly owing to the rarity of deep-ocean temperature and salinity constraints. Here we show that the temperature of the glacial deep (>1.5 km) Northwest Atlantic was approximately 0–2 °C (only 1.8 ± 0.5 °C (2 s.e.) colder than today), and, after accounting for the whole-ocean change, seawater ÎŽ 18 O was 0.3 ± 0.1‰ (2 s.e.) higher and can be traced back to the surface subtropics via the subpolar Northeast Atlantic and Nordic Seas. Together, our hydrographic data reveal the thermal and isotopic structure of the deep Northwest Atlantic and suggest sustained production of relatively warm and probably salty North Atlantic Deep Water during the Last Glacial Maximum. Furthermore, our results provide updated constraints for benchmarking Earth system models used to project future climate change.
GPT-4o mini: Non-social science research article
Collective intelligence for AI-assisted chemical synthesis
Haote Li, Sumon Sarkar, Wenxin Lu, Patrick O. Loftus, Tianyin Qiu, Yu Shee, Abbigayle E. Cuomo, John-Paul Webster, H. Ray Kelly, Vidhyadhar Manee, Sanil Sreekumar, Frederic G. Buono, Robert H. Crabtree, Timothy R. Newhouse, Victor S. Batista
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The exponential growth of scientific literature presents an increasingly acute challenge across disciplines. Hundreds of thousands of new chemical reactions are reported annually, yet translating them into actionable experiments becomes an obstacle1,2. Recent applications of large language models (LLMs) have shown promise3,4,5,6, but systems that reliably work for diverse transformations across de novo compounds have remained elusive. Here we introduce MOSAIC (Multiple Optimized Specialists for AI-assisted Chemical Prediction), a computational framework that enables chemists to harness the collective knowledge of millions of reaction protocols. MOSAIC is built upon the Llama-3.1-8B-instruct architecture7, training 2,498 specialized chemical experts within Voronoi-clustered spaces. This approach delivers reproducible and executable experimental protocols with confidence metrics for complex syntheses. With an overall 71% success rate, experimental validation demonstrates the realizations of over 35 novel compounds, spanning pharmaceuticals, materials, agrochemicals, and cosmetics. Notably, MOSAIC also enables the discovery of new reaction methodologies that are absent from the expert’s training, a cornerstone for advancing chemical synthesis. This scalable paradigm of partitioning vast domains into searchable expert regions enables a generalizable strategy for AI-assisted discovery wherever accelerating information growth outpaces efficient knowledge access and application.
GPT-4o mini: Non-social science research article
Common variation in meiosis genes shapes human recombination and aneuploidy
Sara A. Carioscia, Arjun Biddanda, Margaret R. Starostik, Xiaona Tang, Eva R. Hoffmann, Zachary P. Demko, Rajiv C. McCoy
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The leading cause of human pregnancy loss is aneuploidy, often tracing to errors in chromosome segregation during female meiosis 1,2 . Although abnormal crossover recombination is known to confer risk for aneuploidy 3,4 , limited data have hindered understanding of the potential shared genetic basis of these key molecular phenotypes. To address this gap, we performed retrospective analysis of pre-implantation genetic testing data from 139,416 in vitro fertilized embryos from 22,850 sets of biological parents. By tracing transmission of haplotypes, we identified 3,809,412 crossovers, as well as 92,485 aneuploid chromosomes. Counts of crossovers were lower in aneuploid versus euploid embryos, consistent with their role in chromosome pairing and segregation. Our analyses further revealed that a common haplotype spanning the meiotic cohesin SMC1B is associated significantly with both crossover count and maternal meiotic aneuploidy, with evidence supporting a non-coding cis -regulatory mechanism. Transcriptome- and phenome-wide association tests also implicated variation in the synaptonemal complex component C14orf39 and crossover-regulating ubiquitin ligases CCNB1IP1 and RNF212 in meiotic aneuploidy risk. More broadly, variants associated with aneuploidy often showed secondary associations with recombination, and several also exhibited associations with reproductive ageing traits. Our findings highlight the dual role of recombination in generating genetic diversity, while ensuring meiotic fidelity.
GPT-4o mini: Non-social science research article
Temporal tissue dynamics from a spatial snapshot
Jonathan Somer, Shie Mannor, Uri Alon
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Physiological and pathological processes such as inflammation and cancer emerge from interactions between cells over time1. However, methods to follow cell populations over time within the native context of a human tissue are lacking because a biopsy offers only a single snapshot. Here we present one-shot tissue dynamics reconstruction (OSDR), an approach to estimate a dynamical model of cell populations based on a single tissue sample. OSDR uses spatial proteomics to learn how the composition of cellular neighbourhoods influences division rate, providing a dynamical model of cell population change over time. We apply OSDR to human breast cancer data2,3,4, and reconstruct two fixed points of fibroblasts and macrophage interactions5,6. These fixed points correspond to hot and cold fibrosis7, in agreement with co-culture experiments that measured these dynamics directly8. We then use OSDR to discover a pulse-generating excitable circuit of T and B cells in the tumour microenvironment, suggesting temporal flares of anticancer immune responses. Finally, we study longitudinal biopsies from a triple-negative breast cancer clinical trial3, in which OSDR predicts the collapse of the tumour cell population in responders but not in non-responders, based on early-treatment biopsies. OSDR can be applied to a wide range of spatial proteomics assays to enable analysis of tissue dynamics based on patient biopsies.
GPT-4o mini: Non-social science research article
Baby-to-baby strain transmission shapes the developing gut microbiome
Liviana Ricci, Vitor Heidrich, Michal Punčocháƙ, Federica Armanini, Matteo Ciciani, Amir Nabinejad, Farnaz Fazaeli, Elisa Piperni, Charlotte Servais, Federica Pinto, Mireia Valles-Colomer, Francesco Asnicar, Nicola Segata
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The early infant microbiome is largely primed by microbial transmission from the mother between birth and the first few weeks of life1,2,3, but how interpersonal transmission further shapes the developing microbiome in the first year remains unexplored. Here we report a metagenomic survey to model microbiome transmission in the nursery setting among babies attending the first year, their educators and their families (n = 134 individuals). We performed dense longitudinal microbiome sampling (n = 1,013 faecal samples) during the first year of nursery and tracked microbial strain transmission within and between nursery groups across 3 different facilities. We detected extensive baby-to-baby microbiome transmission within nursery groups even after only 1 month of nursery attendance, with nursery-acquired strains accounting for a proportion of the infant gut microbiome comparable to that from family by the end of the first term. Baby-to-baby transmission continued to grow over the nursery year, in an increasingly intricate transmission network with single strains spreading in some classes, and with multiple baby-acquisition and species-transmissibility patterns. Having siblings was associated with higher microbiome diversity and reduced strain acquisition from nursery peers, while antibiotic treatment was the condition that most accounted for the increased influx of strains. This study shows that microbiome transmission between babies is extensive during the first year of nursery, and points to social interactions in infancy as crucial drivers of infant microbiome development.
GPT-4o mini: Non-social science research article
Symmetry, microscopy and spectroscopy signatures of altermagnetism
Tomas Jungwirth, Jairo Sinova, Rafael M. Fernandes, Qihang Liu, Hikaru Watanabe, Shuichi Murakami, Satoru Nakatsuji, Libor Ć mejkal
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The recent discovery of altermagnetism was in part motivated by the research of compensated magnets towards highly scalable spintronic technologies. Simultaneously, altermagnetism shares the anisotropic higher-partial-wave nature of ordering with unconventional superfluid phases, which have been at the forefront of research for the past several decades. These examples illustrate the interest in altermagnetism from a broad range of science and technology perspectives. Here we review the symmetry, microscopy and spectroscopy signatures of altermagnetism. We describe the spontaneously broken and retained symmetries that delineate altermagnetism as a distinct phase of matter with d-, g- or i-wave compensated collinear spin ordering. In materials ranging from weakly interacting metals to strongly correlated insulators, the microscopic crystal-structure realizations of the altermagnetic symmetries feature a characteristic ferroic order of anisotropic higher-partial-wave components of atomic-scale spin densities. These symmetry and microscopy signatures of altermagnetism are directly reflected in spin-dependent electronic spectra and responses. We review salient band-structure features originating from the altermagnetic ordering, and from its interplay with spin–orbit coupling and topological phenomena. Throughout, we compare altermagnetism with traditional ferromagnetism and NĂ©el antiferromagnetism, and with magnetic phases with symmetry-protected compensated non-collinear spin orders. We accompany the theoretical discussions with references to relevant experiments.
GPT-4o mini: Non-social science research article
Publisher Correction: Polyamine-dependent metabolic shielding regulates alternative splicing
Amaia Zabala-Letona, Mikel Pujana-Vaquerizo, Belen Martinez-Laosa, Maria Ponce-Rodriguez, Saioa Garcia-Longarte, Isabel Mendizabal, Ana Gimeno, Malgorzata Rogalska, Joycelyn Tan, Diana Cabrera, Sebastiaan van Liempd, Pilar Ximenez-Embun, Sergio Espinosa, Maider Fagoaga-Eugui, Francesca Peccati, Maciej Zakrzewski, Ianire Astobiza, Mikel Arana-Castañares, Sarah Cherkaoui, Maria Sendino, InĂ©s MartĂ­n-Barros, Amaia Ercilla, Laura Bozal-Basterra, Onintza Carlevaris, Amaia Arruabarrena-Aristorena, EncarnaciĂłn PĂ©rez-AndrĂ©s, Telmo SantamarĂ­a-Zamorano, Juan A. Ferrer-Bonsoms, Fernando Carazo, Maciej Cieƛla, Cesar Lobato, Joan Seoane, Natalia MartĂ­n-MartĂ­n, Rosa Barrio, James D. Sutherland, Ana M. Aransay, Juan Manuel FalcĂłn-PĂ©rez, Barbara MartĂ­nez-Pastor, Angel Rubio, Francisco J. Blanco, Michael D. Hogarty, Raphael J. Morscher, Edurne Berra, Remigiusz A. Serwa, JesĂșs JimĂ©nez-Barbero, Gonzalo JimĂ©nez-OsĂ©s, Alejo Efeyan, Lydia Finley, Jose M. Lizcano, Javier Muñoz, Juan Valcarcel, Arkaitz Carracedo
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GPT-4o mini: Non-social science research article
Large-scale dynamos driven by shear-flow-induced jets
B. Tripathi, A. E. Fraser, P. W. Terry, E. G. Zweibel, M. J. Pueschel, R. Fan
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At every scale they occupy, magnetic fields affect various phenomena, including star formation, cosmic-ray transport, charged-particle acceleration, space weather, transport in planetary atmospheres and laboratory plasmas. These fields are often generated and sustained by turbulent flows in a process called the dynamo. In 1955, E. N. Parker parameterized the effects of small-scale turbulence to propose a mean-field dynamo theory1. The widely used theory reproduces observed large-scale fields but suffers from difficulty in tuning parameters as they are not justified from first principles: studies of turbulent flows show tangled magnetic fields, which are folded and fragmented into small-scale structures owing to shear-flow straining2,3. Here, considering a shear flow that is unstable and driven, we develop analytic theory and perform three-dimensional, advanced computer simulations of turbulence with up to 4,096 × 4,096 × 8,192 grid points, showing ab initio generation of quasi-periodic, large-scale magnetic fields. The generation occurs via the mean-vorticity effect—an additional mean-field dynamo process postulated4 in 1990. Crucial to this dynamo is the prior generation of large-scale three-dimensional jets, robustly produced as topologically protected and exact nonlinear solutions of the magnetohydrodynamic equations. The jet-driven dynamo applies to shear-driven laboratory and astrophysical systems. These include binary neutron star mergers5,6, where the reported dynamo probably operates on microsecond timescales to produce in milliseconds some of the strongest magnetic fields in the Universe7, providing signals for multi-messenger astronomy8.
GPT-4o mini: Non-social science research article
Publisher Correction: Multiple oestradiol functions inhibit ferroptosis and acute kidney injury
Wulf Tonnus, Francesca Maremonti, Shubhangi Gavali, Marlena Nastassja Schlecht, Florian Gembardt, Alexia Belavgeni, Nadja Leinung, Karolin Flade, Natalie Bethe, Sofia Traikov, Anne Haag, Danny Schilling, Sider Penkov, Melodie Mallais, Christine Gaillet, Claudia Meyer, Melika Katebi, Anushka Ray, Louisa M. S. Gerhardt, Anne Brucker, Jorunn Naila Becker, Mirela Tmava, Lisa Schlicker, Almut Schulze, Nina Himmerkus, Andrej Shevchenko, Mirko Peitzsch, Uladzimir Barayeu, Sonia Nasi, Juliane Putz, Kenneth S. Korach, Joel Neugarten, Ladan Golestaneh, Christian Hugo, Jan Ulrich Becker, Joel M. Weinberg, Svenja Lorenz, Bettina Proneth, Marcus Conrad, Eckhard Wolf, Bernd Plietker, Raphaël Rodriguez, Derek A. Pratt, Tobias P. Dick, Maria Fedorova, Stefan R. Bornstein, Andreas Linkermann
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GPT-4o mini: Non-social science research article
Dissecting gene regulatory networks governing human cortical cell fate
Jingwen W. Ding, Chang N. Kim, Megan S. Ostrowski, Yashodara Abeykoon, Bryan J. Pavlovic, Jenelle L. Wallace, Nathan K. Schaefer, Tomasz J. Nowakowski, Alex A. Pollen
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Human cortical neurogenesis involves conserved and specialized developmental processes during a restricted window of prenatal development. Radial glia (RG) neural stem cells shape cortical cell diversity by giving rise to excitatory neurons, oligodendrocytes and astrocytes, as well as olfactory bulb interneurons (INs) and a recently characterized population of cortical INs 1,2 . Complex genetic programs orchestrated by transcription factor (TF) circuits govern the balance between self-renewal and differentiation, and between different cell fates 3–8 . Despite progress in measuring gene regulatory network activity during human cortical development 9–12 , functional studies are required to evaluate the roles of TFs and effector genes in human RG lineage progression. Here we establish a human primary culture system that allows sensitive discrimination of cell fate dynamics and apply single-cell CRISPR interference (CRISPRi) screening 13,14 to examine the transcriptional and cell fate consequences of 44 TFs active during cortical neurogenesis. We identified several TFs with new roles in cortical neurogenesis, including ZNF219 —previously uncharacterized—that represses neural differentiation and NR2E1 and ARX that have opposing roles in regulating RG lineage plasticity and progression across developmental stages. We also detected convergent effector genes downstream of multiple TFs enriched in neurodevelopmental and neuropsychiatric disorders and observed conserved mechanisms of RG lineage plasticity across primates. We further uncovered a post-mitotic role for ARX in safeguarding IN subtype specification through repressing LMO1 . Our study provides a framework for dissecting regulatory networks driving cell fate consequences during human neurogenesis.
GPT-4o mini: Non-social science research article
Extreme barocaloric effect at dissolution
Kun Zhang, Yifang Liu, Ying Gao, Zhe Zhang, Haoyu Wang, Wanwu Li, Xiaoyan Fan, Jiayu Ding, Ziqi Guan, Shogo Kawaguchi, Zhaoxu Du, Jiaqing Zhang, Lei Su, Yiming Li, Runjian Jiang, Yifan Li, Yating Jia, Yanxu Wang, Jianchao Lin, Jinlong Zhu, Peng Tong, Suxin Qian, Kuo Li, Zhidong Zhang, Bing Li
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Refrigeration is indispensable to modern society1, yet the dominant vapour-compression systems rely on environmentally harmful fluorocarbon refrigerants with high global warming potential2,3,4. Solid-state caloric refrigeration offers a low-carbon alternative5,6,7, but its practical deployment has been hindered by limited cooling capacity and the inefficient indirect heat transfer that requires secondary fluids. Here we report an extreme barocaloric effect in NH4SCN aqueous solutions enabled by pressure-tuned dissolution and precipitation. This mechanism delivers an exceptionally large cooling capacity and markedly enhanced cooling efficiency. We obtain an in situ temperature drop of 26.8 K in the solution at room temperature, surpassing all known caloric materials. A Carnot-like cycle is designed to deliver 67 J g−1 cooling capacity per cycle with a second-law efficiency of 77%, benefiting from the extremely large temperature drops and direct heat transfer due to the self-circulating aqueous solution. Beyond the phase-transition scenario, this dissolution-based approach that combines the merits of current leading technologies emerges as a promising sustainable refrigeration solution.
GPT-4o mini: Non-social science research article
Core–envelope miscibility in sub-Neptunes and super-Earths
Travis Gilmore, Lars Stixrude
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Sub-Neptunes and super-Earths, the most abundant types of planet in the galaxy, are unlike anything in the Solar System, with radii between those of Earth and Neptune 1,2 . Fundamental questions remain regarding their structure and origin. Although super-Earths have a rocky composition 3 , sub-Neptunes form a distinct population at larger radii and are thought to consist of a rocky core overlain by a hydrogen-rich envelope 4,5 . At the extreme conditions of the core–envelope interface (exceeding several gigapascals and several thousand kelvin 4,6 ), reaction between core and envelope seems possible, but the nature and extent of these reactions are unknown. Here we use first-principles molecular dynamics driven by density functional theory to show that silicate and hydrogen are completely miscible over a wide range of plausible core–envelope pressure–temperature conditions. We find the origin of miscibility in extensive chemical reaction between hydrogen and silicate, producing silane, SiO and water species, which may be observable with ongoing or future missions. Core–envelope miscibility profoundly affects the evolution of sub-Neptunes and super-Earths, by dissolving a large fraction of the hydrogen of the planet in the core and driving exchange of hydrogen between core and envelope as the planet evolves.
GPT-4o mini: Non-social science research article
Fibroblastic reticular cells direct the initiation of T cell responses via CD44
Xavier Y. X. Sng, Valentina Voigt, Iona S. Schuster, Peter Fleming, Felix A. Deuss, Mohammed H. Abuwarwar, Serani L. H. van Dommelen, Georgia E. G. Neate, Riley M. Arnold, Harry L. Horsnell, Sheridan Daly, Bagher Golzarroshan, Antiopi Varelias, Stewart D. Lyman, Anthony A. Scalzo, Geoffrey R. Hill, Scott N. Mueller, Matthew E. Wikstrom, Richard Berry, Jamie Rossjohn, Anne L. Fletcher, Christopher E. Andoniou, Mariapia A. Degli-Esposti
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The movement of dendritic cells and T cells within secondary lymphoid organs is critical for the development of adaptive immune responses 1,2 . Central to this process is the fibroblastic reticular cell (FRC) network, which forms a highly organized conduit system that facilitates the movement of and interactions between dendritic cells and T cells 3–6 . Previous studies have partly characterized how FRCs support these interactions 7,8 . However, the molecular mechanisms that operate under physiological conditions remain unknown. Here we show that the viral protein m11, encoded by the herpesvirus murine cytomegalovirus (CMV), inhibits antiviral immunity by targeting the FRC network and interfering with a critical function of cellular CD44. We found that m11 binds to CD44 and established that m11 perturbs the molecular interactions of CD44 with its natural ligand, hyaluronic acid. The interaction of m11 with CD44 impairs the trafficking of dendritic cells within the spleen, thereby impeding efficient priming of naive T cells and the initiation of antiviral CD8 T cell responses. The targeting of CD44 by CMV reveals CD44 as a molecule that is essential to the functioning of the FRC network and uncovers a previously unrecognized stroma-based mechanism that is critical for the generation of effective T cell responses.
GPT-4o mini: Non-social science research article
The potential for bridgmanite megacrysts to drive magma ocean segregation
Jie Deng, Junwei Hu, Yidi Shi, Jina Lee, Haiyang Niu, Lars Stixrude
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Earth’s early mantle probably existed as a deep, vigorously convecting magma ocean, and its solidification is considered central to the long-term chemical and dynamical evolution of the planet. Yet a notable uncertainty is the grain size of bridgmanite—the dominant lower-mantle phase—whose nucleation behaviour at extreme pressure has remained experimentally inaccessible. Here we show, using a combination of cutting-edge techniques, including large-scale molecular dynamics simulations consisting of up to 1 million atoms driven by machine learning potentials (MLPs), seeding and enhanced sampling, that crystal–melt interfacial energies of MgSiO3 bridgmanite increase substantially with pressure, surpassing those of silicate–liquid systems at ambient pressure by a factor of up to ten (refs. 1,2,3). In a deep basal magma ocean (BMO), this amplified interfacial energy, combined with the potential sluggish cooling, may permit the formation of unusually large bridgmanite crystals, up to centimetre-to-metre-scale sizes. Such potentially large crystals could drive efficient fractional crystallization and cause substantial chemical differentiation and mantle compaction. If operative, this mechanism would provide a new physical pathway linking lower-mantle material properties to early Earth stratification and it motivates future geodynamic models that explicitly incorporate supercooling, compositional convection and elemental partitioning. Our findings thus offer a plausible hypothesis connecting microscopic nucleation processes with macroscopic planetary structure, refining present views of how the Earth’s interior acquired its initial compositional architecture.
GPT-4o mini: Non-social science research article
Atmospheric microplastic emissions from land and ocean
Ioanna Evangelou, Silvia Bucci, Andreas Stohl
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Microplastics (MPs) are global pollutants 1 , yet their atmospheric distribution is poorly understood 2 . Although atmospheric MP measurements have become more abundant, estimates of emissions into the atmosphere vary by orders of magnitude 3,4 . Here we compile a global atmospheric MPs dataset and compare it with size-aligned MP model simulations. Our model simulations show two to four orders of magnitude overestimation of the measured global median atmospheric MP concentrations. Measured median concentrations over the ocean are 27 times lower than over the land (0.003 and 0.08 particles m −3 , respectively). Applying a simple scaling method, we estimate that oceanic emissions are lower in number than land-based emissions. The total global land-based and oceanic emissions are 6.1 × 10 17 (1.3 × 10 17 to 1.1 × 10 18 ) particles year −1 and 2.6 × 10 16 (2.7 × 10 15 to 5.0 × 10 16 ) particles year −1 , respectively. Our results indicate that fewer MP particles are emitted into the atmosphere than previously thought. Land sources dominate the number but not the mass emissions, indicating that MPs emission size distributions should be investigated further.
GPT-4o mini: Non-social science research article
Construction of complex and diverse DNA sequences using DNA three-way junctions
Noah Evan Robinson, Weilin Zhang, Rajesh Ghosh, Bryan Gerber, Hanqiao Zhang, Charles Sanfiorenzo, Sixiang Wang, Dino Di Carlo, Kaihang Wang
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The ability to construct entirely new synthetic DNA sequences de novo is essential to engineering and studying biology. However, the ability to produce long complex synthetic DNA sequences and libraries currently lags behind the ability to sequence and edit DNA 1,2 . All existing DNA-assembly technologies rely on DNA sequence information found within the final construct to direct assembly between DNA molecules 3–11 . As a result of this paradigm, these sequences cannot be extensively optimized specifically for assembly without affecting the final sequence. To fundamentally address this challenge, here we show the development of a new DNA assembly technique named Sidewinder that separates the information that guides assembly from the final assembled sequence using DNA three-way junctions. We demonstrate the transformative nature of the Sidewinder technique with highly robust and accurate construction of a 40-piece multifragment assembly, complex DNA sequences of both high GC content and high repeats, parallel assembly of multiple distinct genes in the same reaction and a combinatorial library with a large number of diversified positions across the entire length of the gene for high coverage of a library of 442,368 variants. This technology enables high-fidelity DNA assembly with a misconnection rate at the three-way junction of approximately 1 in 1,000,000.
GPT-4o mini: Non-social science research article
Convergent evolution of scavenger cell development at brain borders
Andrea U. Gaudi, Michelle Meier, Oguzhan F. Baltaci, Sayali Chowdhary, Frank J. Tulenko, Stefanie Dudczig, Sebastian-Alexander Stamatis, Scott Paterson, Hujun Yu, Maria Cristina Rondon Galeano, Elizabeth Mason, Lee B. Miles, Robert J. Bryson-Richardson, Andrew J. Pask, Jana Vukovic, Anne K. Lagendijk, Kelly A. Smith, Jan Kaslin, Michael RM Harrison, Peter D. Currie, Neil I. Bower, Benjamin M. Hogan
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The vertebrate central nervous system is protected by the blood–brain barrier and meningeal membranes, which ensure immune privilege1. In the mammalian brain, microglia and barrier-associated or border-associated macrophages (BAMs) provide immune surveillance and scavenge wastes2, yet how evolution shaped immune-cell diversity and function is not understood. In zebrafish, a vascular-derived mural lymphatic endothelial cell (muLEC) lineage fulfils scavenger cell functions at central nervous system borders3,4,5. Here we identify the transcription factor odd-skipped related 2 (osr2) as a specific marker and regulator of muLEC differentiation and maintenance. osr2 controls the transition of muLECs from interconnected endothelial cells to individual scavenger cells in part by means of control of cadherin-6. muLECs are more transcriptionally similar to BAMs than to other mammalian meningeal cells and share several functions in tissue homeostasis. However, BAMs are absent from zebrafish and muLECs from mice and humans. Analysis of osr2, lymphatic endothelial cell (LEC) and BAM markers in diverse vertebrate species reveals muLECs as an ancient lineage and BAMs a recent mammalian specialization. muLECs and BAMs share functional analogies but are not homologous, providing an example of convergent evolution. This highlights the physiological importance of meningeal scavenger cells and the developmental plasticity of LECs in generating specialized cell types throughout evolution.
GPT-4o mini: Non-social science research article
Oxygen-free metabolism in the bird inner retina supported by the pecten
Christian Damsgaard, Mia Viuf SkĂžtt, Catherine J. A. Williams, Hans Malte, Camilla Kruse Kidmose, Morten Busk, Karin Dedek, Andreas H. Konradsen, Anne Sofie Stengel Rasmussen, Jesper Skovhus Thomsen, Anna V. G. T. Mikkelsen, Katrine S. Johannsen, Mikkel Vendelbo, Niels Peter Revsbech, Coen P. H. Elemans, Henrik Mouritsen, Joanna Kalucka, Lin Lin, Nina Kerting Iversen, Tobias Wang, Henrik Lauridsen, Jens Randel Nyengaard
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Neural tissues are exceptionally sensitive to oxygen deprivation and rely on a dense network of blood vessels to support their extraordinarily high metabolic demands for oxygen, nutrients and clearance of waste products1,2,3,4. In birds, one of the metabolically most demanding neural tissue—the retina—lacks internal blood vessels5,6. This raises the question of how such a metabolically demanding neural tissue can function without blood perfusion. Here we show that, while the photoreceptor outer segments in the outer retina have access to oxygen, the inner bird retina operates under chronic anoxia, supported by anaerobic glycolysis in the retinal neurons. We provide evidence that the pecten oculi—a uniquely vascularized structure in the vitreous humour of birds, the function of which has been debated for centuries5,6,7,8,9—supplies the anoxic inner retina with glucose and removes lactic acid. We suggest that the pecten’s metabolic support of the bird retina’s anoxia tolerance enabled first the evolution of a thick cell-dense, avascular retina, which secondarily served as an exaptation enabling retinal function during high-altitude migrations.
GPT-4o mini: Non-social science research article
Four camera-type eyes in the earliest vertebrates from the Cambrian Period
Xiangtong Lei, Sihang Zhang, Peiyun Cong, Jakob Vinther, Sarah Gabbott, Fan Wei, Xing Xu
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Vertebrate vision is mainly accommodated by a pair of lateral image-forming camera-type eyes and is supplemented in non-mammalian vertebrates by a dorsal pineal complex (pineal and parapineal organs) functioning as photoreceptive and/or endocrine organs1. The pineal complex shares a common genetic and embryological basis with the lateral eyes, both derived from evaginations during the development of diencephalon2. Despite being widely heralded as the ‘third eye’ in crown vertebrates3, the nature of the pineal complex and its presumed visual capability in early vertebrates2 remain unknown. Here we describe two pigmented features situated between the lateral eyes in two species of myllokunmingids, the earliest known fossil vertebrates (approximately 518 million years ago), and interpret these as pineal/parapineal organs. In both myllokunmingid species, the pineal complex contains abundant melanin-containing melanosomes identical to those in the retinal pigment epithelium in the lateral eyes, together with a distinctive, regularly ovoid structure interpreted as a lens. Our results indicate that the lateral eyes and pineal complex in myllokunmingids probably functioned as camera-type eyes capable of image formation. Thus, we propose that the four camera-type eyes represent an ancestral vertebrate character, corroborating hypotheses about the deep homology between the eyes and pineal complex.
GPT-4o mini: Non-social science research article
Probing quantum mechanics with nanoparticle matter-wave interferometry
Sebastian Pedalino, Bruno E. RamĂ­rez-Galindo, Richard Ferstl, Klaus Hornberger, Markus Arndt, Stefan Gerlich
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The quantum superposition principle is a fundamental concept of physics 1 and the basis of numerous quantum technologies 2,3 . Yet, it is still often regarded counterintuitive because we do not observe its key features on the macroscopic scales of our daily lives. It is, therefore, interesting to ask how quantum properties persist or change as we increase the size and complexity of objects 4 . A model test for this question can be realized by matter-wave interferometry, in which the motion of individual massive particles becomes delocalized and needs to be described by a wave function that spans regions far larger than the particle itself 5 . Over the years, this has been explored with a series of objects of increasing mass and complexity 6–9 and a growing community aims at pushing this to ever larger limits. Here we present an experimental platform that extends matter-wave interference to large metal clusters, a qualitatively new material class for quantum experiments. We specifically demonstrate quantum interference of sodium nanoparticles, which can each contain more than 7,000 atoms at masses greater than 170,000 Da. They propagate in a Schrödinger cat state with a macroscopicity 10 of ÎŒ = 15.5, surpassing previous experiments 5,9,11 by an order of magnitude.
GPT-4o mini: Non-social science research article
Publisher Correction: A fault-tolerant neutral-atom architecture for universal quantum computation
Dolev Bluvstein, Alexandra A. Geim, Sophie H. Li, Simon J. Evered, J. Pablo Bonilla Ataides, Gefen Baranes, Andi Gu, Tom Manovitz, Muqing Xu, Marcin Kalinowski, Shayan Majidy, Christian Kokail, Nishad Maskara, Elias C. Trapp, Luke M. Stewart, Simon Hollerith, Hengyun Zhou, Michael J. Gullans, Susanne F. Yelin, Markus Greiner, Vladan Vuletić, Madelyn Cain, Mikhail D. Lukin
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GPT-4o mini: Non-social science research article
Identification of an allosteric site on the E3 ligase adapter cereblon
Vanessa N. Dippon, Zeba Rizvi, Anthony E. Choudhry, Chun-wa Chung, Ibrahim F. Alkuraya, Wenqing Xu, Xavier B. Tao, Anthony J. Jurewicz, Jessica L. Schneck, Wenqian Chen, Nicole M. Curnutt, Farah Kabir, Kwok-Ho Chan, Markus A. Queisser, Caterina Musetti, Han Dai, Gabriel C. Lander, Andrew B. Benowitz, Christina M. Woo
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Cereblon (CRBN) is the target of thalidomide derivatives1 that achieve therapeutic efficacy against some haematologic neoplasias2,3,4 by recruiting neosubstrates for degradation5,6,7. Despite the intense investigation of orthosteric thalidomide derivatives, little is known about alternate binding sites on CRBN. Here we report an evolutionarily conserved cryptic allosteric binding site on CRBN. Small-molecule SB-405483 binds the allosteric site to cooperatively enhance the binding of orthosteric ligands and alter their neosubstrate degradation profiles. A survey of over 100 orthosteric ligands and their degradation targets reveals trends in the classes of compounds and neosubstrates in which degradation outcomes are enhanced or inhibited by SB-405483. Structural investigations provide a mechanistic basis for the effects of the allosteric ligand by shifting the conformational distribution of CRBNopen to a novel CRBNint and increasing the CRBNclosed state. The discovery of a cryptic allosteric binding site on CRBN that alters the functional effects of orthosteric ligands opens new directions with broad implications for improving the selectivity and efficacy of CRBN therapeutics.
GPT-4o mini: Non-social science research article
Rock art from at least 67,800 years ago in Sulawesi
Adhi Agus Oktaviana, Renaud Joannes-Boyau, Budianto Hakim, Basran Burhan, Ratno Sardi, Shinatria Adhityatama, Andrea Jalandoni, Hamrullah, Iwan Sumantri, M. Tang, Rustan Lebe, Iswadi, Imran Ilyas, Abdullah Abbas, Andi Jusdi, Dewangga Eka Mahardian, Fadhlan S. Intan, Sofwan Noerwidi, Marlon N. R. Ririmasse, Irfan Mahmud, Akin Duli, Laode M. Aksa, M. Nur, Nasrullah Aziz, Sri Wigati, Iksam, Faiz, M. Sabri, Fardi Ali Syahdar, Eriani, N. A. Hidayatullah, Suryatman, Laode Darma, Nurmin, Laode Zulman, S. H. Sindara, Andi Muhammad Saiful, Pindi Setiawan, Adam Brumm, Maxime Aubert
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The Indonesian archipelago is host to some of the earliest known rock art in the world1,2,3,4,5. Previously, secure Pleistocene dates were reported for figurative cave art and stencils of human hands in two areas in Indonesia—the Maros-Pangkep karsts in the southwestern peninsula of the island of Sulawesi1,3,4,5 and the Sangkulirang-Mangkalihat region of eastern Kalimantan, Borneo2. Here we describe a series of early dated rock art motifs from the southeastern portion of Sulawesi. Among this assemblage of Pleistocene (and possibly more recent) motifs, laser-ablation U-series (LA-U-series) dating of calcite overlying a hand stencil from Liang Metanduno on Muna Island yielded a U-series date of 71.6 ± 3.8 thousand years ago (ka), providing a minimum-age constraint of 67.8 ka for the underlying motif. The Muna minimum (67.8 ± 3.8 ka) exceeds the published minimum for rock art in Maros-Pangkep by 16.6 thousand years (kyr) (ref. 5) and is 1.1 kyr greater than the published minimum for a hand stencil from Spain attributed to Neanderthals6, which until now represented the oldest demonstrated minimum-age constraint for cave art worldwide. Moreover, the presence of this extremely old art in Sulawesi suggests that the initial peopling of Sahul about 65 ka7 involved maritime journeys between Borneo and Papua, a region that remains poorly explored from an archaeological perspective.
Nature DOI suffix ≠ "/s...": Not a research article
Forget formalism: mathematics was built on infighting and emotional turmoil
Ananyo Bhattacharya
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US science after a year of Trump: what has been lost and what remains
Max Kozlov, Jeff Tollefson, Dan Garisto
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Can ‘toxic masculinity’ be measured? Scientists try to quantify controversial term
Nicola Jones
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Nature DOI suffix ≠ "/s...": Not a research article
Study decision-making to understand how technology will affect behaviour
Shahar Hechtlinger, L. A. Paul, M. J. Crockett
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Seven technologies to watch in 2026
Michael Eisenstein
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To gain public trust, make art central to science communication
Palina Kot
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More than half of authors of leading research say funding is declining
Anna McKie
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Nature DOI suffix ≠ "/s...": Not a research article
Untangling the connection between dopamine and ADHD
Jyoti Madhusoodanan
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Six highlights from ADHD research
Simon Makin
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I’m going to halve my publication output. You should consider slow science, too
Adrian Barnett
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Fossil-fuel phase out is not enough: countries must remove atmospheric carbon
Richard H. Clarke, Mark Maslin
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Sending babies to nursery completely reshapes their microbiomes
Chris Simms
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Briefing Chat: Can NASA return rocks from Mars? And why dogs have long ears
Benjamin Thompson, Nick Petrić Howe
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‘Shattered’: US scientists speak out about how Trump policies disrupted their careers
Virginia Gewin
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The rich stopped buying yachts the year time went on sale
Sara E. Pour
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‘Greed is the iron cage of our times’ — why nationalism is here to stay
Roberto Patricio Korzeniewicz
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Why teens with ADHD are so vulnerable to the perils of social media
Elie Dolgin
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Quantum effect observed for biggest objects yet
Tim Kovachy
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Illuminating how the bird inner retina works without oxygen solves a 350-year-old structural mystery
Michael Berenbrink, Jenni M. Prokkola
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ADHD is on the rise, but why?
Brian Owens
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Floating science stations: my month on a research vessel looking after buoys
Christine Ro
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A variety of early hominin species shared the Afar region of Ethiopia
Carol V. Ward
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US funding cuts harm aspiring young scientists, too
William Y. Xuan
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Is paracetamol in pregnancy a risk factor for ADHD?
Carolyn Brown
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‘Remote controlled’ proteins illuminate living cells
Ewen Callaway
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Daily briefing: Symbols on ancient pottery could be earliest evidence of mathematics
Flora Graham
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Humanoid robots step up their game: how useful are the latest droids?
Elizabeth Gibney
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Schrödinger’s cat just got bigger: quantum physicists create largest ever ‘superposition’
Elizabeth Gibney
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US Congress set to reject Trump’s sweeping science budget cuts
Jeff Tollefson, Max Kozlov
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The biggest ‘Schrödinger’s cat’ yet — physicists put 7,000 atoms in superposition
Nick Petrić Howe, Benjamin Thompson
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The US is quitting 66 global agencies: what does it mean for science?
Davide Castelvecchi, Ehsan Masood
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My PI is not offering any support or guidance on my PhD project, what should I do?
Sarah Wells
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What happens if fewer children get vaccinated? Japan holds lessons for US
Heidi Ledford
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Girls are starting puberty younger — why, and what are the risks?
Cassandra Willyard
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Daily briefing: Cancer cells stay hidden using stolen mitochondria
Jacob Smith
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How much protein do you actually need?
Nick Petrić Howe, Elizabeth Gibney
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Trump one year on: How six US researchers plan to protect science amid chaos and cuts
Amander Clark, Hank Greely, Eric Topol, Salim S. Abdool Karim, Quarraisha Abdool Karim, Ramanan Laxminarayan
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An eye-popping discovery: early vertebrates had four eyes rather than two
Michael S. Levine
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Why ADHD goes undiagnosed in girls
Niki Wilson
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ADHD treatments move beyond stimulants
Nicola Jones
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Daily briefing: The first documented case of tool use in cattle
Flora Graham
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A ‘time capsule’ for cells stores the secret experiences of their past
Ewen Callaway
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Daily briefing: Gifted dogs have word-learning skills on a par with human toddlers
Flora Graham
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Daily briefing: Trump — one year in
Flora Graham
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Nature Human Behaviour

GPT-4o mini: Non-social science research article
Population attributable fractions of a wide range of peripheral diseases for the burden of dementia
Zhenhong Deng, Yuxin Yang, Queran Lin, Songhua Xiao, You Zuo, Jinyuan Wang, Yongteng Xu, Honghong Li, Dongshu Xie, Qingyuan Dai, Junfeng Luo, Dame Louise Robinson, Naaheed Mukadam, Yamei Tang
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Growing evidence suggests that peripheral diseases serve as risk factors for dementia, but the population-level burden of dementia associated with various peripheral diseases has remained unknown. Here, by conducting a systematic review and Bayesian meta-analyses to estimate the relative risks of 26 peripheral diseases across 9 systems with dementia, including 202 articles searched from the PubMed until 6 September 2024, we identified 16 peripheral diseases as associated with increased risk of dementia. With the relative risks estimated from meta-analyses, prevalences extracted from the Global Burden of Disease Study, and communalities among these 16 peripheral diseases derived from the UK Biobank, we analysed the population attributable fractions (PAFs) of these 16 peripheral diseases for dementia, stratified by sex, age, sociodemographic index level, world region and country, and trends from 1990 to 2021. Globally, these peripheral diseases collectively were related to a combined PAF of 33.18% (95% confidence interval (CI) 16.80–48.43) of dementia burden, corresponding to 18.8 million prevalent cases. The leading ten PAF contributors were periodontal diseases (6.10%, 95% CI 0.95–10.28), cirrhosis and other chronic liver diseases (5.51%, 95% CI 1.77–8.86), age-related and other hearing loss (4.70%, 95% CI 3.51–6.06), blindness and vision loss (4.30%, 95% CI 3.43–5.05), type 2 diabetes mellitus (3.80%, 95% CI 3.06–4.53), chronic kidney disease (2.74%, 95% CI 1.53–4.02), osteoarthritis (2.26%, 95% CI 0.41–4.12), stroke (1.01%, 95% CI 0.86–1.17), ischaemic heart disease (0.97%, 95% CI 0.69–1.29) and chronic obstructive pulmonary disease (0.92%, 95% CI 0.34–1.54). This study revealed that a series of peripheral diseases were associated with increased risk of dementia and collectively were related to about one-third of the global dementia burden, highlighting the need for targeted public health strategies.
GPT-4o mini: Non-social science research article
Evidence for the representation of non-hierarchical structures in language
Yngwie A. Nielsen, Morten H. Christiansen
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A long-standing assumption in the language sciences is that the mental representation of language is based on constituents—that is, hierarchical structures rooted in grammar. We provide evidence from English for a more basic kind of linguistic representation involving smaller, linear chunks of structure akin to sequences of parts-of-speech elements—such as verb preposition determiner shared between the strings added to a and defined by the. Across four preregistered phrasal decision experiments (total N = 497), we show that it is possible to prime such linear structures, even in the absence of constituents. In two additional corpus analyses of eye-tracked reading (N = 68) and conversation (N = 358), we establish the external validity of the effect. These results provide evidence of multiword language structures that are not explainable in terms of constituents as traditionally construed. This poses a challenge for accounts of linguistic representation, including generative and constructionist approaches.
Indecision and recency-weighted evidence integration in non-clinical and clinical settings
Magdalena del RĂ­o, Nadescha Trudel, Gita Prabhu, Laurence T. Hunt, Michael Moutoussis, Raymond J. Dolan, Tobias U. Hauser
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Biases in information gathering are common in the general population and reach pathological extremes in paralysing indecisiveness, as in obsessive–compulsive disorder (OCD). Here we adopt a new perspective on information gathering and demonstrate an information integration bias whereby there is over-weighting of most recent information via evidence strength updates (ΔES). In a crowd-sourced sample ( N = 5,237), we find that a reduced ΔES weighting drives indecisiveness along an obsessive–compulsive spectrum. We replicate this attenuated ΔES weighting in a second lab-based study ( N = 105) that includes a transdiagnostic obsessive–compulsive spectrum encompassing OCD and generalized anxiety patients. Using magnetoencephalography (MEG), we trace ΔES signals to a late neural signal peaking at ~920 ms. Critically, highly obsessive–compulsive participants, across diagnoses, show an attenuated neural ΔES signal in mediofrontal areas, while other decision-relevant processes remain intact. Our findings establish biased information weighting as a driver of information gathering, where attenuated ΔES is linked to indecisiveness across an obsessive–compulsive spectrum.

Proceedings of the National Academy of Sciences

GPT-4o mini: Non-social science research article
Towards CRISPR-based editing of the mitochondrial genome in yeast
Sifei Yin, Daniel F. Jarosz, Alice Y. Ting
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Mitochondria, which evolved from symbiotic bacteria, possess their own genomes (mtDNA) and support independent transcription and translation within the organelle. Given the essential role of mtDNA in energy production, metabolism, as well as cellular homeostasis, and the high density of confirmed pathogenic mutations that map to mtDNA, there is a pressing need for versatile methods to study and manipulate this genome. Although CRISPR technology has revolutionized the editing of nuclear genomes, it has not been successfully extended to mtDNA, primarily due to the challenge of delivering single guide RNAs (sgRNAs) across both outer and inner mitochondrial membranes. Here we develop a survival-based reporter in Saccharomyces cerevisiae to screen for potential RNA import motifs. We identify a 40-nucleotide aptamer (IM83) that facilitates sgRNA entry into the mitochondrial matrix, enabling CRISPR editing by a mitochondrially-localized adenine base editor. We show that mitochondrial import of IM83 is ATP-dependent and enhanced by the tRNA synthetase Msk1. Further investigations identify barriers to efficient CRISPR editing of mtDNA, including loss of membrane potential associated with mitochondrial targeting of the base editor. These insights lay the groundwork for future improvements in CRISPR-based editing of mtDNA in eukaryotes.
GPT-4o mini: Non-social science research article
An accurate cellular assay to determine pathogenicity of coding and noncoding variants in Lynch syndrome genes
Iris E. Glykofridis, Marleen Dekker, Chantal Stoepker, Thomas W. van Ravesteyn, Yvonne Tiersma, Cédric G. van der Ham, Beaunelle de Bruijn, Salma Ebrahim, Renée X. de Menezes, Esmee Kasteleijn, Frans Verheijen, Tjakko J. van Ham, Hein te Riele
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Lynch syndrome (LS) is a genetic predisposition to mainly colorectal and endometrial cancer due to heterozygous disruptive germline mutations in the DNA mismatch-repair (MMR) genes MSH2 , MSH6 , MLH1, or PMS2 . Beyond clearly pathogenic mutations, germline sequencing often reveals variants of uncertain significance (VUS), predominantly single base-pair alterations in coding or noncoding regions. These uncertain variants obstruct LS diagnosis, hampering personalized surveillance. To address this challenge, we developed a highly accurate functional assay that interrogates VUS pathogenicity in human cells. Building on a mouse-based cellular assay, we adapted oligonucleotide-directed mutation screening (ODMS) for human cells and introduced a refined approach named “coselection ODMS.” To ensure physiological expression, the variant is introduced into the endogenous MMR gene by replication-coupled gene editing. Coselection ODMS demonstrated 100% accuracy in classifying 50 benign and 86 pathogenic variants spanning coding and noncoding regions in all four MMR genes. Among 109 patient-derived VUS, 51 were identified as deleterious for MMR function. Importantly, coselection ODMS delivered 100% concordant results in a clinical diagnostic laboratory. With >93% sensitivity and >92% specificity, coselection ODMS provides a highly reliable functional assay in the diagnosis of enigmatic LS variants, enabling risk assessment and personalized surveillance or treatment for affected families.
GPT-4o mini: Non-social science research article
Bioresponsive immunomodulator nanocomplex for selective immunoengineering in metastatic lymph nodes
Yueyang Deng, Mo Chen, Tianxu Fang, Tianwen Luo, Xiaona Cao, Guojun Chen
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Lymph node (LN) metastasis (LNM) frequently occurs in various cancer types and is associated with high aggressiveness, poor prognosis, and low survival rates. However, effective clinical interventions remain limited primarily due to the distinctive immunosuppressive microenvironment found in metastatic LNs. Targeted delivery of immunomodulators and selective immunoengineering in metastatic LNs offers a promising avenue for repurposing these LNs as an effective antitumor system while mitigating the risk of unwanted immune activation elsewhere. Here, we develop a bioresponsive LN-targeted immunomodulator nanocomplex designed to selectively reprogram the immune microenvironment in metastatic LNs for LNM inhibition. The immunomodulator nanocomplex can target LNs due to specific chemokine receptor 7 modification and selectively release anti-PD-1 antibodies in response to glutathione that is found elevated in the extracellular matrix of metastatic LNs. In two mouse models, our data suggested that the immunomodulator nanocomplex can selectively activate T cell–mediated antitumor immune responses in metastatic LNs and thus effectively inhibit tumor growth and prolong the survival of animals. Importantly, the modular design of this platform could enable facile incorporation of alternative immunotherapeutic agents that exhibit significant systemic toxicities in the clinic, allowing broader application to payloads that may particularly benefit from localized, LNM-selective activation. This approach holds significant promises for reducing the necessity for complete LN dissection, thereby presenting a valuable therapeutic option for a broad spectrum of cancer patients.
GPT-4o mini: Non-social science research article
David Baltimore: Scientist, leader, and mentor
Nancy C. Andrews, George Q. Daley
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Fifty years ago, at the remarkably young age of 37, David Baltimore received the Nobel Prize (with Howard Temin and Renato Dulbecco) for “discoveries concerning the interaction between tumor viruses and the genetic material of the cell.” David was a prolific scientist whose work spanned many topics, but he was first and foremost a virologist. His recent passing invites us to reflect on a remarkable intellectual trajectory that began with seminal discoveries in virology, broadened to encompass major advances in cancer biology and immunology, and culminated in a legacy—sustained by the many scientists he trained—that will continue to shape modern biomedicine for years to come.
GPT-4o mini: Non-social science research article
Predicting epistasis across proteins by structural logic
Michelle Tang, Gareth A. Cromie, Anowarul Kabir, Martin S. Timour, Julee Ashmead, Russell S. Lo, Nathaniel Corley, Frank DiMaio, Hiroki Morizono, Ljubica Caldovic, Nicholas Ah Mew, Andrea Gropman, Amarda Shehu, Aimée M. Dudley
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Accurately predicting the phenotypic consequences of genetic variation is a major challenge for precision medicine. The problem is exacerbated by epistatic interactions, nonadditive effects between genetic variants that produce unexpected phenotypes. Here, we explore an understudied form of positive epistasis: intragenic complementation, in which pairs of loss-of-function variants restore near wild-type protein function. Using mutational scanning in yeast, we identify thousands of such interactions in a clinically important enzyme, human argininosuccinate lyase (ASL). Restoration of protein function is not due to the biochemical properties of the substituted amino acids, but rather to a structural feature of the protein, the active site assembly. We develop a machine learning algorithm that uses protein language model embeddings to predict intragenic complementation in ASL with 99.6% accuracy. Additionally, the model trained on ASL generalizes to a structurally related but sequence-divergent enzyme, fumarase, with accuracy over 90%. Our findings reveal a structural basis for this form of epistasis and provide a predictive framework that could extend to at least 4% of human proteins.
GPT-4o mini: Non-social science research article
Differential Hes1 activation defines neural stem cell lineage commitment and niche maintenance in embryonic and adult mouse cortex
Paul Ann Riya, Rahul Jose, Vadakkath Meera, Budhaditya Basu, Suresh Surya, Ramankunju Aryasree, Nair Pradeep Jyothi, Surendran Parvathy, Sivadasan Bindu Dhanesh, Rajendran Sanalkumar, Viviane Praz, Nicolo Riggi, Jackson James
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Mode of Hes1 activation and its differential expression are crucial for the maintenance of neural stem cells/progenitor cells (NSCs/NPCs) in the embryonic cortex. This differential mode of Hes1 activation has been translated into a heterogeneous population of NSCs comprising Notch-independent Hes1- expressing (NIHes1) NSCs and Notch-dependent Hes1- expressing (NDHes1) radial glial cells (RGCs). Using single-cell transcriptomics and a Nestin-CreERT2;NIHes1 fl/fl conditional knock-out mouse model, we have characterized the NIHes1 NSCs. Our analyses show that NIHes1 NSCs are the ancestral precursor NSCs that generate RGCs and intermediate progenitor cells during development. Loss of NIHes1 expression significantly alters the NSC niche, leading to increased gliogenesis and aberrant migration of projection neurons. NIHes1 NSCs are set aside at embryonic stages as adult neural stem cells and are maintained by NIHes1 expression even at adult stage. Our findings suggest that NIHes1 NSCs are functionally distinct Hes1 -expressing NSCs, which are critical for establishing both embryonic and adult NSC niches, thereby contributing to the overall cortical development.
GPT-4o mini: Non-social science research article
Emergent ferromagnetism and unusual irreversible magnetoresistance in an intercalated van der Waals antiferromagnet
Zixin Zhai, Wenhao Liu, Xiaoyu Guo, Daniel J. Schulze, Ting-Wei Kuo, Nishkarsh Agarwal, Alex Stangel, Pramanand Joshi, J. Ping Liu, Liangzi Deng, Robert Hovden, Liuyan Zhao, Ching-Wu Chu, Bing Lv
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Orthorhombic air-stable two-dimensional (2D) antiferromagnet (AFM) CrSBr has attracted much research interest lately thanks to its rich magnetic behaviors together with its remarkable electronic, excitonic, and polaritonic properties. Here, we report a reliable electrochemical intercalation method by inserting large tetrabutylammonium (TBA + ) ions into CrSBr layers. Magnetically, such intercalation efficiently suppresses the interlayer AFM and induces a ferromagnetic (FM) order with a much-enhanced transition temperature up to 200 K, nearly 70 K higher than the AFM onset of 132 K in pristine CrSBr. Electronically, the TBA + intercalation not only increases the electric conductivity of CrSBr, which is further enhanced by magnetic fields, but also introduces a giant negative irreversible magnetoresistance. This work demonstrates the tunable magnetic and electronic properties of CrSBr as well as their interplay, paving the way for advanced spintronic and magnetic memory devices.
GPT-4o mini: Non-social science research article
GFP-free live neuron quantitative imaging reveals compartmentalization and growth dynamics of polyQ aggregates
Xiaotian Bi, Berea Suen, Li-En Lin, Kun Miao, Lu Wei
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Huntington’s Disease (HD), the most prevalent polyglutamine (polyQ) neurodegenerative disorder, features brain aggregates induced by mutant huntingtin (mHtt) proteins harboring expanded polyQ tracts. Despite extensive efforts, molecular mechanisms of polyQ aggregates remain elusive. Here, we establish quantitative stimulated Raman scattering imaging of polyQ aggregates (q-aggSRS) for noninvasive investigations in live neuronal cocultures using deuterated glutamine labeling. Q-aggSRS allows for specific visualization by targeting the distinct Raman peak from carbon–deuterium bonds, eliminating the need for bulky fluorescent protein tagging (e.g., EGFP). Coupled with analysis from aggregate-tailored expansion microscopy, newly designed two-color imaging, and pulse–chase visualization, we comprehensively quantified the mHtt and non-mHtt proteins within the same aggregates across varying sizes, cell types, mHtt constructs, and subcellular locations. Our findings demonstrate a two-phase aggregate model with a distinct core–shell spatial organization, reveal significant heterogeneity in nucleus/cytoplasm compartmentalization specific to neurons, and identify previously unrecognized loosely packed aggregates specifically in neuronal nuclei. These insights should advance our understanding of native polyQ aggregates, and our proposed interaction coefficients may offer quantitative parameters for developing effective HD therapies.
GPT-4o mini: Non-social science research article
Platelet-derived growth factor receptor alpha regulates fetal testis differentiation via an ERK–CREB axis
Shu-Yun Li, Satoko Matsuyama, Sarah Whiteside, Xiaowei Gu, Jonah Cool, Blanche Capel, Tony DeFalco
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Platelet-derived growth factor receptor alpha ( Pdgfra ) plays a crucial role in mesenchymal cell differentiation, but the molecular signaling involved in this process remains unclear, particularly within the fetal testis. Here, we use XY Pdgfra -null gonads to investigate the molecular mechanisms underlying testicular organogenesis, focusing on the formation of testicular architecture and the differentiation of fetal Leydig cells (FLCs), the steroidogenic lineage arising from mesenchymal precursors within the testicular interstitial compartment. The extracellular signal-regulated kinase (ERK) pathway, a well-known mitogen-activated signaling pathway, was significantly inhibited in XY Pdgfra -null gonads, suggesting that ERK signaling is activated downstream of PDGFRA. Using ex vivo whole-organ culture, small interfering RNA cell culture methods, transwell assays, and a genetic mouse model to disrupt ERK signaling in gonadal cells, we found that the ERK pathway promotes testis cord formation via early growth response 1 -mediated cell migration and regulates the expression of steroidogenic enzymes in FLCs via activating the transcription factor cAMP responsive element binding protein 1. These findings highlight the significance of the PDGFRA signaling network in fetal testis organogenesis, thus providing insights into mesenchymal cell differentiation and the etiology of congenital disorders related to gonadal development.
GPT-4o mini: Non-social science research article
A single-domain expansin-like protein from Gloeophyllum trabeum able to cleave xylan
Ignacio Delgado Santamaría, Heidi Østby, Vincent G. H. Eijsink, Anikó Vårnai
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Expansin-related proteins (ERPs) are a broad group of plant cell wall–loosening proteins and are considered noncatalytic, as, to date, no cell wall–derived products have been observed as a result of catalysis, despite the presence of a domain that resembles the catalytic domains of GH45 endoglucanases. Here, we report catalytic activity for a single-domain ERP, Gt EXPN_133317, from the brown-rot fungus Gloeophyllum trabeum , which is highly expressed in the early phase of spruce colonization. We demonstrate enzyme-dependent formation of xylan-derived products, such as glucuronylated xylo-oligosaccharides, using high-performance anion exchange chromatography with pulsed amperometric detection. Structure-based multiple sequence alignment of ERPs with GH45 endoglucanases showed that, next to a single conserved aspartate (Asp87 in Gt EXPN_133317) present in all ERPs and GH45s, fungal ERPs contain a second conserved acidic residue (Asp25 in Gt EXPN_133317). Mutation of these two conserved amino acids, Asp87 and Asp25, led to a nearly complete loss of xylanolytic activity. While these findings do not exclude the possibility of a noncatalytic plant cell wall–loosening mechanism, they show that ERPs likely have other modes of action besides what the current paradigm states.
GPT-4o mini: Non-social science research article
“Excluded phenotypes” restrict genetic paths toward adaptation in declining populations
James S. Andon, Charles D. Kocher, Ken A. Dill, Tina Wang
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Evolutionary rescue is the process by which declining populations adapt to conditions that would otherwise cause their extinction. Considering the spectrum of mutant phenotypes that can arise within a declining population, there exists the interesting case of mutations which improve fitness relative to the wild-type, but do not restore population growth. Here, we hypothesize that mutations within this phenotype space are functionally inaccessible to populations in decline and term it an “evolutionary excluded zone.” We experimentally demonstrate that this excluded zone disallows certain mutational paths from causing evolutionary rescue in declining populations of M13 bacteriophage. We then integrate this observation into Fisher’s Geometric Model to extrapolate it to other evolutionary rescue scenarios. Our findings indicate that the excluded zone significantly reduces the likelihood of evolutionary rescue by de novo mutation and that evolution is fundamentally different in declining populations than in ones that are constant or growing.
GPT-4o mini: Non-social science research article
Post-encoding administration of oxytocin selectively enhances memory consolidation of male faces in females
Wei Liu, Jiashen Li, Zhengyue Chen, Qingbai Zhao, Xiaojun Sun
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Oxytocin plays a critical role in modulating social cognition and enhancing human memory for faces. However, it remains unclear which phase of memory oxytocin affects to enhance face memory. Our study explored oxytocin’s potential to selectively enhance the consolidation of social memories, specifically human faces, and whether this effect varies between genders. In three preregistered, randomized, double-blind, placebo-controlled trials with heterosexual participants (total N = 445, comprising 227 males and 218 females), we explored how oxytocin affects memory consolidation. We administered oxytocin immediately after encoding (i.e., Study 1), before retrieval (i.e., Study 2), and before encoding (i.e., Study 3) in three parallel studies. This design allowed us to confirm that oxytocin’s effects were indeed due to consolidation rather than retrieval or encoding. We found that administering oxytocin post-encoding, but not before-retrieval or before-encoding, significantly improved female participants’ ability to recognize male faces 24 h later, with no similar enhancement observed in males recognizing opposite-gender faces. Together with our analyses of the social placebo effect—where the belief in receiving oxytocin produces effects similar to those of actual intranasal oxytocin administration—and the approachability ratings during encoding, we concluded that oxytocin specifically enhances the consolidation of long-term social memories in women recognizing male faces. These findings imply that oxytocin selectively enhances the consolidation of human social memory, potentially deepening our understanding of the mechanisms underlying social memory processes.
GPT-4o mini: Non-social science research article
Proteasomal proteolysis in p62 condensates directs tumor suppression or growth depending on their subcellular localization
Chen Lulu-Shimron, Zhiwen Luo, Vera Brekhman, Lina Huang, Ido Livneh, Hidetaka Kosako, Victoria Cohen-Kaplan, Aaron Ciechanover
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p62/SQSTM1 generates liquid–liquid phase-separated condensates that participate in diverse processes, including protein quality control (PQC) and autophagy. Nuclear p62 condensates were shown to act as ubiquitin- and proteasome-mediated degradation hubs, whereas the involvement of cytoplasmic condensates in this pathway has remained unclear. Here, we show that cytoplasmic p62 condensates serve as a hub for proteasomal degradation that displays distinct substrate preferences compared with nuclear condensates. Specifically, cytoplasmic condensates mediate accelerated degradation of the tumor suppressor p53 through recruitment MDM2, its E3 ligase, while nuclear condensates are selectively enriched with USP7, a deubiquitinating enzyme (DUB) that stabilizes p53. Immunohistochemical analysis of human tissues reveal that p62 in healthy tissues is largely localized to the nucleus, whereas in the corresponding malignant tissues, it is largely in the cytosol, which is correlated with reduced p53 abundance in tumors. Nuclear p62 condensates also promote the degradation of oncogenic c-Myc, underscoring compartment-specific differences in protein turnover. Experiments in cancer cells and xenografts demonstrate that cytoplasmic p62 condensates drive tumor growth, whereas nuclear p62 condensates suppress it. Moreover, condensate formation rather than p62 expression alone is required for both enhanced proteolytic activity and tumor growth modulation. Proteomic analysis reveals that nuclear p62, unlike its cytosolic counterpart, is linked to enrichment of proteins associated with apoptosis, p53 stabilization, DNA damage response, and cellular senescence—all related to tumor suppression. These findings establish that p62 condensates provide compartment-specific regulation of ubiquitin and proteasomal degradation and suggest that manipulating their localization or affecting their dynamics can offer different therapeutic opportunities.
GPT-4o mini: Non-social science research article
Ubiquitination of BAM1 attenuates CLE peptide–mediated signaling in the root apical meristem
Yuanyuan Zhou, Fei Liu, Yongfeng Han, Jiaojiao Bai, Baowen Zhang, Wenqiang Tang, Xiaoping Gou, Yan Zhang, Dongping Lu
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The plasma membrane-resident receptor-like kinases (RLKs) and their cognate peptide ligands play crucial roles in plant growth and development. The RLK BARELY ANY MERISTEM1 (BAM1) promotes phloem formation and regulates other aspects of root development. However, the mechanisms governing BAM1 protein degradation remain unclear. In this study, we demonstrate that two closely related ubiquitin ligases, RING DOMAIN LIGASE 1 (RGLG1) and RGLG2, specifically interact with BAM1 and its closest homolog BAM2. RGLG1/2 ubiquitinate BAM1/2 and mediate their degradation, thereby dampening BAM1/2 signaling. Treatment with the peptide CLE13 (CLV3/EMBRYO SURROUNDING REGION-RELATED 13) enhances the BAM1/2-RGLG2 interaction and the ubiquitin ligase activity of RGLG2, resulting in increased ubiquitination and degradation of BAM1/2 by RGLG1/2. The rglg1 rglg2 double mutant exhibits increased sensitivity to CLE13 compared to the wild type. Collectively, our findings demonstrate that RGLG1/2-mediated ubiquitination and degradation of BAM1/2 attenuate CLE13-mediated signaling in root meristem.
GPT-4o mini: Non-social science research article
Evolution of environmental sex determination via juvenile hormone–induced gene co-option in Daphnia
Yugo Takahata, Moe Kusajima, Shione Abe, Misato Okamoto Miyakawa, Tomohiro Suzuki, Hideo Dohra, Hitoshi Miyakawa
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Juvenile hormone (JH) exerts pleiotropic effects in insects, regulating not only metamorphosis and reproduction but also caste differentiation, morphogenesis, and diapause. How such diverse functions evolved from the ancestral role of JH remains poorly understood. The water flea, Daphnia , provides a striking case in which JH governs environmental sex determination (ESD) by inducing male production. Nonetheless, the molecular pathway linking maternal JH signaling to sex determination has remained unknown. Here, we identify the circadian gene, vrille ( Dpvri ), as a direct transcriptional target of JH signaling. Reporter assays revealed that Dpvri is activated by the JH receptor complex (Methoprene-tolerant/steroid receptor coactivator) via newly acquired 9-bp JH response elements (9 bp-JHREs) in its regulatory region, whereas the beetle ( Tribolium ) vri gene lacks such elements and did not show JH-responsive expression. This demonstrates that the presence or absence of specific regulatory sequences underlies interspecific differences in JH responsiveness. CRISPR/Cas9 mutagenesis of a single JHRE substantially reduced JH-dependent Dpvri expression and elevated the threshold for male induction, demonstrating its causal role in vivo. Comparative sequence analyses showed that JHREs in vri are conserved in the Cladocera, but absent in the crustacean, Artemia , suggesting that their emergence coincided with the origin of ESD in this lineage. These findings reveal the evolutionary co-option of vri into the JH pathway via acquisition of a JHRE, providing a mechanistic explanation for diversification of JH functions in arthropods.
GPT-4o mini: Non-social science research article
Forest loss and landscape pattern change cause watersheds to release more young water
Ming Qiu, Xiaohua Wei, Yiping Hou
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The hydrological functions of forests are well recognized, but their influence on water storage and release dynamics remains poorly quantified. The fraction of young water ( F yw )—the proportion of streamflow younger than 2 to 3 mo—serves as an integrative indicator of a watershed’s capacity to retain and release precipitation. Here, by analyzing F yw across 657 watersheds worldwide, we found that forest cover exhibited a significant negative relationship with F yw . The causality was further corroborated through a meta-analysis of postdeforestation F yw trends, confirming that forest loss accelerates the conversion of recent precipitation into streamflow. This effect was most pronounced in watersheds with shallow groundwater, highlighting the role of forests in regulating rapid, near-surface flowpaths. Beyond total forest cover, we found that forest landscape patterns also exerted influences: A lower proportion of forest edge was associated with higher F yw , but only in sparsely forested watersheds ( ≀ ∌ 40% forest cover), where the edge-enhanced evapotranspiration was most pronounced. This global synthesis not only reinforces the hydrological value of forest conservation and restoration but also highlights that deliberate planning of forest landscape patterns can help mitigate the hydrological consequences of forest loss. Together, these findings demonstrate that integrating forest protection with forest landscape planning is essential for sustaining hydrological functions.
GPT-4o mini: Non-social science research article
Coral reef fish may be more important than we thought
Jason S. Link
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GPT-4o mini: Non-social science research article
The molecular mechanism of lipid uptake by membrane-anchored bridge-like lipid transfer proteins
Daniel Álvarez, Paige Chandran Blair, Cristian Rocha-Roa, Michael Davey, Elizabeth Conibear, Stefano Vanni
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Lipid transport by bridge-like lipid transfer proteins (BLTPs) is emerging as a key process in lipid and cellular metabolism in both physiological and pathological conditions. However, the precise mechanism of lipid transport by BLTPs has remained elusive. Here, we use extensive all-atom molecular dynamics simulations to characterize the precise mechanism of lipid transfer into the BLTP hydrophobic cavity from donor membranes. For multiple BLTPs, we observe the ability to extract and solubilize lipids without lipid selectivity, and we identify membrane destabilization as a critical parameter to achieve effective lipid desorption. We rationally design a mutant BLTP with altered ability to destabilize lipid bilayers, and we show that this abolishes lipid desorption in silico and protein function in vivo. Taken together, our data provide an atomic-level description of the mechanism of lipid transport by BLTPs, ultimately suggesting alternative strategies to interfere with their activity.
GPT-4o mini: Non-social science research article
Structural characterization of the HDV virion and its ribonucleoprotein
Samuel Itskanov, Beatrice Ary, Upasana Mehra, Irene Lew, Nikolai Novikov, Uli Schmitz, Meghan M. Holdorf, Rudolf K. Beran, Eric B. Lansdon
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Hepatitis D virus (HDV) is a small RNA satellite virus of hepatitis B virus (HBV) which encodes a single protein, HDV delta antigen (HDAg), that is required for replication. Viral replication occurs independently from HBV and relies primarily on host RNA polymerase(s). Bulevirtide, a viral entry inhibitor, is the only approved treatment for chronic HDV but has a low cure rate as a monotherapy, and most patients rebound following cessation of therapy. It is likely that an inhibitor targeting HDV replication is necessary to achieve HDV cure, but the paucity of HDV-derived elements and limited understanding of HDV replication presents a significant therapeutic challenge. Understanding the precise mechanism of interactions between HDAg and viral RNA, and how it is packaged within the virion can inspire structure-guided drug design targeting replication. Using cryoelectron tomography and single particle cryoelectron microscopy, we present reconstructions of the virion and viral RNPs. We observed multiple binding configurations in vitro that suggest a propensity to arrange four RNA segments around repeating units of HDAg in a ladder-like formation. The oligomerization domains of a homo-octameric HDAg complex are directly involved in RNA binding by utilizing the vertices and sides of its square-shaped architecture to bind RNA in a sequence-promiscuous fashion. Structure–function analysis reveals that these RNA contact sites are important for viral replication and their disruption may be a potential avenue for next-generation antivirals to treat HDV.
GPT-4o mini: Non-social science research article
An activator of a two-component system controls cell separation and intrinsic drug resistance in Mycobacterium tuberculosis
Liam D. McDonough, Shuqi Li, Vanisha Munsamy-Govender, Celena M. Gwin, Jeremy M. Rock, E. Hesper Rego
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Unlike commonly studied rod-shaped bacteria, mycobacteria grow from their poles, requiring precise coordination between division and initiation of new pole growth. The mechanisms that mediate this transition are largely unknown, but likely represent a rich source of drug targets for the treatment of mycobacterial infections, including tuberculosis. Here, we identify TapA (MSMEG_3748/Rv1697) as a key regulator of this transition. TapA interacts with the sensor kinase MtrB at the septum to initiate a signaling cascade that ultimately results in the expression of the essential peptidoglycan hydrolases RipAB, among others, at the end of division. Loss of TapA disrupts division, dysregulates pole formation, and sensitizes Mycobacterium tuberculosis and other mycobacteria to several first and second-line TB antibiotics, establishing TapA as a potential therapeutic target, and defining a link between cell cycle progression, envelope remodeling, and intrinsic antibiotic resistance in mycobacteria.
GPT-4o mini: Non-social science research article
Polar vortex dynamics on gas giants: Insights from 2D energy cascades
Jiaru Shi, Wanying Kang
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The distinct polar vortex dynamics observed on Jupiter and Saturn may provide insights into their interiors. In this study, we examine how the number and structure of polar vortices vary with forcing strength, dissipation rate, and interior stratification using a 1.5-layer quasi-geostrophic model. This simplified setup enables a broad exploration of the parameter space, revealing that vortex characteristics are determined by the sequence in which three key length scales—the deformation radius L d , the zonostrophic scale L Îł , and the dissipative scale L ÎŒ —are encountered as energy cascades from small to large scales. Four distinct vortex patterns are identified, including a vortex crystal resembling Jupiter’s polar vortices and a single-vortex state akin to that of Saturn. The conditions under which these patterns emerge provide constraints on the stratification of Jupiter and Saturn.
GPT-4o mini: Non-social science research article
An active matter model captures spatial dynamics of actomyosin oscillations in larval epithelial cells during Drosophila morphogenesis
Euan D. Mackay, Aimee Bebbington, Jens Januschke, Jochen Kursawe, Marcus Bischoff, Rastko Sknepnek
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The apicomedial actomyosin network is crucial for generating mechanical forces in cells. Oscillatory behavior of this contractile network is commonly observed before or during significant morphogenetic events. For instance, during the development of the Drosophila adult abdominal epidermis, larval epithelial cells (LECs) undergo pulsed contractions before being replaced by histoblasts. These contractions involve the formation of contracted regions of concentrated actin and myosin. The emergence and control of pulsed contractions are not fully understood. Here, we combined in vivo 4D microscopy with numerical simulations of an active elastomer model applied to realistic cell geometries and boundary conditions informed by cell polarity to study in vivo subcellular spatial patterns of LEC actomyosin dynamics. The active elastomer model quantitatively reproduced in vivo observations. When compared to rectangular domains, simulations on realistic cell geometries showed systematically better agreement with experiments. We found that cell shape, cell polarity, and organization of the cell’s actomyosin network codetermine spatiotemporal network dynamics both in vivo and in simulations. Furthermore, the model predicted changes to LEC contractile activity under genetic perturbation of the actomyosin network. Our results show that cell geometry, accompanied by boundary conditions which reflect the cells’ polarity, is important to understanding the dynamics of the apicomedial actomyosin network. Moreover, our findings support the notion that spatiotemporal oscillatory behavior of the actomyosin network is an emergent property of the actomyosin network, rather than driven by upstream signaling.
GPT-4o mini: Non-social science research article
Functionally heterogeneous intratumoral CD4 + CD8 + double-positive T cells can give rise to single-positive T cells
Tony Li, Arielle Ilano, Marcel Arias-Badia, Diamond Luong, Hewitt Chang, Serena S. Kwek, Kathryn Allaire, Arun Chumber, Mason Sakamoto, Matthew Clark, Averey Lea, Mark Bridge, Brandon Chen, Eric Liu, Sima Porten, Maxwell V. Meng, Lauren I. R. Erlich, David Y. Oh, Lawrence Fong
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Conventional single-positive (SP) CD4 + and CD8 + T cells recognize tumor antigens and help mediate clinical responses with cancer immunotherapy. Double-positive CD4 + CD8 + (DP) T cells have also been described in human cancers, but their role in the tumor microenvironment remains unclear. By generating a multiomic single cell atlas of DP and SP T cells, we find that DP T cells possess phenotypic heterogeneity similar to SP T cells that includes multiple clonally expanded populations of cytotoxic DP T cells in human renal cell carcinoma (RCC). These intratumoral DP T cells can mediate both MHC class I- and class II-dependent killing of autologous tumor cells. In addition, transcriptional profiling of DP TCR-bearing T cells revealed a gene signature enriched for clinical responders to PD-1 blockade in advanced RCC. We confirm prior observations of SP T cells transitioning into DP T cells and more notably, demonstrate that intratumoral T cells are capable of bidirectional differentiation in which DP T cells serve as precursors to SP T cell sin vivo. In the latter scenario, intratumoral DP T cells are shown to express Rag2 , suggesting that the tumor may act as an extrathymic site of T cell development. These findings reveal the multiple roles that DP T cells can possess in antitumor immunity.
GPT-4o mini: Non-social science research article
Spatially regulated mRNA translation enables functional membrane protein integration in synthetic cells
Hang Fu, Lijuan Ma, Chunhua Xu, Jinghua Li, Haochen Ouyang, Congbao Xie, Yunhai Sun, Yuanxiao Tao, Hao Wang, Shuxin Hu, Meifang Fu, Hai Zheng, Honghong Zhang, Chenli Liu, Fangfu Ye, Yan Qiao, Ming Li, Ying Lu
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Synthetic cells aim to emulate living systems by reconstituting essential cellular processes within lipid-bound architectures. However, their functional complexity remains constrained by a key challenge: the synthesis and correct integration of hydrophobic membrane proteins via cell-free approaches. Here, inspired by natural cells, we developed a spatially regulated translation strategy in which membrane-anchored mRNAs recruit ribosomes to drive the cotranslational insertion of membrane proteins into lipid bilayers. This design enables efficient in situ synthesis and integration of multiple transmembrane proteins within giant unilamellar vesicles, supporting selective small-molecule transport across membranes. Importantly, the method allows for precise stoichiometric control of membrane protein composition. Together, this work establishes a minimal yet versatile framework for the direct synthesis and integration of membrane proteins, advancing the construction of functional synthetic cells.
GPT-4o mini: Non-social science research article
Stochastic motility energetics reveals cooperative bacterial swarming in optical tweezers
Clara Luque-Rioja, Horacio LĂłpez-MenĂ©ndez, Macarena Calero, NiccolĂČ Caselli, Diego HerrĂĄez-Aguilar, Juan Pedro G. Villaluenga, Francisco Monroy
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Bacterial flagellar swarming enables dense microbial populations to migrate collectively across surfaces, often resulting in emergent, coordinated behaviors. However, probing the underlying energetics of swarming at the single-cluster level remains a challenge. Here, we combine optical tweezers and multiparticle tracking within a stochastic thermodynamic framework to characterize the active motility of confined Proteus mirabilis clusters. Using the photon momentum method to directly measure trapping forces, we show that swarming clusters generate persistent, dissipative flows indicative of nonequilibrium stationary motility within confined solenoidal mesostructures. These flagellar rotational dynamics break detailed balance in mesoscopic force space and exceed the limits of passive friction, as evidenced by force-velocity correlations and vortex-like circulations. By coarse-graining cluster trajectories into an active Brownian phase space, we quantify the work performed by bacterial swarms at cooperative coupling to thermal fluctuations, resulting in dissipative Ohmic-like currents overcoming conservative trapping. Our findings establish a generalizable approach to quantify collective motility and energetic dissipation in active bacterial clusters under confinement, offering insights into the physical principles governing microbial cooperativity.
GPT-4o mini: Non-social science research article
Spatial clustering modifies competition in a diverse annual plant community
Theo L. Gibbs, Zachary J. Gold, Haylee Oyler, Jonathan M. Levine, Nathan J. B. Kraft
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Spatial patterns are widespread in nature, and their formation has been studied extensively. However, the effects of spatial aggregation on the strength of species interactions are less well understood, especially in diverse ecological communities. In a field experiment with annual grassland plants in California, we manipulated the spatial arrangement—but not the number or identity—of two competitors and measured how they jointly affected a focal individual. We found that focal plants produced more seeds when their competitors were clustered than when they were mixed. These results suggest that mixed competitors generally had a more negative effect than clustered competitors. However, the effect of clustering varied across the pairs of competitor species. Competitor species that exhibited greater differences in size and/or functional traits across the spatial arrangements resulted in larger effects of clustering on focal plant seed production. Additionally, a competitive hierarchy among our study species predicted the effects of clustered versus mixed competitors on focal plant seed production. Altogether, our work suggests that the spatial arrangement of competitors changes the realized strength of competition in diverse plant communities. Given the extensive variation in spatial aggregation in plant communities, this mechanism is likely to be a powerful but underappreciated force shaping competition in nature.
GPT-4o mini: Non-social science research article
A bacterial translation activator with an intrinsically disordered RNA-binding region
Pallabi Basu, Elizabeth A. Farland, James C. Charity, Kade A. Townsend, Simon L. Dove
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Bacterial RNA-binding proteins (RBPs) that control the translation of multiple transcripts act largely as negative regulators. Here, we report the identification and characterization of a positive regulator of translation (called PhaF) in the opportunistic pathogen Pseudomonas aeruginosa . Using CLIP-seq and CLAP-seq we identify upward of 50 transcripts targeted by PhaF. We demonstrate that PhaF acts to stimulate the translation of target mRNAs by binding upstream of the Shine–Dalgarno sequence using one or more of the multiple KPAA motifs located in an intrinsically disordered region of the protein. Importantly, we show that PhaF plays a key physiological role in P. aeruginosa through its translational control of the pslA transcript required for exopolysaccharide synthesis and biofilm formation. Our findings uncover an activator of translation in bacteria that binds target transcripts using an RNA-binding region reminiscent of those that are prominent in eukaryotic RBPs.
GPT-4o mini: Non-social science research article
Molecular underpinnings of induced degenerative heterogeneity in the retinal pigment epithelium
Krishna Kumar Singh, Yang Jin, Ming-Wen Hu, Isabella Palazzo, Marisol Cano, Thanh Hoang, Imran Bhutto, Shusheng Wang, Debasish Sinha, Seth Blackshaw, Jiang Qian, James T. Handa
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Cigarette smoking induces epigenetic changes that can cause degenerative heterogeneity with aging and disease. In disease such as age-related macular degeneration (AMD), the leading worldwide cause of blindness among the elderly, retinal pigment epithelial (RPE) cell heterogeneity is a key change. Since smoking is a powerful risk factor for AMD, we hypothesized that smoke induces epigenetic-mediated degenerative RPE heterogeneity. We administered cigarette smoke condensate (CSC) to young and aged mice. Using snRNA-seq and single nuclear ATAC sequencing, we identified distinct healthy and dedifferentiated RPE clusters in both aged vehicle- and young CSC-treated mice. Dedifferentiated RPE had globally decreased chromatin accessibility and expression of genes linked to “hallmarks of aging.” Notably, young, dedifferentiated RPE also exhibited a compensatory upregulation of hallmarks of aging-related genes including mitochondrial function and proteostasis while aged dedifferentiated RPE did not, which decreased their survival following CSC treatment, as experimentally verified with TUNEL labeling. Similar populations of dedifferentiated and healthy RPE were identified both in mice exposed to cigarette smoke for 4 mo and in macular RPE from a donor who smoked and another with early AMD, but not from a nonsmoker donor. Degenerative cellular heterogeneity that includes an abnormal cluster can jeopardize cell survival and represents a hallmark of ocular aging.
GPT-4o mini: Non-social science research article
Sleep loss induces cholesterol-associated myelin dysfunction
Reyila Simayi, Eleonora FiciarĂ , Oluwatomisin Faniyan, Antonio CerdĂĄn CerdĂĄ, Amina Aboufares El Alaoui, Rosamaria Fiorini, Adele Cutignano, Fabiana Piscitelli, Aroa S. Maroto, Alexandra Santos, Federico Del Gallo, Luisa de Vivo, Silvia De Santis, Michele Bellesi
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The increasing prevalence of sleep deprivation poses a public health challenge in modern society. Manifestations of reduced alertness, such as slowed reaction times and increased errors, are well-documented behavioral indicators of sleep loss (SL). Yet, the biological consequences of sleep deprivation and their role in behavioral impairment remain elusive. Our study reveals significant effects of sleep deprivation on myelin integrity. As a result, we identify increased conduction delays in nerve signal propagation, hindered interhemispheric synchronization, and impaired cognitive and motor performance associated with SL. By profiling oligodendrocyte transcriptome and lipidome, we observe SL-induced endoplasmic reticulum stress and lipid metabolism dysregulation, particularly affecting cholesterol homeostasis. Boosting cholesterol transport to myelin sheaths prevents SL effects on nerve signal propagation and behavior. Our findings highlight a possible role of oligodendrocyte cholesterol dysregulation in behavioral deficits associated with SL and unveil a novel target for intervention.
GPT-4o mini: Non-social science research article
Real-time spatiotemporal tracking of infectious outbreaks in confined environments with a host–pathogen agent-based system
Suhas Srinivasan, Jeffrey King, Jacob M. Collins, Andres Colubri, Dmitry Korkin
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Deadly infection outbreaks in confined spaces, whether it is a COVID-19 outbreak on a cruise ship or measles and stomach flu outbreaks in schools, can be characterized by their rapid spread due to the abundance of common spaces, shared airways, and high population density. Preventing future outbreaks and developing efficient mitigation protocols can benefit from advanced computational modeling approaches. Here, we developed an agent-based modeling approach to study the spatiotemporal dynamics of an infection outbreak in a confined environment caused by a specific pathogen, and to determine effective containment protocols. The approach integrates the 3D geographic information system of a confined environment, behavior of the hosts, key biological parameters about the pathogen obtained from the experimental data, and the general mechanics of host–pathogen and pathogen–fomite interactions. To assess our approach, we applied it to the historical data of infectious outbreaks caused by norovirus, H1N1 influenza A, and SARS-CoV-2 viruses. Our AI-GIS Infection Dynamics (AGID) model accurately predicted daily infection numbers, correctly identified the day when the CDC vessel sanitation protocol would be triggered, singled out key biological parameters affecting the infection spread, and propose pathogen-specific changes to existing containment protocols. Our work advances the understanding of infection spread on cruise ships while offering insights applicable to other similar confined settings, such as nursing homes, schools, and hospitals. By providing a robust framework for real-time outbreak modeling, this study proposes more effective containment protocols and enhances our preparedness for managing infectious diseases and emerging pathogens in confined environments.
GPT-4o mini: Non-social science research article
Soft giant magnetoimpedance electronics enable contact-free human–machine interactions
Yizhang Wu, Sicheng Xing, Dingyi Yang, Yihan Liu, Chi Ding, Zifeng Li, Qizhang Jiao, Anran Zhang, Ziheng Guo, Siyuan Liu, Wei Luo, Gongkai Yuan, Meixiang Wang, Yong Wang, Michael D. Dickey, Wubin Bai
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Magnetic sensing enables contact-free, three-dimensional human–machine interactions (HMI) with high selectivity and resilience to environmental noise. However, conventional magnetic films, mostly obtained via vacuum deposition, remain constrained by rigidity, instantaneous response, and single-mode. Here, we report a giant magnetoimpedance ionogel (GelGMI) in which electrostatically self-assembled ferromagnetic (FM) domains are uniformly dispersed in a soft ionogel matrix. Under a magnetic field, domain moments realign to reconfigure ionic pathways, yielding pronounced magnetoimpedance while maintaining performance at >1,000% strain and across orientations. The hysteretic relaxation of domain magnetization imparts retrospective neuron-like temporal summation, realizing sequence- and context-aware interaction. In addition, the self-healable matrix supports a complementary tactile mode whose impedance contrasts with contact-free magnetic proximity, enabling expandable and bimodal recognition. GelGMI delivers a record-high sensitivity while unifying stretchable, neuromorphic, and healable capabilities for contact-free HMI systems.
GPT-4o mini: Non-social science research article
Quantifying the compressibility of the human brain
Nicholas J. Weaver, Joshua Faskowitz, Richard F. Betzel, Christopher W. Lynn
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In the human brain, the allowed patterns of activity are constrained by the correlations between brain regions. Yet it remains unclear which correlations—and how many—are needed to predict large-scale neural activity. Here, we present an information-theoretic framework to identify the most important correlations, which provide the most accurate predictions of neural states. Applying our framework to cortical activity in humans, we find that the vast majority of variance in activity is explained by a small number of correlations. This means that the brain is highly compressible: Only a sparse network of correlations is needed to predict large-scale activity. We find that this compressibility is strikingly consistent across different individuals and cognitive tasks and that, counterintuitively, the most important correlations are not necessarily the strongest. Together, these results suggest that nearly all correlations are not needed to predict neural activity, and we provide the tools to uncover the key correlations that are.
GPT-4o mini: Non-social science research article
α2-macroglobulin function of thioester-containing proteins guards Drosophila from a bacterial protease via two immune-induced peptides
Chuping Cai, Adrian Acker, Jianqiong Huang, Yingying Liu, Maria Victoria Molino, Javier F. Mariscotti, Eleonora Garcia-VĂ©scovi, Philippe Bulet, Philippe Hammann, Johana Chicher, Samuel Liegeois, Zi Li, Jules A. Hoffmann, Nicolas Matt, Dominique Ferrandon
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RNAseq analysis of the Drosophila genome has revealed further immune-induced genes. Two genes initially annotated as lncRNAs, CG44404 ( yulĂŒ ) and CG45045 ( shenshu ), are strongly induced. We report here that these two genes actually encode highly related secreted peptides found in the Sophophora subgenus of Drosophila species. We have generated single and double null mutants of these loci and found that the double mutant line did not display any enhanced susceptibility to an immune challenge with a panel of bacterial and fungal pathogens, except for Pseudomonas aeruginosa . We did not observe any increased P. aeruginosa burden in yulĂŒ-shenshu mutants, suggesting that the two peptides may not be required for resistance to infection. Rather, we find that they provide a level of protection against Outer Membrane Vesicles (OMVs) purified from either P. aeruginosa or Serratia marcescens culture supernatants. We have recently reported that S. marcescens OMVs induce the paralysis of flies through the induction of apoptosis in at least some neurons. Much of the virulence of these OMVs is mediated by the metalloprotease PrtA. While YulĂŒ/Shenshu do not display any protease inhibition activity, the detection of an association between YulĂŒ and the Drosophila complement thioester-containing protein 2 (Tep2) led to the finding that both Tep2 and Tep4 mutants are sensitive to the injection of PrtA while their overexpression significantly protects wild-type flies from the effects of this protease. Both Tep2 and Tep4 are able to inhibit the activity of PrtA in a thioester- and yulĂŒ/shenshu -dependent manner. Thus, these Teps may also function as α2-macroglobulins.
GPT-4o mini: Non-social science research article
No deep insights into the alignment between human and deep learning reasoning processes: Thoughts on de Varda et al. (2025)
Marin Dujmović
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GPT-4o mini: Non-social science research article
A cytokine receptor–targeting chimera toolbox for expanding extracellular targeted protein degradation
Kaan Kumru, Zi Yao, Brandon B. Holmes, Fangzhu Zhao, Yun Zhang, Emilio Ferrara, Trenton M. Peters-Clarke, Kevin K. Leung, James A. Wells
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Extracellular targeted protein degradation (eTPD) is an important new modality for manipulating the extracellular proteome. However, most eTPD receptors are expressed broadly or are restricted to the liver, limiting specific degradation in other tissues. Cytokine receptor–targeting chimeras (kineTACs) are genetically encoded bispecifics for eTPD that fuse a natural ligand like CXCL12 to an antibody, directing soluble or membrane proteins for lysosomal degradation using the widely expressed chemokine receptor CXCR7 (K. Pance et al. , Nat. Biotechnol. 41 , 273–281 (2023)]. Here, we dramatically expand the kineTAC toolbox by constructing 81 different kineTACs based on an unbiased list of cytokines, chemokines, and growth factors. Remarkably, 55 of these expressed at suitable levels for analysis without any optimization. Many of these kineTACs bind receptors that have unique cell-type expression profiles, allowing for eTPD in specific cells and tissues, and some were more potent than the original CXCL12-based kineTAC against specific targets. We further show the internalizing capability of a kineTAC can enhance the performance of antibody drug conjugates. We believe these simple, genetically encoded tools will be useful for expanding the applications for optimized or cell type–selective eTPD.
GPT-4o mini: Non-social science research article
Regulating ion transport and solvation chemistry in zwitterionic gel polymer electrolyte for high-performance quasi-solid-state batteries
Lu Nie, Xinru Wu, Haotian Qu, Runhua Gao, Xiao Xiao, Zhihong Piao, Gongxun Lu, Wenqiang Fang, Yanfei Zhu, Guangmin Zhou
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Gel polymer electrolytes (GPEs) are promising electrolyte candidates for next-generation Li metal batteries (LMBs). However, the reverse migration of free anions causes uneven distribution of space charges and Li + flux, ultimately accelerating dendrite growth. Additionally, strong ion–solvent interactions lead to high Li + desolvation barriers and sluggish Li + transfer kinetics. To address these issues, we design a zwitterionic GPE, where the synergistic effects of zwitterionic groups promote Li-salt dissociation through ion–dipole interactions and simultaneously restrict anion migration, effectively suppressing space charge-induced dendrite growth. Moreover, the competitive coordination of zwitterions with Li + weakens the Li + -solvent interaction, accelerating interfacial Li + desolvation. Zwitterions in the inner solvation shell of Li + are preferentially reduced before the solvents, forming a conductive N- and S-rich inorganic interphase that enhances cycling stability. As a result, the zwitterionic GPE enables the Li||SPAN cells to deliver a high discharge capacity of 528.3 mAh g −1 at −20 °C, and achieve 79.6% capacity retention after 1,000 cycles. Besides, the Li||SPAN pouch cell, with an active mass loading of 10.5 mg cm −2 , delivers a high discharge capacity of 1.63 Ah and an impressive areal capacity of 16.3 mAh cm −2 . This work highlights the importance of regulating ion transport and ion–solvent chemistry for advanced quasi-solid-state LMBs.
GPT-4o mini: Non-social science research article
Conservation should assume realistic adaptive capacities
Mark C. Urban, Chris S. Elphick, Daniel I. Bolnick
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Conservation actions often assume implicitly that heritabilities are zero and that threatened populations cannot adapt to changing environments. To illustrate, we evaluated the last 10 y of recovery plans for US threatened and endangered species and found that only 4% assessed within-population adaptability. This omission reflects the common assumption that population adaptation is too slow or inconsequential to affect conservation practice in the short term. Yet, the median heritability (h 2 ) and evolvability (I A ) across many studies are not zero as assumed, but 0.3 and 0.4, respectively, based on a compilation of estimated values. This moderate heritability could rescue some populations. By compiling literature on conservation assessments, we detail how considering adaptability can shift conservation priorities, alter management recommendations, and provide additional ways to rescue declining populations and species. Based on these findings, we advocate for including population adaptability into conservation plans and adopting the prior expectation of moderate adaptability (h 2 = 0.3, I A = 0.4) along with its uncertainty, as a starting point when better information is lacking. This moderate adaptability could allow some species to respond naturally to environmental change while directing limited resources toward the species that need it most.
GPT-4o mini: Non-social science research article
Structural basis for iterative methylation by a cobalamin-dependent radical S -adenosylmethionine enzyme in cystobactamids biosynthesis
Jiayuan Cui, Bo Wang, Ravi K. Maurya, Squire J. Booker
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Cystobactamids are nonribosomal peptide natural products that function as DNA gyrase inhibitors, exhibiting significant antibacterial activity. They are isolated from Cystobacter sp. Cbv34 and contain various alkoxy groups on para-aminobenzoic acid moieties, which are believed to play a crucial role in antibacterial functions. The alkoxy groups are generated by iterative methylations on a methoxy group by the cobalamin (Cbl)-dependent radical S -adenosylmethionine (SAM) enzyme CysS. CysS catalyzes up to three methylations to give ethoxy, isopropoxy, sec-butoxy, and tert-butoxy groups. For each methylation, CysS uses a ping–pong mechanism in which two molecules of SAM are consumed. One SAM is used to methylate cob(I)alamin, while another generates a 5â€Č-deoxyadenosyl 5â€Č-radical to initiate substrate methylation. However, little is known about how the enzyme promotes both Cbl methylation and iterative substrate methylation, which occur by polar S N 2 and radical processes, respectively. Here, we report three X-ray crystal structures of a homolog of CysS from Corallococcus sp. CA054B . Two were determined in the presence of methoxy- and ethoxy-containing substrates, showing how CysS accommodates substrates and products during iterative methylation. The third structure, determined in the absence of a substrate, exhibits structural changes that reorient the SAM’s conformation to allow for the methylation of cob(I)alamin.
GPT-4o mini: Non-social science research article
Aging populations threaten conservation goals of zoos
JoĂŁo Pedro Meireles, Max Hahn-Klimroth, Laurie Bingaman Lackey, Nick van Eeuwijk, Mads Frost Bertelsen, Severin Dressen, Paul Wilhelm Dierkes, Andrew J. Abraham, Marcus Clauss
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Improvements in wildlife husbandry mean that many zoo animals are living longer. This has put pressure on the finite holding capacity of zoos, which has often been addressed through a curtailing of reproduction to reduce population growth rates. Here, we explore how such actions have impacted the demographic trends of 774 mammal populations in European and North American zoo populations between 1970 and 2023. Irrespective of whether the data are clustered by region, taxonomic group, conservation status, or breeding program type, the proportion of old individuals has increased continuously, mirrored by a decrease in juveniles and actively reproducing adults. This aging demographic trend compromises the long-term sustainability of zoo populations and thus the ability of zoos to meet ex situ conservation goals. As the observed trends do not show signs of abating, reflection on current zoo population management is required.
GPT-4o mini: Non-social science research article
A neural circuit basis for reward-induced suppression of fear generalization and enhancement of fear extinction
Yong Sang Jo, Mi-Seon Kong, Ekayana Sethi, Gyeong Hee Pyeon, Larry S. Zweifel
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How positive and negative affective stimuli interact in the brain to influence behavioral outcomes remains poorly understood. Here, we show that recall of a positively valenced reward-associated cue (reward-conditioned stimulus, CS Rew +) can prevent or reverse fear generalization in mice. Modification of generalized fear by recall of a CS Rew + is dependent on the midbrain dopamine system and the regulation of discriminatory fear encoding by the central amygdala (CeA). Precisely timed, transient elevations in dopamine are necessary to reverse fear generalization and nondiscriminatory fear encoding in the CeA. Recall of a positive association is also effective at enhancing the extinction of a conditioned fear response in a dopamine-dependent manner. These data demonstrate that recall of a positive experience can be an effective means to suppress generalized fear and show that dopamine projections to the CeA are an important neural substrate for this phenomenon.
GPT-4o mini: Non-social science research article
Beyond species ranges: How functional diversity and integrated life history can inform conservation priorities
Patrick R. Roehrdanz
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GPT-4o mini: Non-social science research article
ER membrane receptors engage core autophagy machinery to initiate ER-phagy
Cha Wu, Haixia Yang, Chen Wang, Peiqi Huang, Ning Yan, Ruobing Ren, Wei Liu, Yi Lu, Chunmei Chang
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Endoplasmic reticulum (ER) phagy is the form of selective autophagy that governs ER abundance and integrity by targeting dysfunctional ER fragments for degradation. How the recognition of ER fragments as autophagy substrates is coupled to engagement of the core autophagic machinery is largely unknown. Here, using a combination of in vitro reconstitution systems, structural modeling, and cell biology, we demonstrate that ER membrane receptors directly engage the core autophagy component ATG9A, as well as the PI3P-binding protein WIPI2, to initiate ER-associated autophagosome biogenesis. ER-phagy receptor–ATG9A association nucleates the recruitment of the other key autophagy proteins required to initiate ER-phagy. In parallel, ER-phagy receptor–WIPI2 engagement promotes rapid LC3 lipidation for autophagic membrane expansion. These data show how ER-phagy receptors trigger the cascade of events leading to ER autophagosome formation.
GPT-4o mini: Non-social science research article
Selective targeting of NRF2-high pancreatic ductal adenocarcinoma with an NQO1-activatable prodrug
Laura Antonucci, Kosuke Watari, Yechen Feng, Jingjing Qi, Mandy Zhu, Tingya Wang, Isabella Ng, Emily A. Vucic, Irene Riahi, Li Huang, Mojgan Hosseini, Evangeline Mose, Randall French, Jonathan Weitz, Dafna Bar-Sagi, David W. Dawson, Beicheng Sun, Herve Tiriac, Jinyi Xu, Shengtao Xu, Andrew M. Lowy, Michael Karin
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Activation of transcription factor NRF2 in pancreatic ductal adenocarcinoma (PDAC) promotes aggressive tumor phenotype and protection from therapy-induced oxidative stress. We postulated that NRF2 high PDAC can be selectively targeted by C29h, a prodrug that is activated by the NRF2-induced enzyme NAD(P)H:quinone oxidoreductase-1 (NQO1), which is elevated in human pancreatic tumors. Initial evaluations of C29h alone or together with the standard-of-care chemotherapeutic drug gemcitabine were conducted on NQO1 high human and mouse PDAC cell lines and patient-derived organoids. As PDAC is enriched in collagen-containing extracellular matrix (ECM) that activates NRF2 and induces NQO1 expression, we examined the ECM effect on the response to C29h, as well as in vivo tumor control in IKKα-deficient Kras G12D /Ikkα ΔPEC mice in which NRF2 is strongly activated, immunocompromised Nu/Nu mice orthotopically transplanted with human PDAC cells and C57BL/6n and NOD/SCID mice transplanted with mouse PDAC. C29h led to NQO1-dependent killing of human and mouse PDAC cell lines and organoids and acted additively with gemcitabine. Furthermore, ECM-plated PDAC cells were more susceptible to C29h cytotoxicity than cells grown on plastic. Importantly, C29h treatment induced tumor regression and increased the survival of PDAC-bearing mice and optimal C29h-induced tumor regression was dependent on CD8 + T lymphocytes whose tumoral recruitment was enhanced by drug treatment. This study supports the use of C29h alone or as part of a drug combination as an effective and promising strategy for selective eradication of NRF2 high PDAC.
GPT-4o mini: Non-social science research article
The contribution of increased global soil salinity to changes in inorganic carbon
Xiaofang Jiang, Xian Xue
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Soil salinization poses a serious environmental challenge, but the impact of global salinity on SIC (Soil Inorganic Carbon) remains unclear. Using 94,515 samples from 0 to 200 cm depth, combined with subregional classification (such as soil type, land use, climate, geomorphology, and soil texture) which helps address spatial heterogeneity, we obtain relatively accurate global distribution data for EC (Electrical Conductivity) and SIC. EC of 0 to 40 cm layer positively influences SIC in most taxonomic subregions, which may be due to the inorganic CO 2 absorption influenced by pH and salinity. EC of 80 to 100 cm layer sometimes negatively influences SIC due to the increase of soil depth. When EC is below 4 dS/m, EC often positively influences SIC. When EC increases by 2 to 4 dS/m, the mean global SIC in 0 to 20, 20 to 40, and 80 to 100 cm layers increases from 66.15, 78.75, and 117.39 to 174.47 to 190.38, 132.76 to 154.98, and 149.14 to 161.37 g/kg, respectively. The increase is relatively high but similar overall, which deserves high attention. These findings elucidate the dynamics of carbon–salt coupling in the soil–atmosphere–water system, offering pivotal scientific insights for carbon-neutrality strategies.
GPT-4o mini: Non-social science research article
Reply to Dujmović: The alignment in cost between human and model reasoning is an empirical phenomenon worth explaining
Andrea Gregor de Varda, Ferdinando Pio D’Elia, Hope Kean, Andrew Lampinen, Evelina Fedorenko
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GPT-4o mini: Non-social science research article
Dynamic regulation of receptor-modulated endothelial NADPH oxidases
Markus Waldeck-Weiermair, Apabrita A. Das, Taylor A. Covington, Jennifer L. Meitzler, James H. Doroshow, Junyi Duan, Yick W. Fong, Jonas Kaynert, Shambhu Yadav, Tanoy Dutta, Fotios Spyropoulos, Arvind K. Pandey, Thomas Michel
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The stable reactive oxygen species (ROS) hydrogen peroxide (H 2 O 2 ) acts as a key signaling molecule for many vital intracellular pathways. In diverse cell types, surface receptors control intracellular H 2 O 2 levels by modulating the activity of NADPH oxidases (NOX), a family of enzymes responsible for ROS synthesis. Most NOX isoforms are regulated through the reversible assembly of protein subunits to form an active oligomeric complex. The NOX isoforms NOX2 and NOX4 are expressed in endothelial cells and generate H 2 O 2 in response to activation of cell surface receptors. The GPCR agonist histamine activates NOX2 independently of NOX4, but the H 2 O 2 response to activation of the receptor tyrosine kinase agonist vascular endothelial growth factor (VEGF) involves both NOX2 and NOX4 by unknown mechanisms [M. Waldeck-Weiermair et al. , Redox Biol. 58 , 102539 (2022); M. Waldeck-Weiermair et al. , Redox Biol. 73 , 103214 (2024)]. Here, we show that endothelial NOX4 is localized to the endoplasmic reticulum (ER). We define the redox states of various subcellular locales in the vascular endothelium and demonstrate that NOX2 is responsible for cytosolic H 2 O 2 signaling, whereas NOX4 contributes to H 2 O 2 generation in the endoplasmic reticulum. Using biochemical assays and structural modeling, we further identify a previously unrecognized regulatory interaction in which the NOX2 subunit p67 associates with NOX4. VEGF stimulation induces dynamic dissociation of p67 from NOX4, unveiling a “cross talk” between NOX isoforms that coordinates the activation of both NOX2 and NOX4 and thereby produces compartment-specific H 2 O 2 signals. This mechanism underscores the pivotal roles of NOX2 and NOX4 subunit interactions in endothelial redox homeostasis controlling cell survival, proliferation, and migration.
GPT-4o mini: Non-social science research article
De novo discovery of bicyclic cysteine-rich peptides targeting gasdermin D
Choi Yi Li, Yin Sun, Alexander A. Vinogradov, Hiroaki Suga
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Gasdermin D (GSDMD) is the principal executor of pyroptosis, a form of proinflammatory programmed cell death misregulation of which is associated with numerous diseases. Despite significant interest, no specific GSDMD inhibitors have been developed for clinical use so far. Here, we developed a strategy to generate mRNA-displayed libraries of bicyclic cysteine-rich peptides (bCRP), and utilized these libraries to develop potent peptide ligands to full-length GSDMD using a two-stage discovery process. Initial hit compounds were de novo discovered from GSDMD affinity selections using Random Nonstandard Peptides Integrated Discovery system, and were then optimized using mRNA display-based saturation mutagenesis. The resulting bCRPs bound to full-length GSDMD (best K D = 125 nM) and stabilized it against cleavage by caspase proteases. The bCRPs prevented the pore formation in liposome leakage assays and inhibited the secretion of IL-1ÎČ and lactate dehydrogenase from pyroptotic THP-1 cells. The potency, high metabolic stability, and synthetic accessibility of the discovered compounds make them promising leads for the development of GSDMD-targeting therapeutics.
GPT-4o mini: Non-social science research article
Chemical tuning reveals a cation–π gating bridge between the voltage-sensor and pore domains in the K v 7.1 potassium channel
Miranda E. Schene, Christopher A. Ahern
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K v 7.1 is a cardiac voltage-gated potassium channel that underlies the delayed rectifier current (I KS ) in the heart. The slow response to membrane depolarization is a hallmark feature of this channel’s physiology, yet the mechanistic basis of how voltage promotes the open potassium conducting state is unknown. We focused on previously identified aromatic residues which might couple the pore and voltage-sensing domains (VSDs) by using a chemical tuning approach whereby aromatic residues are modified by serial fluorination. The data show that serial fluorination at one site (F232 on the S4 helix, within the VSD) resulted in a stepwise voltage-gating shift, where each added fluorine atom further biased channel opening to more negative voltages. Mutant-cycle analysis of proximal positively charged amino acids indicates that F232 likely forms a cation–π interaction with K285, a residue at the tip of the S5 segment in the pore domain. Using cryoelectron microscopy, a partial structure of the F232 penta-F-Phe K v 7.1 (KCNQ1) open channel was resolved to 6 Å. The data support a gating mechanism whereby the F232–K285 cation–π interaction represents an intermediate activated state that is broken prior to channel opening.
GPT-4o mini: Non-social science research article
Molecular structure of the ESCRT-III-based archaeal CdvAB cell division machinery
Tina Drobnič, Ralf Salzer, Tim Nierhaus, Margaret Ke Xin Jiang, Dom Bellini, Astrid Steindorf, Sonja-Verena Albers, Buzz Baum, Jan Löwe
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Most prokaryotes divide using filaments of the tubulin-like FtsZ protein, while some archaea employ instead ESCRT-III-like proteins and their filaments for cell division and cytokinesis. The alternative archaeal system comprises Cdv proteins and is thought to bear some resemblance to ESCRT-III-based membrane remodeling in other domains of life, including eukaryotes, especially during abscission. Here, we present biochemical, crystallographic, and cryo-EM studies of the Sulfolobus Cdv machinery. CdvA, an early non-ESCRT component, adopts a PRC‐domain/coiled-coil fold and polymerizes into long double-stranded helical filaments, mainly via hydrophobic interfaces. Monomeric CdvB adopts the canonical ESCRT-III fold in both a closed and a distinct “semiopen” conformation. Soluble CdvB2 filaments are composed of subunits in the closed state, appearing to transition to the open, active state only when polymerized on membranes. Short N-terminal amphipathic helices in all CdvB paralogues, B, B1, and B2, mediate membrane binding and are required for liposome recruitment in vitro. We provide a molecular overview of archaeal ESCRT-III-based cytokinesis machinery, the definitive demonstration that CdvB proteins are bona fide ESCRT-III homologues, and reveal the molecular basis for membrane engagement. Thus, we illuminate conserved principles of ESCRT-mediated membrane remodeling and extend them to an anciently diverged archaeal lineage.
GPT-4o mini: Non-social science research article
Anharmonicity driven unusual particle-to-wave-like phonon crossover leads to ultralow thermal conductivity in Tl 2 AgI 3
Riddhimoy Pathak, Sayan Paul, Shuva Biswas, Swapan K. Pati, Kanishka Biswas
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Realization of unusual particle-to-wave-like crossover in phonon transport and understanding its fundamental structural origin can guide the design of materials with ultralow thermal conductivity. Here, we report such a crossover from particle-like phonon propagation to wave-like coherence with increasing temperature in the zero-dimensional (0D) metal halide, Tl 2 AgI 3 . Composed of discrete (Tl 6 I) 5+ and (Ag 3 I 8 ) 5− subunits, the structure exhibits intrinsic lattice instability governed by Pauling’s third rule where face-sharing of polyhedra drives Coulombic cationic repulsion causing local distortion of Ag atoms, as confirmed by synchrotron X-ray pair distribution function (X-PDF) analysis and ab initio molecular dynamics (AIMD) simulations. Anharmonic low-energy rattling of Tl is evidenced within the (Tl 6 I) 5+ framework. These structural disorders generate low-frequency localized and anharmonic optical phonons that hybridize with acoustic branches, strongly suppressing lattice thermal conductivity ( Îș l ). Consequently, Îș l drops to ~0.18 W/m.K at 125 K and remains nearly temperature independent, signaling a breakdown of the phonon-gas model, attributed to phonon localization and wave-like coherence, modeled using the linearized Wigner transport equation (LWTE). The phonon localization in the 0D crystal structure results in a crossover from populations conductivity ( Îș p ) associated with particle-like phonon propagation to coherence conductivity ( Îș c ) through wave-like tunneling, at 175 K. Our study reveals 0D structural confinement along with anharmonic local structural dynamics can enable particle-to-wave-like phonon crossover, establishing a pathway to mixed phononic regimes and suppressed thermal transport.
GPT-4o mini: Non-social science research article
Human-induced biospheric carbon sink: Impact from the Taklamakan Afforestation Project
Salma Noor, Xun Jiang, Xinyue Wang, Jiani Yang, Sally Newman, King-Fai Li, Liming Li, Le Yu, Xiyu Li, Yuk L. Yung
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The Taklamakan Desert, one of the world’s largest and driest deserts, has traditionally been considered a biological void. Here, we demonstrate that large-scale ecological restoration is transforming this hyperarid environment into a carbon sink. By analyzing satellite and ground-based data, we find strong seasonal dynamics: During the wet season (Jul to Sep), precipitation increases to 16.3 mm/mo, enhancing vegetation coverage and photosynthetic activity and drawing down atmospheric CO 2 by approximately three parts per million (ppm) relative to the dry-season levels. Long-term trends reveal significant increases in vegetation cover (6.8 × 10 −4 /y) and photosynthetic activity (6.1 × 10 −3 W/m 2 /sr/”m/y), accompanied by a strengthening net CO 2 uptake (NEE trend: −5.2 × 10 −12 kg/m 2 /s/y). These changes are spatially concentrated along the desert margins and their timing aligns with implementation of China’s Three-North Shelterbelt Program. Our results provide the direct evidence that human-led intervention can effectively enhance carbon sequestration in even the most extreme arid landscapes, demonstrating the potential to transform a desert into a carbon sink and halt desertification. This underscores the critical role of dryland restoration in global carbon management strategies and highlights the Taklamakan Desert as a model for climate change mitigation through nature-based solutions and ecological engineering.
GPT-4o mini: Non-social science research article
BORC assemblies integrate BLOC-1 subunits to diversify endosomal trafficking functions
Mariana E. G. de Araujo, Sascha J. Amann, Taras Stasyk, Alexander Schleiffer, Eva Rauch, Paula FlĂŒmann, Isabel I. Singer, Leopold Kremser, Vojtech Dostal, Thanida Laopanupong, Nikolaus Obojes, Moritz H. Wallnöfer, Flora S. Gradl, Robert Kurzbauer, Caroline Krebiehl, Samuel Kofler, Irina Grishkovskaya, Georg F. Vogel, Michael W. Hess, Bettina Sarg, Tim Clausen, David Haselbach, Lukas A. Huber
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BORC and BLOC-1 are multisubunit complexes that regulate endolysosomal trafficking. Although they are presumed to be distinct, their paralogous origins and shared subunits suggest the potential for higher-order assembly. Here, we reveal the conserved octameric architecture of BORC formed by two intertwined tetramers and present the structure of C. elegans BORC. Through cross-linking mass spectrometry of endogenous complexes, we validate this model for human BORC and demonstrate that the integrity of the complex, which is essential for lysosomal transport, relies on specific interfacial residues. We also clarify the disruptive nature of disease-causing mutations and propose that the formation and function of BORC are likely regulated by specific cues. These cues might include the phosphorylation of Snapin and a pH-sensitive histidine residue in BORCS5. Additionally, we present direct biochemical and structural evidence of BORC–BLOC-1 hybrid complexes. Finally, we link a specific hybrid complex to the regulation of transferrin receptor recycling via interaction with the EARP complex. Our work challenges the paradigm of BORC and BLOC-1 as separate entities, establishing a model of dynamic complex formation wherein modular assembly creates functional specialization to meet diverse cellular demands.
GPT-4o mini: Non-social science research article
Human action shapes the beaks of backyard birds
John M. Marzluff
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GPT-4o mini: Non-social science research article
Calumenin prevents fibroblast senescence and lung aging by promoting vimentin proteostasis
Ting Dong, Xue Jiao, Huirui Wang, Yinghui Gao, Yuliang Xu, Hui Li, Senbiao Fang, Xinyi Chen, Mengmeng Wang, Hanbing Zhu, Nianyu Li, Bo Han, Mei Qi, Kaige Lyu, Kaicheng Ma, Ke Li, Haigen Fu, Bowen Gu, Wenfei Li, Yingying Qin, Zi-Jiang Chen, Xiaohui Liu, Hongxiang Lou
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Progressive lung fibrosis is linked to aging-related dysfunction in fibroblasts, which remains poorly understood. To investigate the alterations in fibroblasts, particularly the molecular programs driving this profibrotic evolution in the aging lung, we isolated senescent lung fibroblasts from aged mice. We observed aberrant vimentin aggregates, which correlate with accelerated fibroblast senescence. CRISPR-based screening identified calumenin as a chaperone protein essential for vimentin proteostasis. A fibroblast-specific knockout of calumenin promotes the accumulation of vimentin aggregates and profibrotic factors migracytosis, exacerbating fibroblast senescence and lung aging. Mechanistically, calumenin collaborates with the TRiC complex to facilitate proper vimentin folding and recruits the chaperonin subunit Chaperonin Containing TCP1 Subunit 2 (CCT2) to degrade misfolded vimentin aggregates. Pathologically, external profibrotic stimuli trigger calcium transients and induce calumenin degradation, resulting in fibroblast senescence and the initiation of fibrosis. The natural product 9-85, derived from high-content screening, specifically targets and disrupts vimentin aggregates upon stimulation, alleviating aging-related lung fibrosis. Our findings reveal that calumenin coordinates vimentin quality control to shape cell structure and suppress the secretome of senescent fibroblasts, providing a promising therapeutic strategy for aging-related organ fibrosis.
GPT-4o mini: Non-social science research article
How much of the forest sink is passive? Case of the United States
Eric C. Davis, Brent Sohngen, David J. Lewis
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Over time, carbon sequestered in temperate forests has increased, but the relative effects of passive and active drivers remain unclear. This study uses plot-level data to disentangle the contributions of six drivers (temperature, precipitation, CO 2 , management, age composition, and area) to these increases in 14 forest groups of the conterminous United States. From 2005 to 2022, the passive drivers (CO 2 , temperature, and precipitation) increased live tree carbon (C) by 66 teragrams (Tg) C y −1 with CO 2 fertilization contributing most of the change. Among the anthropogenic drivers, declining forest area reduced live tree C by 31 Tg C y −1 while tree planting increased it by 23 Tg C y −1 . Changes in age composition, driven by both passive traits and anthropogenic choices, increased live tree C by 89 Tg C y −1 . By quantifying the share of removals attributable to passive uptake, this approach enables nations with national forest inventories to better utilize their forests to meet net-zero requirements.
GPT-4o mini: Non-social science research article
Scaling the glassy dynamics of active particles: Tunable fragility and reentrance
Puneet Pareek, Peter Sollich, Saroj Kumar Nandi, Ludovic Berthier
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Understanding the influence of activity on dense amorphous assemblies is crucial for biological processes such as wound healing, embryogenesis, or cancer progression. Here, we study the effect of self-propulsion forces of amplitude f 0 and persistence time τ p in dense assemblies of soft repulsive particles by simulating a model particle system that interpolates between particulate active matter and biological tissues. We identify the fluid and glass phases of the three-dimensional phase diagram obtained by varying f 0 , τ p , and the packing fraction ϕ . The morphology of the phase diagram accounts for a nonmonotonic evolution of the relaxation time with τ p , which is a direct consequence of the crossover in the dominant relaxation mechanism, from glassy to jamming. A second major consequence is the evolution of the glassy dynamics from sub-Arrhenius to super-Arrhenius. We show that this tunable glass fragility extends to active systems analogous observations reported for passive particles. This analogy allows us to apply a dynamic scaling analysis proposed for the passive case, in order to account for our results for active systems. Finally, we discuss similarities and differences between our results and recent findings in the context of computational models of biological tissues.
GPT-4o mini: Non-social science research article
Constraints on the impactor flux to the Earth–Moon system from oxygen isotopes of the lunar regolith
Anthony M. Gargano, Justin I. Simon, Erick Cano, Karen Ziegler, Charles K. Shearer, James M. D. Day, Zachary Sharp
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The impactor flux record to Earth has largely been erased by active tectonics, weathering, and continual reworking of the crust. Instead, a record of highly siderophile elements (HSE: Re, Os, Ir, Ru, Rh, Pt, Pd, and Au) in lunar impactites has been used as a proxy for the type of impactor material added to the Earth–Moon system. Quantifying impactor mass and flux with the HSE can potentially be complicated by numerous secondary processes, however, including silicate–metal segregation and multiple impact heritage. In contrast, because oxygen has an invariant geochemical affinity, triple oxygen isotope compositions have the potential to offer a robust long-term record of impactor fluxes in complex mixtures such as regolith. Here, we use high-precision triple oxygen isotopes to deconvolve the influences of meteorite addition and silicate vaporization and identify a ubiquitous impactor contaminant comprised of partially evaporated CM or ureilite-like material representing at least 1 wt% of the lunar regolith. Water delivered to Earth by meteorite material over 4 billion years therefore is only a fraction of an ocean’s worth of water but is a significant contributor to the ice reservoir of the lunar cold traps.
GPT-4o mini: Non-social science research article
The intrinsic impact of mechanical stress on the maintenance of oocyte dormancy
Go Nagamatsu, Kenjiro Shirane, Yuzuru Kato, Hiroko Nakamura, Norio Hamada, Kiyoko Kato, Hiroshi Kimura, Katsuhiko Hayashi
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In the mammalian ovary, most oocytes remain dormant, and their dormant status plays a central role in maintaining the reservoir population of the female germ line. The equilibrium between the dormant and active states, the latter of which is responsible for producing mature oocytes, is therefore crucial for ensuring the sustained reproductive capability of females. We have previously reported that mechanical stress in the ovary plays a crucial role in oocyte dormancy. However, the mechanism underlying this relation remains unclear. Here, we demonstrated that the mechanical stress is directly transduced into the oocytes, rather than to the surrounding granulosa cells. Culture experiments and live-imaging analysis revealed the nuclear localization of FOXO3, a hallmark of oocyte dormancy, within oocytes cultured alone in response to mechanical stress. Interestingly, we found that the cytological response to mechanical stress was accompanied by ligand-independent internalization of the c-kit receptor, which dampens intracellular signaling and prevents oocyte activation. These results shed light on the relation between mechanical stress and oocyte dormancy and provide clues toward a greater understanding of female reproductive capability.
GPT-4o mini: Non-social science research article
Evolutionary adaptations to the hormonal regulation of vascular tissue development
Wei Xiao, Eline Verhelst, Ling Yang, Yuji Ke, Bert De Rybel
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Vascular tissues provide long-distance transport and physical support in the vascular plant lineage, providing a significant adaptive advantage. Although the cross talk between auxin and cytokinin in promoting both vascular cell proliferation and differentiation has been well studied in angiosperms such as Arabidopsis thaliana , little is known about this regulation in other vascular plant lineages. Here, we found that unlike the hormonal cross talk found in all other species under study, the lycophyte Selaginella moellendorffii shows clear task separation, with auxin driving vascular cell proliferation only and cytokinin specifically triggering cell differentiation. Using a cross-species transcriptomics approach, we found that members of the AUXIN / INDOLE-ACETIC ACID ( AUX / IAA ) and CYTOKININ OXIDASE ( CKX ) gene families exhibited divergent expression patterns in response to auxin and cytokinin treatments. Despite these regulatory differences, we show that AUX/IAA and CKX proteins are functionally conserved between Arabidopsis and Selaginella. Taken together, our findings suggest an evolutionary adaptation to the hormonal regulation of vascular tissue development in which core protein functions are conserved, but regulatory circuits diverged in lycophytes.
GPT-4o mini: Non-social science research article
The role of fibration symmetries in geometric deep learning
Osvaldo M. Velarde, Lucas C. Parra, Paolo Boldi, HernĂĄn A. Makse
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Geometric Deep Learning (GDL) unifies a broad class of machine learning techniques from the perspectives of symmetries, offering a framework for introducing problem-specific inductive biases like Graph Neural Networks (GNNs). However, the current formulation of GDL is limited to global symmetries. We propose to relax GDL to allow for local symmetries, specifically fibration symmetries, which only require isomorphic input trees—a property that is much more common in real-world graphs. We show that GNNs apply the inductive bias of fibration symmetries and derive a tighter upper bound for their expressive power. Additionally, by identifying symmetries in networks, we compress network nodes, thereby increasing their computational efficiency during both inference and training of deep neural networks. The mathematical extension introduced here applies beyond graphs to manifolds, bundles, and grids for the development of models with inductive biases induced by local symmetries that can lead to better generalization.
GPT-4o mini: Non-social science research article
Widespread terrestrial ecosystem disruption at the onset of the Paleocene–Eocene Thermal Maximum
Mei Nelissen, Debra A. Willard, Han van Konijnenburg-van Cittert, Gabriel J. Bowen, Teuntje Hollaar, Appy Sluijs, Joost Frieling, Henk Brinkhuis
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The Paleocene–Eocene Thermal Maximum (PETM, ~56 Mya) interval was marked by massive 13 C-depleted carbon emissions into the ocean/atmosphere system, manifested as a negative carbon isotope excursion (CIE) in sedimentary components, and ~5 °C global average warming. Episodes of hydrological perturbations and soil-erosion have been widely documented for the PETM but their link with vegetation- and carbon cycle changes remain poorly constrained. Here, we present organic microfossil evidence showing a strong increase in fern-dominated pioneer vegetation that replaced coniferous forests on the margin of the Norwegian Sea during the first millennia of the CIE. With the present stratigraphic constraints, the “fern spike” occurred simultaneously in terrestrial settings along the North Sea, Arctic Ocean, the US east coast and in southern Australia, indicating that pioneer vegetation persisted for several millennia following a partial collapse of previously stable terrestrial ecosystems. Both the ferns and influx of microcharcoal imply recurrent physical disturbance, including soil destabilization and erosion, potentially linked to droughts, wildfires, and strong hydrological forcing resulting from extreme climate change. Together with evidence for reworked clay minerals and ancient organic matter (kerogen), these findings show that highly disturbed terrestrial ecosystems were widespread across mid- and high-latitude regions globally. Carbon cycle model simulations suggest that a substantial loss of standing and buried biomass, along with oxidation of soil organic matter, acted as important positive feedbacks during the onset of the CIE. Additionally, enhanced kerogen weathering likely contributed as another major positive feedback throughout both the onset and main phase of the CIE.
GPT-4o mini: Non-social science research article
Noncanonical genetic markers resolve the pre-GOE emergence of aerobic bacteria in Earth’s history
Tianhua Liao, Shanshan Chen, Sishuo Wang, Yongjie Huang, Stephen Kwok Wing Tsui, Eva E. StĂŒeken, Qin Cao, Haiwei Luo
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The transition from anaerobic to aerobic life was a pivotal adaptation in Earth’s history, yet the timing and genomic drivers remain poorly resolved. Traditional approaches relying on oxygen-utilizing genes need improvement for obligate anaerobes and fragmentary environmental genomes, where gene absence may reflect poor assembly rather than phenotype. We developed a machine learning model (GBDT40-LR) to predict microbial oxygen requirements using 40 broadly conserved genes, 35 without direct oxygen roles. This approach overcomes incompleteness biases in environmental genomes. Applied to 80,787 bacterial genomes [including metagenome-derived assemblies (MAGs)], the model classified 42,014 aerobes and 38,775 anaerobes, enabling large-scale ancestral reconstruction. Molecular clock dating indicates an emergence of aerobic bacterium prior to the Great Oxidation Event (GOE, 2.5 to 2.3 Ga), likely around ~2.7 Ga. Aerobic lineages subsequently diversified during the GOE and Neoproterozoic Oxygenation Event (NOE, 0.8 to 0.55 Ga), with persistent anaerobe diversity across Earth’s oxygenation. This establishes that aerobic bacteria originated planetary oxygenation, potentially by 200 to 400 My, providing insights into phenotypic evolution and prolonged anaerobe–aerobe coexistence.
GPT-4o mini: Non-social science research article
Distinct contributions of hippocampal pathways in learning regularities and exceptions revealed by functional footprints
Melisa Gumus, Michael L. Mack
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Fundamental aspects of learning are theorized to be supported by hippocampal pathways: The monosynaptic pathway (MSP) extracts regularities, whereas the trisynaptic pathway (TSP) rapidly encodes exceptional items. Yet, the empirical evidence for the dynamic involvement of MSP and TSP in learning remains unresolved. We leveraged diffusion-weighted imaging to estimate the endpoints of MSP- and TSP-related white matter structures (i.e., footprints) within hippocampal subfields and the entorhinal cortex. We then measured the activation of pathway-specific footprints with functional MRI while participants learned novel concepts defined by regularities and exceptions. The functional footprint method revealed links between MSP-related footprint activation and regularity encoding early in learning and TSP-related footprint activation and exception encoding late in learning. These findings provide empirical evidence that learning concept regularities and exceptions is preferentially supported by hippocampal pathways. The pathway footprint approach provides insights into the functional dynamics of the human hippocampus, translating theoretical and computational work into empirically testable questions in humans.
GPT-4o mini: Non-social science research article
A shear-induced limit on bacterial surface adhesion in fluid flow
Edwina F. Yeo, Benjamin J. Walker, Philip Pearce, Mohit P. Dalwadi
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Controlling bacterial surface adhesion and subsequent biofilm formation in fluid systems is crucial for the safety and efficacy of medical and industrial processes. Here, we theoretically examine the transport of bacteria close to surfaces, isolating how the key processes of bacterial motility and fluid flow interact and alter surface adhesion. We exploit the disparity between the fluid velocity and the swimming velocity of common motile bacteria and, using a hybrid asymptotic-computational approach, we systematically derive the coarse-grained bacterial diffusivity close to surfaces as a function of swimming speed, rotational diffusivity, and shape. We calculate an analytical upper bound for the bacterial adhesion rate by considering the scenario in which bacteria adhere irreversibly to the surface on first contact. Our theory predicts that maximal adhesion occurs at intermediate flow rates: At lower flow rates, increasing flow increases surface adhesion, while at higher flow rates, adhesion is decreased by shear-induced cell reorientation.
GPT-4o mini: Non-social science research article
Liganded LolCDE structures reveal a common substrate-LolE interaction guiding bacterial lipoprotein transport
Paul Szewczyk, Nicholas P. Greene, Martyn F. Symmons, Steven W. Hardwick, Vassilis Koronakis
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Bacterial lipoproteins are key structural components of the outer membrane in Gram-negative bacteria and vital components of machineries required for its biosynthesis and maintenance. The Lol system, essential for viability, directs transport of lipoproteins from the site of biosynthesis on the inner membrane to the outer membrane and has been the target of extensive efforts to develop novel antimicrobial drugs. In the first stage of this transport process, newly synthesized lipoproteins are released from the inner membrane by the ABC transporter LolCDE and passed to the periplasmic chaperone, LolA. Here, we show cryo-EM structures of LolCDE in complex with three different lipoprotein substrates, Lpp, Pal, and LolB, with the latter two bearing a disordered peptide linker between the acyl chains and the globular domain. Our work reveals that when the mature lipoprotein lacks an unstructured linker, the N-terminal portion of the protein is in an unfolded state for transport. The lipoproteins make a sequence-independent but structurally conserved interaction with a cleft on the surface of the periplasmic domain of LolE that promotes efficient transport. We propose a model of lipoprotein export where this interaction acts as pivot point for the peptide portion of the lipoprotein allowing the acyl chains to rotate 180° from their initial position in LolCDE to their binding site in LolA. Our results demonstrate how LolCDE can extrude lipoproteins of diverse sequence and structure and reveal an important detail of a transport process fundamental to bacterial physiology.
Mangrove restoration and coastal flood adaptation: A global perspective on the potential for hybrid coastal defenses
Timothy Tiggeloven, Vincent van Zelst, Eric Mortensen, Bregje K. van Wesenbeeck, Thomas A. Worthington, Mark Spalding, Hans de Moel, Philip J. Ward
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To reduce current and future coastal flood risk, it is critical to better understand how adaptation measures, including nature-based solutions, can reduce that risk. Globally, hybrid coastal defenses, including a combination of coastal vegetation, such as salt marshes and mangroves, with a dike or sea wall, have been highlighted as a promising adaptation measure. Here, we present a global-scale assessment of the potential risk reduction from mangrove restoration in combination with foreshore dike systems under scenarios of climate and socioeconomic change. We provide a quantitative assessment of the benefits in terms of reduced economic damage, exposed population, and poverty exposure. We evaluate mangrove restoration fronting dikes by accounting for wave–vegetation interaction. If mangrove foreshore dike systems were established along coastlines susceptible to flooding, restoration could potentially reduce expected annual damage by US$800 million and reduce expected affected population by 140,000 annually. These values increase under future projections. Our benefit–cost analysis finds mangrove restoration economically viable for about half of the subnational regions assessed (85 to 105 out of 208). At the global scale, the benefit–cost ratio under future conditions ranges from 3 to 6, with a net present value between US$44 billion and US$125 billion. Because absolute risk values and benefit–cost analysis do not differentiate between relative wealth impacts, we also estimated restoration impacts across different wealth levels. We show that restoring mangroves disproportionately benefits people with lower incomes, as they are often more exposed to coastal flooding and located in areas suitable for mangrove restoration. As such, mangrove restoration in low- and middle-income countries could contribute to the resilience of people in poverty.
Genetic associations with education have increased and are patterned by socioeconomic context: Evidence from 3 studies born 1946–1970
Tim T. Morris, Liam Wright, Gemma Shireby, David Bann
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Social scientists have long sought to investigate whether the predictors of educational attainment (EA) have changed across time. Here, we provide insights by incorporating genetic predictors of education in three nationally representative British birth cohorts born in 1946, 1958, and 1970. We investigated whether individual characteristics as proxied by polygenic indexes (PGIs) for EA and cognition have become more relevant to educational success over time and whether returns to genetic predisposition were moderated by early life socioeconomic background. We present three findings. First, associations between the EA PGI and attainment increased over time, with increasing incremental variance explained by the EA PGI. Second, associations between the cognition PGI and attainment were broadly consistent across cohorts, and there was no clear change in explained variance. Since the EA PGI captures multiple traits related to educational success, factors other than those related to cognition may have become more relevant over time. Third, we observed strong evidence of interaction: Associations between the EA PGI and EA were disproportionately larger among those from more advantaged socioeconomic backgrounds. The strength and pattern of associations varied when using EA PGIs that were less conservatively filtered for SNPs. Our findings suggest EA is influenced by social and genetic factors both independently and jointly. Genetic liability and social background could be considered as two forms of inherited advantage which synergistically influence education attainment.
Quantifying racial disparities in media representations of gun violence at scale
Ruth Bagley, Susan Burtner, Andrew V. Papachristos, Rob Voigt
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Previous research has documented racial disparities in gun violence news coverage in limited and small-scale contexts. This study curates and analyzes a large-scale dataset of news articles linked to specific incidents of gun violence to test for systematic race-related differences in representation across the US news media. Using computational techniques, we quantify how much media attention an incident gets, the topics and linguistic style of articles, and how participants in the incidents are framed. We find significant generalized disparities in media coverage and portrayal of incidents depending on whether they occur in neighborhoods that are majority white or majority people of color (POC), including increased media attention on police shootings if they occur in majority POC neighborhoods, greater focus on the people involved in incidents in majority white neighborhoods, and increased racialization and framing related to crime in majority POC neighborhoods.

Science Advances

GPT-4o mini: Non-social science research article
Artificial intelligence–enabled “inherited noninvasive intracellular recording” for prolonged monitoring of cardiac action potentials
Suhang Liu, Xingyuan Xu, Yijing Cai, Chuanjie Yao, Zhengjie Liu, Lisheng Hou, Minghao Li, Xiaotong Li, Yan Li, Guanbin Li, Mingqiang Li, Shuang Huang, Xinshuo Huang, Xi Chen, Ji Wang, Jing Liu, Hui-jiuan Chen, Xi Xie
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Intracellular action potential (AP) recording that allows long-term monitoring is challenging because permanent membrane penetration is impossible due to cell death or resealing of perforated cell membrane. Herein, an “inherited noninvasive intracellular recording” methodology was proposed, which was based on the fusion of artificial intelligence (AI) with microelectrode array (MEA)–electroporation system (AI-MEA-EP) to enable prolonged monitoring of intracellular APs in cardiomyocytes. It used MEA-electroporation (MEA-EP) for minimally invasive collection of intracellular signals transiently (~1 minute), as well as noninvasive recording of extracellular signals in long term. The recorded extracellular APs were converted into corresponding intracellular APs by a convolutional neural network–long short-term memory–based AI model enhanced by model self-calibration. The intracellular APs detected by the AI-MEA-EP exhibited high consistency with those physically obtained through MEA-EP. It was demonstrated to monitor cardiac intracellular AP under drug treatments and glucose challenging during >5 consecutive days. This method offers a unique solution to achieve prolonged recording of intracellular signals for advancing cardiac research.
GPT-4o mini: Non-social science research article
Unpacking the growth of global agricultural greenhouse gas emissions
Ariel Ortiz-Bobea, Simone Pieralli
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Agriculture, forestry, and other land use contribute about a fifth of total anthropogenic greenhouse gas (GHG) emissions. Mitigation efforts have emphasized “decoupling” that sustains production while lowering emissions per unit of output. However, the underlying decoupling mechanisms have not been fully characterized. We rely on a mathematical identity to decompose agricultural GHG emission growth ( Δ E ) into three parts: output ( Δ Y ), emissions per unit of input ( Δ E / X ), and output per unit of input ( Δ Y / X ) or total factor productivity (TFP). We then rely on official country-level data to quantify the historical contribution of these components. Over 1961 to 2021, we find that TFP growth—which captures the sector’s ability to produce more output per unit of measured input—has consistently remained one of the main sources of GHG emission reduction within farms. Further decomposition reveals a key role for rising land productivity in reducing emission intensity.
GPT-4o mini: Non-social science research article
Healing of ischemic injury in the retina
Silke Becker, Zia L’Ecuyer Morison, Jordan Allen, Sama Saeid, Lee Sturgis, Austin Adderley, Ari Koskelainen, Frans Vinberg
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Neuro- and retinal degenerative diseases, including Alzheimer’s, stroke, age-related macular degeneration, and central retinal artery occlusion, rob millions of their independence. Studying these diseases in human retinas has been hindered by the rapid loss of neuronal activity after death. While some CNS activity has been restored postmortem, synchronized neuronal transmission beyond 30 min has remained elusive. We overcome this barrier by reviving and sustaining light signal transmission in human retinas recovered up to 4 hours after death and stored for up to 48 hours. We also introduce infrared-based ex vivo imaging for precise sampling, a closed perfusion system for drug testing, and an ex vivo ischemia-reperfusion model in mouse and human retina. This platform enables testing of neuroprotective and neurotoxic effects of drugs targeting oxidative stress and glutamate excitotoxicity. Our advances question the irreversibility of ischemic injury, support preclinical studies in vision restoration, offer insights into treating CNS ischemia, and pave the way for human donor eye transplantation.
GPT-4o mini: Non-social science research article
Aberrant methylation limits antitumoral inflammation in lung adenocarcinoma by restricting RIPK3 expression
Deepti Agrawal, Katarina Cisarova, Sebastian Vosberg, Fabian Allmendinger, Enkhtsetseg Munkhbaatar, Nadia Dandachi, Francisco Jose Fernandez Hernandez, Marta Tonietto, Vanessa JĂ€ger, Martina Anton, Eva C. Keller, Moritz Jesinghaus, Anna-Lena Meinhardt, Verena Haefner, Tobias Stoeger, Katja Steiger, Nicholas McGranahan, Michael A. Dengler, Adam Wahida, Philipp J. Jost
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Evasion of programmed cell death is a critical hallmark of cancer. However, the contribution of inflammatory forms of cell death in lung carcinogenesis and their effects on the composition of the tumor-immune microenvironment remain unclear. Our multi-omics analyses of samples from patients with primary lung adenocarcinoma revealed that necrosome signaling is repressed because of reduced expression of receptor-interacting protein kinase 3 ( RIPK3 ). Distinct methylation signatures, both in the RIPK3 promoter and nonpromoter regions, correlated with lower transcription levels of RIPK3 . This resulted in limited expression of inflammatory genes, advanced histologic features, reduced immune cell invasion, and decreased patient survival. Mechanistically, we confirmed the tumor-suppressive role of necrosome signaling through the genetic deletion of Ripk3 in two independent, clinically relevant mouse models of lung adenocarcinoma. Functionally, RIPK3 shaped a diverse immune environment by promoting the invasion of innate and adaptive immune cells in patient samples and experimental mice. Thus, RIPK3-mediated inflammatory signaling enhances a diverse immune microenvironment and hinders progression in lung adenocarcinoma.
GPT-4o mini: Non-social science research article
Perovskite nanocrystals-in-glass hierarchical structures enable stable continuous-wave random lasers
Xinkuo Li, Chenduan Chen, Ke Sun, Linhan Li, Zhu Xiao, Zhou Li, Yuanzheng Yue, Jianrong Qiu, Dezhi Tan
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Encapsulating perovskite nanocrystals (PNCs) in glass enables enhanced stability of PNCs and numerous applications such as random lasers. However, preparing PNCs and tuning their properties in glass is energy consuming because of high processing temperature and long processing time, and continuous-wave (CW) random lasers have not been achieved. Here, we report modulation of the structure, photoluminescence, and lasing properties of PNCs in glass at temperatures well below the glass transition temperature with a short processing period. We generate tunable PNCs in glass via nanophase separation and ion exchange in the perovskite domains. PNCs-in-glass hierarchical structures are created by controlling nanophase separation and crystallization of PNCs. Substantially increased scattering in the hierarchical structures enables stable CW single-mode random lasing with an ultralow threshold of 52.6 milliwatts per square centimeter. We achieve flexible CW random lasers by incorporating hierarchical structures into the polydimethylsiloxane film. The random lasers are used in speckle-free laser imaging and dynamic holographic displays.
GPT-4o mini: Non-social science research article
Lactate derived from cancer-associated fibroblasts promotes alternative splicing and castration resistance in prostate cancer
Diwei Zhao, Zijun Mo, Tianyou Zhang, Xinyang Cai, Zhenyu Yang, Dong Chen, Junliang Zhao, Yuanwei Li, Fangjian Zhou, Zhen Li, Yonghong Li, Jun Wang
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Lactate in the tumor microenvironment (TME) is typically generated by cells exhibiting high glycolytic flux, exemplified by tumor cells. However, in glycolysis-low malignancies such as prostate cancer, stroma-derived lactate may drive noncanonical signaling and functions that remain unclear. Here, we identified APCDD1 + cancer-associated fibroblasts (CAFs) as a distinct stromal population that secretes lactate into the TME in response to androgen deprivation therapy (ADT). Lactate uptake by prostate cancer cells induces androgen receptor variant 7 expression, thereby conferring resistance to ADT. Mechanistically, lactate-induced lactylation of the spliceosome component SNRPA at Lys 123 (K123) enhances its recognition of cis-acting elements, increases chromatin binding, and promotes androgen receptor splicing. Targeting lactate transport with monocarboxylate transporter inhibitors effectively restores ADT sensitivity. These findings reveal a metabolic-epigenetic axis linking lactate in the microenvironment to alternative splicing regulation and suggest a promising therapeutic strategy to overcome ADT resistance.
GPT-4o mini: Non-social science research article
Two-dimensional lamellar nanosheet membranes with intrinsic size-sieving nanopores for ultrafast hydrogen separation
Yufeng Liu, Rui Wang, Xinyi Ma, Yiduo Wang, Shaohua Shen, Bofeng Bai, Chengzhen Sun
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Hydrogen separation and purification are essential for the large-scale application of green hydrogen energy. Two-dimensional (2D) material-based membrane technology provides an energy-efficient approach; however, the existing 2D lamellar membranes and nanoporous membranes struggle with low permeability and complex preparation procedures. Here, we constructed 2D lamellar nanosheet membranes with intrinsic size-sieving nanopores by assembling nanoporous polymeric carbon nitride (PCN) nanosheets into a lamellar membrane. These membranes exhibit high selectivity and permeance and ease of preparation. By applying MXene as the strong interaction patch for covering and repairing defects on PCN nanosheets, the resultant membranes demonstrated an ultrahigh H 2 permeance of 870 to 8046 GPU, considerable selectivity, and superior long-term stability, outperforming most current state-of-the-art membranes. Economic analysis revealed that MXene/PCN membranes achieved ultralow energy consumption and minimal membrane area demands for practical applications. This study inspires the construction of 2D lamellar membranes with intrinsic nanopores and provides a simple and scalable approach to preparing high-performance 2D nanosheet membranes for hydrogen separation.
GPT-4o mini: Non-social science research article
COBRA-k: A powerful framework bridging constraint-based and kinetic metabolic modeling
Pavlos Stephanos Bekiaris, Steffen Klamt
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Mathematical modeling is key to understanding cellular metabolism. Two common approaches are kinetic modeling and constraint-based reconstruction and analysis (COBRA). COBRA models analyze steady-state fluxes using linear constraints but lack kinetic detail. Kinetic models offer mechanistic descriptions via differential equations but require (often unknown) kinetic parameters and enzyme concentrations. To bridge this gap, we introduce COBRA-k, a framework integrating nonlinear kinetic rate laws into COBRA models to consistently constrain metabolic fluxes, enzyme abundances, and metabolite concentrations. COBRA-k enables flexible exploration of metabolic steady states with optimization techniques, even with incomplete parametrization. COBRA-k models require solving computationally demanding mixed-integer nonlinear programs. We therefore developed a dedicated iterative algorithm, implemented in an open-source Python package. We applied COBRA-k to a large-scale Escherichia coli model, demonstrating its effectiveness and revealing holistic metabolic insights. For example, it accurately predicts and explains the phenomenon of high intracellular glutamate concentration. COBRA-k combines the flexibility of COBRA with kinetic precision, offering a powerful tool for predictive metabolic modeling and engineering.
GPT-4o mini: Non-social science research article
Plasmonic tuning of dark-exciton radiation dynamics and far-field emission directionality in monolayer WSe 2
Shuaiyu Jin, Feihong Liu, Ilya Razdolski, Tsz Wing Lo, Yaorong Wang, Zhiwei Peng, Kuan Liang, Ye Zhu, Wang Yao, Anatoly V. Zayats, Dangyuan Lei
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Manipulation of excitonic emission properties is important for numerous photonic applications. Of particular interest are developing easy-to-implement yet effective approaches for controlling the radiation dynamics and directionality of spin-forbidden dark excitons (X D ) in two-dimensional semiconductors. Here, we investigate the spectral, temporal, and directional characteristics of room-temperature X D emission from a tungsten diselenide monolayer coupled to a dissipative plasmonic nanocavity. Under resonant plasmon-exciton coupling, the radiative decay rate of X D is accelerated by nearly four orders of magnitude, and correspondingly, the X D lifetime is shortened to a subnanosecond level, making it comparable to that of bright excitons. Fitting the measured lifetimes with a Purcell-formalism–based cavity quantum electrodynamics model allows estimating of the intrinsic room-temperature X D lifetime to be about 24 ± 2.3 microseconds. Furthermore, the measured radiation patterns of the dark excitons show that subtle variations in the nanocavity orientation can effectively tailor the X D emission directionality, important for quantum technologies and optoelectronics applications.
GPT-4o mini: Non-social science research article
A causal coding variant regulating alternative splicing of DOC2A at 16p.11.2 GWAS locus influences susceptibility to schizophrenia
Danyang Zhou, Yue Zhang, Zhihui Yang, Chuyi Zhang, Qing Zhang, Jinhua Huo, Kesi Cui, Yong Wu, Hong Chang, Chuang Wang, Xiao Xiao, Xin Cai, Ming Li
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Although genome-wide association studies (GWASs) have identified many schizophrenia-associated variants, their biological mechanisms remain unclear. Using transcriptomic data from human brain tissues, we performed splicing quantitative trait locus (sQTL) analyses of schizophrenia-associated single-nucleotide polymorphisms and identified more than 17,000 sQTLs linked to previously unidentified splicing junctions. Functional prioritization and experimental validation highlighted the synonymous variant rs3935873 within the 16p11.2 GWAS locus strongly associated with an unannotated isoform DOC2A ∆ Val217-Pro218 . rs3935873 was significantly associated with hippocampal volume, and hippocampal overexpression of DOC2A ∆Val217-Pro218 in mice recapitulated schizophrenia-relevant behavioral deficits, phenotypes absent in DOC2A Full-Length -overexpressing mice. Overexpression of both isoforms altered excitatory synaptic transmission, structural modeling revealed divergent tertiary configurations between DOC2A ∆Val217-Pro218 and DOC2A Full-Length , and interactome profiling highlighted that DOC2A ∆Val217-Pro218 unique interactors are enriched in the myosin II complex and ankyrin binding, suggesting the acquisition of previously unknown structural and regulatory functions by DOC2A ∆Val217-Pro218 . Our study implicates dysregulated splicing in DOC2A as a functional mechanism for schizophrenia genetic risk and demonstrates how unannotated isoforms can reveal disease-relevant pathways.
GPT-4o mini: Non-social science research article
Crotonate suppresses breast cancer metastasis and promotes immunotherapy response by inducing ACSS2-mediated EZH2-K348 crotonylation
Bo Liu, Xinwei Duan, Ge Wang, Youzhi Tang, Kunhao Zhou, Jing Zhang, Yu Yu, Hongquan Zhang
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Crotonate, a short-chain fatty acid, generates protein crotonylation. However, the role of crotonate in cancer progression is unknown. Here, we present a crotonate–crotonyl–coenzyme A (CoA)–enhancer of zeste homolog 2 (EZH2) crotonylation cascade blocking breast cancer growth and metastasis. We demonstrated that crotonate promotes EZH2 degradation via crotonyl-CoA–mediated crotonylation at Lys 348 in EZH2 (EZH2-K348cr). EZH2-K348cr leads to reduced genome-wide H3K27me3 (trimethylation of lysine-27 on histone-3) occupancy. Crotonate metabolizes to crotonyl-CoA by ACSS2 (acyl-CoA synthetase 2), and then, acyltransferase p300 catalyzes crotonyl-CoA and generates EZH2-K348cr. Crotonylated EZH2 triggers EZH2 ubiquitination and degradation. Administration of crotonate markedly inhibits breast cancer cell growth and metastasis via a crotonate-crotonyl-CoA-EZH2-K348cr cascade. In comparison, crotonate showed better blocking effect than EZH2 inhibitor tazemetostat in suppressing breast cancer metastasis. The combination of crotonate and anti-PD-L1 (programmed cell death ligand 1) antibody enhances responses of breast cancer cells to immunotherapy. Together, our findings indicate that crotonate is a promising anticancer drug candidate that suppresses breast cancer growth and metastasis by specifically inducing EZH2 degradation.
GPT-4o mini: Non-social science research article
Adaptable thermoresponsive polymer for long-term electrical coupling in plant electrophysiology monitoring
Yi Jing Wong, Yifei Luo, Wenlong Li, Eden Vina Lamoste Grate, Feilong Zhang, Zhisheng Lv, Qianyu Lin, Mengyuan Zhang, Yansong Miao, Xian Jun Loh, Xiaodong Chen
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Electrophysiological signals provide valuable insights into plant health, facilitating measures to enhance crop productivity. Despite advances in measurement methods, long-term (>1 day) acquisition techniques remain limited, hindering continuous monitoring. Current long-term techniques rely on invasive electrodes, as noninvasive electrodes fall short in operational duration and conformability. Here, a capacitively coupled electrode with an adaptable coupling layer is developed for noninvasive, month-long electrophysiological monitoring on diverse plants. The adaptable coupling layer is formed by in situ sol-gel transition, followed by dehydration of thermoresponsive hydrogel on plants, achieving high conformability to complex surfaces and stable electrical coupling. For 1 month on trichome-covered plant surfaces, the electrode maintains a high signal-to-noise ratio comparable to a gold-standard noninvasive electrode, which typically lasts a few hours. Long-term monitoring reveals drought-specific signal features that correlate with plant water status. Physiological investigations indicate an essential role of calcium and reactive oxygen species, highlighting the potential of our electrode in generating biological insights and inspiring plant sensing innovations.
GPT-4o mini: Non-social science research article
Piezoelectric surface acoustic wave memristor neural network
Yi Zhang, Yi Deng, Dingchen Wang, Zilong Xiong, Yang Jiang, Chenkai Deng, Chuying Tang, Shaocong Wang, Mujun Li, Xiaohui Wang, Fangzhou Du, Qiaoyu Hu, Xiaojuan Qi, Han Wang, Qing Wang, Hongyu Yu, Zhongrui Wang
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Processing wireless RF signals using analog electromagnetic (EM) wave-based neural networks enables energy efficiency and parallelism by integrating sensing, memory, and computation, avoiding analog-to-digital conversions (ADCs) and the von-Neumann bottleneck. Yet, a notable challenge remains: the absence of compact and programmable building blocks for EM wave-based neural networks. To overcome this limitation, we propose a piezoelectric surface acoustic wave (SAW) memristor that integrates an Ag/SiO 2 /Au memristor with an acoustoelectric phase shifter. Operating at shorter wavelengths than EM waves, it offers a compact footprint and encodes tunable neural network parameters via nonvolatile programmability and the acoustoelectric effect. A proof-of-concept SAW memristor neural network was experimentally demonstrated on a vector classification task, achieving 91.7% accuracy on par with software while reducing footprint by 10 5 times versus EM systems and energy consumption by 37 times versus digital systems. This work paves the way for compact, energy-efficient RF signal processing at the edge.
GPT-4o mini: Non-social science research article
Dual-mode microfluidic immunostaining device for diagnostic biomarkers detection and tumor microenvironment evaluation
Yu Zhang, Yanhua Huang, Jing Jia, Xiaoguang Guo, Fuxiu Liu, Bing Shi, Zhen-li Huang
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The limited availability of tissue samples from rare tumors poses a major barrier to advances in precise diagnosis, prognostic evaluation, and therapeutic research—challenges exemplified by primary central nervous system diffuse large B cell lymphoma (PCNS-DLBCL). Here, we developed a dual-mode microfluidic immunostaining (Dumi) device, which integrates diagnostic and research workflows into a single, automated platform, reducing tissue section consumption by more than 90%. Using just one to two slides, it enables both regional detection of biomarkers for diagnostic subtyping (≀16) and construction of multiplex tumor microenvironment (TME) maps. Joint analysis of multiregion diagnostic biomarkers in the TME map indicates that tumor cell subpopulations defined by specific diagnostic biomarkers can actively shape their in situ microenvironmental niche. Dumi offers an efficient, cost-effective, and multifunctional immunostaining method, overcoming the limitations of scarce tissue resources and providing a clinically accessible solution to the diagnostic and therapeutic challenges with rare tumors.
GPT-4o mini: Non-social science research article
A genome-wide genetic screen reveals the P2Y2-integrin axis as a stabilizer of EGFR mutants in non–small cell lung cancer (NSCLC)
Yafei Du, Wenjing Wang, Hui Chin Goh, Thamil Selvan Vaiyapuri, Anandhkumar Raju, Yu-Chun Hsiao, Cheng Chun Wang, Vanisha Agrawal, Noorul Farzana Mohideen, Norhidayah Binte Mohd Mazian, Feride Karatekin, Wendy Kehan Wang, Manikandan Lakshmanan, Komal Gupta, Han Chang, Xavier Le Guezennec, Frederic Bard, Daniel S. W. Tan, Vinay Tergaonkar, Mien-Chie Hung, Xiaogang Liu, Wanjin Hong, Gandhi T. K. Boopathy
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Activating mutations in the epidermal growth factor receptor ( EGFR ) gene drive non–small cell lung cancer (NSCLC). Oncogenic EGFR mutants are ligand-independent and more stable, but the underlying mechanism remains unclear. We hypothesized that EGFR mutants selectively leverage cellular stabilizers to evade degradation. Genome-wide RNA interference screens identified genes (encoding for stabilizers) responsible for mutant EGFR stability, with P2Y2 receptor (P2Y2) emerging as a bona fide stabilizer. Mechanistically, high extracellular adenosine triphosphate (ATP) levels transactivate EGFR mutants via P2Y2 activation, previously shown to signal through Src kinase–dependent EGFR phosphorylation. Our study reveals that ATP-driven P2Y2 activation stabilizes EGFR mutants by forming a P2Y2-integrin ÎČ1-EGFR complex enriched in endosomes. Targeting this axis destabilizes EGFR mutants and offers a strategy against drug resistance. Elevated P2Y2 and integrin ÎČ1 expression in patients with NSCLC implies clinical relevance. Our results provide previously unidentified insight that EGFR mutants enhance extracellular ATP levels to activate P2Y2-integrin for enhanced stability of EGFR mutants to drive the oncogenic program.
GPT-4o mini: Non-social science research article
Superenhancers shape the landscape and repair dynamics of transcription-associated DNA breaks in cancer
Osama Hidmi, Diala Shatleh, Sara Oster Flayshman, Jonathan Monin, Rami I. Aqeilan
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Cancer is characterized by uncontrolled proliferation accompanied by oncogene hypertranscription, leading to transcription stress, a key source of DNA double-strand breaks (DSBs) that jeopardize genomic stability. Despite its importance, the landscape and consequences of transcription stress remain underexplored. Here, we used maps of DSBs identified through sBLISS (in-suspension break labeling in situ and sequencing) with transcription stress markers to delineate the transcription stress landscape in cancer. We found that transcription stress sites are shaped by the superenhancer regulatory landscape. Notably, ÎłH2AX is enriched at transcription stress sites; however, not all DSB-enriched genes show similar ÎłH2AX marking. Instead, genes with DSBs tied to transcription stress are distinctly marked. Genes with high DSBs marked by ÎłH2AX exhibited substantially higher DSB turnover and repair than those with low ÎłH2AX, and are associated with vulnerability to mutagenesis. These findings underscore superenhancer activity as a determinant of the transcription stress landscape in cancer, posing a threat to the genomic stability of oncogenes.
GPT-4o mini: Non-social science research article
Far-reaching hunter-gatherer networks during the Last Glacial Maximum in Western Europe
Marta Sånchez de la Torre, Xavier Mangado, Samuel Castillo-Jiménez, Felipe Cuartero, Richard J. Hewitt, Luis Luque, Bernard Gratuze, Miguel Almeida, María de Andrés-Herrero, Guilhem Constans, Louis Marguet, Thierry Aubry, José J. Alcolea-Gonzålez, Manuel Alcaraz-Castaño
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Social networking is an essential feature of hunter-gatherer societies. It fosters the circulation of goods and information and enables kinship ties across different scales, including long-distance contacts. While such behaviors are known since at least the Upper Palaeolithic, evidence for geographically extensive social networks remains scarce. This evidence is limited to indirect inferences based on shared cultural traits, “art” styles, and symbolic items, while lithic raw material movements are mostly local and regional, with few cases exceeding 300 kilometers. We provide geochemical evidence for the largest confirmed distance between the source and discard location of a knapped lithic object in Palaeolithic Europe. Solutrean artifacts discarded at Peña CapĂłn, Central Iberia, were sourced in Southwest France, 600 to 700 kilometers away. This demonstrates social networks of unprecedented geographic scale maintained during ∌1400 years during the Last Glacial Maximum. It also suggests that stone tools were exchanged as symbolic items to solidify social contacts and sustain far-reaching networks as risk-buffering mechanisms among widely dispersed hunter-gatherers.
GPT-4o mini: Non-social science research article
Remodeling of XIST regulatory landscape during primate evolution
Emmanuel Cazottes, Charbel Alfeghaly, Cloé Rognard, Anamaria Necsulea, Agnese Loda, Gaël Castel, Laura Villacorta, Michael Dong, Edith Heard, IrÚne Aksoy, Pierre Savatier, Céline Morey, Claire Rougeulle
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Unraveling how gene regulations are remodeled during evolution is central to understanding how biological processes evolve. We explored this question in the frame of X-chromosome inactivation, a process under strong selective constraint, governed by the XIST lncRNA and its cis-regulators. Using functional approaches on closely related primate species, we show that XIST regulation has uniquely diverged over a short evolutionary timescale. In human and marmoset embryonic stem cells (ESCs), the JPX lncRNA gene is a major regulator of XIST expression. In contrast, JPX has a minor effect on XIST in macaque ESCs, where it acts together with a macaque-specific enhancer. This occurs within a reshuffled 3D organization of the XIST neighborhood triggered by the insertion of a HERVK transposon in the macaque lineage. Retrospective sequence comparisons revealed that many XIST regulators are not evolutionarily constrained, supporting the hypothesis that neutrally evolving noncoding elements harbor adaptive potential. These results illuminate how evolutionary recent elements are integrated into preexisting regulatory landscapes.
GPT-4o mini: Non-social science research article
Manipulating metal growth in hollow ionic-electronic conductor for anode-free lithium metal batteries
Lianqiang Peng, Xiaotian Wang, Xu Liu, Zihang Xi, Yawen Li, Jie Zhang, Yujie Ning, Qing Zhao
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Anode-free lithium metal batteries (AFLMBs) demonstrate promising high energy density yet suffer from irregular Li deposition, parasitic reactions, and severe volume expansion. The current anode modulation strategies such as tailored solid electrolyte interphase (SEI) and lithiophilic host architectures can hardly simultaneously resolve all above issues, especially at high-capacity Li deposition. Here, we design a Li-rich, hollow ionic-electronic conductor (HIEC) interlayer, which integrates metallic Li encapsulation and interfacial protection, thus guiding highly reversible thick Li deposition (5 milliampere-hours per square centimeter). In addition, the built-in electron-deficient domains in the HIEC facilitate the formation of the hierarchical SEI and further mitigate active Li corrosion. These synergistic effects of the interlayer enable stable cycling in batteries under both anode-less and anode-free configurations, attaining >99% coulombic efficiency under industrial-level cathode loading and lean electrolyte conditions. This study highlights the significance of interlayers in integrating the SEI and host functions and provides a viable and scalable solution for energy-dense batteries.
GPT-4o mini: Non-social science research article
Mechanics-informed fabric actuators with aligned fiber crossings
Huapeng Zhang, Herbert Shea
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Engineering unobtrusive mechanical assistance into daily-life clothing requires energy-dense yet compliant actuators with thin profiles. We report textile actuators by interlacing shape memory alloy (SMA) fibers in a periodic X-Crossing geometry, where fiber crossings align in the actuation contraction axis. An X-Crossing actuator design of 4.5 grams can be passively stretched to 160% and contracts by 50% when heated, lifting 1 kg, outperforming knitted and knotted SMAs. We developed a variable-stiffness mechanics model to predict material-level stress-strain behavior across temperatures and thus the force-contraction relation of device level. This model informs actuator design and control, geometric scaling, peak points in the force-contraction relation, and the theoretical upper bound of contraction strain. The maximum measured contraction strain of our actuators is 55%, a large step toward the upper bound that we calculate for general SMA fabric actuators. We demonstrate applications of the developed actuators and model in lifting weight and on-body compression.
GPT-4o mini: Non-social science research article
Optimally engineered HLA/peptide-specific CAR-T cells outperform TCR-T cells to eradicate solid tumors
Corinne E. Decker, Jacqueline Idun, Katja Mohrs, Thomas Craig Meagher, Iryna Petriv, Jonathon Golas, Robert Salzler, Timothy Helms, Dharani Ajithdoss, Suhasini Avvaru, Jiaxi Wu, Tong Zhang, Eric Smith, Gavin Thurston, John C. Lin, Jessica R. Kirshner, David J. DiLillo
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Tumor-specific HLA/peptides (pHLA) represent attractive therapeutic targets for cancer. Two cell-based modalities can target pHLA-expressing tumors: T cell receptors (TCRs) or TCR-mimetic (TCRm) antibodies reformatted as chimeric antigen receptors (CARs). Using HLA-A2/MAGEA4 230–239 as a model pHLA, we discerned the relative potency of TCR-T and CAR-T cells, informing how to best deploy these for clinical benefit. Although TCR-T cells were more sensitive at detecting low-density pHLA, TCR-T cells exerted only transient in vivo antitumor efficacy followed by tumor relapse due to deficient TCR-T cell proliferation and persistence that was associated with a more differentiated and dysfunctional phenotype. By contrast, CAR-T cells with encoded costimulatory signaling fully regressed tumors. Insufficient TCR-T cell durability was overcome by coengaging 41BB or IL-2 signaling pathways, thereby enhancing tumor control in vivo. These data establish differential activities of human TCR-T and CAR-T cells targeting the same pHLA and inform the development of optimal targeting strategies to induce durable clinical responses.
GPT-4o mini: Non-social science research article
Cell surface engineering with a pseudofibrotic ECM reprograms the antifibrotic activity of mesenchymal stromal cells
Xianghua Zhong, Xinchao Liu, Jiajia Luo, Xinyang Liu, Xueting Wei, Xi Peng, Lu Wang, Huaimin Wang, Kunyu Zhang, Liming Bian, Peng Shi
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Fibrotic diseases, which impair tissue function and contribute to organ failure, remain a major clinical challenge with limited treatment options. Mesenchymal stromal cells (MSCs) offer promise for antifibrotic therapy via paracrine signaling, but their clinical efficacy is hindered by poor survival and limited functional activity after transplantation. Here, we present a cell surface engineering strategy that reprograms the antifibrotic function of MSCs by constructing a pseudofibrotic extracellular matrix (ECM) on their surface. Through in situ self-assembly of peptide-modified hyaluronic acid, we generate a nanofiber-based matrix that mimics the dense, disordered architecture of fibrotic ECM. This matrix activates the Piezo1/PI3K-Akt signaling pathway, inducing up-regulation of Mmp13—a key collagen-degrading matrix metalloproteinase—in engineered MSCs. In a rat model of myocardial infarction–associated fibrosis, engineered MSCs exhibit robust antifibrotic activity compared to unmodified MSCs. These findings establish a bioinspired strategy for MSC reprogramming and offer a path toward more effective cell-based therapies for fibrotic disease.
GPT-4o mini: Non-social science research article
Dynamic context–based updating of object representations in the visual cortex
Giacomo Aldegheri, Surya Gayet, Marius V. Peelen
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Objects in real-world scenes are often poorly or partially visible, for example because they are occluded or appear in the periphery. An additional challenge of real-world vision is that it is dynamic, causing the appearance of objects (e.g., their size and orientation) to change as we move. Notably, however, these changes are predictable from the three-dimensional structure of the surrounding scene. In two functional magnetic resonance imaging studies, we find that the visual cortex dynamically updates object representations using this predictive contextual information. First, visual cortical representations of objects were enhanced when they rotated congruently (versus incongruently) with the surrounding scene. Second, the inferred orientation of the object could be decoded from visual cortex activity even when the object was fully occluded. These findings indicate that predictive processes in the visual cortex follow the geometric structure of the environment, providing a mechanism to support object perception in dynamic natural vision.
GPT-4o mini: Non-social science research article
Autocrine TGFÎČ2 enforces a transcriptionally hybrid cell state in Ewing sarcoma
Emma D. Wrenn, Jacob C. Harris, April A. Apfelbaum, Jonah R. Valenti, Patricia A. Lipson, Stephanie I. Walter, Nicolas M. Garcia, Aya Miyaki, Steven C. Chen, Jim M. Olson, Jason P. Price, Kelly M. Bailey, Elizabeth R. Lawlor
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Subpopulations of cancer-associated fibroblast (CAF)–like tumor cells deposit extracellular matrix (ECM) proteins that support Ewing sarcoma (EwS) progression and metastasis. We previously showed a hallmark of CAF-like EwS cells is their hybrid transcriptional state wherein the driver fusion oncogene, EWS::FLI1, maintains activation of proliferative programs but loses capacity to repress mesenchymal genes. Here, we studied primary patient tumors and cell line models to identify molecular drivers of this hybrid state. Our data reveal that hybrid EwS cells are induced and maintained by a transforming growth factor–ÎČ (TGFÎČ) signaling positive feedback loop. Hybrid cells derepress TGFBR2 and up-regulate expression and secretion of TGFÎČ2 to sustain pathway activation and ECM deposition. Although TGFÎČ ligands can potently induce growth arrest in cells of epithelial origin, we show that TGFÎČ1 and TGFÎČ2 promote cell invasion of EwS cells without affecting proliferation. Thus, stroma-derived and tumor-derived TGFÎČ ligands induce and maintain hybrid EwS cells to promote pro-metastatic cell phenotypes.
GPT-4o mini: Non-social science research article
The earliest elephant-bone tool from Europe: An unexpected raw material for precision knapping of Acheulean handaxes
Simon A. Parfitt, Silvia M. Bello
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Organic knapping tools made from bone, antler, and wood were essential to early human toolkits but are rarely preserved in the archeological record. The earliest known soft hammers, dating to ~480,000 years ago, come from Boxgrove (UK), where modified antlers and large mammal bones were used alongside flint hard hammers. These tools facilitated complex knapping techniques, such as platform preparation and tranchet flake removal, contributing to the production of finely worked ovate handaxes typical of the Boxgrove Acheulean industry. This study presents a cortical bone fragment from an elephant, deliberately shaped into a percussor for resharpening flint tools. It represents the earliest known use of elephant bone in Europe and the first documented case of its use as a knapping hammer. Reconstructing its life history offers further insights into Middle Pleistocene hominin technological adaptations, resourcefulness, and survival strategies that enabled humans to endure harsh northern environments.
GPT-4o mini: Non-social science research article
Tissue-adhesive hydrogel–MXene biosensor for in situ intraoral TNF-α detection
Tsz Hung Wong, Weijia Liu, Jiaoli Li, Jie Ma, Yijie Cheng, Ruihao Lu, Kent J. Koster, Jeffrey D. Cirillo, Xinyue Liu, Hajime Sasaki, Chenglin Wu, Shaoting Lin
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Current dental care relies on subjective assessments or sophisticated diagnostics, both struggling to balance efficiency and accuracy. In situ biosensors offer a promising solution for real-time biomarker detection, yet their practical deployment in oral tissue is hindered by challenges in sensitivity, specificity, and stability due to low biomarker concentrations, molecular-level heterogeneity, and dynamic intraoral interactions. Here, we develop a tissue-adhesive hydrogel–MXene (TAHM) biosensor, integrating a graphene/MXene sensing probe, a tissue-adhesive patch, and a selective-permeable hydrogel membrane, for in situ detection of tumor necrosis factor–α, a proinflammatory cytokine. Our TAHM biosensor achieves high sensitivity with a limit of detection of 18.2 femtograms per milliliter, excellent selectivity with an interference coefficient below 7%, and mechanical stability with resistance variation under 0.5% under varying stretch ratio and loading rates. The sensor’s performance is further validated through in vitro, in vivo, and ex vivo experiments. The work highlights the potential of in situ biosensor as a transformative tool for real-time oral diagnostics.
GPT-4o mini: Non-social science research article
Cooperativity and communication between the active sites of the dimeric SARS-CoV-2 main protease
Sarah N. Zvornicanin, Ala M. Shaqra, Julia Flynn, Lauren E. Intravaia, Heidi Carias Martinez, Weiping Jia, Devendra Kumar Gupta, Stephanie Moquin, Dustin Dovala, Daniel N. Bolon, Brian A. Kelch, Celia A. Schiffer, Nese Kurt Yilmaz
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The coronaviral main protease (M pro ) has been the subject of various biochemical and structural studies and a drug target against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. SARS-CoV-2 M pro is active as a dimer, but despite apparent cooperativity in catalytic activity, how the two distal active sites communicate and modulate binding and/or catalysis is unclear. Here, we have investigated the interplay between cooperativity, dimerization, and substrate cleavage in SARS-CoV-2 M pro through a combination of enzymatic assays, crystal structures, and protein characterization. To disentangle the contribution of each active site to the observed enzymatic activity, we developed a cleavage assay involving heterodimers of active and inactive (catalytic residue mutated or inhibitor-bound) monomers. Notably, we found that heterodimerization increased cleavage efficiency per active monomer. In addition, we mapped a network of critical residues bridging the two active sites and probed this network through engineered mutations. By dissecting the cooperativity and communication between the active sites, we provide insights into the M pro reaction cycle and functional significance of its dimeric architecture.
GPT-4o mini: Non-social science research article
FLIPs: Genetically encoded molecular biosensors for functional imaging of cell signaling by linear dichroism microscopy
Paul Miclea, Vendula Nagy-MarkovĂĄ, Robin Van den Eynde, Wim Vandenberg, Alina Sakhi, Alexey Bondar, Jitka MyĆĄkovĂĄ, Peter Dedecker, Josef Lazar
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Genetically encoded fluorescent biosensors convert specific biomolecular events into optically detectable signals. However, imaging biomolecular processes often requires modifying the proteins involved, and many molecular processes are still to be imaged. Here, we present a biosensor design that uses a hitherto overlooked detection principle: directionality of optical properties of fluorescent proteins. The biosensors (termed FLIPs) offer an extremely simple design, high sensitivity, multiplexing capability, ratiometric readout, and other advantages, without requiring modifications to their targets. We demonstrate the sensor performance by real-time imaging activity of G protein–coupled receptors (GPCRs), G proteins, arrestins, and other membrane-associated proteins, as well as by identifying a previously undescribed, pronounced, endocytosis-associated conformational change in a GPCR–ÎČ-arrestin complex. In combination with an original tri-scanning linear dichroism confocal microscope, FLIPs allow unparalleled imaging of activity of nonmodified, endogenously expressed G proteins. Thus, FLIPs establish a powerful molecular platform for imaging cell signaling, allowing numerous future developments and insights.
GPT-4o mini: Non-social science research article
Mapping pan-Arctic riverine particulate organic carbon from space (1985 to 2022)
Xianghan Sun, Liqiao Tian, Hongwei Fang, Desmond E. Walling, Jaia Syvitski, Lei Huang, Deren Li, Chunmiao Zheng, Lian Feng
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Carbon release from high-latitude regions is intensifying, with profound consequences for the Arctic carbon cycle. Here, we provide a comprehensive analysis of changes in fluvial particulate organic carbon (POC) concentrations ( C POC ) and fluxes ( F POC ) during ice-free seasons of pan-Arctic rivers from 1985 to 2022 on the basis of satellite observations. Across 578,000 kilometers of river length, 18% of the total length experienced a significant increase in C POC , which exceeds the 11% that exhibited declines, resulting in a net rise. Most increases occurred after 2005, contributing to a 12.6% (0.49 teragrams per year) increase in total F POC to the Arctic Ocean between 1985 to 2005 and 2006 to 2022. Regional contrasts highlight distinct possible drivers: increased precipitation in the North American Arctic and atmospheric warming in the Eurasian Arctic. Deepening of the permafrost active layer is also significantly correlated with C POC increases. These findings highlight climate-driven fluvial POC export as a key contributor to the Arctic carbon budget and provide a high-resolution, satellite-based dataset that can inform carbon cycle models and data assimilation efforts.
GPT-4o mini: Non-social science research article
High-precision and low-depth quantum algorithm design for eigenstate problems
Jinzhao Sun, Pei Zeng, Tom Gur, M. S. Kim
Full text
Estimating the eigenstate properties of quantum systems is a long-standing, challenging problem for both classical and quantum computing. Existing universal quantum algorithms typically rely on ideal and efficient query models (e.g., time evolution operator or block encoding of the Hamiltonian), which, however, become suboptimal for actual implementation at the quantum circuit level. Here, we present a full-stack design of quantum algorithms for estimating the eigenenergy and eigenstate properties, which can achieve high precision and good scaling with system size. The gate complexity per circuit for estimating generic Hamiltonians’ eigenstate properties is O ˜ ( log Δ − 1 ) , which has a logarithmic dependence on the inverse precision Δ. For lattice Hamiltonians, the circuit depth of our design achieves near-optimal system-size scaling, even with local qubit connectivity. Our full-stack algorithm has low overhead in circuit compilation, which thus results in a small actual gate count ( cnot and non-Clifford gates) for lattice and molecular problems compared to advanced eigenstate algorithms. The algorithm is implemented on IBM quantum devices using up to 2000 two-qubit gates and 20,000 single-qubit gates and achieves high-precision eigenenergy estimation for Heisenberg-type Hamiltonians, demonstrating its noise robustness.
GPT-4o mini: Non-social science research article
Isotopic constraints on the origin of reactive chlorine in the troposphere
Zheng Zong, Men Xia, Chunshui Lin, Xiaorui Chen, Likun Xue, Qinyi Li, Yifan Jiang, Chongguo Tian, Xuehua Fan, Qi Yuan, Xinfeng Wang, Yujiao Zhu, Jisheng Zhang, Shuncheng Lee, Yujing Mu, Jun Li, Xiao Fu, Chuanhua Ren, Xin Huang, Chao Yan, Wei Nie, Alba Badia, Gan Zhang, Aijun Ding, Ru-Jin Huang, Markku Kulmala, Alfonso Saiz-Lopez, Tao Wang, Wenxing Wang
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Oceanic and anthropogenic processes, such as sea-salt emissions and combustion activities, release substantial amount of reactive chlorine into the troposphere, affecting air quality, ozone depletion, and climate change. However, distinguishing between these sources for reactive chlorine remains challenging. Here, we establish isotopic constraints on the origin of tropospheric reactive chlorine using chemical ionization mass spectrometry to analyze nitryl chloride (ClNO 2 ). Field observations from four regions in China reveal a much broader isotopic value (ÎŽ 37 Cl) range for ClNO 2 (−21 to +39‰) than previously documented for Earth’s chlorine reservoirs. Notably, significant ÎŽ 37 Cl differences for ClNO 2 from sea-salt emissions (−9 ± 4‰) and anthropogenic combustion sources (+20 ± 7‰) were identified. These distinct isotopic signatures, combined with field data, highlight the important role of oceanic chlorine in air pollution, with its chemical cycling affecting not only coastal regions but also extending into inland areas. This research advances our understanding of chlorine’s behavior and cycling in the troposphere.
GPT-4o mini: Non-social science research article
Lifecourse genome-wide association study meta-analysis refines the critical life stages for adiposity’s influence on breast cancer risk
Grace M. Power, Laxmi Bhatta, Amanda M. Hughes, Carolina Medina-Gomez, Anne Richmond, Genevieve Leyden, Bethan Lloyd-Lewis, Eleanor Sanderson, Rebecca Richmond, Elizabeth C. Corfield, Daniel McCartney, Caroline Hayward, Irene Fontes Marques, Fernando Rivadeneira, Bjþrn Olav Åsvold, Gibran Hemani, Janine F. Felix, Ben Brumpton, Alexandra Havdahl, George Davey Smith
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Previous evidence suggests that higher prepubertal adiposity protects against breast cancer risk. Whether this protection extends into early adulthood remains uncertain. We conducted genome-wide association studies on body mass index (BMI) in nulliparous women from menarche to <40 years across five cohorts, with additional analyses in three subintervals of this life stage. Results were meta-analyzed, and two-sample univariable and multivariable Mendelian randomization was applied within a lifecourse framework to assess the effect of BMI on breast cancer risk. Between menarche and <40 years, we observed heterogeneity in genetic effects. Genome-wide correlations further suggest that BMI during this early adult period may be partly influenced by distinct genetic factors compared with adiposity at other life stages. Higher genetically proxied BMI between menarche and 40 years reduced breast cancer risk. This protective effect attenuated after adjusting for prepubertal adiposity. These findings refine our understanding of adiposity’s role in breast cancer and highlight earlier life stages as critical windows for risk modulation.
GPT-4o mini: Non-social science research article
Pairing particles into holonomies
Vera Neef, Matthias Heinrich, Tom A. W. Wolterink, Alexander Szameit
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Holonomies are of great interest to quantum computation and simulation. The geometrical nature of holonomies offers increased stability to quantum gates. Furthermore, symmetries of particle physics are naturally reflected in holonomies, making them ideally suited for quantum simulation of quantum chromodynamics and grand unified theories. Yet, practically designing quantum holonomies with the required properties and scale is challenging. Here, we construct a new class of holonomies by increasing the particle number. We show that multiparticle holonomies can even exist in systems devoid of any single-particle holonomies. We present a comprehensive framework for multiparticle quantum holonomies and experimentally realize various two-particle holonomies in integrated photonics. Our results enable the number of particles to be harnessed as a design parameter, offering increased freedom in constructing holonomic systems.
GPT-4o mini: Non-social science research article
Dynamic redox–promoted iron and nutrient cycling drove graptolite evolution across the Ordovician-Silurian transition
Zhen Qiu, Caineng Zou, Jiaqiang Zhang, Aiguo Dong, Weiliang Kong, Yijun Xiong, Paul B. Wignall, Ming Li, Zaicong Wang, Xiangkun Zhu, Simon W. Poulton
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Graptolites were abundant and cosmopolitan zooplankton in Early Paleozoic oceans, but a prominent change in species occurred across the Late Ordovician mass extinction. We use ocean redox, iron isotope (ÎŽ 56 Fe), and phosphorus phase partitioning records from shelf and deep-ocean settings to evaluate the drivers behind this major reshaping of the pelagic marine ecosystem. A marked decrease in mesopelagic graptolites coincided with a stepwise negative ÎŽ 56 Fe shift on the shelf, driven by partial seawater Fe drawdown resulting from episodic intensification of mid-depth euxinia. Subsequently, a positive ÎŽ 56 Fe shift in both deep-ocean and shelf sediments reflects extensive seawater Fe removal during the development of more widespread euxinia. This led to enhanced sedimentary phosphorus recycling from sediments, which ultimately fueled the radiation of epipelagic graptolites. Thus, wide-scale changes in Fe cycling, linking the global oceanic redox state to phosphorus cycling, were ultimately responsible for the initial demise and subsequent radiation of select graptolite species.
GPT-4o mini: Non-social science research article
Enterococcus faecalis redox metabolism activates the unfolded protein response to impair wound healing
Aaron Ming Zhi Tan, Cenk Celik, Stella Yue Ting Lee, Mark Veleba, Caroline S. Manzano, Rahim M. K. Abdul, Guillaume Thibault, Kimberly A. Kline
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Enterococcus faecalis is an opportunistic pathogen that thrives in biofilm-associated infections and delays wound healing, yet how it impairs host tissue responses is unclear. Here, we identified extracellular electron transport (EET) as a previously unrecognized source of reactive oxygen species (ROS) in E. faecalis and showed that this activity directly triggers the unfolded protein response (UPR) in epithelial cells and delays epithelial cell migration. ROS detoxification with catalase suppressed E. faecalis –induced UPR and rescued epithelial cell migration, while exogenous hydrogen peroxide was sufficient to restore UPR activation in EET-deficient strains. UPR disruption by pharmacological inhibition also impaired cell migration, highlighting a critical role for UPR homeostasis in wound repair. Our findings establish EET as a virulence mechanism that links bacterial redox metabolism to host cell stress and impaired repair, offering previously unidentified avenues for therapeutic intervention in chronic infections.
GPT-4o mini: Non-social science research article
Prototaxites fossils are structurally and chemically distinct from extinct and extant Fungi
Corentin C. Loron, Laura M. Cooper, Sean McMahon, SeĂĄn F. Jordan, Andrei V. Gromov, Matthew Humpage, Niall Rodgers, Laetitia Pichevin, Hendrik Vondracek, Ruaridh Alexander, Edwin Rodriguez Dzul, Alexander T. Brasier, Michael Krings, Alexander J. Hetherington
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Prototaxites was the first giant organism to live on the terrestrial surface, represented by columnar fossils of up to eight meters from the Early Devonian. However, its systematic affinity has been debated for over 165 years. There are now two remaining viable hypotheses: Prototaxites was either a fungus, or a member of an entirely extinct lineage. Here, we investigate the affinity of Prototaxites by contrasting its organization and molecular composition with that of Fungi. We report that fossils of Prototaxites taiti from the 407-million-year-old Rhynie chert were chemically distinct from contemporaneous Fungi and structurally distinct from all known Fungi. This finding casts doubt upon the fungal affinity of Prototaxites , instead suggesting that this enigmatic organism is best assigned to an entirely extinct eukaryotic lineage.
GPT-4o mini: Non-social science research article
Granuloma dual RNA-seq reveals composite transcriptional programs driven by neutrophils and necrosis within tuberculous granulomas
Gopinath Viswanathan, Erika J. Hughes, Mingyu Gan, Ana MarĂ­a Xet-Mull, Jacob P. Lowy, Charlie J. Pyle, Graham Alexander, Devjanee Swain-Lenz, Qingyun Liu, David M. Tobin
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Mycobacterial granulomas lie at the center of tuberculosis (TB) pathogenesis and represent a unique niche where infecting bacteria survive under nutrient-restricted conditions and in the face of a host immune response. The granuloma’s necrotic core, where bacteria reside extracellularly in humans, is difficult to assess in many experimentally tractable models. Here, using necrotic mycobacterial granulomas in adult zebrafish, we develop dual RNA sequencing (RNA-seq) across different host genotypes to identify the transcriptional alterations that enable bacteria to survive within this key microenvironment. Using pharmacological and genetic interventions, we find that neutrophils within mature, necrotic granulomas promote bacterial growth, in part through up-regulation of the bacterial devR regulon. We identify conserved suites of bacterial transcriptional programs induced only in the context of this unique necrotic extracellular niche, including bacterial modules related to K + transport and rpf genes. Analysis of Mycobacterium tuberculosis strains across diverse lineages and human populations suggests that granuloma-specific transcriptional modules are targets for bacterial genetic adaptation in the context of human infection.
GPT-4o mini: Non-social science research article
Geometric principles of dendritic integration of excitation and inhibition in cortical neurons
Soroush Darvish-Ghane, Pankaj Gaur, Graham C. R. Ellis-Davies
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We use two-color uncaging of glutamate and Îł-aminobutyric acid (GABA) on layer 5 (L5) pyramidal neurons of the cingulate cortex to define how inhibitory control of excitation is determined by dendritic geometry. Traditionally, GABAergic input was considered as the gatekeeper; thus, receptors closest to the soma were ideally placed to veto excitation. However, recently modeling has advanced several counterintuitive hypotheses. Since laser uncaging can be directed at will to any position, we used photostimulation to show that inhibition near the sealed end of dendrites distal to excitation is more effective than inhibition near the soma in modulating excitation. Further, dendritic inhibition was found to be branch specific. Last, we demonstrate that inhibitory input from multiple thin basal dendrites can centripetally elevate to effectively tune distant excitation at the soma. These findings provide direct experimental evidence supporting theoretical predictions based on dendritic cable properties, revealing the critical role of dendritic geometry in shaping the interaction between excitatory and inhibitory neurotransmission.
GPT-4o mini: Non-social science research article
Photovoltaic nanoassembly of nanowire arrays sensitized with colloidal nanocrystals for near-infrared retina photostimulation
Tarik S. Kaya, Humeyra N. Kaleli, Antoine Chaffiol, Andrea Corna, Corentin Joffrois, Ridvan Balamur, Ugur B. Caliskan, Asim Onal, Cigdem Pehlivan, Eren Tekinay, Alp Yilmaz, Roya Mohajeri, Arif E. Cetin, GĂŒnther Zeck, Serge Picaud, Sedat Nizamoglu
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Nanowires have served as a transformative platform for advanced neural and tissue interfaces. While their photovoltaic properties hold exceptional promise for neural modulation, existing photostimulation approaches predominantly rely on visible light–activated photoelectrochemical mechanisms. Here, we present a solution-processed photovoltaic nanoassembly comprising a ZnO nanowire array sensitized with AgBiS 2 nanocrystals that enables efficient near-infrared (NIR) neural stimulation through capacitive photocurrents. By optimizing nanowire morphology and nanocrystal interdigitation, the platform achieves high charge injection densities (tens of microcoulombs per square centimeter) at low NIR intensities (<1 milliwatt per square millimeter). The nanoassembly was subretinally placed in an ex vivo blind rat retina, where it elicited repeatable and robust responses in retinal ganglion cells under NIR pulses. Notably, these responses were achieved at light intensities substantially below established ocular safety limits. The nexus of neuronal systems and nanoassemblies offers potential for enabling unconventional visual prosthetics and advanced neuromodulation therapies.
GPT-4o mini: Non-social science research article
Slowing planetary rotation influences ocean nutrient cycling and oxygenation
Ashika Capirala, Stephanie L. Olson
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Marine habitability for complex life on Earth and Earth-like planets requires bioavailable nutrients and dissolved oxygen. The cycling of nutrients and oxygen is controlled by physical ocean circulation. However, our understanding of how circulation has varied through time and space is incomplete for Earth and unconstrained for Earth-like exoplanets. Earth’s rotation has slowed over time, affecting ocean circulation by modifying the Coriolis effect. We use a three-dimensional Earth system model to explore how slowing planetary rotation influences ocean circulation and biogeochemistry. We show that slower rotation enhances wind-driven upwelling and global circulation. Nutrient recycling is consequently more efficient, increasing photosynthetic productivity. Additionally, enhanced ocean oxygenation improves habitability for aerobic life under a well-oxygenated atmosphere. However, under a poorly oxygenated atmosphere, slowing rotation increases oxygen fluxes from the ocean to the atmosphere. Therefore, Earth’s rotational history may have been a long-term background control on surface oxygenation and the evolution of animals.
GPT-4o mini: Non-social science research article
Genome-wide screenings identify BAP1 as a synthetic-lethality target with CDK4/6 inhibitors
Mei Feng, Hong Liu, Lu Zheng, Yang Liu, Hao Zhuang, Hao Xu, Tingting Zhang, Zhen Wu, Xiaolong Qian, Huikai Li, Tengfei Xiao, Yisheng Pan, Shaokun Shu, Ning Zhang
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The nongenetic mechanisms by which cancer cells escape cell cycle inhibition remain inadequately understood. Here, we uncover an epigenetic pathway driving adaptive resistance to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in hepatobiliary cancers using integrative approach combining genome-wide CRISPR screenings with transcriptional, epigenetic, and proteomic profiling. Sustained CDK4/6 inhibition triggers BAP1-dependent chromatin remodeling that induces a stem cell–like epigenetic state. Specifically, BAP1 removes ubiquitin modification (H2AK119ub) at the TCF4 promoter, activating WNT and EMT signaling to enhance cellular plasticity and survival under therapy. Notably, genetic and pharmacologic inhibition of BAP1 markedly improves abemaciclib efficacy in multiple mouse models and patient-derived organoids (PDOs). These findings establish BAP1 as a key regulator of tumor plasticity and adaptive resistance through epigenetic reprogramming and suggest a promising strategy for overcoming adaptive therapeutic CDK4/6i resistance by targeting quiescent, drug-resistant cancer cells.
GPT-4o mini: Non-social science research article
Expanding DNA alphabet adds a previously unknown dimension to nanostructures
Kun Zhou, Shuichi Hoshika, Jing Cheng, Chenxiang Lin, Steven Benner, Yonggang Ke
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DNA nanotechnology has created nanostructures with astonishing complexity. However, with nanostructures becoming increasingly larger and more intricate, they have become more difficult to obtain in high yields and quality. Expanding the alphabet beyond the canonical base pairs can therefore be the key to push the technology to the next level. Here, we describe examples of DNA nanostructures built from an “anthropogenic evolvable genetic information system (AEGIS).” Because AEGIS uses the same backbone as DNA, the existing rules for designing DNA nanostructures can be readily applied to AEGIS nanostructures, which also show greater stability, both thermal and enzymatic, greater control over autonomous assembly, and good phase separation. AEGIS can have as many as 12 different units and six different pairs with Watson-Crick-Franklin geometry. Thus, if further developed, then these nanostructures may represent a previously unexplored frontier in DNA nanoscience and nanotechnology, expanding the space of “soft” biomaterial design.
GPT-4o mini: Non-social science research article
Removal of trace gases can both increase and decrease cloud droplet formation
Elavarasi Ravichandran, Sanghee Han, Abigail S. Williams, Veronica Berta, Jeremy L. Dedrick, Christian Pelayo, Nattamon Maneenoi, Lynn M. Russell, Michael Wheeler, Jeremy Wentzell, John Liggio, Markus D. Petters
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Aerosols consist of liquid or solid particles dispersed in a gas. Aerosol measurements generally rely on drying the particles before quantifying their physicochemical properties. This drying can potentially remove semivolatile compounds from the particles. Here, we show size-resolved cloud condensation nuclei (CCN) measurements quantifying the hygroscopicity parameter in the presence and absence of a denuder. The denuder efficiently removed alkanes and weakly functionalized acids, aldehydes, and alcohols with fewer than 10 carbon atoms from the gas phase. Denuding organic compounds perturbed the CCN-derived hygroscopicity parameter by up to 50%. Denuding either rendered the particles more or less CCN active, and the direction of the effect depended on sample relative humidity and trace gas concentration. The effect was weakest in early spring and strongest in late spring and summer. The measurements demonstrate an unexpectedly strong coupling between the particle and gas phase, influencing CCN activity through either volatilization or surface adsorption, or both.
GPT-4o mini: Non-social science research article
Cryo-EM of autoantibody-bound NMDA receptors reveals antigenic hotspots in an active immunization model of anti-NMDAR encephalitis
Junhoe Kim, Farzad Jalali-Yazdi, Brian E. Jones, Gary L. Westbrook, Eric Gouaux
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Autoantibodies targeting synaptic membrane proteins are associated with autoimmune encephalitis manifested by seizures, psychosis, and memory dysfunction. Anti- N -methyl- d -aspartate receptor (NMDAR) encephalitis, a prototype of these autoimmune synaptic disorders, is unexpectedly common. Unfortunately, how the native repertoire of anti-NMDAR autoantibodies recognizes NMDARs and the precise locations of antigenic epitopes remain poorly understood. Here, we used an active immunization model that closely mimics the human disease to immunize adult mice with intact GluN1/GluN2A receptors, resulting in fulminant autoimmune encephalitis. Serum was collected at 6 weeks postimmunization for single-particle cryo–electron microscopy of GluN1/GluN2A receptors complexed with purified polyclonal anti-NMDAR autoantibody fragments. Native autoantibodies recognized two distinct binding sites on the GluN1 amino-terminal domain, which we confirmed using monoclonal antibodies bound to native NMDARs purified from mouse brain. Structural analysis of autoantibody-bound NMDAR complexes identified antigenic hotspots within the GluN1 amino-terminal domain. These hotspots provide potential targets for therapeutic intervention.
GPT-4o mini: Non-social science research article
YAP/TAZ-VGLL3 governs adipocyte fate via epigenetic reprogramming of PPARÎł and its target enhancers
Taejun Seol, Ju-Gyeong Kang, Kwangmin Ryu, Woojae Kim, Daehee Hwang, Suhyeon Cho, Daeun Song, Bomin Ku, Yen T. H. Tran, Sun-Hye Jeong, Won-Ki Cho, Dae-Sik Lim
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Adipocyte differentiation from mesenchymal stem cells is governed by tightly regulated transcriptional and epigenetic programs. The Hippo pathway effectors YAP and TAZ impede this process, yet the underlying molecular mechanisms remain unclear. Here, we demonstrate how YAP/TAZ regulate transcription of the adipocyte lineage specification factor PPARÎł and its target genes at the chromatin level. TAZ represses PPARÎł-bound target enhancers as evidenced by a markedly reduced histone H3 acetylated at lysine-27 occupancy, resulting in the transcriptional repression of adipogenic genes, including Pparg2 . Single-nucleus genomic analyses of mouse adipose tissue further revealed that YAP/TAZ activation drives extensive epigenetic modulation. Notably, the repressive effect of TAZ on adipogenic enhancers requires TEAD-dependent transcriptional activity, but not a direct interaction with PPARÎł through the WW domain as previously reported. Last, we identified Vestigial-like 3 ( Vgll3 ) as a transcriptional target of TAZ critical for repressing adipogenic enhancers. These findings reveal that the YAP/TAZ-VGLL3 axis regulates adipocyte fate by repressing the PPARÎł program at its target enhancers.
GPT-4o mini: Non-social science research article
Widespread abyssal turbidites record megathrust earthquake-triggered landslides and coseismic deformation in the Cascadia subduction zone
Jenna C. Hill, Janet T. Watt, Charles K. Paull, David W. Caress, Daniel S. Brothers, Kevin Arizmendi, Roberto Gwiazda, Jared Kluesner, Eve Lundsten, Nora M. Nieminski, Jason S. Padgett, Jennifer B. Paduan, George Snyder
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Abyssal marine turbidites provide some of the longest and most spatially extensive records of subduction zone earthquake recurrence globally; however, correlation of these deposits over long distances and interpretation of synchronous emplacement requires both an understanding of the turbidite generating systems and precise dating. Here, we present an integrated suite of high-resolution bathymetry, subbottom profiles, and sediment cores from combined autonomous underwater vehicle, remotely operated vehicle, and ship-based studies at a key paleoseismic site in the southern Cascadia subduction zone. We demonstrate how widespread, earthquake-triggered landslides on the lower slope deposit discrete, proximal mass transport deposits (MTDs) that grade offshore into complex, interfingered abyssal turbidites, which correspond to records of megathrust earthquake history. We propose accretion and oversteepening of thrust folds on the lower slope both preconditions the slope to fail and provides a perpetual source of unstable material to fail during every earthquake cycle. Furthermore, we suggest the periodic and pervasive landsliding indicates coseismic deformation of the outer accretionary wedge during megathrust rupture.
GPT-4o mini: Non-social science research article
Reversible phase dynamics of PsAF5 regulate mitophagy to balance redox levels in Phytophthora sojae
Jinzhu Chen, Wenhao Li, Qin Peng, Hongwei Zhu, Tan Dai, Jianqiang Miao, Xili Liu
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Redox balance is essential for normal cellular functions. PsAF5, a FYVE domain–containing protein, functions as an essential sensor and adapter, particularly in mitophagy triggered by reactive oxygen species in Phytophthora sojae . However, the regulatory role of PsAF5 in maintaining the dynamic equilibrium of the intracellular redox state has not yet been fully elucidated. Here, we identify that specific cysteine residues in the FYVE domain of PsAF5 sense cellular redox states to form and resolve disulfide bonds in a redox-dependent manner. Under reducing conditions, PsAF5 undergoes redox-dependent phase separation to form cytoplasmic condensates that are functionally decoupled from mitophagy execution. Under oxidative conditions, PsAF5 exhibits increased cytosolic solubility and enhanced interaction with PsATG8, thereby promoting mitophagy. This mechanism enables P. sojae to toggle between “detoxification” (oxidizing stress) and “metabolic resilience” (reducing stress) states, ensuring survival across hostile host niches.
GPT-4o mini: Non-social science research article
A transposase-derived gene required for human brain development
Luz Jubierre Zapater, Sara A. Lewis, Rodrigo Lopez Gutierrez, Makiko Yamada, Elias Rodriguez-Fos, Merce Planas-Felix, Daniel Cameron, Phillip Demarest, Anika Nabila, Helen S. Mueller, Junfei Zhao, Paul Bergin, Casie Reed, Tzippora Chwat-Edelstein, Alex Pagnozzi, Caroline Nava, Emilie Bourel-Ponchel, Patricia Cornejo, Ali Dursun, R. Köksal ÖzgĂŒl, Halil Tuna Akar, Henry Houlden, Huma Arshad Cheema, Muhammad Nadeem Anjum, Giovanni Zifarelli, Peter Bauer, Miriam Essid, Hanene Benrhouma, Meriem Ben Hafsa, Ichraf Kraoua, Carolina I. Galaz-Montoya, Alex Proekt, Xiaolan Zhao, Nicholas D. Socci, Matthew Hayes, Yves Bigot, Raul Rabadan, Reza Maroofian, David Torrents, Claudia L Kleinmann, Michael C. Kruer, Miklos Toth, Alex Kentsis
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Vertebrate brain development is associated with prominent neuronal cell death and DNA breaks, but their causes and functions are not well understood. DNA transposable elements could contribute to somatic genome rearrangements; however, their contributions to brain development are largely unknown. PiggyBac transposable element derived 5 (PGBD5) is an evolutionarily conserved vertebrate DNA transposase–derived gene with DNA remodeling activities in human cells. Here, we show that PGBD5 contributes to normal brain development in mice and humans, and its deficiency causes disorder of intellectual disability, movement disorders, and epilepsy. In mice, Pgbd5 is required for the developmental induction of postmitotic DNA breaks and recurrent somatic brain genome rearrangements. In the cerebral cortex, loss of Pgbd5 leads to aberrant neuronal gene expression, including of specific types of glutamatergic neurons, which partly explains the features of PGBD5 deficiency in humans. Thus, PGBD5 is a transposase-derived gene required for brain development in mammals.
GPT-4o mini: Non-social science research article
DLX2 acts as a pioneer factor and drives Msx1 + ectomesenchyme formation from embryonic stem cells
Ziwei Zhang, Zhiheng Xu, Hong Hu, Yao Li, Youmei Jin, Yi Zhong, Yunqiu Zhang, Yike Yin, Jing Chen, Yufeng Duan, Hao Yang, Zhonghan Li
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The ectomesenchyme generates much of the craniofacial skeleton, sutures, and diverse connective tissues in the mammalian head, yet its derivation from embryonic stem cells (ESCs) and the underlying molecular drivers remain poorly defined. Here, we identified Dlx2 as a key regulator that efficiently directed murine ESCs toward Msx1 + ectomesenchyme, recapitulating the developmental trajectory. These Msx1 + progenitors expressed classical craniofacial markers, exhibited robust osteochondral differentiation potential as a group, and supported craniofacial regeneration. Mechanistically, Distal-less homeobox 2 (DLX2) formed a complex with lamina-associated polypeptide 2, isoform alpha (LAP2α) through a 38–amino-acid homeodomain motif, interacting with nucleosomes to promote chromatin remodeling and activate a procraniofacial ectomesenchymal gene network. Disrupting DLX2-LAP2α interaction or silencing Dlx2 targets markedly diminished ectomesenchymal differentiation. Our findings established DLX2 as a pioneer factor in ectomesenchyme specification, offering insights into craniofacial development and stem cell engineering.
GPT-4o mini: Non-social science research article
Lipid self-assembly dependence on hyaluronic acid size reveals biolubrication and osteoarthritic degeneration mechanisms
Kangdi Sun, Mark W. Rutland, Rosa M. Espinosa-Marzal
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Hyaluronic acid (HA) and phospholipids (PLs) are key components of joint lubrication. In osteoarthritis (OA), the molecular weight (MW) of HA is reduced, which has been proposed to weaken the anchoring capacity of PL and impair lubrication. This study reveals a different mechanism by directly linking the MW to the structure of HA-PL (hybrid) assemblies and frictional properties. Using mixed-MW HA and PL to model this difference between healthy and OA synovial composition, we found interfacial lamellar structures form under healthy-like conditions, while hybrid vesicles predominate in OA-like conditions. At physiologically relevant shear rates, lamellar assemblies maintain ultralow friction, whereas vesicles are removed, causing a tenfold friction increase. These findings provide mechanistic insight into how HA-PL structural organization controls lubrication. While this simplified system does not capture the biochemical complexity of synovial fluid, this study advances understanding and offers a framework for designing structure-informed therapeutic strategies and biomimetic lubricants.
GPT-4o mini: Non-social science research article
Flexible thermal array sensor for imperceptible monitoring of multidimensional vascular dynamics
Shuo Tian, Shiqiang Liu, Rong Zhu
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Wearable electronics for monitoring vascular dynamics are crucial in assessing cardiovascular health. However, current vascular sensors hold challenges in limited perceptive dimension and accuracy and poor interface robustness. Here, we report 18-channel flexible thermal array sensor using active thermal penetration sensing principle for imperceptible monitoring of deep and superficial vasculature. Leveraging contact-free thermal penetration and natural piezo-thermic transduction of human skin, the sensor implements spatiotemporal mapping of vascular dynamics with high sensitivity, good-linearity, fast-response, low cross-talk, and excellent interfacial robustness. It enables real-time and in situ measurements of multimodal vascular characteristics including deep arterial pulsation, superficial capillary perfusion, relative blood flow velocity, skin temperature, and continuous blood pressure via data-efficient vascular feature extraction method. Imperceptible and comprehensive cardiovascular dynamics tracking by wearable electronics provides a promising avenue for advancing personal health care and clinic medicine.
GPT-4o mini: Non-social science research article
Dendritic compartment-specific spine formation in layer 5 neurons underlies cortical circuit maturation during adolescence
Ryo Egashira, Meng-Tsen Ke, Nao Nakagawa-Tamagawa, Satoshi Fujimoto, Shigenori Inagaki, Tsuyoshi Takagi, Tsuyoshi Miyakawa, Yoshiaki Tagawa, Takeshi Imai
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The development of cognitive functions continues into adolescence. However, it is not fully understood how cortical circuitry changes during adolescence. Here, we performed a comprehensive super-resolution mapping of dendritic spines in layer 5 extratelencepharic-projecting (L5 ET) neurons in the primary somatosensory cortex in mice. In adults, the dendritic spines are highly enriched in the middle compartment of the apical dendrites (spine density “hotspot”), where dendritic calcium spikes are generated. In early development, dendritic spines are evenly distributed. During adolescence, however, the spine density increases specifically in the middle compartment of the apical dendrites in an experience-dependent manner, while other dendritic compartments show a slight reduction. Furthermore, spine accumulation at the hotspot was specifically impaired in mouse models of schizophrenia, demonstrating a link between adolescent spine formation and neuropsychiatric disorders. Our finding suggests that the dendritic compartment-specific spine formation during adolescence shapes nonlinear dendritic integration in L5 ET neurons and supports the maturation of cognitive functions.
GPT-4o mini: Non-social science research article
Cryo-EM structure of the vaccinia virus entry fusion complex reveals a multicomponent fusion machinery
Chang Sheng-Huei Lin, Ching-An Li, Chun-Hsiung Wang, Chi-Fei Kao, Hsiao-Jung Chiu, Min-Chi Yeh, Hua-De Gao, Meng-Chiao Ho, Hsien-Ming Lee, Wen Chang
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Membrane fusion is essential for viral entry. Unlike class I-III fusion proteins, vaccinia virus (VACV) uses a multicomponent entry fusion complex (EFC). Using cryo–electron microscopy, we determined the full-length structure of the VACV EFC at near-atomic resolution, revealing a 15-protein asymmetric assembly organized into three layers. The central A16/G9/J5 heterotrimer forms the fusion core, stabilized by conserved PXXCW and Delta motifs, and anchors two A28/H2 adaptor dimers linked to peripheral G3/L5/A21/O3 scaffolds. Structural and evolutionary analyses identify a conserved N-terminal domain in A16 containing a myristoyl-binding pocket and a phenylalanine-rich region that stabilizes the trimer and may regulate lipid engagement. An additional component, F9, binds peripherally to J5, A21, and H2 through Delta-like motifs, reinforcing the prefusion architecture. Together, these results define the VACV EFC as a unique multiprotein fusion machinery and provide a structural framework for understanding the mechanism of poxvirus entry and membrane fusion.
GPT-4o mini: Non-social science research article
Resilient high-temperature reverse osmosis desalination membranes
Jishan Wu, Minhao Xiao, Jinlong He, Rachel Tang, Katie Soares, Ziwei Hou, Xinyi Wang, David Jassby, Menachem Elimelech, Eric M. V. Hoek
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Conventional thin-film composite (TFC) reverse osmosis (RO) membranes experience irreversible performance loss at high temperatures, restricting their use in industries with high-temperature streams, including oil and gas, pharmaceuticals, electronics, power generation, food production, and hybrid desalination plants. However, the mechanisms driving the performance decline of TFC membranes at high temperatures remain poorly understood. Herein, we combine controlled experiments, molecular dynamics simulations, and micromechanical modeling to elucidate TFC failure mechanisms and to evaluate thermally resilient thin-film cross-linked (TFX) composite membrane. Upon exposure to elevated temperatures (>60°C), salt rejection of TFC dropped from ~99 to <90%, with irreversible structural damage in the polysulfone layer, confirmed by scanning electron microscopy. In contrast, the TFX membrane maintained ~99% salt rejection and showed no signs of physical degradation up to 80°C. Our combined analyses revealed that TFC membrane failure arises from irreversible pore expansion in the thermoplastic polysulfone support, leading to polyamide film rupture and delamination. TFX membranes resist thermal deformation, enabling ultrahigh-temperature RO desalination and water reuse.
GPT-4o mini: Non-social science research article
An ancient genome duplication event drives the development and evolution of spinnerets in spiders
Fengyuan Li, Han Yang, Yiming Zhang, Shuhui Wang, Qi Gu, Meiming Wu, Pengyu Jin, Xin Huang, Yu Zhong, Xianting Huang, Yejie Lin, Xinyue Guo, Yunyun Li, Wei Zhang, Shuqiang Li
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Key appendage innovations have driven the origin and expansion of arthropods, such as spinnerets enabling spiders to occupy three-dimensional space and diversify into more than 53,000 species. Here, we investigate the genetic basis of spinneret emergence in spiders by examining the complex history and functional importance of arachnid genome evolution. Using chromosome-scale genomes from newly sequenced spiders and the whip scorpion, we integrate evidence from macrosynteny and phylogenetic analyses to provide further strong support for a whole-genome duplication (WGD) event that occurred during early Arachnopulmonata evolution. Following this event, the abdominal-A gene pair not only exhibits functional divergence but also jointly facilitates the emergence of spinnerets. Furthermore, we integrated single-cell transcriptomic analyses and functional validation to confirm that the dachshund-1 gene also regulates spinneret development. The network of duplicated gene pairs may form a cornerstone in the origin and evolution of key morphological traits, revealing that the long-term effects of ancient WGDs on innovation and diversification also occurred in arthropods.
GPT-4o mini: Non-social science research article
Revitalizing poly(urea)s via disulfide reconfiguration
Zezhou Zong, Da-Hui Qu, He Tian, Qi Zhang
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Weak bonds are well-known to construct soft materials. Elaborating molecule-level self-assembly via supramolecular engineering could generate performance materials that exhibit high strength at mild temperatures. However, the entropy penalty of assembled materials, meanwhile, compromises robustness at elevated temperatures. Herein, we report that simply replacing two carbons with disulfide bonds in poly(urea)s enables unprecedented structural reconfigurability without trading off material robustness. Introducing disulfide bonds maintains the ordered urea-based H-bond assembly in bulk polymers while simultaneously suppressing secondary crystallization of these H-bonded arrays and offering secondary H-bonding sites by forming S─S·H─N interactions. This two-atom structural change revitalizes semicrystalline homopoly(urea) materials by allowing chain mobility and reconfiguration below melting temperatures to enable thermoplastic-like (re)processability and thermoset-like robustness, including more than 2-gigapascal storage modulus, a broad creep-resistant temperature range (up to 150°C), ceramic-like hardness, and resistance to common solvents. Furthermore, these materials exhibit acid-catalyzed depolymerization potential, enabling closed-loop recyclability.
GPT-4o mini: Non-social science research article
Ancient Yellow River ancestry and divergent admixture histories in the Qiang people
Weishun Zeng, Zhaoqing Yang, Yan Lu, Chang Lei, Yang Gao, Yuhan Yang, Xu Wang, Jiayou Chu, Shuhua Xu
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The Qiang people are widely recognized as a basal layer of the Chinese gene pool, yet their genetic origins and evolutionary history remain unclear. We analyzed 20 deep-sequenced Qiang genomes together with genomic data from Tibetan highlanders and neighboring lowlanders. The Qiang genetic structure has been profoundly shaped by historical admixture with Han and Tibetans, giving rise to distinct subpopulations. Using ~450 ancient Asian genomes, we traced the most recent common ancestor of the Qiang to ancient Yellow River farmers ~5300 years ago, indicating shared ancestry with other Chinese populations. We identified several highly differentiated variants related to ethanol metabolism and pigmentation between Qiang subpopulations, which likely arose from joint effects of admixture and selection. Notably, a highly prevalent missense variant in a blood pressure regulation gene was detected, suggesting a potential role in altitude adaptation. Collectively, our findings illuminate the genetic history of the Qiang and highlight how admixture and selection shaped the diversity of Tibetan-Plateau fringe populations.
GPT-4o mini: Non-social science research article
Quantum-elevated chiral discrimination for biomolecules
Yiquan Yang, Xiaolong Hu, Wei Du, Shuhe Wu, Peiyu Yang, Guzhi Bao, Weiping Zhang
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Chiral discrimination of enantiomeric biomolecules is vital in chemistry, biology, and medicine. Conventional methods, relying on circularly polarized light, face weak chiroptical signals and potential photodamage. Despite extensive efforts to improve sensitivity under low-photon exposure, classical chiral probes remain fundamentally bound by the shot noise limit due to quantum fluctuations. To beat these limitations, we demonstrate quantum-elevated chiral discrimination using continuous-variable polarization-entangled states as moderate–photon flux, high-sensitivity, quantum noise–squeezed chiral probes. We achieve a 5-decibel improvement beyond the shot noise limit in distinguishing l - and d -amino acids in liquid phase. This nondestructive, biocompatible protocol enables high-sensitivity chiral analysis, with broad implications for drug development, biochemical research, environmental monitoring, and asymmetric synthesis.
GPT-4o mini: Non-social science research article
Consecutive phase transformations of inorganic-organic assembly in the synthesis of single-walled zeolitic nanotube
Zhaoning Song, Hanlin Wang, Zhenyuan Zhao, Zimu Zhou, Siting Yu, Jie Zhu, Xiao Chen, Limin Ren, Toru Wakihara, Zhendong Liu
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Single-walled zeolitic nanotube features a one-dimensional, hollow tubular structure with double-layered zeolitic walls, which represents a unique type of open framework materials. The formation mechanism underlying this characteristic structure, however, remains largely unexplored. We herein demonstrate that the hydrothermal synthesis of single-walled zeolitic nanotubes involves a cascade of phase transformations driven by intricate inorganic-organic interactions. As a critical step, the rearrangement of short-range ordered aluminosilicate networks enriched with five-membered rings, coupled with geometric matching to the cylindrical micelles of the bolaform organic structure-directing agent, synergistically drives the development and closure of curvature-induced interfaces, ultimately leading to the formation of single-walled zeolitic nanotubes. The proposed mechanism provides a distinctive understanding into structure-directing behaviors for ordered porous materials. This study offers valuable insights for guiding the rational synthesis and precise property tuning of the single-walled zeolitic nanotube, which hold vast potential for applications in diverse fields.
GPT-4o mini: Non-social science research article
Structures of Vibrio cholerae transcription complexes reveal how ToxR and TcpP recruit the RNA polymerase and activate virulence genes
AdriĂ  Alcaide-JimĂ©nez, Albert Canals, Florence Baudin, Cristina MachĂłn, Montserrat FĂ brega-Ferrer, Olga Bantysh, Rosa PĂ©rez-Luque, Brice Murciano, Ali A. Mohammad, Michael J. Rowse, Joseph M. Ferracciolo, Eric S. Krukonis, Christoph W. MĂŒller, Miquel Coll
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Activation of virulence in Vibrio cholerae , the etiological agent of cholera disease, is mediated by two transmembrane one-component signal-transduction proteins, ToxR and TcpP, which are also transcription factors. Using cryo–electron microscopy, we have solved five structures of the ompU and toxT transcription activation complexes, including the RNA polymerase (RNAP) holoenzyme, promoter DNAs, transcribed RNA, and their corresponding transcription factors, ToxR or TcpP and ToxR-TcpP, respectively. Activation is achieved through the interaction of ToxR or TcpP with the α–C-terminal repeat domain of RNAP where a single residue of the activator, a phenylalanine, appears to be the most critical contact, as confirmed by mutagenesis. No interactions of the transcription factors were observed with other subunits of the RNAP, i.e., the σ subunit as it occurs in the structurally related PhoB family of two-component transcription factors. The structures, and their comparison with our previously solved DNA promoter–ToxR x-ray structures, unveil the molecular mechanism of cholera virulence gene activation.
GPT-4o mini: Non-social science research article
Post-2000 faster ENSO phase transitions amplify autumn sea ice loss in the Laptev–East Siberian Sea
Cen Wang, Hui Su, Jianqiu Zheng, Yana Li, Yanjia Wang, Kuilin Zhu, Linwei Jiang
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Sea ice variability in the Laptev and East Siberian Seas (LESS) notably affects Arctic climate and maritime safety. While El Niño–Southern Oscillation (ENSO) winter sea surface temperature anomalies influence global climate, their effect on subsequent autumn LESS ice remains unclear. This study reveals a post-2000 intensification of winter ENSO’s impact on subsequent autumn LESS ice, driven by accelerated ENSO phase transitions compared to the pre-2000 era. Rapid phase transitions of El Niño after 2000 generate persistent cold anomalies in the tropical central–eastern Pacific during the subsequent autumn, strengthening and displacing the Western North Pacific anticyclone (WNPAC) northward. This WNPAC triggers Rossby waves establishing an Arctic anticyclone, warming, and moistening the LESS atmosphere, thereby driving substantial ice loss. In contrast, pre-2000 slower El Niño decay exhibited weaker tropical-Arctic connectivity. These results identify ENSO phase transitions rate as a critical regulator of Arctic sea ice variability, with important implications for seasonal forecasting.
GPT-4o mini: Non-social science research article
Productivity-driven decoupling of microbial carbon use efficiency and respiration across global soils
Yongxing Cui, Shushi Peng, Manuel Delgado-Baquerizo, Daryl L. Moorhead, Robert L. Sinsabaugh, César Terrer, Thomas P. Smith, Yakov Kuzyakov, Josep Peñuelas, Biao Zhu, Feng Tao, Songbai Hong, Ji Chen, Matthias C. Rillig
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Despite extensive research on soil microbial carbon (C) use efficiency (CUE), its linkage to actual soil C storage remains ambiguous. A key uncertainty is that CUE estimates from short-term labeling incubations assume a linear negative relationship with respiration rates, overlooking nonlinear interactions and long-term microbial acclimation. Here, we use a stoichiometry-based approach to estimate CUE (CUE ST ), which links soil resource availability to microbial demand and captures microbial adaptability under resource constraints. We synthesized 1094 paired observations of CUE ST and heterotrophic respiration rate ( R h ) across natural ecosystems and found a nonlinear relationship between them governed by ecosystem productivity. In low-productivity arid and cold regions, CUE ST declined with increasing R h , whereas in productive tropical and temperate regions, CUE ST stabilized at a low level (0.27 ± 0.11) as R h exceeded 340 ± 10.8 grams of C per square meter per year. This shift reflects microbial trade-offs between C assimilation and stoichiometric homeostasis, revealing a decoupling of microbial growth from respiration that limits the capacity of productive ecosystems to store additional soil C.
GPT-4o mini: Non-social science research article
A programmable genetic platform for engineering noninvasive biosensors
Asish N. Chacko, Kaamini M. Dhanabalan, Jinyang Wan, Roy Chien, Nolan T. Anderson, Binzhi Xu, Katie Pham, Ritu Tiwari, Arnab Mukherjee
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Creating genetic sensors for noninvasive visualization of biological activities in optically opaque tissues holds immense potential for basic research and the development of genetic and cell-based therapies. Magnetic resonance imaging (MRI) stands out among deep tissue imaging methods for its ability to generate high-resolution images without ionizing radiation. However, the adoption of MRI as a mainstream biomolecular technology has been hindered by the lack of adaptable methods to link molecular events with genetically encodable contrast. Here, we introduce modular aquaporin-based protease-activatable probes for enhanced reporting (MAPPER), a platform for the systematic creation of genetic sensors for MRI. To develop MAPPER, we engineered protease-activatable MRI reporters using two approaches: protein stabilization and subcellular trafficking. We established the applicability of MAPPER in distinct mammalian cell types and demonstrated its versatility by assembling genetic sensors for diverse targets without requiring extensive customization for each target. MAPPER provides a programmable platform for streamlining the development of noninvasive, nonionizing genetic sensors for biomedical research and in vivo diagnostics.
GPT-4o mini: Non-social science research article
The genesis of citrated ultrathin hydroxyapatite nanorods
Yuqi Wang, Su Yan, Xinyu Tan, Ethan Gerhard, Hui Xu, Haiyue Jiang, Jian Yang
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Ideal orthopedic biomaterials should replicate both the hierarchical structure and exceptional mechanical strength of natural bone. Traditional polymer-hydroxyapatite composites, typically limited up to 40 wt % hydroxyapatite, offer only modest mechanical improvements. Efforts to enhance strength by using stiffer polymers have largely failed, as increased polymer stiffness does not translate to improved composite mechanics. In contrast, natural bone’s load-bearing capability arises from the synergy between citrate, soft collagen, and ultrathin hydroxyapatite nanocrystals (~3 nanometers). Here, we show that elastic poly(octamethylene citrate) enables up to 60 wt % hydroxyapatite incorporation, mimicking the bone’s mineral content. Through a top-down “citrification” process and hot pressing, hydroxyapatite microparticles are partially dissolved and recrystallized into superthin (~5 nanometers) nanorods, enhancing organic-inorganic integration and replicating bone’s Ca/P ratios and architecture. The resulting composites exhibit compressive strengths exceeding 250 megapascals, unprecedented in polymer-mineral systems, offering a molecular design strategy for next-generation load-bearing orthopedic implants.
GPT-4o mini: Non-social science research article
On-demand cancer immunotherapy via single-cell encapsulation of synthetic circuit–engineered cells
Yue Zhao, Rui Li, Yirui Han, Chaochen Shi, Kyubae Lee, Guangjun Nie, Yazhou Chen
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Despite the therapeutic potential of engineered immune cell therapy against metastases, it faces challenges including cytokine-driven systemic toxicity, off-target biodistribution, and host rejection. Here, we develop red/far-red light-regulated individually encapsulated (RL/FRL-EnE) cells, integrating optogenetics with biomaterial encapsulation for precise immunomodulation. This system uses a phytochrome A–based photoswitch (ΔPhyA-PCB) that enables bidirectional control. RL (660 nanometers) triggers interferon-γ, interleukin-6, and anti-CD47 expression via ΔPhyA-PCB–far-red elongated hypocotyl 1 heterodimerization, while FRL (740 nanometers) rapidly reverses production, minimizing toxicity. Single-cell nanoencapsulation prevents intercellular cross-talk and immune clearance, enabling strict light-dependent regulation and extended tumor residence. In vivo, RL/FRL-EnE cells remodeled the tumor microenvironment, reducing immunosuppressive myeloid cells (1.3- to 1.7-fold), while enhancing dendritic cell (1.4-fold) and CD8 + T cell (2.8-fold) infiltration. Collectively, this work establishes a paradigm for closed-loop cellular immunotherapy, where light-regulated living therapeutics achieve on-demand immune reprogramming.
GPT-4o mini: Non-social science research article
Inflammation-triggered self-immolative conjugates enable oral peptide delivery by overcoming gastrointestinal barriers
Juan Cheng, Peng Wu, Chenwen Li, Ying Han, Menglong Sun, Yin Dou, Sheng Chen, Jianxiang Zhang
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Oral delivery of peptide therapeutics remains challenging due to gastrointestinal (GI) degradation and poor intestinal absorption. Here, we propose a self-immolative peptide prodrug conjugate (SIPPC) platform for inflammation-targeted oral delivery, integrating a hydrophilic polyethylene glycol segment, a reactive oxygen species (ROS)–responsive hydrophobic self-immolative module, and a hydrolyzable scaffold, which collectively enable spontaneous assembly into micelle-like nanoparticles. Using three anti-inflammatory peptides (KPV, Ac-QAW, and IRW), we demonstrated that the engineered conjugates exhibit remarkable GI stability, efficient mucus penetration, and ROS-responsive release at inflamed sites. In colitis mice, the KPV-based conjugate (proKPV) achieved a 3.8-fold greater colonic accumulation than free KPV, with enhanced efficacy even at a 20-fold lower dose. Beyond therapeutic effects in the colitis model, oral proKPV substantially accumulated in inflamed lungs and exhibited potent anti-inflammatory efficacy in mice with acute lung injury. Ac-QAW and IRW-based conjugates exhibited comparable benefits, underscoring SIPPC as a transformative paradigm for oral peptide therapeutics, offering substantial promise for clinical translation in inflammatory disorders.