data.csv

"title","doi","altmetric_jid","score","X1d","X3d","X1w","X1m","authors","author_corresponding","author_corresponding_institution","date","version","type","license","category","jatsxml","abstract","funder","published","server","upupdate_time"
"Ascending nociceptive pathways drive rapid escape and sustained avoidance in adult Drosophila","10.1101/2025.10.28.684868","biorxiv",25.450000000000006,25.450000000000006,25.450000000000006,25.450000000000006,25.450000000000006,"Jones, J. M.; Sustar, A.; Mamiya, A.; Walling-Bell, S.; Chou, G. M.; Cook, A.; Tuthill, J. C.","John C Tuthill","University of Washington","2025-10-29","1","new results","cc_by_nd","neuroscience","https://www.biorxiv.org/content/early/2025/10/29/2025.10.28.684868.source.xml","Nociception -- the detection of harmful stimuli by the nervous system -- contributes to both rapid escape and long-term avoidance behaviors. Drosophila larvae detect damaging heat, mechanical, and chemical stimuli with specialized multidendritic (md) neurons, and these cells are among the only sensory neurons that survive metamorphosis. However, it remains unknown which somatosensory neurons contribute to nociception in adult flies. In an optogenetic screen, we found that abdominal md neurons were the only somatosensory class to induce rapid escape and sustained place avoidance. Calcium imaging from abdominal md axons revealed that they are activated by thermal nociceptive stimuli (>40 {degrees}C). Connectomic reconstruction showed that md axons form their strongest synaptic connections with ascending interneurons that project to the brain. Among these, we identified two classes of ascending neurons that mediate rapid escape responses and a third that supports sustained avoidance. Our findings reveal that adult Drosophila meet several core criteria commonly used to define pain: dedicated nociceptors, ascending pathways connecting peripheral sensors to integrative brain centers, and a capacity for sustained avoidance of noxious stimuli.","NA","NA","bioRxiv",1761862207167
"Structural basis for substrate specificity and MSMEG_0435-0436 binding by the mycobacterial long-chain acyl-CoA carboxylase complex","10.1101/2025.10.28.685139","biorxiv",19.2,19.2,19.2,19.2,19.2,"Liang, Y.; Rubinstein, J. L.","John L Rubinstein","The Hospital for SIck Children","2025-10-29","1","new results","cc_no","biochemistry","https://www.biorxiv.org/content/early/2025/10/29/2025.10.28.685139.source.xml","The presence of mycolic acid is a defining feature of the mycobacterial cell wall, which provides a highly impermeable barrier to many antibiotics. Biosynthesis of this fatty acid, as well as tuberculostearic acid, requires precursor molecules produced by the essential long-chain acyl-coenzyme A (CoA) carboxylase (LCC) complex. The LCC complex catalyzes carboxylation of the -carbon of long-chain acyl-CoA, but also short-chain acetyl-CoA and propionyl-CoA. The complex includes the subunits AccA3, which contains a biotin carboxylase (BC) domain and a biotin carboxyl carrier protein (BCCP) domain, the long-chain acyl-CoA carboxyltransferase AccD4, the short-chain acyl-CoA carboxyltransferase AccD5, and the incompletely characterized protein AccE. We used electron cryomicroscopy (cryo-EM) to determine structures of the LCC complex from Mycobacterium smegmatis. In the structures, two AccE subunits tether eight AccA3 subunits to an AccD42AccD54 heterohexamer core. Cryo-EM of the enzyme during catalysis reveals how AccD4 and AccD5 achieve substrate specificity, with AccD5 binding tightly to CoA and AccD4 binding long acyl chains. The BCCP domains of AccA3 undergo long-distance translocation to transfer a carboxyl group from the BC domain of AccA3 to the acyl-CoA substrate bound in AccD5. Further, we find that two copies of a protein complex formed from MSMEG_0435 and MSMEG_0436 can bind the LCC complex, sequestering the biotin moiety of BCCP domains near AccD5. Rv0263c, the Mycobacterium tuberculosis ortholog of MSMEG_0435, has a role in bacterial survival during transmission, suggesting that these proteins may regulate production of branched fatty acid precursors for the mycobacterial cell wall.","[{""name"":""Canadian Institutes of Health Research"",""id"":""https://ror.org/01gavpb45"",""id-type"":""ROR"",""award"":""Canada Graduate Scholarship - Doctoral;""},{""name"":""Canada Research Chairs"",""id"":""https://ror.org/0517h6h17"",""id-type"":""ROR"",""award"":""Canada Research Chair - Tier 1;""}]","NA","bioRxiv",1761862207167
"Ancient amino acid sets enable stable protein folds","10.1101/2025.10.29.685319","biorxiv",12.8,12.8,12.8,12.8,12.8,"Giacobelli, V. G.; Andersson, S.; Srb, P.; Neuwirthova, T.; Ruszova, Z.; Marhoul, J.; Psenicka, S.; Knetl, A.; Bednarova, L.; Veverka, V.; Hlouchova, K.; Andre, I.","Ingemar André","Division of Biochemistry and Structural Biology, Lund University","2025-10-29","1","new results","cc_by_nc_nd","biochemistry","https://www.biorxiv.org/content/early/2025/10/29/2025.10.29.685319.source.xml","Early proteins likely arose from a chemically limited set of amino acids available through prebiotic chemistry, raising a central question in molecular evolution: could such primitive compositions yield stable, functional folds? Using de novo design, we constructed three ancient protein architectures using a reduced, evolution-inspired alphabet of ten amino acids, e.g. lacking all basic and aromatic residues. The resulting structures adopted their intended topologies and showed exceptional resistance to thermal and chemical denaturation. Computational simulations further revealed that proteins built from this restricted alphabet were as mutation-resilient as those using all twenty canonical residues. Besides their evolutionary implications, our results provide a foundation for minimalist protein design and generation of simplified, robust systems in minimal cell engineering.","[{""name"":""International Human Frontier Science Program Organization"",""id"":""https://ror.org/02ebx7v45"",""id-type"":""ROR"",""award"":""RGEC27/2023;""},{""name"":""Knut and Alice Wallenberg Foundation"",""id"":""https://ror.org/004hzzk67"",""id-type"":""ROR"",""award"":""WASP;""},{""name"":""European Regional Development Fund"",""id"":"""",""id-type"":""ROR"",""award"":""UP CIISB;""},{""name"":""Primus grant, Charles University"",""id"":"""",""id-type"":""ROR"",""award"":""PRIMUS/20/SCI/012;""},{""name"":""MEYS CR"",""id"":"""",""id-type"":""ROR"",""award"":""LM2018127;""},{""name"":""Ministry of Education, Youth and Sports of the Czech Republic, Infra CZ"",""id"":"""",""id-type"":""ROR"",""award"":""90254;""}]","NA","bioRxiv",1761862207167
"CREation of an expanded plant memory gene circuit toolkit","10.1101/2025.10.28.684748","biorxiv",12.399999999999999,12.399999999999999,12.399999999999999,12.399999999999999,12.399999999999999,"Gong, P.; Khan, A.; Ly, F.; Zhu, J. Y.; Herring, G.; Jadhav, H.; Pflueger, C.; Lloyd, J. P. B.; Lister, R.","Ryan Lister","The University of Western Australia","2025-10-28","1","new results","cc_by_nc_nd","synthetic biology","https://www.biorxiv.org/content/early/2025/10/28/2025.10.28.684748.source.xml","Genetic circuits rely on modular, well-characterized genetic parts to achieve predictable cellular behaviour. Despite their widespread adoption, biological parts are complex and when used in a new molecular context can result in unexpected outcomes. Site-specific recombinases have been widely used due to their unique ability to induce precise, irreversible changes to a DNA sequence, making them ideal tools for memory logic operations. However, unexpected context-specific failures of even the most widely used recombinase, Cre, has limited the expansion and complexity of synthetic gene circuits in diverse species. Here, through a systematic analysis of Cre failure in plant gene circuits, we uncovered multiple unexpected post-recombination interactions within the transcriptional unit between the promoter region, recombinase, and their cognate recognition sites. These significantly inhibit transcriptional activity, preventing circuit functionality. Specifically, post-recombination Cre recombinase exhibits an inhibitory property by binding to lox sites, with the remaining lox site repressing transcription. By thoroughly characterizing these dynamics, we restored Cre functionality and expanded the plant-based recombinase toolkit for Cre-related recombinases, developing combinations of recombinases and cognate sites with different activation levels for constructing logic gates with stable memory functions. We further developed multiple functional split-recombinase systems for simultaneous logic using a range of dimerization domains and constructed complex logic gates, including 3-input and 6-input AND gates. Together, this exploration of component context dependency in genetic circuits, even with commonly used parts like the Cre/lox system, has implications extending beyond plant systems, and significantly expands plant memory circuit capabilities.","[{""name"":""Australian Research Council"",""id"":""https://ror.org/05mmh0f86"",""id-type"":""ROR"",""award"":""DP240103385;DP210103954;""},{""name"":""ARC Centre of Excellence in Plant Energy Biology"",""id"":""https://ror.org/01a1mq059"",""id-type"":""ROR"",""award"":""CE140100008;""},{""name"":""ARC Centre of Excellence in Plants for Space"",""id"":"""",""id-type"":""ROR"",""award"":""CE230100015;""},{""name"":""NHMRC"",""id"":"""",""id-type"":""ROR"",""award"":""GNT1178460;""},{""name"":""Howard Hughes Medical Institute"",""id"":""https://ror.org/006w34k90"",""id-type"":""ROR"",""award"":""""},{""name"":""UWA Research Training Program"",""id"":"""",""id-type"":""ROR"",""award"":""""},{""name"":""Twist Bioscholar Program"",""id"":"""",""id-type"":""ROR"",""award"":""""},{""name"":""The University of Western Australia"",""id"":""https://ror.org/047272k79"",""id-type"":""ROR"",""award"":""""},{""name"":""Grains Research and Development Corporation"",""id"":""https://ror.org/02xwr1996"",""id-type"":""ROR"",""award"":""""}]","NA","bioRxiv",1761862207167
"Neuronal architecture of the mouse insular cortex underlying its diverse functions","10.1101/2025.10.23.683697","biorxiv",11.399999999999999,8.65,8.65,11.399999999999999,11.399999999999999,"Jongbloets, B. C.; Chen, Y.; Gingerich, I. K.; Muniak, M. A.; Mao, T.","Tianyi Mao","Oregon Health and Science University","2025-10-24","1","new results","cc_by_nc","neuroscience","https://www.biorxiv.org/content/early/2025/10/24/2025.10.23.683697.source.xml","The insular cortex integrates interoceptive and exteroceptive information to mediate bodily homeostasis, emotion, learning, and potentially consciousness.1-4 However, the cellular and circuit substrates governing the insula and other associative cortices are poorly understood compared to primary cortices. Here, we quantify the dendritic morphology together with electrical properties, local inputs, and/or projections of 1,093 insular pyramidal neurons. These neurons are mapped onto a quantitative anatomical model of the insula based on a Nissl-staining coordinate framework. Using improved algorithms, we define 21 morphological, 12 electrical, and 9 input neuronal types, and identify several morphological and input types that are unique to the insula. Further, we find that morphological properties constrain and often predict inputs, electrical properties, or projection targets. Several morphological types are differentially distributed between the functionally distinct anterior and posterior insula, providing the substrates for a quantitative demarcation between the anterior and posterior insular subregions. Surprisingly, certain neuronal types receive intra-insular inputs originating far beyond canonical cortical columns. Functionally, these connections bridge a long-range thalamus-to-amygdalar circuit that potentially links sensory information to valence. Our work establishes a structure-and-function foundation for investigating the insular cortex.","[{""name"":""Dutch Research Council"",""id"":""https://ror.org/04jsz6e67"",""id-type"":""ROR"",""award"":""VI.Veni.192.231;""},{""name"":""NIH Common Fund"",""id"":""https://ror.org/001d55x84"",""id-type"":""ROR"",""award"":""RF1MH120119;R01NS104944;RF1NS133599;R01NS081071;""},{""name"":""Lacroute Fellowship"",""id"":"""",""id-type"":""ROR"",""award"":""""}]","NA","bioRxiv",1761862207167
"Distinct mechanisms decommission redundant enhancers to facilitate phenotypic evolution","10.1101/2025.10.27.684981","biorxiv",8.6,8.6,8.6,8.6,8.6,"Said-Ahmad, A.; Shimron, N.; Fainitsky, E.; Naik, S.; Roy, S.; Frankel, N.; Prege-Ben Noon, E.","Ella Prege-Ben Noon","Technion - Israel Institute of Technology","2025-10-28","1","new results","cc_by_nc_nd","evolutionary biology","https://www.biorxiv.org/content/early/2025/10/28/2025.10.27.684981.source.xml","The evolutionary loss of morphological traits is often driven by changes in gene regulation. Many developmental genes are controlled by multiple, redundant enhancers, raising the question of how robust regulatory systems can be dismantled to permit phenotypic transitions. We show that the loss of larval trichomes in Drosophila sechellia resulted from the independent inactivation of four embryonic enhancers of the shavenbaby gene. Each enhancer was extinguished by a distinct mechanism: (1) a large deletion that removed essential sequences, (2) the loss of activator sites and gain of repressor sites, (3) the acquisition of a long-range silencer, and (4) the unmasking of pre-existing repression. Notably, three of these mechanisms relied on repression, pointing to repression as a rapid route for the evolutionary loss of robust regulatory elements. These results show that robustness in gene regulation does not prevent morphological change but instead provides multiple opportunities for mutations to reduce enhancer activity, giving selection many paths to reshape form.","[{""name"":""Israel Science Foundation"",""id"":""https://ror.org/04sazxf24"",""id-type"":""ROR"",""award"":""No. 2567/20;""}]","NA","bioRxiv",1761862207167
"AutoSpectral improves spectral flow cytometry accuracy through optimised spectral unmixing and autofluorescence-matching at the cellular level","10.1101/2025.10.27.684855","biorxiv",63.050000000000026,6.699999999999999,63.050000000000026,63.050000000000026,63.050000000000026,"Burton, O. T.; Buecken, L.; De Vuyst, L.; Humblet-Baron, S.; De Leon, A. L. M.; Khan, S.; Cerveira, J.; Dooley, J.; Liston, A.","Adrian Liston","University of Cambridge","2025-10-27","1","new results","cc_no","immunology","https://www.biorxiv.org/content/early/2025/10/27/2025.10.27.684855.source.xml","The advent of spectral flow cytometry has seen a rapid rise in the complexity of flow cytometry experiments, allowing the construction of assays with at least 50 fluorescent parameters. To correctly determine the contributions of each fluorophores signal to the high parameter data an accurate unmixing matrix needs to be generated. Even with single-stained controls, however, these matrixes include errors such as spillover spread, which compounds with each additional parameter, functionally limiting panel design. An additional source of errors is heterogeneity of cellular autofluorescence, which can affect both the unmixing matrix and misalign signals when the matrix is applied to individual cells in complex cell mixtures. Here we developed AutoSpectral, a statistical approach to automate the production of minimal-residual error unmixing matrixes and pair multiple distinct multifluorescent spectra to individual cells within a mixed sample, via an R-based software tool. AutoSpectral improves unmixing accuracy, improving incorrectly assigned cell positions by up to 9000-fold, reduces spread, particularly in samples with variable autofluorescence, and allows multi-lineage analysis of mixed populations, providing superior data for spectral flow cytometry experiments.","[{""name"":""Medical Research Council"",""id"":""https://ror.org/03x94j517"",""id-type"":""ROR"",""award"":""MR/Y004450/1;""},{""name"":""Wellcome Trust"",""id"":""https://ror.org/029chgv08"",""id-type"":""ROR"",""award"":""222442/A/21/Z;""}]","NA","bioRxiv",1761862207167
"Cholinergic heterogeneity facilitates synchronization and information flow in a whole-brain model","10.1101/2025.10.28.685048","biorxiv",5.95,5.95,5.95,5.95,5.95,"Dalla Porta, L.; Fousek, J.; Destexhe, A.; Sanchez-Vives, M. V.","Leonardo Dalla Porta","August Pi i Sunyer Biomedical Research Institute (IDIBAPS)","2025-10-29","1","new results","cc_by","neuroscience","https://www.biorxiv.org/content/early/2025/10/29/2025.10.28.685048.source.xml","The human brain displays substantial regional variability in molecular, anatomical, and physiological organization. Yet, how this heterogeneity shapes large-scale neuronal dynamics remains poorly understood. To address this question, we employed a biologically informed whole-brain computational model capable of generating distinct brain states, from awake-like to sleep-like regimes. Our model was constrained by empirical human structural connectivity and spatial maps of cholinergic receptor gene expression, thereby embedding regional neuromodulatory variability into a macroscopic framework. We found that incorporating cholinergic heterogeneity had a significant impact on brain dynamics: it not only facilitated network synchronization but also enhanced information flow between brain regions. Furthermore, we addressed a particularly intricate dynamic regime characterized by the coexistence of localized sleep-like activity within otherwise awake-like states. We showed that the emergence of these slow waves was a byproduct of both regional levels of neuronal adaptation and structural connectivity. In summary, our findings highlight the critical role of molecular and anatomical heterogeneity in shaping global brain dynamics, suggesting new avenues for linking microscale diversity to macroscale function.","NA","NA","bioRxiv",1761862207167
"Ventral tegmental area dopamine controls timing variability","10.1101/2025.10.27.684913","biorxiv",5.85,5.85,5.85,5.85,5.85,"Weber, M. A.; Sivakumar, K.; Bova, A.; Tabakovic, E.; Conlon, M.; Oya, M.; Cole, R.; Espinoza, A.; Kim, Y.; Narayanan, N.","Nandakumar Narayanan","Dr.","2025-10-28","2","new results","cc_no","neuroscience","https://www.biorxiv.org/content/early/2025/10/28/2025.10.27.684913.source.xml","Precision defines successful behavior, yet the brain mechanisms promoting precision are unclear. Here, we dissect dopaminergic circuits controlling precision along a single behavioral dimension - the timing of action. We use an interval timing paradigm that requires participants to indicate their estimate of an interval of several seconds with a motor response. We find that humans with Parkinson's disease (PD) had increased timing variability that predicted PD-related cognitive deficits and executive dysfunction. Surprisingly, lesioning ventral tegmental area (VTA) dopamine neurons increased temporal variability. Further, GCaMP6s fiber photometry demonstrated that VTA dopamine neuron activity is strongly modulated at the start of temporal intervals, and that this trial start related activity predicted temporal variability. Finally, we found that stimulation of VTA dopamine neurons improved timing by decreasing temporal variability in both intact and dopamine depleted animals. Our data establish a model of cognitive symptoms of human PD and provide insight into the neuronal control of temporal variability, which impacts a wide range of executive functions.","[{""name"":""nih"",""id"":"""",""id-type"":""ROR"",""award"":""NS120987;""}]","NA","bioRxiv",1761862207167
"Self-esteem modulates beneficial causal attributions in the formation of novel self-beliefs","10.1101/2025.10.27.684784","biorxiv",8.45,5.25,8.45,8.45,8.45,"Mayer, A. V.; Schroeder, A.; Stolz, D. S.; Czekalla, N.; Paulus, F. M.; Mueller-Pinzler, L.; Krach, S.; Kube, T.","Annalina V Mayer","University of Luebeck","2025-10-27","1","new results","cc_by_nc_nd","neuroscience","https://www.biorxiv.org/content/early/2025/10/27/2025.10.27.684784.source.xml","Healthy individuals typically attribute successes to internal causes, such as their abilities, and failures to external factors, like bad luck. In contrast, individuals with depression and low self-esteem are more likely to attribute failures to internal causes and successes to external causes. At the same time, depression and low self-esteem are associated with negatively biased self-related learning and self-beliefs. Although causal attributions have been shown to influence belief formation and updating, the dynamic interaction between real-time attributions and self-related learning remains poorly understood. In this study, we used a validated self-related learning task to investigate how internal versus external attributions of performance feedback affect the formation of self-beliefs and how these processes relate to depressive symptoms and self-esteem. Drawing on a computational model that incorporates prediction error valence and causal attributions, we found that participants updated their self-beliefs less when feedback was attributed to external causes. Furthermore, individuals with higher levels of depression and lower self-esteem showed a stronger negativity bias in learning. Lower self-esteem was also linked to a reduced self-serving bias in attributions. These findings provide insight into the cognitive mechanisms that may contribute to the development and maintenance of negative self-beliefs commonly observed in depression.","[{""name"":""Deutsche Forschungsgemeinschaft"",""id"":""https://ror.org/018mejw64"",""id-type"":""ROR"",""award"":""KU 3955/3-1;MU 4373/1-1; MU 4373/1-3; KR 3803/11-1; 3803/14-1;""}]","NA","bioRxiv",1761862207167
"Regulation of cell proliferation by a novel feedback system on Cdk function","10.1101/2025.10.28.685054","biorxiv",5.2,5.2,5.2,5.2,5.2,"Ryan, J. R.; Leray, B.; Jain, A.; Coehlo, N.; Domingo-Sananes, M. R.; Aspert, T.; Charvin, G.; Krockenberger, M.; Chica Blaguera, N.; Lopez Aviles, S.; Takacs, L.; Uhlmann, F.; Yang, L.; Yue, J.-X.; Liti, G.; Cochard, V.; Chevreux, G.; Sugiyama, H.; Goto, Y.; Aoki, K.; Wu, P.-Y. J.; Mackereth, C. D.; Tyson, J.; Novak, B.; Coudreuse, D.","Damien Coudreuse","Institute of Biochemistry and Cellular Genetics","2025-10-29","1","new results","cc_by_nc_nd","cell biology","https://www.biorxiv.org/content/early/2025/10/29/2025.10.28.685054.source.xml","The proliferation of eukaryotic cells is regulated by a complex network of regulatory systems that promotes efficient cell cycle progression and ensures proper responses to the environment. Despite this complexity, the core inputs that are necessary and sufficient for robust alternation of DNA replication and mitosis are surprisingly simpler than anticipated. Indeed, fission yeast cells operating with an engineered minimal cell cycle network that lacks the highly conserved Wee1+Cdc25 feedback loops on Cdk1 function are viable, although slow growing. This provides a unique entry for evaluating how such simplified cells can evolve and improve their proliferation potential while exploring unknown mechanisms modulating cell cycle progression. Taking advantage of this model, we applied laboratory evolution assays to minimal fission yeast backgrounds and selected for the emergence of faster growing populations. We found that loss of the small disordered protein Spo12 brings about enhanced population growth in cells lacking the Wee1+Cdc25 mitotic switch. Importantly, we demonstrate that Spo12 defines a new and conserved family of inhibitors of the Cdk-counteracting phosphatase PP2A that are directly regulated by Cdk-dependent phosphorylation. Our results also reveal a trade-off associated with Spo12-dependent regulation, which may have implications for our understanding of the principles underlying the evolution of cell cycle control. Finally, our study highlights how combining simplified circuits with experimental evolution allows for uncovering regulatory elements that may be obscured by network complexity.","[{""name"":""Agence Nationale de la Recherche"",""id"":""https://ror.org/00rbzpz17"",""id-type"":""ROR"",""award"":""ANR-18-CD13-0009;""},{""name"":""Région Nouvelle Aquitaine"",""id"":"""",""id-type"":""ROR"",""award"":""CHESS 15963520;CHESS 15964420;""},{""name"":""La Ligue Contre le Cancer"",""id"":""https://ror.org/00rkrv905"",""id-type"":""ROR"",""award"":""Comités déparmentaux Gironde et Dordogne;""},{""name"":""European Research Council"",""id"":""https://ror.org/0472cxd90"",""id-type"":""ROR"",""award"":""310849;""},{""name"":""University of Bordeaux"",""id"":""https://ror.org/057qpr032"",""id-type"":""ROR"",""award"":""France 2030 Programme IdEx;""},{""name"":""University of Oslo"",""id"":""https://ror.org/01xtthb56"",""id-type"":""ROR"",""award"":""""},{""name"":""Cancer Research UK"",""id"":""https://ror.org/054225q67"",""id-type"":""ROR"",""award"":""UKRI Medical Research Council;""},{""name"":""Wellcome Trust"",""id"":""https://ror.org/029chgv08"",""id-type"":""ROR"",""award"":""CC2137;""},{""name"":""National Natural Science Foundation of China"",""id"":""https://ror.org/01h0zpd94"",""id-type"":""ROR"",""award"":""32470663;""},{""name"":""JSPS KAKENHI"",""id"":"""",""id-type"":""ROR"",""award"":""21J01354;22K15115;JP24H01416;22K15110;""},{""name"":""Dr. Yoshifumi Jigami Memorial Fund"",""id"":"""",""id-type"":""ROR"",""award"":""""},{""name"":""JST ACT-X"",""id"":"""",""id-type"":""ROR"",""award"":""JPMJAX22B8;""},{""name"":""ExCELLS program"",""id"":"""",""id-type"":""ROR"",""award"":""25EXC603;""},{""name"":""Ministère de l’Enseignement Supérieur et de la Recherche"",""id"":"""",""id-type"":""ROR"",""award"":""""}]","NA","bioRxiv",1761862207167
"ADHD-like traits reshape the balance between inhibitory control and predictive processes","10.1101/2025.10.28.685045","biorxiv",5.2,5.2,5.2,5.2,5.2,"Horvath, K.; Brezoczki, B.; Holczer, A.; Vekony, T.; Nemeth, D.","Dezso Nemeth","Centre de Recherche en Neurosciences de Lyon CRNL U1028 UMR5292, INSERM, CRNS, Universite Claude Bernard Lyon 1, 69500 Bron, France","2025-10-29","1","new results","cc_by_nc_nd","neuroscience","https://www.biorxiv.org/content/early/2025/10/29/2025.10.28.685045.source.xml","Adaptive behavior relies on a dynamic balance between flexible, goal-directed control and efficient, automatic processes. This equilibrium is often disrupted in Attention-Deficit/Hyperactivity Disorder (ADHD), a condition understood to exist along a continuum of traits in the general population. While ADHD is consistently linked to response inhibition deficits, its relationship with statistical learning (a mechanism for habit learning) and, crucially, the interaction between these functions, remains underexplored. Here, using a novel paradigm in a non-clinical sample of university students (n = 226), we investigated how ADHD-like traits modulate the interplay between response inhibition and statistical learning. We found that higher ADHD-like traits were associated with poorer response inhibition, confirming previous research. Importantly, we uncovered an antagonistic relationship between inhibition and statistical learning, where weaker inhibitory control typically led to enhanced learning of environmental regularities. However, this learning advantage progressively diminished across the ADHD trait continuum, becoming markedly reduced in individuals with high symptom prevalence. These findings provide novel evidence that ADHD-like traits influence not only isolated neurocognitive processes but also their dynamic interaction, highlighting a spectrum-based mechanism that may underlie the transition from adaptive variability to maladaptive behavioral patterns. This work advocates for a dimensional approach to ADHD, emphasizing early detection and targeted interventions for individuals with varying levels of symptomatic expression, broadening support beyond traditional diagnostic boundaries.","[{""name"":""French National Grant Agency"",""id"":"""",""id-type"":""ROR"",""award"":""ANR-22-CPJ1-0042-01;ANR-24-CE37-5807;""},{""name"":""National Brain Research Program"",""id"":"""",""id-type"":""ROR"",""award"":""NAP2022-I-2/2022;""},{""name"":""EKÖP-24 University Excellence Scholarship Program of the Ministry for Culture and Innovation from the Source of the National Research, Development and Innovation Fund"",""id"":"""",""id-type"":""ROR"",""award"":""EKÖP-24-3-II-ELTE-1159;""}]","NA","bioRxiv",1761862207167
"Landscape of parental postzygotic mutations in >11,000 rare disease trios","10.1101/2025.10.17.25337713","medrxiv",8.049999999999999,5.1,7.799999999999999,7.799999999999999,8.049999999999999,"Garcia-Salinas, O. I.; Sanghvi, R.; Sayer, J. A.; Torra I Benach, M.; Pham, M. H.; Martin, H. C.; Rahbari, R.","Raheleh Rahbari","Wellcome Trust Sanger Institute","2025-10-19","1","PUBLISHAHEADOFPRINT","cc_by","genetic and genomic medicine","https://www.medrxiv.org/content/early/2025/10/19/2025.10.17.25337713.source.xml","Postzygotic mutations (PZMs) arising post-fertilisation, prior to primordial germ cell specification, may be subsequently inherited by both somatic and germ cells, causing somatic mosaicism in the parent as well as being passed to offspring. These early embryonic mutations often go undetected in clinical sequencing due to their low variant allele fraction (VAF) and are typically excluded by standard variant filtering pipelines. To overcome this limitation, we developed a bioinformatic approach to detect PZMs using standard-depth ([~]30X) whole genome sequencing data from 12,015 parent-offspring trios in the Genomics England 100,000 Genomes Project. We identified 1,015 high-confidence autosomal early PZMs. These mutations showed no parental sex-bias and exhibited a monomodal VAF distribution centred around 5% in blood. PZMs displayed a mutational spectrum distinct from de novo mutations, although both appeared to be driven by mutational signatures SBS1 and SBS5. Notably, we identified a subset of PZMs likely contributing to the clinical phenotype in affected children. This work demonstrates that postzygotic mosaicism represents a rare but clinically relevant source of diagnostic variation in rare disease and can be detected from standard sequencing data. Incorporating PZM detection into clinical workflow could improve diagnostic yield and provide more accurate recurrence risk estimates for affected families.","NA","NA","medRxiv",1761862207167
"Bimanual Postural Similarity Facilitates Haptic Memory-Guided Reaching","10.1101/2025.10.27.684813","biorxiv",5.050000000000001,5.050000000000001,5.050000000000001,5.050000000000001,5.050000000000001,"Camponogara, I.; Volcic, R.","Ivan Camponogara","Zayed University","2025-10-28","1","new results","cc_by_nc_nd","neuroscience","https://www.biorxiv.org/content/early/2025/10/28/2025.10.27.684813.source.xml","In the visual domain, the precision of memory-guided reaching movements gradually decays as the delay between vision withdrawal and movement onset increases. Such a decrease is often linked to the impact of visual memory decay and the sensory transformation of visual target positional information into haptic-specific coordinates. It is, however, unclear whether this holds for haptically encoded spatial locations, where the target and reaching arm positions are both defined through haptics. Here, we asked participants to perform memory-guided right-handed reaching movements toward targets held with the left hand. In the Delay block, the left hand was removed after 2 seconds, and a right-handed reach was performed after a variable delay of 2, 4, or 6 seconds. In the No-delay block, the left hand was on the target for the entire duration of the trial. Targets were positioned in front (Center) and to the Left of the participants, such that the posture of the left arm during encoding was either the same or different from the final posture of the contralateral reaching arm. The introduction of the shortest delay caused a decrease in accuracy and precision, indicating that on-line haptic inputs play a crucial role in guiding reaching movements. However, performance did not worsen with longer delays, particularly when the two arms were in similar postures. Our findings suggest that postural information may contribute to guiding actions when on-line haptic feedback is unavailable.","NA","NA","bioRxiv",1761862207167
"Mechanical polarity links adhesion-tuned protrusions to directional stability in glioblastoma cell migration","10.1101/2025.10.23.684087","biorxiv",8,5,5,8,8,"Tagawa, H.; Kanematsu, D.; Katsuma, A.; Inagaki, N.; Kanemura, Y.; Sakumura, Y.","Yuichi Sakumura","Nara Institute of Science and Technology","2025-10-24","1","new results","cc_by","systems biology","https://www.biorxiv.org/content/early/2025/10/24/2025.10.23.684087.source.xml","Glioblastoma invasion critically limits therapeutic outcomes, and understanding the physical principles that govern cell motility is essential for developing effective therapies. Here, to clarify the mechanical links between cell adhesion, protrusions, and migration, we analyzed glioblastoma-derived cells migrating on fibronectin- and laminin-coated extracellular matrix (ECM) substrates using time-lapse imaging and mathematical modeling. We quantified cell motility on each ECM and constructed a coarse-grained biophysical model that incorporates catch- and slip-bond kinetics. We treated the ECM as an external boundary condition that modulates adhesion dynamics, distinct from the intrinsic mechanical parameters of the cell. The model reproduced ECM-dependent differences in cell motility. The results suggest that adhesions and protrusion elongation on fibronectin are less stable than on laminin, and opposing forces between protrusions reduce net displacement more strongly on fibronectin than on laminin, leading to less coordinated tensile forces. Based on these results, we establish mechanical polarity, defined as an imbalance of protrusion- and adhesion-mediated forces that drive directional migration, as a quantifiable physical principle of cell protrusion and migration. This principle likely extends beyond glioblastoma biology, providing a generalizable mechanism that links adhesion dynamics to migration stability and offering a physical basis for strategies to suppress invasive cell behavior.","[{""name"":""The Japan Society for the Promotion of Science (JSPS) KAKENHI"",""id"":"""",""id-type"":""ROR"",""award"":""20H04283;23H04707;""},{""name"":""The Japan Science and Technology Agency (JST) SPRING"",""id"":"""",""id-type"":""ROR"",""award"":""JPMJSP2140;""},{""name"":""the Japan Agency for Medical Research and Development (AMED)"",""id"":"""",""id-type"":""ROR"",""award"":""JP17gm0810011;""}]","NA","bioRxiv",1761862207167
"Elevation of the mechanically-sensitive protein emerin links nuclear mechanotransduction to tau-induced cytoskeletal remodeling in neurons","10.1101/2025.10.15.682650","biorxiv",12.2,5,5,5,12.2,"Sohn, C.; Pardo, S.; Molleur, D.; Paduri, S. R.; Lambert, M.; Thomas, M. G.; Sohn, E. J.; Weintraub, S. T.; Frost, B.","Bess Frost","Brown University Center for Alzheimer\'s Disease Research","2025-10-15","1","new results","cc_by_nd","cell biology","https://www.biorxiv.org/content/early/2025/10/15/2025.10.15.682650.source.xml","Tauopathies are a group of neurodegenerative disorders, including Alzheimers disease, that are neuropathologically defined by deposition of pathological forms of tau in the brain. While tau is reported to drive neurotoxicity by negatively affecting cytoskeletal, nucleoskeletal, and genomic architecture, the mechanisms mediating tau-induced dysfunction of the cytoskeleton and nucleoskeleton are incompletely understood. Based on proteomic profiling, we identify a suite of cytoskeletal and nucleoskeletal proteins with differing abundance in a cellular model of tauopathy, iTau. Building upon previous findings that pathogenic forms of tau reduce nuclear tension, we find that protein levels of emerin, a central regulator of nuclear mechanotransduction, are significantly elevated in iTau cells and in induced pluripotent stem cell (iPSC)-derived neurons carrying a mutation in the microtubule-associated protein tau (MAPT) gene that causes autosomal dominant frontotemporal dementia. We find that neuronal emerin overexpression is sufficient to drive neurotoxicity, increase overall levels of filamentous actin (F-actin), and induce nuclear invagination, cellular phenotypes that also occur in settings of tauopathy. Mass spectrometry-based identification of emerin-interacting proteins in iTau-derived neurons reveals increased interactions with cytoskeletal proteins and reduced interactions with nuclear proteins. Indeed, we find that emerin relocalizes from the nucleus to the cytosol in the setting of tauopathy, suggesting that pathogenic tau impacts nuclear mechanotransduction pathways. Overall, we identify emerin as a mediator of cytoskeletal remodeling in tauopathy and provide a foundation for future studies into the mechanosensitive function of emerin in neurons.

SIGNIFICANCE STATEMENTCells experience and respond to diverse mechanical forces that shape their morphology, function, and survival through a process termed ""mechanotransduction."" While well studied in non-neuronal cells, neuronal mechanotransduction remains poorly understood despite exposure of the brain to vascular flow, movement, injury, and disease. We identify the mechanosensitive protein emerin as a key regulator of nuclear mechanotransduction in neurons. Emerin overexpression is sufficient to increase filamentous actin, induce nuclear invagination, and drive neurotoxicity, revealing a novel function for emerin in neurons. In cellular models of tauopathy, emerin is elevated and relocalizes from the nucleus to the cytoplasm, where it alters cytoskeletal structure. These findings establish emerin as a mechanosensitive regulator in neurons and link disrupted nuclear neuronal mechanotransduction to neurodegeneration.","[{""name"":""National Institute on Aging"",""id"":""https://ror.org/049v75w11"",""id-type"":""ROR"",""award"":""R01 AG057896;""},{""name"":""National Institute of Neurological Disorders and Stroke"",""id"":""https://ror.org/01s5ya894"",""id-type"":""ROR"",""award"":""F31 NS137774;""}]","NA","bioRxiv",1761862207167
"Probability Distribution for Rare Neutral Mutations in Cancers and Application to Dynamic Precision Medicine of Cancer","10.1101/2025.10.10.681641","biorxiv",8.25,5,5,5,8.25,"He, W.; McCoy, M. D.; Yeang, C.-H.; Riggins, R. B.; Beckman, R. A.","Robert A Beckman","Georgetown University","2025-10-11","1","new results","cc_by_nc_nd","systems biology","https://www.biorxiv.org/content/early/2025/10/11/2025.10.10.681641.source.xml","Cancers exhibit genetic diversity between individual cancer cells. Previous work shows greater diversity than heretofore expected (1) and that also increases more quickly during a patients clinical course than previously thought (1, 2). Rare subclones will harbor pre-existing resistance to any single agent and may cause medium to late term relapse (1), which may evolve further variants that have simultaneous resistance to non-cross resistant therapies (3, 4). We now present a probability distribution function (PDF) of the variant allele fraction (VAF) or prevalence of a rare subclone, derived from previous evolutionary theory (1, 2). We show that current clinical sequencing protocols fail to detect the vast majority of rare subclones. By the time of detection, simultaneous multiple resistance may evolve. We then apply the PDF to simulation of dynamic precision medicine (DPM) (3), an evolutionary guided precision medicine paradigm that attempts to proactively eliminate singly-resistant subclones before they evolve multiple resistance, with significant potential to extend survival. We show that the simulated benefit of DPM with perfect information is degraded by inability to detect rare subclones if they are assumed to be absent when undetectable. But this benefit is restored if the PDF is used to calculate the likelihood of the subclone being present below the level of detection and incorporated into the DPM simulation and therapy recommendations in a probabilistic fashion. Moreover, other common statistical distributions are less effective. This theoretical advance facilitates DPM and potentially other evolutionary guided approaches to precision cancer medicine in spite of the limitations of clinical sequencing.

Significance StatementCancers contain many cells, each genetically unique. These variations can include pre-existing resistance to therapy, enabling relapse. DNA sequencing cannot detect minority cellular populations (subclones) below a certain size, by which time they may have evolved simultaneous resistance to multiple therapies. We present a mathematical approach that enables assigning a risk that a subclone is present, and at what prevalence in the cellular population, even when undetected. We simulate applying this approach to dynamic precision medicine (DPM), which attempts to proactively eliminate singly resistant cells before they become resistant to multiple therapies. Using this probability distribution, we can retain the benefit of DPM even when most rare subclones are undetectable, in contrast to just assuming undetected subclones are absent.","[{""name"":""Department of Defense (DoD) Breast Cancer Research Program Awards"",""id"":"""",""id-type"":""ROR"",""award"":""W81XWH-20-1-0759;W81XWH-20-1-0760;""},{""name"":""National Institutes of Health Cancer Center Support Grant"",""id"":"""",""id-type"":""ROR"",""award"":""5P30CA051008;""},{""name"":""National Science & Technology Council in the Republic of China (Taiwan)"",""id"":"""",""id-type"":""ROR"",""award"":""108-2118-M-001-001-MY2;""},{""name"":""National Science Foundation Grants"",""id"":"""",""id-type"":""ROR"",""award"":""#2138259;#2138286;#2138307;#2137603;#2138296;""}]","NA","bioRxiv",1761862207167
"MAP4-MAP7D1 partitioning on tyrosinated-detyrosinated microtubules coordinates lysosome positioning in nutrient signalling","10.1101/2025.10.07.680844","biorxiv",9.35,5,5,5,9.35,"Khushalani, D. M.; Kar, J.; Nayak, S. B.; Chaudhary, S. C.; Mohan, N.","Nitin Mohan","Indian Institute of Technology Kanpur","2025-10-07","1","new results","cc_by_nc","cell biology","https://www.biorxiv.org/content/early/2025/10/07/2025.10.07.680844.source.xml","Microtubule-associated proteins (MAPs) and tubulin post-translational modifications (PTMs) together shape a dynamic intracellular landscape for motor-driven transport, yet how the ""MAP-PTM crosstalk"" regulates organelle positioning remains unclear. Here, we show that MAP4 and MAP7D1 selectively partition onto distinct microtubule subsets demarcated by tyrosination and detyrosination, respectively, creating specialized tracks for kinesin motors. MAP4s preferential binding depends on its projection domain, while expanded microtubule lattice states mediate MAP7D1s enrichment on detyrosinated microtubules. Remarkably, rigor kinesin-1 (KIF5B-R) predominantly localizes to detyrosinated, MAP7D1-coated tracks, whereas rigor kinesin-3 (KIF1A) prefers tyrosinated, MAP4-decorated microtubules. We further find that the local density of MAP4 and MAP7D1 on microtubules fine-tunes lysosomal movement and directional transport. Moreover, MAP density is modulated to coordinate lysosomal reorganization in response to nutrient availability. During starvation MAP7D1 density on microtubules increases while MAP4 density decreases, localizing lysosomes to the perinuclear region. Conversely, with nutrient stimulation, MAPD1 density declines, allowing lysosomes to migrate towards the cell periphery. Altering the cellular levels of MAP4 and MAP7D1, either up or down, hinders lysosomal motility, trapping them near the nucleus and impairing their responsiveness to nutrient stimulation. Together, our findings reveal two distinct MAP-PTM circuits, a MAP4-tyrosination-kinesin-3 axis and a MAP7D1- detyrosination-kinesin-1 axis, that govern lysosome positioning for nutrient signaling, highlighting the combinatorial logic of MAP and tubulin codes in shaping microtubule function.","[{""name"":""Department of Biotechnology, Ministry of Science and Technology, India (DBT)"",""id"":"""",""id-type"":""ROR"",""award"":""BT/RLF/Re-entry/39/2018;""},{""name"":""Science and Engineering Research Board"",""id"":""https://ror.org/03ffdsr55"",""id-type"":""ROR"",""award"":""CRG/2022/008391;""}]","NA","bioRxiv",1761862207167
"Matrix stiffness induces endothelial network senescence","10.1101/2025.10.05.680536","biorxiv",7.75,5,5,5,7.75,"Song, J.; Rindone, A. N.; Guan, Y.; Daswani, P. S.; Elisseeff, J.; Gerecht, S.","Sharon Gerecht","Duke University","2025-10-06","1","new results","cc_by","bioengineering","https://www.biorxiv.org/content/early/2025/10/06/2025.10.05.680536.source.xml","Identifying the drivers of cellular senescence that contribute to the decline in tissue function related to aging- and disease is critical for developing restorative interventions. Here, we investigated how increased mechanical stress from extracellular matrix (ECM) stiffening shapes endothelial cell (EC) senescence. We developed a 3D human in vitro model that decouples mechanical stress from inflammatory or biochemical inputs, enabling the study of senescence responses to tissue stiffening alone. We found that matrix stiffening induces an EC senescence phenotype with elevated p16/p21 and an immunomodulatory senescence-associated secretory phenotype (SASP), in the absence of inflammatory signals. This mechano-induced senescence state engaged a Notch-JNK-FOS signaling axis, and pharmacologic inhibition of Notch attenuated stiffness-induced senescence. Supporting the translational relevance of this mechanism, analysis of fibrotic capsule tissue from patients with synthetic breast implants, a model of localized, mechanically driven fibrosis, revealed increased p16+Notch1+ endothelial populations. Complementary single-cell RNA sequencing data confirmed their enrichment in Notch/JNK- and SASP-related gene programs. Together, these findings define vascular senescence as a mechanosensitive process and identify tissue stiffening as an upstream aging signal. Our work offers a human-relevant platform for studying targetable stages of endothelial mechanoaging.","[{""name"":""American Heart Association"",""id"":""https://ror.org/013kjyp64"",""id-type"":""ROR"",""award"":""25POST1359525;""},{""name"":""Edna and Fred Mandel Jr Foundation C/o Edwin Ruthman"",""id"":"""",""id-type"":""ROR"",""award"":""""},{""name"":""Duke Regeneration Center"",""id"":"""",""id-type"":""ROR"",""award"":""""},{""name"":""Duke Science and Technology"",""id"":"""",""id-type"":""ROR"",""award"":""""}]","NA","bioRxiv",1761862207167
"A framework for efficient CRISPRi-mediated silencing of retrotransposons in human pluripotent stem cells","10.1101/2025.10.24.684366","biorxiv",5.6499999999999995,4.8999999999999995,5.6499999999999995,5.6499999999999995,5.6499999999999995,"Adami, A.; Garza, R.; Dorazehi, F.; Douse, C. H.; Jakobsson, J.","Johan Jakobsson","Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden","2025-10-28","1","new results","cc_by","genomics","https://www.biorxiv.org/content/early/2025/10/28/2025.10.24.684366.source.xml","This protocol describes the workflow for transcriptional silencing of transposable elements (TEs) in human induced pluripotent stem cells (hiPSCs). The protocol illustrates how to design gRNAs to target families of TEs (or a unique TE locus) and how to validate the efficiency and specificity of large-scale CRISPRi-based silencing using a multiome approach that combines bulk RNA sequencing, CUT&RUN epigenetic profiling, and proteomics. This protocol offers a unique framework to perform and interpret in vitro functional studies based on TEs transcriptional manipulation in hiPSC models. For complete details on the use and execution of this protocol, please refer to Adami et al. (2025).","[{""name"":""Aligning Science Across Parkinson's"",""id"":""https://ror.org/03zj4c476"",""id-type"":""ROR"",""award"":""ASAP-000520;ASAP-024296;ASAP-025170;""},{""name"":""Swedish Research Council"",""id"":""https://ror.org/03zttf063"",""id-type"":""ROR"",""award"":""2022-02673;2021-03494;""},{""name"":""Swedish Brain Foundation"",""id"":"""",""id-type"":""ROR"",""award"":""""},{""name"":""Cancerfonden"",""id"":"""",""id-type"":""ROR"",""award"":""""},{""name"":""Barncancerfonden"",""id"":""https://ror.org/05072yv34"",""id-type"":""ROR"",""award"":""""}]","NA","bioRxiv",1761862207167
"Visualizing TERRA RNA G-quadruplex unfolding in FUS biomolecular condensates","10.1101/2025.10.29.685336","biorxiv",4.85,4.85,4.85,4.85,4.85,"Zheng, T.; Fawzi, N. L.","Nicolas L Fawzi","Brown University","2025-10-29","1","new results","cc_by_nc","biochemistry","https://www.biorxiv.org/content/early/2025/10/29/2025.10.29.685336.source.xml","RNA G-quadruplexes (rG4s) are remarkably stable secondary structures with critical regulatory roles in gene expression, RNA metabolism, and telomere maintenance. However, their behavior within cells remains controversial, partly due to challenges in detecting rG4s in complex environments. Here, we use solution NMR spectroscopy to investigate how condensates formed by the low-complexity and RGG domains of the RNA-binding protein FUS affect the structure of TERRA, a highly stable model rG4 RNA. We show that FUS LC-RGG1 interacts with TERRA in dilute solution and that binding perturbs, but does not disrupt, the G-quadruplex structure. When co-phase separated with FUS LC-RGG1, however, NMR signatures of TERRA's folded state disappear, and the remaining observable resonances indicate an unfolded conformation, even in buffer containing potassium where TERRA rG4 is exceptionally stable when outside a condensate. Quantitative comparisons with a mutant form of TERRA, used as a baseline for fully unfolded RNA, suggest that at minimum a third of TERRA RNA becomes unfolded in the condensed phase. Thus, our results demonstrate that condensates can shift the structural ensemble of rG4 towards unfolded species, offering a potential mechanistic explanation for their apparent lack of stability in vivo and revealing how phase-separated environments may actively modulate RNA structure and function.","[{""name"":""National Institute of General Medical Sciences"",""id"":""https://ror.org/04q48ey07"",""id-type"":""ROR"",""award"":""R01GM147677;""},{""name"":""Amyotrophic Lateral Sclerosis Association"",""id"":""https://ror.org/00mwp5989"",""id-type"":""ROR"",""award"":""23-PDF-629;""},{""name"":""Carney Institute for Brain Science, Brown University"",""id"":"""",""id-type"":""ROR"",""award"":""""}]","NA","bioRxiv",1761862207167
"Improving long-read somatic structural variant calling with pangenome and de novo personal genome assembly","10.1101/2025.10.28.685154","biorxiv",9.2,4.75,9.2,9.2,9.2,"Qin, Q.; Heinz, J.; Li, H.","Heng Li","Dana-Farber Cancer Institute and Harvard University","2025-10-28","1","new results","cc_by_nc_nd","genomics","https://www.biorxiv.org/content/early/2025/10/28/2025.10.28.685154.source.xml","Accurate detection of mosaic and somatic structural variants (SVs) provides early diagnostic and therapeutic evidence for cancers. While long-read whole-genome sequencing leads to more accurate SV detection than short read sequencing, existing long-read SV callers only look at alignment against a single reference genome and are susceptible to systematic false discovery caused by germline differences between the individual genome and the reference genome. Here we develop a new SV calling method that jointly considers the alignment against a pangenome and the de novo assembly of the germline genome. It dramatically reduces false positive mosaic SVs in normal samples and somatic SVs in cancer cell lines with little loss in sensitivity. Our study highlights the essential need for pangenome or personal genome assembly to integrate SV calls for both SV discoveries and clinical diagnostics.","[{""name"":""NCI"",""id"":"""",""id-type"":""ROR"",""award"":""U24CA294203;""},{""name"":""nih"",""id"":"""",""id-type"":""ROR"",""award"":""R01HG010040;U01HG013748;""}]","NA","bioRxiv",1761862207167
"Vitamin B2 Production by Vaginal Lactobacilli Promotes Symbiosis","10.1101/2025.10.28.684342","biorxiv",4.9,4.65,4.9,4.9,4.9,"Dricot, C. E. M. K.; Selegato, D. M.; Van Rillaer, T.; Cauwenberghs, E.; Erreygers, I.; Hiel, M.; Brauer-Nikonow, A.; Breynaert, A.; Wijnants, S.; Pintelon, I.; Condori-Catachura, S.; Ahannach, S.; Gehrmann, T.; Bakelants, S.; Hermans, N.; Van Dijck, P.; France, M.; Spacova, I.; Ravel, J.; Zimmermann, M.; Lebeer, S.","Caroline E.M.K Dricot","University of Antwerp","2025-10-28","1","new results","cc_no","microbiology","https://www.biorxiv.org/content/early/2025/10/28/2025.10.28.684342.source.xml","The human vaginal microbiome, particularly with lactobacilli as the main inhabitants, plays a key role in maintaining women's health. While lactic acid-mediated pathogen exclusion is well known, broader metabolic functions of vaginal lactobacilli remain underexplored. In this study, we analyzed the vaginal microbiome and metabolome of 258 healthy women from the Isala program. Using targeted metabolomics analysis, we detected a high prevalence with strong interpersonal differences of most B-vitamins, their precursors, and vitamin A in the vaginal microenvironment. Riboflavin (B2) and biotin (B7) showed strong associations with Lactobacillus crispatus and Limosilactobacillus sp. Comparative genomics, phenotypic assays, and in vivo metatranscriptomic data (VIRGO) collectively confirmed riboflavin biosynthesis by these taxa. Using a riboflavin overproducing Lim. reuteri as a functional model, we showed that microbially derived riboflavin and its pathway intermediates are transported across the vaginal epithelium and modulate host redox balance, cytokine production, and activation of mucosal-associated invariant T (MAIT) cells via induction of MR1 (Major histocompatibility complex, class I-related protein receptor), revealing a potential immunometabolic interface between the vaginal microbiota and its host.","[{""name"":""European Research Council"",""id"":""https://ror.org/0472cxd90"",""id-type"":""ROR"",""award"":""26850;101213306;101078353;""},{""name"":""Research Foundation - Flanders"",""id"":""https://ror.org/03qtxy027"",""id-type"":""ROR"",""award"":""1S28622N;1S89826N;1277222N;1271225N;G049022N;G031222N;S006424N;GOH421GN;AUHA-08-004;""}]","NA","bioRxiv",1761862207167
"Multitaxon assessment reveals inconsistent biodiversity responses to forest structural complexity in temperate forests","10.1101/2025.10.28.685007","biorxiv",4.55,4.55,4.55,4.55,4.55,"Pacioni, C.; Verheyen, K.; Martel, A.; Baeten, L.; Pasmans, F.; Catfolis, B.; Vanroy, T.; Lammens, L.; Lens, L.; Strubbe, D.","Cesare Pacioni","Ghent University","2025-10-28","1","new results","cc_by","ecology","https://www.biorxiv.org/content/early/2025/10/28/2025.10.28.685007.source.xml","Increasing forest structural complexity is a key objective of future-proof forest management, with potential benefits for biodiversity. However, empirical evidence for consistent biodiversity-structure relationships across taxa is still limited. We investigated whether structurally more complex forests support greater species richness and higher multidiversity across taxonomic and functional groups in 19 mature forest plots in Flanders, Belgium. As one of the most densely populated and urbanized regions in Europe, with limited and highly fragmented forest cover, Flanders provides a particularly informative and policy-relevant context to test structure-biodiversity relationships. Its forests, often dominated by a few tree species and subject to long-term anthropogenic pressures and management, represent a realistic gradient of structural complexity. Structural complexity was quantified using a Structural Complexity Index (SCI), and biodiversity was assessed using a multidiversity index integrating scaled species richness across five taxonomic and seven arthropod functional groups. Using mixed-effects models and multivariate Bayesian analyses, we tested both direct effects of SCI on biodiversity and the covariation in species richness among groups. Contrary to expectations, SCI was not a consistent predictor of multidiversity, and most groups showed weak or inconsistent responses. These findings might suggest that structural complexity alone may be insufficient to enhance biodiversity in simplified forests.","[{""name"":""GOA project"",""id"":"""",""id-type"":""ROR"",""award"":""BOF20/GOA/009;""}]","NA","bioRxiv",1761862207167
"Consensus Pituitary Atlas, a scalable resource for annotation, novel marker discovery and analyses in pituitary gland research","10.1101/2025.10.28.685060","biorxiv",4.35,4.35,4.35,4.35,4.35,"Köver, B.; Willis, T. L.; Sherwin, O.; Kaufman-Cook, J.; Kemkem, Y.; Vazquez Segoviano, M.; Lodge, E. J.; Zamojski, M.; Mendelev, N.; Zhang, Z.; Smith, G. R.; Bernard, D. J.; Lu, H.-C.; Sealfon, S. C.; Ruf-Zamojski, F.; Andoniadou, C. L.","Cynthia Lilian Andoniadou","King\'s College London","2025-10-29","1","new results","cc_by","bioinformatics","https://www.biorxiv.org/content/early/2025/10/29/2025.10.28.685060.source.xml","Previous single-cell profiling studies of the pituitary gland have yielded minimally reproducible insights largely due to their low statistical power and methodological inconsistencies. To address this problem, we generated a uniformly pre-processed Consensus Pituitary Atlas (CPA) using all existing mouse pituitary single-cell datasets (267 biological replicates, >1.1 million high-quality cells). The CPA revealed novel cell typing and lineage markers, including low-expression transcripts that previous analyses could not detect. The scale of the CPA enabled the development of machine learning models to automate and standardize cell type annotation and doublet identification for future studies. Leveraging the curated metadata, we identified sex-biased and age-dependent gene expression patterns at cell type resolution. To identify drivers of cell fates, first we determined consensus cell communication patterns. Secondly, we used RNA-sequencing and chromatin accessibility data to identify transcription factors associated with cell fates across modalities. The epitome platform acts as an interface with the CPA, allowing streamlined user-friendly analyses.","NA","NA","bioRxiv",1761862207167
"PRSformer: Disease Prediction from Million-Scale Individual Genotypes","10.1101/2025.10.26.684578","biorxiv",15.5,4.35,15.5,15.5,15.5,"Dibaeinia, P.; German, C.; Shringarpure, S.; Auton, A.; Khan, A. A.","Aly A. Khan","23andMe","2025-10-27","1","new results","cc_by_nc_nd","genetics","https://www.biorxiv.org/content/early/2025/10/27/2025.10.26.684578.source.xml","Predicting disease risk from DNA presents an unprecedented emerging challenge as biobanks approach population scale sizes (N > 106 individuals) with ultra-high-dimensional features (L > 105 genotypes). Current methods, often linear and reliant on summary statistics, fail to capture complex genetic interactions and discard valuable individual-level information. We introduce PRSformer, a scalable deep learning architecture designed for end-to-end, multitask disease prediction directly from million-scale individual genotypes. PRSformer employs neighborhood attention, achieving linear O(L) complexity per layer, making Transformers tractable for genome-scale inputs. Crucially, PRSformer utilizes a stacking of these efficient attention layers, progressively increasing the effective receptive field to model local dependencies (e.g., within linkage disequilibrium blocks) before integrating information across wider genomic regions. This design, tailored for genomics, allows PRSformer to learn complex, potentially non-linear and long-range interactions directly from raw genotypes. We demonstrate PRSformers effectiveness using a unique large private cohort (N {approx} 5M) for predicting 18 autoimmune and inflammatory conditions using L {approx} 140k variants. PRSformer significantly outperforms highly optimized linear models trained on the same individual-level data and state-of-the-art summary-statistic-based methods (LDPred2) derived from the same cohort, quantifying the benefits of non-linear modeling and multitask learning at scale. Furthermore, experiments reveal that the advantage of non-linearity emerges primarily at large sample sizes (N > 1M), and that a multi-ancestry trained model improves generalization, establishing PRSformer as a new framework for deep learning in population-scale genomics.","NA","NA","bioRxiv",1761862207167
"mAIcrobe: an open-source framework for high-throughput bacterial image analysis","10.1101/2025.10.21.683709","biorxiv",35.80000000000001,4.35,14.049999999999999,21.549999999999997,35.80000000000001,"Brito, A. D.; Alwardt, D.; Mariz, B. d. P.; Filipe, S. R.; Pinho, M. G.; Saraiva, B. M.; Henriques, R.","Ricardo Henriques","Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa","2025-10-21","1","new results","cc_by","microbiology","https://www.biorxiv.org/content/early/2025/10/21/2025.10.21.683709.source.xml","Quantitative analysis in bacterial microscopy is often hindered by diverse cell morphologies, population heterogeneity, and the requirement for specialised computational expertise. To address these challenges, mAIcrobe is introduced as an opensource framework that broadens access to advanced bacterial image analysis by integrating a suite of deep learning models. mAIcrobe incorporates multiple segmentation algorithms, including StarDist, CellPose, and U-Net, alongside comprehensive morphological profiling and an adaptable neural network classifier, all within the napari ecosystem. This unified platform enables the analysis of a wide range of bacterial species, from spherical Staphylococcus aureus to rod-shaped Escherichia coli, across various microscopy modalities within a single environment. The biological utility of mAIcrobe is demonstrated through its application to antibiotic phenotyping in E. coli and the identification of cell cycle defects in S. aureus DnaA mutants. The modular design, supported by Jupyter notebooks, facilitates custom model development and extends AI-driven image analysis capabilities to the broader microbiology community. Building upon the foundation established by eHooke, mAIcrobe represents a substantial advancement in automated and reproducible bacterial microscopy.","[{""name"":""European Research Council"",""id"":""https://ror.org/0472cxd90"",""id-type"":""ROR"",""award"":""101001332;101096393;""},{""name"":""Fundação para a Ciência e Tecnologia"",""id"":"""",""id-type"":""ROR"",""award"":""UIBD/06849/2021;UIBD/12215/2022;UIBD/151527/2021;UIDB/04612/2020;UIDP/04612/2020;LA/P/0087/2020;""},{""name"":""European Molecular Biology Organization"",""id"":""https://ror.org/04wfr2810"",""id-type"":""ROR"",""award"":""EMBO-2020-IG-4734;""},{""name"":""Chan Zuckerberg Initiative (United States)"",""id"":""https://ror.org/02qenvm24"",""id-type"":""ROR"",""award"":""EOSS6-0000000260;""},{""name"":""European Innovation Council"",""id"":""https://ror.org/05cx8cy07"",""id-type"":""ROR"",""award"":""101099654-RTSuperES;101057970-AI4LIFE;""}]","NA","bioRxiv",1761862207167
"Inflammatory Biomarkers of Asymptomatic and Symptomatic Tuberculosis","10.1101/2025.10.26.684319","biorxiv",4.2,4.2,4.2,4.2,4.2,"Awany, D.; Ariefdien, D.; Mendelsohn, S.; Rozot, V.; Mulenga, H.; Nyangu, S.; Tameris, M.; Moloantoa, T.; Katona, A.; Maruri, F.; Noor, F.; Panchiar, R.; Hlongwane, K.; Stanley, K.; Van der Heijden, Y.; Hadley, K.; Fiore-Gartland, A.; Innes, C.; Brumskine, W.; Dheda, K.; Jaumdally, S.; Perumal, T.; Martinson, N.; Leslie, A.; Fourie, B.; Hiemstra, A.; Malherbe, S.; Walzl, G.; Naidoo, K.; Churchyard, G.; Chegou, N.; Sterling, T.; Hatherill, M.; Scriba, T. J.","Thomas J Scriba","University of Cape Town","2025-10-29","1","new results","cc_by_nd","immunology","https://www.biorxiv.org/content/early/2025/10/29/2025.10.26.684319.source.xml","A large proportion of individuals with tuberculosis (TB) are asymptomatic. The biological and inflammatory underpinnings of asymptomatic TB are unknown and may differ from symptomatic TB. We characterised blood transcriptomic and proteomic profiles in South African community screening vs. health facility-based triage cohorts. Asymptomatic TB shared core transcriptomic and proteomic features with symptomatic TB, including upregulation of innate, interferon and inflammatory pathways and downregulation of T and B cell pathways. Integration of transcriptomic and proteomic data from asymptomatic TB individuals identified two distinct sub-clusters characterized by higher or lower bacterial burden, blood IFN-{gamma} responses, BMI, and chest radiographic abnormalities, suggesting different disease severity. We identified a new blood transcriptomic signature of asymptomatic TB. However, diagnostic performance of transcriptomic and proteomic markers was weaker for asymptomatic TB than symptomatic TB, suggesting that policy development for community-based, asymptomatic TB screening should not adopt biomarkers developed for symptomatic TB triage without further optimization.","[{""name"":""National Institutes of Health"",""id"":""https://ror.org/01cwqze88"",""id-type"":""ROR"",""award"":""U01AI152075;""},{""name"":""CRDF Global"",""id"":""https://ror.org/01zpbb709"",""id-type"":""ROR"",""award"":""G-DAA3-19-66875-1;G-DAA9-20-66870-1;G-DAA9-20-66918-1;G-DAA9-20-66878-1;""},{""name"":""South African Medical Research Council (SAMRC)"",""id"":"""",""id-type"":""ROR"",""award"":""""},{""name"":""Gates Foundation"",""id"":""https://ror.org/0456r8d26"",""id-type"":""ROR"",""award"":""OPP1116632;OPP1137034;""},{""name"":""Strategic Health Innovation Partnerships (SHIP) Unit of the South African Medical Research Council with funds received from the South African Department of Science and Technology"",""id"":"""",""id-type"":""ROR"",""award"":""""}]","NA","bioRxiv",1761862207167
"INPP5D/SHIP1 is a dual regulator of endo-lysosome function and selective phagocytosis in human microglia","10.1101/2025.10.27.684632","biorxiv",5.85,4.1,5.85,5.85,5.85,"Terzioglu, G.; Karp, E. S.; Heuer, S. E.; Haage, V. C.; De Jager, P. L.; Young-Pearse, T. L.","Tracy L. Young-Pearse","Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women\'s Hospital and Harvard Medical School, Boston, MA, USA","2025-10-27","1","new results","cc_by_nd","neuroscience","https://www.biorxiv.org/content/early/2025/10/27/2025.10.27.684632.source.xml","INPP5D, the gene encoding SHIP1, is genetically associated with Alzheimers disease (AD) risk and plays a central role in regulating immune function. Here, we aimed to elucidate the mechanism by which SHIP1 mediates its role in suppressing inflammatory pathways, with a focus on human microglia. Our findings illuminate an essential role for SHIP1 in endosome maturation and lysosomal function. We show that SHIP1 localizes to both the plasma membrane and to endo-lysosomal compartments and binds to the CapZ family of proteins, which are important for endosome maturation. Reduction of SHIP1 levels via genome editing impairs endosome maturation and lysosomal function, leading to lipid droplet accumulation and leakage of lysosomal cathepsin B into the cytosol, which in turn activates the NLRP3 inflammasome. CITE-seq profiling of SHIP1-deficient microglia revealed a shift from an immune-responsive state toward a DAM-like, phagocytic state, accompanied by impaired response to LPS and enhanced phagocytosis of synaptic material and apoptotic neurons via TREM2. While amyloid-{beta} uptake was not affected, amyloid-{beta} accumulated intracellularly due to defective lysosomal degradation, further driving lipid droplet formation. Together, these results identify SHIP1 as a regulator of endo-lysosomal function and selective phagocytosis of lipid-rich substrates in microglia. These findings have important implications for therapeutic hypotheses that target SHIP1 for treatment of AD, autoimmune diseases, and cancer.","[{""name"":""National Institutes of Health"",""id"":""https://ror.org/01cwqze88"",""id-type"":""ROR"",""award"":""U01AG072572;R01AG055909;""},{""name"":""Chan Zuckerberg Initiative (United States)"",""id"":""https://ror.org/02qenvm24"",""id-type"":""ROR"",""award"":""CS-02018-191971;""},{""name"":""Alzheimer's Association"",""id"":""https://ror.org/0375f4d26"",""id-type"":""ROR"",""award"":""Zenith Award;""},{""name"":""Harvard Medical School"",""id"":""https://ror.org/03wevmz92"",""id-type"":""ROR"",""award"":""Edward R. and Anne G. Lefler Center Predoctoral Fellowship;""}]","NA","bioRxiv",1761862207167
"Robust pan-junctional reinforcement preserves the gut epithelial barrier under mechanical stress","10.1101/2025.10.04.680144","biorxiv",12.649999999999999,3.95,3.95,3.95,12.649999999999999,"Krishnakumar, V.; Ferran, A.; Bernat-Fabre, S.; Creff, J.; Cenac, N.; Krndija, D.","Denis Krndija","CNRS","2025-10-24","2","new results","cc_by","cell biology","https://www.biorxiv.org/content/early/2025/10/24/2025.10.04.680144.source.xml","Epithelia are specialized tissue barriers that safeguard the organisms internal milieu from the hostile external environment, a function critically dependent on intercellular junctions. In the colon, this barrier is repeatedly challenged by mechanical distension from faeces and it is unknown whether and how the colon adapts to such stress, which could otherwise compromise barrier integrity. Here, we show that faeces-mediated mechanical distension triggers coordinated remodelling at cell- and tissue-scale, suggestive of mechanoadaptation. This response includes recruitment of junctional proteins at all three types of adhesive cell-cell junctions (tight junctions, adherens junctions and desmosomes). We identified two modes of recruitment: stable responders (ZO-1, E-cad, plakoglobin) with sustained junctional enrichment, and adaptive responders (desmoplakin, keratin 8) with progressive accumulation during distension. Distension was also accompanied by perijunctional recruitment and activation of non-muscle myosin II (NMMII). Through genetic, pharmacological, and mechanical perturbations, we demonstrated that NMMII activation is an early and critical step for mechanoadaptation. This process requires extracellular calcium influx, and Piezo1 activation is sufficient to trigger NMMII activation and junctional recruitment. Loss of NMMII function abrogated the junctional response to distension across all three junctional complexes, including desmosomes, resulting in disorganised junctions and barrier breach. Together, our findings uncover a robust physiological mechano-adaptive response of the adult colonic epithelium to an extrinsic mechanical stress, whereby coordinated reinforcement of all junctional complexes, controlled by myosin II and mechanosensitive calcium influx, plays an essential role in preserving intestinal barrier integrity.","[{""name"":""Centre National de la Recherche Scientifique (CNRS)"",""id"":"""",""id-type"":""ROR"",""award"":""ATIP-Avenir;""},{""name"":""Fondation pour la Recherche Médicale"",""id"":"""",""id-type"":""ROR"",""award"":""""}]","NA","bioRxiv",1761862207167
"Benchmarking large-scale single-cell RNA-seq analysis","10.1101/2025.10.28.681564","biorxiv",3.5,3.5,3.5,3.5,3.5,"Billato, I.; Pages, H.; Carey, V.; Waldron, L.; Sales, G.; Romualdi, C.; Risso, D.","Davide Risso","University of Padova, Department of Statistical Sciences","2025-10-29","1","new results","cc_by","bioinformatics","https://www.biorxiv.org/content/early/2025/10/29/2025.10.28.681564.source.xml","The increasing size of single-cell RNA sequencing (scRNA-seq) datasets poses major computational challenges. This work benchmarks the scalability, efficiency, and accuracy of five widely used analysis frameworks (Seurat, OSCA, scrapper, Scanpy, and rapids_singlecell), focusing on the impact of algorithmic and infrastructural choices on performance. We performed a systematic comparison of these workflows using representative datasets, including the 1.3M mouse brain dataset for scalability and three smaller datasets (BE1, sc_mixology, and cord blood CITE-seq) with ground truth labels to assess clustering accuracy. Principal Component Analysis (PCA) was used as a paradigmatic step to evaluate the computational performance of six SVD algorithms (exact, ARPACK, IRLBA, randomized, Jacobi, and incremental PCA) across multiple data representations (dense, sparse, HDF5) and hardware configurations (CPU vs GPU). All methods showed high concordance in PCA results, with negligible loss of accuracy in truncated approaches. GPU-based computation using rapids_singlecell provided a 15x speed-up over the best CPU methods, with moderate memory usage. On CPU, ARPACK and IRLBA were the most efficient for sparse matrices, while randomized SVD performed best for HDF5-backed data. Among full pipelines, rapids_singlecell was the fastest, whereas OSCA and scrapper achieved the highest clustering accuracy (ARI up to 0.97) in datasets with known cell identities. Performance differences were largely driven by the choice of highly variable genes (HVGs) and PCA implementation. The study highlights that scalability in scRNA-seq analysis depends critically on both algorithmic and infrastructural factors. GPU acceleration and optimized BLAS/LAPACK configurations markedly enhance performance, while Bioconductor-based pipelines remain robust in accuracy. The provided benchmarks offer practical guidelines for efficient and reliable analysis of large-scale single-cell datasets.","[{""name"":""Italian Association for Cancer Research"",""id"":""https://ror.org/02g2x7380"",""id-type"":""ROR"",""award"":""IG29071;""},{""name"":""National Center for HPC, BIG DATA AND QUANTUM COMPUTING"",""id"":"""",""id-type"":""ROR"",""award"":""CN00000013 CN1;""},{""name"":""National Cancer Institute of the National Institutes of Health"",""id"":"""",""id-type"":""ROR"",""award"":""5U24CA289073-02;2U24HG004059-17;""},{""name"":""Chan Zuckerberg Initiative"",""id"":"""",""id-type"":""ROR"",""award"":""EOSS6-0000000644;""}]","NA","bioRxiv",1761862207167
"Single human fingertip mechanoreceptive afferents simultaneously encode multidimensional aspects of touch","10.1101/2025.10.28.685066","biorxiv",3.2,3.2,3.2,3.2,3.2,"Lang, V. A.; Backlund Wasling, H.; Ackerley, R.; Wessberg, J.","Victoria Ashley Lang","University of Gothenburg","2025-10-29","1","new results","cc_by","physiology","https://www.biorxiv.org/content/early/2025/10/29/2025.10.28.685066.source.xml","Touch using the hands is essential for recognizing surface features and manipulating objects, where different aspects are encoded by four main types of low-threshold mechanoreceptors (LTMs) in glabrous skin. Although factors such as movement, vibration, and pressure are often studied individually, touch requires their integration to produce complex sensations. We investigated these processes jointly by recording single-unit activity via microneurography from human LTM afferents in the median nerve as periodic gratings slid across their receptive fields, varying the normal force and sliding velocity per trial. Mixed-effects models revealed that fast-adapting type 1 (FA-1) afferent firing was influenced by all three parameters - force, velocity, and spatial period. Slowly-adapting type 1 (SA-1) afferent firing was primarily driven by force, and to a lesser extent, velocity. These findings support the view that FA-1 afferents encode stimulus intensity in an approximately linear manner, while SA-1 afferents function mainly as force detectors, demonstrating that mechanoreceptive afferents provide a complementary and multidimensional representation of texture during sliding contact. This distributed encoding challenges the notion that LTMs are dedicated to single stimulus features, suggesting that tactile information is represented across LTM populations where each class contributes differently-weighted inputs to capture skin-object interactions.","[{""name"":""Swedish Research Council"",""id"":""https://ror.org/03zttf063"",""id-type"":""ROR"",""award"":""K2007-63X-03548;K2010-62X-03548;2021-02552;""},{""name"":""European Commission"",""id"":""https://ror.org/00k4n6c32"",""id-type"":""ROR"",""award"":""EU FP6 NANOBIOTACT 33287;EU Horizon 2020 MSCA NEUTOUCH 813713;""}]","NA","bioRxiv",1761862207167
"AI-based supervised treatment response prediction from tumor transcriptomics: A large-scale pan-cancer study","10.1101/2025.10.24.684491","biorxiv",4.2,3.2,3.2,4.2,4.2,"Pal, L. R.; Gertz, E. M.; Ulhas Nair, N.; Mukherjee, S.; Patiyal, S.; Cantore, T.; Campagnolo, E. M.; Chang, T.; Dhruba, S. R.; Kim, Y.; Shulman, E. D.; Rajagopal, P. S.; Hoang, D.-T.; Schaffer, A. A.; Ruppin, E.","Lipika Ray Pal","NIH/NCI/CCR/CDSL","2025-10-26","1","new results","cc_by_nc_nd","cancer biology","https://www.biorxiv.org/content/early/2025/10/26/2025.10.24.684491.source.xml","Precision oncology aims to guide treatment decisions using biomarkers. While DNA-based panels are increasingly applied, RNA transcriptomics remain underused due to limited datasets and the absence of robust models. We assembled the largest transcriptomic resource for drug response prediction to date, spanning 69 cohorts, 3,729 patients, nine cancer types, and six frontline therapies: anti-PD-1/PD-L1 immune-checkpoint inhibitors, trastuzumab, bevacizumab, BRAF inhibitors, paclitaxel, and FAC/FEC (Fluorouracil-Adriamycin-Cyclophosphamide/Fluorouracil-Epirubicin-Cyclophosphamide) chemotherapy. We developed EXPRESSO (EXpression-Profile-RESponSe-Optimizer), a supervised AI-based framework that predicts treatment response from pre-treatment transcriptomes by integrating drug targets and context-specific biomarkers. EXPRESSO achieves ROC-AUCs of 0.64-0.73 and odds ratios of 2.4-4.6 across therapies, outperforming 20 published transcriptomic signatures. Robustness analysis reveals that predictive performance plateaued for some therapies with increasing training cohorts but continued to improve for others. These findings suggest inherent limits of supervised brute-force learning for certain treatments, but additional data and deeper mechanistic modeling may further enhance transcriptomics-based predictors.","[{""name"":""National Institutes of Health (NIH), National Cancer Institute"",""id"":"""",""id-type"":""ROR"",""award"":""Intramural Research Program;""}]","NA","bioRxiv",1761862207167
"A non-invasive method to genotype cephalopod sex by quantitative PCR","10.1101/2025.10.28.685099","biorxiv",3.1,3.1,3.1,3.1,3.1,"Rubino, F. A.; Coffing, G. C.; Gibbons, C. J.; Small, S. T.; Desvignes, T.; Pessutti, J.; Petersen, A. M.; Arkhipkin, A.; Shcherbich, Z.; Postlethwait, J. H.; Kern, A. D.; Montague, T. G.","Tessa G. Montague","Columbia University","2025-10-29","1","new results","cc_by","genetics","https://www.biorxiv.org/content/early/2025/10/29/2025.10.28.685099.source.xml","Coleoid cephalopods (cuttlefish, octopus, and squid) are emerging model organisms in neuroscience, development, and evolutionary biology, and are of major economic importance in global fisheries. However, they are notoriously difficult and expensive to culture. The ability to determine sex early in development would enable more efficient and sustainable population management in both lab and wild settings. Here, we present a non-invasive method to genotype the sex of dwarf cuttlefish (Ascarosepion bandense) as young as three hours post-hatching using a skin swab and quantitative PCR assay, which detects a two-fold dosage difference between ZZ and Z0 sex chromosomes of males and females, respectively. Furthermore, we designed and validated primers for four additional cephalopod research species with assembled genomes (Octopus bimaculoides, Sepia officinalis, Euprymna berryi, Doryteuthis pealeii), and for a wild-caught species of economic value (Illex illecebrosus) for which we generated low-coverage whole genome sequencing data. This sex-genotyping method enables accurate sex determination from hatchlings to adults across cephalopods, independent of genome quality or availability.","[{""name"":""Howard Hughes Medical Institute"",""id"":""https://ror.org/006w34k90"",""id-type"":""ROR"",""award"":""""},{""name"":""National Institutes of Health"",""id"":""https://ror.org/01cwqze88"",""id-type"":""ROR"",""award"":""R01HG010774;R35GM148253;R35GM139635;""},{""name"":""National Science Foundation"",""id"":""https://ror.org/021nxhr62"",""id-type"":""ROR"",""award"":""2232891;""}]","NA","bioRxiv",1761862207167
"Integrated cell atlas and tumoroids chart pancreatic cancer therapeutic targets","10.1101/2025.09.30.679518","biorxiv",20.45,2.75,18.95,18.95,20.45,"Xu, Q.; Okuda, R.; Gjeta, B.; Harmel, C.; Signer, M.; Lucioli, M.; Rall, I.; Santel, M.; Seimiya, M.; Esposito, C.; Guja-Jarosz, K.; Maynard, A.; Morinaga, S.; Miyagi, Y.; Yamaguchi, T.; Ueno, Y.; Piscuoglio, S.; Muller, D. J.; Taniguichi, H.; Treutlein, B.; Camp, J. G.","J. Gray Camp","Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center Basel, Switzerland; University of Basel, Basel, Switzerla","2025-10-06","1","new results","cc_by_nc_nd","cancer biology","https://www.biorxiv.org/content/early/2025/10/06/2025.09.30.679518.source.xml","Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense, fibroblast-rich stroma that actively shapes the tumor microenvironment. Most PDAC cases arise from conserved genetic transformations initiated by oncogenic KRAS mutations, developing into metastatic disease with high mortality rates. To chart universal PDAC cell states and identify therapeutic inroads, we integrated published single-cell transcriptomes from 200 patient samples, and used the atlas to define prevalent cancer cell and cancer-associated fibroblast (CAF) states, gene expression programs, and ligand-receptor interactions. We established modular tumoroids incorporating patient-derived cancer cells and CAFs that recapitulate aspects of ductal architecture and desmoplastic stroma. Single-cell and spatial transcriptomic profiling confirmed preservation of key cellular states and signaling networks in vitro. We identified Syndecan-1 (SDC1) as a CAF-responsive cancer cell receptor correlating with poor patient survival. Functional SDC1 blockade disrupted cancer growth in tumoroids, highlighting therapeutic relevance. This study provides a framework for dissecting cancer-stroma dynamics and identifying actionable targets using patient-derived tumoroid models.","[{""name"":""Chan Zuckerberg Initiative DAF, an advised fund of the Silicon Valley Community Foundation"",""id"":"""",""id-type"":""ROR"",""award"":""CZF2019-002440;""},{""name"":""Swiss National Science Foundation"",""id"":""https://ror.org/00yjd3n13"",""id-type"":""ROR"",""award"":""310030_84795;310030_192604;""}]","NA","bioRxiv",1761862207167
"Structural and phenotypic plasticity of the RBD loop2 region is a key determinant for HKU5r-CoVs' emergence in mink","10.1101/2025.10.22.684003","biorxiv",15.549999999999997,0,14.549999999999999,15.549999999999997,15.549999999999997,"Tolentino, J. E.; Jefferson, V. A.; Catanzaro, N.; Baric, R. S.; Letko, M. C.; Lytras, S.; Sato, K.","Kei Sato","The Institute of Medical Science, The University of Tokyo","2025-10-22","1","new results","cc_by_nc_nd","microbiology","https://www.biorxiv.org/content/early/2025/10/22/2025.10.22.684003.source.xml","The emergence of novel coronaviruses from animal reservoirs continues to pose a significant zoonotic threat. Here, we investigate the evolutionary origins and virological properties of a recently reported mink-derived HKU5-related coronavirus (nvHKU5r-CoV). Phylogenetic and recombination analyses reveal that nvHKU5r-CoV originated from bat HKU5-like viruses circulating in southeastern China. We characterize the spike loop2 region as a critical determinant of ACE2 receptor specificity, directly interacting with the receptor, and show that the bat HKU5r-CoV with the closest loop2 sequence to nvHKU5r-CoV could already utilize mink ACE2. Using AlphaFold3, we predicted spike-ACE2 binding interfaces consistent with our experimental infectivity results. Targeted mutagenesis demonstrates that a single amino acid substitution (R548S) enables robust entry of nvHKU5r-CoV via human ACE2. We further show that this substitution can arise in vitro during hACE2-expressing cell infection with a replication-competent VSV system. Molecular dating suggests that nvHKU5r-CoV transmitted from bats to mink within the last decade, consistent with an expansion of mink fur farming in China. Overall, our findings highlight the zoonotic potential of these viruses and the molecular and structural determinants underlying it, while emphasizing fur farming as a major risk factor for how bat HKU5r-CoVs can transmit to farmed animals and ultimately humans.","NA","NA","bioRxiv",1761862207168
"Hierarchical lineage architecture of human and avian spinal cord revealed by single-cell genomic barcoding","10.1101/2025.10.24.684328","biorxiv",41.00000000000002,0.85,12.449999999999998,41.00000000000002,41.00000000000002,"Boezio, G. L. M.; Depotter, J. R. L.; Frith, T. J. R.; Radley, A.; Strohbuecker, S.; Cunha, A. C.; Howell, M.; Briscoe, J.","James Briscoe","The Francis Crick Institute","2025-10-24","1","new results","cc_by","developmental biology","https://www.biorxiv.org/content/early/2025/10/24/2025.10.24.684328.source.xml","The formation of neural circuits depends on the precise spatial and temporal organisation of neuronal populations during development. In the vertebrate spinal cord, progenitors are patterned into molecularly defined domains, but how lineage relationships shape neuronal diversity and function has remained unclear. Here, we combine genomic barcoding with single- cell RNA sequencing in chick and human embryos to generate cell-type-resolved clonal maps. We find that spinal neurogenesis follows a hierarchical organisation in which the neural tube first partitions into five broad subdivisions that resolve into the eleven progenitor domains generating the cardinal neuronal classes. This bifurcating architecture implies a patterning mechanism of sequential binary decisions. The most prominent lineage restriction occurs at the embryonic alar-basal boundary, separating sensory-processing from motor-control circuits. Individual progenitors generate neurons across multiple temporal waves while remaining constrained within their lineage subdivision, demonstrating persistence of spatial identity despite temporal competence changes. Among sensory populations, we identify two developmental routes, via unifated or bifated progenitors, to pain- and itch-processing interneurons. These principles are conserved between chick and human, with clonal analysis in human embryos revealing that most fate choices are resolved by six weeks post-conception. Together, these findings provide a framework for spinal cord development and reveal lineage compartmentalisation as a fundamental principle in neural circuit assembly and evolution.","[{""name"":""Medical Research Council"",""id"":""https://ror.org/03x94j517"",""id-type"":""ROR"",""award"":""CC001051),;""},{""name"":""Wellcome"",""id"":"""",""id-type"":""ROR"",""award"":""CC001051;220379/D/20/Z;218670/Z/19/Z;215116/Z/18/Z;""},{""name"":""Cancer Research UK"",""id"":""https://ror.org/054225q67"",""id-type"":""ROR"",""award"":""CC001051;""},{""name"":""European Research Council"",""id"":""https://ror.org/0472cxd90"",""id-type"":""ROR"",""award"":""742138;""},{""name"":""EMBO"",""id"":"""",""id-type"":""ROR"",""award"":""792-2021;""},{""name"":""UKRI"",""id"":"""",""id-type"":""ROR"",""award"":""EP/X031225/1;""}]","NA","bioRxiv",1761862207168
"Improving conformational ensembles of folded proteins in GoMartini","10.1101/2025.10.24.684331","biorxiv",12.099999999999998,0,11.099999999999998,12.099999999999998,12.099999999999998,"Kalutskii, M.; Wilson, C. J.; Grubmüller, H.; Igaev, M.","Maxim Igaev","Max Planck Institute for Multidisciplinary Sciences","2025-10-25","1","new results","cc_by_nc","biophysics","https://www.biorxiv.org/content/early/2025/10/25/2025.10.24.684331.source.xml","The Martini coarse-grained (CG) force field enables efficient simulations of biomolecular systems but cannot reliably maintain folded protein structures. To stabilize proteins during simulation, Martini is typically combined with structure-based force fields such as elastic network models (ENMs) or G[o] models. While these approaches preserve global folds and capture protein flexibility, their ability to reproduce conformational dynamics remains unclear. Here, we benchmark Martini combined with ENMs or G[o] models on three folded proteins and show that both approaches struggle to sample the conformational space observed in atomistic simulations, even when uniform interaction strengths or equilibrium bond distances are adjusted. This limitation arises from the assumption of a uniform interaction network, in which all bond energies are equal. To overcome this, we present a fully automated, perturbation-based optimization approach for G[o] networks, PoG[o], that iteratively refines a non-uniform G[o] network against a pre-computed atomistic free energy landscape in essential conformational space. Our approach converges rapidly, yielding CG ensembles in close agreement with reference atomistic simulations. As a cross-validation, the optimization also improves the root-mean-square fluctuation profile.","[{""name"":""Deutsche Forschungsgemeinschaft"",""id"":""https://ror.org/018mejw64"",""id-type"":""ROR"",""award"":""449750155 – RTG 2756, Project A1;""},{""name"":""Natural Sciences and Engineering Research Council"",""id"":""https://ror.org/01h531d29"",""id-type"":""ROR"",""award"":""PGSD-599306-205;""}]","NA","bioRxiv",1761862207168
"The proton motive force maintains mtDNA euploidy by balancing mtDNA replication with cell proliferation","10.1101/2025.10.27.684790","biorxiv",10.95,2.25,10.95,10.95,10.95,"Rath, S. P.; Mootha, V. K.","Vamsi K Mootha","1. Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA. 2. Broad Institute, Cambridge, MA 02","2025-10-27","1","new results","cc_by","cell biology","https://www.biorxiv.org/content/early/2025/10/27/2025.10.27.684790.source.xml","Human mitochondrial DNA (mtDNA) encodes 13 essential components of the electron transport chain (ETC)1. A typical cell contains [~]1000s of copies of mtDNA, but how this copy number is stably maintained is unclear. Here, we track mtDNA copy number (mtCN) recovery in K562 cells following transient, chemically induced depletion to uncover principles of mtCN stability. Below a critical mtCN, ETC activity fails to sustain the proton motive force (PMF) and de novo pyrimidine synthesis--both required for mtDNA replication. PMF-dependent processes like Fe-S cluster biogenesis are also disrupted and stress responses are activated that impair cell proliferation and limit further mtCN dilution by cell division. Nonetheless, mtDNA replication and recovery remain possible via mtDNA-independent PMF, generated by complex V reversal, and uridine salvage. Once mtCN is restored, the ETC and forward complex V activity re-engage, stress responses subside, and proliferation recommences. Each cell division then dilutes mtDNA, serving as a built- in brake on mtCN. Our findings suggest that mtCN homeostasis emerges from the balance of two opposing PMF-driven processes -- mtDNA replication and cell proliferation -- revealing a bioenergetic logic that preserves mtDNA euploidy through repeated cell divisions.","[{""name"":""nih"",""id"":"""",""id-type"":""ROR"",""award"":""K00CA212468;K99GM145848;""},{""name"":""Howard Hughes Medical Institute"",""id"":""https://ror.org/006w34k90"",""id-type"":""ROR"",""award"":""""}]","NA","bioRxiv",1761862207168
"Genome-wide association studies identify 77 loci for suicidality and provide novel biological insights","10.1101/2025.10.22.25338076","medrxiv",9.55,0,9.3,9.55,9.55,"Colbert, S. M. C.; the Psychiatric Genomics Consortium Suicide Working Group,  ; Ruderfer, D.; Docherty, A. R.; Mullins, N.","Sarah Mary Carlton Colbert","Icahn School of Medicine at Mount Sinai","2025-10-23","1","PUBLISHAHEADOFPRINT","cc_by_nc_nd","genetic and genomic medicine","https://www.medrxiv.org/content/early/2025/10/23/2025.10.22.25338076.source.xml","Suicidality is heritable and a leading cause of global morbidity and mortality, yet its biological etiology remains largely elusive. We conducted multi-ancestry genome-wide association study meta-analyses of suicidal ideation (259,747 cases), suicide attempt (64,993 cases), suicide death (9,197 cases), and suicidal behavior (suicide attempt/ death, 75,300 cases), across 54 cohorts (e.g., the Psychiatric Genomics Consortium, Million Veteran Program, UK Biobank). We identified 77 significant loci across meta-analyses, including 59 previously unreported for suicidality. SNP-based heritability ranged from 2.0-6.7% and there were strong, yet incomplete, genetic correlations between suicidality phenotypes (0.70-0.88). Fine-mapping prioritized 27 putative causal SNPs and 20 credible genes. Enrichment analyses implicated synaptic pathways and neuronal populations predominantly in subcortical brain regions (e.g., amygdala excitatory, medium spiny, hippocampal CA1-3). Together, these findings establish suicidality as a polygenic set of traits with both shared and distinct genetic influences, providing a foundation for future studies of suicide biology and etiology.","NA","NA","medRxiv",1761862207168
"Enriching for Answers in Rare Diseases","10.1101/2025.10.21.25338483","medrxiv",10.25,1.35,7.65,10.25,10.25,"Fu, Y.; English, A. C.; Paulin, L. F.; Jhangiani, S. N.; Weissenberger, G.; Vee, V.; Han, Y.; Mehta, H. H.; Posey, J. E.; Muzny, D. M.; Gibbs, R. A.; Calame, D. G.; Sedlazeck, F. J.","Fritz J. Sedlazeck","Baylor college of medicine","2025-10-24","1","PUBLISHAHEADOFPRINT","cc_no","genetic and genomic medicine","https://www.medrxiv.org/content/early/2025/10/24/2025.10.21.25338483.source.xml","We present Trio-barcoded ONT Adaptive Sampling (TBAS), a cost-efficient long-read sequencing strategy combining sample barcoding and adaptive enrichment to sequence rare-disease trios on a single PromethION flow cell. TBAS achieved near-complete variant phasing and detection of small variants, structural variants, and tandem repeats with high accuracy and 77% potential solve rate. This scalable approach retains methylation data and enables clinically relevant, phenotype-guided long-read diagnostics at a fraction of current costs.","NA","NA","medRxiv",1761862207168
"Directed evolution of compact RNA-guided nucleases for homology-directed repair in mammalian cells","10.1101/2025.10.27.684765","biorxiv",7.05,2.7,7.05,7.05,7.05,"Gorbenko, F.; Sala, I.; Lee, Y.-Y.; Venn, L. v. d.; Yeh, C. D.; Karvelis, T.; Druteika, G.; Bechter, L. V.; Vykhlyantseva, I.; Schroder, M. S.; Gvozdenovic, A.; Siksnys, V.; Corn, J. E.","Jacob E Corn","Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland","2025-10-27","1","new results","cc_no","bioengineering","https://www.biorxiv.org/content/early/2025/10/27/2025.10.27.684765.source.xml","RNA-guided nucleases enable DNA editing and offer promise for treating genetic diseases, particularly when used for precise sequence replacement. However, many of the most effective enzymes, such as S. pyogenes Cas9, are too large for delivery using vectors like adeno-associated virus (AAV). This has prompted interest in smaller alternatives from the Cas12f and TnpB families. Yet, these nucleases often show low activity in mammalian cells, limiting their utility. To address this, we used directed evolution in human cells to select variants with greatly improved homology-directed repair (HDR) activity. The resulting variants, Cas12f1Super and TnpBSuper, exhibited up to 11-fold increase in editing efficiency without increased off-target effects. When tested as a base editor, Cas12f1Super showed up to 10-fold improvement relative to the previously engineered CasMINI, suggesting utility beyond HDR. These compact and efficient genome editors expand the current toolkit and hold promise for both research and therapeutic use in mammalian systems.","NA","NA","bioRxiv",1761862207168
"Ultrasensitive proteomics uncovers nociceptor diversity and novel pain targets","10.1101/2025.09.20.677124","biorxiv",14.95,0,7,7,7,"Chakrabarti, S.; Makhmut, A.; Mohammadi, A.; Luo, W.; Wang, L.; Lewin, G. R.; Coscia, F.","Fabian Coscia","Max Delbrueck Center for Molecular Medicine","2025-09-21","1","new results","cc_by","systems biology","https://www.biorxiv.org/content/early/2025/09/21/2025.09.20.677124.source.xml","The richness of our somatosensory experience is reflected in the functional diversity of somatic sensory neurons. Single-cell sequencing (scRNA) of sensory neurons has revealed a molecular basis for such diversity1-3. However, sensory neuron diversity has yet to be captured at the level of the proteome. Here, we combined electrophysiology with deep visual proteomics (DVP)4 to quantify over 6,000 proteins from phenotypically-defined sensory neurons and identified novel proteomic markers of sensory neuron subtypes. Comparative analysis revealed both concordance and meaningful divergence between transcriptomes and proteomes. We further show that up to 3,000 proteins can be quantified from one-fourth of a single neuron, demonstrating subset-specific protein signatures. In culture, nociceptive neurons can be acutely sensitized to mechanical stimuli by nerve growth factor (NGF) which normally drives inflammatory pain in vivo5. Indeed, overnight exposure of peptidergic nociceptors to NGF and a protein kinase C (PKC) activator produced functional sensitization associated with proteome changes. Functional knockdown experiments identified the up-regulated B3GNT2 enzyme as a potential effector of nociceptor sensitization. In summary, we present a high-resolution proteomic resource linking molecular identity to function, enabling the discovery of novel mechanisms underlying somatic sensation and pain sensitization.","[{""name"":""European Research Council"",""id"":""https://ror.org/0472cxd90"",""id-type"":""ROR"",""award"":""101142488;101115681;""},{""name"":""Bundesministerium für Forschung, Technologie und Raumfahrt"",""id"":"""",""id-type"":""ROR"",""award"":""161L0222;""},{""name"":""EFIC-Grünenthal award"",""id"":"""",""id-type"":""ROR"",""award"":""""}]","NA","bioRxiv",1761862207168
"TRANCERs: Engineering enhancers into autonomous tissue-specific expression cassettes","10.1101/2025.10.27.684763","biorxiv",6.85,2.35,6.85,6.85,6.85,"Barrow Molina, E. K.; Smith, A. L.; Lopez-Cuevas, P.; Nicholls, M.; White, R. M.; Milne, T. A.; Hughes, J. R.","Jim R Hughes","University of Oxford","2025-10-27","1","new results","cc_by","synthetic biology","https://www.biorxiv.org/content/early/2025/10/27/2025.10.27.684763.source.xml","The process by which a foreign gene is introduced into a cell and translated into a functional protein is referred to as transgene expression. Understanding and optimising transgene expression is crucial for a wide variety of applications which range from investigating basic biology, synthetic biology, recombinant protein production to gene therapy. However, precise control over the timing and location of transgene expression remains a key limitation, particularly in therapeutic contexts where specificity and compactness are critical.

To address limitations of traditional promoter-based transgene construct approaches, we developed TRANCERs (TRanscriptionally Autonomous enhaNCERs), a modular and compact system that transforms cell type-specific enhancers into standalone sources of productive transcription. To accomplish this, we leveraged basic facets of enhancer function as well as known and novel principles of transcript stability and nuclear export.

We demonstrate that TRANCERs can drive lineage-restricted expression of both reporter and therapeutic genes across multiple mammalian cell types both in vitro and in vivo, and that this expression pattern faithfully mirrors the activity of the enhancer element used. Enhancer elements are the most cell type specific element in the mammalian genome and are used to drive development, differentiation and cellular responses to extrinsic signals. Therefore, the TRANCER system allows for the generation of specific stable expression constructs for all conceivable situations for which a native enhancer exists with the required activity pattern. Furthermore, we show that the TRANCER system is compatible with previously published machine learning derived artificial enhancer sequences suggesting the possibility even for specific bespoke expression patterns that do not exist in nature. This, combined with a significantly reduced vector footprint ideal for size-constrained delivery systems such as lentiviral vectors, means that the TRANCER system represent a significant step forward in our ability to control gene expression for both basic biology and therapeutic applications.","[{""name"":""Medical Research Council"",""id"":""https://ror.org/03x94j517"",""id-type"":""ROR"",""award"":""MC_UU_00016/14;MC_UU_00029/3;""},{""name"":""Biotechnology and Biological Sciences Research Council"",""id"":""https://ror.org/00cwqg982"",""id-type"":""ROR"",""award"":""""},{""name"":""Wellcome Trust"",""id"":""https://ror.org/029chgv08"",""id-type"":""ROR"",""award"":""225220/Z/22/Z;""}]","NA","bioRxiv",1761862207168
"Induction of menstruation in mice reveals the regulation of menstrual shedding","10.1101/2025.10.08.681007","biorxiv",98.44999999999992,1.5,6.65,12.1,98.44999999999992,"Cevrim, C.; Hilgert, N. J.; Kaage, A. M.; Russell, A. J. C.; Goldstein, A. E.; Ang, C. J.; Gable, J. L. R.; Bagamery, L. E.; Breznik, A.; Di Bella, D. J.; Talay, M.; Peng, J.; O'Neill, K. E.; Chen, F.; Eddy, S. R.; McKinley, K. L.","Kara L. McKinley","Harvard University and Howard Hughes Medical Institute","2025-10-09","1","new results","cc_by","developmental biology","https://www.biorxiv.org/content/early/2025/10/09/2025.10.08.681007.source.xml","During menstruation, an inner layer of the endometrium is selectively shed, while an outer, progenitor-containing layer is preserved to support repeated regeneration. Progress in understanding this compartmentalization has been hindered by the lack of suitable animal models, as mice and rats do not menstruate. Here, we present transgenic mouse models that recapitulate the key anatomical, functional, and transcriptional features of human menstruation through targeted chemogenetic activation of premenstrual differentiation. Using single-cell spatial transcriptomics, we define a new paradigm for spatially regulated fibroblast differentiation that drives pre-menstrual endometrial layering and ultimately determines the extent of tissue shedding. Our results revise a century-old view of endometrial shedding and regeneration and establish new transgenic mice as powerful tools to advance menstruation research.","[{""name"":""National Institutes of Health"",""id"":""https://ror.org/01cwqze88"",""id-type"":""ROR"",""award"":""DP2HD111708;R00HD101021;""},{""name"":""New York Stem Cell Foundation"",""id"":""https://ror.org/03n2a3p06"",""id-type"":""ROR"",""award"":""Robertson Stem Cell Investigator;""},{""name"":""Howard Hughes Medical Institute"",""id"":""https://ror.org/006w34k90"",""id-type"":""ROR"",""award"":""""},{""name"":""Charles H. Hood Foundation"",""id"":""https://ror.org/0550wc655"",""id-type"":""ROR"",""award"":""""},{""name"":""David and Lucile Packard Foundation"",""id"":""https://ror.org/032atxq54"",""id-type"":""ROR"",""award"":""""},{""name"":""Searle Scholars Program"",""id"":"""",""id-type"":""ROR"",""award"":""""},{""name"":""Damon Runyon Cancer Research Foundation"",""id"":""https://ror.org/01gd7b947"",""id-type"":""ROR"",""award"":""""},{""name"":""Massachusetts Life Sciences Center"",""id"":""https://ror.org/033km2469"",""id-type"":""ROR"",""award"":""""},{""name"":""Richard and Susan Smith Family Foundation"",""id"":""https://ror.org/05j95n956"",""id-type"":""ROR"",""award"":""""},{""name"":""U.S. National Science Foundation"",""id"":""https://ror.org/021nxhr62"",""id-type"":""ROR"",""award"":""""}]","NA","bioRxiv",1761862207168
"Comparison of dimensionality reduction and feature selection for cognitive task decoding in functional magnetic resonance imaging","10.1101/2025.10.27.684660","biorxiv",6.1,1.85,6.1,6.1,6.1,"Richier, C. J.; Baacke, K. A.; Olshan, S. M.; Heller, W.","Corey J Richier","University of Illinois at Urbana-Champaign","2025-10-28","1","new results","cc_by","neuroscience","https://www.biorxiv.org/content/early/2025/10/28/2025.10.27.684660.source.xml","Background Advances in functional magnetic resonance imaging (fMRI) have led to the ability to study the brain across many contexts. However, the large number of features generated by functional connectivity approaches may overfit the data. These problems can be overcome with either feature selection (FS) or dimensionality reduction (DR), which can be applied to less complex models. We utilize two open-source datasets to compare the performance of DR/FS methods on cognitive task decoding using a suite of ML classifiers. New Method While DR and FS methods have been used previously in decoding research, no systematic comparison of their performance has been undertaken. Here, we compare available methods using commonly utilized machine learning libraries to establish which methods provide the best predictive performance. We then conduct statistical tests to examine the relative contributions of DR and FS methods and classifiers on decoding accuracy. Results Neither DR or FS was found to be superior. However, differences were identified across datasets and tasks. In the majority of methods and datasets, a peak in predictive performance was found using a small percentage of the total number of original features. Comparison with existing methods Some methods perform better than the baseline method of prediction with all available features or selecting features randomly. Decoding performance utilizing the HCP datasets with certain DR/FS methods exceeds that of deep learning approaches. Conclusions Simple machine learning models with DR/FS have competitive decoding performance. These results suggest a sweet spot for the tradeoff between the retention of features and predictive accuracy.","NA","NA","bioRxiv",1761862207168
"velotest: Statistical assessment of RNA velocity embeddings reveals quality differences for reliable trajectory visualizations","10.1101/2025.10.26.683064","biorxiv",9.9,0.25,5.949999999999999,9.9,9.9,"Bischoff, S.; Policar, P. G.; Mukherjee, S.; Macke, J. H.; Claassen, M.; Schröder, C. H.","Cornelius H Schröder","University of Tübingen","2025-10-26","1","new results","cc_by","bioinformatics","https://www.biorxiv.org/content/early/2025/10/26/2025.10.26.683064.source.xml","Contemporary single-cell RNA-sequencing studies typically use RNA velocity analyses to investigate cellular dynamics. Commonly, RNA velocities are assessed with two-dimensional projections. Although it is well established that nonlinear embeddings of gene expression data cannot comprehensively preserve the structure of the original high-dimensional data across scales, there is no tool that systematically assesses and quantifies the faithfulness of velocity embeddings. This situation potentially leads to misleading velocity visualizations and putative cell state transitions. To this end, we introduce velotest, a cell-level statistical test that quantifies the faithfulness of a velocity embedding with respect to its high-dimensional counterpart. Applying velotest across multiple datasets and embedding methods, we find strong differences in the embedding qualities between embedding methods, datasets, and regions in individual datasets. velotest thus provides an essential validation step and enables researchers to select a suitable visualization of high-dimensional velocities, ensuring that hypotheses drawn from velocity projections are grounded in accurately represented dynamics.","[{""name"":""Deutsche Forschungsgemeinschaft"",""id"":""https://ror.org/018mejw64"",""id-type"":""ROR"",""award"":""390727645;520388526;""},{""name"":""Bundesministerium für Forschung, Technologie und Raumfahrt"",""id"":"""",""id-type"":""ROR"",""award"":""01IS18039;""}]","NA","bioRxiv",1761862207168
"Programmed DNA elimination was present in the last common ancestor of Caenorhabditis nematodes","10.1101/2025.10.23.681605","biorxiv",7.8999999999999995,1,5.3999999999999995,7.8999999999999995,7.8999999999999995,"Stevens, L.; Sun, S.; Haruta, N.; Xiao, L.; Uwatoko, N.; Kieninger, M.; Sato, K.; Yoshida, A.; Absolon, D.; Collins, J.; Sugimoto, A.; Kikuchi, T.; Blaxter, M.","Lewis Stevens","Tree of Life, Wellcome Sanger Institute, Hinxton, CB10 1SA UK","2025-10-24","1","new results","cc_by","evolutionary biology","https://www.biorxiv.org/content/early/2025/10/24/2025.10.23.681605.source.xml","In most organisms, all cells inherit the same genome, and many mechanisms exist to preserve genome integrity across cell divisions. However, some species undergo programmed DNA elimination (PDE), whereby specific genome regions are removed from somatic cell lineages early during development, leading to distinct germline and somatic genomes. Since its discovery in parasitic nematodes over a century ago, PDE has been observed in diverse eukaryotes, including ciliates, arthropods, and vertebrates. However, the function, mechanisms, and evolutionary origins of PDE remain poorly understood. Here, we report the unexpected discovery of PDE in three early-diverging Caenorhabditis species. Using long-read and chromatin conformation capture sequencing, we reconstructed germline and somatic genomes for all three species, and found that between 0.7 and 2.3% of the genome is eliminated during the 8- to 16-cell stage of embryogenesis, including the telomeres and regions within chromosomes. Elimination of regions within chromosomes results in fragmentation of the six germline chromosomes into 8-15 somatic chromosomes. The sites of elimination are precise, and we identified conserved motifs that likely recruit a nuclease to induce double-strand breaks. The newly formed somatic chromosome ends are healed by de novo telomere addition. A small number of genes are eliminated in each species, some of which have C. elegans orthologues with essential germline functions. A subset of elimination sites are orthologous across species, and some coincide with genome rearrangement sites. The phylogenetic distribution of PDE suggests that it was present in the last common Caenorhabditis ancestor and subsequently lost early during the evolution of many species, including C. elegans.","[{""name"":""Wellcome Trust"",""id"":""https://ror.org/029chgv08"",""id-type"":""ROR"",""award"":""220540/Z/20/A;""},{""name"":""Japan Science and Technology Agency"",""id"":""https://ror.org/00097mb19"",""id-type"":""ROR"",""award"":""JPMJCR18S7;JPMJCR24B4;""},{""name"":""Japan Society for the Promotion of Science"",""id"":""https://ror.org/00hhkn466"",""id-type"":""ROR"",""award"":""JP23K17400;JP24H00549;""}]","NA","bioRxiv",1761862207168
"Reverse transcribed ssDNA derepresses translation of a retron antiviral protein","10.1101/2025.10.22.683967","biorxiv",41.099999999999994,0,1,41.099999999999994,41.099999999999994,"Zhang, K.; Rojas-Montero, M.; Poola, D.; Klas, J.; Carabias, A.; Zhang, D.; Mestre, M. R.; Zhao, R.; Davila-Hidalgo, A.; Montoya, G.; Pinilla-Redondo, R.; Gonzalez-Delgado, A.; Shipman, S. L.","Seth L Shipman","Gladstone Institute of Data Science and Biotechnology","2025-10-22","1","new results","cc_by","microbiology","https://www.biorxiv.org/content/early/2025/10/22/2025.10.22.683967.source.xml","Retrons are bacterial immune systems that prevent the spread of phages by initiating a toxic response within infected hosts. All previously characterized retrons produce high levels of multicopy single-stranded DNA (msDNA) in the cell by reverse transcription, which acts as an antitoxin in the absence of phage infection. However, we describe here a non-canonical mechanism for Type VI retrons, which do not produce detectable msDNA in the absence of phage, yet still provide phage defense. Focusing primarily on Retron-Vpa2, a Type VI retron from Vibrio parahaemolyticus, we show broad defense against phages and identify triggers of the system within phage recombination systems. Within the Retron-Vpa2 operon, we find a highly enriched, structured transcript that we term a hybrid RNA (hyRNA), which contains both the retrons reverse transcription template and a translationally repressed toxic effector coding sequence. We find that phage infection induces the accumulation of high levels of msDNA and that this msDNA is necessary for derepressing translation of the antiviral toxin. These findings present key biological and mechanistic insights into a distinct group of retrons while highlighting the diversity of systems that participate in bacterial immunity.","NA","NA","bioRxiv",1761862207168
"VPS13C/PARK23 initiates lipid transfer and membrane remodeling for efficient lysosomal repair","10.1101/2025.10.23.684214","biorxiv",28.30000000000001,0,4.8,28.30000000000001,28.30000000000001,"Adeosun, O. A.; Schroer, C.; Suedhoff, E.; Bergenthal, F.; Sommer, K.; Doeffinger, E.; Fiedler, B.; Hilderink, A.; Lehmann, A.-K.; Pohle, L.-S.; Froehlich, F.; Maeda, K.; Kurre, R.; Holtmannspoetter, M.; Esch, B. M.; Holthuis, J. C. M.","Joost C.M. Holthuis","Osnabrueck University","2025-10-24","1","new results","cc_by","cell biology","https://www.biorxiv.org/content/early/2025/10/24/2025.10.23.684214.source.xml","Perturbations in lysosome integrity are tightly linked to neurological disorders and ageing, but the underlying pathogenic mechanisms are incompletely understood. Using an unbiased proteomic approach, we here identified the bridge-like lipid transport protein VPS13C/PARK23 as a key component of a global early response pathway to lysosome damage. VPS13C readily binds lysosomes under mechanical or osmotic tension in anticipation of membrane lesions. The latter trigger a conformational change in the proteins C-terminus, involving its ATG2C domain acting as sensor of damage-induced lipid packing defects. We show that ER-lysosome contacts formed by VPS13C provide critical binding platforms for OSBP/ORPs to enable efficient ER wrapping of damaged lysosomes. A chemical approach to assess directional ER-to-lysosome lipid transport revealed that VPS13C is essential for large-scale lipid delivery to acutely damaged lysosomes to facilitate their repair. Our findings offer new mechanistic insights into how loss-of-function mutations in VPS13C may enhance the risk of Parkinsons disease.","[{""name"":""Deutsche Forschungsgemeinschaft"",""id"":""https://ror.org/018mejw64"",""id-type"":""ROR"",""award"":""512783018;467522186/SFB1557–P9;467522186/SFB1557–P6;467522186/SFB1557–Z1;467522186/SFB1557–Z2;""},{""name"":""Novo Nordisk Foundation"",""id"":""https://ror.org/04txyc737"",""id-type"":""ROR"",""award"":""NNF17OC0029432;""},{""name"":""German Academic Exchange Service"",""id"":""https://ror.org/039djdh30"",""id-type"":""ROR"",""award"":""57552340;""}]","NA","bioRxiv",1761862207168
"Barbell Resolves Demultiplexing and Trimming Issues in Nanopore Data","10.1101/2025.10.22.683865","biorxiv",27.80000000000001,0.25,1.6,27.80000000000001,27.80000000000001,"Beeloo, R.; Groot Koerkamp, R.; Jia, X.; Broekhuizen-Stins, M. J.; van Ijken, L.; Dutilh, B. E.; Zomer, A. L.","Rick Beeloo","Utrecht University","2025-10-23","1","new results","cc_by","bioinformatics","https://www.biorxiv.org/content/early/2025/10/23/2025.10.22.683865.source.xml","BackgroundOxford Nanopore sequencing enables long-read sequencing across diverse applications, yet the experimental artifacts introduced by Nanopore barcoding are not well characterized. These artifacts can affect demultiplexing accuracy and downstream analyses.

ResultsWe performed a rapid barcoding experiment on 66 diagnostic samples and found that 83% of reads carried the expected single-barcode pattern, while 17% contained multiple barcodes or other artifacts. Current demultiplexers, including the widely used Dorado, fail to correctly handle these complex cases, leaving approximately 7% of reads partially trimmed and contaminated with adapter fragments. Additional issues include the presence of two barcodes at the same read end--either identical, originating from the same sample, or different, introduced after pooling. The latter can lead to barcode bleeding when the outer barcode is incorrectly selected. To address these challenges, we developed Barbell, a pattern-aware demultiplexer that detects all barcode configurations. Barbell reduces trimming errors by three orders of magnitude, minimizes barcode bleeding, and supports custom experimental setups such as shorter barcodes, dual-end barcodes, and custom flank sequences.

ConclusionsOur results highlight the impact of complex barcode attachments in Nanopore sequencing and demonstrate that Barbell drastically reduces their effects on downstream analyses. Barbell is open source and available at https://github.com/rickbeeloo/barbell.","[{""name"":""ZonMw, The Dutch Organisation for knowledge and innovation in health, healthcare and well-being"",""id"":""https://ror.org/01yaj9a77"",""id-type"":""ROR"",""award"":""541003001;""},{""name"":""European Research Council"",""id"":""https://ror.org/0472cxd90"",""id-type"":""ROR"",""award"":""865694;""},{""name"":""DiversiPHI, Deutsche Forschungsgemein schaft (DFG, German Research Foundation) under Germany's Excellence Strategy - EXC 2051"",""id"":"""",""id-type"":""ROR"",""award"":""390713860;""},{""name"":""Alexander von Humboldt Foundation in the context of an Alexander von Humboldt-Professorship founded by German Federal Ministry of Education and Research."",""id"":"""",""id-type"":""ROR"",""award"":""""}]","NA","bioRxiv",1761862207168
"Disulfide bond sculpts a peptide fold that mediates phytocytokine recognition","10.1101/2025.10.24.684422","biorxiv",23.449999999999996,0,5,23.449999999999996,23.449999999999996,"Jimenez Sandoval, P.; Johanndrees, O.; Snoeck, S.; Harshith, C. Y.; Omary, M.; Broyart, C.; Rhodes, J.; Bender, K. W.; Zipfel, C.; Santiago, J.","Julia Santiago","University of Lausanne","2025-10-24","1","new results","cc_no","plant biology","https://www.biorxiv.org/content/early/2025/10/24/2025.10.24.684422.source.xml","Precise ligand recognition by closely related leucine-rich repeat receptor kinases (LRR-RKs) is essential for plants to coordinate immunity, development, and environmental adaptation. Here, we show how HAESA-LIKE 3 (HSL3) specifically recognizes the folded, disulfide-stabilized CTNIP/SCREW phytocytokines in Arabidopsis. Quantitative binding assays define a minimal CTNIP4 region required for high-affinity HSL3 interaction and signaling activation. A 2.12 [A] crystal structure of the HSL3-CTNIP4 complex reveals a unique C-terminal receptor pocket that accommodates the peptides cyclic architecture through a combination of hydrophobic and polar contacts, a feature absent in the closely related HAE/HSL LRR-RKs. The cyclic CTNIP4 fold further establishes a largely hydrophobic interface that bridges HSL3 to the SERK co-receptor, forming a distinct activation surface. Together, these structural, biochemical and physiological insights uncover a previously unrecognised mechanism of peptide perception and receptor activation, highlighting how subtle architectural variations enable precise ligand selectivity among highly conserved plant receptor kinases.","[{""name"":""Swiss National Science Foundation"",""id"":""https://ror.org/00yjd3n13"",""id-type"":""ROR"",""award"":""310030_204526;10001549;""},{""name"":""EMBO"",""id"":"""",""id-type"":""ROR"",""award"":""ALTF 1061-2023;""},{""name"":""European Research Council"",""id"":""https://ror.org/0472cxd90"",""id-type"":""ROR"",""award"":""773153;""}]","NA","bioRxiv",1761862207168
"TF-MAPS: fast high-resolution functional and allosteric mapping of DNA-binding proteins","10.1101/2025.10.20.683418","biorxiv",26.099999999999994,0.85,1.7,20.9,26.099999999999994,"Li, X.; Lehner, B.","Ben Lehner","Wellcome Sanger Institute; Centre for Genomic Regulation (CRG), Barcelona, Spain","2025-10-20","1","new results","cc_by_nc_nd","genomics","https://www.biorxiv.org/content/early/2025/10/20/2025.10.20.683418.source.xml","Transcription factors (TFs) bind specific DNA sequences to control gene expression. Modulating TF activity is of considerable therapeutic interest but very few TFs have been successfully drugged. TF DNA-binding interfaces are large and most TFs have no known allosteric ligands or allosteric sites. Here, we introduce TF-MAPs, a scalable and general platform to chart complete functional maps of sequence-specific DNA-binding proteins. We apply TF-MAPS to three human disease TFs: HNF1A, FOXG1 and FOXP1. Allostery in all three proteins is distance-dependent, anisotropic, and couples the DNA-binding interface to the protein surface. The allosteric surfaces of FOXG1 and FOXP1 are quite diverged, revealing a potential for protein-specific regulation in protein families. All three TFs have potentially druggable pockets where mutations have strong functional effects on binding, either within the binding interface or distant from it. Using TF-MAPS it should be possible to chart functional and allosteric maps for hundreds of human TFs and other DNA-binding proteins to understand DNA recognition and TF regulation, to mechanistically interpret clinical variants, and to guide the development of TF-modulating therapeutics.","[{""name"":""Wellcome Sanger Institute"",""id"":""https://ror.org/05cy4wa09"",""id-type"":""ROR"",""award"":""Grant reference: 220540/Z/20/A, ‘Wellcome Sanger Institute Quinquennial Review 2021-2026’;""}]","NA","bioRxiv",1761862207168
"Cell-stereotyped DNA repair outcomes are widespread during genome editing","10.1101/2025.10.23.684114","biorxiv",20.799999999999997,0.85,4.8999999999999995,20.799999999999997,20.799999999999997,"Schlapansky, M. F.; Schröder, M.; Santinha, A.; Rothgangl, T.; Ioannidi, E.; Cullot, G.; Lewkow, B.; Ortega, G. C.; Nouraiz, A.; Mailänder, D.; Selbert, L.; Lam, S.; Egea, A.; Shin, J. J.; Bordi, M.; DeWitt, M.; Gvozdenovic, A.; Jackson, S. P.; Schroeder, T.; Gehart, H.; Schwank, G.; Platt, R.; Corn, J. E.","Jacob E Corn","Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.","2025-10-23","1","new results","cc_no","genomics","https://www.biorxiv.org/content/early/2025/10/23/2025.10.23.684114.source.xml","Genome editing outcomes are governed by DNA repair pathways that vary with cell type and state. We developed scOUT-seq (single-cell Outcomes Using Transcript sequencing), a scalable approach that jointly profiles transcriptomes and matched multi-allelic editing outcomes ranging from homology directed repair (HDR) to inter-chromosomal translocations. We mapped editing outcomes in human CD34 hematopoietic stem and progenitor cells (HSPCs), mouse LSK HSPC equivalents, human upper airway organoids, and mouse multi-organ in vivo editing. Profiling 500,000 alleles across 74 cell types, scOUT-seq revealed that outcomes in most cell subtypes differ markedly from the bulk average. Various cell types shifted major repair classes, preferred different molecular sequences, and even enriched large structural variants, with distinctive patterns of allelic co-occurrence. Surprisingly, rare stem subtypes diverged from prevalent progenitors, and inhibitory neuron subtypes efficiently incorporated HDR alleles. These data suggest the potential for tailored therapeutic editing that may have been missed by bulk measurements.","[{""name"":""Boehringer Ingelheim Fonds"",""id"":""https://ror.org/00dkye506"",""id-type"":""ROR"",""award"":""BIF 18919;""},{""name"":""NOMIS Foundation"",""id"":""https://ror.org/01zkd3118"",""id-type"":""ROR"",""award"":""310030_188858;""},{""name"":""Lotte and Adolf Hotz-Sprenger Stiftung"",""id"":"""",""id-type"":""ROR"",""award"":""310030_201160;""},{""name"":""European Research Council"",""id"":""https://ror.org/0472cxd90"",""id-type"":""ROR"",""award"":""855741-DDREAMM-ERC-2019-SyG;""},{""name"":""NCCR RNA and Disease"",""id"":"""",""id-type"":""ROR"",""award"":""182880;205601;""},{""name"":""Swiss National Science Foundation"",""id"":""https://ror.org/00yjd3n13"",""id-type"":""ROR"",""award"":""51NF40-182895;""},{""name"":""Fickel Family Fund"",""id"":"""",""id-type"":""ROR"",""award"":""""},{""name"":""Cancer Research UK"",""id"":""https://ror.org/054225q67"",""id-type"":""ROR"",""award"":""DRCPBM100005;SEBINT-2024/100003;""}]","NA","bioRxiv",1761862207168
"Visceral signaling of post-ingestive malaise directs memory updating in Drosophila","10.1101/2025.10.21.683769","biorxiv",18.599999999999998,0,0,18.599999999999998,18.599999999999998,"Senapati, B.; Treiber, C. D.; Waddell, S.","Scott Waddell","University of Oxford","2025-10-22","1","new results","cc_by_nc_nd","neuroscience","https://www.biorxiv.org/content/early/2025/10/22/2025.10.21.683769.source.xml","Consolidation is a time when labile memories transition to a stable form. Malaise learning in Drosophila reveals consolidation to also permit memory updating. Flies taught to associate one of two odors with toxin-tainted sugar initially express conditioned odor approach, that following consolidation switches to avoidance. Behavioral reversal emerges from dopaminergic update of parallel memories for the two trained odors. Differential serotoninergic modulation of specific aversive and rewarding dopaminergic neuron subtypes permits post-ingestive intoxication to suppress consolidation of initial odor-sugar memory and simultaneously invert reward memory plasticity into ""safety"" memory for the odor experienced without food. Fat body release of the Toll-ligand activating protease modSP, and resilience factor Turandot A, instruct malaise updates by triggering autocrine Toll signaling in the same brain dopaminergic neurons that form and consolidate initial sugar memory. This neural mechanism overcomes the credit assignment problem of delayed post-ingestive reinforcement by updating earlier memories of the trained odors.","[{""name"":""Wellcome Trust"",""id"":""https://ror.org/029chgv08"",""id-type"":""ROR"",""award"":""200846;225192;203261;209235;""},{""name"":""European Research Council"",""id"":""https://ror.org/0472cxd90"",""id-type"":""ROR"",""award"":""789274;""}]","NA","bioRxiv",1761862207168
"Icecream: High-Fidelity Equivariant Cryo-Electron Tomography","10.1101/2025.10.17.682746","biorxiv",20.250000000000004,0,1.85,16.65,20.250000000000004,"Kishore, V.; Debarnot, V.; Righetto, R. D.; Engel, B. D.; Dokmanic, I.","Valentin Debarnot","CREATIS, INSA Lyon","2025-10-17","1","new results","cc_by_nc","bioinformatics","https://www.biorxiv.org/content/early/2025/10/17/2025.10.17.682746.source.xml","Cryo-electron tomography (cryo-ET) visualizes 3D cellular architecture in near-native states. Recent deep-learning methods (CryoCARE, IsoNet, DeepDeWedge, CryoLithe) improve denoising and artifact correction, but performance remains limited by very low signal-to-noise ratio, a restricted angular range ( missing wedge), and the lack of ground truth. Here, we present Icecream, which follows the broad template of earlier self-supervised approaches, but treats symmetry in a way consistent with the recent equivariant imaging framework (Chen et al., 2021). Coupled with several engineering refinements, including mixed-precision arithmetic, Icecream achieves substantially better denoising and more reliable missing-wedge recovery, while reducing training and inference time relative to comparable baselines. Across diverse experimental datasets, we observe consistent gains in reconstruction quality, both visually and as quantified by Fourier shell correlation (FSC). Our framework extends to any tomography problem that provides two statistically independent reconstructions of the same volume; in cryo-ET these are obtained by dose splitting or angular partitioning of the tilt series.","[{""name"":""European Research Council"",""id"":""https://ror.org/0472cxd90"",""id-type"":""ROR"",""award"":""852821;""},{""name"":""Agence Nationale de la Recherche"",""id"":""https://ror.org/00rbzpz17"",""id-type"":""ROR"",""award"":""""},{""name"":""Ministère de l’Enseignement Supérieur et de la Recherche"",""id"":"""",""id-type"":""ROR"",""award"":""""}]","NA","bioRxiv",1761862207168
"Cold-water gut isolate from threespine stickleback (Gasterosteus aculeatus) reveals polypropylene surface oxidation and co-culture inhibition","10.1101/2025.10.22.682630","biorxiv",16.25,0,0.85,16.25,16.25,"Pasqualetti, S. M.; Atwood, J.; Aderibigbe, A.; Russell, E.; O'Keefe, K.; Rosario, V.; Ireland, K.; Sparks, K.; Campbell, K.; Isenberg, R. Y.; Lucas, R.; Dhage, P.; Milligan-McClellan, K.","Kathryn Milligan-McClellan","University of Connecticut","2025-10-22","1","new results","cc_by_nc","microbiology","https://www.biorxiv.org/content/early/2025/10/22/2025.10.22.682630.source.xml","Polyethylene terephthalate (PET) and polypropylene (PP), two of the most widely produced plastics in the United States, persist in cold-water environments where plastic-degrading microbes have been poorly characterized. Understanding how gut microbes interact and contribute to plastic degradation is essential for developing potential microbiome-based bioremediation strategies. We isolated 184 microbes from wild Alaskan threespine stickleback (Gasterosteus aculeatus) guts across six lakes and screened for plastic degrading potential using lipase/esterase assays and biofilm formation on PET and PP. During the screen for microbes with plastic degrading potential, we discovered that stickleback gut microbiota members enhance and suppressed the lipase, esterase, and biofilm activity of other microbes. Isolates with the highest plastic degrading potential were incubated in minimal media with PET or PP as the sole carbon source to determine whether plastic degradation potential is enhanced. Surface analysis identified a Pseudomonas trivialis strain that exhibited degradation of PP in monoculture; however, this activity was suppressed in the presence of another gut isolate, Pseudomonas germanica. These results demonstrate that microbes associated with the wild threespine stickleback gut microbiome possess plastic degradation potential and provide insights into how microbial interactions can either promote or inhibit bioremediation of plastic pollution in cold-water environments.","[{""name"":""Chan Zuckerberg Initiative (United States)"",""id"":""https://ror.org/02qenvm24"",""id-type"":""ROR"",""award"":""2022-253562-5022;""},{""name"":""National Institutes of Health"",""id"":""https://ror.org/01cwqze88"",""id-type"":""ROR"",""award"":""R15GM122038;""},{""name"":""U.S. National Science Foundation"",""id"":""https://ror.org/021nxhr62"",""id-type"":""ROR"",""award"":""1126100;""}]","NA","bioRxiv",1761862207168
"End-to-end automation of repeat-target cryo-EM structure determination in CryoSPARC","10.1101/2025.10.17.682689","biorxiv",55.85000000000001,0.85,0.85,15.2,55.85000000000001,"CryoSPARC Team Structura Biotechnology Inc.,  ; Barber, K.; Bridges, H.; Dawood, S.; Elder, K.; Frasser, N.; Hu, F.; Liu, S.; McLean, M.; Narine, R.; Ng, T.; Peretroukhin, V.; Punjani, A.; Snyder, H.; Stachowski, K.; Tempel, W.; Virani, S.; Waldo, R.; Wang, C.; Wong, N.","Ali Punjani","Structura Biotechnology Inc.","2025-10-20","1","new results","cc_by_nc_nd","biophysics","https://www.biorxiv.org/content/early/2025/10/20/2025.10.17.682689.source.xml","Single particle cryo-EM is a valuable and growing technique for life science and drug discovery. Currently, obtaining state-of-the-art results from cryo-EM data analysis requires a human in the loop to analyze intermediate results and make image processing decisions. This bottleneck limits the achievable throughput of structure determination, especially in high-throughput settings such as structure-based drug design. In this work, we develop an end-to-end automation strategy for repeat-target structure determination using new tools in CryoSPARC. We demonstrate completely hands-off processing of 21 challenging G protein-coupled receptor (GPCR) datasets. In 17 of 21 cases, automated processing meets or exceeds published resolution and map quality and, in several cases, provides significant improvement in receptor and ligand density that allows improved model building. Our results on both active and inactive state GPCRs show that our automation strategy generalizes easily to new target classes, and that complete automation of data processing is straightforward to achieve in CryoSPARC. We provide downloadable CryoSPARC Workflow files so that users can import, replicate, adapt and extend our automated workflow for their own targets, enabling cryo-EM to be applied at larger scales and to answer larger biological questions.","NA","NA","bioRxiv",1761862207168
"Stress drives the hippocampus to prioritize statistical prediction over episodic encoding","10.1101/2025.10.25.683838","biorxiv",15.049999999999999,0,3.95,15.049999999999999,15.049999999999999,"Zhou, I.; Bai, Z.; Huang, Y.; Wijaya, E. G.; Sherman, B. E.; Turk-Browne, N. B.; Goldfarb, E. V.","Irene Zhou","Department of Psychology, Yale University","2025-10-26","1","new results","cc_by_nc_nd","neuroscience","https://www.biorxiv.org/content/early/2025/10/26/2025.10.25.683838.source.xml","The hippocampus plays a critical role in encoding individual experiences into episodic memory, while also detecting patterns shared across these experiences that allow us to anticipate future events via statistical learning. Acute stress is known to impact the hippocampus but may have opposite effects on these competing functions. That is, although stress impairs episodic encoding, it may instead enhance statistical learning. Using functional magnetic resonance imaging, we tested how stress influences the hippocampal pathways and subfields that support episodic encoding and statistical learning while participants performed a task that engaged both processes. Across several analyses, stress biased hippocampal processing in favour of statistical learning, suppressing pattern separation between events in the dentate gyrus and enhancing the representation of statistically predictive features. Furthermore, stress drove the hippocampal monosynaptic pathway to support statistical learning rather than episodic encoding during predictive situations. Together, these data suggest that acute stress elicits targeted, adaptive changes in hippocampal pathways which may facilitate predicting and responding to upcoming events.","[{""name"":""NIMH"",""id"":"""",""id-type"":""ROR"",""award"":""R21MH128740;""}]","NA","bioRxiv",1761862207168
"Enhancer-promoter compatibility is mediated by the promoter-proximal region","10.1101/2025.10.14.682013","biorxiv",60.050000000000054,0,0,11.999999999999998,60.050000000000054,"Majchrzycka, B. M.; Mundlos, S.; Krebs, A.; Ibrahim, D. M.","Daniel M Ibrahim","Berlin Institute of Health","2025-10-15","1","new results","cc_by_nc_nd","genetics","https://www.biorxiv.org/content/early/2025/10/15/2025.10.14.682013.source.xml","Gene promoters induce transcription in response to distal enhancers. How enhancers specifically activate their target promoter while bypassing other promoters remains unclear. Here, we find that the promoter-proximal region is critical for cell-type specific enhancer-promoter compatibility. Using high-throughput genome-engineering in mouse embryonic stem cells (mESC), we systematically replace the endogenous Sox9 promoter with different libraries of core and extended (i.e. full) promoters and assess their response to long-range regulatory elements in mESCs and neural progenitor cells. We find that only a subset of full promoters is activated by distal neuronal enhancers and that the promoter-proximal region is necessary for this enhancer-promoter compatibility. Core promoters alone are insufficient to respond to distal enhancers but modulate the transcriptional output of responsive promoters. Our results suggest that within multipartite regulatory domains, the promoter-proximal region fulfills a facilitator-like function that filters and transmits signal from distal enhancers, ultimaltely conferring enhancer-promoter compatibility.","[{""name"":""European Commission"",""id"":""https://ror.org/00k4n6c32"",""id-type"":""ROR"",""award"":""101076709;101125530;813327;""},{""name"":""Deutsche Forschungsgemeinschaft"",""id"":""https://ror.org/018mejw64"",""id-type"":""ROR"",""award"":""IB 139/6-1;KR 5247/1-1;KR 5247/1-2;KR 5247/1-3;""}]","NA","bioRxiv",1761862207168
"A high-coverage genome from a 200,000-year-old Denisovan","10.1101/2025.10.20.683404","biorxiv",130.65000000000003,0,1.35,9.6,130.65000000000003,"Peyregne, S.; Massilani, D.; Swiel, Y.; Boyle, M. J.; Iasi, L. N. M.; Suemer, A. P.; Bossoms Mesa, A.; de Filippo, C.; Viola, B.; Essel, E.; Nagel, S.; Richter, J.; Weihmann, A.; Schellbach, B.; Zeberg, H.; Visagie, J.; Kozlikin, M. B.; Shunkov, M. V.; Derevianko, A. P.; Pruefer, K.; Peter, B. M.; Meyer, M.; Paabo, S.; Kelso, J.","Stephane Peyregne","Max Planck Institute for Evolutionary Anthropology","2025-10-20","1","new results","cc_by_nc_nd","genomics","https://www.biorxiv.org/content/early/2025/10/20/2025.10.20.683404.source.xml","Denisovans, an extinct sister group of Neandertals who lived in Eastern Eurasia during the Middle and Late Pleistocene, are known only from a handful of skeletal remains and limited genetic data, including the high-coverage genome of a woman who lived [~]65,000 years ago. Here, we present a second high-quality Denisovan genome, reconstructed from a molar found at Denisova Cave. It belonged to a man who lived [~]200,000 years ago in a small Denisovan group. This group mixed with early Neandertals and was then replaced by Denisovans who had mixed with later Neandertals. We show that in addition Denisovans received gene flow from hominins that diverged before the split of the ancestors of Denisovans and modern humans. The two Denisovan genomes allow us to disentangle Denisovan ancestry in present-day humans revealing contributions from at least three distinct Denisovan groups. In particular, Oceanians and South Asians independently inherited DNA from a deeply diverged Denisovan population which was likely isolated in South Asia. This supports an early migration of the ancestors of Oceanians through South Asia followed by the later arrival of the ancestors of present-day South Asians. East Asians do not share this Denisovan component in their genomes, suggesting that their ancestors arrived independently, perhaps by a northerly route. Finally, the two high-quality Denisovan genomes allow us to refine the catalogue of genetic changes that arose on the Denisovan lineage, some of which were contributed to present-day humans.","[{""name"":""Max Planck Society"",""id"":""https://ror.org/01hhn8329"",""id-type"":""ROR"",""award"":""""},{""name"":""European Research Council"",""id"":""https://ror.org/0472cxd90"",""id-type"":""ROR"",""award"":""694707;""},{""name"":""Russian Science Foundation"",""id"":""https://ror.org/03y2gwe85"",""id-type"":""ROR"",""award"":""24-18-00069;""}]","NA","bioRxiv",1761862207168
"Non-synaptic exocytosis along the axon shaft and its regulation by the submembrane periodic skeleton","10.1101/2025.09.17.676728","biorxiv",64.15000000000003,0,0,0,64.15000000000003,"Wiesner, T.; Parperis, C. L.; Boroni-Rueda, F.; Jullien, N.; Mendes, A.; Marie, L.; Mezache, L.; Papandreou, M.-J.; Henriques, R.; Leterrier, C.","Christophe Leterrier","Aix Marseille Université, CNRS, INP UMR7051, NeuroCyto, Marseille, France","2025-09-17","1","new results","cc_by_nc","cell biology","https://www.biorxiv.org/content/early/2025/09/17/2025.09.17.676728.source.xml","Neuronal communication relies on signaling molecules transferred via exo- and endocytosis throughout the brain. Historically, studies have focused on vesicle exo- and endocytosis and their release machinery at synapses, and much less is known about non-synaptic exocytosis. If and how vesicles can access the plasma membrane along the axonal shaft, overcoming the insulating layer of the membrane-associated periodic scaffold, remains unclear. Here, we used fast live-cell imaging of mature cultured hippocampal neurons expressing the vamp2-pHluorin reporter to map sponta-neous exocytosis along axons. We detected non-synaptic exocytic events along the axon shaft that concentrated at the axon initial segment. Perturbation of the membrane-associated actin-spectrin skeleton revealed its role in regulating shaft exocytosis, similarly to its recently demonstrated role in shaping axonal endocytosis. To visualize the nanoscale arrangement of exocytic locations, we developed a novel correlative live-cell/two - color, single-molecule localization microscopy (SMLM) approach. We observed that regions of exocytosis are devoid of the submembrane spectrin mesh, with these spectrin-free areas being spatially separated from the spectrin clearings that contain clathrin-coated pits. Overall, our work reveals a new process of spontaneous exocytosis along the axon shaft, and how the axonal submem-brane skeleton shapes a heterogeneous landscape that uniquely segregates vesicular trafficking events.","[{""name"":""Agence Nationale de la Recherche"",""id"":""https://ror.org/00rbzpz17"",""id-type"":""ROR"",""award"":""ANR-20-CE13-0024;ANR-21-CE42-0015;ANR-20-CE16-0021;""},{""name"":""Fondation pour la Recherche Médicale"",""id"":"""",""id-type"":""ROR"",""award"":""EQ202103012966;""},{""name"":""Fédération pour la Recherche sur le Cerveau"",""id"":"""",""id-type"":""ROR"",""award"":""AOE 16 “Espoir en tête” 2021;""},{""name"":""CPER-FEDER"",""id"":"""",""id-type"":""ROR"",""award"":""PA0014842;""},{""name"":""AMIDEX"",""id"":"""",""id-type"":""ROR"",""award"":""AMX-19-IET-002;""},{""name"":""European Research Council"",""id"":""https://ror.org/0472cxd90"",""id-type"":""ROR"",""award"":""101001332;""},{""name"":""European Innovation Council"",""id"":""https://ror.org/05cx8cy07"",""id-type"":""ROR"",""award"":""Pathfinder Open;""},{""name"":""European Molecular Biology Organization"",""id"":""https://ror.org/04wfr2810"",""id-type"":""ROR"",""award"":""EMBO-2020-IG-4734;""},{""name"":""Chan Zuckerberg Initiative (United States)"",""id"":""https://ror.org/02qenvm24"",""id-type"":""ROR"",""award"":""EOSS6-0000000260;""}]","NA","bioRxiv",1761862207168
"Large-scale single-cell phylogenetic mapping of clonal evolution in the human aging esophagus","10.1101/2025.10.11.681805","biorxiv",60.550000000000004,0.85,0.85,2.1,60.550000000000004,"Prieto, T.; Yuan, D. J.; Zinno, J.; Hughes, C.; Midler, N.; Kao, S.; Huuhtanen, J.; Raviram, R.; Fotopoulou, F.; Ruthen, N.; Rajagopalan, S.; Schiffman, J. S.; D Avino, A. R.; Yoon, S.-H.; Sotelo, J.; Omans, N. D.; Wheeler, N.; Garces, A.; Pradhan, B.; Cheng, A. P.; Robine, N.; Potenski, C.; Godfrey, K.; Kakiuchi, N.; Yokoyama, A.; Ogawa, S.; Abrams, J.; Raimondi, I.; Landau, D. A.","Dan A Landau","New York Genome Center, New York, New York, United States","2025-10-13","1","new results","cc_by_nc_nd","genomics","https://www.biorxiv.org/content/early/2025/10/13/2025.10.11.681805.source.xml","The human somatic genome evolves throughout our lifespan, producing mosaic individuals comprising clones harboring different mutations across tissues. While clonal expansions in the hematopoietic system have been extensively characterized and reported to be nearly ubiquitous, clonal mosaicism (CM) has more recently also been described across multiple solid tissues. However, outstanding questions remain about the parameters and processes of human somatic evolution in non-cancerous solid human tissues, including when clones arise, how they evolve over time, and what mechanisms lead to their expansion. Questions of timing and clonal dynamics can be addressed through phylogenetic reconstruction, which serves as a  temporal microscope, while uncovering the mechanisms of expansion necessitates simultaneous phenotypic profiling. To address this gap, here we develop Single-cell Miniaturized Automated Reverse Transcription and Primary Template-directed Amplification (SMART-PTA) for joint single-cell whole-genome and whole-transcriptome sequencing for large scale and cost efficient interrogation of solid tissue CM. We established a workflow that generates hundreds of matched single-cell whole genome and transcriptome libraries within a week. We profiled phenotypically normal esophagus tissue from four aged donors and used somatic variants to build high-resolution single-cell lineages from >2,700 cells with accompanying transcriptomic information, reconstructing >70 years of somatic evolution. T cell expansions identified from T cell receptor (TCR) sequences validated the clonal structure of the single-nucleotide variant (SNV)-based phylogenies and phylogenetic cross-correlation analysis showed that epithelial cells had higher degrees of shared ancestry by spatial location compared to immune cells. Mapping mutation signatures to the phylogenetic tree revealed the emergence of tobacco/alcohol exposure-related signatures later in life, consistent with the donors exposure histories. We identified variants in driver genes that were previously reported in the phenotypically normal esophagus, detecting clonal expansions harboring mutations in genes including TP53 and FAT1. We mapped the evolution of clones with both monoallelic as well as biallelic TP53 loss, including a clone associated with high expression of cell cycling genes and higher chromosome instability. Leveraging the matched transcriptome data, we uncovered cell type biases in mutant clones, with a higher proportion of TP53 or FAT1-mutant cells in an earlier basal epithelial cell state compared to wild-type cells. We further observed copy-neutral loss of heterozygosity (CNLOH) events on chromosome 9q that spanned the NOTCH1 locus in up to [~]35% of epithelial cells. Mapping CNLOH events to the phylogenetic tree revealed a striking pattern in which CNLOH was separately acquired many times, reflecting convergent evolution. Cells with CNLOH events were biased towards the earlier basal epithelial state, suggestive of a selective advantage that leads to prevalent recurrence of chr9q CNLOH. Together, we demonstrate that SMART-PTA is an efficient, scalable approach for single-cell whole-genome and whole-transcriptome profiling to build phenotypically annotated single-cell phylogenies with enough throughput and power for application to normal tissue somatic evolution. Moreover, we reconstruct the evolutionary history of the esophageal epithelium at high scale and resolution, providing a window into the dynamics and processes that shape clonal expansions in phenotypically normal tissues throughout a lifespan.","[{""name"":""NIH Common Fund"",""id"":""https://ror.org/001d55x84"",""id-type"":""ROR"",""award"":""UG3NS132139;""},{""name"":""National Cancer Institute"",""id"":""https://ror.org/040gcmg81"",""id-type"":""ROR"",""award"":""R33 CA267219;""},{""name"":""NIDDK"",""id"":"""",""id-type"":""ROR"",""award"":""P30 DK132710;""},{""name"":""National Human Genome Research Institute"",""id"":""https://ror.org/00baak391"",""id-type"":""ROR"",""award"":""RM1HG011014;""},{""name"":""Burroughs Wellcome Fund"",""id"":""https://ror.org/01d35cw23"",""id-type"":""ROR"",""award"":""Career Award for Medical Scientists;""},{""name"":""Vallee Foundation"",""id"":""https://ror.org/05nmp3276"",""id-type"":""ROR"",""award"":""Scholar Award;""},{""name"":""Blood Cancer United"",""id"":"""",""id-type"":""ROR"",""award"":""""},{""name"":""The Mark Foundation for Cancer Research"",""id"":""https://ror.org/00v7th354"",""id-type"":""ROR"",""award"":""""},{""name"":""MacMillan Family Foundation"",""id"":"""",""id-type"":""ROR"",""award"":""""}]","NA","bioRxiv",1761862207168
"Mixture models for domain-adaptive brain decoding","10.1101/2025.10.05.680511","biorxiv",59.550000000000026,0,0,0.5,59.550000000000026,"Dempster, A.; Laschowski, B.","Brokoslaw Laschowski","University of Toronto","2025-10-06","1","new results","cc_by","neuroscience","https://www.biorxiv.org/content/early/2025/10/06/2025.10.05.680511.source.xml","A grand challenge in brain decoding is to develop algorithms that generalize across multiple subjects and tasks. Here, we developed a new computational framework to minimize negative transfer for domain-adaptive brain decoding by reframing source selection as a mixture model parameter estimation problem, allowing each source subject to contribute through a continuous mixture weight rather than being outright included or excluded. To compute these weights, we developed a novel convex optimization algorithm based on the Generalized Method of Moments. By using model performance metrics as the generalized moment functions in our GMM optimization, our algorithm also provides theoretical guarantees that the mixture weights are an optimal approximation of the importance weights that underlie domain adaptation theory. When tested on a large-scale brain decoding dataset (n=105 subjects), our new mixture model weighting framework achieved state-of-the-art performance--increasing accuracy up to 2.5% over baseline fine-tuning, double the performance gain compared to previous research in supervised source selection. Notably, these improvements were achieved using significantly less training data (i.e., 62% smaller effective sample sizes), suggesting that our performance gains stem from reduced negative transfer. Collectively, this research advances toward a more principled and generalizable brain decoding framework, laying the mathematical foundation for scalable brain-computer interfaces and other applications in computational neuroscience.","[{""name"":""Schroeder Institute for Brain Innovation and Recovery"",""id"":"""",""id-type"":""ROR"",""award"":""""}]","NA","bioRxiv",1761862207168
"Multiplex design and discovery of proximity handles for programmable proteome editing","10.1101/2025.10.13.681693","biorxiv",54.35000000000001,0,0.5,0.5,54.35000000000001,"Suiter, C. C.; Ahn, G.; Chiu, M.; Fu, Y.; Sadre, S.; Simon, J. J.; Lee, D. S.; Fowler, D. M.; Maly, D. J.; Baker, D.; Shendure, J.","Jay Shendure","University of Washington","2025-10-13","1","new results","cc_by","synthetic biology","https://www.biorxiv.org/content/early/2025/10/13/2025.10.13.681693.source.xml","Although we now have a rich toolset for genome editing, an equivalent framework for manipulating the proteome with a comparable flexibility and specificity remains elusive. A promising strategy for ""proteome editing"" is to use bifunctional molecules (e.g. PROteolysis-Targeting Chimeras or PROTACs1) that bring a target protein into proximity with a degradation or stabilization effector, but their broader application is constrained by a limited repertoire of well-characterized target or effector ""handles"". We asked whether coupling de novo protein design to a multiplex screening framework could address this gap by accelerating the discovery of effector handles for intracellular protein degradation, stabilization, or relocalization. Using LABEL-seq2, a sequencing-based assay that enables multiplex, quantitative measurement of protein abundance, we screened 9,715 de novo designed candidate effector handles for their ability to recruit a target protein to components of the ubiquitin-proteasome system3 (UPS) (FBXL12, TRAF2, UCHL1, USP38) or the autophagy pathway4 (GABARAP, GABARAPL2, MAP1LC3A). In a single experiment, we discovered hundreds of de novo designed effector handles that reproducibly drove either intracellular degradation (n = 277) or stabilization (n = 204) of a reporter protein. Validation of a subset of these hits in an orthogonal assay confirmed that sequencing-based measurements from the primary screen reliably reflected changes in intracellular abundance of the target protein. Successful effector handles were discovered for both the UPS (n = 194) and autophagy (n = 287) pathways, which provide complementary routes for programmable proteome editing. Autophagy-recruiting effector handles generalized to endogenous targets, as substituting the reporter-specific target handle with a high-affinity MCL1 binder5 reduced endogenous levels of this intracellular oncoprotein6. Moreover, directing autophagy-recruiting effector handles to the outer mitochondrial membrane dramatically perturbed mitochondrial networks in a manner consistent with synthetic tethering and sequestration7,8. Beyond generating a diverse repertoire of protein abundance or localization effector handles, our results establish a scalable, low-cost platform that links deep learning-guided protein design to functional cellular readouts, and chart a course toward a general framework for programmable proteome editing.","[{""name"":""National Heart Lung and Blood Institute"",""id"":""https://ror.org/012pb6c26"",""id-type"":""ROR"",""award"":""F31HL168982;""},{""name"":""National Institute of General Medical Sciences"",""id"":""https://ror.org/04q48ey07"",""id-type"":""ROR"",""award"":""T32GM136534;""},{""name"":""Gates Foundation"",""id"":""https://ror.org/0456r8d26"",""id-type"":""ROR"",""award"":""INV-043758;""},{""name"":""National Human Genome Research Institute"",""id"":""https://ror.org/00baak391"",""id-type"":""ROR"",""award"":""R01HG010632;""},{""name"":""Howard Hughes Medical Institute"",""id"":""https://ror.org/006w34k90"",""id-type"":""ROR"",""award"":""""}]","NA","bioRxiv",1761862207168
"3D multi-omic mapping of whole nondiseased human fallopian tubes at cellular resolution reveals a large incidence of ovarian cancer precursors","10.1101/2025.09.21.677628","biorxiv",94.65000000000005,0,0,0,42.150000000000006,"Forjaz, A.; Queiroga, V.; Li, Y.; Hernandez, A.; Crawford, A.; Qin, X.; Zhong, M.; Tsapatsis, M.; Joshi, S.; Kramer, D.; Nizet, O.; Bea, H.; Li, Y.; Qin, S.; O Flynn, R.; Yang, M.; Pratt, B.; Wu, F.; Gensbigler, P.; Blecher, M.; Wu, P.-H.; Kagohara, L. T.; Shih, I. M.; Zwicker, D.; Atkinson, M. A.; Shi, L.; Fan, R.; Kiemen, A. L.; Wirtz, D.","Denis Wirtz","Johns Hopkins University","2025-09-21","1","new results","cc_by_nd","bioinformatics","https://www.biorxiv.org/content/early/2025/09/21/2025.09.21.677628.source.xml","Uncovering the spatial and molecular landscape of precancerous lesions is essential for developing meaningful cancer prevention and early detection strategies. High-Grade Serous Carcinoma (HGSC), the most lethal gynecologic malignancy, often originates from Serous Tubal Intraepithelial Carcinomas (STICs) in the fallopian tubes, yet their minute size and our historical reliance on standard 2D histology contribute to their underreporting. Here, we present a spatially resolved, multi-omics framework that integrates whole-organ 3D imaging at cellular resolution with targeted proteomic, metabolomic, and transcriptomic profiling to detect and characterize microscopic tubal lesions. Using this platform, we identified a total of 99 STICs and their presumed precursors that harbor TP53 mutations in morphologically unremarkable tubal epithelium in all five specimens obtained from cancer-free organ donors with average-risk of developing ovarian cancer. Although these lesions comprised only 0.2% of the epithelial compartment, they displayed geographic diversity, immune exclusion, metabolic rewiring, and DNA copy number changes among lesions and normal fallopian tube epithelium discovered alterations in STIC-associated genes and the pathways they control. In sum, this platform provides a comprehensive 3D atlas of early neoplastic transformation, yielding mechanistic insights into tumor initiation and informing clinical screening strategies for detecting cancer precursors in whole organs at cellular resolution.","[{""name"":""nih"",""id"":"""",""id-type"":""ROR"",""award"":""U54CA268083;RO1CA300052;UG3CA275681;P50CA228991;R01GM149976;U01AI167892;5R01NS111039;R21NS125395;U54 HL165443;U54 DK 134301;R01 HL170107;U2CCA271891;""},{""name"":""Sloan research fellow award, a CZI Scialog award, and UCSD Startup funds"",""id"":"""",""id-type"":""ROR"",""award"":""""},{""name"":""the Johns Hopkins University and Instituto Superior Técnico student exchange program (HOPTEC and FLAD)"",""id"":"""",""id-type"":""ROR"",""award"":""""},{""name"":""the Richard W. TeLinde Endowment at Johns Hopkins University"",""id"":"""",""id-type"":""ROR"",""award"":""""},{""name"":""nPOD, a collaborative project supported by Breakthrough T1D and The Leona M. & Harry B. Helmsley Charitable Trust"",""id"":"""",""id-type"":""ROR"",""award"":""3-SRA-2023-1417-S-B;""}]","NA","bioRxiv",1761862207168
"mBER: Controllable de novo antibody design with million-scale experimental screening","10.1101/2025.09.26.678877","biorxiv",43.30000000000001,0,0,0,41.80000000000001,"Swanson, E.; Nichols, M.; Ravichandran, S.; Ogden, P.","Pierce Ogden","Manifold Bio","2025-09-28","1","new results","cc_no","synthetic biology","https://www.biorxiv.org/content/early/2025/09/28/2025.09.26.678877.source.xml","AO_SCPLOWBSTRACTC_SCPLOWRecent machine learning approaches have achieved high success rates in designing protein binders that demonstrate in vitro binding to their targets. While open models for unconstrained ""minibinder"" design have shown great experimental promise, methods for designing binders in specific formats, such as antibodies, have lagged behind in experimental success rates. In this work, we present mBER, an open-source protein binder design system capable of designing antibody-format binders with state-of-the-art experimental success rates. mBER builds on the ColabDesign framework, achieving successful antibody design primarily through the inclusion of informative sequence and structure conditioning information. Using mBER, we designed two libraries comprising over 1 million VHH binders against 436 diverse targets. We experimentally screened the two libraries against 145 of these targets, resulting in a dataset of over 100 million binding interactions. We achieved specific and significant design success against 45% of targets. In a filtered set of designs, we detect binding rates to specific epitopes as high as 38%. Through mBER, we demonstrate that format-specific binder design is possible with no additional training of underlying folding and language models. This work represents the largest reported de novo protein design and validation campaign, and one of the first open-source methods to demonstrate double-digit percentage experimental success rates for antibody binder design.","NA","NA","bioRxiv",1761862207168
"Chemotherapy accelerated bone ageing is reversed by NMN","10.1101/2025.10.13.679926","biorxiv",41.45000000000002,0,0,0,41.45000000000002,"Marinova, M. B.; Madawala, R.; Ho, W.-H. J.; Lovric, V.; Bertoldo, M. J.; Oliver, R. A.; Maniam, J.; Morris, M. J.; Sinclair, D. A.; Homer, H. A.; Walters, K. A.; Erlich, J. H.; Walsh, W. R.; Gilchrist, R. B.; Wu, L. E.","Lindsay E. Wu","School of Biomedical Sciences, UNSW Sydney, NSW 2052, Australia","2025-10-14","1","new results","cc_by_nc_nd","physiology","https://www.biorxiv.org/content/early/2025/10/14/2025.10.13.679926.source.xml","Cancer patients face an array of long-term chronic diseases and accelerated biological ageing, due largely to the off-target effects of broadly cytotoxic chemotherapy drugs. This is especially a problem in children, where cancer survivors experience a subsequent high risk of bone mineral deficits and fractures, normally seen in the older population. Here, we model this to show that early-life treatment with a single dose of the commonly used chemotherapy cisplatin profoundly impairs late-life bone health, and that these bone deficits are completely resolved through treatment with the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide mononucleotide (NMN). While we had previously shown that this same strategy protects against chemotherapy induced female infertility, this maintenance of aged bone health appears to be unrelated to endocrine changes due to protection of the ovarian reserve. Rather, this is driven by altered phosphorus homeostasis and protection against renal damage, which otherwise increases parathyroid hormone secretion to mobilise calcium stores from bone. Overall, this work highlights a new approach for maintaining healthy bone ageing in cancer survivors.","[{""name"":""American Federation for Aging Research"",""id"":""https://ror.org/000r61a05"",""id-type"":""ROR"",""award"":""Hevolution/AFAR New Investigator Award in Aging Biology;""},{""name"":""National Health and Medical Research Council"",""id"":""https://ror.org/011kf5r70"",""id-type"":""ROR"",""award"":""APP1139763;APP1127821;APP2009940;""}]","NA","bioRxiv",1761862207168
"Phages communicate across species to shape microbial ecosystems","10.1101/2025.10.13.681337","biorxiv",40.95000000000002,0,0,0,40.95000000000002,"Gallego-del-Sol, F.; Sin, D.; Chmielowska, C.; Mancheno-Bonillo, J.; Li, Y.; Zamora-Caballero, S.; Quiles-Puchalt, N.; Penades, J.; Marina, A.","Alberto Marina","Instituto de Biomedicina de Valencia (IBV)-CSIC and CIBER de Enfermedades Raras (CIBERER)-ISCIII, 46010 Valencia, Spain","2025-10-14","2","new results","cc_no","microbiology","https://www.biorxiv.org/content/early/2025/10/14/2025.10.13.681337.source.xml","Arbitrium is a communication system that helps bacteriophages decide between lysis and lysogeny via secreted peptides. In arbitrium, the AimP peptide binds its cognate AimR receptor to repress aimX expression, promoting lysogeny. It has been assumed that each AimR responds exclusively to its own AimP. Here, we question this view by demonstrating cross-communication between distinct arbitrium systems. Using prototypical arbitrium phages, we demonstrate that AimP peptides bind and repress unrelated AimR receptors, promoting lysogeny and reducing prophage induction. Structural and binding assays reveal conserved residues enabling cross-recognition while preserving specificity. In mixed lysogenic cultures, these interactions shape induction outcomes, demonstrating ecological relevance. We extent these findings to infection contexts, showing that arbitrium signalling influences outcomes in cells harbouring prophages with compatible communicating systems. These findings reveal that phages engage in cross-species communication, a trait restricted to more complex life forms, challenging our understanding of how these elements reshape microbial communities.","[{""name"":""Spanish Government (Ministerio de Ciencia e Innovación)"",""id"":"""",""id-type"":""ROR"",""award"":""PID2022-137201NB-I00;""},{""name"":""Valencian Government"",""id"":"""",""id-type"":""ROR"",""award"":""CIPROM/2023/30;""},{""name"":""European Commission NextGenerationEU fund"",""id"":"""",""id-type"":""ROR"",""award"":""(EU 2020/2094);""},{""name"":""European Research Council grant"",""id"":"""",""id-type"":""ROR"",""award"":""101118890 (TalkingPhages);""},{""name"":""Medical Research Council (UK)"",""id"":"""",""id-type"":""ROR"",""award"":""MR/X020223/1;MR/M003876/1;MR/V000772/1;""},{""name"":""Biotechnology and Biological Sciences Research Council (BBSRC, UK)"",""id"":"""",""id-type"":""ROR"",""award"":""BB/V002376/1;BB/V009583/1;""},{""name"":""Engineering and Physical Sciences Research Council (EPSRC, UK)"",""id"":"""",""id-type"":""ROR"",""award"":""EP/X026671/1;""}]","NA","bioRxiv",1761862207168
"Oxidative stress sensing by the translation elongation machinery promotes production of detoxifying selenoproteins","10.1101/2025.10.13.682107","biorxiv",39.75000000000001,0,0,0,39.75000000000001,"Rehfeld, F.; Lundstrom, C.; Zhang, H.; Mendell, J. T.","Joshua T Mendell","HHMI and UT Southwestern Medical Center","2025-10-13","1","new results","cc_by","molecular biology","https://www.biorxiv.org/content/early/2025/10/13/2025.10.13.682107.source.xml","Selenocysteine, incorporated into polypeptides at recoded termination codons, plays an essential role in redox biology. Using GPX1 and GPX4, selenoenzymes that mitigate oxidative stress, as reporters, we performed genome-wide knockout screens to identify regulators of selenocysteine incorporation. This revealed that selenoprotein production is limited by ribosome collisions that occur at inefficiently decoded selenocysteine codons. Accordingly, slowed translation elongation reduced collisions and enhanced selenocysteine decoding. Oxidative stress also slowed translation elongation and augmented selenoprotein production. We identified translation elongation factor EEF1G as a sensor of oxidized glutathione that couples the cellular redox state to translation elongation rate. Oxidative stress sensing by EEF1G slows translation, enhancing production of detoxifying selenoproteins to restore homeostasis. These findings reveal how programmed ribosome collisions enable gene regulation in response to stress.","[{""name"":""National Institutes of Health"",""id"":""https://ror.org/01cwqze88"",""id-type"":""ROR"",""award"":""R01CA282036;U01CA305105;S10OD030312-01;""},{""name"":""Welch Foundation"",""id"":""https://ror.org/00np6vq88"",""id-type"":""ROR"",""award"":""I-1961;""},{""name"":""Cancer Prevention and Research Institute of Texas"",""id"":""https://ror.org/0003xa228"",""id-type"":""ROR"",""award"":""RP220309;""},{""name"":""Howard Hughes Medical Institute"",""id"":""https://ror.org/006w34k90"",""id-type"":""ROR"",""award"":""""}]","NA","bioRxiv",1761862207168
"Ecological constraints foster both extreme viral-host lineage stability and mobile element diversity in a marine community","10.1101/2025.10.10.681744","biorxiv",39.15000000000003,0,0,0,39.15000000000003,"Liang, J.; Cahier, K.; Piel, D.; Cueva Granda, D.; Goudenege, D.; Labreuche, Y.; Ma, L.; Monot, M.; Bernard, C.; Rocha, E. P.; Le Roux, F.","Frederique Le Roux","University of Montreal","2025-10-11","1","new results","cc_by_nc_nd","microbiology","https://www.biorxiv.org/content/early/2025/10/11/2025.10.10.681744.source.xml","Phages are typically viewed as very rapidly evolving biological entities. Little is known, however, about whether and how phages can establish long-term genetic stability. We addressed this eco-evolutionary question in an open marine animal associated system, through two longitudinal samplings years apart in an oyster farm, obtaining >1,000 virulent phages and >600 Vibrio crassostreae strains. Surprisingly, lineages of phage and bacteria were very persistent, with some phages remaining strictly identical after four years. The phage-vibrio infection network remained modular with multiple lineages co-habitating within individual oysters for long periods of time. Seasonal restriction of V. crassostreae, overwintering in wild oysters, and limited viral decay may explain phage stability. Oysters also act as hotspots of activity of diverse mobile genetic element (MGE), hosting plasmids, prophages, phage-plasmids and entirely new classes of satellite-plasmids. Our findings demonstrate how nested ecological constraints can stabilize viral lineages: oysters house vibrio populations that escape host immunity, vibrios restrict phages via receptors and defenses, and satellites parasitize their cognate helper phages. We suggest that ecological context can favor the long-term maintenance of viral lineages and stabilize MGE persistence in the ocean, even amid ongoing mutation and antagonistic co-evolution.","[{""name"":""European Research Council"",""id"":""https://ror.org/0472cxd90"",""id-type"":""ROR"",""award"":""884988;""},{""name"":""Canada Excellence Research Chairs"",""id"":""https://ror.org/02tvrwm90"",""id-type"":""ROR"",""award"":""2022-00051;""},{""name"":""FRQ-NT, Fonds des leaders John-R.-Evans"",""id"":"""",""id-type"":""ROR"",""award"":""44584;""},{""name"":""ANR"",""id"":"""",""id-type"":""ROR"",""award"":""20-CE35-0014;""}]","NA","bioRxiv",1761862207168
"The functional landscape of the human ubiquitinome","10.1101/2025.10.08.681129","biorxiv",36.05000000000002,0,0,0,36.05000000000002,"van Gerwen, J.; Fottner, M.; Wang, S.; Busby, B.; Boswell, E.; Schnacke, P.; Carrano, A. C.; Bakowski, M. A.; Troemel, E. R.; Studer, R.; Strumillo, M.; Martin, M.-J.; Harper, J. W.; Lang, K.; Jones, A. R.; Bennett, E. J.; Vizcaino, J. A.; Barrio-Hernandez, I.; Beltrao, P.","Pedro Beltrao","ETH Zurich","2025-10-08","1","new results","cc_by","cell biology","https://www.biorxiv.org/content/early/2025/10/08/2025.10.08.681129.source.xml","Protein ubiquitination regulates cell biology through diverse avenues, from quality control-linked protein degradation to signaling functions such as modulating protein-protein interactions and enzyme activation. Mass spectrometry-based proteomics has allowed proteome-scale quantification of hundreds of thousands of ubiquitination sites (ubi-sites), however the functional importance and regulatory roles of most ubi-sites remain undefined. Here, we assembled a human reference ubiquitinome of 108,341 ubi-sites by harmonizing public proteomics data. We identified a core subset of ubi-sites under evolutionary constraint through alignment of ubiquitin proteomics data from six non-human species, and determined ultra-conserved ubi-sites recurring at regulatory hotspots within protein domains. Perturbation proteomics revealed that these highly conserved ubi-sites are more likely to regulate signaling functions rather than proteasomal degradation. To further prioritize functional ubi-sites with roles in cellular signaling, we constructed a functional score for more than 100,000 ubi-sites by integrating evolutionary, proteomic, and structural features using machine learning. Our score identifies ubi-sites regulating diverse protein functions and rationalizes mechanisms of genetic disease. Finally, we employed chemical genomics to validate the functional relevance of high-scoring ubi-sites and leveraged genetic code expansion to demonstrate that ubiquitination of K320 in the RNA-regulator ELAVL1 disrupts RNA binding. Our work reveals systems-level principles of the ubiquitinome and provides a powerful resource for studying protein ubiquitination.","NA","NA","bioRxiv",1761862207168
"De novo design of RNA and nucleoprotein complexes","10.1101/2025.10.01.679929","biorxiv",35.55000000000001,0,0,0,35.55000000000001,"Favor, A. H.; Quijano, R.; Chernova, E.; Kubaney, A.; Weidle, C.; Esler, M. A.; McHugh, L.; Carr, A.; Hsia, Y.; Juergens, D.; Carr, K. D.; Kim, P. T.; Politanska, Y.; Sehgal, E.; Kwon, P. S.; Pecoraro, R. J.; Glasscock, C.; Borst, A. J.; DiMaio, F.; Stoddard, B. L.; Baker, D.","David Baker","University of Washington","2025-10-02","1","new results","cc_by","biochemistry","https://www.biorxiv.org/content/early/2025/10/02/2025.10.01.679929.source.xml","Nucleic acids fold into sequence-dependent tertiary structures and carry out diverse biological functions, much like proteins. However, while considerable advances have been made in the de novo design of protein structure and function, the same has not yet been achieved for RNA tertiary structures of similar intricacy. Here, we describe a generative diffusion framework, RFDpoly, for generalized de novo biopolymer (RNA, DNA and protein) design, and use it to create diverse and designable RNA structures. We design RNA structures with novel folds and experimentally validate them using a combination of chemical footprinting (SHAPE-seq) and electron microscopy. We further use this approach to design protein-nucleic acid assemblies; the crystal structure of one such design is nearly identical to the design model. This work demonstrates that the principles of structure-based de novo protein design can be extended to nucleic acids, opening the door to creating a wide range of new RNA structures and protein-nucleic acid complexes.","NA","NA","bioRxiv",1761862207168
"Functional independence of entorhinal grid cell modules enables remapping in hippocampal place cells","10.1101/2025.09.24.677985","biorxiv",35.200000000000024,0,0,0,35.200000000000024,"Lykken, C. M.; Kanter, B. R.; Nagelhus, A.; Carpenter, J.; Guardamagna, M.; Moser, E. I.; Moser, M.-B.","Edvard I Moser","Kavli Institute for Systems Neuroscience and Centre for Algorithms in the Cortex, Norwegian University of Science and Technology; Trondheim, Norway","2025-09-24","1","new results","cc_by_nc_nd","neuroscience","https://www.biorxiv.org/content/early/2025/09/24/2025.09.24.677985.source.xml","A systems-level understanding of cortical computation requires insight into how neural codes are transformed across distinct brain circuits. In the mammalian cortex, one of the few systems where such transformations are tractable is the spatial mapping circuit. This circuit comprises interconnected regions of medial entorhinal cortex (MEC) and hippocampus, which encode location using fundamentally different neural codes. A key distinction is that neural activity in MEC, including that of directionally tuned cells and grid cells, evolves along low-dimensional manifolds, preserving stable phase relationships across different environments and behaviors1-8. In contrast, hippocampal place cells frequently undergo global remapping: their collective firing patterns reorganize randomly across different environments9-12, revealing an apparently limitless repertoire of orthogonal spatial representations12-14. The mechanisms by which spatial maps are transformed between the two coding schemes remain unresolved. Here, we used large-scale multi-area Neuropixels recordings to show that when rats were transferred from one familiar environment to another, each module of grid cells underwent a unique change in phase on its low-dimensional manifold, at the same time as simultaneously recorded place cells exhibited global remapping. In contrast, training conditions that produced smaller differences in the phase shifts of simultaneously recorded grid modules resulted in incomplete place cell remapping, mirroring previous reports of  partial remapping15-19. Hippocampal remapping was not associated with rotational differences between grid modules under any condition. Taken together, these findings suggest that differential phase shifts across grid cell modules form the basis for the orthogonalization of downstream hippocampal spatial codes during remapping. The transformation from low-dimensional spatial representations in the MEC to high-dimensional codes in the hippocampus may underlie the hippocampus ability to support high-capacity memory storage3,13,14,20-22.","[{""name"":""European Research Council"",""id"":""https://ror.org/0472cxd90"",""id-type"":""ROR"",""award"":""951319;""},{""name"":""The Research Council of Norway"",""id"":""https://ror.org/00epmv149"",""id-type"":""ROR"",""award"":""223262;332640;295721;""},{""name"":""The Kavli Foundation"",""id"":""https://ror.org/00kztt736"",""id-type"":""ROR"",""award"":""""},{""name"":""Ministry of Education and Research"",""id"":""https://ror.org/051aqjh92"",""id-type"":""ROR"",""award"":""""}]","NA","bioRxiv",1761862207168
"Non-photosynthetic Plastid Replacement by a Primary Plastid in the Making","10.1101/2025.10.07.680570","biorxiv",34.25000000000002,0,0,0,34.25000000000002,"Phua, Y. H.; Langlet, D.; Humbel, B. M.; Hagenbeek, A.; Vaskivskyi, V.; Wakeman, K.; Husnik, F.","Filip Husnik","Okinawa Institute of Science and Technology Graduate University","2025-10-08","1","new results","cc_by_nc_nd","evolutionary biology","https://www.biorxiv.org/content/early/2025/10/08/2025.10.07.680570.source.xml","The integration of a cyanobacterium into a heterotrophic eukaryote gave rise to the primary plastid [~]1.5 Gya. This rare cyanobacterium-to-plastid transition has only been reported once more in Paulinella chromatophora [~]100 Mya. Unfortunately, the order and relative importance of organellogenesis events have been blurred by time in primary plastids and obscured by P. chromatophora becoming phototrophic. Here, we characterize the tripartite symbiosis in a benthic dinoflagellate (Sinophysis sp.) using diverse single-cell methods. Sinophysis houses a photosynthetic cyanobacterium closely interacting with an alphaproteobacterial endosymbiont. The cyanobacterium is in the intermediate stage of symbiont-to-organelle transition, with the host likely supporting it with metabolites and proteins, and controlling its cell division. Surprisingly, it seems to have replaced the hosts remnant non-photosynthetic plastid. Our results support mixotrophy, horizontal gene transfer, co-symbioses, and cell division control as early drivers of primary plastid origin and highlight the importance of protists for deciphering organellogenesis events.","[{""name"":""Japan Society for the Promotion of Science"",""id"":""https://ror.org/00hhkn466"",""id-type"":""ROR"",""award"":""23K14256;23K05942;20K15856;""},{""name"":""Human Frontier Science Program"",""id"":"""",""id-type"":""ROR"",""award"":""RGEC29/2024;""}]","NA","bioRxiv",1761862207168
"Development of a non-invasive diagnostic method for pathogenic RNA viruses using sebum wiped from the cat's body surface","10.1101/2025.10.15.682697","biorxiv",32.70000000000002,0,0,0,32.70000000000002,"Fukushima, Y. V.; Saito, N.; Mekata, H.; Saito, A.","Akatsuki Saito","University of Miyazaki","2025-10-15","1","new results","cc_by","microbiology","https://www.biorxiv.org/content/early/2025/10/15/2025.10.15.682697.source.xml","The development of non-invasive diagnostic methods for zoonotic viral infections is increasingly important for both animal welfare and public health. Sebum-based diagnostic methods using commercial oil-blotting films have been applied to SARS-CoV-2 detection in humans, yet equivalent strategies for veterinary use remain largely unexplored. Severe fever with thrombocytopenia syndrome (SFTS), caused by the SFTS virus (SFTSV), presents a major health threat in Asia--especially in Japan, where multiple cases of cat-to-veterinarian transmission have been reported. To address the need for safer diagnostics, we sought to establish a sebum-based RNA virus detection method for cats. We designed primers that efficiently detected RNA from feline sebum while distinguishing it from human and feline DNA/RNA. Using this platform, we determined the ear to be the optimal sebum collection site and confirmed that feline immunodeficiency virus (FIV) RNA can be reliably identified from ear sebum with sensitivity comparable to conventional blood-based testing. In addition, we detected SFTSV RNA from sebum samples of infected cat. Our findings introduce a minimally invasive, safe diagnostic platform for feline viral infections, reducing animal distress while safeguarding veterinarians and pet owners from zoonotic risks. This strategy marks an important step toward realizing the One Health framework by advancing the well-being of both animals and humans.","[{""name"":""Japan Agency for Medical Research and Development (AMED)"",""id"":"""",""id-type"":""ROR"",""award"":""""},{""name"":""Japan Society for the Promotion of Science"",""id"":""https://ror.org/00hhkn466"",""id-type"":""ROR"",""award"":""""},{""name"":""G-7 Grants"",""id"":"""",""id-type"":""ROR"",""award"":""""},{""name"":""Ito Foundation Research Grant"",""id"":"""",""id-type"":""ROR"",""award"":""""},{""name"":""Kao Corporation (Japan)"",""id"":""https://ror.org/016t1kc57"",""id-type"":""ROR"",""award"":""""}]","NA","bioRxiv",1761862207168
"The eukaryotic replisome intrinsically generates asymmetric daughter chromatin fibers","10.1101/2025.09.18.677126","biorxiv",32.65000000000002,0,0,0,32.65000000000002,"Eckhardt, B. V.; Richter, H. J.; Rondeel, I.; Renduchintala, K.; Mattiroli, F.; Ramani, V.","Francesca Mattiroli","Hubrecht Institute","2025-09-18","1","new results","cc_by_nc_nd","biochemistry","https://www.biorxiv.org/content/early/2025/09/18/2025.09.18.677126.source.xml","DNA replication is molecularly asymmetric, due to distinct mechanisms for lagging and leading strand DNA synthesis. Whether chromatin assembly on newly replicated strands is also asymmetric remains unknown, as visualizing this short-lived state in cells is impossible. To circumvent this limitation, we combine in vitro reconstitution of the Saccharomyces cerevisiae DNA and chromatin replication machineries with replication-aware single-molecule chromatin footprinting, to study how chromatin is re-assembled on replicated DNA. Leveraging the non-destructive, single-molecule, and strand-specific nature of our data, we discover an intrinsic asymmetry in nucleosome positioning patterns and organization between lagging- and leading-strand chromatin created by the yeast replisome. This asymmetry is only partially restored upon addition of chromatin assembly factors involved in de novo histone deposition and the ATP-dependent chromatin remodeler Isw1a, implying that other regulatory factors must resolve this asymmetry in cells. In sum, our data reveal the complexity of chromatin re-establishment following DNA replication, and suggest an asymmetric chromatin assembly intermediate on each daughter chromatid. These pathways have implications for essential chromatin-templated processes such as DNA repair, transcription, and gene silencing at replication forks.","[{""name"":""European Research Council"",""id"":""https://ror.org/0472cxd90"",""id-type"":""ROR"",""award"":""851564;""},{""name"":""Dutch Research Council"",""id"":""https://ror.org/04jsz6e67"",""id-type"":""ROR"",""award"":""VI.Vidi.233.038;""},{""name"":""National Institutes of Health"",""id"":""https://ror.org/01cwqze88"",""id-type"":""ROR"",""award"":""DP2-HG012442;""},{""name"":""W. M. Keck Foundation"",""id"":""https://ror.org/000dswa46"",""id-type"":""ROR"",""award"":""-;""},{""name"":""Searle Scholars Program"",""id"":"""",""id-type"":""ROR"",""award"":""-;""}]","NA","bioRxiv",1761862207168