{"messages":[{"status":"ok","category":"all","interval":"2025-04-10:2025-07-10","funder":"European Commission : https:\/\/ror.org\/00k4n6c32","cursor":"45","count":12,"count_new_papers":"40","total":"57"}], "collection":[{"title":"A mouse model of PTEN Hamartoma Tumour Syndrome reveals that loss of the nuclear function of PTEN drives macrocephaly, lymphoid overgrowth, and late-onset cancer","authors":"Tibarewal, P.; Rathbone, V.; Conduit, S.; Classen, G. A. E.; Black, F.; Danesh, M. A.; Constantinou, G.; Asgarian, Z.; Tohyama, K.; Nisha, N.; Alvarez Garcia, V.; Foxall, E.; Belarbi, D.; Leverve, M.; Pearce, W.; Adil, M.; Varyova, Z.; Conde, L.; Alves, A.; Masson, G.; Williams, R. L.; Flanagan, A. M.; Herrero, J.; Stroud, K.; Tischkowitz, M.; Lachlan, K.; Scott, M.; Leslie, N.; Kessaris, N.; Vanhaesebroeck, B.","author_corresponding":"Priyanka Tibarewal","author_corresponding_institution":"UCL Cancer Institute","doi":"10.1101\/2025.06.20.660297","date":"2025-06-25","version":"1","type":"new results","license":"cc_by","category":"genetics","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/06\/25\/2025.06.20.660297.source.xml","abstract":"PTEN Hamartoma Tumour Syndrome (PHTS) is a rare disorder characterized by germline heterozygous mutations in the PTEN tumour suppressor gene, leading to multi-organ\/tissue overgrowth, autism spectrum disorder and increased cancer risk. PHTS individuals display heterogeneity in phenotypes, which has been linked in part to the diverse genetic alterations in the PTEN gene and the multifaceted functions of this protein. Indeed, while PTEN primarily functions as a PIP3 lipid phosphatase in the cytosol, regulating PI3K\/AKT signalling, a pathway commonly deregulated in cancer, it also plays crucial roles in maintaining chromosomal stability through nuclear activities such as double strand (ds) DNA damage repair. Recent studies have identified a subset of missense PHTS variants that cause nuclear exclusion of PTEN, impairing its nuclear functions. Here, we present our findings from one such pathogenic variant, PTEN-R173C, frequently found in PHTS and somatic cancers. Using cell biological and mouse modelling approaches, we show that PTEN-R173C has higher PIP3 phosphatase activity than wild-type PTEN, resulting in effective regulation of canonical PI3K\/AKT signalling. However, PTEN-R173C is unstable and excluded from the nucleus. Aligning with their near normal PI3K\/AKT signalling, Pten+\/R173Cmice display a low incidence of solid tumours compared to Pten+\/-mice. Pten+\/R173C mice also exhibit lymphoid hyperplasia and macrocephaly which correlates with compromised nuclear functions of PTEN-R173C. That nuclear functions are compromised is demonstrated by reduced dsDNA damage repair in Pten+\/R173Cmice. Integrating PHTS patient data with findings from our mouse model, our study indicates that nuclear dysfunction of pathogenic PTEN variants is a key factor in predicting the onset of the different PHTS-associated phenotypes. We speculate that late-onset cancer in individuals with nuclear-excluded PTEN results from genetic alterations unrelated to PTEN itself, facilitated by impaired PTEN-mediated dsDNA damage repair.","funder":[{"name":"PTEN Research Foundation","id":"https:\/\/ror.org\/04b98dz04","id-type":"ROR","award":"UCL-16-001UCL-20-001UOC-17-001"},{"name":"Cancer Research UK","id":"https:\/\/ror.org\/054225q67","id-type":"ROR","award":"C416\/A29287CANTAC721\\100022C23338\/A25722C416\/A25145"},{"name":"European Commission","id":"https:\/\/ror.org\/00k4n6c32","id-type":"ROR","award":"H2020-MSCA-IF-2018 GA: 838559"},{"name":"Biotechnology and Biological Sciences Research Council","id":"https:\/\/ror.org\/00cwqg982","id-type":"ROR","award":"BB\/W007460\/1BB\/N009061\/1"},{"name":"Jean Shanks Foundation","id":"https:\/\/ror.org\/00wf6bs47","id-type":"ROR","award":""},{"name":"Fondation ARC pour la Recherche sur le Cancer","id":"https:\/\/ror.org\/0489qz649","id-type":"ROR","award":"ARCPJA2022060005118"},{"name":"La Ligue Contre le Cancer","id":"https:\/\/ror.org\/00rkrv905","id-type":"ROR","award":""},{"name":"Wellcome Trust","id":"https:\/\/ror.org\/029chgv08","id-type":"ROR","award":"108726\/Z\/15\/Z"},{"name":"NIHR Cambridge Biomedical Research Centre","id":"https:\/\/ror.org\/0","id-type":"ROR","award":"NIHR203312"},{"name":"Medical Research Council","id":"https:\/\/ror.org\/03x94j517","id-type":"ROR","award":"MC-A024-5PF91"}],"published":"10.1242\/dmm.052527","server":"bioRxiv"},{"title":"Gut microbial diversity and inferred capacity to produce butyrate modulate cortisol reactivity following acute stress in healthy adults","authors":"Karner, T.; Forbes, P. A. G.; Berry, D.; Wagner, I. C.","author_corresponding":"Isabella C. Wagner","author_corresponding_institution":"University of Vienna","doi":"10.1101\/2025.06.24.661294","date":"2025-06-25","version":"1","type":"new results","license":"cc_by","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/06\/25\/2025.06.24.661294.source.xml","abstract":"Acute stress triggers the release of stress hormones such as cortisol, increasing stress reactivity and aiding post-stress recovery. Rodent studies revealed that stress reactivity is modulated by the gut microbiota, and few interventional studies have provided evidence for an effect on human cortisol dynamics. However, it remains unclear whether stress reactivity is related to interindividual variations in gut microbial composition and to ones capacity to produce microbial metabolites such as short-chain fatty acids (SCFAs). To close this gap, we analyzed data from 74 healthy human adults who completed the study in the laboratory and were either exposed to a well-established, standardized intervention that induced acute stress or to a non-stressful control condition (n = 35\/39 per stress\/control group). Stool samples were obtained at baseline, and the gut microbiota were characterized through 16S rRNA gene amplicon sequencing. Cortisol changes were assessed from repeated saliva sampling, paralleled by measurements of subjectively experienced stress. We found that higher gut microbial alpha diversity was associated with higher cortisol and subjective stress reactivity across individuals of the stress group, but not in controls. Cortisol stress reactivity was also associated with the relative abundance of bacterial taxa inferred to encode metabolic pathways for the production of butyrate and propionate, two key SCFAs. The results are the first to highlight the link between gut microbial diversity, inferred SCFA production capacity, and the acute stress response in healthy adults, underscoring the microbiotas potential to flexibly modulate human psychophysiology in the aftermath of stress.","funder":[{"name":"FWF Austrian Science Fund","id":"https:\/\/ror.org\/013tf3c58","id-type":"ROR","award":"10.55776\/P3477510.55776\/COE710.55776\/FG29"},{"name":"Brain & Behavior Research Foundation","id":"https:\/\/ror.org\/03a63f080","id-type":"ROR","award":"31532"},{"name":"European Research Council","id":"https:\/\/ror.org\/0472cxd90","id-type":"ROR","award":"101164099"},{"name":"European Commission","id":"https:\/\/ror.org\/00k4n6c32","id-type":"ROR","award":"101107160"}],"published":"NA","server":"bioRxiv"},{"title":"Genetic mapping of lifespan and mitochondrial stress response in C. elegans","authors":"Li, X.; Li, W.; Gao, A. W.; Zhu, Y.; Katsyuba, E.; Overmyer, K. A.; Li, T.; Wang, Z.; Legon, L.; Plantade, L.; Mouchiroud, L.; Cornaglia, M.; Li, H.; Houtkooper, R.; Auwerx, J.","author_corresponding":"Johan Auwerx","author_corresponding_institution":"Laboratory of Integrative Systems Physiology, Ecole Polytechnique Federale de Lausanne","doi":"10.1101\/2025.06.26.661693","date":"2025-06-26","version":"1","type":"new results","license":"cc_by_nc","category":"genetics","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/06\/26\/2025.06.26.661693.source.xml","abstract":"The mitochondrial unfolded protein response (UPRmt) is one of the mito-nuclear regulatory circuits that restores mitochondrial function upon stress conditions, promoting metabolic health and longevity. However, the complex gene interactions that govern this pathway and its role in aging and healthspan remain to be fully elucidated. Here, we activated the UPRmt using doxycycline (Dox) in a genetically diverse C. elegans population comprising 85 strains and observed large variation in Dox-induced lifespan extension across these strains. Through multi-omic data integration, we identified an aging-related molecular signature that was partially reversed by Dox. To identify the mechanisms underlying Dox-induced lifespan extension, we applied quantitative trait locus (QTL) mapping analyses and found one UPRmt modulator, fipp-1\/FIP1L1, which was functionally validated in C. elegans and humans. In the human UK Biobank, FIP1L1 was associated with metabolic homeostasis, underscoring its translational relevance. Overall, our findings demonstrate a novel UPRmt modulator across species and provide insights into potential translational research.","funder":[{"name":"European Research Council","id":"https:\/\/ror.org\/0472cxd90","id-type":"ROR","award":"ERC-AdG-787702"},{"name":"Swiss National Science Foundation","id":"https:\/\/ror.org\/00yjd3n13","id-type":"ROR","award":"SNSF 31003A_179435Sinergia CRSII5_202302SNSF-IZLCZ0- 206069"},{"name":"GRL grant of the National Research Foundation of Korea","id":"","id-type":"ROR","award":"NRF 2017K1A1A2013124"},{"name":"National Institutes of Health","id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","award":"P41GM108538R35GM118110"},{"name":"United Mitochondrial Disease Foundation","id":"https:\/\/ror.org\/0528q0t18","id-type":"ROR","award":"PF-19-0232"},{"name":"European Commission","id":"https:\/\/ror.org\/00k4n6c32","id-type":"ROR","award":"101108082"},{"name":"International Human Frontier Science Program Organization","id":"https:\/\/ror.org\/02ebx7v45","id-type":"ROR","award":"LT000731\/2018-L"},{"name":"Velux Stiftung","id":"https:\/\/ror.org\/00kgf1c95","id-type":"ROR","award":"1063"},{"name":"the Netherlands Organisation for Scientific Research","id":"","id-type":"ROR","award":"91118006"},{"name":"National Natural Science Foundation of China","id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","award":"82300951"}],"published":"NA","server":"bioRxiv"},{"title":"A mouse model of PTEN Hamartoma Tumour Syndrome reveals that loss of the nuclear function of PTEN drives macrocephaly, lymphoid overgrowth, and late-onset cancer","authors":"Tibarewal, P.; Rathbone, V.; Conduit, S.; Classen, G. A. E.; Black, F.; Danesh, M. A.; Constantinou, G.; Asgarian, Z.; Tohyama, K.; Kriplani, N.; Alvarez Garcia, V.; Foxall, E.; Belarbi, D.; Leverve, M.; Pearce, W.; Adil, M.; Varyova, Z.; Conde, L.; Alves, A.; Masson, G.; Williams, R. L.; Flanagan, A. M.; Herrero, J.; Mohamed, I. A.; Stroud, K.; Tischkowitz, M.; Lachlan, K.; Scudamore, C.; Scott, M.; Leslie, N.; Kessaris, N.; Vanhaesebroeck, B.","author_corresponding":"Priyanka Tibarewal","author_corresponding_institution":"UCL Cancer Institute","doi":"10.1101\/2025.06.20.660297","date":"2025-06-27","version":"2","type":"new results","license":"cc_by","category":"genetics","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/06\/27\/2025.06.20.660297.source.xml","abstract":"PTEN Hamartoma Tumour Syndrome (PHTS) is a rare disorder characterized by germline heterozygous mutations in the PTEN tumour suppressor gene, leading to multi-organ\/tissue overgrowth, autism spectrum disorder and increased cancer risk. PHTS individuals display heterogeneity in phenotypes, which has been linked in part to the diverse genetic alterations in the PTEN gene and the multifaceted functions of this protein. Indeed, while PTEN primarily functions as a PIP3 lipid phosphatase in the cytosol, regulating PI3K\/AKT signalling, a pathway commonly deregulated in cancer, it also plays crucial roles in maintaining chromosomal stability through nuclear activities such as double strand (ds) DNA damage repair. Recent studies have identified a subset of missense PHTS variants that cause nuclear exclusion of PTEN, impairing its nuclear functions. Here, we present our findings from one such pathogenic variant, PTEN-R173C, frequently found in PHTS and somatic cancers. Using cell biological and mouse modelling approaches, we show that PTEN-R173C has higher PIP3 phosphatase activity than wild-type PTEN, resulting in effective regulation of canonical PI3K\/AKT signalling. However, PTEN-R173C is unstable and excluded from the nucleus. Aligning with their near normal PI3K\/AKT signalling, Pten+\/R173Cmice display a low incidence of solid tumours compared to Pten+\/-mice. Pten+\/R173C mice also exhibit lymphoid hyperplasia and macrocephaly which correlates with compromised nuclear functions of PTEN-R173C. That nuclear functions are compromised is demonstrated by reduced dsDNA damage repair in Pten+\/R173Cmice. Integrating PHTS patient data with findings from our mouse model, our study indicates that nuclear dysfunction of pathogenic PTEN variants is a key factor in predicting the onset of the different PHTS-associated phenotypes. We speculate that late-onset cancer in individuals with nuclear-excluded PTEN results from genetic alterations unrelated to PTEN itself, facilitated by impaired PTEN-mediated dsDNA damage repair.","funder":[{"name":"PTEN Research Foundation","id":"https:\/\/ror.org\/04b98dz04","id-type":"ROR","award":"UCL-16-001UCL-20-001UOC-17-001"},{"name":"Cancer Research UK","id":"https:\/\/ror.org\/054225q67","id-type":"ROR","award":"C416\/A29287CANTAC721\\100022C23338\/A25722C416\/A25145"},{"name":"European Commission","id":"https:\/\/ror.org\/00k4n6c32","id-type":"ROR","award":"H2020-MSCA-IF-2018 GA: 838559"},{"name":"Biotechnology and Biological Sciences Research Council","id":"https:\/\/ror.org\/00cwqg982","id-type":"ROR","award":"BB\/W007460\/1BB\/N009061\/1"},{"name":"Jean Shanks Foundation","id":"https:\/\/ror.org\/00wf6bs47","id-type":"ROR","award":""},{"name":"Fondation ARC pour la Recherche sur le Cancer","id":"https:\/\/ror.org\/0489qz649","id-type":"ROR","award":"ARCPJA2022060005118"},{"name":"La Ligue Contre le Cancer","id":"https:\/\/ror.org\/00rkrv905","id-type":"ROR","award":""},{"name":"Wellcome Trust","id":"https:\/\/ror.org\/029chgv08","id-type":"ROR","award":"108726\/Z\/15\/Z"},{"name":"NIHR Cambridge Biomedical Research Centre","id":"https:\/\/ror.org\/0","id-type":"ROR","award":"NIHR203312"},{"name":"Medical Research Council","id":"https:\/\/ror.org\/03x94j517","id-type":"ROR","award":"MC-A024-5PF91"}],"published":"10.1242\/dmm.052527","server":"bioRxiv"},{"title":"Alignment-free Bacterial Taxonomy Classification with Genomic Language Models","authors":"Leske, M.; FitzGerald, J. A.; Coughlan, K.; Bottacini, F.; Afli, H.; Andrade, B. G. N.","author_corresponding":"Mike Leske","author_corresponding_institution":"Munster Technological University","doi":"10.1101\/2025.06.27.662019","date":"2025-06-28","version":"1","type":"new results","license":"cc_by","category":"bioinformatics","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/06\/28\/2025.06.27.662019.source.xml","abstract":"Advances in natural language processing, including the ability to process long sequences, have paved the way for the development of Genomic Language Models (gLM). This study evaluates the feasibility of four models for bacterial classification using 16S rRNA sequences and demonstrates that gLM embeddings can be applied to effectively classify sequences at the species level, matching or outperforming the accuracy of established bioinformatics tools like BLAST+ and VSEARCH. We adopt cosine similarity as a computationally efficient metric, enabling classification orders of magnitude faster than current methods, and show that it carries biologically relevant signals. In addition, we demonstrate how sequence embeddings can be used to identify mislabeled sequences. Our findings place gLM embeddings as a promising alternative to traditional alignment-based methods, especially in large-scale applications such as metataxonomic assignments. Despite its wide potential, key challenges remain, including the sensitivity of embeddings to sequences of different lengths.","funder":[{"name":"European Commission","id":"https:\/\/ror.org\/00k4n6c32","id-type":"ROR","award":"101182801"}],"published":"NA","server":"bioRxiv"},{"title":"Behavioral algorithms of ontogenetic switching in larval and juvenile zebrafish phototaxis","authors":"Capelle, M. Q.; Slangewal, K.; Bahl, A.","author_corresponding":"Armin Bahl","author_corresponding_institution":"University of Konstanz","doi":"10.1101\/2025.06.13.659371","date":"2025-07-02","version":"2","type":"new results","license":"cc_by_nc","category":"animal behavior and cognition","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/07\/02\/2025.06.13.659371.source.xml","abstract":"Animals undergo major behavioral adjustments during ontogeny, but how the underlying cognitive algorithms change during this process remains elusive. Here, we describe that zebrafish shift from light-seeking to dark-seeking, as they grow from larval to juvenile stage, within the first few weeks of their life. We apply a combination of complementary phototaxis assays in virtual reality and modeling to dissect the computational basis of this transition. We identify three parallel pathways, one analyzing ambient whole-field luminance levels, one spatially comparing light levels across the eyes, and one computing eye-specific temporal derivatives. Larvae mostly use the latter two spatio-temporal computations for navigation, while juveniles largely employ the first one. We build a library of agent-based models to predict animal behavior across stimulation conditions and in more complex environments. Model-based extraction of latent cognitive variables points towards potential neural correlates of the observed behavioral inversion and illustrates a novel way to explore the processes of vertebrate ontogeny. We suggest that zebrafish phototaxis is regulated via parallel processing streams, which could be a universal implementation to change strategies depending on developmental stage, context, or internal state, making behavior flexible and goal-oriented.\n\nGRAPHICAL ABSTRACT\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC=\"FIGDIR\/small\/659371v3_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (49K):\norg.highwire.dtl.DTLVardef@40848forg.highwire.dtl.DTLVardef@1bed6c6org.highwire.dtl.DTLVardef@68a10org.highwire.dtl.DTLVardef@1525f06_HPS_FORMAT_FIGEXP  M_FIG C_FIG HIGHLIGHTSO_LIWe provide a framework to describe how behavioral strategies evolve during ontogeny.\nC_LIO_LIZebrafish switch their phototactic behavior within the first weeks of their life.\nC_LIO_LIBrightness navigation strategies can be described with a three-pathway model.\nC_LIO_LILarvae use spatial cues, while juveniles use ambient whole-field luminance for phototaxis.\nC_LI","funder":[{"name":"European Commission","id":"https:\/\/ror.org\/00k4n6c32","id-type":"ROR","award":"101075541"},{"name":"DFG","id":"","id-type":"ROR","award":"BA 5923\/1-1EXC 2117 \u2013 422037984"}],"published":"10.1016\/j.isci.2026.116190","server":"bioRxiv"},{"title":"Sex-biased gene expression under sexually antagonistic and sex-limited selection","authors":"Wiberg, R. A. W.; Zwoinska, M. K.; Kaufman, P.; Howie, J.; Immonen, E.","author_corresponding":"R Axel W Wiberg","author_corresponding_institution":"Stockholm University","doi":"10.1101\/2024.11.29.622017","date":"2025-07-03","version":"3","type":"new results","license":"cc_by_nc_nd","category":"evolutionary biology","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/07\/03\/2024.11.29.622017.source.xml","abstract":"Sex differences in gene expression are ubiquitous, evolve quickly, and are expected to underlie phenotypic sexual dimorphism. Despite long-standing interest, the impact of sex- specific selection on the transcriptome remains poorly understood. Here, we test fundamental questions on the role of constraints on gene expression evolution arising from the mode of selection and genetic architecture. We also test the relationship between sex-biased expression and evolved sexual dimorphism (SD). We assess these using body size selection lines in the seed beetle, Callosobruchus maculatus, that have evolved variation in SD in response to either sex-limited (SL) or sexually antagonistic (SA). We find that sex differences in the phenotypic responses and expression changes are generally well aligned. SL selection, despite a phenotypic response similar to SA selection in males, but not in females, resulted in a more extensive expression differentiation and increase of sex-biased expression than SA selection. These patterns show that SA selection imposes a transcriptomic constraint and is not required for sex-bias to evolve. Sex-biased transcripts show lower cross-sex correlations in expression changes than unbiased transcripts, suggesting greater sex differences in their underlying genetic architecture. Although male-biased transcripts are disproportionately affected when selection targeted males, we find no support for a transcriptome-wide association between sex-bias and SD. In the light of these unique experimental insights into how sex-specific selection on size changes adult transcription, our findings have important implications for inferring selection history and mode from patterns of sex-biased gene expression in natural populations.","funder":[{"name":"Swedish Research Council","id":"https:\/\/ror.org\/03zttf063","id-type":"ROR","award":"2019-050382023-048692022-03701"},{"name":"European Commission","id":"https:\/\/ror.org\/00k4n6c32","id-type":"ROR","award":"101061664"},{"name":"Nilsson-Ehe Endowment","id":"","id-type":"ROR","award":"40933"},{"name":"Lars Hierta Memorial Foundation","id":"https:\/\/ror.org\/03cpsrf24","id-type":"ROR","award":"FO2019-0329"},{"name":"Birgitta Sintring Foundation","id":"","id-type":"ROR","award":"S2024-0007"}],"published":"10.1093\/molbev\/msaf178","server":"bioRxiv"},{"title":"Genetics of growth rate in induced pluripotent stem cells","authors":"Lee, B. N.; Taylor, H. J.; Cipriani, F.; Narisu, N.; Robertson, C. C.; Swift, A. J.; Sinha, N.; Yan, T.; Bonnycastle, L. L.; Dale, N.; Butt, A.; Parsaud, H.; Semrau, S.; NYSCF Global Stem Cell Array Team,  ; GENESiPS Consortium,  ; iPSCORE Consortium,  ; Knowles, J. W.; Carcamo-Orive, I.; D'Antonio-Chronowska, A.; Frazer, K. A.; Biesecker, L. G.; Noggle, S.; Erdos, M. R.; Paull, D.; Collins, F. S.; Taylor, D. L.","author_corresponding":"D Leland Taylor","author_corresponding_institution":"National Human Genome Research Institute, National Institutes of Health","doi":"10.1101\/2025.07.02.662844","date":"2025-07-03","version":"1","type":"new results","license":"cc0","category":"developmental biology","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/07\/03\/2025.07.02.662844.source.xml","abstract":"Human induced pluripotent stem cells (iPSCs) have transformed biomedical research by enabling the generation of diverse cell types from accessible somatic tissues. However, certain fundamental biological properties, such as the genetic and epigenetic determinants of iPSC proliferation, remain poorly characterized. We measured the growth of iPSC lines derived from 602 unique donors using high-throughput time-lapse imaging, quantified proliferation through a growth Area-Under-the-Curve (gAUC) phenotype, and correlated gAUC with the gene expression and genotype of the cell lines. We identified 3,091 genes associated with gAUC, many of which are well established regulators of cell proliferation. We also found that rare deleterious variants in WDR54 were associated with reduced iPSC growth and that WDR54 was differentially expressed with respect to gAUC. Although no common variants showed a genome-wide association with gAUC, iPSC lines from monozygotic twins were highly correlated, and common genetic variation explained approximately 71-75% of the variance in iPSC growth rates. These results indicate a complex genetic architecture of iPSC growth rates, where rare, large-effect variants in important growth regulators, including WDR54, are layered onto a highly polygenic background. These findings have important implications for the design of pooled iPSC-based studies and disease models, which may be confounded by intrinsic growth differences.","funder":[{"name":"New York Stem Cell Foundation","id":"https:\/\/ror.org\/03n2a3p06","id-type":"ROR","award":"NYSCF Druckenmiller Fellowship"},{"name":"National Institutes of Health","id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","award":"ZIAHG000024K99DK13917501U01HL107388R01DK106236P30DK116074R01DK116750R01DK120565R01DK137889DP3DK112155U01HL107442Oxford-Cambridge scholars\u2019 program"},{"name":"European Commission","id":"https:\/\/ror.org\/00k4n6c32","id-type":"ROR","award":"H2020-MSCA-COFUND-2020-101034228-WOLFRAM2PID2023-148986OB-I00"},{"name":"Gates Cambridge Trust","id":"https:\/\/ror.org\/033sn5p83","id-type":"ROR","award":"Gates Cambridge Scholarship"}],"published":"10.1016\/j.stemcr.2026.102928","server":"bioRxiv"},{"title":"Mechanical Coordination of Intestinal Cell Extrusion by Supracellular 3D Force Patterns","authors":"Matejcic, M.; Wang, M.; Lopez Serrano, E.; Perez-Gonzalez, C.; Houtekamer, R.; Ceada, G.; Roca-Cusachs, P.; Gloerich, M.; Trepat, X.","author_corresponding":"Xavier Trepat","author_corresponding_institution":"Institute for Bioengineering of Catalonia","doi":"10.1101\/2025.07.03.661686","date":"2025-07-03","version":"1","type":"new results","license":"cc_by_nc_nd","category":"cell biology","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/07\/03\/2025.07.03.661686.source.xml","abstract":"Every day, the mammalian intestinal epithelium extrudes millions of cells to sustain tissue self-renewal. Despite its fundamental role in intestinal homeostasis, the mechanisms that trigger, compartmentalize, and execute intestinal cell extrusion remain largely unknown. Here, using intestinal organoids, we map the three-dimensional forces and cytoskeletal dynamics that drive intestinal cell extrusion. We show that, unlike in other epithelia, extrusion is initiated by the sudden dissolution of a contractile myosin 2A meshwork triggered by a calcium influx. Following meshwork dissolution, the extruding cell and its neighbors generate an upwards traction force that requires myosin contractility but is generated by lamellipodial protrusions in neighboring cells. Importantly, these lamellipodia not only act as force generators but also determine whether extrusion occurs apically or basally, serving as symmetry breakers of the process. Finally, we show that compartmentalization of cell extrusion to the outside of the intestinal crypt does not require curvature and instead depends on myosin 2A. Our findings reveal that the intestinal epithelium exhibits a distinctive mode of extrusion, in which tension differentials--rather than compressive stresses from crowding--trigger and compartmentalize cell removal.","funder":[{"name":"Spanish Ministry for Science and Innovation","id":"","id-type":"ROR","award":"FJC2018-037440-IPID2022-142672NB-I00PID2021-128635NB-I00 MCIN\/AEI\/ 10.13039\/501100011033ERDF-EU A way of making Europe"},{"name":"EMBO","id":"","id-type":"ROR","award":"ALTF-1169"},{"name":"European Research Council","id":"https:\/\/ror.org\/0472cxd90","id-type":"ROR","award":"Adv-101097753Adv-883739"},{"name":"Generalitat de Catalunya","id":"https:\/\/ror.org\/01bg62x04","id-type":"ROR","award":"2017-SGR-1602AGAUR SGR-2017-01602"},{"name":"Fundaci\u00f3 la Marat\u00f3 de TV3","id":"","id-type":"ROR","award":"201903-30-31-32"},{"name":"European Commission","id":"https:\/\/ror.org\/00k4n6c32","id-type":"ROR","award":"H2020-FETPROACT-01-2016-731957"},{"name":"La Caixa Foundation","id":"","id-type":"ROR","award":"LCF\/PR\/HR24\/00326"},{"name":"Human Frontiers Science Program","id":"","id-type":"ROR","award":"HFSPRGP022\/2024"}],"published":"NA","server":"bioRxiv"},{"title":"Autism-associated oxysterol regulates GABAergic neurogenesis and subtype fates","authors":"Cruz-Santos, M.; Kidd, E.; Li, Z.; De la Fuente, D. C.; Davies, S.; Vinh, N.-N.; Fjodorova, M.; Li, M.","author_corresponding":"Meng Li","author_corresponding_institution":"Cardiff University","doi":"10.1101\/2025.07.01.662540","date":"2025-07-03","version":"1","type":"new results","license":"cc_by","category":"developmental biology","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/07\/03\/2025.07.01.662540.source.xml","abstract":"Distorted GABAergic neurodevelopment is believed to underscore cortical network dysfunction that lies at the heart of neurodevelopmental disorders (NDD) such as autism and schizophrenia. GABAergic neuron diversity is sculptured by cortical environmental cues during protracted postmitotic differentiation. However, the mechanism by which the NDD environment influences GABAergic neuronal development remains largely unknown. Oxysterols are oxidized metabolites of cholesterol that can interact with developmental signaling pathways. Using an iPSC model recapitulating human forebrain GABAergic neuron development and single-cell transcriptomic profiling, we show that 24S, 25-epoxysterol, an NDD-affected oxysterol highly enriched in the fetal brain, promotes neurogenesis, and disturbs the composition of GABAergic neuronal subtypes. Moreover, pharmacological and genetic interrogation identified the liver X receptor as a regulatory pathway mediating the action of 24S, 25-epoxysterol. These findings provide insights into the roles of cholesterol metabolism in neuronal development and a potential mechanism by which dysregulated brain oxysterols contribute to the pathogenesis of NDD.","funder":[{"name":"Medical Research Council","id":"https:\/\/ror.org\/03x94j517","id-type":"ROR","award":"MR\/L020807"},{"name":"European Commission","id":"https:\/\/ror.org\/00k4n6c32","id-type":"ROR","award":"874758"}],"published":"NA","server":"bioRxiv"},{"title":"Identification of transporters essential for survival of Leishmania promastigotes in the digestive tract of sand flies","authors":"Sadlova, J.; Vojtkova, B.; Becvar, T.; Dobramysl, U.; Moeri, S.; Alagoez, C.; Wheeler, R. J.; Volf, P.; Gluenz, E.; Albuquerque-Wendt, A.","author_corresponding":"Andreia Albuquerque-Wendt","author_corresponding_institution":"Swiss TPH, PCU","doi":"10.1101\/2025.07.07.663555","date":"2025-07-10","version":"1","type":"new results","license":"cc_by","category":"cell biology","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/07\/10\/2025.07.07.663555.source.xml","abstract":"Leishmania amastigotes ingested by female phlebotomine sand flies are exposed to a harsh and dynamic environment that differs markedly from the intracellular niche in the mammalian host in temperature, pH and nutrient availability. Membrane transporter proteins, channels and pumps play a crucial role in maintaining cellular physiology under changing environments. A systematic loss-of-function screen of the L. mexicana transporter deletion mutants in macrophage and mouse infections previously identified transporter genes important for the amastigote stage. To test which transporters are important for the promastigote stage in the insect vector, we measured the fitness of gene deletion mutants in Lu. longipalpis sand flies. Pooled libraries of different complexities, consisting of 71 to 317 barcoded parasite lines allowed for an estimation of the bottleneck size in experimental infections, providing a foundation for similar experimental bar-seq studies. The fitness of each mutant parasite line was measured by tracking population composition over a course of 9 days in the sand flies and compared with the growth fitness of promastigotes over 7 days in laboratory cultures. There was a high correlation of fitness scores in vitro and in vivo, but 34 mutants showed a loss of fitness only in vivo, including deletion mutants of vacuolar H+ ATPase (V-ATPase) subunits. V-ATPase deletion mutants expressed low levels of the metacyclic-specific transcript sherp in vitro and failed to generate metacyclic promastigotes in sand flies, indicating that V-ATPase function is required for parasite differentiation and progression through the Leishmania life cycle.\n\nAuthor SummaryLeishmania parasites cause leishmaniases - a group of neglected tropical diseases that affect millions of people worldwide. These parasites must survive in two radically different environments: inside a mammalian host and within the gut of a blood-feeding sand fly. To thrive in the sand fly, Leishmania undergo extensive physiological changes and depend on transporter proteins to move nutrients and other molecules across their cell membranes. In this study, we focused on identifying which of these transporters are critical for the parasites survival inside the sand fly. We used a library of genetically engineered Leishmania promastigotes - the parasite form adapted to the insect vector - to assess the importance of more than 300 different transporter genes. We discovered that 34 of these transporters are essential for successful colonization of the sand fly. Among them, one key protein complex - the vacuolar H+ ATPase (V-ATPase) pump - was found to be crucial for parasite survival in the insect vector. Our findings deepen our understanding of how Leishmania adapts to life within the sand fly and highlight potential molecular targets for disrupting its transmission.","funder":[{"name":"European Commission","id":"https:\/\/ror.org\/00k4n6c32","id-type":"ROR","award":"trans-LEISHion-EU FP7, No. 798736LeishBlock-Horizon, No. 101148623"},{"name":"Wellcome Trust","id":"https:\/\/ror.org\/029chgv08","id-type":"ROR","award":"104111\/Z\/14\/Z104627\/Z\/14\/Z200807\/Z\/16\/Z211075\/Z\/18\/Z221944\/A\/20\/Z"},{"name":"Medical Research Council","id":"https:\/\/ror.org\/03x94j517","id-type":"ROR","award":"MR\/V000446\/1"},{"name":"Swiss National Science Foundation","id":"https:\/\/ror.org\/00yjd3n13","id-type":"ROR","award":"310030_220011"}],"published":"NA","server":"bioRxiv"},{"title":"Distinct dynamic stability patterns among three Atlantic cod subpopulations in the North Sea","authors":"Tao, H.-H.; Hidalgo, M.; Dakos, V.","author_corresponding":"Hsiao-Hang Tao","author_corresponding_institution":"Institut des Sciences de l'Evolution de Montpellier","doi":"10.1101\/2025.07.07.663450","date":"2025-07-10","version":"1","type":"new results","license":"cc_by_nc_nd","category":"ecology","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/07\/10\/2025.07.07.663450.source.xml","abstract":"Atlantic cod (Gadus morhua) in the North Sea and adjacent waters has been extensively studied due to its continued population decline despite reduced fishing pressure. Recent evidence reveals that it forms a metapopulation consisting of three subpopulations-- Northwestern, Southern, and Viking--highlighting the need to understand their distinct dynamics to support spatially targeted fisheries management. We applied a dynamical systems approach to quantify two key properties for each subpopulation from 1983 to 2023: dynamic stability, indicating whether subpopulations tend to return to or move away from their state each year, and the relative sensitivity of age groups, reflecting the magnitude of change in each groups abundance in response to perturbations in the age-structured interaction network. We found distinct dynamic stability patterns among the three subpopulations. The Northwestern subpopulation fluctuated between stable and unstable states before stabilizing at low abundance. The Southern subpopulation shifted from high-abundance, stable states toward low abundance at a transient with an uncertain future. The Viking subpopulation remained stable with relatively constant abundance over time. Throughout the study period, the age-1 group remained highly sensitive to perturbations in both the Southern and Viking subpopulations, whereas no single age group showed dominant sensitivity in the Northwestern subpopulation. Fishing mortality causally influenced the abundance and\/or stability of the Northwestern and Southern subpopulations, but not the Viking subpopulation. In contrast, sea bottom temperature did not affect the abundance or stability of any of the subpopulations. Our findings reveal distinct patterns in abundance, dynamic stability, relative sensitivity of age groups, and responses to external drivers across the three subpopulations, highlighting the importance of accounting for the complex population structure of Atlantic cod in future research, assessments, and management efforts.","funder":[{"name":"European Commission","id":"https:\/\/ror.org\/00k4n6c32","id-type":"ROR","award":"HORIZON-MSCA-2021-PF-01, LSP 244267"}],"published":"NA","server":"bioRxiv"}]}