{"messages":[{"status":"ok","category":"all","interval":"2025-04-10:2025-07-10","funder":"European Commission : https:\/\/ror.org\/00k4n6c32","cursor":0,"count":30,"count_new_papers":"40","total":"57"}], "collection":[{"title":"Precision RNAi in Tomato Using Synthetic Trans-Acting Small Interfering RNAs Derived From Minimal Precursors","authors":"Tomassi, A. H.; Juarez-Molina, M.; Cisneros, A. E.; Alarcia, A.; Toledano, S.; Orlando, F.; Presa, S.; Granell, A.; Carbonell, A.","author_corresponding":"Alberto Carbonell","author_corresponding_institution":"IBMCP (CSIC-UPV)","doi":"10.1101\/2025.04.10.648111","date":"2025-04-16","version":"1","type":"new results","license":"cc_by_nc_nd","category":"plant biology","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/04\/16\/2025.04.10.648111.source.xml","abstract":"RNA interference (RNAi) is a highly conserved gene silencing mechanism regulating gene expression at transcriptional and post-transcriptional levels in plants. Synthetic trans-acting small interfering RNAs (syn-tasiRNAs) have emerged as powerful tools for highly specific and efficient gene silencing. However, their application in crops has been constrained by the need for transgene integration and the relatively long length of TAS-derived precursors. Here, we developed a novel syn-tasiRNA platform for Solanum lycopersicum (tomato) based on minimal precursors targeted by endogenous SlmiR482b microRNA. These minimal precursors, comprising only a 22-nt miRNA target site, an 11-nt spacer and the syn-tasiRNA sequence(s), effectively produced functional syn-tasiRNAs in both transgenic and transient virus-induced gene silencing (syn-tasiR-VIGS) systems. To facilitate their broader application, we engineered a series of vectors for high-throughput cloning and efficient syn-tasiRNA expression from SlmiR482b-based minimal precursors in tomato. Our results show that minimal precursors induce robust gene silencing of endogenous tomato genes and confer antiviral resistance to the economically important tomato spotted wilt virus. Furthermore, we show that syn-tasiR-VIGS can be applied in a transgene-free manner through crude extract delivery, leading to efficient silencing of endogenous genes. This study establishes minimal syn-tasiRNA precursors as a versatile and efficient tool for precision RNAi in tomato, with applications in functional genomics and crop improvement.","funder":[{"name":"Maidstone Hospital","id":"https:\/\/ror.org\/047v2cv91","id-type":"ROR","award":"PID2021-122186OB-100PDC2022-133241-I00CNS2022135107"},{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"HORIZON-MSCA-2023-PF-01-101149036"}],"published":"10.1111\/pbi.70410","server":"bioRxiv"},{"title":"A community-consensus reconstruction of Chinese Hamster metabolism enables structural systems biology analyses to decipher metabolic rewiring in lactate-free CHO cells","authors":"Di Giusto, P.; Choi, D.-H.; Antonakoudis, A.; Duraikannan, V. G.; Craveur, P.; Cowie, N. L.; Ganapathy, T.; Ramesh, K.; Benavidez-Lopez, S.; Orellana, C. A.; Jimenez, N. E.; Dworkin, L. A.; Morrissey, J.; Marin de Mas, I.; Strain, B.; Valdez-Cruz, N. A.; Trujillo-Roldan, M. A.; Marzluf, J.; Martinez, V. S.; Zehetner, L.; Altamirano, C.; Vega-Letter, A. M.; Priem, B.; Cao, H. C.; Hold, M.; Ma, J.; Hong, Y.; Gopalakrishnan, S.; Enuh, B. M.; Tarzi, C.; Pang, K. T.; Angione, C.; Zanghellini, J.; Kontoravdi, C.; Hefzi, H.; Betenbaugh, M. J.; Nielsen, L. K.; Lakshmanan, M.; Lee, D.-Y.; Richelle, A.;","author_corresponding":"Nathan E Lewis","author_corresponding_institution":"University of Georgia","doi":"10.1101\/2025.04.10.647063","date":"2025-04-17","version":"1","type":"new results","license":"cc_no","category":"systems biology","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/04\/17\/2025.04.10.647063.source.xml","abstract":"Genome-scale metabolic models (GEMs) are indispensable for studying and engineering cellular metabolism. Here, we present iCHO3K, a community-consensus, manually-curated reconstruction of the Chinese Hamster metabolic network. In addition to accounting for 11004 reactions associated with 3597 genes, iCHO3K includes 3489 protein structures and structural descriptors for >70% of its 7377 metabolites, enabling deeper exploration of the link between molecular structure and cellular metabolism. We used iCHO3K to contextualize transcriptomics and metabolomics data from a CHO cell line in which lactate secretion is abolished. We found the reduced glycolytic flux and enhanced TCA cycle flux were accompanied by an elevated NADH and PEP levels in these cells, consistent with experimental measurements. Leveraging iCHO3Ks structural annotations, we identified candidate binding interactions of NADH and PEP with glycolytic enzymes showing model-predicted differential flux, suggesting novel allosteric regulation associated with the observed decrease in glucose uptake and glycolysis. Overall, iCHO3K offers a valuable framework for systematic integration of omics data, improved flux predictions, and structure-guided insights, thus advancing CHO cell engineering and enhancing biomanufacturing efficiency.","funder":[{"name":"Sint Lucas Andreas Hospital","id":"https:\/\/ror.org\/016jc2h42","id-type":"ROR","award":"R35 GM119850"},{"name":"St. James Hospital and Health Centers","id":"https:\/\/ror.org\/00bmwjh97","id-type":"ROR","award":"RS-2024-00341312RS-2024-00351458"},{"name":"Dorn Research Institute","id":"https:\/\/ror.org\/0343gdk92","id-type":"ROR","award":"IP23242264BTNFSC009058"},{"name":"Advanced Circulatory System (United States)","id":"https:\/\/ror.org\/009mjd053","id-type":"ROR","award":"IN210822IN218725IN211422"},{"name":"La Jolla Bioengineering Institute","id":"https:\/\/ror.org\/03sgbh608","id-type":"ROR","award":"CF-2023-I-1549CF-2023-I-1248"},{"name":"Saifee Hospital","id":"https:\/\/ror.org\/05d871a36","id-type":"ROR","award":"NNF20CC0035580NNF14OC0009473F-22010-24"},{"name":"Sree Balaji Dental College and Hospital","id":"https:\/\/ror.org\/039tm4h11","id-type":"ROR","award":"BB\/Y01278X\/1BB\/V509619\/1BB\/V509620\/1"},{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"101182278"},{"name":"Mitsubishi Kyoto Hospital","id":"https:\/\/ror.org\/053658081","id-type":"ROR","award":"2114716"},{"name":"Washington Adventist Hospital","id":"https:\/\/ror.org\/01r5r0r56","id-type":"ROR","award":"112412511241453ID23I100181220549NCN2024037"}],"published":"NA","server":"bioRxiv"},{"title":"Ploidy variation modulates outbreeding response and promotes mating system evolution in a selfing plant lineage.","authors":"Olmedo-Castellanos, C.; Garcia-Munoz, A.; Ferron, C.; Bakkali, M.; Munoz-Pajares, A. J.; Abdelaziz, M.","author_corresponding":"Mohamed Abdelaziz","author_corresponding_institution":"University of Granada","doi":"10.1101\/2025.04.15.648901","date":"2025-04-19","version":"1","type":"new results","license":"cc_no","category":"plant biology","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/04\/19\/2025.04.15.648901.source.xml","abstract":"O_LIOutbreeding response, the phenotypic differences observed between selfed parental lines and their outcrossed offspring, can influence the evolution of selfing strategies. However, such effect remains poorly understood in non-crop species. We investigated the phenotypic outbreeding response variation across ploidy levels in Erysimum incanum, a predominantly selfing plant complex with diploid, tetraploid, and hexaploid populations distributed across the Iberian Peninsula and Morocco.\nC_LIO_LIWe performed controlled within-population crosses to generate offspring with varying heterozygosity levels across ploidy types. We quantified individual, flower, and reproductive traits, and we estimated fitness components, and assessed trait modularity and phenotypic integration to see how heterozygosity affects trait coordination.\nC_LIO_LITetraploid showed the strongest and most consistently positive outbreeding responses, particularly in gamete production. Trait-specific outbreeding responses were positively associated with fitness across ploidy levels. Increasing heterozygosity was linked to a reduction in phenotypic integration, suggesting a loosening of trait correlations.\nC_LIO_LIOur results show that outbreeding response is ploidy-dependent and functionally connected to fitness. This suggests it may act as a selective force promoting outcrossing in highly inbred lineages. We suggest that outbreeding response is a dynamic and evolvable trait, with implications for mating system transitions and diversification in selfing plant populations.\nC_LI","funder":[{"name":"Beijing Center for Disease Prevention and Control","id":"https:\/\/ror.org\/058dc0w16","id-type":"ROR","award":"2415\/2017"},{"name":"Maidstone Hospital","id":"https:\/\/ror.org\/047v2cv91","id-type":"ROR","award":"PID2019-111294GB-I00\/SRA\/10.13039\/501100011033PID2022-139405OB-I00\/AEI \/10.13039\/501100011033"},{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"Marie Sklodowska-Curie Action Cofund 2016 EU agreement 75444"},{"name":"Beijing Academy of Science and Technology","id":"https:\/\/ror.org\/05ct4fn38","id-type":"ROR","award":"Athenea3iContratos Predoctorales (FPU) Universidad de Granada-Banco Santander 2021"}],"published":"NA","server":"bioRxiv"},{"title":"Tissue scarring provides a biomechanical framework to promote mammalian bile duct regeneration through the activation of integrin-SRC\/FAK signalling.","authors":"Walker, A.; Olaizola, P.; Brennan, E.; Jarman, E. J.; Yao, Y.; Carmichael, E.; Gradinaru, A.; Loftus, A. E. P.; Wilson, D. H.; Martinez Lyons, A.; Charlton, L.; Ober-Vliegen, K.; Mi, W.; Broeders, A.; Davies, K.; Carragher, N.; Unciti-Broceta, A.; Kendall, T. J.; J.W. van der Laan, L.; Verstegen, M.; Frame, M. C.; Waddell, S. H.; Boulter, L.","author_corresponding":"Luke Boulter","author_corresponding_institution":"University of Edinburgh","doi":"10.1101\/2025.04.21.649531","date":"2025-04-22","version":"1","type":"new results","license":"cc_by","category":"cell biology","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/04\/22\/2025.04.21.649531.source.xml","abstract":"Following chronic injury, the adult mammalian bile duct regenerates by forming new branches, essentially replumbing the ductular system to overcome blockages and breaks. To regenerate effectively, biliary epithelial cells (BECs) receive a range of pro-mitogenic signals from myofibroblasts, which concurrently deposit a collagen-rich scar around the duct as it regrows. Despite epithelial regeneration and scarring occurring side-by-side, whether the deposition of scar tissue regulates ductular regeneration per se remains unclear.\n\nBy inducing ductular fibrosis and regeneration in vivo, we show that the formation of collagen-I-rich scars around regenerating ducts changes the local biomechanical properties of these tissues, promoting the growth of ducts. Critically, this changing structural landscape is perceived by a spatially restricted population of biliary epithelial cells which forms a \"leading-tip\" of integrin-2-high cells. This leading-tip undergoes partial-EMT-type reprogramming, allowing it to become migratory and coordinate ductular regeneration. We show that this process is directly driven through an integrin-2-SRC\/FAK signalling axis; thereby connecting epithelial regeneration directly to the changing fibrotic environment in chronic ductular disease.\n\nHighlightsO_LIChronic liver disease results in the formation of stiff, collagen scars around ducts.\nC_LIO_LINew ducts acquire high levels of integrin-2 which is spatially localised to a \"leading-tip\", which loses epithelial features.\nC_LIO_LIIntegrin-2{beta}1-SRC\/FAK signalling regulates ductular migration by linking changes in the bio-structural composition of the liver with ductular cells.\nC_LI","funder":[{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"EP\/Y028546\/1"},{"name":"D.F. Chebotarev Institute of Gerontology","id":"https:\/\/ror.org\/038mdqs58","id-type":"ROR","award":"COCOON KWF-14364"},{"name":"Hong Kong Jockey Club","id":"https:\/\/ror.org\/015ygrv52","id-type":"ROR","award":"EPD\/22\/12"},{"name":"Faculdade de Medicina de Mar\u00edlia","id":"https:\/\/ror.org\/00pm9hx30","id-type":"ROR","award":"RIG012508"},{"name":"Higashi Nagoya National Hospital","id":"https:\/\/ror.org\/05x2sza30","id-type":"ROR","award":"C52499\/A27948"},{"name":"Lovelace Health System","id":"https:\/\/ror.org\/05xjxp170","id-type":"ROR","award":"MR\/Z506199\/1"}],"published":"NA","server":"bioRxiv"},{"title":"Bioengineering of the implantable vascularized endocrine constructs for insulin delivery suitable for clinical upscaling","authors":"Bellofatto, K.; Lebreton, F.; Hassany, M.; Hanna, R.; Bignard, J.; Marteyn, A.; Mar Fonseca, L.; Campo, F.; Olgasi, C.; Wolf-van Buerck, L.; Honarpisheh, M.; MARTINEZ DE TEJADA WEBER, B.; Follenzi, A.; Citro, A.; Piemonti, L.; THAUNAT, O.; Seissler, J.; COMPAGNON, P.; cohen, m.; BERISHVILI, E.; VANGUARD consortium,  ","author_corresponding":"Ekaterine BERISHVILI","author_corresponding_institution":"University of Geneva","doi":"10.1101\/2025.04.19.647461","date":"2025-04-23","version":"1","type":"new results","license":"cc_by_nd","category":"bioengineering","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/04\/23\/2025.04.19.647461.source.xml","abstract":"Beta cell replacement therapy for type 1 diabetes is hindered by poor graft survival and suboptimal function, largely due to inadequate vascularization and lack of supportive microenvironment. To address these challenges, we developed a clinically scalable, extracellular matrix (ECM)-mimetic hydrogel, termed Amniogel, derived from human amniotic membrane via streamlined, clinically compliant process. Co-encapsulation of pancreatic islets with blood outgrowth endothelial cells (BOECs) within Amniogel facilitated the formation of prevascularized endocrine constructs (VECs). These constructs demonstrated enhanced {beta}-cell viability and function through ECM-bound pro-survival signals, rapid self-assembly of perfusable endothelial networks enabling efficient glucose sensing, and deposition of laminin-rich basement membranes enhancing {beta}-cell coupling and insulin secretion kinetics. In preclinical diabetic mouse models, VECs rapidly integrated with the host vasculature and provided sustained glycemic control when implanted subcutaneously. This integrative approach, combining a scalable, cost-effective biological scaffold with autologous vascularization potential, represents a significant advancement toward durable and clinically translatable {beta}-cell replacement therapies for T1DM.\n\nOne Sentence SummaryA clinically scalable, biological hydrogel based vascularized endocrine constructs show sustained diabetes reversal.","funder":[{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"874700"},{"name":"Aptagen (United States)","id":"https:\/\/ror.org\/0115kp792","id-type":"ROR","award":"3-SRA-2020-926-S-B3-SRA-2023-1441-S-B"},{"name":"Rotunda Hospital","id":"https:\/\/ror.org\/05t4vgv93","id-type":"ROR","award":"310030_213013CRSII5_209417"}],"published":"NA","server":"bioRxiv"},{"title":"From climate warming to accelerated cellular ageing: an experimental study in a wild passerine bird","authors":"STIER, A.; Hsu, B.-Y.; Cossin-Sevrin, N.; Garcin, N.; Ruuskanen, S.","author_corresponding":"Antoine  STIER","author_corresponding_institution":"University of Turku","doi":"10.1101\/2021.12.21.473625","date":"2025-04-24","version":"2","type":"new results","license":"cc_by_nc_nd","category":"physiology","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/04\/24\/2021.12.21.473625.source.xml","abstract":"Climate change is increasing both the average ambient temperature and the frequency and severity of heat waves. While direct mortality induced by heat waves is increasingly reported, sub-lethal effects are also likely to impact wild populations. We hypothesized that accelerated ageing could be a cost of being exposed to higher ambient temperature, especially in early-life when thermoregulatory capacities are not fully developed. We tested this hypothesis in wild great tits (Parus major) by experimentally increasing nest box temperature by ca. 2{degrees}C during postnatal growth and measuring telomere length, a biomarker of cellular ageing predictive of survival prospects in many bird species. While increasing early-life temperature had no detectable effect on growth or survival to fledging, it accelerated telomere shortening, and although non-significantly, reduced medium-term survival from 34% to 19%. Heat-induced telomere shortening was not explained by oxidative stress, but more likely by an increase in energy demand (i.e. higher thyroid hormones levels, increased expression of glucocorticoid receptor, increased mitochondrial density) leading to a reduction in telomere maintenance mechanisms (i.e. non-significant decrease in the gene expression of telomerase and protective shelterin). Our results thus suggest that climate warming can affect rate of ageing in wild birds, with potential impact on population dynamics and persistence.","funder":[{"name":"Sir Paul Boffa Hospital","id":"https:\/\/ror.org\/05j5y0r89","id-type":"ROR","award":"286278"},{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"894963"}],"published":"NA","server":"bioRxiv"},{"title":"Bioengineering of the implantable vascularized endocrine constructs for insulin delivery suitable for clinical upscaling","authors":"Bellofatto, K.; Lebreton, F.; Hassany, M.; Hanna, R.; Bignard, J.; Marteyn, A.; Mar Fonseca, L.; Campo, F.; Olgasi, C.; Wolf-van Buerck, L.; Honarpisheh, M.; MARTINEZ DE TEJADA WEBER, B.; Follenzi, A.; Citro, A.; Piemonti, L.; THAUNAT, O.; Seissler, J.; COMPAGNON, P.; cohen, m.; BERISHVILI, E.; VANGUARD consortium,  ","author_corresponding":"Ekaterine BERISHVILI","author_corresponding_institution":"University of Geneva","doi":"10.1101\/2025.04.19.647461","date":"2025-04-24","version":"2","type":"new results","license":"cc_by_nd","category":"bioengineering","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/04\/24\/2025.04.19.647461.source.xml","abstract":"Beta cell replacement therapy for type 1 diabetes is hindered by poor graft survival and suboptimal function, largely due to inadequate vascularization and lack of supportive microenvironment. To address these challenges, we developed a clinically scalable, extracellular matrix (ECM)-mimetic hydrogel, termed Amniogel, derived from human amniotic membrane via streamlined, clinically compliant process. Co-encapsulation of pancreatic islets with blood outgrowth endothelial cells (BOECs) within Amniogel facilitated the formation of prevascularized endocrine constructs (VECs). These constructs demonstrated enhanced {beta}-cell viability and function through ECM-bound pro-survival signals, rapid self-assembly of perfusable endothelial networks enabling efficient glucose sensing, and deposition of laminin-rich basement membranes enhancing {beta}-cell coupling and insulin secretion kinetics. In preclinical diabetic mouse models, VECs rapidly integrated with the host vasculature and provided sustained glycemic control when implanted subcutaneously. This integrative approach, combining a scalable, cost-effective biological scaffold with autologous vascularization potential, represents a significant advancement toward durable and clinically translatable {beta}-cell replacement therapies for T1DM.\n\nOne Sentence SummaryA clinically scalable, biological hydrogel based vascularized endocrine constructs show sustained diabetes reversal.","funder":[{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"874700"},{"name":"Aptagen (United States)","id":"https:\/\/ror.org\/0115kp792","id-type":"ROR","award":"3-SRA-2020-926-S-B3-SRA-2023-1441-S-B"},{"name":"Rotunda Hospital","id":"https:\/\/ror.org\/05t4vgv93","id-type":"ROR","award":"310030_213013CRSII5_209417"}],"published":"NA","server":"bioRxiv"},{"title":"Directing stem cell differentiation by chromatin state approximation","authors":"Montano-Gutierrez, L. F.; Mueller, S.; Kutschat, A. P.; Seruggia, D.; Halbritter, F.","author_corresponding":"Florian Halbritter","author_corresponding_institution":"St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria","doi":"10.1101\/2025.04.24.650451","date":"2025-04-25","version":"1","type":"new results","license":"cc_by","category":"genomics","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/04\/25\/2025.04.24.650451.source.xml","abstract":"A prime goal of regenerative medicine is to replace dysfunctional cells in the body. To design protocols for producing target cells in the laboratory, one may need to consider exponentially large combinations of culture components. Here, we investigated the potential of iteratively approximating the target phenotype by quantifying the distance between chromatin profiles (ATAC-seq) of differentiating cells in vitro and their in-vivo counterparts. We tested this approach on the well-studied generation of erythroblasts from haematopoietic stem cells, evaluating a fixed number of components over two sequential differentiation rounds (8x8 protocols). We found that the most erythroblast-like cells upon the first round yielded the most erythroblast-like cells at the second round, suggesting that greedy selection by chromatin approximation can be a viable optimisation strategy. Furthermore, by analysing regulatory sequences in incompletely reprogrammed chromatin regions, we uncovered transcriptional regulators linked to roadblocks in differentiation and made a data-driven selection of ligands that further improved erythropoiesis. In future, our methodology can help craft notoriously difficult cells in vitro, such as B cells.","funder":[{"name":"Royal Edinburgh Hospital","id":"https:\/\/ror.org\/04jxcef68","id-type":"ROR","award":"10.55776\/TAI73210.55776\/P3630210.55776\/PAT130022310.55776\/EFP910.55776\/P3413610.55776\/PAT9825423"},{"name":"University Medical Center Rizk Hospital","id":"https:\/\/ror.org\/05yjz6y13","id-type":"ROR","award":"947803856529"},{"name":"Institut za Zdravstvenu Zastitu Majke i Deteta","id":"https:\/\/ror.org\/02dx8kd29","id-type":"ROR","award":"20-17258"},{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"101061151"}],"published":"10.1093\/nar\/gkag124","server":"bioRxiv"},{"title":"Intrahost dynamics, together with genetic and phenotypic effects predict the success of viral mutations","authors":"Tan, C. C. S.; Escalera-Zamudio, M.; Yavlinsky, A.; van Dorp, L.; Balloux, F.","author_corresponding":"Cedric C.S. Tan","author_corresponding_institution":"UCL Genetics Institute, University College London","doi":"10.1101\/2024.10.18.619070","date":"2025-04-28","version":"2","type":"new results","license":"cc_by_nc_nd","category":"genomics","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/04\/28\/2024.10.18.619070.source.xml","abstract":"Predicting the fitness of mutations in the evolution of pathogens is a long-standing and important, yet largely unsolved problem. In this study, we used SARS-CoV-2 as a model system to explore whether the intrahost diversity of viral infections could provide clues on the relative fitness of single amino acid variants (SAVs). To do so, we analysed [~]15 million complete genomes and nearly [~]8000 sequencing libraries generated from SARS-CoV-2 infections, which were collected at various timepoints during the COVID-19 pandemic. Across timepoints, we found that many of the SAVs that went on to reach high frequency could be detected in the intrahost diversity of samples collected at a median of 3-22 months prior. Additionally, we found that genetic linkage patterns observed at the interhost level can also be observed in the intrahost diversity of infections. Application of machine learning models allowed us to learn highly generalisable intrahost, physiochemical and phenotypic patterns to forecast the future fitness of intrahost SAVs (r2=0.48-0.63). Most of these models performed significantly better when considering genetic linkage between mutations (r2=0.53-0.67), pointing to epistasis being an important determinant in the evolution of SARS-CoV-2. Overall, our results highlight the predictive power of intrahost diversity data, and document the evolutionary forces shaping the fitness of mutations. Such insights offer potential to forecast the emergence of future variants and ultimately inform the design of vaccine targets.","funder":[{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":""},{"name":"St. Joseph's Children's Hospital","id":"https:\/\/ror.org\/03j7t7330","id-type":"ROR","award":""},{"name":"Fondazione Ospedale Salesi","id":"https:\/\/ror.org\/02tp2kq68","id-type":"ROR","award":""}],"published":"NA","server":"bioRxiv"},{"title":"How does urbanization shape shell phenotype, behaviour and parasite prevalence in the snail Cornu aspersum?","authors":"Dahirel, M.; de Tombeur, Y.; Gerard, C.; Ansart, A.","author_corresponding":"Maxime Dahirel","author_corresponding_institution":"Ghent University","doi":"10.1101\/2025.01.10.632424","date":"2025-05-01","version":"2","type":"new results","license":"cc_by_nc","category":"ecology","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/05\/01\/2025.01.10.632424.source.xml","abstract":"Urbanization is a complex and multivariate environmental change, leading to e.g. habitat fragmentation and loss, changes in local climate, soil imperviousness, pollution, etc. This is likely to exert pressures simultaneously on various dimensions of organisms multivariate phenotypes, leading to trait shifts with potential ecological consequences. However, responses to urbanization are often studied one (type of) trait at a time. In this context, we studied how, in the brown garden snail Cornu aspersum, shell phenotype (shell size and colour\/reflectance), behaviour (food intake, mobility) and metazoan parasite prevalence respond to urbanization. Within an urbanization gradient spanning the French city of Rennes, we found that snails from more urbanized sites closer to the urban centre were smaller, whereas urbanization had no detectable effect on shell reflectance, parasite prevalence or behaviour. Larger snails and snails with paler shells were more likely to be infected by trematode metacercariae and sexually-transmitted nematodes (Nemhelix bakeri), respectively. Snails harbouring trematode sporocysts ate typically less, while those infected by N. bakeri moved more slowly. We discuss the decrease of snail size along the urbanization gradient in relation with the Urban Heat Island effect and the potential decrease of resource quality and availability in urban sites. The absence of detectable effects of urbanization on shell reflectance, mobility and parasite prevalence may be due to scale mismatches between how urbanization is measured and how snails experience microhabitats. We propose further experimental and field studies to decipher interactions between urbanization effects, shell phenotype, life-history traits and parasitism.","funder":[{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"101022802"}],"published":"NA","server":"bioRxiv"},{"title":"A structure-based modelling approach identifies effective drug combinations for RAS-mutant acute myeloid leukemia","authors":"Jones, L.; Rukhlenko, O. S.; Dias, T.; Imoto, H.; Carmody, C.; Wynne, K.; Kholodenko, B. N.; Bond, J.","author_corresponding":"Jonathan Bond","author_corresponding_institution":"University College Dublin","doi":"10.1101\/2025.04.29.651188","date":"2025-05-03","version":"1","type":"new results","license":"cc_by_nc_nd","category":"cancer biology","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/05\/03\/2025.04.29.651188.source.xml","abstract":"Mutations activating RAS\/RAF\/MEK\/ERK signaling are associated with poor outcome in acute myeloid leukemia (AML), but therapeutic targeting of this pathway is challenging. Here, we employ a structure-based, dynamic RAS pathway model to successfully predict RAF inhibitor (RAFi) combinations which synergistically suppress ERK signaling in RAS-mutant AML.\n\nOur in silico models predicted therapeutic synergy of two iterations of conformation-specific RAF inhibitors: Type I[1\/2] + Type II and Type I + Type II. Predictions were validated in vitro in AML cell lines and patient samples, with synergy verified by the Loewe Additivity model. Lifirafenib (Type II) + encorafenib (Type I[1\/2]) was highly synergistic against both NRAS- and KRAS-mutant lines, while synergy of lifirafenib + SB590885 (Type I) was specific to NRAS-mutants. Immunoblotting confirmed that combination efficacy correlated strongly with decreased RAS pathway activation.\n\nLeveraging the pharmacokinetic predictions of our in silico model, both combinations were then assessed in a pre-clinical NRAS-mutant AML patient-derived xenograft (PDX) model, showing significantly improved leukaemia growth delay and event-free survival compared with single agent approaches. Assessment of leukemia burden in bone marrow and spleen during treatment further showed site-specific efficacy against circulating and spleen-resident blasts for both combinations.\n\nIn summary, we report that our structure based-modelling approach can effectively identify novel, non-obvious, and well-tolerated RAFi combinations that are highly effective against in vitro and in vivo models, thereby suggesting alternative potential therapeutic strategies for high-risk RAS-mutant AML.","funder":[{"name":"KDH Research & Communication (United States)","id":"https:\/\/ror.org\/01nda5g26","id-type":"ROR","award":"CRF20JON"},{"name":"Kelly Services (United States)","id":"https:\/\/ror.org\/00xwgwv92","id-type":"ROR","award":"A-18-3"},{"name":"Hyogo Brain and Heart Center","id":"https:\/\/ror.org\/03rzm8h15","id-type":"ROR","award":"18\/SPP\/352220\/FFP-P\/884422\/PATH-S\/1087518\/RI\/570218\/CRT\/6214"},{"name":"Sint Lucas Andreas Hospital","id":"https:\/\/ror.org\/016jc2h42","id-type":"ROR","award":"R01CA244660R01HL171773"},{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"101136926"}],"published":"NA","server":"bioRxiv"},{"title":"Concentration- and time-dependence of phosphorylation events stimulated by fibroblast growth factor-4 (FGF-4) in Rama 27 fibroblasts","authors":"Alsadum, M. M.; Su, D.; Yates, E. A.; Fernig, D. G.","author_corresponding":"David G Fernig","author_corresponding_institution":"University of Liverpool","doi":"10.1101\/2025.05.09.652961","date":"2025-05-11","version":"1","type":"new results","license":"cc_by_nc_nd","category":"biochemistry","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/05\/11\/2025.05.09.652961.source.xml","abstract":"Gradients of FGFs are an essential feature of many developmental processes. Thus, FGF2 stimulates different responses at high and low concentrations, while FGF4 gradients are critical, e.g., in limb development., but it is not known if responses to FGF4 differ in a concentration-dependent manner. Employing rat mammary (Rama) 27 fibroblasts, we therefore measured the FGF4 concentration- and time-dependence of the simulation of phosphorylation of FRS2, MAPK1 and MAPK3 which are downstream of the FGF receptor (FGFR1c). At 10 pg\/mL FGF4 caused a very weak phosphorylation of FRS2 at Y435 and Y196 and a stronger one of MAPK1 and MAPK3 that oscillated with maximum levels after 30 min and 240 min stimulation. The phosphorylation of these proteins at 1 ng\/mL FGF4 was considerably stronger and showed a similar oscillation. At 10 ng\/mL FGF4, the phosphorylation of FRS2 reached an early peak after 5 min, declined at 15 min and then rose again at 30 min before declining to the end of the time-course at 240 min, whereas the phosphorylation of MAPK1 and MAPK3 was strong after 5 minutes, reached a maximum after 30 minutes and then declined gradually. At 1 {micro}g\/mL and 3 {micro}g\/mL FGF4 after 15 min and 60 min the phosphorylation of FRS2, MAPK1 and MAPK3 was much lower at 60 min compared to that observed at lower concentrations of FGF4. The data indicate that at low concentrations FGF4 elicits an oscillatory response at the level of phosphorylation of FRS2 and of MAPK1 and MAPK3, whereas a bell-shaped dose response may occur at the highest concentrations of FGF4. The addition of exogenous heparin, an effective mimic of endogenous heparan sulfate, suggests that there may be an influence of the interaction of FGF4 with pericellular matrix and the dose-and time-dependence of the phosphorylation of FRS2 and MAPK1and MAPK3.","funder":[{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"FET-OPEN ArrestAD 737390"}],"published":"NA","server":"bioRxiv"},{"title":"ERAP1 allotypes 2 and 10 differentially regulate the immunopeptidome of melanocytes","authors":"Nikopaschou, M.; Samiotaki, M.; Kannavou, A.; Angelis, N.; Tsitsilonis, O.; Panayotou, G.; Stratikos, E.","author_corresponding":"Efstratios Stratikos","author_corresponding_institution":"National and Kapodistrian University of Athens","doi":"10.1101\/2025.05.08.652898","date":"2025-05-14","version":"1","type":"new results","license":"cc_by_nc_nd","category":"immunology","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/05\/14\/2025.05.08.652898.source.xml","abstract":"Endoplasmic reticulum aminopeptidase 1 (ERAP1) is a polymorphic enzyme that shapes the peptide repertoire presented by MHC class I molecules and can regulate adaptive immune responses in cancer and autoimmunity. Common missense polymorphisms in ERAP1 modulate its activity and are found in specific allotypes in humans. ERAP1 allotypes are linked to predisposition to HLA-associated inflammatory diseases. ERAP1 allotypic variation has been correlated with the development of psoriasis and Bechets disease, through the generation of specific CD8+ T cell populations targeting disease-specific HLAs. Given the established broad effects of ERAP1 activity on the cellular immunopeptidome, we hypothesized that ERAP1 allotypic variation may lead to broad immunopeptidome shifts that underlie antigenic responses. To test this hypothesis, we generated two A375 melanoma cell lines, each one expressing one of the most common, disease-associated, ERAP1 allotypes, namely allotypes 2 or 10. Comparison of the immunopeptidome of these two cell lines showed only minor differences in peptide sequences presented but extensive changes in abundance that included alterations in length distribution, binding affinity and sequence motifs. Our results suggest that enzymatic differences between ERAP1 allotypes are reflected primarily on the quantitative composition of the cellular immunopeptidome. These quantitative changes may constitute a mechanism that underlies ERAP1-allotypic associations with HLA-associated autoimmunity and variable anti-tumor responses.","funder":[{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"954992 \u2013 CAPSTONE \u2013 H2020-MSCA-ITN-2020"},{"name":"Bucks County Division of Human Services","id":"https:\/\/ror.org\/04y727f83","id-type":"ROR","award":"MIS 5002802"}],"published":"10.1111\/imm.70056","server":"bioRxiv"},{"title":"Atlas-scale metabolic activities inferred from single-cell and spatial transcriptomics","authors":"Armingol, E.; Ashcroft, J.; Mareckova, M.; Prete, M.; Lorenzi, V.; Icoresi Mazzeo, C.; Lee, J. T. H.; Moullet, M.; Bayraktar, O. A.; Becker, C.; Zondervan, K.; Garcia-Alonso, L.; Lewis, N. E.; Vento-Tormo, R.","author_corresponding":"Roser Vento-Tormo","author_corresponding_institution":"Wellcome Sanger Institute","doi":"10.1101\/2025.05.09.653038","date":"2025-05-14","version":"1","type":"new results","license":"cc_by_nc","category":"bioinformatics","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/05\/14\/2025.05.09.653038.source.xml","abstract":"Metabolism supplies energy, building blocks, and signaling molecules vital for cell function and communication, but methods to directly measure it at single-cell and\/or spatial resolutions remain technically challenging and inaccessible for most researchers. Single-cell and spatial transcriptomics offer high-throughput data alternatives with a rich ecosystem of computational tools. Here, we present scCellFie, a computational framework to infer metabolic activities from human and mouse transcriptomic data at single-cell and spatial resolution. Applied to [~]30 million cell profiles, we generated a comprehensive metabolic atlas across human organs, identifying organ- and cell-type-specific activities. In the endometrium, scCellFie reveals metabolic programs contributing to healthy tissue remodeling during the menstrual cycle, with temporal patterns replicated in data from in vitro cultures. We also uncover disease-associated metabolic alterations in endometriosis and endometrial carcinoma, linked to proinflammatory macrophages, and metabolite-mediated epithelial cell communication, respectively. Ultimately, scCellFie provides a scalable toolbox for extracting interpretable metabolic functionalities from transcriptomic data.","funder":[{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"Marie Sk&#322odowska-Curie Actions Postdoctoral Fellowship (Project 101208051)"},{"name":"Sint Lucas Andreas Hospital","id":"https:\/\/ror.org\/016jc2h42","id-type":"ROR","award":"R35 GM119850"}],"published":"NA","server":"bioRxiv"},{"title":"Discovery of late intermediates in methylenomycin biosynthesis active against drug-resistant Gram-positive bacterial pathogens","authors":"Corre, C.; Idowu, G.; Song, L.; Whitehead, M.; Alkhalaf, L.; Challis, G.","author_corresponding":"Gregory Challis","author_corresponding_institution":"University of Warwick","doi":"10.1101\/2025.05.11.653355","date":"2025-05-15","version":"1","type":"new results","license":"cc_by_nc_nd","category":"biochemistry","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/05\/15\/2025.05.11.653355.source.xml","abstract":"The methylenomycins are highly functionalized cyclopentanone antibiotics produced by Streptomyces coelicolor A3(2). A biosynthetic pathway to the methylenomycins has been proposed based on sequence analysis of the proteins encoded by the methylenomycin biosynthetic gene cluster and incorporation of labelled precursors. However, the roles played by putative biosynthetic enzymes remain experimentally uninvestigated. Here, the biosynthetic functions of enzymes encoded by mmyD, mmyO, mmyF and mmyE were investigated by creating in-frame deletions in each gene and investigating the effect on methylenomycin production. No methylenomycin-related metabolites were produced by the mmyD mutant, consistent with the proposed role of MmyD in an early biosynthetic step. The production of methylenomycin A, but not methylenomycin C, was abolished in the mmyF and mmyO mutants, consistent with the corresponding enzymes catalyzing epoxidation of methylenomycin C, as previously proposed. Expression of mmyF and mmyO in a S. coelicolor M145 derivative engineered to express mmr, which confers methylenomycin resistance, enabled the resulting strain to convert methylenomycin C to methylenomycin A, confirming this hypothesis. A novel metabolite (pre-methylenomycin C), which readily cyclizes to form the corresponding butanolide (pre-methylenomycin C lactone), accumulated in the mmyE mutant, indicating the corresponding enzyme is involved in introducing the exomethylene group into methylenomycin C. Remarkably, both pre-methylenomycin C and its lactone precursor were one to two orders of magnitude more active against various Gram-positive bacteria, including antibiotic-resistant Staphylococcus aureus and Enterococcus faecium isolates, than methylenomycins A and C, providing a promising starting point for the development of novel antibiotics to combat antimicrobial resistance.","funder":[{"name":"Sree Balaji Dental College and Hospital","id":"https:\/\/ror.org\/039tm4h11","id-type":"ROR","award":"BB\/E008003\/1"},{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"005224"},{"name":"Nyack Hospital","id":"https:\/\/ror.org\/0378zg266","id-type":"ROR","award":"WM130033UF090255"}],"published":"NA","server":"bioRxiv"},{"title":"The roles of space and food web complexity in mediating ecological recovery","authors":"Gawecka, K. A.; Barbour, M. A.; Bullock, J. M.; Bascompte, J.","author_corresponding":"Klementyna A Gawecka","author_corresponding_institution":"UK Centre for Ecology and Hydrology","doi":"10.1101\/2025.05.13.653715","date":"2025-05-16","version":"1","type":"new results","license":"cc_by","category":"ecology","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/05\/16\/2025.05.13.653715.source.xml","abstract":"Landscape-scale ecological restoration is a key strategy for halting and reversing biodiversity decline. However, ensuring the long-term sustainability of restoration efforts requires guiding the recovery of complex ecological systems with many interdependent species at a landscape scale. Due to these challenges, our understanding of recovery trajectories remains limited. Using experiments and metapopulation models, we explore how the spatial configuration of communities and food web complexity jointly influence species recovery at different spatial scales. We find that the number and spatial placement of communities affects the colonisation of empty habitat patches, but does not influence population recovery in patches where communities are introduced. Food web complexity reduces the recovery of lower trophic levels, both at population and metapopulation scales. However, this negative effect may be partially mitigated at higher levels of food web complexity. Our results demonstrate that the joint consideration of spatial configuration and species interactions could enhance the effectiveness of restoration actions.","funder":[{"name":"\u00c1llami Sz\u00edvk\u00f3rh\u00e1z","id":"https:\/\/ror.org\/027grcd37","id-type":"ROR","award":"FK-22-114"},{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"EP\/Z000831\/1"},{"name":"Saiseikai Fukuoka General Hospital","id":"https:\/\/ror.org\/05c8e3213","id-type":"ROR","award":"NE\/V006525\/1"},{"name":"Rotunda Hospital","id":"https:\/\/ror.org\/05t4vgv93","id-type":"ROR","award":"310030_197201"}],"published":"NA","server":"bioRxiv"},{"title":"Sex-biased gene expression under sexually antagonistic and sex-limited selection","authors":"Wiberg, R. A. W.; Zwoinska, M.; 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":"2025-05-16","version":"2","type":"new results","license":"cc_by_nc_nd","category":"evolutionary biology","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/05\/16\/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":"Marion duPont Scott Equine Medical Center","id":"https:\/\/ror.org\/00ft41876","id-type":"ROR","award":"2019-050382023-048692022-03701"},{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"101061664"},{"name":"National Disaster Medical Center","id":"https:\/\/ror.org\/056qqqn18","id-type":"ROR","award":"40933"},{"name":"Ohkawara Neurosurgical Hospital","id":"https:\/\/ror.org\/00xzbkw82","id-type":"ROR","award":"FO2019-0329"},{"name":"Cystic Fibrosis Foundation","id":"https:\/\/ror.org\/00ax59295","id-type":"ROR","award":"S2024-0007"}],"published":"10.1093\/molbev\/msaf178","server":"bioRxiv"},{"title":"Personalized whole-brain models of seizure propagation","authors":"Lopez-Sola, E.; Mercadal, B.; Lleal-Custey, E.; Salvador, R.; Sanchez-Todo, R.; Bartolomei, F.; Wendling, F.; Ruffini, G.","author_corresponding":"Giulio Ruffini","author_corresponding_institution":"Neuroelectrics Barcelona, Spain","doi":"10.1101\/2025.05.15.654238","date":"2025-05-19","version":"1","type":"new results","license":"cc_by_nc_nd","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/05\/19\/2025.05.15.654238.source.xml","abstract":"Objective: Computational modeling has recently emerged as a powerful tool to better understand seizure dynamics and guide new treatment strategies. This work aims to develop and personalize whole-brain computational models in epilepsy using multimodal clinical data to simulate and evaluate individualized therapeutic strategies. Approach: We present a computational framework that constructs patient-specific whole-brain models of seizure propagation by integrating SEEG, MRI, and diffusion MRI data. The pipeline uses neural mass models for each node in the network, simulating whole-brain dynamics. Model personalization involves adjusting global and local parameters representing the excitability of individual brain areas, using an evolutionary algorithm that aims to maximize the correlation between empirical and synthetic functional connectivity matrices derived from SEEG data. Main results: The resulting personalized models successfully reproduce individual seizure propagation patterns and can be used to simulate therapeutic interventions like surgery, stimulation, or pharmacological interventions within a unified physiological framework. Notably, model predictions reveal distinct patient-specific responses across interventions, including variable sensitivity to different pharmacological agents and identification of critical regions whose removal or modulation reduced seizure spread. Significance: This framework provides a mechanistic, interpretable approach to simulate and compare individualized treatment strategies. By integrating multimodal data into a unified whole-brain model, it has the potential to improve clinical decision-making in epilepsy by identifying accessible and functionally relevant targets.","funder":[{"name":"University Medical Center Rizk Hospital","id":"https:\/\/ror.org\/05yjz6y13","id-type":"ROR","award":"855109"},{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"101017716"}],"published":"10.1088\/1741-2552\/ae08e9","server":"bioRxiv"},{"title":"Personalized whole-brain models of seizure propagation","authors":"Lopez-Sola, E.; Mercadal, B.; Lleal-Custey, E.; Salvador, R.; Sanchez-Todo, R.; Bartolomei, F.; Wendling, F.; Ruffini, G.","author_corresponding":"Giulio Ruffini","author_corresponding_institution":"Neuroelectrics Barcelona, Spain","doi":"10.1101\/2025.05.15.654238","date":"2025-05-19","version":"2","type":"new results","license":"cc_by_nc_nd","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/05\/19\/2025.05.15.654238.source.xml","abstract":"Objective: Computational modeling has recently emerged as a powerful tool to better understand seizure dynamics and guide new treatment strategies. This work aims to develop and personalize whole-brain computational models in epilepsy using multimodal clinical data to simulate and evaluate individualized therapeutic strategies. Approach: We present a computational framework that constructs patient-specific whole-brain models of seizure propagation by integrating SEEG, MRI, and diffusion MRI data. The pipeline uses neural mass models for each node in the network, simulating whole-brain dynamics. Model personalization involves adjusting global and local parameters representing the excitability of individual brain areas, using an evolutionary algorithm that aims to maximize the correlation between empirical and synthetic functional connectivity matrices derived from SEEG data. Main results: The resulting personalized models successfully reproduce individual seizure propagation patterns and can be used to simulate therapeutic interventions like surgery, stimulation, or pharmacological interventions within a unified physiological framework. Notably, model predictions reveal distinct patient-specific responses across interventions, including variable sensitivity to different pharmacological agents and identification of critical regions whose removal or modulation reduced seizure spread. Significance: This framework provides a mechanistic, interpretable approach to simulate and compare individualized treatment strategies. By integrating multimodal data into a unified whole-brain model, it has the potential to improve clinical decision-making in epilepsy by identifying accessible and functionally relevant targets.","funder":[{"name":"University Medical Center Rizk Hospital","id":"https:\/\/ror.org\/05yjz6y13","id-type":"ROR","award":"855109"},{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"101017716"}],"published":"10.1088\/1741-2552\/ae08e9","server":"bioRxiv"},{"title":"BroodScan: A Honeybee Brood Scanner Technology","authors":"Stefanec, M.; Hofstadler, D. N.; Kaercher, M. H.; Schmickl, T.","author_corresponding":"Martin Stefanec","author_corresponding_institution":"University of Graz","doi":"10.1101\/2025.05.17.651227","date":"2025-05-19","version":"1","type":"new results","license":"cc_by","category":"animal behavior and cognition","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/05\/19\/2025.05.17.651227.source.xml","abstract":"Observing honeybee (Apis mellifera) brood dynamics and host-parasite interactions, especially within sealed cells, is vital for colony health research but traditionally relies on disruptive or destructive methods. Here we present BroodScan, a monitoring system employing a modified consumer-grade Charge-Coupled Device (CCD) flatbed scanner for continuous, high-resolution basal imaging of brood cells directly within an active beehive. Our experiments, conducted over a 35-day period, demonstrate BroodScans capacity to track the complete honeybee brood development cycle from egg to adult emergence, yielding quantitative data such as an average egg stage duration of 72.93 {+\/-} 2.04 hours (n=58). Notably, the system provided detailed, time-lapse visual documentation of the complete intra-cellular reproductive cycle of the parasitic mite Varroa destructor within sealed worker cells, including the progression from foundress mite to multiple distinct offspring stages and their maturation. BroodScan offers a valuable, non-invasive tool that overcomes key limitations of previous techniques, opening new avenues for research into honeybee biology, colony health, and the impacts of diverse stressors like Varroa destructor, thereby promising to enhance our understanding and stewardship of these vital pollinators.","funder":[{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"824069"}],"published":"NA","server":"bioRxiv"},{"title":"Meta-analysis on the effects of chemical stressors on freshwater ecosystem functions","authors":"Feckler, A.; Schulz, R.; Schaefer, R. B.","author_corresponding":"Alexander Feckler","author_corresponding_institution":"RPTU Kaiserslautern-Landau","doi":"10.1101\/2023.10.25.563649","date":"2025-05-21","version":"2","type":"new results","license":"cc_no","category":"ecology","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/05\/21\/2023.10.25.563649.source.xml","abstract":"Despite considerable progress in our predictive capacity for the response of different trophic levels to chemical stressors, generalizable relations between chemical stressors and ecosystem functions are lacking. We addressed this knowledge gap by conducting a meta-analysis (153 studies; 350 observations) on the responses of freshwater ecosystem functions (community respiration, organic matter decomposition, nutrient cycling, photosynthesis, and primary production) under controlled conditions (laboratory or outdoor mesocosms) to pesticides, pharmaceuticals, and metals. We identified monotonic dose-response relationships between standardized chemical concentrations, in terms of toxic units, for selected chemical use groups and organic matter decomposition by decomposer-detritivore-systems as well as photosynthesis by algae and macrophytes. By contrast, consistent relationships were not found for other ecosystem functions, such as organic matter decomposition by microbial decomposers alone and primary production under the conditions studied. Importantly, the shape and direction of the relationships identified here match those reported in field-based studies, indicating a decrease in functioning as chemical stress increases, strengthening the ecological relevance of our findings. Finally, we found a disconnect between regulatory ecological quality targets and ecological outcomes, highlighting a need to re-evaluate risk assessment approaches if they are supposed to be ecologically meaningful and protective of ecosystem functions.","funder":[{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"101057014"}],"published":"10.1186\/s12302-025-01167-w","server":"bioRxiv"},{"title":"The influence of bee movements on patterns of pollen transfer between plants: an exploratory model","authors":"Mailly, J.; Besognet, T.; Lihoreau, M.; Riotte-Lambert, L.","author_corresponding":"Mathieu Lihoreau","author_corresponding_institution":"Research Center on Animal Cognition (CRCA), Center for Integrative Biology (CBI); CNRS, Toulouse University","doi":"10.1101\/2025.05.19.654816","date":"2025-05-21","version":"1","type":"new results","license":"cc_no","category":"animal behavior and cognition","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/05\/21\/2025.05.19.654816.source.xml","abstract":"Most -if not all- pollinators make foraging decisions based on learning and memory. In interaction with environmental conditions and competitive pressure, pollinators cognition shapes their movement patterns, which in turn determine pollen transfers. However, models of animal-mediated pollination often make simplifying assumptions about pollinator movements, notably by not incorporating learning and memory. Better considering cognition as a driver of pollinators movements may thus provide a powerful mechanistic understanding of pollen dispersal. In this exploratory study, we connect pollinator behaviour and plant reproduction by using an agent-based model of bee movements implementing reinforcement learning. Simulations of two bees foraging together in environments containing twenty flowers shows how learning can improve foraging efficiency as well as plant pollination quality through larger mating distances and smaller self-pollination rates, while creating spatially heterogeneous pollen flows. This suggests that pollinators informed foraging decisions contribute to genetic differentiation between plant subpopulations. We believe this theoretical exploration will pave the way for a more systematic analysis of animal-mediated plant mating patterns, as model predictions can be tested experimentally in real bee-plant systems.","funder":[{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"ERC Cog 101002644"}],"published":"10.1093\/icb\/icaf051","server":"bioRxiv"},{"title":"Massively parallel quantification of mutational impact on IAPP amyloidformation","authors":"Badia, M.; Batlle, C.; Bolognesi, B.","author_corresponding":"Benedetta Bolognesi","author_corresponding_institution":"Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028 Barcelona, Spain.","doi":"10.1101\/2025.05.19.654797","date":"2025-05-23","version":"1","type":"new results","license":"cc_by_nc","category":"biophysics","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/05\/23\/2025.05.19.654797.source.xml","abstract":"Amyloid fibrils formed by the islet amyloid polypeptide (IAPP) cause pancreatic beta-cell damage, resulting in reduced insulin secretion and Type 2 diabetes (T2D). Variations in the primary amino acid sequence of IAPP can influence its aggregation rate and animals expressing IAPP variants that do not form amyloids, do not develop T2D. Conversely, specific single amino-acid changes in IAPP are enough to accelerate its aggregation rate. Understanding how mutations impact IAPP aggregation can help gain mechanistic understanding into the process of pathogenic amyloid formation of this peptide and preventively identify mutations that may contribute to the risk of developing T2D. Here, we employ deep mutational scanning to measure the ability to nucleate amyloids for 1663 IAPP variants, including substitutions, insertions, truncations and deletions and identify variants that increase amyloid formation in all mutation classes. Our results point at a continuous stretch of residues (15-32) which likely is structured in IAPP amyloids and that matches the core of the early aggregated species formed by IAPP in vitro. Inside this region, mutations have a more drastic effect in the 21-27 NNFGAIL segment, suggesting tighter structural constraints for this stretch in IAPP amyloids. Finally, by comparing this mutational atlas to that of another amyloid, Amyloid beta (A{beta}42), the peptide that aggregates in Alzheimers Disease, we find that the effects of mutations that slow down nucleation correlate between the two amyloids, but that when it comes to mutations that accelerate nucleation one single amyloid dataset cannot be used to predict mutational effects in the other.","funder":[{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"101125484"},{"name":"Tung Wah Hospital","id":"https:\/\/ror.org\/05pc9cb65","id-type":"ROR","award":"PID2021-127761OB-I00RYC2020-028861-I"}],"published":"10.1038\/s41467-026-70611-z","server":"bioRxiv"},{"title":"Cryo-Correlative Light and X-ray microscopies: Expanding the Intracellular Chemical Map","authors":"Karpov, D.; Cuau, L.; Shishkov, R.; Gramaccioni, C.; Dallerba, E.; Schwehr, B.; Hackett, M.; Plush, S.; Massi, M.; Lerouge, F.; Cloetens, P.; Bohic, S.","author_corresponding":"Sylvain Bohic","author_corresponding_institution":"ESRF, The European Synchrotron, Grenoble, France; University Grenoble Alpes, Synchrotron Radiation for Biomedical Research, Grenoble, France","doi":"10.1101\/2025.05.23.655741","date":"2025-05-23","version":"1","type":"new results","license":"cc_by","category":"cell biology","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/05\/23\/2025.05.23.655741.source.xml","abstract":"We introduce a powerful, integrated workflow that fuses cryo-optical fluorescence microscopy with cryogenic synchrotron radiation X-ray fluorescence nanoimaging to unlock unprecedented nanoscale insights into cellular ultrastructure and composition. Our method delivers sharp 2D and 3D visualizations enabling simultaneous elemental mapping, nanoparticle tracking, and imaging of mitochondrial features via a luminescent cyclometalated iridium complex. We further demonstrated that combining well-chosen molecular probes possessing different heavy elements (e.g. rhenium, iridium, bromine and iodine) allows elemental multiplex \"painting\" of different organelle to provide X-ray fluorescent elemental contrast of some intracellular structure. By eliminating the need for separate sample preparations, this streamlined approach maximizes limited synchrotron beamtime and dramatically accelerates data acquisition, setting a new benchmark for advanced cryo-nanoscale imaging studies.","funder":[{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"Horizon 2020, Grant Agreement No. 899549"},{"name":"Rush Children's Hospital","id":"https:\/\/ror.org\/0219djn76","id-type":"ROR","award":"DP220103901"},{"name":"Western Maine Health","id":"https:\/\/ror.org\/05j2wxx71","id-type":"ROR","award":"IN-1118IHLS-3625"}],"published":"10.1021\/acsnano.5c10637","server":"bioRxiv"},{"title":"Development of Paclitaxel Resistance in Triple-Negative Breast Cancer Is Associated with Extensive DNA Methylation Changes That Are Partially Reversed by Decitabine","authors":"Trnkova, L.; Burikova, M.; Soltysova, A.; Ficek, A.; Plava, J.; Cumova, A.; Rojikova, L.; Jakic, K.; Sedlackova, E.; Tichy, B.; Bystry, V.; Busato, F.; Shen, Y.; Matuskova, M.; Kucerova, L.; Tost, J.; Miklikova, S.; Cihova, M.; Buocikova, V.; Smolkova, B.","author_corresponding":"Bozena Smolkova","author_corresponding_institution":"Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava,","doi":"10.1101\/2025.05.22.655519","date":"2025-05-24","version":"1","type":"new results","license":"cc_by_nc","category":"cancer biology","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/05\/24\/2025.05.22.655519.source.xml","abstract":"AimsChemotherapy resistance remains a major challenge in breast cancer (BC) treatment. This study investigated whether resistance development is associated with DNA methylation changes and assessed the potential of the DNA methyltransferase inhibitor decitabine (DAC) to reverse these alterations and enhance chemosensitivity.\n\nMethodsMolecular profiling and functional assays were used to characterize paclitaxel-(PAC) and doxorubicin-(DOX) resistant BC cell lines derived from luminal A (T-47D), triple-negative (MDA-MB-231), and HER2-positive trastuzumab-resistant (JIMT-1) models. Therapeutic responses to DAC and DOX, alone and in combination, were evaluated in MDA-MB-231 xenografts. DNA methylation-associated gene expression changes were analyzed through integrative approaches.\n\nResultsChemoresistant cells exhibited a slow-cycling phenotype, reduced tumorigenicity, and extensive genomic alterations. Upregulation of RELB and downregulation of PPARG were observed across several resistant cell lines, while CDA expression was uniformly elevated in all DOX-resistant models. PAC-resistant xenografts displayed widespread methylation and transcriptomic reprogramming. DAC treatment partially restored aberrant methylation patterns and increased Ki-67 expression, potentially enhancing DOX responsiveness.\n\nConclusionsChemoresistance in BC involves extensive genomic and epigenetic reprogramming. DAC modulates methylation and tumor phenotype but is insufficient to overcome resistance, highlighting the need for rational combination strategies.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC=\"FIGDIR\/small\/655519v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (36K):\norg.highwire.dtl.DTLVardef@8c6b06org.highwire.dtl.DTLVardef@c67805org.highwire.dtl.DTLVardef@1f1b282org.highwire.dtl.DTLVardef@feb046_HPS_FORMAT_FIGEXP  M_FIG C_FIG","funder":[{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":""},{"name":"Shri Maharaja Hari Singh Hospital","id":"https:\/\/ror.org\/04fw3kw37","id-type":"ROR","award":""},{"name":"Nambour General Hospital","id":"https:\/\/ror.org\/04wbsx459","id-type":"ROR","award":""}],"published":"10.1016\/j.drup.2026.101350","server":"bioRxiv"},{"title":"Coevolution of phenological traits shapes plant-pollinator coexistence","authors":"Duchenne, F.; Dominguez-Garcia, V.; Molina, F.; Bartomeus, I.","author_corresponding":"Fran\u00e7ois Duchenne","author_corresponding_institution":"Estaci\u00f3n Biol\u00f3gica de Do\u00f1ana (EBD - CSIC)","doi":"10.1101\/2024.08.08.607160","date":"2025-05-26","version":"3","type":"new results","license":"cc_by_nc","category":"ecology","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/05\/26\/2024.08.08.607160.source.xml","abstract":"Previous research has revealed how species traits determine species interactions, and how species interactions influence species coexistence. However, this hierarchical view ignores the coevolutionary feedback from species interactions to species traits and its consequences for species coexistence. Here, we developed a theoretical model of quantitative genetics to explore how the coevolution of morphological and phenological traits shapes the structure and stability of mutualistic interaction networks. We found that, in comparison to morphological traits, phenological traits led to distinctive species evolutionary trajectories, resulting in different emergent properties at community level. This is because phenological traits promoted facilitation over competition. While morphological coevolution gave rise to modular and specialized interaction networks with a negative diversity-stability trade-off, phenological coevolution was required for the emergence of nested interaction networks that exhibited a positive relationship between diversity and structural stability. Empirical observations from 17 pollination networks were consistent with the theoretical results: we found many phenological motifs promoting facilitation over competition, suggesting an important role of phenological coevolution in community assembly. The seasonal organization of empirical interactions enhanced the community stability and dampened the diversity-stability trade-off that was observed when aggregating interactions across time. Our results highlight the importance of phenological coevolution in the emergence of diverse and stable communities.","funder":[{"name":"Rotunda Hospital","id":"https:\/\/ror.org\/05t4vgv93","id-type":"ROR","award":"P500PB_217801"},{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"PCIG14-GA-2013-631653101064340"}],"published":"10.1098\/rspb.2025.2808","server":"bioRxiv"},{"title":"Modelling Glomerular Filtration using Multispectral Optoacoustic Tomography and a Novel Near-infrared Dye","authors":"Littlewood, J.; Harwood, R.; Vajpayee, S.; Perciaccante, R.; Trivino-Cepeda, K.; Sharkey, J.; Sardella, T.; Burton, N.; Taylor, A.; Wilm, B.; Bearon, R.; Murray, P.","author_corresponding":"Patricia Murray","author_corresponding_institution":"University of Liverpool","doi":"10.1101\/2025.05.31.657147","date":"2025-06-03","version":"1","type":"new results","license":"cc_by","category":"physiology","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/06\/03\/2025.05.31.657147.source.xml","abstract":"Kidney disease carries significant morbidity, mortality, and financial cost. Preclinical work exploring more accurate methods for assessing renal function is key for monitoring disease progression and the efficacy of future therapies. Measuring kidney function by dynamic contrast enhanced imaging allows us to measure left and right kidney function separately. This provides an internal control where a unilateral injury model is used. Multispectral optoacoustic tomography (MSOT) can measure the renal clearance of administered near infrared absorbers and, via the application of mathematical models, allows for the calculation of glomerular filtration rate. ABZWCY-HP{beta}CD is a cyanine dye bound to 2-hydroxylpropyl-{beta}-cyclodextrin and has shown promise as a glomerular filtration marker. Here we combine MSOT, ABZWCY-HP{beta}CD, and a modified Patlak-Rutland model to measure the glomerular filtration rate of healthy mice and following ischaemic reperfusion injury.","funder":[{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"Marie Sklodowska-Curie grant agreement No. 813839"}],"published":"NA","server":"bioRxiv"},{"title":"How individual vigor shapes human-human physical interaction","authors":"Verdel, D.; Berret, B.; Burdet, E.","author_corresponding":"Dorian Verdel","author_corresponding_institution":"Bioengineering department, Imperial College of Science, Technology and Medicine","doi":"10.1101\/2025.06.01.657232","date":"2025-06-03","version":"1","type":"new results","license":"cc_by_nc_nd","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/06\/03\/2025.06.01.657232.source.xml","abstract":"The speed of voluntary movements varies systematically, with some individuals moving consistently faster than others across different actions. These variations, conceptualized as vigor, reflect a time-effort-accuracy tradeoff in motor planning. How do two mechanically coupled partners with different individual vigors collaborate, e.g. to move a table together? Here, we show that such dyads coordinate goal-directed movements with minimal interaction force, exhibiting a dyadic vigor with similar characteristics as individual vigor. The emerging dyadic motor plan is strongly influenced by the slower partner, whose vigor predicts dyadic vigor, with effects lasting beyond practice. Computational modeling with stochastic optimal control reveals the critical role of partners movement timings uncertainty and vigor in shaping coordination, allowing to predict dyadic movements from individual behavior across diverse conditions. These findings shed light on the mechanisms underlying human collaboration, and may be used in applications ranging from physical training and rehabilitation to collaborative robotics for manufacturing.","funder":[{"name":"University Medical Center Rizk Hospital","id":"https:\/\/ror.org\/05yjz6y13","id-type":"ROR","award":"810346"},{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"899626871767"}],"published":"10.7554\/eLife.109781.3","server":"bioRxiv"},{"title":"Single-cell morphological profiling reveals insights into programmed cell death","authors":"Frey, B.; Holmberg, D.; Bystrom, P.; Bergman, E.; Georgiev, P.; Johansson, M. M.; Hennig, P.; Rietdijk, J.; Rosen, D.; Carreras-Puigvert, J.; Spjuth, O.","author_corresponding":"Ola Spjuth","author_corresponding_institution":"Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden Phenaros Pharmaceuticals AB, Uppsala, Sweden","doi":"10.1101\/2025.01.15.633042","date":"2025-06-04","version":"2","type":"new results","license":"cc_by","category":"bioinformatics","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/06\/04\/2025.01.15.633042.source.xml","abstract":"Analysis at the single-cell level is a powerful approach to study biological processes and responses to perturbations. However, its application in morphological profiling with phenomics remains underexplored. Here, we use the Cell Painting assay to investigate morphological effects of 53 small molecule compounds, associated with six distinct programmed cell death mechanisms, across six concentrations in MCF7 cells. To compare single-cell and aggregated analysis strategies, we conduct both supervised and unsupervised evaluations aimed at identifying features linked to programmed cell death. We apply an energy distance as a metric to quantify morphological perturbation strength, enabling efficient filtering. Among three tested feature extraction methods, self-supervised DINO embeddings applied to single-cell data captured high-resolution morphological patterns. Focused analyses of apoptosis-inducing compounds revealed biological heterogeneity attributable to specific molecular targets and concentration-dependent effects, which were not apparent in aggregated profiles. In contrast, multi-class classification models for the six programmed cell death mechanisms trained on single-cell features achieved F1 scores of 79.86%, while models trained on aggregated features reached F1 scores of up to 89.97%. Our results highlight the advantages of single-cell data for unsupervised exploration and show that aggregated representations yield more robust and accurate performance in supervised models.","funder":[{"name":"Marion duPont Scott Equine Medical Center","id":"https:\/\/ror.org\/00ft41876","id-type":"ROR","award":"2022-067252021-001792024-045762020-03731_VR2024-035662022-00940_Formas"},{"name":"Marie Curie","id":"https:\/\/ror.org\/02aqv1x10","id-type":"ROR","award":"22 2412 Pj 03 H"},{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"101057014101057442"}],"published":"NA","server":"bioRxiv"},{"title":"PKP2 orchestrates OXPHOS expression in cardiomyocytes via a PGC1\u03b1-dependent mechanism","authors":"Han, S. J.; den Berg, D.; de Ruiter, H.; Tsui, H.; Kyriakopoulou, E.; Koopmans, T.; Perini, I.; Monshouwer-Kloots, J.; van Kampen, S. J.; te Riele, A. S. J. M.; Kelters, I. R.; Gianoli, M.; Burgering, B. M. T.; van Rooij, E.","author_corresponding":"Eva van Rooij","author_corresponding_institution":"Hubrecht Institute","doi":"10.1101\/2025.06.02.656790","date":"2025-06-04","version":"1","type":"new results","license":"cc_no","category":"molecular biology","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2025\/06\/04\/2025.06.02.656790.source.xml","abstract":"Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease where the majority of ACM patients carry a (likely) pathogenic variant in desmosomal genes, predominantly in plakophilin-2 (PKP2). While the genetic cause of the disease is well studied, the molecular disease-driving mechanisms and how exercise can drive disease progression remain poorly understood. In this study, we identified the oxidative phosphorylation (OXPHOS) pathway to be downregulated in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and human explanted hearts carrying pathogenic PKP2 variants. The reduced expression of OXPHOS related genes was a result of lower PPARGC1A expression which led to decreased mitochondrial spare capacity in PKP2 mutant hiPSC-CMs. Induction of PPARGC1A expression partially restored the expression of OXPHOS components and improved contractility in PKP2 mutant cells. These results suggest that improving oxidative capacity through modulation of PPARGC1A in cardiomyocytes could be considered as a new therapeutic target for ACM patients in the future.","funder":[{"name":"Sengenia (United Kingdom)","id":"https:\/\/ror.org\/04wjhaz81","id-type":"ROR","award":"045100120100410903223231004210250022110004"},{"name":"Rize Devlet Hastanesi","id":"https:\/\/ror.org\/04mc4md34","id-type":"ROR","award":"101115536101080204801540"},{"name":"St Mark's Hospital","id":"https:\/\/ror.org\/05am5g719","id-type":"ROR","award":"09150181910020"}],"published":"NA","server":"bioRxiv"}]}