Biology subjects

Cohen, P.

Publications and source records attributed to Cohen, P..

At least 19 recordsLinked to original sources

bioRxiv2026

Activation of perivascular thermogenic fat improves aortic stenosis

Aim: Aortic stenosis (AS) is a common condition with exponential increases in incidence in aging populations. Perivascular adipose tissue (PVAT) forms the outer layer of the aortic wall and has - especially in the thoracic area - characteristics of thermogenic adipose tissue, which dissipates energy and releases endocrine factors. Here, we set out to investigate the role of thermogenic PVAT in AS. Methods and results: We studied the role of (PVAT) in the development of AS in a murine model of AS. To specifically delineate the role of PVAT activity in AS, we used a pharmacological {beta}3-adrenergic agonist as well as cold exposure in combination with a genetic mouse model with deficient PVAT development. To investigate the role of thermogenic adipose tissue in human AS, we used 18F-FDG PET-CT imaging. We found that pharmacological activation of thermogenic adipose tissue resulted in an improvement of AS, but not in mice genetically deficient in PVAT. Similarly, PVAT was found to be protective against AS during physiological stimulation of PVAT using cold exposure. Mechanistically, PVAT activation resulted in enhanced aortic distensibility and cellular remodeling of the aortic wall, possibly via release of polyunsaturated fatty acids and oxylipins from perivascular adipocytes. Finally, analysis of thermogenic fat activity in humans revealed that mediastinal thermogenic fat activity correlated negatively with diagnostic criteria of AS severity, suggesting an important role for PVAT activity in human AS. Conclusion: Our data indicate that PVAT activation reduces aortic stenosis and supports aortic remodeling to improve ascending aorta hemodynamics. PVAT activation might be a novel therapeutic target to ameliorate AS progression. Translational perspective: Currently, there are no effective strategies for treating AS other than valve replacement. Since the molecular mechanisms underlying the disease progression remain unclear, there are no pharmacological agents approved for either treatment or prevention of this disease. Furthermore, AS development cannot currently be predicted and is often only diagnosed when patients develop symptoms, which may be 10-20 years after disease onset. Therefore, identifying novel mechanisms that improve aortic valve function and prevent AS is of high medical need. This study identifies activation of PVAT-dependent aortic remodeling as a potential new therapeutic approach to improve or prevent AS.

physiology↗

bioRxiv2026

Temporal control of mitochondrial mutagenesis reveals the fate of mtDNA mutations with age

Mutations in the mitochondrial genome (mtDNA) play a critical role in the aging process and a wide variety of age-related diseases. However, it remains unclear when the mutations that drive physiological decline arise. To answer this question, we generated a new mouse model in which mitochondrial mutagenesis can be confined to a defined window of time. Surprisingly, we found that mutations that arise during the first two months of life are sufficient to drive a wide variety of age-related pathologies, and that the severity of this pathology is broadly regulated by distinct, tissue-specific selective pressures that control the fate of mtDNA mutations with age. Further, we found that selection against deleterious variants can be modulated by manipulation of mitochondrial fusion in vitro and in vivo. These observations raise the possibility that in some tissues, the pace of aging is pre-determined by events that occur early in life and that interventions targeting mitochondrial fusion may be able to slow down or reverse the expansion of these pathogenic variants. These results carry far-reaching implications for strategies aimed at preventing or delaying age-related decline.

genetics↗

bioRxiv2026

A mammalian-specific domain of MSH5 drives the transition from crossover licensing to designation during meiotic prophase I

SUMMARYMeiotic recombination initiates with DNA double-strand breaks (DSBs) repaired as either crossovers (COs) or non-crossovers. Across eukaryotes, MSH4/MSH5 (MutS{gamma}) licenses DSB repair intermediates, directing repair into the class I CO pathway via recruitment of MLH1/MLH3 (MutL{gamma}). In mammals, excess MutS{gamma} sites relative to final MutL{gamma} foci suggest additional MutS{gamma} functions, including directing repair through the minor class II CO pathway. We investigated the role of a mammalian-specific 38-amino acid C-terminal domain of MSH5 using mice lacking this domain (Msh5{Delta}C/{Delta}C). Spermatocytes and oocytes load MSH4 normally to achieve CO licensing in zygonema, but these numbers decline precipitously in pachynema, leading to dramatically reduced MutL{gamma} foci and associated pro-CO factors HEI10 and CNTD1. Despite this, licensing factors RNF212B and MutS{gamma}-associated kinase CDK4 remain persistently upregulated in pachynema. Strikingly, the switch from licensing-associated CDK4 to CO-site-associated CDK2 fails to occur in Msh5{Delta}C/{Delta}C mice, even at residual class I CO events. The result is rapid germ cell death prior to prophase I completion in both sexes. Thus, the loss of the MSH5 C-terminus functionally uncouples the regulatory proteins that define the stepwise patterning of class I COs. Our findings reveal novel early roles for the C-terminus of mammalian MSH5 in converting licensed DSB repair intermediates to designated class I COs.

genetics↗

bioRxiv2026

Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of interorganellar lipid cycling

Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature. Yet how these diverse signals are molecularly integrated remains unknown. Here we show that clock, diet, and temperature cues converge on the orphan mitochondrial transporter, SLC25A34, to orchestrate thermogenic cycling of lipid synthesis and oxidation. During sleep, the clock suppresses Slc25a34 transcription through REV-ERB. Waking, lipid-rich diets, or cold exposure abolish this repression, allowing lipolytic signals to stimulate Slc25a34 expression via PPAR. SLC25A34 then imports oxaloacetate into mitochondria to accelerate the export of substrates used for acetyl-CoA production in the cytosol. This feeds into cytosolic lipid synthesis and transcriptional induction of mitochondrial biogenesis, which collectively promote mitochondrial lipid oxidation. Thus, SLC25A34 confers circadian, dietary, and environmental control of thermogenic metabolism through interorganellar lipid cycling.

molecular biology↗

bioRxiv2026

Digital Chromosome Banding Reveals Distinct Spatiotemporal Dynamics and Sexual Dimorphism in Meiotic Silencing

In mammals, meiotic silencing of unsynapsed chromatin (MSUC) is initiated by the DNA damage response (DDR) pathway, as marked by {gamma}H2AX. During normal male meiosis, MSUC is restricted to the unsynapsed sex chromosomes, a process known as meiotic sex chromosome inactivation (MSCI). While the initiation of MSCI has been well studied, its full silencing dynamics and underlying structural mechanisms remain unclear. In contrast to MSCI, broader MSUC can occur on autosomes in response to synapsis failure, but its cell-to-cell variability obscures its quantification. To address these challenges, we introduce "digital-chromosome-banding", a single-cell-based approach that allows quantitative analysis of MSCI and MSUC at chromosomal resolution. Using this approach, we identified two distinct silencing transitions during MSCI, occurring from zygonema to early pachynema and from early to mid-pachynema. The latter step coincides with mature sex body formation and involves a gel-like diffusion barrier to enforce transcriptional repression. Applying this approach to synapsis-defective mouse models (Spo11-/-, Tardbp cKO, and Nelfb cKO), we observed divergent MSUC patterns that correlate with the severity of asynapsis. Comparative analysis between sexes also uncovered notable sexual dimorphisms in meiotic silencing. Together, our data provide a quantitative framework to dissect the spatiotemporal dynamics and sexual differences of meiotic silencing.

cell biology↗

bioRxiv2026

Nutrient content estimation of the world's fishes

Seafood nutrients from global fisheries are of increasing importance for research and policy in food security and nutrition. As the chemical composition of fish is determined by what they eat, their energetic demands, and the environment in which they live, nutrient content reflects aspects of physiology and life history, ecological and environmental traits, as well as evolutionary history. Here we present data from Bayesian model estimates of 12 key nutrients (calcium, iron, phosphorus, magnesium, selenium, zinc, vitamin A, vitamin B9, vitamin B12, vitamin D, omega-3 fatty acids, and protein) in wild fish, using a database of reported nutrient content for freshwater and marine species. We then predict the nutrient content of 5588 fish species with traits available from FishBase. We compare our previous model using traits alone with a new model of both traits and phylogeny, and present the data, code, and predictions for models coded in PyMC. These models and predictions, made freely available through FishBase, can be used to explore the historical, current, and future nutrient content of fisheries catch.

ecology↗

bioRxiv2026

Gene regulatory networks define human airway epithelial cell types and their distinct responses to type I interferon

The human airway epithelium (HAE) is composed of diverse cell types that coordinate essential functions and host defenses. Among these defenses, interferons (IFNs) are central to antiviral programs. However, the gene regulatory networks (GRNs) governing HAE cellular identities and their IFN responses are incompletely defined. At single-cell resolution, we characterized the transcriptomes and accessible chromatin landscapes of HAE cell types, at steady state and following IFN{beta} stimulation. The resulting scRNA-seq and snATAC-seq data informed genome-scale GRN construction and inference of transcriptional circuits underlying cell identities. In response to IFN, we identified a shared transcriptional program across HAE cell types, and an expanded set of interferon-responsive genes exhibiting cell type-associated expression patterns. Cell type-associated transcription factors and chromatin accessibility contribute to distinct IFN-responsive gene expression programs. Together, these data provide a blueprint for molecular regulation of complex HAE responses and a foundation for therapeutic strategies to enhance host antiviral defense.

systems biology↗

bioRxiv2026

Impaired non-shivering thermogenesis in the desert-dwelling antelope ground squirrel

Adaptations in animals occupying environments of extreme cold or heat offer unique insights into thermoregulation. The antelope ground squirrel, a desert-dwelling rodent situated within a clade of hibernators, provides a notable example of these thermoregulatory extremes. As a non-hibernator closely related to hibernators, antelope ground squirrels may represent a rare case of trait reversal, with a striking ability to maintain core body temperatures exceeding 43{degrees}C while displaying poor tolerance to prolonged cold. Here, we explore the genetic and phenotypic basis of these unique traits by generating the first genome assembly for this species, which we use to conduct comparative genomics across the squirrel family. We complement this with acute and chronic cold-exposure experiments coupled with transcriptomic profiling of thermogenic organs: brown adipose tissue, white adipose tissue, and skeletal muscle. Together, these findings reveal a shift away from non-shivering thermogenesis toward metabolically demanding shivering thermogenesis, a perilous strategy for sustained heat generation.

evolutionary biology↗

bioRxiv2026

Nuclear Mitochondrial Interaction Test Reveals Sex-Dependent Mitochondrial SNPs Interacting with Klotho Variants on Diabetes Risk

ContextThe environmental or other genetic factors might influence the effect of Klotho (KL) on glucose metabolism. ObjectiveWe investigated mitochondrial genetic variants that interact with KL single nucleotide polymorphisms (SNPs) to modulate diabetes risk. MethodsWe used the data from 7,047 non-Hispanic white participants of the Health and Retirement Study, a prospective observational study including adults aged 50 years and older from the United States. First, we performed single gene-wide association scans to identify KL SNPs associated with diabetes. Next, we performed a nuclear-by-mitochondrial interaction test (NuMIT) in which we use an identified KL SNP from the gene-wide scan to evaluate potential interactions with 85 mitochondrial SNPs in relation to diabetes. ResultsWe failed to identify a significant association between diabetes and the KL SNP in our single gene-wide association test. However, we identified a novel variant (KL rs9563121) which showed a trend of increasing klotho mRNA levels with each additional minor allele. A NuMIT analysis identified mitochondrial SNPs, which showed significant interactions with rs9563121 in relation to diabetes risk. MitoG15929A showed significant interactions with rs9563121 in both men and women. MitoG15929A diminished the potential beneficial effect of KL rs9563121 on diabetes risk in women. Among men with the MitoG15929A variant, KL rs9563121 was associated with higher prevalence of diabetes. ConclusionThe NuMIT approach revealed significant interactions between mitochondrial and nuclear DNA variants of KL. Furthermore, MitoG15929A may have a role in the interaction between diabetes and KL in a sex-dependent manner.

genetics↗

bioRxiv2026

Evaluating the applicability of kinship analyses for sedimentary ancient DNA datasets

Kinship reconstruction in ancient populations provides key insights into past social organization and evolutionary history. Sedimentary ancient DNA (sedaDNA) enables access to deep-time human populations in the absence of skeletal remains. However, it is characterized by severe degradation and the potential mixture of genetic material from multiple individuals, raising questions about its suitability for kinship inference. Here, we use extensive simulations to evaluate the feasibility and limitations of kinship inference in sparse and damaged sedaDNA data, with a focus on Neandertals. We find that the main obstacle to accurate kinship inference in sedaDNA is the presence of multiple contributors to a given sample. To address this, we introduce a simple heterozygosity-based test to identify samples containing DNA from multiple individuals. Guided by these results, we analyze published Neandertal sedaDNA from the Galeria de las Estatuas site to assess the practical limits of kinship inference in real sedimentary ancient DNA data. Together, our results define methodological considerations and practical limits for kinship inference in sedimentary ancient DNA.

bioinformatics↗

bioRxiv2026

Uncovering the function of Wisp1 in whole-body glucose homeostasis: insights from Wisp1 knockout mice

WNT1-inducible signaling pathway protein 1 (Wisp1/CCN4) is a matricellular protein implicated in inflammation and metabolic dysfunction in obesity, yet its role in whole-body glucose metabolism remains unclear. In this study, Wisp1 knockout (KO) mice were analysed under physiological and high-fat (HF) diet conditions to define its impact on metabolic regulation. Neither physiological nor HF diet conditions revealed an effect of Wisp1 deficiency on whole-body glucose tolerance. However, male KO mice on a HF diet exhibited enhanced insulin sensitivity, lower insulin levels, and a marked reduction in adipose tissue inflammation, as evidenced by diminished macrophage infiltration and decreased pro-inflammatory cytokine expression in visceral fat. Additionally, beta cell mass expansion was attenuated in KO mice under HF diet, aligning with lower macrophage infiltration in islets. These findings suggest that improved insulin sensitivity in KO mice occurs independently of changes in glucose tolerance, likely due to mitigated adipose tissue inflammation. Thus, Wisp1 primarily modulates local adipose inflammatory responses, indirectly affecting islet adaptation to metabolic stress, rather than serving as a direct regulator of systemic glucose homeostasis.

physiology↗

bioRxiv2026

Cell type-specific proximity labeling of organ secretomes reveals energy balance-dependent proteomic remodeling.

Intercellular communication is critical for maintaining organismal metabolic homeostasis. Here, we present a new method enabling temporally controlled, cell type-specific labeling of secreted and membrane proteins in key metabolic tissues. The method employs a genetically encoded proximity-labeling strategy by targeting a Cre-dependent TurboID ligase to the endoplasmic reticulum (ER) in ES cell-derived mice. Expression of TurboID in liver, adipose tissue, and spleen enabled the characterization of organ-specific ER proteomes at baseline and in response to fasting, inflammation, and dietary obesity, revealing tissue-and perturbation-specific changes and augmenting our understanding of how the proteomes of individual tissues change to regulate systemic energy balance. This comprehensive resource represents an important advance toward understanding both how cell-to-cell communication changes in response to energy homeostasis and how it contributes to these alterations. This method is broadly applicable and provides a means for identifying biomarkers and therapeutic targets across a wide range of tissues.

physiology↗

bioRxiv2025

Chromosome length is not the sole determinant of sexually dimorphic crossover rates during mammalian meiosis: Insights from genetically diverse mouse strains

Meiotic recombination generates crossovers (COs), reciprocal exchanges between homologous chromosomes critical for accurate chromosome segregation. Inappropriate CO frequency and distribution drive aneuploidy in human oocytes, with error rates up to 10-fold higher than in sperm despite females exhibiting higher CO frequencies. COs form in the context of the proteinaceous synaptonemal complex (SC) that tethers homologs during prophase I. SC length strongly correlates with CO number, and sexual dimorphism in recombination has long been attributed to longer SCs in females. However, this model is challenged by wild-derived PWD mice in which males consistently generate more COs despite having shorter SCs. Here, we exploit natural genetic variation among inbred mouse strains to dissect the structural and regulatory basis of sexually dimorphic CO regulation. Using cytological markers of SC assembly (SYCP3), recombination progression (RAD51, MSH4), class I CO designation (HEI10, MLH1/MLH3), and chiasmata, we show that SC length is not the sole predictor of CO number. PWD males exhibit stronger CO interference and higher CO number than females, despite reduced SC length. Notably, females show reduced efficiency in designating recombination intermediate to become COs, whereas PWD males display exceptional proficiency. Unexpectedly, although class II COs are rare, they play a disproportionate role in ensuring that every chromosome pair receives at least one CO, thereby safeguarding against aneuploidy. Together, these findings challenge the prevailing view that SC length is the primary determinant of sexually dimorphic CO rates and instead highlight sex-specific regulation of CO designation and pathway usage as key drivers of recombination outcomes.

genetics↗

bioRxiv2025

Environmental phylogenetics supports a steady diversification of crown eukaryotes starting from the mid Proterozoic

1.Molecular clock and preservation of early microfossil assemblages suggest that eukaryotes were present and already diverse more than [~]1600 million years ago (Ma). Yet, the earliest identifiable eukaryotic crown group fossil only appeared around 1050 Ma, leaving a [~]600 million years gap in the Mesoproterozoic during which the evolution and diversification of early eukaryotes remain poorly understood. Here, we inferred a timeline of eukaryote evolution using molecular clock and birth-death diversification models, including the great diversity of environmental sequences to take into account the uncultured majority of microbial life. Our analyses, based on a unique dataset of 75,975 non-redundant Operational Taxonomic Units and 77 well-supported fossil calibrations, indicate a steady diversification of crown group eukaryotes during the Proterozoic after the Last Eukaryotic Common Ancestor (LECA). We show that Archaeplastida was one of the earliest diversifying supergroups and the most diverse throughout the Proterozoic, suggesting that the first successful plastid endosymbiosis gave Archaeplastida a measurable evolutionary advantage. Discoba, Amoebozoa and Rhizaria followed Archaeplastida in phylogenetic diversity throughout the Proterozoic, suggesting that crown eukaryotes were already thriving in this Era. These results contrast with the common view that the geologically stable Proterozoic Era experienced little eukaryotic evolutionary innovation, and indicate that it was already at the dawn of eukaryote evolution that all current supergroups were established.

evolutionary biology↗

bioRxiv2025

VRC01 Selects Rare HIV Escape Mutations After Acquisition in Antibody-Mediated Prevention Trials

Broadly neutralizing antibodies (bnAbs) show promise in HIV prevention, yet viral escape remains a challenge. In the Antibody Mediated Prevention (AMP) trials, the CD4 binding site (CD4bs) bNAb VRC01 blocked acquisition by VRC01-sensitive strains. However, its influence on viral evolution post-acquisition is not fully understood. Here we analyzed >12,000 HIV env sequences from 47 participants from the AMP trials, identifying VRC01-mediated de novo escape mutations in 8 of 26 VRC01-treated participants but none in 21 placebo participants. These mutations were found at very low frequency (<1%) in global viruses. Escape mutations, primarily located in the Loop-D and {beta}23/V5 regions of Env, conferred cross-resistance to several CD4bs bnAbs, while more potent CD4bs bnAbs like N6 and 1-18 largely retained their activity. Our findings demonstrate that prophylactic VRC01 can select for viral escape after infection, underscoring the need for next-generation bnAbs with improved breadth and potency to enhance durability and efficacy of antibody-based HIV prevention.

microbiology↗

bioRxiv2025

Exercise intensity modulates the human plasma secretome and interorgan communication

Exercise is recognized as first-line therapy for many cardiometabolic diseases, including obesity, type 2 diabetes, and hypertension. Despite the abundant health-promoting effects of exercise, in-depth characterization of circulatory factors that mediate these benefits in humans remains incomplete. Moreover, how different modes and intensities of exercise uniquely regulate these processes is unclear. Here, we address these questions by conducting a multi-cohort human exercise intervention, incorporating sprint-interval exercise (SIE) and moderate-intensity exercise (MIE) to analyze intensity-dependent regulation of interorgan crosstalk. We find that exercise intensity distinctly influences the plasma proteome and metabolome in both untrained and trained participants. SIE led to immediate and robust changes to the plasma proteome, whereas MIE resulted in delayed secretory kinetics. By leveraging large, multi-organ gene and protein expression datasets, in combination with in vitro and in vivo tissue sampling, we map the differentially regulated proteins to their predicted tissue of origin and destination. We find that adipocytes are particularly sensitive to exercise intensity, undergoing broad transcriptomic remodeling following in vitro incubation with SIE as compared to MIE plasma. These findings underscore the integrated whole-body response following acute exercise and highlight exercise intensity as a key factor influencing interorgan communication.

physiology↗

bioRxiv2025

Influence of the broadly neutralizing antibody VRC01 on HIV breakthrough virus populations in antibody-mediated prevention trials

In the HIV antibody mediated prevention (AMP) trials, the broadly neutralizing antibody VRC01 demonstrated protective efficacy against new diagnoses with susceptible HIV strains. To understand how VRC01 shaped breakthrough infections, we performed deep sequencing on 172 participants in the placebo and treatment arms, generating 63,444 gag-{Delta}pol (2.5 kb) and 53,088 rev-env-{Delta}nef (3 kb) sequences. Sequences were classified into transmitted founder lineages (TFLs), and infections with multiple distinct lineages were determined. Multilineage infections were detected in [~]38% of participants in both the African (HVTN 703/HPTN 081) and Americas/Europe (HVTN 704/HPTN 085) cohorts, regardless of placebo or treatment group, or cohort. The high levels of multilineage infections could be attributed to minor lineages (<5% abundance) identified in 20% of participants. Infection with VRC01 discordant viruses (IC80s >3-fold different) was observed in 40% of multilineage infections, with a trend toward greater intra-host neutralization differences with increasing VRC01 dose (Jonckheere-Terpstra test, p=0.072). In six VRC01 treated participants who acquired both sensitive (IC80<1{micro}g/ml) and resistant viruses (IC80>3{micro}g/ml), the sensitive lineages declined over time. Recombination was pervasive, observed in 63% of multilineage infections at the time of HIV diagnosis. In one treated participant infected with VRC01 discordant lineages, recombinant viruses preferentially inherited the resistance mutation (binomial p=0.004). In conclusion, our in-depth analysis of breakthrough viruses in the AMP trials revealed a high frequency of multilineage infections, including infections with viruses with different VRC01 sensitivities. This analysis also highlights the role of recombination in shaping intra-host viral evolution and facilitating escape from VRC01. SignificanceThis work advances our understanding of the diversity of initial viral infection and evolution and in vivo activity of broadly neutralizing antibodies (bNAbs). Deep sequencing revealed [~]38% of HIV acquisitions with multiple transmitted founder lineages, higher than previous studies. These occurrences were similar in the placebo and VRC01 groups. Viral recombination among post-acquisition variants was common under antibody selection and appeared to favor resistant sequences in the treatment group. These data suggest as with single antiviral therapy, passive and active immunization of bNAbs should be directed at multiple antigen targets of HIV-1.

molecular biology↗

bioRxiv2025

Acute cold exposure in humans shifts the circulating proteome to a cardioprotective and anti-aging profile

Cold exposure has been proposed to provide a constellation of salutary effects, yet its molecular correlates remain largely unknown. Brown adipose tissue (BAT) is the main site of adaptive thermogenesis, and its prevalence is linked with cardiometabolic health. Since the benefits of BAT activation and cold exposure more generally may be mediated through blood-borne factors, we conducted an extensive analysis of the circulating proteome linked with an acute cold challenge in healthy adults. Our goal was to uncover early molecular changes triggered by cooling and establish their specific relationships with the human brown adipocyte secretome as well as various phenotypic traits. Based on comprehensive inter-cohort validations, we provide the first reproducible proteomic signature of cold exposure in humans. Our data demonstrate that cooling favorably modulates circulating mediators linked with chronological aging, as well as metabolic and cardiovascular diseases, providing new potential biochemical transducers of the benefits associated with cold therapy. HighlightsO_LICooling alters the plasma proteome with striking concordance in independent human cohorts. C_LIO_LICooling represses circulating proteins linked with type 2 diabetes, hypercholesterolemia, hypertension, coronary heart disease and heart failure. C_LIO_LIThe circulating signature of cooling resembles a cardioprotective and anti-aging profile. C_LI

physiology↗