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bioRxiv2025

Variations in the root-soil system influence the grapevine holobiont by shaping plant physiology and root microbiome

Soil-dwelling bacteria and fungi play a crucial role in plant health and productivity by engaging in complex interactions that shape and are shaped by soil physico-chemical properties. In this study, we employed a multi-omics approach to investigate how variations in soil composition affect the grapevine holobiont. Grape plantlets were grown in three distinct soil types, namely sand, peat, and peat-manure. To further assess how variation in soil and root conditions affects the holobionts response, we included treatments involving soil autoclaving and root surface sterilisation across all soil types. We found that soil type significantly influences leaf multielement composition and concentration, while also shaping the bacterial and fungal communities associated with the plant rhizosphere. This shift led to changes in taxa involved in nitrogen fixation, biocontrol, and pathogenicity. Autoclaving soils consistently reduced bacterial diversity across all soil types, whereas fungal communities were less affected. In contrast, thermal treatment of roots had only a minor impact on microbial community composition but did induce transcriptional changes in the root and altered leaf macronutrient concentrations. Our findings indicate that differences in soil composition reshape the entire root-soil continuum, ultimately affecting plant physiology at multiple levels--from root function to leaf nutrient status. This highlights that the soil is not a passive growth medium but a key determinant of grape holobiont structure and function. These results reinforce the view that plant health and adaptation arise from integrated, dynamic interactions among the host, its associated microbiome, and the surrounding soil matrix.

plant biology↗

bioRxiv2025

Physiologically-based pharmacokinetic model for CAR-T cells delivery and efficacy in solid tumors

Abnormal blood vessels limit the delivery and function of endogenous T cells as well as adoptively transferred Chimeric Antigen Receptor (CAR)-T cells in the tumor microenvironment (TME). We recently showed that vascular normalization using anti-VEGF therapy can overcome these challenges and improve the outcome of CAR-T therapy in glioblastoma models in mice. Here, we developed a physiologically based pharmacokinetic model to simulate the dynamics of both adoptively transferred CAR-T cells and endogenous immune cells in solid tumors following vascular normalization. Similar to our data, our model simulations show that vascular normalization reprograms the TME from immunosuppressive to immunosupportive--enhancing infiltration of endogenous CD8 T cells and CAR-T cells, increasing M1 macrophages, and reducing M2 macrophages and regulatory T cells--thereby improving efficacy. Strikingly, vascular normalization reduces the number of infused CAR-T cells needed for tumor control by an order of magnitude. Moreover, synchronizing a second CAR-T infusion at their peak proliferative phase maximizes antitumor function. Furthermore, the efficacy of CAR-T cells engineered to secrete anti-VEGF antibody depends on the ability of CAR-T cells to induce vascular normalization. Additionally, combining vascular and stromal normalization can improve the efficacy of anti-VEGF antibody-producing FAP-CAR-T cells for the treatment of desmoplastic tumors such as pancreatic ductal adenocarcinoma. Finally, the model predicts that local CAR-T delivery can sustain high concentrations within the TME and induce recruitment of other antitumor immune cells, improving outcomes. Our model provides a versatile framework to optimize dosing strategies, treatment sequencing, and delivery routes for improving CAR-T therapies for solid tumors. Significance Statement Preclinical studies and early clinical trials of CAR-T therapy show encouraging responses in glioblastoma, diffuse midline gliomas, and neuroblastoma, yet substantial obstacles remain for effective CAR-T therapy for solid tumors. Building on our discovery that judicious VEGF blockade normalizes tumor vessels and enhances CD8T-cell infiltration, we developed a mathematical model to optimize CAR-T therapy for solid tumors. Simulations predict that vascular normalization can render the TME immunosupportive and decrease CAR-T doses tenfold. In desmoplastic tumors, FAP-CAR-T efficacy is improved by combining anti-VEGF and stromal normalizing agents. Optimal scheduling and direct intratumoral delivery can mitigate T-cell exhaustion and improve tumor control further. Thus, our model serves as a strategic roadmap for optimal CAR-T deployment in solid tumors.

cancer biology↗

bioRxiv2025

A physiological microfluidic blood-brain-barrier model for in vitro study of nanoparticle trafficking and accumulation

Although the blood-brain barrier (BBB) restricts passage of most molecules, various naturally occurring and synthetic nanoparticles are nonetheless found within the brain parenchyma. To study the mechanisms underlying this phenomenon, we developed a microfluidic BBB model (mBBB) using human cerebral microvascular endothelial cells (HCMECs) in direct contact with primary human astrocytes and pericytes within a physiologically relevant extracellular matrix. The horizontal architecture enables high-resolution imaging across the full barrier interface and allows direct assessment of nanoparticle transport and accumulation. This in vitro platform recapitulates key features of the BBB, including selective permeability, junctional protein expression, and receptor-mediated uptake pathways. Using this system, the trafficking and accumulation of structurally distinct nanoparticles, including liposomes, nanoplastics, and extracellular vesicles (EVs), were compared. Among these, heterologous EVs exhibit the highest transport efficiency. Analysis of nanoparticle properties suggest that ligand presentation and membrane composition, rather than size or stiffness, primarily govern BBB penetration. The mBBB platform provides a high-throughput, imaging-based framework to systematically interrogate nanoparticle trafficking across the BBB and offers a translational tool for both drug delivery and neurotoxicity screening.

bioengineering↗

bioRxiv2025

Genomic and physiological characterization of 'Candidatus Methylocystis sumavensis', a novel acid-tolerant methanotroph from peatland

Methanotrophic bacteria in peatlands mitigate emissions of methane (CH4), a potent greenhouse gas, yet the mechanisms enabling them to remain active under the acidic conditions typical of many peatlands remain poorly understood. Using enrichment cultivation and single-cell sorting, we isolated a novel peatland methanotroph from Czech soil, Methylocystis sumavensis. This species is moderately acidotolerant and active across broad pH and temperature ranges, with growth optima at pH 6.8 and 24-37 {degrees}C. The genome of M. sumavensis encodes two particulate methane monooxygenase isozymes, a clade I nitrous oxide reductase, multiple terminal oxidases, and two [NiFe]-hydrogenases, including a complete complex of the previously uncharacterised membrane-bound hydrogenase group 4f, indicating substantial metabolic versatility. To link genomic potential with physiological function, we compared transcriptomes under acidic (pH 5.0) and alkaline (pH 9.0) conditions relative to the optimum pH (6.8). Under both stresses, M. sumavensis increased transcription of genes involved in membrane remodelling, ion transport across both membranes, and stress response and repair, while reducing transcription of genes associated with methane oxidation and cell division. Alkaline stress additionally suppressed growth through reduced transcription of the carbon-assimilating Serine cycle. In contrast, acidic stress triggered a coordinated response requiring greater energetic investment. Among the most strongly upregulated genes were those encoding two formate dehydrogenases, the branched-chain alpha-keto-acid dehydrogenase complex, and all seven group 4f [NiFe]-hydrogenase-related genes, suggesting enhanced respiratory redox balancing under elevated external proton concentrations. These results reveal key mechanisms of pH-stress adaptation and highlight metabolic plasticity as a major determinant of methanotroph resilience in ecosystems.

microbiology↗

bioRxiv2025

Integrating molecular and physiological approaches to quantify genetic controls for wheat development and improve phenotyping

Disentangling genotype x environment (GxE) effects is critical to understand the performance of wheat across different environments. A framework for doing this was previously presented in a model that integrated knowledge of crop physiology and the Vrn gene feedback loop to explain and predict the time of anthesis. The aims of this study were: 1) provide an updated description of the Cereal Anthesis Molecular Phenology (CAMP) model; 2) to verify the models assumptions regarding the relationship between Vrn gene expression and the timing of phenological stages in a set of diverse genotypes and environments; 3) to use the CAMP model to establish a phenotyping strategy for use in genetic studies and model parameterisation. Six wheat genotypes with a range of cool temperature and photoperiod sensitivities were evaluated. Apical development, final leaf number (FLN) and temporal expression of Vrn1, Vrn2 and Vrn3 were compared with model predictions. There was a clear relationship between FLN responses to cool temperature and photoperiod, the timing of phenological events and the patterns of Vrn gene expression for all genotypes. There was general agreement between the temporal patterns of foliar gene expression observed with those assumed by CAMP, but some obvious discrepancies. These may be related to differences between gene expression in foliar (observed) and apical (assumed by the model) parts of the plant, or differences in the way observed and modelled gene expression are scaled. Overall, the model described all the observed development responses to environment and provides a basis for building quantitative predictions of field-based development from genotypic and environmental data. A protocol is presented for phenotyping wheat using FLN measured in specific combinations of temperature and photoperiod. It allows easy and unconfounded measure of key developmental phenotypes that clearly relate to the genetic make-up of the plants and underlying gene expression profiles.

plant biology↗

bioRxiv2025

Interdependent regulation of trabecular meshwork cell physiology and intraocular pressure by KALRN and TMCO1

Glaucoma is a leading cause of irreversible blindness. Primary open-angle glaucoma (POAG) is its most common form. Higher intraocular pressure (IOP), resulting from impaired aqueous humour outflow, is the cardinal mediating factor, and all proven treatments aim to lower IOP. POAG is a complex genetic disease with numerous loci linked to POAG and higher IOP. The mechanisms by which risk alleles cause disease remain unclear. Here, using primary trabecular meshwork (TM) cells, a cell type controlling outflow, and mice, we found that the POAG-associated gene KALRN encodes an endoplasmic reticulum (ER)-associated Rac regulator essential for TM homeostasis and normal IOP. KALRN loss caused widespread disruption from ER to calcium homeostasis and energy metabolism, leading to induction of cell senescence. KALRN-depletion also led to suppression of the ER translocase and calcium regulator TMCO1, encoded by a gene at one of the most significantly associated genomic loci for POAG. TMCO1-depletion in vitro and in vivo phenocopied KALRN-induced phenotypes, and reduced KALRN expression. These findings establish KALRN and TMCO1 as interdependent regulators of TM homeostasis and IOP, that link regulation of ER and intracellular calcium homeostasis to cell and tissue physiology, and illustrate how different genes linked to glaucoma can form regulatory pathways.

cell biology↗

bioRxiv2025

Modeling the Memory of Unmyelinated Axons: Integration of a Data-Driven Approach with Physiological Memory Concept

In this study, we present a simplified and resource-efficient computational model to predict activity-dependent conduction velocity changes of action in unmyelinated axons. This model serves as a complementary tool to Hodgkin-Huxley models. Our approach is based on the concept of "memory," where the speed of subsequent action potentials is modulated by prior activity. We utilized microneurography data from 95 mechano-insensitive C-fibers of healthy human participants, including both sexes, across various stimulation protocols to optimize model parameters. The model incorporates linear long-term and non-linear short-term memory components. By convolving the history of recorded action potentials with the memory function, the model can effectively predict the propagation speed of subsequent action potentials with low mean squared errors for the proposed one-dimensional and two-dimensional memory functions. This computational framework provides insights into the dynamics of unmyelinated axons under varying conditions and thus in signal processing along the axon and the short-term memory of axons. The models rapid computation times make it suitable for real-time applications in electrophysiological experiments. Significance StatementThis study introduces a novel model for simulating activity-dependent conduction velocity changes in unmyelinated axons, which crucially shape signal processing during conduction. While traditional Hodgkin-Huxley (HH) models offer valuable physiological insights, they are computationally intensive and challenging to adapt due to numerous parameters. Our approach leverages the concept of fiber "memory," capturing how prior activity shapes conduction. It requires fewer parameters and therefore makes it easier to fit to diverse datasets, including patient data. Importantly, our model is highly efficient and suitable for real-time applications, enabling rapid simulation and analysis that are not feasible with HH models.

neuroscience↗

bioRxiv2025

Unraveling the Molecular and Physiological Roles of Signal Peptide Peptidase A (SppA) in Flavobacterium columnare

Columnaris disease, caused by Flavobacterium columnare, represents one of the most economically devastating bacterial infections in global freshwater aquaculture. Despite its significant impact, the molecular mechanisms underlying F. columnare pathogenesis remain largely unexplored due to the challenge in targeted genomic manipulation. Signal peptide peptidase A (SppA) plays a crucial role in bacterial protein secretion by degrading residual signal peptides after protein translocation, yet its function in F. columnare physiology and virulence has not been characterized. Here, we employed a targeted gene deletion approach to investigate the role of sppA in F. columnare. The {Delta}sppA mutant exhibited pleiotropic phenotypes including increased outer membrane vesicle (OMV) production (3.8-fold higher compared to the wild type), reduced biofilm formation, and loss of gliding motility. Transcriptomic analysis of the {Delta}sppA mutant revealed significant upregulation of genes involved in membrane stress response and efflux pump system, including algU, osmC and the genes in the MacAB-TolC efflux system, compared to the wild-type state. Importantly, the artificial infection experiment demonstrated the mutants significantly attenuated virulence in freshwater Medaka (Oryzias latipes), with a 20% higher survival rate of fish compared to the wild type. Our findings reveal that SppA is essential for maintaining membrane homeostasis in F. columnare and serves as one of the virulence factors during columnaris infection. These results provide important insights into the biological function of the sppA gene in F. columnare and highlight the complex relationship between bacterial protein secretion, membrane integrity, and pathogenesis. ImportanceF. columnare causes significant economic loss in freshwater aquaculture. Understanding the molecular mechanisms underlying F. columnare pathogenesis is crucial for developing new ways for disease control. Our findings reveal that SppA is essential for gliding motility, adhesion, biofilm formation and maintaining membrane homeostasis in F. columnare, which serves as one of the virulence factors during columnaris infection. In addition, outer membrane vesicles (OMVs) and MacA/MacB/TolC tripartite efflux pump served as a compensatory mechanism for enhanced peptide metabolites secretion to manage the accumulation of misfolded proteins resulting from the sppA deficiency. These results provide important insights into the biological function of the sppA gene in F. columnare and highlight the complex relationship between bacterial protein secretion, membrane integrity, and pathogenesis.

genetics↗

bioRxiv2025

Exploring the likelihood of the membrane pollution hypothesis with a physiologically plausible biophysical model.

Epilepsy affects more than 52 million people worldwide and has been known since ancient times. Despite this long history, available therapeutic methods--both pharmacological and non-pharmacological--fail to control seizures in over 10% of patients. At the same time, there exists a diversity of theories regarding the fundamental mechanisms underlying epilepsy. Understanding the biophysical basis of the simplest manifestation of epileptic activity--the paroxysmal depolarization shift (PDS)--could therefore be highly valuable. Prevailing ideas consider PDS as exaggerated synaptic excitatory potentials, but experimental evidence shows that PDS can be generated in isolated neurons devoid of synaptic input. Ulrich Altrup proposed an alternative view, suggesting that PDS represent aberrantly large pacemaker potentials rather than giant excitatory postsynaptic potentials. Theoretical work by Hernandez-Caceres and Brenes supported this concept, demonstrating a bifurcation-like transformation from physiological pacemaker potentials to PDS and finally to long-duration sustained depolarizations. According to Altrups membrane pollution hypothesis (MPH), epileptic activity emerges as a consequence of incorporating amphiphilic pollutants into neuronal membranes, which leads to an increase in membrane micro-viscosity. Using a biophysically sound model for pacemaker activity, we explored the possibility of eliciting PDS through increased membrane micro-viscosity. Provided results suggest that this is theoretically plausible. Further experimental and theoretical research is needed to refine details of the MPH and to develop new strategies for combating epilepsy.

neuroscience↗

bioRxiv2025

Reducing Glioblastoma Cell Aggressiveness via Static and Dynamic Magneto-Mechanical Stimulation with Vortex Microdiscs on Substrates of Physiological Stiffness

External mechanical stresses acting on cellular compartments critically regulate cell behaviour and can induce cell death. Magnetically actuated particles present a promising strategy to apply such forces in a controlled manner, with potential applications in cancer therapy. In this study, we investigate the effects of actuating vortex magnetic microdiscs on a glioblastoma cell line cultured on soft, biomimetic substrates that mimic in vivo stiffness. Using a Halbach array, we applied either static mechanical compression or a combination of compressive and low-frequency vibrational stresses (2-20 Hz). Our results demonstrate that both compressive and vibrational stresses impair important cellular functions associated with glioblastoma persistence in a dose-dependent and stiffness-dependent manner. In particular on soft 2D substrates, sufficiently strong compressive loads limit proliferation, while the addition of vibrations alter cell motility, cell morphology and the acto-myosin machinery. Our findings demonstrate that magnetic particles-mediated mechanical stimulation can disrupt glioblastoma cell aggressiveness in physiologically relevant 2D substrates, supporting its potential as an adjunct to conventional chemo-and radiotherapies by both inducing cell death and limiting resistant populations.

biophysics↗

bioRxiv2025

Industrialization drives convergent microbial and physiological shifts in the human metaorganism

Understanding how host lifestyle and industrialization shape the human gut microbiome and intestinal physiology requires multimodal analyses across diverse global host contexts. Here, we generate multivariate data from the Global Microbiome Conservancy cohort, including gut microbiome, IgA-sequencing, host genotyping, diet, lifestyle and fecal biomarker profiles, to investigate host-microbiome interactions across gradients of industrialization and geography. We show that industrialization is associated with homogenized microbial compositions, reduced microbial diversity, and lower community stability, independent of host confounders. We further show that industrialization is linked to elevated markers of gut stress, increased IgA secretion, and altered patterns of IgA-bacteria interactions. Finally, we show that microbiome-based disease predictors trained on industrialized populations lose accuracy in less industrialized cohorts, highlighting limited cross-population transferability. Together, our results suggest profound restructuring of host-microbiome interactions due to industrialized lifestyles, and emphasize the need for inclusive, globally representative data to improve translational microbiome applications across diverse human populations.

microbiology↗

bioRxiv2025

Dicloxacillin and flucloxacillin inhibit hepatic uptake transporters - in vitro investigations and physiological based pharmacokinetic modelling

Dicloxacillin and flucloxacillin are {beta}-lactamase-resistant penicillin antibiotics that have been in clinical use for over 50 years. While both antibiotics are known to induce cytochrome P450 enzymes, there is limited information available regarding their interactions with drug transporters. Here, we investigated the in vitro transport and inhibition of hepatic organic anion transporting polypeptides (OATPs) and renal organic anion transporters (OATs) by these antibiotics in recombinant transporter overexpressing HEK293 cells. We also investigated the transport of these antibiotics by efflux transporters, as well as their inhibition of breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) using a HEK293 membrane vesicle transport assay. Dicloxacillin and flucloxacillin inhibited rosuvastatin transport by OATP1B1, OATP1B3 and OATP2B1, and the inhibition was strongest for OATP1Bs with IC50 values of 3.9 {micro}M and 31 {micro}M (OATP1B1) and 6.7 {micro}M and 21 {micro}M (OATP1B3) for dicloxacillin and flucloxacillin, respectively. Both antibiotics also inhibited BCRP-mediated rosuvastatin transport with IC50 values of 166 {micro}M (dicloxacillin) and 379 {micro}M (flucloxacillin), while P-gp-mediated transport of N-methyl-quinidine was inhibited to a lesser extent. All OATPs and OATs transported dicloxacillin and flucloxacillin. Static model predictions indicated that the inhibition of OATPs, BCRP and P-glycoprotein by both compounds may be clinically relevant. We further developed and verified physiologically based pharmacokinetic (PBPK) models for dicloxacillin and flucloxacillin. PBPK model simulations predicted no major change in rosuvastatin, a substrate for OATPs and BCRP, pharmacokinetics, when co-administered with dicloxacillin or flucloxacillin. Simulations with dicloxacillin and P-gp substrates dabigatran or digoxin also predicted limited inhibition of P-gp transport.

pharmacology and toxicology↗

bioRxiv2025

Hot cue: Physiologically controlled release from an in situ forming liposomal depot

Poor treatment adherence, often referred to as the "silent epidemic", is a growing global issue that significantly contributes to preventable illness, premature death, and rising healthcare costs. Among compliance-enhancing strategies, controlled-release depots designed for intermediate treatment cycles represent a suitable approach, particularly in contexts where frequent dosing is impractical. Current long-acting injectable formulations, though, are often hindered by challenges in injectability, delayed onset, and complex manufacturing. Here, we present a thermoresponsive, in situ forming liposomal depot (TILD) designed to modulate the release of membrane-associated drugs following subcutaneous administration. Using buprenorphine as a model analgesic, we demonstrate that TILD responds to subcutaneous divalent cations with immediate surface-drug release and to body temperature with sustained diffusion through a fluidized bilayer. Molecular simulations guided the system design, and structural and colloidal characterizations validated its responsiveness to physiological cues. In vivo, TILD formed stable depots and maintained therapeutic drug levels for up to four days in both rats and Beagle dogs. Pharmacodynamics studies in rats confirmed the delivery of prolonged analgesia.

pharmacology and toxicology↗

bioRxiv2025

Humidity Controls the Timing and Persistence of Ozone Injury in Citrus: Linking Leaf Physiology and Regional Canopy Responses

Tropospheric ozone (O3) is a major air pollutant that threatens crop productivity, yet its effects depend strongly on environmental conditions that regulate plant O3 uptake. Here, we explore how citrus, an O3-sensitive perennial crop, responds to O3 exposure under humid subtropical (Florida) and semi-arid (California) climates. In controlled chamber experiments, Meyer lemon trees exposed to moderate O3 concentrations (80 ppb for 4 h d-1 over four days) showed a faster and more persistent decline in the maximum photosystem II efficiency (Fv/Fm) under humid air, while under dry air the response was delayed by one day and reversible. This humidity-dependent behavior reflects differences in stomatal conductance (gs) where high humidity maintains open stomata and accelerates O3 flux and dry air limits uptake but enhances slower non-stomatal injury pathways. At regional scale, satellite solar-induced chlorophyll fluorescence (SIF) from Sentinel-5P TROPOMI revealed similar patterns. In Florida, SIF decreased significantly during O3-episode weeks and remained low for up to three weeks, while in California it showed a brief rebound before a delayed decline - mirroring the timing observed in the chamber experiment. Analysis of the SIF and gross primary productivity (GPP) relationship further showed that O3 decoupled canopy fluorescence from productivity in the dry region, whereas drought stress weakened this coupling in the humid region, indicating a climate-specific shift in the dominant stressor. We demonstrate and argue that humidity governs both the timing and persistence of O3 injury, linking leaf-level physiology to regional canopy responses. These findings emphasize that effective O3-risk assessments for perennial crops must incorporate local humidity and vapor pressure deficit conditions and both stomatal and non-stomatal deposition pathways.

biochemistry↗

bioRxiv2025

Effects of Social Status on Reproductive Success, Physiology and Maternal Care in Socially housed Female Rhesus Macaques

This study examined the long-term effects of low social status on reproductive success and seasonal changes in reproductive and stress hormones of adult female rhesus macaques. Rhesus are a matriarchal, matrilineal species that form hierarchical social hierarchies maintained by aggression. Thus, animals in the bottom of the hierarchy (low social status: subordinate) experience high levels of aggression from those in higher social ranks and therefore must remain vigilant. Social subordination generates chronic psychosocial stress and could negatively impact reproductive function. Twenty-seven adult female rhesus monkeys (13 dominant -DOM-, 14 subordinate -SUB-; 8-11 years old) were studied for stress neuroendocrine function -measuring basal plasma levels of cortisol-, as well as for reproductive endocrine function -measuring basal levels of estradiol (E2). In addition, we examined the reproductive success rates of these females (defined as number of live births/years with male access), their success rates raising infants that survived to 1 year, and the characteristics and effectiveness of their maternal care. Our findings show significantly lower reproductive success rates in SUB than DOM females, blunted E2 seasonal changes, driven by higher E2 levels in the anovulatory season and more attentive maternal care of offspring early in life than dominant females. Age at first birth was negatively associated with infant survival rate across ranks. Interestingly, higher levels of reproductive hormones (E2) during the anovulatory season predicted lower reproductive success, although the effect was driven by animals lactating at that point. Overall, these findings suggest that subordinate female macaques show a phenotype consistent with impaired reproductive function. Simple SummaryThis study examined the long-term effects of low social status on reproductive success and seasonality of reproductive and stress physiology of female rhesus monkeys. The despotic rhesus social hierarchy is matrilineal and maintained by aggression. Males leave their natal group in bachelor groups around puberty, but females remain, so social status of group members is passed down the female line. Rhesus with low social status (subordinate) experience significantly more aggression and harassment than their higher-ranking counter parts (dominant). This makes rhesus macaques an ideal model for studying chronic psychosocial stress and its long-term effects. Our findings show significantly lower reproductive success rates (number of live births based on access to males; lower infant survival rates) in subordinate than dominant females. Subordinate females also show blunted seasonal changes of the gonadal hormone estradiol (E2), driven by higher E2 levels in the anovulatory season than dominant animals, as well as more attentive maternal care of offspring early in life than dominant animals. Age at first birth was negatively associated with infant survival rate across ranks. Interestingly, higher levels of reproductive hormones (E2) during the anovulatory season were associated with lower reproductive success, although the effect was driven by animals lactating at that point. Overall, these findings suggest that female macaques with lower social status show a phenotype consistent with impaired reproductive function, though the biological mechanisms involved need to be further explored.

developmental biology↗

bioRxiv2025

The mammalian rapid tRNA decay pathway is critical for N⁷-methylguanosine-hypomodified tRNA degradation under physiological conditions

Chemical modifications of transfer RNAs (tRNAs) are integral to their stability and to translation. Loss of N7-methylguanosine (m7G) on specific tRNAs reduces their steady-state abundance and impairs translation in mammals, but whether these decreases reflect active degradation under physiological growth conditions is unresolved. Here, using human HCT116 cells, we show that knockdown of the 5'[->]3' exonuclease, XRN2, restores tRNA levels diminished by METTL1 depletion. Leveraging conditional protein knockdown, we performed time-resolved measurements of mature tRNA levels and directly quantified decay kinetics. We show that in the absence of heat stress, mG-hypomodified tRNAs undergo XRN2-dependent accelerated decay. Finally, partial loss of the Drosophila XRN2 ortholog, Rat1, genetically rescues male sterility of mettl1 mutants, demonstrating organismal relevance. These findings define a conserved constitutive rapid tRNA decay pathway in mammals and indicate inhibition of tRNA decay as a potential therapeutic strategy in disorders caused by tRNA hypomodification.

molecular biology↗

bioRxiv2025

Structural basis and physiological significance of non-canonical Gs coupling to the prototypical Gi-coupled melatonin MT1 receptor

G protein-coupled receptors (GPCRs) transduce extracellular stimuli into intracellular signals by coupling to various heterotrimeric G proteins. However, the rules governing G protein preference remain largely elusive. MT1 and MT2 are prototypical Gi/o-coupled GPCRs responding to melatonin, a hormone secreted in a circadian manner. We show here that MT1, but not MT2, couples also to Gs proteins in vitro and activates the Gs/cAMP pathway upon long-term melatonin exposure in vivo, mimicking physiological dawn conditions. We solved the cryo-electron microscopy structure of the melatonin-MT1-Gs complex at 3.0[A] resolution, which revealed a strikingly distinct binding mode compared to the MT1-Gi complex. The third intracellular loop of MT1 emerges as a key stabilizer for Gs coupling, a feature previously unrecognized. This is the first solved receptor-Gs complex of a primary Gi-coupled GPCRs, providing new structural and functional insights into G protein selectivity and circadian switch of G protein coupling.

molecular biology↗

bioRxiv2025

Machine Learning Identifies Common Risk Variants and Implicates Abnormal Vision Physiology in ASD

Genomic technology advancements have facilitated associations between genetic variants and disease risk. Rare deleterious variants can independently induce disease, while common variants collectively enhance susceptibility with minimal individual effects. The nuanced nature of common variant consequences attenuates their identification. Autism spectrum disorders (ASD) are hereditary neurodevelopmental disorders. Atypical eye-gaze responses frequently occur in ASD; however, this phenotype has been overlooked in genetic studies. Using WizWhy, an interpretable machine learning tool, to analyze the Autism Sequencing Consortium (ASC) data, 210 common variants across 177 genes were associated with ASD risk. This association is supported by significant overlap with the SFARI gene database and relevant gene ontologies. Individuals with a higher variant burden are at increased ASD risk. Notably, 52 genes were linked to abnormal eye physiology, underscoring the role of this pathway in ASD etiology. Focusing on specific hub genes as potential pharmacological targets may benefit patients with ASD.

genetics↗