Biology subjects

Martin, M.

Publications and source records attributed to Martin, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Functional heterogeneity, tumor vascularization, and the nonlinear dynamics of metastatic cancer treated by oncolytic viral therapy

Oncolytic viral therapy (OVT) is an emerging cancer treatment where therapeutic viruses are injected into a patient. Models have been developed which describe the interactions of the virus, tumor and immune system through systems of nonlinear ordinary differential equations (ODEs). Some suggest that an initial phase of treatment with immunosuppressants could improve the efficacy of OVT by preventing the immune system from attacking the oncolytic viruses before they can infect many tumor cells. However, all such models have focused on a single, localized tumor. Here, we model a primary tumor and its continuous metastatic seeding of a secondary organ under simplifying assumptions about tumor vascularization. Bifurcation analysis and simulations reveal regions in parameter space for which immune modulation encourages distant metastasis, leading to the dangerous scenario where the elimination of a primary tumor creates the false impression of a good prognosis. We also suggest that vascular disrupting agents may be useful for treating small tumors while they may promote OVT resistance in larger tumors.

cancer biology↗

bioRxiv2026

HIV remodels germinal centers through T follicular helper cell loss

T follicular helper cells (Tfh) within germinal centers are among the most permissive cells for HIV infection and serve as a critical part of the viral reservoir. Given the key role of Tfh in affinity maturation and the production of plasma cells and memory B cells, an understanding of this critical viral reservoir is fundamental not only for cure strategies but also for understanding immunodeficiency in people living with HIV (PLWH). Using rare clinical specimens from PLWH, we demonstrate that HIV causes both a change in the cellular composition of germinal centers and changes in their overall architecture in ways that are consistent with the immunodeficiency seen in PLWH, independent of their CD4 count. We note a significant decrease in the number of GC Tfh cells and an increase in the number of follicular CD8 T cells in lymphoid tissues obtained from PLWH. Our data further show that GC size is decreased both by HIV and with increased age. Single-cell RNA sequencing data demonstrate that HIV acutely decreases the expression of Tfh B-cell support pathways and disrupts Tfh expression of cell trafficking receptors. Additionally, in a lymphoid organoid model of acute infection that forms GC-like structures, these findings are recapitulated, suggesting that New Approach Methodologies could be germane to understanding the impact of HIV on the reservoir and immunodeficiency. This study describes previously undocumented remodeling of the germinal center niche in PLWH, providing insight into the immune microenvironment of a key HIV reservoir that may help inform future cure strategies.

microbiology↗

bioRxiv2026

Relaxin-3 neurons of the zebrafish periaqueductal gray mediate behavioral responses evoked by darkness

Ambient illumination influences many aspects of brain function, including responses to threats. One brain region proposed to mediate these effects is the periaqueductal gray (PAG), an evolutionarily conserved midbrain structure that contains multiple subpopulations of peptidergic neurons. Here we ask which cell types in the larval zebrafish PAG respond to changes in ambient illumination. By registering post hoc gene expression to neurons recorded during exposure to sensory stimuli, we show that GABAergic PAG neurons expressing the neuropeptide Relaxin-3 (rln3a+) are persistently activated by darkness, while a neighboring subpopulation of GABAergic PAG neurons expressing penka is not. Zebrafish lacking rln3a show a reduction in locomotion during darkness. We propose that darkness recruits Relaxin-3-releasing PAG neurons to promote vigilance and potentiate defense circuits. These results identify a specific peptidergic population of PAG neurons that are potentially relevant to behavioral state dysregulation associated with excessive darkness.

neuroscience↗

bioRxiv2026

The two-component microbial system of the black soldier fly larvae (BSFL) gut: a plastic microbiota in the midgut, but a stable one in the hindgut

Due to their highly polyphagous capacities, black soldier fly (Hermetia illucens) larvae (BSFL) are increasingly valued for their ability to convert organic waste into valuable biomass that can be used for a variety of purposes. These remarkable digestive capabilities are highly dependent on an extremely plastic gut microbiota. However, the distribution and functioning of bacterial communities in the various gut compartments - particularly in the hindgut - remain little understood. In this study, we used a metabarcoding approach based on 16S gene sequencing to investigate the effect of three carbohydrate-rich diets with distinct molecular compositions on the functional diversity of the BSFL gut microbiota. Our results showed that the midgut harbors a highly substrate-sensitive microbiota, with a high abundance of Actinomyces spp., regardless of the substrate. A bacterial diversity oriented toward fatty acid biosynthesis pathways is promoted by starch-rich environment, whereas a lignocellulosic substrate fosters a midgut microbiota dominated by Paenibacillus spp. In contrast, the hindgut exhibits a distinctly stable and homogeneous bacterial composition dominated by Dysgonomonas spp. Overall, our results provide clear evidence of a two-compartment microbial system, in which the midgut primarily serves as a substrate-adaptive primary degradation chamber, while the hindgut functions as a stable terminal compartment for the final processing of residual substrates and the recycling of nutrients. These findings contribute to our understanding of the functional diversity of the bacterial microbiota along the BSFL digestive tract, which is a key factor in explaining this insect's remarkable polyphagous behavior and optimizing its use for industrial purposes.

microbiology↗

bioRxiv2026

In utero barcoding of mouse mesoderm reveals the clonal architecture of organ mesenchyme

The mesoderm coordinates organogenesis and generates the cardiovascular, visceral and musculoskeletal systems, yet in mammals this germ layer is difficult to access, impeding its genetic manipulation and study. Here, we establish embryonic day (E) 7.5 exocoelomic cavity nano-injection as a scalable route for selective genetic targeting of mouse mesoderm. Combining in utero lentiviral barcoding with single-cell and spatial transcriptomics, we reconstructed mesodermal and neural crest clonal relationships across >590,000 cells and 31,000 multicellular clones from E9.5-E10.5 embryos and E16.5 livers and hearts. In liver, capsular mesothelium was closely related to hepatic stellate cells, whereas fibroblast and vascular smooth muscle lineages diverged earlier. In heart, epicardium was clonally coupled to three spatially restricted mesenchymal sub-lineages but not to cardiomyocytes, and lineage tracing separated epicardial- and neural crest-derived populations within transcriptionally convergent valve mesenchyme. This approach enables Cre-independent manipulation of mammalian mesoderm and resolves organ mesenchyme development at clonal resolution.

developmental biology↗

bioRxiv2026

The folding, dimerization and allosteric landscapes of the ALS protein SOD1: a comprehensive mutational atlas

Mutations in superoxide dismutase 1 (SOD1) can disturb monomer folding and dimerization, ultimately leading to the development of amyotrophic lateral sclerosis (ALS). Genotype-phenotype knowledge of SOD1 monomer folding and dimerization is largely incomplete, impeding our ability to treat and understand SOD1-ALS. To address this issue, we performed multidimensional deep mutational scanning of [~]6,000 SOD1 variants (amino acid substitutions, insertions, deletions), quantifying folded monomer abundance, and measuring wild-type-variant heterodimerization. Importantly, both abundance and heterodimerization capture pathogenicity, with heterodimerization being a slightly better classifier of pathogenic variants. Notably, [~]80% of pathogenic variants and [~]70% of variants of uncertain significance in SOD1 perturb both monomer abundance and heterodimerization, pointing to protein destabilization as a major driver of SOD1-ALS. Orthogonal validation in mammalian cells shows that protein abundance strongly correlates with other disease-relevant phenotypes, including protein aggregation and toxicity. Although monomer abundance and heterodimerization are strongly coupled, residual effects identify variants that perturb the heterodimer beyond their impact on monomer folding. Mapping residual effects uncovers potential allosteric sites that modulate dimer stability independently of monomer folding, revealing mechanistic insights and potential therapeutic entry points to stabilize SOD1 as a dimer. Together, these results demonstrate that multidimensional phenotype variant mapping improves mechanistic understanding of SOD1 variants and clinical variant interpretation, while uncovering structural targets for SOD1-ALS treatment.

biophysics↗

bioRxiv2026

A High-Confidence Atlas of Protein Methylation Enables AI-Driven Detection of Methylated Peptides

Lysine and arginine methylation regulate chromatin dynamics, transcription, and cellular signaling, however confident mass spectrometry (MS)-based detection and localization of this modification remain challenging. We reanalyzed eight public human methylation-enriched datasets using an open and standardized workflow that integrates database searching via the Trans-Proteomic Pipeline with a decoy-based statistical method for the independent estimation of false localization rates (FLR). This yielded a high-confidence Human Methylation Atlas of 1,828 sites (57 methyl-lysine, 1,771 methyl-arginine) across 1,021 proteins, classified into Gold, Silver, and Bronze confidence tiers. This is far fewer sites than reported in previous studies, reflecting the application of stringent FLR control, and what we hypothesise is potential high-false discovery in previous analyses. We then leveraged this resource to adapt a deep learning-based methodology for the improved detection of methylated peptides. Three mouse methylation-enriched datasets were reanalysed to augment training, and the phosphoproteomics-trained AHLF (ad hoc learning of peptide fragmentation) model was fine-tuned by transfer learning to create AHLF-Methylation. The model achieved mean ROC-AUC values of 0.824 on human spectra, and 0.829 on combined human-mouse spectra. The atlas is available through PTMeXchange and PRIDE, with curated site evidence integrated into UniProt and PeptideAtlas.

bioinformatics↗

bioRxiv2026

The EGFR inhibitor osimertinib promotes a dynamic Drug Tolerant Persister state marked by replication defects and genome instability

Osimertinib is the current standard-of-care for treatment-naive patients with EGFR mutation-positive advanced/metastatic non-small cell lung cancer (NSCLC), however resistance inevitably emerges. Osimertinib does not eradicate all cancer cells even in culture, leaving a long-lasting sub-population of Drug Tolerant Persister (DTP) cells that is common to many chemotherapeutics. The DTP population is non-proliferative and seemingly dormant, but resistant clones eventually emerge from the DTP state. Here we show that extensive DNA replication occurs in the DTP state and cells frequently progress through the cell cycle, though cell death is also frequent, such that cell division and cell loss are balanced and the population remains approximately constant. Cell cycling occurs with aberrant gene expression and abnormal DNA replication pattern, leading to DNA damage, extrachromosomal circular DNA formation and mitotic defects, such that replicating DTP cells are hypersensitive to low doses of ATM and ATR inhibitors. Our findings suggest that the DTP state is highly mutagenic and that targeting DNA repair in DTP cells has the potential to prevent the emergence of resistance through de novo mutations.

Cancer Biology↗

bioRxiv2026

Life-history traits may buffer genetic erosion under isolation in mountain sky-island systems

Sky-island systems provide natural case studies for understanding how geography and Quaternary history shape genomes, phenotypes and life-history traits in mountain endemics. We investigated Xatartia scabra (Apiaceae), a monotypic scree specialist plant species restricted to sky-island summits in the eastern Pyrenees, by integrating population genomics with abiotic condition-informed distribution modeling. Using a ddRAD-seq-like protocol (nGBS), we genotyped 125 individuals (21,970 SNPs), and applied species distribution modeling to identify suitable environmental conditions from the Last Glacial Maximum to 2100. Genetic analyses revealed unexpected genetic "resilience", with moderate genome-wide diversity (HE = 0.17, Ho = 0.15) and low inbreeding (FIS = 0.07), despite small census sizes and strong isolation. Significant overall genetic differentiation (FST = 0.16), with pronounced summit-level structure and strong isolation-by-distance, supports deep valleys as barriers to gene flow. Abiotic niche reconstructions recovered extensive Heinrich Stadial 1 connectivity (+ 58,4% relative to present), followed by postglacial loss of suitable habitats at lower elevations and increasing fragmentation; projections under climate change forecast contraction (-61,2%, relative to present) of climatic suitability, expected to intensify drift in small, isolated populations. Demographic inferences align with this narrative, indicating postglacial decline in effective population sizes. Taken together, genetic, climatic, and demographic evidence supports a transition from historically connected lowland corridors to modern sky islands where distance-limited drift dominates. The maintenance of moderate genetic diversity and low inbreeding under strong isolation suggests that X. scabra may have evolved life-history strategies including outcrossing and monocarpy that allow limiting genetic erosion in such extreme and fragmented environments.

genomics↗

bioRxiv2026

A novel method to select Reference Proteomes in UniProt

MotivationThe ongoing revolution in genome sequencing is delivering an unprecedented number of genome assemblies to global repositories, resulting in an overwhelming amount of data imported to UniProt in the form of proteomes. To manage this growth sustainably, there is a need for a systematic workflow to select the best proteomes. ResultsWe propose a novel pipeline for cellular organisms to select the best Reference Proteomes, i.e. those that best represent the protein space of a species. The pipeline uses a clustering algorithm based on MMseqs2 to select the minimum number of Reference Proteomes whilst maximising the representation of the protein space for each species. Additionally, we aligned our viral Reference Proteomes with the exemplar genome set defined by the International Committee on Taxonomy of Viruses. Because this method ensures that all species are represented with at least one Reference Proteome, the UniProt Knowledgebase increased the number of Reference Proteomes of 36% and covering 34% more species in the Tree of Life. The UniProt Knowledgebase will mainly retain proteins from Reference Proteomes and therefore this method reduces the overall number of proteins by 43%, leading to a more concise yet representative knowledgebase. Availability and Implementationhttps://www.uniprot.org/proteomes Contactraposo@ebi.ac.uk Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2026

PDBe-SIFTS: an open-source tool for Structure Integration with Function, Taxonomy, and Sequences, featuring improved alignment, scoring scheme, and accelerated search

Structure Integration with Function, Taxonomy and Sequences (SIFTS) provides residue-level mappings between UniProt Knowledgebase sequences and Protein Data Bank structures and has historically been generated through internal Protein Data Bank in Europe (PDBe) pipelines. Here, PDBe-SIFTS is presented as a fully open-source, locally deployable implementation of this mapping framework. The pipeline combines fast, scalable sequence search using MMseqs2, an improved bounded scoring scheme for ranking candidate mappings, and residue-level mapping refinement based on backbone connectivity. PDBe-SIFTS is distributed as a Python package with command-line tools for 1) building a sequence search database, 2) identifying the best sequence-structure match, 3) one-to-one mapping at the residue level, and 4) generating SIFTS annotations in PDBx/mmCIF format. Benchmarking on the complete Protein Data Bank archive showed that MMseqs2 reduced archive-scale UniProtKB searches from hours with BLASTP to minutes, approximately 22-36 times faster, while curated mappings were recovered at top rank in 93.1% of cases. The remaining discrepancies mainly involved biologically ambiguous cases such as highly conserved proteins, chimeric constructs, or closely related orthologs. These results show that PDBe-SIFTS enables fast mapping, improving structural coherence in residue-level alignments while delivering the most up-to-date and accurate mappings, comparable to expert curation. Tool: https://github.com/PDBeurope/SIFTS Quick start notebook with example: https://github.com/PDBeurope/SIFTS/tree/master/notebooks Broader audience statementMatching protein sequences to their three-dimensional structures, and mapping annotations across both, is essential for understanding protein function, interactions, and molecular mechanisms. This integrated view enables richer interpretation of biological data and underpins advances in drug discovery, disease research, and protein engineering. PDBe-SIFTS provides an open and functional framework for structure-sequence mapping, allowing researchers and databases to run, inspect, and extend these mappings locally, while benefiting from faster searches, transparent scoring, and structurally informed residue-level alignments. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/721839v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@5e6ea6org.highwire.dtl.DTLVardef@1b2754dorg.highwire.dtl.DTLVardef@1334f9forg.highwire.dtl.DTLVardef@1b083a1_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2026

Otenabant is a Selective Antagonist of Human PIEZO1

Background and purposePIEZO1 mechanosensitive cation channels translate mechanical cues into intracellular Ca2+ and Na+ elevations, enabling cells to respond to physical alterations in their environment. PIEZO1 contributes to red blood cells (RBC) volume homeostasis and gain-of-function PIEZO1 mutations cause hereditary xerocytosis (HX), a rare mostly compensated hemolytic anemia, and aberrant channel activation exacerbates sickling and vascular dysfunction in sickle cell disease. Despite strong genetic and physiological evidence supporting PIEZO1 as a therapeutic target, potent and selective inhibitors are limited, and existing compounds show modest specificity or poorly explored mechanisms. Improved pharmacological tools are needed. Experimental approachWe conducted a high-throughput screen of FDA-approved drugs to identify PIEZO1 inhibitors. Compounds were tested at concentrations of 10 {micro}M in a monocytic cell line, using intracellular Ca2+ elevations evoked by the PIEZO1 agonist Yoda1 as read-out. The inhibitory activity of the best hit was validated and compared to existing PIEZO1 inhibitors using electrophysiological analysis, orthogonal PIEZO1-dependent assays across cell lines and human RBCs. As functional proof, we investigated the impact of three PIEZO1 inhibitors on RBC deformability by ektacytometry, after Yoda1 pre-stimulation. Key resultsThis screen identified Otenabant, a selective Cannabinoid Receptor Type 1 (CB1) antagonist, as a potent PIEZO1 inhibitor. Otenabant dose-dependently inhibited Ca2+ elevations mediated by endogenous or exogenously expressed human PIEZO1, but was ineffective against mouse Piezo1, revealing species-specific channel differences. Otenabant inhibited mechanosensitive currents elicited by shear stress in fibroblasts and by repeated poking in PIEZO1-expressing HEK-293 cells, altering the currents activation and inactivation kinetics, and prevented Yoda1-induced hyperpolarization in RBCs. Otenabant was able to reverse the negative impact of Yoda1 on RBC deformability. Conclusions and implicationsThese findings demonstrate the utility of Yoda-based screening for discovering PIEZO1 antagonists and identify Otenabant as a promising chemical scaffold for developing selective PIEZO1 inhibitors with therapeutic potential.

pharmacology and toxicology↗

bioRxiv2026

Sound-evoked facial motion in ferrets: evidence for species differences in sensorimotor coupling

Sensory stimuli elicit uninstructed movements in the mouse, and cortical activity covaries with these movements, raising the question of how much apparent sensory encoding reflects behaviorally driven signals. Still, whether sounds systematically elicit uninstructed movements in non-rodent species is an open question. Here we characterize sound-evoked facial motion and pupil dynamics in head-fixed ferrets, a carnivore species, passively exposed to broadband, natural, and synthetic auditory stimuli. Ferrets reliably produced facial responses to sounds, but unlike mice, these responses were dominated by a single onset-locked component scaling with sound loudness, tracked only temporal modulations below 2 Hz, and carried no information about sound identity or category. Paradoxically, synthetic sounds, which preserved spectrotemporal statistics but lacked higher-order natural structure, elicited stronger responses than their natural counterparts for several sound categories, suggesting that ferret behavioral responses reflect selective sensitivity to acoustic novelty rather than ecological salience. Pupil dynamics mirrored facial motion, consistent with a shared arousal mechanism. Together, these results show that sound-evoked facial motion in ferrets is less stimulus-specific than in mice, and suggest that the tight sensorimotor integration observed in rodents may reflect a species-specific organization rather than a general mammalian principle.

animal behavior and cognition↗

bioRxiv2026

RNA-DNA triplex-forming miRNAs define an evolutionarily recent chromatin regulatory mechanism

MicroRNAs (miRNAs) are best known for their role in post-transcriptional gene regulation in the cytoplasm. However, a subset of miRNAs has been detected in the nucleus, suggesting additional regulatory functions. Here, we systematically characterize chromatin-associated small non-coding RNAs in the human pancreatic cancer cell line PANC-1. Using chromatin RNA immunoprecipitation coupled with small RNA sequencing, we show that the chromatin-associated small RNA population differs markedly from the bulk nuclear RNA pool and is strongly enriched in miRNAs. Among these, miR-21 represents the most abundant chromatin-associated species. Sequence analyses revealed that a subset of these miRNAs fulfills the requirements for RNA-DNA triplex formation at genomic regulatory regions. Gel-shift assays further demonstrate that Argonaute2 (Ago2) directly interacts with triple-helical nucleic acid structures in vitro, suggesting a potential mechanistic link between triplexes and Ago2-chromatin engagement. Evolutionary analyses indicate that these triplex-forming chromatin-associated miRNAs are largely restricted to anthropoid primates, in contrast to broadly conserved non-triplex-forming miRNAs. Together, our results identify a population of chromatin-associated miRNAs and provide evidence for a potential structural mechanism linking miRNAs, Ago2, and chromatin.

molecular biology↗

bioRxiv2026

Systematic mutational mapping reveals optimal amyloid formation for RIPK function

Amyloid formation, typically associated with neurodegeneration, can also serve essential biological functions. RIPK1 and RIPK3 kinases assemble functional amyloids via their RHIM domains to drive necrosome formation and necroptosis. Here, we systematically map the sequence-function relationship of these domains using deep mutagenesis combined with massively parallel assays that directly report on amyloid nucleation and necroptotic signaling. Analysis of [~]3,000 mutations across RIPK1 and RIPK3 reveals that both proteins rely on a conserved aliphatic tetrad to nucleate amyloids, but diverge mechanistically: RIPK3 nucleation is largely driven by this core interface, whereas RIPK1 requires a second aliphatic surface to achieve efficient nucleation. Cross-species comparisons with mutational atlases from mouse RIPKs show conservation of these principles, underscoring their evolutionary selection. Strikingly, functional outcomes depend on finely balanced nucleation: variants that either reduce or enhance amyloid formation impair necroptosis. Consistently, human population genetics indicates that such variants are extremely rare, suggesting evolutionary optimization of the RHIM domain at a "sweet-spot" of amyloid propensity required for signaling. By linking quantitative mutational landscapes to functional amyloid assembly, this work uncovers how evolution has tuned the amyloid propensity of RIPKs to enable robust cell death signaling. These insights not only advance our understanding of amyloid biology but also provide a framework for therapeutic modulation of necroptosis and for engineering synthetic amyloids with tailored activities.

biophysics↗

bioRxiv2026

A cryptic hybrid zone reveals the genomic basis of flower colour variation in a plant with a large and complex genome

Flower colour is known to be a classic magic trait, undergoing divergent selection pressures exerted by distinct pollinators and involved in reproductive isolation. However, variation at this trait may also results from other eco-evolutionary factors whose interpretation requires throughout context-specific analyses. Here, we investigated the eco-evolutionary causes of pink- and yellow-flowered morphs in Pedicularis comosa where their parapatric ranges form a contact zone in the East of the Pyrenees Mountains. First, we generated a near-chromosome-scale reference genome assembly for this species. We then used a Genotyping By Sequencing approach to infer patterns of genetic diversity and differentiation between populations and morphs at a total of 158 individuals from 11 localities. We found that neutral genetic structure is primarily consistent with geography rather than with colour. However, admixture analyses and clines suggest the existence of a cryptic hybrid zone between morphs. Outlier detection methods and examination of locus-by-locus cline features, then allowed to pinpoint candidate loci to explain colour variation. To gain insight into the functional aspects of these loci, we finally analysed floral transcriptomes and quantified pigments using Liquid Chromatography coupled with Mass Spectrometry (LC-MS) and confirmed the involvement of key genes in the anthocyanin metabolic pathway (e.g. DFR, FLS) and associated pigments (e.g. cyanidin and delphinidin). Our results show that implementing a highly integrative multi-omic approach can allow unraveling the genetic basis and the eco-evolutionary significance of adaptive traits with even very limited previous knowledge, on species with large and complex genomes.

evolutionary biology↗

bioRxiv2026

Shared Maturation Pathways of HIV-1 Envelope-reactive V3-glycan bnAb Lineages in Human and Rhesus Macaque

ABSTRACTUnderstanding broadly neutralizing antibody (bnAb) lineage development in rhesus macaques (RMs) infected with Simian-HIV (SHIV) may inform HIV-1 vaccine designs. We analyzed HIV-1 envelope-antibody coevolution in 18 RMs infected by SHIV.BG505 (subtype A) and found highly conserved patterns of antibody recognition and Env escape, including in three animals that developed V3-glycan bnAbs. From one RM with V3-glycan targeted plasma breadth, we isolated 203 members of a single clonal Ab lineage designated DH1030. DH1030 Abs demonstrated striking genetic, functional and structural similarities with the human V3-glycan bnAb lineage DH270, which was isolated from an individual with subtype C HIV-1 CH848 infection. Notably, human-DH270 and macaque-DH1030 bnAbs shared early improbable mutations in HCDR2 that were critical for bnAb development. Thus, key improbable mutations and convergent patterns of antibody evolution and epitope recognition were shared across primate species and distinct HIV-1 subtypes, findings that may be leveraged in new HIV-1 vaccine designs. ONE SENTENCE SUMMARYBroadly neutralizing antibodies targeting HIV-1 envelope surface protein develop via a common maturation pathway across primate phylogeny.

immunology↗

bioRxiv2026

2-AG as a potential biomarker for predicting response to short-term fluoxetine treatment in a mouse model of depression

Major depressive disorder (MDD) is a complex psychiatric condition with significant individual and social impact and marked variability in treatment response. Identifying biomarkers that predict antidepressant efficacy remains a major challenge, and metabolomic approaches offer a powerful tool to uncover biochemical changes associated with depression and treatment outcome. The prefrontal cortex and the hippocampus are key brain regions involved in the pathophysiology of MDD and antidepressant response. Fluoxetine, one of the most commonly prescribed antidepressants, influences not only serotonergic signaling but also the endocannabinoid system. Accordingly, evaluating endocannabinoid levels in these brain regions might provide critical insight into their contribution to mood disorders and the effect of fluoxetine. To identify biomarkers associated with early antidepressant response, male mice were exposed for 5 weeks to the unpredictable chronic mild stress (UCMS) protocol, with fluoxetine treatment administered during the final week. Liquid chromatography-tandem mass spectrometry analyses of hippocampal and prefrontal cortex samples revealed that the depression-like phenotype induced by UCMS was associated with increased hippocampal anandamide (AEA) levels. Behavioral improvement following short-term fluoxetine treatment was accompanied by enhanced hippocampal 2-arachidonoylglycerol (2-AG), which was associated with reduced GABA and glutamate levels in the prefrontal cortex. These findings suggest that increased 2-AG levels may serve as a predictor of early response to fluoxetine.

neuroscience↗