Biology subjects

Martinez, C.

Publications and source records attributed to Martinez, C..

At least 19 recordsLinked to original sources

bioRxiv2026

Habitat impacts the diversification of adhesive discs and skull shape in clingfishes

Specialized suction discs are functional innovations that enable fishes to attach to diverse surfaces and resist hydrodynamic forces. The adhesive discs of clingfishes (Gobiesocidae) vary in size and shape, but it is unclear how ecological factors have influenced their morphological evolution. Here we analyzed the disc and skull shape of 74 clingfish species using micro-CT scanning and 3D geometric morphometrics to investigate the role of habitat and substrate use on patterns of diversification. We also present novel comparisons of adhesive performance for 10 clingfish species. Clingfish interface directly with their environment using their adhesive discs, but we found that the disc and skulls are evolutionary integrated and share similar responses to habitat. Transitions from coastal habitats to coral reefs promoted elevated rates of evolution and morphological disparity across the body, whereas transitions to freshwater did not. Concurrently, repeated shifts from living on hard substrates to softer substrates (i.e., macroalgae and seagrass) were associated with more constrained disc shapes, convergent morphologies, and differences in adhesive performance. We propose that habitat and substrate use make complementary contributions to skeletal diversification in clingfishes, but the adhesive system requires further investigation to disentangle the complex interactions between form and function.

evolutionary biology↗

bioRxiv2026

Nuclear adenosine metabolism defines a metabolic vulnerability unmasked by TP53 loss

Metabolic adaptation is essential for cells experiencing chronic genomic stress, yet how such adaptations are organized at the nuclear level remains poorly understood. Loss of TP53 is associated with elevated genomic instability, DNA damage and altered metabolic requirements, creating context specific dependencies. Here, we identify a requirement for de novo purine biosynthesis in TP53-deficient cells, with a pronounced dependence on adenosine related metabolism. Perturbation of purine synthesis increases DNA damage and reduces nuclear ATP availability, particularly in TP53-deficient cells, and is accompanied by a rapid increase in histone methylation. This chromatin response is also induced by acute DNA damage and occurs with fast kinetics, indicating that histone methylation is an early, intrinsic feature of the nuclear stress response rather than a secondary epigenetic remodeling. Interfering with histone methylation is associated with reduced nuclear ATP levels and impaired DNA damage resolution, linking chromatin state to nuclear energy homeostasis. Genetic disruption of the purine biosynthesis enzyme PFAS selectively impairs the growth of TP53-deficient tumours in vivo, establishing the physiological relevance of this metabolic dependency. Together, these findings reveal nuclear adenosine metabolism as a compartmentalised adaptive response to genotoxic stress and highlight chromatin associated methylation as a key feature of nuclear metabolic regulation unmasked by TP53 loss.

cancer biology↗

bioRxiv2026

Macroevolutionary consequences of twin neck innovations in deep-sea dragonfishes

The origin of novel phenotypes can influence access to new ecological resources, which may have positive, neutral, or negative effects on subsequent phenotypic diversification. In this study, we tested the macroevolutionary consequences of a pair of putative functional innovations occurring in deep-sea fishes of the order Stomiiformes. Integrating phylogenetic comparative methods, micro-CT scans, and external body measurements, we recover a mosaic of diversification trends associated with these innovations. We found some evidence for elevated evolutionary rates in tooth morphology associated with the predatory dragonfishes, which possess a gap between their vertebral column and skull that exposes the notochord and enables neck-like flexibility. However, a second novelty building upon the first, a functional neck joint enabling extreme cranial kinesis, was linked to faster rates of skull evolution. Our results suggest that innovations that help shift ecological roles and overcome functional constraints related to those roles, like gape-limitation in prey depauperate habitats, may play an important role in promoting phenotypic diversification. This work builds on a growing body of evidence highlighting how the deep sea promotes phenotypic diversity, generating the extreme forms that are celebrated by scientists and the public alike.

evolutionary biology↗

bioRxiv2026

Focal radiotherapy improves CAR T cell therapy targeting prostate cancer

Chimeric antigen receptor (CAR) T cell therapy has limited efficacy against solid tumors such as prostate cancer due to the immunosuppressive tumor microenvironment (TME). Combining CAR T cells with existing therapies that remodel the TME and promote endogenous immune responses, such as radiation therapy and chemotherapies, may strengthen antitumor responses. Here, we assessed the potency of combining focal radiotherapy (RT), cyclophosphamide (Cy) preconditioning, and prostate stem cell antigen (PSCA)-CAR T cells against syngeneic prostate cancer models. Focal RT alone increased T cell and dendritic cell infiltration and activation in the irradiated tumor. Furthermore, the combination of all three therapies was critical for enhanced antitumor responses and survival across multiple subcutaneous, bone-metastatic, and multifocal disease models. This combination, in the irradiated TME and tumor-draining lymph nodes (tdLN), led to greater antigen presentation by myeloid cells and endogenous T cell activation and cytotoxicity. Our study demonstrates the potency of combining focal RT with PSCA-CAR T cells, significantly improving therapeutic responses in the irradiated tumor and contributing to a more robust systemic immune response against metastatic burden in prostate cancer.

Cancer Biology↗

bioRxiv2026

A single-nucleus multiome analysis of transcriptome and chromatin accessibility reveals cell-type-specific immune modulation for chronic cannabis use among people with HIV infection

As cannabis use continues to rise among people with HIV (PWH), understanding its impact on immune function in this population is becoming increasingly important. To provide new insights on how cannabis modulates immune function, we analyzed single-nucleus multi-omic profiles of peripheral blood mononuclear cells (PBMCs) from PWH to characterize the changes in gene expression and chromatin accessibility associated with chronic cannabis exposure. We identified numerous differentially expressed genes (DEGs) between cannabis users and non-users in each cell type, approximately half of which were unique to individual cell types. Changes in pro- and anti-inflammatory gene expression associated with cannabis use are dependent on cell lineage and type. We identified hundreds of differential chromatin accessibility regions in each cell type, including cis-regulatory elements correlated with cell-type-dependent DEGs (e.g. NFKBIA in CD4+ T cells and CCL3L1 in classical monocytes). Multiple cannabis-associated transcription factors (e.g., NFKB1, FOS, and TCF7) emerge as regulators of the differentially expressed inflammatory genes. Furthermore, cannabis altered the communication between classical monocytes and lymphocytes. These findings indicate that cannabis-induced immunomodulatory effects are profound, dynamic and complex among cell types and that transcriptional changes are regulated at least in part by epigenetic mechanisms.

genomics↗

bioRxiv2025

Oral immune priming modulates microbiota composition and supports pathogen control in the Manila clam (Ruditapes philippinarum)

Immunological memory was long considered an exclusive feature of vertebrates. However, extensive evidence now shows that invertebrates possess forms of innate immune memory--known as immune priming-- where previous exposure to a pathogen enhances subsequent immune responses and host protection. Immune priming has been proposed as a promising strategy for disease prevention in shellfish aquaculture. However, immune priming remains largely unexplored in marine bivalves, particularly in the Manila clam (Ruditapes philippinarum), a top-ten global aquaculture species. Here, we investigated for the first time the effects of oral immune priming on host survival, pathogen dynamics, and microbiota composition in R. philippinarum against the emergent bivalve pathogen V. europaeus. Priming was induced using the live bacterial pathogen at a sublethal dose, followed by a lethal secondary exposure. Primed clams exhibited a significant survival following the second challenge (87% survival vs. 0% in non-primed clams), demonstrating robust protection against reinfection. Quantitative PCR (qPCR) revealed that primed clams rapidly reduced pathogen loads after 48 h during the second challenge, reaching concentrations below the mortality threshold observed in non-primed clams ([~]105 copies mg-{superscript 1}). Interestingly, the pathogen was able to persist at low and non-harmful concentration ([~]102 copies mg-{superscript 1}) in primed clams along both challenges. Full-length 16S rRNA metabarcoding analyses showed that immune priming shifts the host microbiota. Alpha and beta diversity indicated a progressive reduction in diversity and the establishment of a specific and resilient bacterial community in primed clams. Clustering analyses identified a priming-associated microbiota dominated by Acinetobacter, Brevundimonas, Sphingobium, and Psychrobacter, which persisted through the secondary challenge but was absent or depleted in non-primed clams. Conversely, members of the Arcobacteraceae (e.g., Arcobacter, Poseidonibacter) were absent after priming and emerged only during second infection, decreasing in primed clams but increasing in non-primed clams coinciding with high mortalities. Our findings provide the first phenotypic and microbiome-level evidence of oral immune priming in Manila clam. Here we demonstrate that priming enhances pathogen control and promotes the establishment of a protective microbiota that may interact with the host immune system to confer resistance against bacterial infection. These results open new avenues for immune-priming and microbiota-based strategies to improve disease resistance in bivalve aquaculture.

microbiology↗

bioRxiv2025

Hybrid modeling framework for bioprocesses with minimal prior knowledge and limited data

Hybrid models that couple mechanistic ordinary differential equations (ODEs) with neural networks are increasingly used in bioprocess engineering, yet most published approaches assume either substantial prior knowledge or relatively large datasets. This work proposes a hybrid modeling framework for early-stage bioprocess development, where only a few batch experiments are available and standard artificial intelligence (AI) techniques are difficult to apply. The mechanistic structure is constructed using only qualitative, widely accepted biological constraints (e.g., non-negativity, zero-invariance, and biomass-mediated interactions), while unknown functional dependencies are learned by a feedforward neural network embedded in the ODE right-hand side. To exploit the natural organization of batch data, we introduce a minibatch training strategy in which each minibatch corresponds to one entire batch experiment, combined with regularization to mitigate overfitting. We demonstrate the approach on (i) synthetic Escherichia coli growth with overflow metabolism and (ii) experimental astaxanthin production by Xanthophyllomyces dendrorhous. In both cases, models trained from as few as three batch experiments accurately predict an unseen validation batch and the learned neural components recover biologically consistent patterns. Thus, the framework contributes to AI by enabling constrained neural differential models that learn interpretable dynamics from limited, structured data, with applications to early-stage bioprocess engineering.

bioengineering↗

bioRxiv2025

MaxGeomHash: An Algorithm for Variable-Size Random Sampling of Distinct Elements

With the surge in sequencing data generated from an ever-expanding range of biological studies, designing scalable computational techniques has become essential. One effective strategy to enable large-scale computation is to split long DNA or protein sequences into k-mers, and summarize large k-mer sets into compact random samples (a.k.a. sketches). These random samples allow for rapid estimation of similarity metrics such as Jaccard or cosine, and thus facilitate scalable computations such as fast similarity search, classification, and clustering. Popular sketching tools in bioinformatics include Mash and sourmash. Mash uses the MinHash algorithm to generate fixed-size sketches; while sourmash employs FracMinHash, which produces sketches whose size scales linearly with the total number of k-mers. Here, we introduce a novel sketching algorithm, MO_SCPLOWAXC_SCPLOWGO_SCPLOWEOMC_SCPLOWHO_SCPLOWASHC_SCPLOW, which for a specified integer parameter b [≥] 1, will produce, without prior knowledge of n (the number of k-mers) a random sample of size b lg(n/b) + [O](b). Notably, this is the first permutation-invariant and parallelizable sketching algorithm to date that can produce sub-linear sketches, to the best of our knowledge. We also introduce a variant, -MO_SCPLOWAXC_SCPLOWGO_SCPLOWEOMC_SCPLOWHO_SCPLOWASHC_SCPLOW, that produces sketches of size{Theta} (n) for a given [isin] (0, 1). We study the algorithms properties, analyze generated sample sizes, verify theoretical results empirically, provide a fast implementation, and investigate similarity estimate quality. With intermediate-sized samples between constant (MinHash) and linear (FracMinHash), MO_SCPLOWAXC_SCPLOWGO_SCPLOWEOMC_SCPLOWHO_SCPLOWASHC_SCPLOW balances efficiency (smaller samples need less storage and processing) with accuracy (larger samples yield better estimates). On genomic datasets, we demonstrate that MO_SCPLOWAXC_SCPLOWGO_SCPLOWEOMC_SCPLOWHO_SCPLOWASHC_SCPLOW sketches can be used to compute a similarity tree (proxy for a phylogenetic tree) more accurately than MinHash, and more efficiently than FracMinHash. Our C++ implementation is available at: github.com/mahmudhera/kmer-sketch. Code to reproduce the analyses and experiments is at: github.com/KoslickiLab/MaxGeomHash.

bioinformatics↗

bioRxiv2025

Assessing the molecular and phenotypic contribution of a horizontally acquired region to yeast adaptation

Horizontal Gene Transfer (HGT) is the movement of genetic material across species. In Saccharomyces cerevisiae, a DNA segment known as Region B was acquired horizontally from a distant yeast species. This region ([~]17 Kb) encodes 5 genes and is present in the genomes of yeast strains from different phylogenetic clades, with its contribution to yeast niche-specific adaptation remaining unclear. In this work, the genomic structure of Region B was analyzed in yeast strains from the ScRAP (Saccharomyces cerevisiae Reference Assembly Panel) collection, identifying 10 variants that maintain a circular continuity. To assess the role of Region B in yeast adaptation, we performed a high-throughput phenotyping of the ScRAP collection under different growth conditions, identifying that Region B is potentially associated with higher tolerance to oxidative stress. Then, we selected a single yeast strain from the ScRAP collection for characterization of the transcriptional activity of each gene within Region B using a fluorescent reporter. The results revealed that gene expression depends on the hosts genetic background and transcription factors encoded within Region B. To identify the genetic determinants involved in Region B expression within different genetic backgrounds, three expression Quantitative Trait Loci (eQTLs) were mapped and validated. Finally, by performing Region B deletion, we determine the contribution of this region to different fermentative phenotypes, including fermentation rate and amino acid consumption. Altogether, our results suggest a complex regulatory interaction between the horizontally acquired genes and the host genome that contributes to yeast adaptation under fermentation conditions.

molecular biology↗

bioRxiv2025

Deciphering the pangenome of the shellfish pathogen Vibrio europaeus: Evolutionary history and functional impact of core and accessory genes in aquaculture.

Vibrio europaeus is an important pathogen in shellfish aquaculture, yet its genomic diversity and adaptive potential remain poorly understood. Here, we present the first comprehensive analysis of the V. europaeus pangenome, integrating genomic data from all strains available to the date sequenced specifically for this study. Those were isolated from different aquaculture facilities (shellfish hatcheries) associated to mass mollusks mortalities from different geographical locations, years and host species. Our findings revealed an open pangenome with the 61% of the genes associated to the accessory genome that contributes to environmental and host adaptations. Phylogenomic analyses of the core-genome (39% of the pangenome size) allowed to evaluate the evolutionary history and intraspecific diversity of V. europaeus and revealed that Spanish strains displayed a much lower genetic variability than French, Chilean or American strains, probably due to a monophyletic radiation event. Functional annotation of core and accessory genes revealed the key virulence factors of the species while it also disclosed that those are located mainly into the core genes. The high number of anti-phage defense systems encoded in the accessory genome explained almost all the variability of the species. The results provide important insights into the evolutionary history and ecological versatility of V. europaeus, with potential implications for diagnostics, epidemiological surveillance, and disease management strategies in aquaculture. Impact statementThis study presents the first comprehensive pangenome analysis of Vibrio europaeus, an emergent pathogen responsible for severe economic losses in shellfish aquaculture, the second most important sector of global aquaculture. Here, we characterized for the first time the V. europaeus pangenome, integrating genomic data from all strains isolated to date, sequenced specifically for this study using NGS and/or third-generation (PacBio) technologies. This work achieved the most complete species pangenome to date and is among the first studies on aquaculture-related bacterial pathogens. Beyond a descriptive framework, the pangenome was critically examined to identify key traits, including virulence factors, secondary metabolite biosynthesis, and antimicrobial resistance genes, essential for host infection and adaptation. Moreover, the study of anti-phage defense systems was shown to account for much of the species genomic variability. The genomic resources and insights generated here substantially expand our understanding of V. europaeus biology and provide valuable information that can be applied for diagnostics, epidemiological surveillance, and sustainable management of this pathogen in aquaculture industry. Data summaryAll genome assemblies have been uploaded to the National Center for Biotechnology Information. The GenBank accession numbers for each of the 39 strains used in this study and detailed information can be found in Table S1. All bioinformatics tools used for comparative genomics have been listed in the Methods section including references, associated databases and analysis parameters.

microbiology↗

bioRxiv2025

Adaptive radiation along ecological and morphological lines of least resistance in Cyprinodon pupfishes

Adaptive radiation results in part from ecological opportunity in a new environment, but it is unclear how pre-existing constraints in the founding population may limit this process. Genetic lines of least resistance, and by proxy morphological variance, are known to limit adaptive divergence, but ecological variance is rarely investigated. Here we test whether ecological or morphological lines of least resistance in generalist populations may have constrained the directions of species divergence in two independent Caribbean adaptive radiations of Cyprinodon pupfishes. We find almost universal congruence between the major multivariate dimensions of intraspecific craniofacial and dietary variance within generalist populations and the major axes of interspecific divergence within each adaptive radiation. This is surprising given that we document unique trophic specialists within each radiation, including a bivalve-specialist, zooplanktivore, molluscivore/ostracod-specialist, and scale-eating specialist, while nearly all generalist populations were observed to feed rarely on these same resources. We conclude that pre-existing genetic constraints within each founding generalist population, resulting in dimensions of greater ecological and morphological variance, may partially constrain and predict the directions of species divergence and dietary specialization during adaptive radiation. We also provide a new framework for examining ecological lines of least resistance.

evolutionary biology↗

bioRxiv2025

CactEcoDB: Trait, spatial, environmental, phylogenetic and diversification data for the cactus family

Integrated datasets linking traits, spatial distributions, environmental variables and phylogenies are essential for comparative research, but remain limited for many plant taxa, including those which are most threatened. Cactaceae are a morphologically and ecologically diverse succulent family that are iconic components of ecosystems across the Americas, and face high extinction risk. To support future comparative research, we present CactEcoDB (The Cactus Ecological Database), an Open Access dataset of curated spatial, ecological, trait, phylogenetic, and diversification data for over 1,000 cactus species. CactEcoDB includes species-level trait data, geographic occurrence records, environmental variables, range size estimates, speciation rates, and the largest time-calibrated phylogeny of cacti to date. By integrating these diverse data in a single platform, CactEcoDB enables analyses of trait evolution, trait-environment interactions, biogeography, climatic niche evolution, and macroevolutionary dynamics in one of the most celebrated and threatened plant families.

evolutionary biology↗

bioRxiv2025

A Single Population Approach to Modeling Growth and Decay in Batch Bioreactors

Fitting dynamic models to population data such as the logistic growth equation is a common practice for describing microbial growth, both in natural ecosystems and under research conditions. However, these models are limited to scenarios where the population stabilizes at equilibrium, making them unsuitable for systems like batch bioreactors, where populations decline after substrate depletion. In this work, we propose two new population models capable of accurately describing such dynamics while maintaining an interpretable structure in which each parameter has a biological meaning. These models incorporate the growth rate as a function of cumulative biomass, rather than solely the biomass concentration, thereby accounting for memory effects. We establish fundamental properties of these models and demonstrate their applicability and accuracy to describe data from batch bioreactors.

bioengineering↗

bioRxiv2025

Solid tumor CAR T cells engineered with fusion proteins targeting PDL1 for localized IL-12 delivery

CAR T cell efficacy in solid tumors is limited due in part to the immunosuppressive TME. To improve anti-tumor responses, we hypothesized that enabling CAR T cells to secrete bifunctional fusion proteins consisting of a cytokine modifier (e.g., TGF{beta}trap, IL15, or IL12) combined with an immune checkpoint inhibitor (e.g., PDL1) will provide tumor localized immunomodulation to improve CAR T cell functionality. To that end, we engineered CAR T cells to secrete TGF{beta}trap, IL15, or IL12 molecules fused to PDL1 scFv, and assessed in vitro functionality and in vivo safety and efficacy in prostate and ovarian cancer models. CAR T cells engineered with PDL1-IL12 were superior in safety and efficacy compared to CAR T cells alone and to those engineered with PDL1 fused with TGF{beta}trap or IL15. Further, PDL1-IL12 engineered CAR T cells improved T cell trafficking and tumor infiltration, localized IFN{gamma} production, TME modulation, and anti-tumor responses, with reduced systemic inflammation-associated toxicities. We believe our PDL1-IL12 engineering strategy presents an opportunity to improve CAR T cell clinical efficacy and safety across multiple solid tumor types.

bioengineering↗

bioRxiv2025

Oral dosing of the nucleoside analog obeldesivir is efficacious against RSV infection in African green monkeys

Respiratory syncytial virus (RSV) is a significant cause of morbidity and mortality in high-risk populations. Although prophylactic options are available, there are no effective oral therapeutics for RSV infection. Obeldesivir (ODV) is an orally bioavailable prodrug of the nucleoside analog GS-441524, which is converted intracellularly to its active nucleoside triphosphate and inhibits the RSV RNA polymerase. Here we report the potent antiviral activity of ODV against geographically and temporally diverse RSV A and B clinical isolates (EC50: 0.20-0.66 M). Resistance selection studies with ODV and GS-441524 against RSV identified a single amino acid substitution, I777L, in the L polymerase with reduced susceptibility (3.3-3.8-fold) to ODV and GS-441524, indicating a high barrier for resistance development. In an African green monkey RSV infection model, once-daily oral ODV doses of 30 or 90 mg/kg initiated [~]24 hours post-infection significantly reduced log10 viral RNA copies/mLxday area under the curve by 69-92% in the upper and lower respiratory tracts. Together, these preclinical data support the clinical evaluation of ODV for the treatment of RSV infection.

microbiology↗

bioRxiv2025

Inhibition of EMT driver PTK6 enhances anti-tumor immune responses against triple-negative breast cancer

The non-receptor tyrosine kinase PTK6 is expressed in 70% of triple negative breast cancers (TNBC) and is an oncogenic driver of epithelial-mesenchymal transition (EMT). EMT promotes metastasis and immune evasion of TNBC. Therefore, targeting EMT drivers could reverse these properties and lead to more favorable outcomes. Treatment of TNBC tumors with a small molecule inhibitor of PTK6 kinase (P21d) suppressed their growth in vivo. Tumor inhibition by P21d is dependent on an induced immune response because: 1) inhibition is observed in immunocompetent, but not immunodeficient, mice; 2) P21d increases tumor-infiltrating CD8+ T and NK cells and decreases immunosuppressive myeloid-derived suppressor cells; and 3) tumor inhibition by P21d is abrogated by co-treatment with NK or CD8+ T cell-depleting antibodies. These effects on tumor growth and cytotoxic TILs are phenocopied by the knockdown of tumoral PTK6 or SNAIL, which supports EMT inhibition as a mechanism for enhanced anti-tumor immune response. RNA sequencing (RNA-seq) profiling of P21d-treated tumors also revealed changes consistent with activation of the immune response and identified CXCL10 as a critical chemokine induced intratumorally by P21d that promotes recruitment of NK/CD8+ T cells to the tumor site, leading to tumor growth inhibition. Our study highlights the novel tumor immune microenvironmental functions of PTK6 with important consequences for tumor growth that could lead to new immunotherapeutic approaches for TNBC.

cancer biology↗

bioRxiv2024

Optogenetic control of a horizontally acquired region in yeast prevent stuck fermentations

Nitrogen limitations in the grape must is the main cause of stuck fermentations during the winemaking process. In Saccharomyces cerevisiae, a genetic segment known as region A, which harbors 12 protein-coding genes, was acquired horizontally from a phylogenetically distant yeast species. This region is mainly present in the genome of wine yeast strains, carrying genes that have been associated with nitrogen utilization. Despite the putative importance of region A in yeast fermentation, its contribution to the fermentative process is largely unknown. In this work, we used a wine yeast strain to evaluate the contribution of region A to the fermentation process. To do this, we first sequenced the genome of the wine yeast strain known as ALL using long-read sequencing and determined that region A is present in a single copy with two possible subtelomeric locations. We then implemented an optogenetic system in this wine yeast strain to precisely regulate the expression of each gene inside this region, generating a collection of 12 strains that allow for light- activated gene expression. To evaluate the role of these genes during fermentation, we assayed this collection using microculture and fermentation experiments in synthetic must with varying amounts of nitrogen concentration. Our results show that changes in gene expression for genes within this region can impact growth parameters and fermentation rate. We additionally found that the expression of various genes in region A is necessary to complete the fermentation process and prevent stuck fermentations under low nitrogen conditions. Altogether, our optogenetics-based approach demonstrates the importance of region A in completing fermentation under nitrogen-limited conditions. IMPORTANCEStuck fermentations due to limited nitrogen availability in grape must represents one of the main problems in the winemaking industry. Nitrogen limitation in grape musts reduce yeast biomass and fermentation rate, resulting in incomplete fermentations with high levels of residual sugar, undesired by-products, and microbiological instability. Here, we used an optogenetic approach to demonstrate that expression of genes within region A is necessary to complete fermentations under low nitrogen availability. Overall, our results support the idea that region A is a genetic signature for wine yeast strains adapted to low nitrogen conditions.

microbiology↗

bioRxiv2024

Synthesis and pharmacological characterization of UVI3502, a novel cannabinoid receptor 1 (CB1) antagonist/inverse agonist

The endocannabinoid (eCB) system regulates several brain functions and is implicated in neurological disorders. The pharmacological blockade of cannabinoid receptors has a therapeutic potential for various cognitive deficits, but also produces severe psychiatric side effects. Hence, new cannabinoid compounds that potentiate therapeutic effects, while minimizing toxicity, are required. In this study, we synthesized and characterized a novel antagonist/inverse agonist of CB1 receptors. UVI3502 showed affinity for two [3H]CP55,940 binding sites (IC50Hi 0.47 {+/-} 1.94 nM and IC50Lo 1470 {+/-} 1.80 nM). Subsequent binding assays performed in CB1 and CB2 overexpressing membranes determined that the low affinity binding site corresponded to CB1, but the high-affinity binding site of UVI3502 did not correspond to CB2 and the possibility of it corresponding to GPR55 was analyzed. The affinity of UVI3502 for CB1 receptors was further confirmed with neuroanatomical specificity by autoradiography in key brain areas, in which functional [35S]GTP{gamma}S assays demonstrated that UVI3502 behaved as an antagonist/inverse agonist of CB1 receptors, blocking the stimulation evoked by potent cannabinoid receptor agonist CP55,940 and decreasing basal [35S]GTP{gamma}S binding. The in silico characterization of the binding to CB1 receptor through molecular docking and molecular dynamics suggests that this activity is explained by the planar and rigid structure of UVI3502, which is optimal for interactions with the inactive state of the receptor. These results indicate that UVI3502 is a novel antagonist/inverse agonist of CB1 receptors, making it a compelling candidate for pharmacologically blocking cannabinoid receptors in the central nervous system. Significance StatementUVI3502 is a novel antagonist/inverse agonist of CB1 receptors, with almost no affinity for CB2 receptors and an additional high-affinity binding site for a third, cannabinoid-like receptor, potentially GPR55. In relevant brain areas for learning and memory processes with a high expression of CB1, UVI3502 blocks the stimulation evoked by the cannabinoid receptor agonist CP55,940, rendering it as an interesting compound for the pharmacological blockade of cannabinoid receptors in the central nervous system.

pharmacology and toxicology↗