Biology subjects

Ramos, I.

Publications and source records attributed to Ramos, I..

17 recordsLinked to original sources

bioRxiv2026

Hepatocyte UBE4A protects against MASLD/MASH by maintaining ER homeostasis via UBXN4 interaction

Molecular understanding of the regulation of endoplasmic reticulum (ER) functions in healthy and MASLD livers is limited. Here, we elucidate that Ube4A, a cytosolic E3 ubiquitin ligase, protects against MASLD development by maintaining ER homeostasis during nutritional stress. Hepatocyte-Ube4A deletion (HUKO) augments Gubra-Amylin-diet (GAN-D)-induced steatosis, inflammation, insulin resistance, ER stress and markers of steatohepatitis of the liver in both sexes of mice. Proteomic studies reveal that in addition to altered metabolic and fibrogenic pathways, levels of many ER proteins are also changed in HUKO livers. Impaired ER functions sensitize HUKO livers to nutrition- or chemical (tunicamycin)-induced ER stress. Moreover, HUKO primary hepatocytes exhibit increased ER stress. Furthermore, Ube4A maintains ER homeostasis by facilitating ER-associated protein degradation (ERAD). The lipogenic protein SCD1 is identified as one of the ERAD targets of Ube4A. SCD1 stability and triglyceride accumulation are amplified in HUKO primary hepatocytes. The liver Ube4A-interactome studies identified the ERAD mediator UBXN4 as a major Ube4A interacting protein. Alphafold3-based molecular modelling and interaction site mapping analyses pinpointed the Ube4A binding residues for UBXN4. ER-localized Ube4A-UBXN4 complex facilitates ERAD (e.g., SCD1) and UBXN4-binding deficient Ube4A mutants fail to enhance this process. Finally, Ube4A and UBXN4 are downregulated in the livers of human MASLD and MASH patients and this complex is diminished in GAN-D-fed mouse livers. In conclusion, Ube4A preserves ER homeostasis by maintaining ERAD via its interaction with UBXN4, which maintains liver health. Enhancing levels and/or preserving interaction of these proteins may offer new therapeutic strategies for MASLD treatment.

physiology↗

bioRxiv2026

Structure-guided vaccination elicits broadly neutralizing antibodies targeting the HIV-1 silent face

An effective HIV-1 vaccine will likely require broadly neutralizing antibodies (bnAbs) targeting multiple complementary epitopes on the Envelope (Env) glycoprotein. Donor-derived bnAbs targeting the conserved silent face (SF) epitope complement established bnAb classes, but the maturation pathways underlying SF bnAb development and their inducibility via vaccination remain poorly understood. Here, we elicit SF-like bnAbs by vaccination and define pathways by which these responses can be guided toward breadth. Structural analysis of the donor-derived bnAb SF10 revealed that broad neutralization depends on a minimal set of heavy chain mutations despite extensive overall somatic hypermutation. We leveraged these insights to engineer Env immunogens that engage an SF10 precursor and selectively favor breadth-associated mutations during sequential immunization in a new immunoglobulin knock-in mouse model. Vaccination reproducibly elicited heterologous neutralizing serum responses and monoclonal antibodies that acquired key SF-like improbable mutations and broad neutralizing activity. Notably, elicited antibodies combined features of distinct human SF bnAbs, demonstrating that vaccination can access alternative mutational solutions rather than precisely recapitulating a donor-derived maturation pathway. These findings establish the silent face as a tractable vaccine target and expand the bnAb specificities available for multi-epitope HIV-1 vaccine strategies.

immunology↗

bioRxiv2026

Genomic variation and ancestry of Helicobacter pylori in the admixed population of Cabo Verde reveal host adaptation, limited host-pathogen ancestry concordance, and signatures of trans-Atlantic slave trade migrations

The genomic structure of the stomach-colonising, gastric cancer-associated bacterium Helicobacter pylori mirrors human evolutionary history, making it difficult to disentangle shared ancestry from true host-pathogen interactions driving disease risk. Recently admixed populations offer opportunities for new coevolutionary trajectories between H. pylori and its host that may disrupt parallel evolution. Here, we analyse host H. pylori IgG, blood serum biomarkers, and paired host-bacterial genomic data from the general population (independent of dyspepsia symptoms) of Cabo Verde. Seropositivity is high (82.8%), as in neighbouring African populations. Serum biomarkers indicate that this unique cohort mainly comprises hosts with limited gastric inflammation. Genomic analyses show that Cabo Verdean H. pylori derive European (hspSWeurope) and West African (hspAfrica1WAfrica) ancestry. The delineation of a reference dataset that includes new strains from Ghana and Portugal, uncovered a distinct West-Central African cluster (hspAfrica1WCAfrica). This dataset allowed inference of within-Africa and within-Europe ancestries in Cabo Verdean and American strains that reflect historical migrations linked to European colonisation and the trans-Atlantic Slave Trade. European strains in Cabo Verde show additional population structure, including two low-diversity clusters. Approximate Bayesian Computation (ABC) inference indicates that the most common cluster represents a clonal expansion, likely driven by host adaptation leading to increased transmission within Cabo Verde. Notably, these strains lack known virulence genes and show significant divergence from gastric cancer strains. Finally, host and bacterial ancestry are uncoupled, indicating disruption of ancestral parallel evolution. Cabo Verde, therefore, provides a unique natural model for studying host-pathogen interactions underlying susceptibility to H. pylori.

evolutionary biology↗

bioRxiv2026

Woodland age, ancient trees, and population size as proxies of genetic diversity

Climatic and biogeographic variables are often used as a proxy for tree genetic diversity, but local factors can also influence it. We propose that woodland age, presence of ancient trees, and population size could impact genetic diversity. Using the RBG Kew UK National Tree Seed Project as a study case, we examined how these factors are accounted for during seed collection. We found 42% of tree seed collections come from ancient woodlands and that 8.4% overlap with ancient trees. Sampled forest patches size ranges from few individuals to several thousand. We then carried out a pilot to examine the role of population size on functional traits variation, testing the relationship between population size and seed germination and seedling thermal stress sensitivity in three populations of the Betula pubescens Ehrh. complex. We found that seeds and seedlings from larger populations showed higher fitness and stress resistance. Our results highlight the importance of local factors to predict variation in functional traits, relevant for tree resilience. Existing seed collections of native species stored in conservation seed banks offer a valuable resource to explore these factors and improve our understanding of genetic diversity in tree populations, with implications for biodiversity conservation and forestry production.

plant biology↗

bioRxiv2026

Small Heat Shock Proteins have a Paramount Role inTrypanosoma cruzi Infection Impacting Intestinal Homeostasis of an Insect Vector of Chagas Disease

Rhodnius prolixus, an insect vector of Chagas disease, ingests blood meals several-fold its own body weight. This nutritional overload triggers specific adaptive responses that prevent or remediate damage from multiple stressors, including oxidative, osmotic, and microbial challenges. Transcriptomic analysis of first-instar nymph guts revealed five members of the Small Heat-Shock Protein (sHSP) family that were highly expressed after blood meals but were downregulated upon Trypanosoma cruzi infection. sHSPs are proteins involved in cellular homeostasis and stress responses. Simultaneous knockdown of all five sHSPs profoundly disrupted insect physiology, causing decreased actin filament network formation, interrupted peristalsis, blocked ER expansion, and reduced ER-mitochondria association, while increasing reactive oxygen species generation and inducing premature epithelial cell mitosis. This apparent loss of gut homeostasis was recapitulated by trypanosome infection and, conversely, sHSP silencing in infected insects increased parasite numbers. Taken together, our data reveal a paramount role for sHSPs in gut cell homeostasis following blood meals and support the hypothesis that sHSP expression down regulation represents an adaptive manipulation of the insect host by the parasite. Significance StatementThis study demonstrates that sHSPs serve as critical regulators of digestive physiology and intestinal homeostasis in a Chagas disease vector. These proteins orchestrate key processes including ROS production and cytoskeletal and endoplasmic reticulum organization, directly influencing T. cruzi proliferation. Conversely, the parasite manipulates their expression, revealing sHSPs as novel determinants of vector competence. Between 6 and 7 million people worldwide suffer from Chagas Disease, with 10,000 deaths annually. Although vector-borne transmission has declined, oral transmission is increasing, underscoring the urgent need to understand molecular factors governing vector competence. Our findings position sHSPs as promising targets for developing innovative strategies to control disease transmission.

microbiology↗

bioRxiv2025

Loss of Vitellogenin Receptor Function Results in Yolk Depletion, Virome Expansion and Reduced Bacterial Load Within the Oocytes of Rhodnius prolixus

The vitellogenin receptor (VgR) mediates yolk protein uptake during oogenesis and is essential for embryogenesis in oviparous species. Here we characterize the single Rhodnius prolixus VgR isoform and uncover an unexpected role in microbial regulation within the reproductive system. The receptor displays a conserved LDLR-like structure and is highly expressed in early oocytes. RNAi-mediated VgR silencing caused defective yolk granule biogenesis, leading to the accumulation of the main yolk protein precursors, Vg and RHBP, in the hemolymph, yet oviposition and fertilization proceeded normally. The resulting eggs were yolk-depleted and non-viable. Remarkably, VgR knockdown reduced bacterial 16S rRNA levels in oocytes while promoting the expansion of several members of the core virome, a phenotype not reproduced by Vg silencing. Neither purified Vg nor changes in immune (defensin) or RNA interference pathways explained the microbial shifts. These findings indicate that VgR governs not only yolk endocytosis but also the trafficking of microbial components into developing oocytes. We propose that VgR contributes to the linking of yolk endocytic dynamics and microbial homeostasis, influencing the balance of microbial components within developing oocytes. This connection broadens the functional scope of the VgR and provides new insight into how vertical transmission processes are shaped in this major Chagas disease vector. Author summaryEgg-laying animals must load their eggs with enough nutrients to support early development. In insects, this process depends on a receptor that brings yolk proteins into the growing egg. Here, we studied this receptor in Rhodnius prolixus, a major vector of Chagas disease, and uncovered an unexpected link between yolk uptake and the microorganisms that enter the egg. When we blocked the receptor, females continued to produce and lay eggs, but these eggs failed to accumulate yolk and could not support embryonic development. Strikingly, the absence of the receptor also shifted the microbial community inside the oocyte: bacterial levels dropped, while several viruses expanded. These changes did not result from differences in yolk proteins, immune activation, or direct antimicrobial effects, indicating that the receptor itself influences microbial entry or persistence in the egg. Our findings reveal that this yolk receptor plays a dual role, providing nutrients and shaping the microbial community that is passed from mother to offspring. This work highlights an unrecognized layer of interaction between reproduction and microbial transmission in an important disease vector, offering new perspectives for understanding and potentially disrupting vertical transmission pathways.

cell biology↗

bioRxiv2025

Phenotypic AI-based design of cell-specific small molecule cytotoxics

Drug discovery is being transformed by artificial intelligence, which enables the exploration of vast chemical spaces and the generation of novel compounds with tailored properties. While most generative approaches focus on optimizing physicochemical features or protein-binding affinities, their application to phenotypic drug discovery remains limited. Here we present an integrated framework to design small molecules with selective cytotoxic effects in pancreatic cancer cells that combines high-throughput cytotoxicity screening, bioactivity signature-based machine learning predictors, and reinforcement learning-driven generative models. We screened over 11,000 compounds across six pancreatic cancer and two control cell lines, confirming 392 hits, and used these data to train cell line-specific classifiers that outperformed fingerprint-based models. We embedded these predictors into the REINVENT platform to generate molecules with desired cytotoxicity profiles, including challenging cases of distinguishing between pancreatic cancer lines with highly similar molecular backgrounds. We generated between 37 and 137 high- scoring candidates in seven different cell selectivity exercises, which were structurally distant from the active compounds in the training set. We tested 45 close analogues to the AI-designed molecules, and 20 of them showed the desired cell-specific cytotoxic effects. Indeed, we validated at least one compound in 5 of the 7 exercises tested, showing over a large increase in hit discovery rate compared to the HTS. Additionally, we benchmarked our strategy against direct predictions on a library of over 150,000 compounds, skipping the generative step, finding that the fraction of hits, and more importantly the dose-response validation, is markedly higher in the AI- designed molecules. Overall, our study demonstrates the feasibility of combining predictive and generative AI methods to design molecules with complex phenotypic outcomes in a target- agnostic manner, paving the way for next-generation phenotype-driven drug discovery strategies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=68 SRC="FIGDIR/small/682546v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@119daf2org.highwire.dtl.DTLVardef@7579b9org.highwire.dtl.DTLVardef@8a62f8org.highwire.dtl.DTLVardef@167a6d5_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

Innate immune epigenomic landscape following controlled human influenza virus infection

Viral infections can induce changes in innate immunity that persist after virus clearance. Here, we used blood samples from a human influenza H3N2 challenge study to perform comprehensive multi-omic analyses. We detected remodeling of immune programs in innate immune cells after resolution of the infection that was proportional in magnitude to the level of prior viral load. We found changes associated with suppressed inflammation including decreased cytokine and AP-1 gene expression as well as decreased accessibility at AP-1 targets and interleukin-related gene promoter regions. We also found decreased histone deacetylase gene expression, increased MAP kinase gene expression, and increased accessibility at interferon-related gene promoter regions. Genes involved in inflammation and epigenetic-remodeling showed modulation of gene-chromatin site regulatory circuit activity. These results reveal a coordinated rewiring of the epigenetic landscape in innate immune cells induced by mild influenza virus infection.

immunology↗

bioRxiv2024

HYL001, a new potent TGFβ signaling inhibitor that is efficacious against microsatellite stable CRC metastasis in combination with immune checkpoint therapy in mice

Blockade of the TGF{beta} signalling pathway has emerged from preclinical studies as a potential treatment to enhance the efficacy of immune checkpoint inhibition in advanced colorectal cancer (CRC) and several other types of cancer. However, clinical translation of first-generation inhibitors has known little success. Here, we report the synthesis and characterization of HYL001, a potent inhibitor of TGF{beta} receptor 1 (ALK5), that is approximately 9 times more efficacious than the structurally related compound galunisertib, while maintaining a favourable safety profile. HYL001 in combination with immune checkpoint blockade (anti-PD1) eradicates liver metastases generated in mice by microsatellite stable, aggressive colorectal cancer tumours at doses where galunisertib is ineffective. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/593510v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1909963org.highwire.dtl.DTLVardef@4644d2org.highwire.dtl.DTLVardef@1506d80org.highwire.dtl.DTLVardef@14504b7_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2024

Bispecific antibodies with broad neutralization potency against SARS-CoV-2 variants of concern

The ongoing emergence of SARS-CoV-2 variants of concern (VOCs) that reduce the effectiveness of antibody therapeutics necessitates development of next-generation antibody modalities that are resilient to viral evolution. Here, we characterized N-terminal domain (NTD) and receptor binding domain (RBD)-specific monoclonal antibodies previously isolated from COVID-19 convalescent donors for their activity against emergent SARS-CoV-2 VOCs. Among these, the NTD-specific antibody C1596 displayed the greatest breadth of binding to VOCs, with cryo-EM structural analysis revealing recognition of a distinct NTD epitope outside of the site i antigenic supersite. Given C1596s favorable binding profile, we designed a series of bispecific antibodies (bsAbs) termed CoV2-biRNs, that featured both NTD and RBD specificities. Notably, two of the C1596-inclusive bsAbs, CoV2-biRN5 and CoV2-biRN7, retained potent in vitro neutralization activity against all Omicron variants tested, including XBB.1.5, EG.5.1, and BA.2.86, contrasting the diminished potency of parental antibodies delivered as monotherapies or as a cocktail. Furthermore, prophylactic delivery of CoV2-biRN5 significantly reduced the viral load within the lungs of K18-hACE2 mice following challenge with SARS-CoV-2 XBB.1.5. In conclusion, our NTD-RBD bsAbs offer promising potential for the design of resilient, next-generation antibody therapeutics against SARS-CoV-2 VOCs. One Sentence SummaryBispecific antibodies with a highly cross-reactive NTD antibody demonstrate resilience to SARS-CoV-2 variants of concern.

immunology↗

bioRxiv2023

Human Immune Cell Epigenomic Signatures in Response to Infectious Diseases and Chemical Exposures

The epigenomic landscape of human immune cells is dynamically shaped by both genetic factors and environmental exposures. However, the relative contributions of these elements are still not fully understood. In this study, we employed single-nucleus methylation sequencing and ATAC-seq to systematically explore how pathogen and chemical exposures, along with genetic variation, influence the immune cell epigenome. We identified distinct exposure-associated differentially methylated regions (eDMRs) corresponding to each exposure, revealing how environmental factors remodel the methylome, alter immune cell states, and affect transcription factor binding. Furthermore, we observed a significant correlation between changes in DNA methylation and chromatin accessibility, underscoring the coordinated response of the epigenome. We also uncovered genotype-associated DMRs (gDMRs), demonstrating that while eDMRs are enriched in regulatory regions, gDMRs are preferentially located in gene body marks, suggesting that exposures and genetic factors exert differential regulatory control. Notably, disease-associated SNPs were frequently colocalized with meQTLs, providing new cell-type-specific insights into the genetic basis of disease. Our findings underscore the intricate interplay between genetic and environmental factors in sculpting the immune cell epigenome, offering a deeper understanding of how immune cell function is regulated in health and disease.

genomics↗

bioRxiv2023

Novel compound inhibits glycolysis, proteotoxicity, inflammation, and impairments in animal models of Alzheimer's, Huntington's, and stroke: Aging as a consequence of glycolysis

Inflammation drives many age-related, especially neurological, diseases, and likely mediates age-related proteotoxicity. For example, dementia due to Alzheimers Disease (AD), cerebral vascular disease, many other neurodegenerative conditions is increasingly among the most devastating burdens on the American (and world) health system and threatens to bankrupt the American health system as the population ages unless effective treatments are developed. Dementia due to either AD or cerebral vascular disease, and plausibly many other neurodegenerative and even psychiatric conditions, is driven by increased age-related inflammation, which in turn appears to mediate Abeta and related proteotoxic processes. The functional significance of inflammation during aging is also supported by the fact that Humira, which is simply an antibody to the pro-inflammatory cytokine TNF-a, is the best-selling drug in the world by revenue. These observations led us to develop parallel high-throughput screens to discover small molecules which inhibit age-related Abeta proteotoxicity in a C. elegans model of AD AND LPS-induced microglial TNF-a. In the initial screen of 2560 compounds (Microsource Spectrum library) to delay Abeta proteotoxicity, the most protective compounds were, in order, phenylbutyrate, methicillin, and quetiapine, which belong to drug classes (HDAC inhibitors, beta lactam antibiotics, and tricyclic antipsychotics, respectably) already robustly implicated as promising to protect in neurodegenerative diseases, especially AD. RNAi and chemical screens indicated that the protective effects of HDAC inhibitors to reduce Abeta proteotoxicity are mediated by inhibition of HDAC2, also implicated in human AD, dependent on the HAT Creb binding protein (Cbp), which is also required for the protective effects of both dietary restriction and the daf-2 mutation (inactivation of IGF-1 signaling) during aging. In addition to methicillin, several other beta lactam antibiotics also delayed Abeta proteotoxicity and reduced microglial TNF-a. In addition to quetiapine, several other tricyclic antipsychotic drugs also delayed age-related Abeta proteotoxicity and increased microglial TNF-a, leading to the synthesis of a novel congener, GM310, which delays Abeta as well as Huntingtin proteotoxicity, inhibits LPS-induced mouse and human microglial and monocyte TNF-a, is highly concentrated in brain after oral delivery with no apparent toxicity, increases lifespan, and produces molecular responses highly similar to those produced by dietary restriction, including induction of Cbp inhibition of inhibitors of Cbp, and genes promoting a shift away from glycolysis and toward metabolism of alternate (e.g., lipid) substrates. GM310, as well as FDA-approved tricyclic congeners, prevented functional impairments and associated increase in TNF-a in a mouse model of stroke. Robust reduction of glycolysis by GM310 was functionally corroborated by flux analysis, and the glycolytic inhibitor 2-DG inhibited microglial TNF-a and other markers of inflammation, delayed Abeta proteotoxicity, and increased lifespan. These results support the value of phenotypic screens to discover drugs to treat age-related, especially neurological and even psychiatric diseases, including AD and stroke, and to clarify novel mechanisms driving neurodegeneration (e.g., increased microglial glycolysis drives neuroinflammation and subsequent neurotoxicity) suggesting novel treatments (selective inhibitors of microglial glycolysis).

neuroscience↗

bioRxiv2022

The oral drug nitazoxanide restricts SARS-CoV-2 infection and attenuates disease pathogenesis in Syrian hamsters

A well-tolerated and cost-effective oral drug that blocks SARS-CoV-2 growth and dissemination would be a major advance in the global effort to reduce COVID-19 morbidity and mortality. Here, we show that the oral FDA-approved drug nitazoxanide (NTZ) significantly inhibits SARS-CoV-2 viral replication and infection in different primate and human cell models including stem cell-derived human alveolar epithelial type 2 cells. Furthermore, NTZ synergizes with remdesivir, and it broadly inhibits growth of SARS-CoV-2 variants B.1.351 (beta), P.1 (gamma), and B.1617.2 (delta) and viral syncytia formation driven by their spike proteins. Strikingly, oral NTZ treatment of Syrian hamsters significantly inhibits SARS-CoV-2-driven weight loss, inflammation, and viral dissemination and syncytia formation in the lungs. These studies show that NTZ is a novel host-directed therapeutic that broadly inhibits SARS-CoV-2 dissemination and pathogenesis in human and hamster physiological models, which supports further testing and optimization of NTZ-based therapy for SARS-CoV-2 infection alone and in combination with antiviral drugs.

immunology↗

bioRxiv2021

mRNA-1273 efficacy in a severe COVID-19 model: attenuated activation of pulmonary immune cells after challenge

The mRNA-1273 vaccine was recently determined to be effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from interim Phase 3 results. Human studies, however, cannot provide the controlled response to infection and complex immunological insight that are only possible with preclinical studies. Hamsters are the only model that reliably exhibit more severe SARS-CoV-2 disease similar to hospitalized patients, making them pertinent for vaccine evaluation. We demonstrate that prime or prime-boost administration of mRNA-1273 in hamsters elicited robust neutralizing antibodies, ameliorated weight loss, suppressed SARS-CoV-2 replication in the airways, and better protected against disease at the highest prime-boost dose. Unlike in mice and non-human primates, mRNA-1273- mediated immunity was non-sterilizing and coincided with an anamnestic response. Single-cell RNA sequencing of lung tissue permitted high resolution analysis which is not possible in vaccinated humans. mRNA-1273 prevented inflammatory cell infiltration and the reduction of lymphocyte proportions, but enabled antiviral responses conducive to lung homeostasis. Surprisingly, infection triggered transcriptome programs in some types of immune cells from vaccinated hamsters that were shared, albeit attenuated, with mock-vaccinated hamsters. Our results support the use of mRNA-1273 in a two-dose schedule and provides insight into the potential responses within the lungs of vaccinated humans who are exposed to SARS-CoV-2.

immunology↗

bioRxiv2018

ImmuneRegulation: A web-based tool for identifying human immune regulatory elements

Humans can vary considerably in their healthy immune phenotypes and in their immune responses to various stimuli. We have developed an interactive web-based tool, ImmuneRegulation, to enable discovery of human regulatory elements that drive some of the phenotypic differences observed in gene expression profiles. ImmuneRegulation currently provides the largest centrally integrated resource available in the literature on transcriptome regulation in whole blood and blood cell types, including genotype data from 23,040 individuals, with associated gene expression data from 30,562 experiments, that provide genetic variant-gene expression associations on [~]200 million eQTLs. In addition, it includes 14 million transcription factor (TF) binding region hits extracted from 1945 TF ChIP-seq peaks and the latest GWAS catalog of 67,230 published SNP-trait associations. Users can interactively explore ImmuneRegulation to visualize and discover associations between their gene(s) of interest and their regulators (genetic variants or transcription factors) across multiple cohorts and studies. These regulators can explain cohort or cell type dependent gene expression variations and may be critical in selecting the ideal cohorts or cell types for follow-up studies. Overall, ImmuneRegulation aims to contribute to our understanding of the effects of eQTLs and TFs on heterogeneous transcriptional responses reported in studies on the blood; in the development of molecular signatures of immune response; and facilitate their future application in patient management. ImmuneRegulation is freely available at http://icahn.mssm.edu/immuneregulation.

immunology↗

bioRxiv2018

Spermatoproteasome-deficient mice are proficient in meiotic DNA repair but defective in meiotic exit

Meiotic recombination generates crossovers which are essential to ensure genome haploidization. The ubiquitin proteasome system regulates meiotic recombination through its association to the synaptonemal complex, a zipper-like structure that holds homologs and provides the structural framework for meiotic recombination. Here we show that the testis-specific 4s subunit (PSMA8) of the spermatoproteasome is located at the synaptonemal complex and is essential for the assembly of its activator PA200. Accordingly, synapsis-deficient mice show delocalization of PSMA8 from the synaptonemal complex. Genetic analysis of Psma8-deficient mice shows normal meiotic DNA repair, crossing over formation and an increase of spermatocytes at metaphase I and metaphase II which either enter into apoptosis or slip to give rise to an early spermatid arrest and infertility. Thus, spermatoproteasome-dependent histone degradation is dispensable for meiotic recombination. We show that PSMA8 deficiency alters the proteostasis of several key meiotic players such as acetylated histones, SYCP3, SYCP1, CDK1 and TRIP13 which in turn leads to an aberrant meiotic exit and early spermatid arrest prior to the histone displacement process that take place subsequently.

cell biology↗

bioRxiv2018

Combined effect of matrix quality and spatial heterogeneity on biodiversity decline

The land-sparing/land-sharing debate remains an oversimplified framework to evaluate landscape management strategies that aim to reconcile food production and biodiversity conservation. Still, biodiversity-yield curves, on which the framework has relied, provide valuable qualitative information on biodiversitys sensitivity to agricultural practices, and much research has studied this relationship. But the potential effect of landscape configuration on biodiversitys response to intensification has rarely been considered; besides, studies have often taken yield as an indicator of agricultural management and have generalized conclusions from studying particular taxonomic groups. In this work we adapt a metacommunity model to analyze factors that shape biodiversitys response to agricultural intensification while addressing some of the simplifications of the land-sparing/land-sharing dichotomy. In particular, we study species richness decline in landscapes encompassing a combined gradient in matrix quality and configurational heterogeneity of habitat patches, and considering community dynamics. We found that species richness along an intensification gradient shifts from following a robust response to presenting an abrupt decline, as landscape heterogeneity increases, as stricter survival thresholds are applied to species or as habitat area is reduced. Our work highlights the interdependent effects of heterogeneity, habitat availability and matrix quality on biodiversity and contributes to a nuanced understanding of ecological and landscape factors that enable a robust response of biodiversity in the face of spatiotemporal perturbations.

ecology↗