Biology subjects

Bombin, A.

Publications and source records attributed to Bombin, A..

7 recordsLinked to original sources

bioRxiv2026

Chronic Mild Stress Impairs Hippocampal Myelination through SOX6-Dependent Dysfunction of Oligodendrocyte Lineage Cells

Chronic stress induces structural and functional changes in the brain, increasing susceptibility to major depressive disorder and other mental illnesses. Myelination deficits are a key pathological feature of stress-related disorders, yet the molecular mechanisms linking chronic stress to oligodendrocyte dysfunction remain poorly understood. Here, we used single-nucleus multiome sequencing to map gene expression and chromatin-accessibility remodeling in the hippocampus of mice exposed to chronic unpredictable mild stress (CUMS), a model that simulates key features of human daily stressors. CUMS induced broad molecular reprogramming across hippocampal cell populations, with stress-responsive gene networks significantly enriched for depression-associated genes. The oligodendrocyte lineage showed heightened vulnerability, with CUMS preferentially disrupting immature OPC/intermediate states and impairing OPC migration, OPC-to-ODC lineage progression, intercellular communication, and myelination. Integrated multiomic analysis identified stage-specific cis-regulatory elements and stress-sensitive gene regulatory networks, converging on SOXD transcription factors, particularly SOX5 and SOX6, as key regulators of OPC dysfunction. SOX6 ChIP-seq confirmed direct SOX6 binding at regulatory elements associated with genes controlling OPC morphogenesis, migration, and glutamatergic signaling. CUMS reduced SOX6 protein levels and SOX6-associated regulatory network activity in OPCs, whereas OPC-specific enhancer-driven restoration of SOX6 rescued stress-induced defects in OPC migration and myelination. Together, these findings define a stress-sensitive SOXD/SOX6 regulatory mechanism linking chronic stress to oligodendrocyte lineage dysfunction and myelination deficits, identifying SOX6 as a functional regulatory node with therapeutic potential for stress-related brain pathology.

neuroscience↗

bioRxiv2025

Mapping of genotype-by-environment interaction loci for Metabolic Syndrome-like traits using the multi-parent Drosophila Synthetic Population Resource determines that main genetic effects are distinct from environment dependent plastic loci

Metabolic Syndrome (MetS) risk, driven by genotype-environment interactions like diet, is rising globally. Due to its genetic and environmental complexity, the genetic architecture and interconnected traits underlying MetS is poorly understood. In Drosophila, genotype-by-diet interactions significantly influence MetS-like traits. This study used the Drosophila Synthetic Population Resource to dissect the genetic architecture of both genotypic and genotype-by-diet interaction effects underlying trait variation. The study hypotheses were: 1) Loci responsible for metabolic phenotypic variation should be shared across traits. 2) Genetic loci responsible for plasticity and epistatic interactions for metabolic traits should also be the loci responsible for the main effects. 3) Genes responsible for variation in metabolic traits should share common functions. Using a round-robin crossing scheme and novel analyses, we mapped additive, dominance, and epistatic loci--some diet-specific, others diet-independent. Main-effect and plastic loci were largely distinct, as were epistatic loci from main-effect loci, highlighting that main genetic effects alone will not explain how genetic variants interact with the environment or the genome to influence disease risk. gene-by-diet or gene-by-gene interactions influencing MetS risk. Further, tremendous cryptic genetic variation for metabolic traits is lurking in natural populations. We explored the function of candidate genes from our study empirically and with bioinformatics. While some of the candidate genes might have been expected, most would not have been identified a priori, thus with this study we have identified many new candidate mechanisms contributing to the genetic and genotype-by-diet interaction effects on MetS variance.

genetics↗

bioRxiv2024

Passive infusion of an S2-Stem broadly neutralizing antibody protects against SARS-CoV-2 infection and lower airway inflammation in rhesus macaques

The continued evolution of SARS-CoV-2 variants capable of subverting vaccine and infection-induced immunity suggests the advantage of a broadly protective vaccine against betacoronaviruses ({beta}-CoVs). Recent studies have isolated monoclonal antibodies (mAbs) from SARS-CoV-2 recovered-vaccinated donors capable of neutralizing many variants of SARS-CoV-2 and other {beta}-CoVs. Many of these mAbs target the conserved S2 stem region of the SARS-CoV-2 spike protein, rather the receptor binding domain contained within S1 primarily targeted by current SARS-CoV-2 vaccines. One of these S2-directed mAbs, CC40.8, has demonstrated protective efficacy in small animal models against SARS-CoV-2 challenge. As the next step in the pre-clinical testing of S2-directed antibodies as a strategy to protect from SARS-CoV-2 infection, we evaluated the in vivo efficacy of CC40.8 in a clinically relevant non-human primate model by conducting passive antibody transfer to rhesus macaques (RM) followed by SARS-CoV-2 challenge. CC40.8 mAb was intravenously infused at 10mg/kg, 1mg/kg, or 0.1 mg/kg into groups (n=6) of RM, alongside one group that received a control antibody (PGT121). Viral loads in the lower airway were significantly reduced in animals receiving higher doses of CC40.8. We observed a significant reduction in inflammatory cytokines and macrophages within the lower airway of animals infused with 10mg/kg and 1mg/kg doses of CC40.8. Viral genome sequencing demonstrated a lack of escape mutations in the CC40.8 epitope. Collectively, these data demonstrate the protective efficiency of broadly neutralizing S2-targeting antibodies against SARS-CoV-2 infection within the lower airway while providing critical preclinical work necessary for the development of pan-{beta}-CoV vaccines. AUTHOR SUMMARYIn this study, we explore the development of a broadly protective vaccine against betacoronaviruses ({beta}-CoVs), including SARS-CoV-2. We focused on monoclonal antibodies (mAbs) from individuals who recovered-vaccinated donors capable of neutralizing many variants of SARS-CoV-2 and other {beta}-CoVs. Unlike current vaccines that target the S1 region of the virus, these mAbs target a highly conserved S2 region of the spike protein. One antibody, CC40.8, showed promising results in small animal models. To further test its effectiveness, we infused CC40.8 into rhesus macaques at different doses and then challenged them with SARS-CoV-2. We found that higher doses of CC40.8 significantly reduced viral loads and inflammation in the lower airway. Additionally, there were no escape mutations in the targeted region, suggesting that the virus could not easily evade the antibody. Our findings highlight the potential of S2-targeting antibodies to protect against SARS-CoV-2 and support the development of vaccines that can broadly protect against various {beta}-CoVs. Conflicting InterestsRA, TFR, and DRB are listed as inventors on pending patent applications describing the SARS-CoV-2 and HCoV-HKU1 S cross-reactive antibodies. DRB and RA are listed as inventors on a pending patent application describing the S2 stem epitope immunogens identified in this study. DRB is a consultant for IAVI. All other authors declare that they have no competing interests. ONE SENTENCE SUMMARYPan-beta-coronavirus neutralizing mAb CC40.8 reduces SARS-CoV-2 viral loads and inflammation within the lower airway of infected rhesus macaques and provides pre-clinical support for S2-directed immunization strategies.

immunology↗

bioRxiv2024

Spatiotemporal dispersion of DENV1 genotype V in western Colombia

Dengue virus (DENV) is a significant public health concern in Colombia, with increased transmission of DENV type 1 (DENV-1) in the departments of Risaralda and Valle del Cauca in the Central-West region of the country following a large outbreak in 2019. However, little is known about the source, genetic diversity, and evolution of circulating viruses. We obtained plasma samples from individuals with acute DENV infection and analyzed DENV-1 genetic diversity, phylodynamics, and phylogeography. We found that most viruses belonged to DENV-1 genotype V, and phylogenetic analysis revealed three distinct clades, each of which was most closely related to viruses from neighboring departments of Colombia sampled over the last 5-10 years. Thus, the 2019 outbreak and subsequent DENV-1 circulation was not due to the introduction of a new lineage but rather reflected local DENV-1V dispersion and evolution. We identified amino acid positions under positive selection in structural proteins and NS1, which may have a role in immune evasion and pathogenesis. Overall, our analysis of DENV1 genotype V diversity, evolution and spread within Colombia highlights the important role of genomic surveillance in understanding virus dynamics during endemic circulation and outbreaks.

evolutionary biology↗

bioRxiv2021

Obesity influences composition of salivary and fecal microbiota and impacts the interactions between bacterial taxa

Obesity is an increasing global health concern and is associated with a broad range of morbidities. The gut microbiota are increasingly recognized as important contributors to obesity and cardiometabolic health. This study aimed to characterize oral and gut microbial communities, and evaluate host:microbiota interactions between clinical obesity classifications. We performed 16S rDNA sequencing on fecal and salivary samples, global metabolomics profiling on plasma and stool samples, and dietary profiling in 135 healthy individuals. We grouped individuals by obesity status, based on body mass index (BMI), including lean (BMI 18-24.9), overweight (BMI 25-29.9), or obese (BMI [≥]30). We analyzed differences in microbiome composition, community inter-relationships, and predicted microbial function by obesity status. We found that salivary bacterial communities of lean and obese individuals were compositionally and phylogenetically distinct. An increase in obesity status was positively associated with strong correlations between bacterial taxa, particularly with bacterial groups implicated in metabolic disorders including Fretibacterium, and Tannerella. Consumption of sweeteners, especially xylitol, significantly influenced compositional and phylogenetic diversities of salivary and fecal bacterial communities. In addition, obesity groups exhibited differences in predicted bacterial metabolic activity, which was correlated with hosts metabolite concentrations. Overall, obesity was associated with distinct changes in bacterial community dynamics, particularly in saliva. Consideration of microbiome community structure, and inclusion of salivary samples may improve our ability to understand pathways linking microbiota to obesity and cardiometabolic disease. IMPORTANCEObesity is a worldwide epidemic that is associated with a wide range of health issues. Microbiota were shown to influence metabolism and obesity development. Our study aimed to evaluate the interactions between obesity, salivary and fecal microbiota, and metabolite concentrations in healthy individuals. The oral bacterial community was more impacted by the obesity status of the host than fecal microbiota. Consistently for oral and fecal microbiota, the number of strong interactions between bacteria increased with the increase in the obesity status. Several predicted microbial metabolic pathways that were shown to be associated with metabolic health were uniquely enriched between obesity groups. In addition, these metabolic pathways were correlated with plasma and stool metabolites. Our results suggest that oral microbiota might better reflect the obesity status of the host than fecal microbiota, and that correlations between microbial taxa are altered during obesity.

microbiology↗

bioRxiv2021

Symbiotic bacterial community of Drosophila melanogaster changes with nutritional modifications of the diet but can alleviate negative effects on larval phenotypes

Obesity is an increasing pandemic and is caused by multiple factors including genotype, psychological stress, and gut microbiota. Our project investigated the effects produced by high fat and high sugar dietary modifications on microbiota and metabolic phenotype of Drosophila melanogaster. Larvae raised on the high fat and high sugar diets exhibited bacterial communities that were compositionally and phylogenetically different from bacterial communities of the larvae raised on normal diets, especially if parental microbiota were removed. Several of the dominant bacteria taxa that are commonly associated with high fat and high sugar diets across model organisms and even human populations showed similar pattern in our results. Corynebacteriaceae and Erysipelotrichaceae were connected with high fat food, while Enterobacteriaceae and Lactobacillaceae were associated with high sugar diets. In addition, we observed that presence of symbiotic microbiota often mitigated the effect that harmful dietary modifications produced on larvae, including elevated triglyceride concentrations and was crucial for Drosophila survival, especially on high sugar peach diets.

microbiology↗

bioRxiv2020

Influence of the lab adopted natural diet, environmental, and parental microbiota on life history and metabolic phenotype of Drosophila melanogaster larvae.

Obesity is an increasing worldwide epidemic and contributes to physical and mental health losses. The development of obesity is caused by multiple factors including genotype, hormonal misregulation, psychological stress, and gut microbiota. Our project investigated the effects produced by microbiota community, acquired from the environment and horizontal transfer, on traits related to obesity. The study applied a novel approach of raising Drosophila melanogaster from ten, wild-derived genetic lines (DGRP) on naturally fermented peaches, thereby preserving genuine microbial conditions. Our results indicated that larvae raised on the natural and standard lab diets were significantly different from each other in every tested phenotype. In addition, sterilized larvae raised on the autoclaved peach diet, therefore exposed to natural nutritional stress but lacking natural microbiota community, were associated with adverse phenotypes such as low survival rate, longer developmental time, smaller weight, and elevated triglyceride and glucose levels. Our findings suggested that frozen peach food provided nutritional conditions similar to the natural ones and preserved key microbial taxa necessary for survival and development of Drosophila larvae. The presence of parental microbiota did not produce a significant effect on any of the tested phenotypes when larvae were raised on the lab diet. Contrarily, on the peach diet, the presence of parental microbiota increased the weight and development rate, even if the original peach microbiota were still present. In addition, we found that larvae raised on the peach diet formed a microbial community distinctive from larvae raised on the lab or peach autoclaved diets. The effect that individual microbial taxa produced on the host varied significantly with changing environmental and genetic conditions, occasionally to the degree of opposite correlations.

microbiology↗