Biology subjects

Hernandez, Y.

Publications and source records attributed to Hernandez, Y..

5 recordsLinked to original sources

bioRxiv2024

Oxydifficidin, a potent Neisseria gonorrhoeae antibiotic due to DedA assisted uptake and ribosomal protein RplL sensitivity

Gonorrhea, which is caused by Neisseria gonorrhoeae, is the second most reported sexually transmitted infection worldwide. The increasing appearance of isolates that are resistant to approved therapeutics raises the concern that gonorrhea may become untreatable. Here, we serendipitously identified oxydifficidin as a potent N. gonorrhoeae antibiotic through the observation of a Bacillus amyloliquefaciens contaminant in a lawn of N. gonorrhoeae. Oxydifficidin is active against both wild- type and multidrug-resistant N. gonorrhoeae. Its potent activity results from a combination of DedA- assisted uptake into the cytoplasm and the presence of an oxydifficidin-sensitive ribosomal protein L7/L12 (RplL). Our data indicates that oxydifficidin binds to the ribosome at a site that is distinct from other antibiotics and that L7/L12 is uniquely associated with its mode of action. This study opens a potential new avenue for addressing antibiotic resistant gonorrhea and underscores the possibility of identifying overlooked natural products from cultured bacteria, particularly those with activity against previously understudied pathogens.

microbiology↗

bioRxiv2020

Genome-wide characterization of human minisatellite VNTRs: population-specific alleles and gene expression differences

Variable Number Tandem Repeats (VNTRs) are tandem repeat (TR) loci that vary in copy number across a population. Using our program, VNTRseek, we analyzed human whole genome sequencing datasets from 2,770 individuals in order to detect minisatellite VNTRs, i.e., those with pattern sizes [≥]7 bp. We detected 35,638 VNTR loci and classified 5,676 as commonly polymorphic (i.e., with non-reference alleles occurring in >5% of the population). Commonly polymorphic VNTR loci were found to be enriched in genomic regions with regulatory function, i.e., transcription start sites and enhancers. Investigation of the commonly polymorphic VNTRs in the context of population ancestry revealed that 1,096 loci contained population-specific alleles and that those could be used to classify individuals into super-populations with near-perfect accuracy. Search for quantitative trait loci (eQTLs), among the VNTRs proximal to genes, indicated that in 187 genes expression differences correlated with VNTR genotype. We validated our predictions in several ways, including experimentally, through the identification of predicted alleles in long reads, and by comparisons showing consistency between sequencing platforms. This study is the most comprehensive analysis of minisatellite VNTRs in the human population to date.

bioinformatics↗

bioRxiv2019

GHSR-1a is not Required for Ghrelin's Anti-inflammatory and Fat-sparing Effects in Cancer Cachexia

Adipose tissue (AT) atrophy is a hallmark of cancer cachexia contributing to increased morbidity/mortality. Ghrelin has been proposed as a treatment for cancer cachexia partly by preventing AT atrophy. However, the mechanisms mediating ghrelins effects are incompletely understood, including the extent to which its only known receptor, GHSR-1a, is required for these effects. This study characterizes the pathways involved in AT atrophy in the Lewis Lung Carcinoma (LLC)-induced cachexia model and those mediating the effects of ghrelin in Ghsr+/+ and Ghsr-/- mice. We show that LLC causes AT atrophy by inducing anorexia, and increasing AT inflammation, thermogenesis and energy expenditure. These changes were greater in Ghsr-/-. Ghrelin administration prevented LLC-induced anorexia only in Ghsr+/+, but prevented WAT inflammation and atrophy in both genotypes, although its effects were greater in Ghsr+/+. LLC-induced increases in BAT inflammation, WAT and BAT thermogenesis, and energy expenditure were not affected by ghrelin. In conclusion, ghrelin ameliorates WAT inflammation, fat atrophy and anorexia in LLC-induced cachexia. GHSR-1a is required for ghrelins orexigenic effect but not for its anti-inflammatory or fat-sparing effects.

cancer biology↗

bioRxiv2019

CD4+ T cells from chronic Chagas disease patients with different degrees of cardiac compromise exhibit distinct expression patterns of inhibitory receptors TIGIT, Tim-3 and Lag-3.

T cells are central to adaptive immune response against T. cruzi infection. In the chronic stage of Chagas disease, circulating parasite-specific memory T cells show reduced functionality and increased expression of inhibitory receptors, possibly as a result of persistent antigenic stimulation. This exhausted phenotype has been linked to progression of cardiac pathology while, contrariwise, the presence of polyfunctional T cells shows association with therapeutic success and more efficient control of infection. Given this, we hypothesized that inhibitory receptors TIGIT, Tim-3 and Lag-3 may be involved in immune modulation of anti-T. cruzi T cell response, and therefore may play a role in the containment or the unleashing of inflammatory phenomena that ultimately lead to tissue damage and pathology. In this preliminary study, we assess the frequency of CD4+ T cells expressing each of these receptors and their relation to cellular activation. Samples from chronic Chagas disease patients with different degrees of cardiac compromise, and non-infected donors were analyzed under different stimulation conditions. Our results show that the frequency of TIGIT+ CD4+ T cells is increased in Chagas patients, while Tim-3+ cells are more abundant in patients with signs of cardiac alterations. In addition, the frequency of Lag-3+ cells increases in non-activated CD4+ T cells from Chagas patients without demonstrable cardiopathy upon pathogen-specific in vitro antigenic stimulation.

immunology↗

bioRxiv2019

Altered frequency of CD24highCD38high transitional B cells in patients with cardiac involvement of chronic Chagas disease.

The cardiomyopathy developed by patients with chronic Chagas disease (CCD), one of the most severe consequences of T. cruzi infection, is mainly associated with an imbalance between an excessive inflammatory reaction and a defective immunomodulatory profile cause by host-parasite interaction. Despite the growing importance of the regulatory function of B-cells in many malignancies, few studies have addressed their immunosuppressive role in chronic Chagas disease. In this work, we tackled this issue by studying the proportion of different B cell subpopulations and their capacity to secrete IL-10 in individuals with distinct clinical forms of CCD. Seven-colour flow cytometry was performed to examine the peripheral blood B cell compartment in chronic Chagas disease (CCD) patients with and without cardiac manifestations (n=10 for each group) and non-infected donors (n=9). Peripheral blood mononuclear cells (PBMC) were incubated for 5h with PMA, ionomicyn and brefeldin A. According to the expression of markers CD19, CD24 and CD38, we showed an expansion of total B cell and transitional CD24highCD38high B cell subsets in CCD patients with cardiac involvement compared to non-infected donors. Furthermore, although no differences were observed in the frequency of total IL-10 producing B cells (B10) among the groups, CCD patients with cardiac involvement showed a statistically significant increased proportion of naive B10 cells and a tendency to an increased frequency of transitional B10 cells compared to non-infected donors. These findings suggest that immature transitional CD24highCD38high B cells are greatly expanded in patients with the cardiac form of chronic Chagas disease and these cells retain their ability to secrete IL-10 compared to non-infected donors. Furthermore, the distribution of naive, transitional and memory B cells inside the B10 cells followed the same pattern in chronic patients without cardiac involvement and non-infected individuals. Our work provides insight into the phenotypic distribution of regulatory B cell in CCD, an important step towards new strategies to prevent cardiomiopathy associated with T. cruzi infection.

immunology↗