Biology subjects

Hernandez, E.

Publications and source records attributed to Hernandez, E..

15 recordsLinked to original sources

bioRxiv2026

Systemic iron sequestration restricts the intratumoral CD8+ T cell landscape in pancreas cancer

Systemic iron sequestration occurs frequently in cancer due to inflammation-driven expression of the iron-regulatory hormone hepcidin. The impact of systemic iron availability on tumoral immunity is unclear. Here, we show that elevated serum hepcidin is associated with reduced survival and decreased intratumoral CD8+ T cells in patients with pancreas cancer. While hepcidin is not induced in murine tumor models, administration of a hepcidin mimetic phenocopies the T-cell-depleted tumor microenvironment seen in patients. Mechanistically, chronic antigen-driven mitochondrial dysfunction disrupts iron metabolism and selectively depletes high avidity CD8+ T cells during iron restriction. These findings establish a direct link between hepcidin-mediated iron sequestration and tumoral immunity and nominate systemic iron dysregulation as a therapeutic target to enhance anti-tumoral CD8+ T cell responses.

immunology↗

bioRxiv2026

Fine mapping of PTSD GWAS reveals a role for amygdala Foxp2 in regulation of fear and threat responses

Post-traumatic Stress Disorder (PTSD) is a debilitating psychiatric condition caused by severe trauma exposure and characterized by ongoing dysregulation of fear processing, hyperarousal, and amygdala activation, but with limited effective treatments. Recent large-scale genome-wide association studies (GWAS) of PTSD have identified the transcription factor FOXP2 as a highly-significant, top putative risk gene. Both fine-mapping of the PTSD GWAS with amygdala-specific expression quantitative trait loci (eQTL) data, and transcriptome-wide association analyses, show that altered expression of FOXP2 is associated with increased PTSD risk. In vertebrates, FOXP2 mRNA is most densely expressed in the intercalated cells (ITCs) of the amygdala. ITC neurons receive excitatory input from external regulatory and sensory brain regions, as well as the basolateral amygdala, and send inhibitory projections to the central amygdala, which regulates downstream fear responses. While ITCs are critical for conditioned fear acquisition and extinction, the role of the FOXP2 gene in modulating fear-related behaviors remains unknown. Here, we used complementary bioinformatic, molecular, circuit, behavioral, and electrophysiological approaches to characterize the function of mouse (Foxp2) and human (FOXP2) orthologs in amygdala-mediated fear learning. To assess Foxp2 function in vivo, we first used shRNA-mediated knockdown (KD) of Foxp2 in ITC neurons of adult mice. Targeted Foxp2 KD robustly and significantly reduced freezing (threat/fear expression) during and after auditory fear conditioning. Whole-cell recordings from individual ITC neurons revealed that Foxp2 KD increased their intrinsic membrane excitability and action potential frequency, consistent with hypothesized enhanced inhibitory output to the central amygdala and thus reduced fear expression. This hyperexcitability was associated with reduced potassium channel conductance. Bulk RNA sequencing (RNA-seq) of mouse amygdala after ITC Foxp2 KD confirmed decreased potassium channel transcription and revealed broader Foxp2-dependent regulation of multiple genes implicated in fear learning, including Wnt, Crh (which encodes corticotropin-releasing hormone), and neurokinin signaling pathways. Consistent with these findings, bulk RNA-seq of medial amygdala postmortem tissue from humans with PTSD versus neurotypical controls showed decreased potassium channel transcription in samples with low FOXP2 expression. Downstream transcriptional changes following Foxp2 KD in the mouse amygdala also showed marked enrichment of genes identified in PTSD risk loci from the largest PTSD GWAS to date. Specifically, downregulated genes were enriched for mouse orthologs of Tier 1 PTSD GWAS risk genes. This enrichment appears to reflect subcortical Foxp2 signaling within the amygdala, driven predominantly by decreased expression of genes lacking promoter-anchored chromatin loops. This finding suggests that Foxp2 may directly bind regulatory elements of multiple top PTSD risk genes, acting as a key regulatory node for fear-related pathways in the amygdala. Collectively, our findings establish FOXP2 as a central transcriptional regulator of fear-related gene networks in the amygdala and potential regulatory hub for PTSD genetic risk.

neuroscience↗

bioRxiv2025

A Meta-Analysis of the Effects of Chronic Stress on the Prefrontal Transcriptome in Animal Models and Convergence with Existing Human Data

BackgroundChronic stress is a major risk factor for psychiatric disorders, including anxiety, depression, and post-traumatic stress disorder. Chronic stress can cause structural alterations like grey matter atrophy in key emotion-related areas such as the prefrontal cortex (PFC). To identify biological pathways affected by chronic stress in the PFC, researchers have performed transcriptional profiling (RNA-sequencing, microarray) to measure gene expression in rodent models. However, transcriptional signatures in the PFC that are shared across different chronic stress paradigms and laboratories remain relatively unexplored. MethodsWe performed a meta-analysis of publicly available transcriptional profiling datasets within the Gemma database. We identified six datasets that characterized the effects of either chronic social defeat stress (CSDS) or chronic unpredictable mild stress (CUMS) on gene expression in the PFC in mice (n=117). We fit a random effects meta-analysis model to the chronic stress effect sizes (log(2) fold changes) for each transcript (n=21,379) measured in most datasets. We then compared our results with two other published chronic stress meta-analyses, as well as transcriptional signatures associated with psychiatric disorders. ResultsWe identified 133 genes that were consistently differentially expressed across chronic stress studies and paradigms (false discovery rate (FDR)<0.05). Fast Gene Set Enrichment Analysis (fGSEA) revealed 53 gene sets enriched with differential expression (FDR<0.05), dominated by glial and neurovascular markers (e.g., oligodendrocyte, astrocyte, endothelial/vascular) and stress-related signatures (e.g., major depressive disorder, hormonal responses). Immediate-early gene markers of neuronal activity (Fos, Junb, Arc, Dusp1) were consistently suppressed. Many of the identified effects resembled those seen in previous meta-analyses characterizing stress effects (CSDS, early life stress), despite minimal overlap in included samples. Moreover, some effects resembled previous observations from psychiatric disorders, including alcohol abuse disorder, major depressive disorder, bipolar disorder, and schizophrenia. ConclusionOur study demonstrates that chronic stress induces a robust, cross-paradigm PFC signature characterized by down-regulation of glia/myelin and vascular pathways and suppression of immediate-early gene activity, highlighting cellular processes linking chronic stress exposure, PFC dysfunction, and psychiatric disorders. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/683091v2_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1062c5eorg.highwire.dtl.DTLVardef@4ae148org.highwire.dtl.DTLVardef@c747corg.highwire.dtl.DTLVardef@1b3a713_HPS_FORMAT_FIGEXP M_FIG C_FIG Key PointsO_LIChronic stress is linked to many human psychiatric disorders involving the prefrontal cortex (PFC). C_LIO_LIMeta-analysis showed that stressed mice had less gene expression for glia and neural activity in the PFC. C_LIO_LIPFC gene expression in chronically stressed mice mirrors patterns seen in psychiatric patients. C_LI Plain Language SummaryChronic stress has been shown to have lasting effects on the brain, contributing to cognitive impairments and the risk of psychiatric disorders such as anxiety, depression, and post-traumatic stress disorder. The prefrontal cortex, a brain region that is important for behavioral and attentional control, is sensitive to chronic stress. We combined information from six public mouse datasets to identify consistent effects of chronic stress on gene expression (mRNA) in the prefrontal cortex. In these studies, mice that had experienced chronic stress showed a decreased amount of mRNA related to a variety of non-neuronal support cells (glia) and blood vessels, and general neural activity. The mouse chronic stress signature overlapped with gene-activity patterns reported in human psychiatric conditions, suggesting a biological bridge between chronic stress and the onset of psychopathology.

neuroscience↗

bioRxiv2025

Short Report: A Meta-Analysis of the Effects of Sleep Deprivation on the Cortical Transcriptome in Animal Models

Sleep deprivation (SD) causes large disturbances in mood and cognition. The molecular basis for these effects can be explored using transcriptional profiling to quantify brain gene expression. In this report, we used a meta-analysis of public transcriptional profiling data to discover SD effects on gene expression that are consistent across studies and paradigms. To conduct the meta-analysis, we used pre-specified search terms related to rodent SD paradigms to identify relevant studies within Gemma, a database containing >19,000 re-analyzed microarray and RNA-Seq datasets. Eight studies met our systematic inclusion/exclusion criteria. These studies characterized the effect of 18 SD interventions on gene expression in the mouse cerebral cortex (collective n=293). For each gene with sufficient data (n=16,290), we fit a random effects meta-analysis model to the SD effect sizes (log(2) fold changes). Our meta-analysis revealed 182 differentially expressed genes in response to SD (false discovery rate: FDR<0.05), most of which (115/182) showed similar effects (FDR<0.05) in an independent large dataset (GSE114845: n=86 RNA-Seq samples from n=222 mice). Gene-set enrichment analysis revealed down-regulation in pathways related to stress response (e.g., glucocorticoid receptor Nr3c1), vasculature, growth and development, and upregulation related to stress, inflammation, and neuropeptide signalling. Exploratory analyses suggested that recovery sleep (included in six contrasts: range: 1-18 hrs), could reverse the impact of SD on gene expression. Our meta-analysis provides a useful reference database illustrating the diverse molecular impact of SD on the rodent cerebral cortex. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/648791v2_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@52984dorg.highwire.dtl.DTLVardef@8d1174org.highwire.dtl.DTLVardef@174ed85org.highwire.dtl.DTLVardef@195e8bf_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

neuroscience↗

bioRxiv2025

The Effects of Antidepressants on the Hippocampus: A Meta-Analysis of Public Transcriptional Profiling Data

Depression can be treated with traditional pharmaceuticals targeting monoaminergic function, non-traditional drug classes and neuromodulatory interventions. To identify mechanisms of action shared across clinically-effective antidepressant treatment categories, we performed two systematic meta-analyses of public transcriptional profiling data from adult laboratory rodents (rats, mice). The outcome variable was gene expression, measured by microarray or RNA-Seq from bulk-dissected tissue from two depression-related brain regions (hippocampus, cortex). Relevant datasets were identified in the Gemma database of curated, reprocessed transcriptional profiling data using predefined search terms and inclusion/exclusion criteria (hippocampus: 6-24-2024, cortex: 7-10-2024). Differential expression results were extracted for all genes, minimizing bias. For each gene, a random effects meta-analysis model was fit to antidepressant vs. control effect sizes (Log2 Fold Changes) from each study for each brain region, with follow-up analyses exploring sources of effect heterogeneity. For the hippocampus, 15 relevant studies were identified, containing 22 antidepressant vs. control group comparisons (collective n=313 samples), with approximately half representing traditional versus non-traditional antidepressants. Of 16,439 analyzed genes, 58 were consistently differentially expressed (False Discovery Rate (FDR)<0.05) following treatment. Antidepressant effects were enriched in the dentate gyrus and in gene sets related to stress regulation, brain growth and plasticity, vasculature and glia, and immune function. Comparisons with single nucleus RNA-Seq confirmed effects on specific hippocampal cell types, including potential rejuvenation of dentate granule neurons. For the cortex, 13 studies were identified, containing 16 antidepressant vs. control group comparisons (collective n=233 samples). Of 15,583 analyzed genes, only one was consistently differentially expressed (FDR<0.05: Atp6v1b2), but overall expression patterns moderately resembled the hippocampus. These genes and pathways showing consistent differential expression across treatment categories may be promising targets for novel therapies. Future work should explore relevance to human clinical populations and potential heterogeneity introduced by sex and subregion. Key PointsO_LIDepression can be treated with traditional antidepressants targeting monoaminergic function, as well as other drug classes and non-pharmaceutical interventions. C_LIO_LIUnderstanding the congruent effects of different types of antidepressant treatments on sensitive brain regions, such as the hippocampus and cortex, can highlight essential mechanisms of action. C_LIO_LIA meta-analysis of public transcriptional profiling datasets identified genes and functional gene sets that are differentially expressed across antidepressant categories. C_LI Plain Language SummaryMajor depressive disorder is characterized by persistent depressed mood and loss of interest and pleasure in life. Worldwide, an estimated 5% of adults suffer from depression, making it a leading cause of disability. The current standard of care for depressed individuals includes psychotherapy and antidepressant medications that enhance signaling by monoamine neurotransmitters, such as serotonin and norepinephrine. Other treatments include non-traditional antidepressants that function via alternative, often unknown, mechanisms. To identify mechanisms of action shared across different categories of antidepressants, we performed a meta-analysis using public datasets to characterize changes in gene expression (mRNA) following treatment with both traditional and non-traditional antidepressants. We focused on the hippocampus and cortex, which are two brain regions that are sensitive to both depression and antidepressant usage. We found 59 genes that had consistently higher or lower levels of expression (mRNA) across antidepressant categories. The functions associated with these genes were diverse, including regulation of stress response, the immune system, brain growth and adaptability. These genes are worth investigating further as potential linchpins for antidepressant efficacy or as targets for novel therapies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/648805v3_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@14538e3org.highwire.dtl.DTLVardef@199c5e3org.highwire.dtl.DTLVardef@8ed8a6org.highwire.dtl.DTLVardef@31b1f8_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Host response during unresolved urinary tract infection alters mammary tissue homeostasis through collagen deposition and TIMP1

Exposure to pathogens throughout a lifetime influences immunity and organ function. Here, we explored how the systemic host-response to bacterial urinary tract infection (UTI) induces tissue-specific alterations to the mammary gland. Utilizing a combination of histological tissue analysis, single cell RNA sequencing and flow cytometry, we identified that mammary tissue from UTI-bearing mice display collagen deposition, enlarged ductal structures, ductal hyperplasia with atypical epithelial transcriptomes and altered immune composition. Bacterial cells were absent in the mammary tissue and blood of UTI-bearing mice, therefore, alterations to the distal mammary tissue were mediated by the systemic host response to local infection. Furthermore, broad spectrum antibiotic treatment resolved the infection and restored mammary cellular and tissue homeostasis. Systemically, unresolved UTI correlated with increased plasma levels of the metalloproteinase inhibitor, TIMP1, which controls extracellular matrix (ECM) remodeling and neutrophil function. Treatment of nulliparous and post-lactation UTI-bearing female mice with a TIMP1 neutralizing antibody, or broad-spectrum antibiotic, prevented mammary collagen deposition, thus providing evidence for an unexpected link between the systemic host response during UTI and mammary alterations. SummaryThe systemic response during urinary tract infection induces TIMP1-driven collagen deposition specifically into the mammary gland.

developmental biology↗

bioRxiv2022

Computational pipeline provides mechanistic understanding of Omicron variant of concern neutralizing engineered ACE2 receptor traps

The SARS-CoV-2 Omicron variant, with 15 mutations in Spike receptor binding domain (Spike-RBD), renders virtually all clinical monoclonal antibodies against WT SARS-CoV-2 ineffective. We recently engineered the SARS-CoV-2 host entry receptor, ACE2, to tightly bind WT-Spike-RBD and prevent viral entry into host cells ("receptor traps"). Here we determine cryo-EM structures of our receptor traps in complex with full length Spike. We develop a multi-model pipeline combining Rosetta protein modeling software and cryo-EM to allow interface energy calculations even at limited resolution and identify interface side chains that allow for high affinity interactions between our ACE2 receptor traps and Spike-RBD. Our structural analysis provides a mechanistic rationale for the high affinity (0.53 - 4.2nM) binding of our ACE2 receptor traps to Omicron-RBD confirmed with biolayer interferometry measurements. Finally, we show that ACE2 receptor traps potently neutralize Omicron- and Delta-pseudotyped viruses, providing alternative therapeutic routes to combat this evolving virus.

biochemistry↗

bioRxiv2022

The fluorescence-activating and absorption-shifting tag (FAST) enables live-cell fluorescence imaging of Methanococcus maripaludis

Live-cell fluorescence imaging in methanogenic archaea has been limited due to the strictly anoxic conditions required for growth and issues with autofluorescence associated with electron carriers in central metabolism. Here, we show that the fluorescence-activating and absorption-shifting tag (FAST) when complexed with the fluorogenic ligand 4-hydroxy-3-methylbenzylidene-rhodanine (HMBR) overcomes these issues and displays robust fluorescence in Methanococcus maripaludis. We also describe a mechanism to visualize cells under anoxic conditions using a fluorescence microscope. Derivatives of FAST were successfully applied for protein abundance analysis, subcellular localization, and determination of protein-protein interactions. FAST fusions to both formate dehydrogenase (Fdh) and F420-reducing hydrogenase (Fru) displayed increased fluorescence in cells grown on formate containing medium, consistent with previous studies suggesting increased abundance of these proteins in the absence of H2. Additionally, FAST fusions to both Fru and the ATPase associated with the archaellum (FlaI) showed membrane localization in single cells observed using anoxic fluorescence microscopy. Finally, a split reporter translationally fused to the alpha and beta subunits of Fdh reconstituted a functionally fluorescent molecule in vivo via bimolecular fluorescence complementation. Together, these observations demonstrate the utility of FAST as a tool for studying members of the methanogenic archaea. ImportanceMethanogenic archaea are important members of anaerobic microbial communities where they catalyze essential reactions in the degradation of organic matter. Developing additional tools for studying the cell biology of these organisms is essential to understanding them at a mechanistic level. Here, we show that FAST, in combination with the fluorogenic ligand HMBR, can be used to monitor protein dynamics in live cells of M. maripaludis. Application of FAST holds promise for future studies focused on the metabolism and physiology of methanogenic archaea.

microbiology↗

bioRxiv2021

The fruit fly Anastrepha obliqua harbors three kingdoms of life in its intestinal tract.

The fruit fly Anastrepha obliqua is an economically important pest for mango fruits in Mexico. The sterile insect technique is used to control this pest; it involves mass production and release of sterile flies to reduce reproduction of the wild population. As noted in different tephritidae, the performance of sterile males may be affected by the assimilation of nutrients under mass-rearing conditions. In the wild, the flys life cycle suggests the acquisition of different organisms that could modulate fitness and physiology of the fly. Therefore, the microorganisms lodged in the gut may be determinative. For A. obliqua, there is no information regarding microorganisms other than bacteria. This study analyzed bacteria, fungi, and archaea communities in the A. obliqua gut through denaturing gradient gel electrophoresis (DGGE) profile of 16S and 18S ribosomal DNA markers. Besides, 16S sequencing and phylogenetic analysis provided a better description of bacteria, and archaea communities. We found that wild flies presented higher microbial diversity than laboratory samples. Phylogeny analyses of wild samples suggest the presence of microbial species related to fructose assimilation while laboratory microbial species suggest the presence of microorganisms leading to a specialized metabolism to process yeast as result of the consumption of an artificial diet. Here, the archaea kingdom is suggested as an important player in fly metabolism. This is the first report of the intestinal microbial (bacteria, archaea and fungi) composition of A. obliqua, which will aid in our understanding of the role of microorganisms in the development and physiology of the flies.

microbiology↗

bioRxiv2021

Essential role of hyperacetylated microtubules in innate immunity escape orchestrated by the EBV-encoded BHRF1 protein

Innate immunity constitutes the first line of defense against viruses, in which mitochondria play an important role in the induction of the interferon (IFN) response. BHRF1, a multifunctional viral protein expressed during Epstein-Barr virus reactivation, modulates mitochondrial dynamics and disrupts the IFN signaling pathway. Mitochondria are mobile organelles that move through the cytoplasm thanks to the cytoskeleton and in particular the microtubule (MT) network. MTs undergo various post-translational modifications, among them tubulin acetylation. In this study, we demonstrated that BHRF1 induces MT hyperacetylation to escape innate immunity. Indeed, the expression of BHRF1 induces the clustering of shortened mitochondria next to the nucleus. This "mito-aggresome" is organized around the centrosome and its formation is MT-dependent. We also observed that the -tubulin acetyltransferase ATAT1 interacts with BHRF1. Using ATAT1 knockdown or a non-acetylatable -tubulin mutant, we demonstrated that this hyperacetylation is necessary for the mito-aggresome formation. Similar results were observed during EBV reactivation. We investigated the mechanism leading to the clustering of mitochondria, and we identified dyneins as motors that are required for mitochondrial clustering. Finally, we demonstrated that BHRF1 needs MT hyperacetylation to block the induction of the IFN response. Moreover, the loss of MT hyperacetylation blocks the localization of autophagosomes close to the mito-aggresome, impeding BHRF1 to initiate mitophagy, which is essential to inhibiting the signaling pathway. Therefore, our results reveal the role of the MT network, and its acetylation level, in the induction of a pro-viral mitophagy.

cell biology↗

bioRxiv2021

CryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes.

The SARS-CoV-2 protein Nsp2 has been implicated in a wide range of viral processes, but its exact functions, and the structural basis of those functions, remain unknown. Here, we report an atomic model for full-length Nsp2 obtained by combining cryo-electron microscopy with deep learning-based structure prediction from AlphaFold2. The resulting structure reveals a highly-conserved zinc ion-binding site, suggesting a role for Nsp2 in RNA binding. Mapping emerging mutations from variants of SARS-CoV-2 on the resulting structure shows potential host-Nsp2 interaction regions. Using structural analysis together with affinity tagged purification mass spectrometry experiments, we identify Nsp2 mutants that are unable to interact with the actin-nucleation-promoting WASH protein complex or with GIGYF2, an inhibitor of translation initiation and modulator of ribosome-associated quality control. Our work suggests a potential role of Nsp2 in linking viral transcription within the viral replication-transcription complexes (RTC) to the translation initiation of the viral message. Collectively, the structure reported here, combined with mutant interaction mapping, provides a foundation for functional studies of this evolutionary conserved coronavirus protein and may assist future drug design.

biophysics↗

bioRxiv2021

Sentinel cells enable genetic detection of SARS-CoV-2 Spike protein

The COVID-19 pandemic has demonstrated the need for exploring different diagnostic and therapeutic modalities to tackle future viral threats. In this vein, we propose the idea of sentinel cells, cellular biosensors capable of detecting viral antigens and responding to them with customizable responses. Using SARS-CoV-2 as a test case, we developed a live cell sensor (SARSNotch) using a de novo-designed protein binder against the SARS-CoV-2 Spike protein. SARSNotch is capable of driving custom genetically-encoded payloads in immortalized cell lines or in primary T lymphocytes in response to purified SARS-CoV-2 Spike or in the presence of Spike-expressing cells. Furthermore, SARSNotch is functional in a cellular system used in directed evolution platforms for development of better binders or therapeutics. In keeping with the rapid dissemination of scientific knowledge that has characterized the incredible scientific response to the ongoing pandemic, we extend an open invitation for others to make use of and improve SARSNotch sentinel cells in the hopes of unlocking the potential of the next generation of smart antiviral therapeutics.

synthetic biology↗

bioRxiv2019

Exposure to parasitic protists and helminths changes the intestinal community structure of bacterial microbiota but not of eukaryotes in a cohort of mother-child binomial from a semi-rural setting in Mexico

Around 3.5 billion people are colonized by intestinal parasites worldwide. Intestinal parasitic eukaryotes interact not only with the host, but also with the intestinal microbiota. In this work, we studied the relationship between the presence of multiple enteric parasites and the community structure of the bacterial and eukaryote intestinal microbiota in an asymptomatic cohort of mother-child binomials from a semi-rural community in Mexico. The intestinal parasites identified were Blastocystis hominis, Entamoeba histolytica/dispar, Endolimax nana, Chilomastix mesnili, Iodamoeba butshlii, Entamoeba coli, Hymenolepis nana and Ascaris lumbricoides. We sequenced bacterial 16S rDNA and eukaryotic 18S rDNA in fecal samples of 46 mothers and their respective children, with ages ranging from two to twenty months. Although we did not find significant alpha-diversity changes, we found a significant effect of parasite exposure on bacterial beta-diversity, which explained between 5.2% and 15.0% of the variation of the bacterial community structure. Additionally, exposure to parasites was associated with significant changes in relative abundances of bacterial taxa, characterized by increases in the Clostridia and decreased Actinobacteria and Bacteroidia abundances. There were no significant changes of intestinal microeukaryote abundances associated with parasite exposure. However, we found several significant positive correlations between intestinal bacteria and eukaryotes, including co-occurrence of the fungi Candida tropicalis with Bacteroides and Actinomyces, and Saccharomycetales with Bifidobacterium and Prevotella copri. These bacterial community structure changes associated with parasite exposure imply effects on microbial metabolic routes, host nutrient uptake abilities and intestinal immunity regulation in host-parasite interactions.\n\nIMPORTANCEThe impact of intestinal eukaryotes on the prokaryotic microbiome composition of asymptomatic carriers has not been extensively explored, especially in children and in hosts with multiple parasites. In this work, we studied the relationship between protist and helminth parasite colonization and intestinal microbiota structure in an asymptomatic population of mother-child binomials from the semi-rural community of Morelos in Mexico. We found that the presence of parasitic eukaryotes correlated with changes in the bacterial community structure in the intestinal microbiota in an age-dependent way. This was characterized by an increase of the relative abundance of the class Clostridia and the decrease of Actinobacteria and Bacteroidia. While there were no significant associations between the presence of parasites and microeukaryote community structure, we observed strong positive correlations between bacterial and eukaryote taxa, identifying novel relationships between prokaryotes and fungi, and reflecting the diet of the human population studied.

microbiology↗

bioRxiv2018

IFN-γ induces epithelial-to-mesenchymal transition of cancer cells via an unique microRNA processing

Interferon-{gamma} (IFN{gamma}) is a potent cytokine in modulating tumor immunity and tumoricidal effects. We demonstrate a new function of IFN{gamma} in inducing epithelial-to-mesenchymal transition (EMT) in normal and cancer cells from different cell types. IFN{gamma} activates JAK-STAT signaling pathway leading to the transcription of IFN-stimulated genes (ISGs), such as interferon-induced tetratricopeptide repeat 5 (IFIT5). We unveil a new function of IFIT5 complex in degrading precursor microRNAs (pre-miRNA) that include pre-miR-363 from the miR-106a-363 cluster, as well as pre-miR-101 and pre-miR-128 with a similar 5-end structure with pre-miR-363. Noticeably, these suppressive miRNAs have similar functions by targeting EMT transcription factors in prostate cancer (PCa) cells. We further demonstrated that IFIT5 plays a critical role in IFN{gamma}-induced cell invasiveness in vitro and lung metastasis in vivo. Clinically, IFIT5 is highly elevated in high-grade PCa and its expression inversely correlates with these suppressive miRNAs. Altogether, this study unveils pro-tumorigenic role of the IFN pathway via a new mechanism of action, which certainly raises concern about its clinical application.

cancer biology↗

bioRxiv2018

Environmental and Socioeconomic Factors Associated with West Nile Virus

Environmental and socioeconomic risk factors associated with West Nile Virus cases were investigated in the Northern San Joaquin Valley region of California, a largely rural area. The study included human West Nile Virus (WNV) cases from the years 2011-2015 in the three county area of San Joaquin, Stanislaus and Merced Counties, and examined whether factors were associated with WNV using census tracts as the unit of analysis. Environmental factors included temperature, precipitation, mosquitoes positive for WNV, and habitat. Socioeconomic variables included age, education, housing age, home vacancies, median income, population density, ethnicity, and language spoken. Chi-squared independence tests were used to examine whether each variable was associated with WNV in each county, and then also used for the three counties combined. Logistic regression was used for a three-county combined analysis, to examine which environmental and socioeconomic variables were most likely associated with WNV cases. The chi-squared tests found that the variables associated with WNV varied in each of the three counties. The chi-squared tests for data combined from the three counties found that WNV cases were significantly associated with mosquitoes positive for WNV, urban habitat, higher home vacancies, higher population density, higher education, and ethnicity. Logistic regression analysis revealed that overall, the environmental factors precipitation, mean temperature, and WNV positive mosquitoes were the strongest predictors of WNV cases. Results support efforts of mosquito control districts, which aim for source reduction of mosquito breeding sites. In addition, findings suggest that residents with higher income and education may be more aware of WNV and its symptoms, and more likely to request testing from physicians. Lower income and education residents may not be aware of WNV. Public health education might increase its prevention messages about vector-borne disease in the various languages of the region, which would contribute overall to public health in the region.

epidemiology↗