Biology subjects

West, J. D.

Publications and source records attributed to West, J. D..

6 recordsLinked to original sources

bioRxiv2026

Microbiome-Derived RNA Promotes Heritable Defense Against Intracellular Pathogens in Caenorhabditis elegans

Intestinal microbiota shape host immunity, but whether they can pre-activate defense against intracellular pathogens remains unclear. Here, we identify a natural microbiome member, Stenotrophomonas indicatrix JUb19, as the first example of a bacterium that partially induces the Intracellular Pathogen Response in Caenorhabditis elegans in the absence of infection. This response is coupled to broader metabolic remodeling, suggesting that combined immune and metabolic changes contribute to defense. We show that bacterial single-stranded RNA contributes to this effect, identifying a novel microbiome-derived signal that links microbial exposure to host defense. JUb19 exposure reduces susceptibility to both viral and microsporidian pathogens and confers inherited protection to unexposed progeny, but at a cost to parental fitness. These findings reveal a mechanism by which microbiome-derived RNA programs immunity against intracellular pathogens across generations.

molecular biology↗

bioRxiv2025

Bidirectional Crosstalk Between Sleep and Pulmonary Arterial Hypertension

BackgroundPulmonary Arterial Hypertension (PAH) is a devastating cardiopulmonary disease characterized by pulmonary vascular remodeling due to vascular cells dysfunction. Among other clinical signs, emerging data suggest poor sleep quality in patients with PAH; however, how poor sleep impacts hemodynamic burden, symptom severity, and pulmonary vascular remodeling during PAH progression remains unknown. MethodsWe used two models of sleep disturbances (sleep fragmentation and chronic jet lag) and different mouse models of PAH to determine the effects of poor sleep on PAH. We carried out timepoint quantitative RT-PCR analyses to define the clock gene oscillations in human pulmonary artery smooth muscle cells (PASMCs) isolated from non-PAH and PAH patients. Bulk RNA-sequencing analysis, immunostaining, and proliferation assays were used to explore the mechanisms by which poor sleep impacts PAH. Electroencephalogram and Electromyogram recordings (EEG/EMG) were used to determine whether PAH affects sleep in mice. ResultsPoor sleep exacerbated right ventricular dysfunction, pulmonary vascular remodeling, and PAH. RNA-seq and immunostaining analyses showed that poor sleep induces lung inflammation. Inflammation affected the pulmonary vascular molecular clock to drive PASMC hyperproliferation and increased migration. SMC-specific deletion of Bmal1 protected mice from RV dysfunction, pulmonary vascular remodeling, and PAH. EEG/EMG measurements demonstrated that PAH causes poor sleep quality in mice. Lastly, we showed that improving sleep via melatonin delivery and blunting inflammation with clodronate inhibited pulmonary vascular remodeling and PAH. ConclusionsOur study demonstrates that PAH causes poor sleep which in turn induces inflammation, increases PASMC proliferation, and exacerbates PAH. This suggests that the relationship between PAH and poor sleep is a self-amplifying cycle, and that a combination of hypnotic and anti-inflammatory drugs may give PAH patients better clinical outcomes. Clinical PerspectiveO_ST_ABSWhat is New?C_ST_ABSO_LIPAH causes poor sleep quality which in turn induces lung inflammation, PASMC proliferation, and exacerbated PAH. C_LIO_LIBmal1 rhythmicity is disrupted, and its expression is increased in lungs of patients with PAH. C_LIO_LISMC-specific deletion of Bmal1 protects from PAH. C_LIO_LIImproving sleep quality and blunting inflammation attenuates PAH. C_LI What Are the Clinical Implications?O_LIBmal1 represents a promising disease-modifying agent with potential for clinical translation in the treatment of PAH. C_LIO_LIA combination of hypnotic and anti-inflammatory drugs has therapeutic potential to treat PAH. C_LI

pathology↗

bioRxiv2024

A novel regulatory pathway recognizes and degrades transcripts with long 3' untranslated regions

Quantitative control of gene expression is fundamental to cellular function, and post-transcriptional regulation is a consequential, additional layer of control over protein output. Within mammalian mRNAs, the 3' untranslated region (3'UTR) acts as a hub of regulatory control, typically mediated by regulatory sequence elements within the 3'UTR. We have found that expression from transcripts with long 3'UTRs is strongly repressed compared to those with short 3'UTRs, and this phenomenon appears to be independent of sequence elements within the 3'UTR. The repression increases with 3'UTR length and is substantial; reporters with 2,000 nucleotide long 3'UTRs are repressed >10-fold compared to 400 nucleotide 3'UTRs. Conversely, increasing the length of the coding region has no effect on expression, demonstrating that it is 3'UTR length, not transcript length, that elicits repression. Reporters with different length 3'UTRs show no difference in transcription rates nor translation efficiency but have clear differences in mRNA half-lives and nucleocytoplasmic distribution, indicating repression of long-3'UTR transcripts is mediated by accelerated RNA decay. However, this transcript degradation does not involve the nonsense-mediated decay (NMD) pathway nor other canonical RNA decay pathways. In order to identify trans factors involved in 3'UTR-length-mediated decay, we quantified the differences in proteins bound to reporters with long and short 3'UTRs, and identified over 100 differentially associated factors. Knockdowns of two differentially associating proteins, the mRNA nuclear export factors DDX39B and ZC3H11A, indicate they play a role in repression of mRNAs with long 3'UTRs. This study establishes a novel length-dependent regulatory feature of 3'UTRs, which potentially regulates many genes.

genetics↗

bioRxiv2023

Repetitive Sulfur Dioxide Exposure in Mice Models Post-Deployment Respiratory Syndrome

Soldiers deployed to Iraq and Afghanistan have a higher prevalence of respiratory symptoms than non-deployed military personnel and some have been shown to have a constellation of findings on lung biopsy termed post-deployment respiratory syndrome (PDRS). Since many of the deployers in this cohort reported exposure to sulfur dioxide (SO2), we developed a model of repetitive exposure to SO2 in mice that phenocopies many aspects of PDRS, including adaptive immune activation, airway wall remodeling, and pulmonary vascular disease (PVD). Although abnormalities in small airways were not sufficient to alter lung mechanics, PVD was associated with the development of pulmonary hypertension and reduced exercise tolerance in SO2 exposed mice. Further, we used pharmacologic and genetic approaches to demonstrate a critical role for oxidative stress and isolevuglandins in mediating PVD in this model. In summary, our results indicate that repetitive SO2 exposure recapitulates many aspects of PDRS and that oxidative stress may mediate PVD in this model, which may be helpful for future mechanistic studies examining the relationship between inhaled irritants, PVD, and PDRS.

pathology↗

bioRxiv2023

Myeloid Cell-Derived IL1β Contributes to Pulmonary Vascular Remodeling in Heart Failure with Preserved Ejection Fraction

BackgroundPulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) is a common and highly morbid syndrome, but mechanisms driving PH-HFpEF are not well understood. We sought to determine whether a well-accepted murine model of HFpEF also displays features of PH in HFpEF, and we sought to identify pathways that might drive early remodeling of the pulmonary vasculature in HFpEF. MethodsEight week old male and female C57/BL6J mice were given either L-NAME and high fat diet (HFD) or control water/diet for 2,5, and 12 weeks. Bulk RNA sequencing and single cell RNA sequencing was performed to identify early and cell-specific pathways that might regulate pulmonary vascular remodeling in PH-HFpEF. Finally, clodronate liposome and IL1{beta} antibody treatments were utilized to deplete macrophages or IL1{beta}, respectively, to assess their impact on pulmonary vascular remodeling in HFpEF. ResultsMice given L-NAME/HFD developed PH, small vessel muscularization, and right heart dysfunction after 2 weeks of treatment. Inflammation-related gene ontologies were over-represented in bulk RNA sequencing analysis of whole lungs, with an increase in CD68+ cells in both murine and human PH-HFpEF lungs. Cytokine profiling of mouse lung and plasma showed an increase in IL1{beta}, which was confirmed in plasma from patients with HFpEF. Single cell sequencing of mouse lungs also showed an increase in M1-like, pro-inflammatory populations of Ccr2+ monocytes and macrophages, and transcript expression of IL1{beta} was primarily restricted to myeloid-type cells. Finally, clodronate liposome treatment prevented the development of PH in L-NAME/HFD treated mice, and IL1{beta} antibody treatment also attenuated PH in L-NAME/HFD treated mice. ConclusionsOur study demonstrated that a well-accepted model of HFpEF recapitulates features of pulmonary vascular remodeling commonly seen in patients with HFpEF, and we identified myeloid cell derived IL1{beta} as an important contributor to PH in HFpEF.

cell biology↗

bioRxiv2020

Robust partitioning of microRNA targets from downstream regulatory changes

The biological impact of microRNAs (miRNAs) is determined by their targets, and robustly identifying direct miRNA targets remains challenging. Existing methods suffer from high falsepositive rates and are unable to effectively differentiate direct miRNA targets from downstream regulatory changes. Here, we present an experimental and computational framework to deconvolute post-transcriptional and transcriptional changes using a combination of RNA-seq and PRO-seq. This novel approach allows us to systematically profile the regulatory impact of a miRNA. We refer to this approach as CARP: Combined Analysis of RNA-seq and PRO-seq. We apply CARP to multiple miRNAs and show that it robustly distinguishes direct targets from downstream changes, while greatly reducing false positives. We validate our approach using Argonaute eCLIP-seq and ribosome profiling, demonstrating that CARP defines a comprehensive repertoire of targets. Using this approach, we identify miRNA-specific activity of target sites within the open reading frame. Additionally, we show that CARP facilitates the dissection of complex changes in gene regulatory networks triggered by miRNAs and identification of transcription factors that mediate downstream regulatory changes. Given the robustness of the approach, CARP would be particularly suitable for dissecting miRNA regulatory networks in vivo.

genomics↗