Biology subjects

Hatch, K.

Publications and source records attributed to Hatch, K..

5 recordsLinked to original sources

bioRxiv2025

Short 5' UTRs serve as a marker for viral mRNA translation inhibition by the IFIT2-IFIT3 antiviral complex

Recognition of "non-self" nucleic acids, including cytoplasmic dsDNA, dsRNA, or mRNAs lacking proper 5 cap structures, is critical for the innate immune response to viruses. Here, we demonstrate that short 5 untranslated regions (UTRs), a characteristic of many viral mRNAs, can also serve as a molecular pattern for innate immune recognition via the interferon-induced proteins IFIT2 and IFIT3. The IFIT2-IFIT3 heterodimer, formed through an intricate domain swap structure resolved by cryo-EM, mediates viral mRNA 5 end recognition, translation inhibition, and ultimately antiviral activity. Critically, 5 UTR lengths <50 nucleotides are necessary and sufficient to sensitize an mRNA to translation inhibition by the IFIT2-IFIT3 complex. Accordingly, diverse viruses whose mRNAs contain short 5 UTRs, such as vesicular stomatitis virus and parainfluenza virus 3, are sensitive to IFIT2-IFIT3-mediated antiviral activity. Our work thus reveals a pattern of antiviral nucleic acid immune recognition that takes advantage of the inherent constraints on viral genome size.

microbiology↗

bioRxiv2023

Organization of an Ascending Circuit that Conveys Flight Motor State

Natural behaviors are a coordinated symphony of motor acts which drive self-induced or reafferent sensory activation. Single sensors only signal presence and magnitude of a sensory cue; they cannot disambiguate exafferent (externally-induced) from reafferent sources. Nevertheless, animals readily differentiate between these sources of sensory signals to make appropriate decisions and initiate adaptive behavioral outcomes. This is mediated by predictive motor signaling mechanisms, which emanate from motor control pathways to sensory processing pathways, but how predictive motor signaling circuits function at the cellular and synaptic level is poorly understood. We use a variety of techniques, including connectomics from both male and female electron microscopy volumes, transcriptomics, neuroanatomical, physiological and behavioral approaches to resolve the network architecture of two pairs of ascending histaminergic neurons (AHNs), which putatively provide predictive motor signals to several sensory and motor neuropil. Both AHN pairs receive input primarily from an overlapping population of descending neurons, many of which drive wing motor output. The two AHN pairs target almost exclusively non-overlapping downstream neural networks including those that process visual, auditory and mechanosensory information as well as networks coordinating wing, haltere, and leg motor output. These results support the conclusion that the AHN pairs multi-task, integrating a large amount of common input, then tile their output in the brain, providing predictive motor signals to non-overlapping sensory networks affecting motor control both directly and indirectly.

neuroscience↗

bioRxiv2020

White matter integrity and nicotine dependence in smokers: evaluating vertical and horizontal pleiotropy

Smoking is a heritable behavior and nicotine dependency is complex mechanism supported by both positive and negative reinforcements. We hypothesized that cerebral white matter (WM) may mediate the individual dependency on nicotine integrity because its integrity is altered in smokers and shows dose-related response to nicotine administration. Two vertical and one horizontal pleiotropy pathways that combined individual genetic variations, measure of WM integrity by fractional anisotropy (FA), and nicotine dependence were evaluated in a large epidemiological sample (N=12,264 and 4,654 participants that have genetic, FA measure and nicotine dependence data available for smoking status and cigarettes per day (CPD), respectively) collected UK Biobank. We started by selecting the candidate genetic regions including genetic risk factors associated with smoking from genome-wide association study (GWAS) for causal pathway analysis. Then we identified pleiotropic loci that influence both nicotine dependence and WM integrity from these regions. We tested a horizontal pleiotropy pathway: (A) genetic risk factors associated with smoking were independently affecting both nicotine dependence and WM integrity. We also evaluated two vertical pleiotropy that assumed that individual genetic factors associated with nicotine dependence impacted B) impacted WM integrity which in turn led to higher nicotine dependence vs. C) led to nicotine dependence and resulting white matter alterations. There were 10 and 23 candidate pleiotropic variants identified for smoking status and CPD traits. All these variants exhibited vertical pleiotropy. For smoking status, the genetic effect on smoking status was mediated by FA measures over multiple brain regions. The variants were located in a gene SARDH, which catalyzes the oxidative demethylation of sarcosine that plays a role in reducing tolerance effect on nicotine. Conversely, CPD was a significant mediator in the vertical pleiotropy pathway to FA. The identified variants were located in gene IREB2, that was reported as a susceptibility gene for both neurodegeneration and smoking-induced diseases.

neuroscience↗

bioRxiv2020

Genetic Fine-mapping with Dense Linkage Disequilibrium Blocks: genetics of nicotine dependence

Fine-mapping is an analytical step to perform causal prioritization of the polymorphic variants on a trait-associated genomic region observed from genome-wide association studies (GWAS). The prioritization of causal variants can be challenging due to the linkage disequilibrium (LD) patterns among hundreds to thousands of polymorphisms associated with a trait. We propose a novel{ell} 0 graph norm shrinkage algorithm to select causal variants from dense LD blocks consisting of highly correlated SNPs that may not be proximal or contiguous. We extract dense LD blocks and perform regression shrinkage to calculate a prioritization score to select a parsimonious set of causal variants. Our approach is computationally efficient and allows performing fine-mapping on thousands of polymorphisms. We demonstrate its application using a large UK Biobank (UKBB) sample related to nicotine addiction. Our results suggest that polymorphic variances in both neighboring and distant variants can be consolidated into dense blocks of highly correlated loci. Simulations were used to evaluate and compare the performance of our method and existing fine-mapping algorithms. The results demonstrated that our method outperformed comparable fine-mapping methods with increased sensitivity and reduced false-positive error rate regarding causal variant selection. The application of this method to smoking severity trait in UKBB sample replicated previously reported loci and suggested the causal prioritization of genetic effects on nicotine dependency. Author summaryDisentangling the complex linkage disequilibrium (LD) pattern and selecting the underlying causal variants have been a long-term challenge for genetic fine-mapping. We find that the LD pattern within GWAS loci is intrinsically organized in delicate graph topological structures, which can be effectively learned by our novel{ell} 0 graph norm shrinkage algorithm. The extracted LD graph structure is critical for causal variant selection. Moreover, our method is less constrained by the width of GWAS loci and thus can fine-map a massive number of correlated SNPs.

genetics↗

bioRxiv2019

Dissecting the heterogeneity of DENV vaccine-elicited cellular immunity using single-cell RNA sequencing and cellular metabolic profiling

Generating effective and durable T cell immunity is a critical prerequisite for vaccination against dengue virus (DENV) and other viral diseases. Understanding the precise molecular mechanisms of vaccine-elicited T cell immunity remains a critical knowledge gap in vaccinology. In this study, we utilized single-cell RNA sequencing (scRNAseq) and TCR clonotype analysis to demonstrate that a unique transcriptional signature is present in acutely-activated and clonally-expanded T cells that become committed to the memory repertoire. This effector-associated transcriptional signature is dominated by a unique metabolic transcriptional program. Based on this transcriptional signature, we were able to define a set of functional markers that identify the most potent and durable vaccine-reactive memory precursor CD8+ T cells. The transferrin receptor (CD71) other important transporters of amino acids, and direct measurements of glucose and fatty acid uptake, were further validated as early markers of durable T cell memory using conventional flow cytometry. These data suggest that generating durable T cell immunity is a process that is determined by metabolic programming and metabolite availability during the acute phase of the immune response. This study illustrates the power of scRNAseq as an analytical tool to assess the molecular mechanisms of host control and vaccine modality in determining the magnitude, diversity, and persistence of vaccine-elicited cell-mediated immunity.

immunology↗