Biology subjects

Patel, S.

Publications and source records attributed to Patel, S..

At least 181 records · Page 10Linked to original sources

bioRxiv2021

Petascale neural circuit reconstruction: automated methods

3D electron microscopy (EM) has been successful at mapping invertebrate nervous systems, but the approach has been limited to small chunks of mammalian brains. To scale up to larger volumes, we have built a computational pipeline for processing petascale image datasets acquired by serial section EM, a popular form of 3D EM. The pipeline employs convolutional nets to compute the nonsmooth transformations required to align images of serial sections containing numerous cracks and folds, detect neuronal boundaries, label voxels as axon, dendrite, soma, and other semantic categories, and detect synapses and assign them to presynaptic and postsynaptic segments. The output of neuronal boundary detection is segmented by mean affinity agglomeration with semantic and size constraints. Pipeline operations are implemented by leveraging distributed and cloud computing. Intermediate results of the pipeline are held in cloud storage, and can be effortlessly viewed as images, which aids debugging. We applied the pipeline to create an automated reconstruction of an EM image volume spanning four visual cortical areas of a mouse brain. Code for the pipeline is publicly available, as is the reconstructed volume.

neuroscience↗

bioRxiv2021

Using Deep Learning to Count Monarch Butterflies in Dense Clusters

Monarch butterflies display one of the most fascinating migration patterns of all species, traveling over 3000 miles from their North American breeding grounds to reach overwintering sites in Central Mexico. Recent studies have suggested that monarchs have experienced an alarming decline in population size due to a combination of deforestation, loss of native milkweed and nectaring plants, and climate change. An issue that conservation efforts face is the lack of principled mechanisms to accurately estimate and count the population size of monarchs. This difficulty occurs due to their small size and existence in dense overwintering clusters in forests. We create an open-source tool to aid conservationists estimate the count of monarch butterflies from images automatically. To the best of our knowledge, our approach, based on deep convolutional neural networks, is the first automated application that can count small insects like monarch butterflies in dense clusters. We demonstrate that our approach achieves high accuracy in counting the number of butterflies even in the presence of occlusion. We also release an open-source dataset containing high resolution images of monarch butterflies along with human annotations for each butterflys position. Our open-source implementation can be readily used by scientists to estimate monarch numbers in overwintering clusters and could also be adapted for use in other clustering species.

bioengineering↗

bioRxiv2021

A modular protein subunit vaccine candidate produced in yeast confers protection against SARS-CoV-2 in non-human primates

Vaccines against SARS-CoV-2 have been distributed at massive scale in developed countries, and have been effective at preventing COVID-19. Access to vaccines is limited, however, in low- and middle-income countries (LMICs) due to insufficient supply, high costs, and cold storage requirements. New vaccines that can be produced in existing manufacturing facilities in LMICs, can be manufactured at low cost, and use widely available, proven, safe adjuvants like alum, would improve global immunity against SARS-CoV-2. One such protein subunit vaccine is produced by the Serum Institute of India Pvt. Ltd. and is currently in clinical testing. Two protein components, the SARS-CoV-2 receptor binding domain (RBD) and hepatitis B surface antigen virus-like particles (VLPs), are each produced in yeast, which would enable a low-cost, high-volume manufacturing process. Here, we describe the design and preclinical testing of the RBD-VLP vaccine in cynomolgus macaques. We observed titers of neutralizing antibodies (>104) above the range of protection for other licensed vaccines in non-human primates. Interestingly, addition of a second adjuvant (CpG1018) appeared to improve the cellular response while reducing the humoral response. We challenged animals with SARS-CoV-2, and observed a ~3.4 and ~2.9 log10 reduction in median viral loads in bronchoalveolar lavage and nasal mucosa, respectively, compared to sham controls. These results inform the design and formulation of current clinical COVID-19 vaccine candidates like the one described here, and future designs of RBD-based vaccines against variants of SARS-CoV-2 or other betacoronaviruses.

immunology↗

bioRxiv2021

CODEC enables 'single duplex' sequencing

Detecting mutations as rare as a single molecule is crucial in many fields such as cancer diagnostics and aging research but remains challenging. Third generation sequencers can read a double-stranded DNA molecule (a single duplex) in whole to identify true mutations on both strands apart from false mutations on either strand but with limited accuracy and throughput. Although next generation sequencing (NGS) can track dissociated strands with Duplex Sequencing, the need to sequence each strand independently severely diminishes its throughput. Here, we developed a hybrid method called Concatenating Original Duplex for Error Correction (CODEC) that combines the massively parallel nature of NGS with the single-molecule capability of third generation sequencing. CODEC physically links both strands to enable NGS to sequence a single duplex with a single read pair. By comparing CODEC and Duplex Sequencing, we showed that CODEC achieved a similar error rate (10-6) with 100 times fewer reads and conferred single duplex resolution to most major NGS workflows.

bioengineering↗

bioRxiv2021

Serine 182 on RORγt regulates T helper 17 and regulatory T cell functions to resolve inflammation

Intestine homeostasis is maintained by the delicate balance of Th17 effector cells and Treg cells. Dysregulation of these cell populations contributes to inflammation, tissue damage, and chronic conditions. ROR{gamma}t is essential for the differentiation of Th17 and a subset of Treg (ROR{gamma}t+ Treg) cells involved in intestinal inflammation. ROR{gamma}t belongs to the nuclear receptor family of transcription factors with hinge regions that are highly flexible for co-activator/co-repressor interactions. Serine 182 at the hinge region of ROR{gamma}t is phosphorylated. This study aims to uncover how S182 on ROR{gamma}t contributes to mucosal homeostasis and diseases. We used CRISRP technology to generate a phosphor-null knock-in mutant mouse line (ROR{gamma}tS182A) to assess its role in intestine physiology. scRNA-seq was performed on WT and ROR{gamma}tS182A cohoused littermates to evaluate colonic T cell heterogeneity under steady state and colitis settings. Single-cell transcriptomics revealed that ROR{gamma}tS182 maintains colonic T cell heterogeneity under steady state, without interfering T cell development and differentiation. In inflamed tissues, ROR{gamma}tS182 simultaneously restricts IL-1{beta}-mediated Th17 activities and promotes anti-inflammatory cytokine IL-10 production in LT-like Treg cells. Phospho-null ROR{gamma}tS182A knock-in mice challenged with DSS induced colitis and EAE experienced delayed recovery and exacerbated pathology. The double switch role of ROR{gamma}tS182 is critical in resolving T cell-mediated inflammation and provides a potential therapeutic target to combat autoimmune diseases.

immunology↗

bioRxiv2021

eIF2α integrates proteotoxic signals both from ER and cytoplasm: Hsp70-Bag3 module regulates HRI-dependent phosphorylation of eIF2α

The major heat shock protein Hsp70 has been implicated in many stages of cancer development. These effects are mediated by a scaffold protein Bag3 that binds to Hsp70 and links it to components of multiple cancer-related signaling pathways. Accordingly, the Hsp70-Bag3 complex has been targeted by small molecules, which showed strong anti-cancer effects. Here, our initial question was how JG-98, an allosteric inhibitor of Hsp70 that blocks its interaction with Bag3, causes cell death. Breast epithelial cells MCF10A transformed with a single oncogene Her2 showed higher sensitivity to JG-98 then parental MCF10A cells. RNA expression analysis showed that this enhanced sensitivity correlated with higher induction of the UPR genes. Indeed, depletion of the pro-apoptotic UPR responsive transcription factor CHOP significantly protected cells from JG-98. Surprisingly, only the eIF2-associated branch of the UPR was activated by JG-98, suggesting that the response was not related to the ER proteotoxicity. Indeed, it was dependent on activation of a distinct cytoplasmic eIF2 kinase HRI. HRI-dependent phosphorylation of eIF2 was also activated by the cytoplasmic proteotoxicity via Hsp70-Bag3 complex, which directly associates with HRI. Dissociation of Hsp70-Bag3 complex led to Bag3-dependent degradation of HRI via autophagy. Therefore, eIF2 integrates proteotoxicity signals from both ER and cytoplasm, and the cytoplasmic response mediates cytotoxicity of the Hsp70-Bag3 inhibitors.

cell biology↗

bioRxiv2021

Activation of GPR116/ADGRF5 by its tethered agonist requires key amino acids in extracellular loop 2 of the transmembrane domain

The mechanistic details of the tethered agonist mode of activation for adhesion GPCRs has not been completely deciphered. We set out to investigate the physiologic importance of autocatalytic cleavage upstream of the agonistic peptide sequence, an event necessary for NTF displacement and subsequent receptor activation. To examine this hypothesis, we characterized tethered agonist-mediated activation of GPR116 in vitro and in vivo. A knock-in mouse expressing a non-cleavable GPR116 mutant phenocopies the pulmonary phenotype of GPR116 knock-out mice, demonstrating that tethered agonist-mediated receptor activation is indispensable for function in vivo. Using site-directed mutagenesis and species swapping approaches we identified key conserved amino acids for GPR116 activation in the tethered agonist sequence and in extracellular loops 2/3 (ECL2/3). We further highlight residues in transmembrane7 (TM7) that mediate stronger signaling in mouse versus human GPR116 and recapitulate these findings in a model supporting tethered agonist:ECL2 interactions for GPR116 activation. Grant supportThis work was supported in part by HL131634 (JPB) from the National Heart, Lung and Blood Institute of the National Institutes of Health.

cell biology↗

bioRxiv2021

GCN5 Maintains Muscle Integrity by Acetylating YY1 to Promote Dystrophin Expression

This work identifies a novel role for the acetyltransferase GCN5 in regulating muscle integrity through inhibition of DNA binding activity of the transcriptional repressor YY1. Here we report that in mice a muscle-specific knockout of GCN5 (Gcn5skm-/-) reduces the expression of key structural muscle proteins, including dystrophin, resulting in myopathy. Supporting our observation, a meta-analysis between the differential transcriptome of Gcn5skm-/- muscle and all available open-access data sets identified top correlations with musculoskeletal diseases in humans. GCN5 was found to acetylate YY1 at two residues (K392 and K393), which disrupts the interaction between the YY1 zinc-finger region and DNA. De/acetylation mimics for these YY1 post-translational modifications modulated muscle structural gene expression and DNA binding. Analysis of human GTEx data also found positive and negative correlations between fiber diameter and GCN5 and YY1 respectively. Collectively, our results demonstrate that GCN5 acetyltransferase activity regulates YY1 DNA binding and expression of dystrophin to modulate muscle integrity.

cell biology↗

bioRxiv2021

Deep Learning Predicts Patterns of Cardiotoxicity in a High-Content Screen Using Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Drug-induced cardiotoxicity and hepatotoxicity are major causes of drug attrition. To decrease late-stage drug attrition, pharmaceutical and biotechnology industries need to establish biologically relevant models that use phenotypic screening to predict drug-induced toxicity. In this study, we sought to rapidly detect patterns of cardiotoxicity using high-content image analysis with deep learning and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). We screened a library of 1280 bioactive compounds and identified those predicted to have cardiotoxic liabilities using a single-parameter score based on deep learning. Compounds with major predicted cardiotoxicity included DNA intercalators, ion channel blockers, epidermal growth factor receptor, cyclin-dependent kinase, and multi-kinase inhibitors. We also screened a diverse library of molecules with unknown targets and identified chemical frameworks with predicted cardiotoxic liabilities. By using this screening approach during target discovery and lead optimization, we can de-risk early-stage drug discovery. We show that the broad applicability of combining deep learning with iPSC technology is an effective way to interrogate cellular phenotypes and identify drugs that protect against diseased phenotypes and deleterious mutations. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=161 HEIGHT=200 SRC="FIGDIR/small/436666v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@695707org.highwire.dtl.DTLVardef@1d0980forg.highwire.dtl.DTLVardef@1af30e7org.highwire.dtl.DTLVardef@b3a312_HPS_FORMAT_FIGEXP M_FIG C_FIG CONTRIBUTION TO THE FIELDIn this article, Grafton and colleagues use induced pluripotent stem cell technology and deep learning to train a neural network capable of detecting patterns of cardiotoxicity. To identify bioactive and chemical classes that lead to cardiotoxicity, they combine the neural network with high-content screening of 2560 compounds. The methods described in this study can be used to de-risk early-stage drug development, triage hits, and identify drugs that protect against disease. This screening paradigm will serve as a useful resource for drug discovery and phenotypic interrogation of stem cells and stem cell-derived cell types.

cell biology↗

bioRxiv2021

Reduced binding and neutralization of infection- and vaccine-induced antibodies to the B.1.351 (South African) SARS-CoV-2 variant

The emergence of SARS-CoV-2 variants with mutations in the spike protein is raising concerns about the efficacy of infection- or vaccine-induced antibodies to neutralize these variants. We compared antibody binding and live virus neutralization of sera from naturally infected and spike mRNA vaccinated individuals against a circulating SARS-CoV-2 B.1 variant and the emerging B.1.351 variant. In acutely-infected (5-19 days post-symptom onset), convalescent COVID-19 individuals (through 8 months post-symptom onset) and mRNA-1273 vaccinated individuals (day 14 post-second dose), we observed an average 4.3-fold reduction in antibody titers to the B.1.351-derived receptor binding domain of the spike protein and an average 3.5-fold reduction in neutralizing antibody titers to the SARS-CoV-2 B.1.351 variant as compared to the B.1 variant (spike D614G). However, most acute and convalescent sera from infected and all vaccinated individuals neutralize the SARS-CoV-2 B.1.351 variant, suggesting that protective immunity is retained against COVID-19.

immunology↗

bioRxiv2021

Targeting Diacylglycerol Lipase to Reduce AlcoholConsumption

Alcohol use disorder (AUD) is associated with substantial morbidity, mortality, and societal cost, and pharmacological treatment options for AUD are limited. The endogenous cannabinoid (eCB) signaling system is critically involved in reward processing and alcohol intake is positively correlated with release of the eCB ligand 2-Arachidonoylglycerol (2-AG) within reward neurocircuitry. Here we show that genetic and pharmacological inhibition of diacylglycerol lipase (DAGL), the rate limiting enzyme in the synthesis of 2-AG, reduces alcohol consumption in a variety of preclinical models ranging from a voluntary free-access model to aversion resistant-drinking, and dependence-like drinking induced via chronic intermittent ethanol vapor exposure in mice. DAGL inhibition also prevented ethanol-induced suppression of GABAergic transmission onto midbrain dopamine neurons, providing mechanistic insight into how DAGL inhibition could affect alcohol reward. Lastly, DAGL inhibition during either chronic alcohol consumption or protracted withdrawal was devoid of anxiogenic and depressive-like behavioral effects. These data suggest reducing 2-AG signaling via inhibition of DAGL could represent a novel approach to reduce alcohol consumption across the spectrum of AUD severity.

neuroscience↗

bioRxiv2021

Metaplasia of respiratory and digestive tissues in the Eastern oyster Crassostrea virginica associated with the Deepwater Horizon oil spill

Metaplasia is a well documented and deleterious effect of crude oil components on bivalved molluscs, including oysters. This reversible transformation of one cell type to another, is a common response to petroleum-product exposure in molluscs. It has been shown experimentally in previous work that eastern oysters (Crassostrea virginica) exposed to petroleum products will exhibit metaplasia of digestive tissues. Here we document for the first time that wild adult oysters inhabiting coastal waters in the northern Gulf of Mexico during and in the aftermath of the Deepwater Horizon oil spill (2010) exhibited metaplasia in both ctenidia and digestive epithelia at significantly higher levels than geographic controls of C. virginica from Chesapeake Bay. Both ctenidial (respiratory and suspension feeding) and digestive tract tissues exhibited significantly higher frequencies of metaplasia in specimens from the Gulf of Mexico compared to those from Chesapeake Bay. Metaplasia included the loss of epithelial cilia, transformations of columnar epithelia, hyperplasia and reduction of ctenidial branches, and vacuolization of digestive tissues. Evidence for a reduction of metaplasia following the oil spill (2010-2013) is suggestive but equivocal.

zoology↗

bioRxiv2021

Assessment of immunogenicity and protective efficacy of ZyCoV-D DNA vaccine candidates in Rhesus macaques against SARS-CoV-2 infection

Vaccines remain the key protective measure to achieve herd immunity to control the disease burden and stop COVID-19 pandemic. We have developed and assessed the immunogenicity and protective efficacy of two formulations (1mg and 2mg) of ZyCoV-D (a plasmid DNA based vaccine candidates) administered through Needle Free Injection System (NFIS) and syringe-needle (intradermal) in rhesus macaques with three dose vaccine regimens. The vaccine candidate 2mg dose administered using Needle Free Injection System (NFIS) elicited a significant immune response with development of SARS-CoV-2 S1 spike region specific IgG and neutralizing antibody (NAb) titers during the immunization phase and significant enhancement in the levels after the virus challenge. In 2 mg NFIS group the IgG and NAb titers were maintained and showed gradual rise during the immunization period (15 weeks) and till 2 weeks after the virus challenge. It also conferred better protection to macaques evident by the viral clearance from nasal swab, throat swab and bronchoalveolar lavage fluid specimens in comparison with macaques from other immunized groups. In contrast, the animals from placebo group developed high levels of viremia and lung disease following the virus challenge. Besides this, the vaccine candidate also induced increase lymphocyte proliferation and cytokines response (IL-6, IL-5).The administration of the vaccine candidate with NFIS generated a better immunogenicity response in comparison to syringe-needle (intradermal route). The study demonstrated immunogenicity and protective efficacy of the vaccine candidate, ZyCoV-D in rhesus macaques.

microbiology↗

bioRxiv2021

Voltage-Gated Potassium Channel Kv1.3 as a Therapeutic Target for Pancreatic Ductal Adenocarcinoma

The mitochondrial voltage-gated potassium channel, Kv1.3, has been emerged as an attractive oncologic target but its function in pancreas cancer (PDAC) is unknown. In this study we evaluated tissue expression of Kv1.3 in resected PDAC from 55 patients and tumor inhibition in orthotopic mouse models using the recently developed Kv1.3 inhibitors PCARBTP and PAPTP. Immunohistochemistry of 55 human PDAC specimens showed that all tumors expressed Kv1.3 with 60% of tumor specimens having high Kv1.3 expression. In pancreas tumor models (Pan02 cells injected into C57BL/6 mice), PCARBTP and PAPTP treatment resulted in tumor reductions of 87% and 70%, respectively. When combined with gemcitabine/abraxane, this increased to 95% and 80% without resultant organ toxicity. In vivo models indicated PCARBTP-mediated cell death occurred through the p38-MAPK pathway. In vitro-generated resistant clones to PCARBTP escaped cell death through upregulation of the anti-oxidant system as determined using SWATH-MS analysis. These data show Kv1.3 is highly expressed in resected human PDAC and the use of novel mitochondrial Kv1.3 inhibitors combined with cytotoxic chemotherapies might be novel, effective treatment for PDAC.

cancer biology↗

bioRxiv2021

Low-Dose Ad26.COV2.S Protection Against SARS-CoV-2 Challenge in Rhesus Macaques

We previously reported that a single immunization with an adenovirus serotype 26 (Ad26) vector-based vaccine expressing an optimized SARS-CoV-2 spike (Ad26.COV2.S) protected rhesus macaques against SARS-CoV-2 challenge. In this study, we evaluated the immunogenicity and protective efficacy of reduced doses of Ad26.COV2.S. 30 rhesus macaques were immunized once with 1x1011, 5x1010, 1.125x1010, or 2x109 vp Ad26.COV2.S or sham and were challenged with SARS-CoV-2 by the intranasal and intratracheal routes. Vaccine doses as low as 2x109 vp provided robust protection in bronchoalveolar lavage, whereas doses of 1.125x1010 vp were required for protection in nasal swabs. Activated memory B cells as well as binding and neutralizing antibody titers following vaccination correlated with protective efficacy. At suboptimal vaccine doses, viral breakthrough was observed but did not show evidence of virologic, immunologic, histopathologic, or clinical enhancement of disease compared with sham controls. These data demonstrate that a single immunization with a relatively low dose of Ad26.COV2.S effectively protected against SARS-CoV-2 challenge in rhesus macaques. Moreover, our findings show that a higher vaccine dose may be required for protection in the upper respiratory tract compared with the lower respiratory tract.

immunology↗

bioRxiv2021

Inhibition of BMP and FGF signaling prior to wound epithelium formation leads to an aberrant regenerative response in teleost fish Poecilia latipinna

The BMP and FGF pathways play a pivotal role in the successful regeneration of caudal fin of teleost fish. Individual inhibition of these pathways led to impaired caudal fin regeneration until the pharmacologic inhibitor of FGF (SU5402) and BMP (LDN193189) were metabolized off. Therefore, in the current study both these pathways were inhibited collectively wherein inhibition of BMP and FGF during the wound epithelium formation led to stalling of the process by bringing down the established levels of shh and runx2. In members of the treatment group, it was observed that, each blastema grows crouched rather than linear and the regrown lepidotrichia therefore remain tilted down. Amongst the other irregularities observed, the transition from epithelial to mesenchymal cells was found hindered due to down-regulation of snail and twist, brought about by BMP and FGF inhibition. Compromised expression of Snail and twist deranged the normal levels of cadherins causing disruption in the transition of cells. Lastly, blocking BMP and FGF delayed blastema formation and proliferation due to diminished levels of fgf2, fgf8, fgf10 and bmp6, while casp3 and casp9 levels remained heightened causing accelerated cell death. This study not only highlights the axial role of BMP and FGF pathways in regeneration but also accentuates the collaboration amongst the two. This ingenious coordination of signalling further reinforces the involvement of relaying messenger molecules between these crucial pathways. Summary StatementBMP and FGF collectively control the process of blastema formation in fish and inhibiting them prior to wound epithelium stage leads to irrevocable damage to the regenerating caudal fin.

developmental biology↗

bioRxiv2021

Human urine alters methicillin-resistant Staphylococcus aureus virulence and transcriptome

Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) is an emerging cause of hospital-associated urinary tract infections, especially in catheterized individuals. Despite being rare, MRSA-UTI are prone to potentially life-threatening exacerbations such as bacteremia that can be refractory to routine antibiotic therapy. Hence, MRSA-UTI is an important of research topic. To delineate molecular mechanisms governing MRSA urinary pathogenesis, we exposed three S. aureus strains, of which two were MRSA, to human urine and analyzed virulence characteristics and gene expression. We also analyzed MRSA-1369 transcriptome following cultivation in human urine for 2h. Our results reveal that human urine induces global changes in MRSA transcriptome, marked by changes in genes encoding proteins involved in metabolic pathways, virulence, and transcriptional regulators. In addition, in vitro assays also showed that human urine alters, in a strain-specific manner, adherence to human bladder epithelial cells and fibronectin, hemolysis of sheep RBCs, and surface hydrophobicity. In summary, our results provide first important insights into how the urine may specifically alter MRSA physiology in turn facilitating MRSA survival in the nutrient-limiting and hostile urinary microenvironment. ImportanceMethicillin-resistant Staphylococcus aureus (MRSA) is an uncommon cause of urinary tract infections (UTI) in the general population. However, it is important to understand MRSA pathophysiology in the urinary tract because isolation of MRSA in urine samples is often secondary to potentially life-threatening MRSA bacteremia. In this report, we describe that cultivation in human urine alters MRSA global gene expression and virulence. We hypothesize that these alterations may aid MRSA adapt to the nutrient-limiting, immunologically hostile conditions within the urinary tract.

microbiology↗

bioRxiv2020

A pH-eQTL interaction at the RIT2-SYT4 Parkinson's disease risk locus in the substantia nigra

Parkinsons disease (PD) causes severe motor and cognitive disabilities that result from the progressive loss of dopamine neurons in the substantia nigra. The rs12456492 variant in the RIT2 gene has been repeatedly associated with increased risk for Parkinsons disease. From a transcriptomic perspective, a meta-analysis found that RIT2 gene expression is correlated with pH in the human brain. To assess these pH associations in relation to PD risk, we examined the two datasets that assayed rs12456492, gene expression, and pH in the postmortem human brain. Using the BrainEAC dataset, we replicate the positive correlation between RIT2 gene expression and pH in the human brain (n=100). Furthermore, we found that the relationship between expression and pH is influenced by rs12456492. When tested across ten brain regions, this interaction is specifically found in the substantia nigra. A similar association was found for the co-localized SYT4 gene. In addition, SYT4 associations are stronger in a combined model with both genes, and the SYT4 interaction appears to be specific to males. In the GTEx dataset, the pH associations involving rs12456492 and expression of either SYT4 and RIT2 was not seen. This null finding may be due to the short postmortem intervals (PMI) of the GTEx tissue samples. In the BrainEAC data, we tested the effect of PMI and only observed the interactions in the longer PMI samples. These previously unknown associations suggest novel mechanistic roles for rs12456492, RIT2, and SYT4 in the regulation of pH in the substantia nigra.

neuroscience↗