Biology subjects

Rajput, A.

Publications and source records attributed to Rajput, A..

18 recordsLinked to original sources

bioRxiv2026

Brain-resident myeloid cells promote rapid leukocyte adhesion in leptomeningeal vessels after anti-Aβ immunotherapy

Anti-amyloid {beta} (A{beta}) immunotherapy improves cognitive outcomes in Alzheimer's disease (AD) but is associated with amyloid-related imaging abnormalities (ARIA), through poorly understood mechanisms. To define how anti-A{beta} antibodies acutely engage brain immune and vascular compartments, we developed a longitudinal in vivo two-photon imaging platform to track microglial dynamics, peripheral immune cell recruitment, and vascular responses in APP/PS1 mice. Anti-A{beta} antibodies, including aducanumab and lecanemab, rapidly initiated microglial activation and spatial reorganization within 24 hours of dosing, with recruitment to plaque-associated regions, stabilizing plaque growth. Aducanumab and lecanemab also triggered a rapid and transient cerebrovascular immune response characterized by rolling and adhesion of peripheral immune cells along leptomeningeal vessels, accompanied by endothelial activation. Immune cell characterization revealed recruitment of innate immune cells (Iba1Ki67 monocytes and Ly6G neutrophils) and proliferative CD3 T cells into the vascular compartment following treatment. Prophylactic treatment with high-dose dexamethasone reduced the number of adherent cells without affecting microglial activation. Depletion of brain-resident immune cells similarly reduced peripheral immune cell recruitment, supporting their contribution to leukocyte recruitment. Postmortem brain tissue from an AD patient treated with lecanemab showed higher proliferation-associated monocyte signature scores, suggesting translational relevance to the proliferative myeloid response observed in our mouse models. These findings demonstrate that anti-A{beta} immunotherapy rapidly initiates a coordinated central and peripheral immune response at the leptomeningeal interface. These early immune-vascular interactions represent a plausible initiating mechanism for ARIA and provide a mechanistic framework to guide strategies for mitigating ARIA risk

neuroscience↗

bioRxiv2026

WDR44 drives de novo α-synuclein aggregation at the lysosomal membrane and promotes neuronal dysfunction in Parkinson's Disease

The aggregation of -synuclein (-SYN) into Lewy bodies (LBs) is a central event in the pathogenesis of Parkinsons disease (PD) and related synucleinopathies1,2. Despite significant advances in understanding -SYN self-assembly, the precise sequence of early aggregation steps has not been directly visualized in living neurons. Here, we use an optogenetic-induced protein aggregation system with a high temporal resolution to monitor the onset of -SYN assembly in neurons. We found that the initiation and accumulation of -SYN aggregates occur predominantly at the lysosomal membrane, an event driven by the -SYN N-terminus and modulated by the membrane-associated adaptor protein WD repeat-containing protein 44 (WDR44). Remarkably, we demonstrate that WDR44 knockdown markedly reduced de novo -SYN aggregation in both neuronal cultures and in vivo, whereas WDR44 overexpression enhances -SYN aggregation in PD patient-derived iPSC neurons. Consistent with its potential pathogenic involvement, WDR44 aberrantly accumulates in vivo and in the brains of PD patients, where it colocalizes with LB inclusions. Finally, we show that lysosome-associated -SYN aggregates compromised lysosomal structure and function, leading to neuronal impairment, a phenotype worsened by WDR44 overexpression, linking early aggregation events to downstream toxicity. Together, these findings reveal the earliest dynamic stages of -SYN oligomerization in living neurons and identify the WDR44--SYN interaction as a promising therapeutic target for reducing -SYN pathology and enabling early intervention in PD.

neuroscience↗

bioRxiv2025

Epigenetic Context Defines the Transcriptional Activity of Canonical and Noncanonical NF-κB Signaling in Pancreatic Cancer

NF-{kappa}B signaling can be subdivided into canonical and noncanonical pathways, culminating in the transcriptional activity of RELA and RELB, respectively. However, the upstream signals that activate these transcription factors and their specific regulatory roles in pancreatic ductal adenocarcinoma (PDAC) remain incompletely understood. Here, we demonstrate that TNF is the primary activator of canonical NF-{kappa}B signaling via RELA, while TWEAK engages noncanonical signaling through RELB in PDAC. Using transcriptome-wide gene expression, genome-wide occupancy profiling, and epigenome mapping, we delineate distinct temporal dynamics and regulatory activities of each pathway. Single-cell RNA-seq analysis and multiplex immunofluorescence staining in primary PDAC samples further reveal extensive and distinct interactions with components of the tumor microenvironment. Motif analysis of RELA- and RELB-bound regions uncovers a particularly strong association of RELB with AP1 elements. Notably, while RELA binds to both open and closed chromatin, RELB exclusively occupies regions with pre-existing chromatin accessibility and AP1 co-binding. Collectively, these findings underscore the distinct and complementary roles of TNF and TWEAK in PDAC, with TNF engaging a broader transcriptional program via RELA and TWEAK selectively targeting genes marked by accessible chromatin and epigenetic activity. This study provides critical insights into the regulatory dynamics of NF-{kappa}B signaling in PDAC, highlighting unique and complementary functions of RELA and RELB in modulating downstream gene expression. SignificanceTNF and TWEAK selectively activate RELA and RELB in pancreatic cancer, revealing that RELB-driven noncanonical signaling depends on chromatin accessibility and AP-1, uncovering distinct, targetable epigenetic dependencies from canonical signaling. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=59 SRC="FIGDIR/small/661561v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@14aa356org.highwire.dtl.DTLVardef@1297741org.highwire.dtl.DTLVardef@1545741org.highwire.dtl.DTLVardef@2c982b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

A single-cell eQTL atlas of the human cerebellum reveals vulnerability of oligodendrocytes in essential tremor

Essential tremor (ET) is a movement disorder characterized by an upper-limb postural and action tremor. It is one of the most common neurological disorders, affecting 1% of the worldwide population. Despite strong evidence for genetic factors driving the aetiology of ET, the underlying pathophysiology remains poorly understood. To understand the effects of genetic risk factors in ET on the cerebellum, the brain region thought to be affected by the disease, we built a population-scale single-cell atlas of the human cerebellar cortex comprised of over 1 million cells from 109 individuals. Using single-cell expression quantitative trait loci and mendelian randomization, we found evidence of ET-associated variants in the BACE2 locus causally linked to its downregulation in cerebellar oligodendrocytes. We highlight a genetically vulnerable population of BACE2-expressing immature oligodendrocytes, suggestive of demyelination. We also find dysfunctional processes affecting interactions between Golgi cells, Purkinje layer interneurons, and oligodendrocytes in ET. Our study suggests a crucial role for cerebellar oligodendrocytes in the pathogenesis of ET.

genomics↗

bioRxiv2023

Reconstructing the Transcriptional Regulatory Network of Probiotic L. reuteri is Enabled by Transcriptomics and Machine Learning

ILimosilactobacillus reuteri, a probiotic microbe instrumental to human health and sustainable food production, adapts to diverse environmental shifts via dynamic gene expression. We applied independent component analysis to 117 high-quality RNA-seq datasets to decode its transcriptional regulatory network (TRN), identifying 35 distinct signals that modulate specific gene sets. This study uncovers the fundamental properties of L. reuteris TRN, deepens our understanding of its arginine metabolism, and the co-regulation of riboflavin metabolism and fatty acid biosynthesis. It also sheds light on conditions that regulate genes within a specific biosynthetic gene cluster and the role of isoprenoid biosynthesis in L. reuteris adaptive response to environmental changes. Through the integration of transcriptomics and machine learning, we provide a systems-level understanding of L. reuteris response mechanism to environmental fluctuations, thus setting the stage for modeling the probiotic transcriptome for applications in microbial food production. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/547516v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@118ec4corg.highwire.dtl.DTLVardef@141b0b7org.highwire.dtl.DTLVardef@1b8cf6forg.highwire.dtl.DTLVardef@3ab181_HPS_FORMAT_FIGEXP M_FIG C_FIG Comprehensive iModulon Workflow Overview. Our innovative workflow is grounded in the analysis of the LactoPRECISE compendium, a curated dataset containing 117 internally sequenced RNA-seq samples derived from a diversity of 50 unique conditions, encompassing an extensive range of 13 distinct condition types. We employ the power of Independent Component Analysis (ICA), a cutting-edge machine learning algorithm, to discern the underlying structure of iModulons within this wealth of data. In the subsequent stage of our workflow, the discovered iModulons undergo detailed scrutiny to uncover media-specific regulatory mechanisms governing metabolism, illuminate the context-dependent intricacies of gene expression, and predict pathways leading to the biosynthesis of probiotic secondary metabolites. Our workflow offers an invaluable and innovative lens through which to view probiotic strain design while simultaneously highlighting transformative approaches to data analytics in the field.

bioinformatics↗

bioRxiv2023

Pangenome analysis reveals the genetic basis for taxonomic classification of the Lactobacillaceae family

Lactobacillaceae represent a large family of important microbes that are foundational to the food industry. Many genome sequences of Lactobacillaceae strains are now available, enabling us to conduct a comprehensive pangenome analysis of this family. We collected 3,591 high-quality genomes from public sources and found that: 1) they contained enough genomes for 26 species to perform a pangenomic analysis, 2) the normalized Heaps coefficient {lambda} (a measure of pangenome openness) was found to have an average value of 0.27 (ranging from 0.07-0.37), 3) the pangenome openness was correlated with the abundance and genomic location of transposons and mobilomes, 4) the pangenome for each species was divided into core, accessory, and rare genomes, that highlight the species-specific properties (such as motility and restriction-modification systems), 5) the pangenome of Lactiplantibacillus plantarum (which contained the highest number of genomes found amongst the 26 species studied) contained nine distinct phylogroups, and 6) genome mining revealed a richness of detected biosynthetic gene clusters, with functions ranging from antimicrobial and probiotic to food preservation, but [~]93% were of unknown function. This study provides the first in-depth comparative pangenomics analysis of the Lactobacillaceae family.

systems biology↗

bioRxiv2022

Advanced transcriptomic analysis reveals the role of efflux pumps and media composition in antibiotic responses of Pseudomonas aeruginosa

Pseudomonas aeruginosa is an opportunistic pathogen and major cause of hospital acquired infections. The pathogenicity and virulence of P. aeruginosa is largely determined by its transcriptional regulatory network (TRN). We used 411 transcription profiles of P. aeruginosa from diverse growth conditions to construct a quantitative TRN by identifying independently modulated sets of genes (called iModulons) and their condition-specific activity levels. The current study focused on the use of iModulons to analyze pathogenicity and antibiotic resistance of P. aeruginosa. Our analysis revealed: 1) 116 iModulons, 81 of which show strong association with known regulators; 2) novel roles of two-component systems in regulating antibiotics efflux pumps; 3) substrate-efflux pump associations; 4) differential iModulon activity in response to beta-lactam antibiotics in bacteriological and physiological media; 5) differential activation of Cell Division iModulon resulting from exposure to different beta-lactam antibiotics; and 6) a role of the PprB iModulon in the stress-induced transition from planktonic to biofilm lifestyle. In light of these results, the construction of an iModulon-based TRN provides a transcriptional regulatory basis for key aspects of P. aeruginosa infection, such as antibiotic stress responses and biofilm formation. Taken together, our results offer a novel mechanistic understanding of P. aeruginosa pathogenicity. SignificanceLarge data sets and machine learning are impacting a growing number of areas of research in the life sciences. Once the compendia of bacterial transcriptomes reached a critical size, we could use source signal extraction algorithms to find lists of co-regulated genes (called iModulons) associated with a transcription factor (TF) to them. The gene composition of iModulons and their condition-dependent activity levels constitute a quantitative description of the composition of bacterial transcriptomes. This study shows how this approach can be used to reveal the responses of P. aeruginosa to antibiotics and thus yield a deep regulatory understanding of pathogenicity properties. This study motivates the execution of similar studies for the other ESKAPEEs to yield a broad understanding of the role of TRNs in antibiotic responses to these urgent threat bacterial pathogens.

systems biology↗

bioRxiv2022

Orphan nuclear receptors Err2 and 3 promote a feature-specific terminal differentiationprogram underlying gamma motor neuron function and proprioceptive movement control

Motor neurons are commonly thought of as mere relays between the central nervous system and the movement apparatus, yet, in mammals about one-third of them function exclusively as regulators of muscle proprioception. How these gamma motor neurons acquire properties to function differently from the muscle force-producing alpha motor neurons remains unclear. Here, we found that upon selective loss of the orphan nuclear receptors Err2 and Err3 (Err2/3) in mice, gamma motor neurons acquire characteristic structural (e.g. synaptic wiring), but not functional (e.g. physiological firing rates) properties necessary for regulating muscle proprioception, thus disrupting gait and precision movements in vivo. Moreover, Err2/3 operate via transcriptional activation of neural activity modulators, one of which (Kcna10) promoted gamma motor neuron functional properties. Our work identifies a long-sought mechanism specifying gamma motor neuron properties necessary for proprioceptive movement control, which implies a feature-specific terminal differentiation program implementing neuron subtype-specific functional but not structural properties. SummaryThe transcription factors Err2 and 3 promote functional properties in a subset of motor neurons necessary for executing precise movements.

neuroscience↗

bioRxiv2021

Simultaneous pathway engagement of translation in astrocytes, circadian rhythm in GABAergic neurons and cytoskeleton in glutamatergic neurons precede electroencephalographic changes in neurodegenerative prion disease

Selective vulnerability is an enigmatic feature of neurodegenerative diseases (NDs), whereby a widely expressed protein causes lesions in specific brain regions and cell types. This selectivity may arise from cells possessing varying capacities to regain proteostasis when stressed by cytotoxic protein conformers. Using the RiboTag method in mice, translational responses of five neural subtypes to acquired prion disease (PrD) were measured. Pre-onset and disease onset timepoints were chosen based on longitudinal electroencephalography (EEG) that revealed a gradual increase in theta power between 10- and 18-weeks after prion injection, resembling a clinical feature of human PrD. At disease onset, marked by significantly increased theta power and histopathological lesions, mice had pronounced translatome changes in all five cell types despite having a normal outward appearance. Remarkably, at a pre-onset stage, prior to EEG and neuropathological changes, we found that 1) translatomes of astrocytes indicated a sharply reduced synthesis of ribosomal and mitochondrial components, 2) excitatory neurons showed increased expression of cytoskeletal genes, and 3) inhibitory neurons revealed reduced expression of circadian rhythm network genes. Further assessment for the role of circadian rhythms using a jet lag paradigm modestly exacerbated disease. These data demonstrate that early translatome responses to neurodegeneration emerge prior to other signs of disease and are unique to different cell types. Therapeutic strategies may need to target multiple pathways, each in specific populations of cells, early in the disease process.

neuroscience↗

bioRxiv2021

A contribution to the larval amphibian microbiome: characterization of bacterial microbiome of Ichthyophis bannanicus (Order: Gymnophiona) and comparison with the other two amphibian orders

It is known that animal-associated microbiomes form indispensable relationships with hosts and are responsible for many functions important for host-survival. Next-gen driven approaches documenting the remarkable diversity of microbiomes have burgeoned, with amphibians too, benefiting from such treatments. The microbiome of Gymnophiona (caecilians), one of the three amphibian orders, constituting of 3% of amphibians, however, remains almost unknown. The present study aims to address this knowledge gap through analysis of the microbiome of Ichthyophis bannanicus. As these caecilian larvae are aquatic and hence exposed to a greater propensity for bacterial microbiomic interchange, we hypothesize that bacterial phyla would overlap between gut and skin. Further, from the host-specificity patterns observed in other vertebrate taxa, we hypothesize that Gymnophiona have different dominant gut bacterial microbiomes at a higher taxonomic level when compared to the larvae of the other two amphibian orders (Anura and Caudata). We used 16S rRNA gene amplicon sequencing based on Illumina Nova sequencing platform to characterize and compare the gut (represented by faecal samples) and skin microbiome of I. bannanicus larvae (N = 13), a species distributed across South-East-Asia and the only caecilian species occurring in China. We compared our gut microbiome results with published anuran and caudate larval microbiomes. For I. bannanicus, a total of 4,053 operational taxonomic units (OTU) across 13 samples were detected. Alpha-diversity indices were significant between gut and skin samples. Non-metric multidimensional scaling analysis suggest that gut and skin samples each contained a distinct microbiome at OTU level. We record significant differences between the bacterial phyla of gut and skin samples in larvae of I. bannanicus. The study provides an overview of gut and skin bacterial microbiomes of a caecilian, while highlighting the major differences between larval microbiomes of the three amphibian orders. We find a partial overlap of gut bacterial microbiomes at phylum level for the three orders; however, the relative abundance of the dominant phyla is distinct. The skin and gut microbiomes are distinct with little overlap of species, highlighting that gut-skin axis is weak. This in turn suggests that many of the microbial species on skin and gut are functionally specialized to those locations. We also show that the skin microbiome is more diverse than the gut microbiome at species level; however, a reason for this could be a portion of the gut microbiome not being represented in faecal samples. These first microbiome information from a caecilian lay the foundation for comparative studies of the three amphibian orders.

microbiology↗

bioRxiv2021

Machine Learning of Pseudomonas aeruginosa transcriptomes identifies independently modulated sets of genes associated with known transcriptional regulators

The transcriptional regulatory network (TRN) of Pseudomonas aeruginosa plays a critical role in coordinating numerous cellular processes. We extracted and quality controlled all publicly available RNA-sequencing datasets for P. aeruginosa to find 281 high-quality transcriptomes. We produced 83 new RNAseq data sets under critical conditions to generate a comprehensive compendium of 364 transcriptomes. We used this compendium to reconstruct the TRN of P. aeruginosa using independent component analysis (ICA). We identified 104 independently modulated sets of genes (called iModulons), among which 81 (78%) reflect the effects of known transcriptional regulators. We show that iModulons: 1) play an important role in defining the genomic boundaries of biosynthetic gene clusters (BGCs); 2) show increased expression of the BGCs and associated secretion systems in conditions that emulate cystic fibrosis (CF); 3) show the presence of a novel BGC named RiPP (bacteriocin producer) which might have a role in worsening CF outcomes; 4) exhibit the interplay of amino acid metabolism regulation and central metabolism across carbon sources, and 5) clustered according to their activity changes to define iron and sulfur stimulons. Finally, we compare the iModulons of P. aeruginosa with those of E. coli to observe conserved regulons across two gram negative species. This comprehensive TRN framework covers almost every aspect of the transcriptional regulatory machinery in P. aeruginosa, and thus could prove foundational for future research of its physiological functions.

bioinformatics↗

bioRxiv2020

EGFR transactivates RON to drive oncogenic crosstalk

SUMMARYCrosstalk between disparate membrane receptors is thought to drive oncogenic signaling and allow for therapeutic resistance. EGFR and RON are members of two unique receptor tyrosine kinase (RTK) subfamilies that engage in crosstalk through unknown mechanisms. We combined high resolution imaging with biochemical studies and structural mutants to understand how EGFR and RON communicate. We found that EGF stimulation results in EGFR-dependent RON phosphorylation. Crosstalk is unidirectional, since MSP stimulation of RON does not trigger EGFR phosphorylation. Two-color single particle tracking captured the formation of complexes between RON and EGFR, supporting a role for direct interactions in propagating crosstalk. We further show that RON is a substrate for EGFR kinase, and transactivation of RON requires the formation of a signaling competent EGFR dimer. These results identify critical structural features of EGFR/RON crosstalk and provide new mechanistic insights into therapeutic resistance.

cancer biology↗

bioRxiv2020

Characterizing the response of Acinetobacter baumannii ATCC 17978 to azithromycin in multiple in vitro growth conditions

Multi-drug resistant (MDR) Acinetobacter baumannii is one of the most concerning pathogens in hospital infections. A. baumannii is categorized as an "Urgent Threat" by the U.S. Centers for Disease Control and the highest priority pathogen by the World Health Organization due to its propensity for broad antibiotic resistance and its associated high mortality rates. New treatment options are urgently needed for MDR A. baumannii infections. Our prior studies have demonstrated an unappreciated utility of the macrolide azithromycin (AZM) against MDR A. baumannii in tissue-culture medium. This finding is all the more surprising since AZM has no appreciable activity against A. baumannii in standard bacteriological media. The basis for this media-dependent activity of AZM against A. baumannii is not fully defined. In this study, we utilize a variety of techniques (growth dynamics, bacterial cytological profiling, RNA sequencing, and LC/MS) to profile the response of MDR A. baumannii to AZM in both standard bacteriological and more physiological relevant mammalian tissue-culture medium. [Table 1]

microbiology↗

bioRxiv2020

Identifying the effect of vancomycin on HA-MRSA strains using bacteriological and physiological media

Healthcare-associated methicillin-resistant Staphylococcus aureus (HA-MRSA) USA100 strains are of major concern due to their evolving antibiotic resistant. They are resistant to a broad class of antibiotics like macrolides, aminoglycosides, fluoroquinolones, and many more. The selection of appropriate antibiotic susceptibility examination media is very important. Thus, we use bacteriological (CA-MHB) as well as physiological (R10LB) media to determine the effect of vancomycin on USA100 strains. The study includes the profiling behaviour of HA-MRSA USA100 D592 and D712 strains in the presence of vancomycin through various high-throughput assays. The US100 D592 and D712 strains were characterized at sub-inhibitory concentrations through growth curves, RNA sequencing, bacterial cytological profiling, and exo-metabolomics high throughput experiments. The study reveals the vancomycin resistance behavior of USA100 strains in dual media conditions using wide-ranging experiments.

microbiology↗

bioRxiv2020

Profiling the effect of nafcillin on HA-MRSA D592 using bacteriological and physiological media

Staphylococcus aureus is a leading human pathogen associated with both hospital-acquired and community-acquired infections. The bacterium has steadily gained resistance to {beta}-lactams and other important first-line antibiotics culminating in its categorization as an urgent threat by the U.S. Centers for Disease Control and Prevention. Observations of a varying response to antimicrobial exposure as a function of media type has revealed that clinical susceptibility testing performed in standard bacteriological media might not adequately represent pharmacological responses in the patient. Such observations have encouraged research designed to identify media types that more closely mimic the in vivo environment. In this study, we examine the response of a hospital-acquired USA100 lineage methicillin-resistant, vancomycin-intermediate S. aureus (MRSA/VISA) strain (D592) to nafcillin in a bacteriological compared to a more physiological tissue culture-based medium. We performed multi-dimensional analysis including growth and bacterial cytological profiling, RNA sequencing, and exo-metabolomics measurements (both HPLC and LC/MS) to shed light on the media-dependent activity of the commonly prescribed {beta}-lactam antibiotic nafcillin. O_TBL View this table: org.highwire.dtl.DTLVardef@85b95borg.highwire.dtl.DTLVardef@14c1504org.highwire.dtl.DTLVardef@1f7e976org.highwire.dtl.DTLVardef@100598dorg.highwire.dtl.DTLVardef@1f770e9_HPS_FORMAT_FIGEXP M_TBL C_TBL

microbiology↗

bioRxiv2020

Pangenome analytics reveal two-component systems as conserved targets in ESKAPEE pathogens

Bacteria sense and respond to environmental stimuli through two-component systems (TCSs), that are composed of histidine kinase sensing and response regulator elements. TCSs are ubiquitous and participate in numerous cellular functions. TCSs across the ESKAPEE pathogens, representing the leading causes of nosocomial infections, were characterized using pangenome analytics, including annotation, mapping, pangenomic status, gene orientation, sequence variation, and structure. Our findings fall into two categories. 1) phylogenetic distribution of TCSs: (i) the number and types of TCSs varies between species of the ESKAPEE pathogens; (ii) TCSs are group-specific, i.e., Gram-positive and Gram-negative, except for KdpDE; (iii) most TCSs are conserved among genomes of an ESKAPEE, except in Pseudomonas aeruginosa. 2) sequence variation: (i) at the operon level, the genomic architecture of a TCS operon stratifies into a few discrete classes; and (ii) at the gene sequence level, histidine kinases, responsible for signal sensing, show sequence and structural variability as compared to response regulators that show a high degree of conservation. Taken together, this first comprehensive pangenomic assessment of TCSs reveals a range of strategies deployed by the ESKAPEE pathogens to manifest pathogenicity and antibiotic resistance. It further suggests that the conserved features of TCSs makes them an attractive group of potential targets with which to address antibiotic resistance.

microbiology↗

bioRxiv2019

Multi-omics integration of the phenome, transcriptome and genome highlights genes and pathways relevant to essential tremor

The genetic factors predisposing to essential tremor (ET), of one of the most common movement disorders, remains largely unknown. While current studies have examined the contribution of both common and rare genetic variants, very few have investigated the ET transcriptome. To understand pathways and genes relevant to ET, we used an RNA sequencing approach to interrogate the transcriptome of two cerebellar regions, the dentate nucleus and cerebellar cortex, in 16 cases and 16 age- and sex-matched controls. Additionally, a phenome-wide association study (pheWAS) of the dysregulated genes was conducted, and a genome-wide gene association study (GWGAS) was done to identify pathways overlapping with the transcriptomic data. We identified several novel dysregulated genes including CACNA1A, a calcium voltage-gated channel implicated in ataxia. Furthermore, several pathways including axon guidance, olfactory loss, and calcium channel activity were significantly enriched. A subsequent examination of the ET GWGAS data (N=7,154) also flagged genes involved in calcium ion-regulated exocytosis of neurotransmitters to be significantly enriched. Interestingly, the pheWAS identified that the dysregulated gene, SHF, is associated with a blood pressure medication (P=9.3E-08), which is commonly used to reduce tremor in ET patients. Lastly, it is also notable that the dentate nucleus and cerebellar cortex have different transcriptomes, suggesting that different regions of the cerebellum have spatially different transcriptomes.

genomics↗

bioRxiv2019

Comparison of expression profiling through microarray and RNA-seq analysis for Nipah virus

The Nipah virus is responsible various outbreaks among countries of south east Asia, most recent is in Kerala, India. It is considered to be highly contagious and having a range of vectors for transmission. The condition worsens due to the lack of effective inhibitors. This study is first study, which focused to detect the differentially expressed genes among two different NiV studies from 2012 and 2017. The transcriptomic profiling data were retrieved from the sequence archives. The multivariate gene enrichment analyses were performed on the log transformed data from them using pathway, gene ontology, disease, reactome, etc. The comparison study suggests that the down regulated differentially expressed genes are common among them as compared to up regulated ones with statistical significance. However, among the diseased category the upregulated genes are mostly from metabolic pathways and diseased category like metabolic pathways, heart failure, cholesterol metabolism while the downregulated genes linked to various cancers, and viral diseases like hepatitis, dengue, influenza, etc. We found various small molecules mapped in the pathways which are differentially expressed among the studies, which could be targeted so as to control the Nipah infection. In order to design the inhibitors, our study would be useful to extract the effective and broad-spectrum drug targets.

bioinformatics↗