Biology subjects

Kaur, S.

Publications and source records attributed to Kaur, S..

98 records · Page 6Linked to original sources

bioRxiv2020

Local computational methods to improve the interpretability and analysis of cryo-EM maps

Cryo-electron microscopy (cryo-EM) maps usually show heterogeneous distributions of B-factors and electron density occupancies and are typically B-factor sharpened to improve their contrast and interpretability at high-resolutions. However, over-sharpening due to the application of a single global B-factor can distort processed maps causing connected densities to appear broken and disconnected. This issue limits the interpretability of cryo-EM maps, i.e. ab initio modelling. In this work, we propose 1) approaches to enhance high-resolution features of cryo-EM maps, while preventing map distortions and 2) methods to obtain local B-factors and electron density occupancy maps. These algorithms have as common link the use of the spiral phase transformation and are called LocSpiral, LocBSharpen, LocBFactor and LocOccupancy. Our results, which include improved maps of recent SARS-CoV-2 structures, show that our methods can improve the interpretability and analysis of obtained reconstructions.

biophysics↗

bioRxiv2020

Temporal ordering of omics and multiomic events inferred from time series data

Temporal changes in omics events can now be routinely measured, however current analysis methods are often inadequate, especially for multiomics experiments. We report a novel analysis method that can infer event ordering at better temporal resolution than the experiment, and integrates omic events into two concise visualizations (event maps and sparklines). Testing our method gave results well-correlated with prior knowledge and indicated it streamlines analysis of time-series data.

bioinformatics↗

bioRxiv2019

Extreme genome selection towards complete antimicrobial resistance in a nosocomial strain of Stenotrophomonas maltophilia complex

We report first complete genome sequence and analysis of an extreme drug resistance (XDR) nosocomial Stenotrophomonas maltophilia that is resistant to the mainstream drugs i.e. trimethoprim/sulfamethoxazole (TMP/SXT) and levofloxacin. Taxonogenomic analysis revealed it to be a novel genomospecies of the Stenotrophomonas maltophilia complex (Smc). Comprehensive genomic investigation revealed fourteen dynamic regions (DRs) exclusive to SM866, consisting of diverse antibiotic resistance genes, efflux pumps, heavy metal resistance, various transcriptional regulators etc. Further, resistome analysis of Smc clearly depicted SM866 to be an enriched strain, having diversified resistome consisting of sul1 and sul2 genes. Interestingly, SM866 does not have any plasmid but it harbors two diverse super-integrons of chromosomal origin. Apart from genes for sulfonamide resistance (sul1 and sul2), both of these integrons harbor an array of antibiotic resistance genes linked to ISCR (IS91-like elements common regions) elements. These integrons also harbor genes encoding resistance to commonly used disinfectants like quaternary ammonium compounds and heavy metals like mercury. Hence, isolation of a novel strain belonging to a novel sequence type (ST) and genomospecies with diverse array of resistance from a tertiary care unit of India indicates extent and nature of selection pressure driving XDRs in hospital settings. There is an urgent need to employ complete genome based investigation using emerging technologies for tracking emergence of XDR at the global level and designing strategies of sanitization and antibiotic regime.\n\nImpact StatementThe hospital settings in India have one of the highest usage of antimicrobials and heavy patient load. Our finding of a novel clinical isolate of S. maltophilia complex with two super-integrons harbouring array of antibiotic resistance genes along with antimicrobials resistance genes indicates the extent and the nature of selection pressures in action. Further, the presence of ISCR type of transposable elements on both integrons not only indicates its propensity to transfer resistome but also their chromosomal origin suggests possibilities for further genomic/phenotypic complexities. Such complex cassettes and strain are potential threat to global health care. Hence, there is an urgent need to employ cost-effective long read technologies to keep vigilance on novel and extreme antimicrobial resistance pathogens in populous countries. There is also need for surveillance for usage of antimicrobials for hygiene and linked/rapid co-evolution of extreme drug resistance in nosocomial pathogens. Our finding of the chromosomal encoding XDR will shed a light on the need of hour to understand the evolution of an opportunistic nosocomial pathogen belonging to S. maltophilia.\n\nRepositoriesComplete genome sequence of Stenotrophomonas maltophilia SM866: CP031058

genomics↗

bioRxiv2019

lncRNA Neat1 drives neuronal histone methylation and age-related memory impairments

Histone methylation is critical for the formation and maintenance of long-term memories. Long noncoding RNAs (lncRNAs) are regulators of histone methyltransferases and other chromatin modifying enzymes (CMEs). We investigated how lncRNA Neat1-mediated histone methylation contributes to hippocampus-dependent long-term memory formation, using a combination of transcriptomics, RNA binding protein immunoprecipitation, CRISPR mediated gene activation, and behavioral approaches. Suppression of the lncRNA Neat1 revealed widespread changes in gene transcription as well as perturbations of histone 3 lysine 9 dimethylation (H3K9me2), a repressive histone modification mark that is dysregulated in the aging hippocampus. We identified a Neat1-dependent mechanism of transcriptional repression via H3K9me2 at the c-Fos promoter corresponding with observed changes in c-Fos mRNA levels. Overexpression of hippocampal Neat1 via CRISPRa is sufficient to impair memory formation in young adults, recapitulating observed memory deficits in old adults, while Neat1 suppression in both young and old adult mice improves memory. These results suggest that lncRNA Neat1 is a potent epigenetic regulator of hippocampus-dependent long-term memory formation.

neuroscience↗

bioRxiv2019

The time course of updating in running span

Running span can be performed by either passively listening to to-be-remembered items or actively updating the target set during presentation. This choice of strategy is influenced by the rate of presentation in the task. Previous research suggests that the active updating process is demanding and time-consuming. It is favored at relatively slow rates of presentation, while the passive strategy is more successful when applied at fast rates. In two experiments the time course of resource demand during task performance and its sensitivity to presentation rate was examined. We hypothesized that running span imposes a high cognitive load only when active updating is employed. Participants performed running span simultaneously with a spatial reaction time (RT) task, and RTs on the concurrent task were used to index the resource demands of the memory task. A slow-paced running span exhibited a large overall resource demand in comparison with the serial recall tasks (Experiment 1) and fast-paced running span (Experiment 2). This demand was observed from the position in the list from which participants are presumed to start updating, suggesting a cognitive shift to a demanding mode of updating. In addition, a demand burst was found approximately 1000ms following item onset at these later positions. These data establish that the process of active updating in running span task is slow and cognitively demanding and indicate that this limits its application during fast presentation rates.

neuroscience↗

bioRxiv2018

Translational initiation factor eIF5 replaces eIF1 on the 40S ribosomal subunit to promote start-codon recognition

In eukaryotic translation initiation AUG recognition of the mRNA requires accommodation of Met-tRNAi in a \"PIN\" state, which is antagonized by the factor eIF1. eIF5 is a GTPase activating protein (GAP) of eIF2 that additionally promotes stringent AUG selection, but the molecular basis of its dual function was unknown. We present a cryo-electron microscopy (cryo-EM) reconstruction of a 48S pre-initiation complex (PIC), at an overall resolution of 3.0 [A], featuring the N-terminal domain (NTD) of eIF5 bound to the 40S subunit at the location vacated by eIF1. eIF5 interacts with and allows a more accommodated orientation of Met-tRNAi. Substitutions of eIF5 residues involved in the eIF5-NTD/tRNAi interaction influenced initiation at near-cognate UUG codons in vivo, and the closed/open PIC conformation in vitro, consistent with direct stabilization of the codon:anticodon duplex by the wild-type eIF5-NTD. The present structure reveals the basis for a key role of eIF5 in start-codon selection.

biophysics↗

bioRxiv2017

Development and molecular characterization of wheat-Aegilops peregrina Introgression Lines with resistance to leaf rust and stripe rust

A wild non-progenitor species from wheat tertiary gene pool Aegilops peregrina accession pau3519 (UUSS) was used for introgression of leaf rust and stripe rust resistance in bread wheat. It was crossed and backcrossed with hexaploid wheat line Chinese Spring PhI to develop two homozygous BC2F6 wheat-Ae. peregrina introgression lines (ILs) viz. IL pau16058 and IL pau16061 through induced homoeologous recombination. Homozygous lines were screened against six Puccinia triticina and two Puccinia striiformis f. sp. tritici pathotypes at the seedling stage and a mixture of prevalent pathotypes of both rust pathogens at the adult plant stage. IL pau16061 showed resistance to leaf rust only while IL pau16058 was resistant to both leaf and stripe rust pathotypes throughout plant life. Molecular characterization of these ILs aided in defining the introgressed regions. Identification of linked markers with advance genomic technologies will aid in marker assisted pyramiding of alien genes in cultivated wheat background.

genetics↗

bioRxiv2016

Drug repurposing for ageing research using model organisms

Many increasingly prevalent diseases share a common risk factor: age. However, little is known about pharmaceutical interventions against ageing, despite many genes and pathways shown to be important in the ageing process and numerous studies demonstrating that genetic interventions can lead to a healthier ageing phenotype. An important challenge is to assess the potential to repurpose existing drugs for initial testing on model organisms, where such experiments are possible. To this end, we present a new approach to rank drug-like compounds with known mammalian targets according to their likelihood to modulate ageing in the invertebrates C. elegans and Drosophila. Our approach combines information on genetic effects on ageing, orthology relationships and sequence conservation, 3D protein structures, drug binding and bioavailability. Overall, we rank 743 different drug-like compounds for their likelihood to modulate ageing. We provide various lines of evidence for the successful enrichment of our ranking for compounds modulating ageing, despite sparse public data suitable for validation. The top ranked compounds are thus prime candidates for in vivo testing of their effects on lifespan in C. elegans or Drosophila. As such, these compounds are promising as research tools and ultimately a step towards identifying drugs for a healthier human ageing.

pharmacology and toxicology↗