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Shrivastava, A.

Publications and source records attributed to Shrivastava, A..

30 records · Page 2Linked to original sources

Synthesis of versatile neuromodulatory molecules by a gut microbial glutamate decarboxylase

Dysbiosis of the microbiome correlates with many neurological disorders, yet very little is known about the chemistry that controls the production of neuromodulatory molecules by gut microbes. Here, we found that an enzyme glutamate decarboxylase (BfGAD) of a gut microbe Bacteroides fragilis forms multiple neuromodulatory molecules such as {gamma}-aminobutyric acid (GABA), hypotaurine, taurine, homotaurine, and {beta}-alanine. We evolved BfGAD and doubled its taurine productivity. Additionally, we increased its specificity towards the substrate L-glutamate. Here, we provide a chemical strategy via which the BfGAD activity could be fine-tuned. In future, this strategy could be used to modulate the production of neuromodulatory molecules by gut microbes.

biochemistry↗

Reversal of Biological Age in Multiple Rat Organs by Young Porcine Plasma Fraction

Young blood plasma is known to confer beneficial effects on various organs in mice and rats. However, it was not known whether plasma from young pigs rejuvenates old rat tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=613 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=1366 human tissue samples to the training data. We employed these six rat clocks to investigate the rejuvenation effects of a porcine plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. An immunoglobulin G (IgG) N-glycosylation pattern shift from pro-to anti-inflammatory also indicated reversal of glycan aging. Overall, this study demonstrates that a young porcine plasma-derived treatment markedly reverses aging in rats according to epigenetic clocks, IgG glycans, and other biomarkers of aging.

developmental biology↗

The prevalence of motility within the human oral microbiota

The human oral and nasal microbiota contains approximately 770 cultivable bacterial species. More than 2000 genome sequences of these bacteria can be found in the expanded Human Oral Microbiome Database (eHOMD). We developed HOMDscrape, a freely available Python software tool to programmatically retrieve and process amino acid sequences and sequence identifiers from BLAST results acquired from the eHOMD website. Using the data obtained through HOMDscrape, the phylogeny of proteins involved in bacterial flagellar motility, Type 4 pilus driven twitching motility, and Type 9 Secretion system (T9SS) driven gliding motility was constructed. A comprehensive phylogenetic analysis was conducted for all components of the rotary T9SS, a machinery responsible for secreting various enzymes, virulence factors, and enabling bacterial gliding motility. Results revealed that the T9SS outer membrane {beta}-barrel protein SprA of human oral microbes underwent horizontal evolution. Overall, we catalog motile microbes that inhabit the human oral microbiota and document their evolutionary connections. These results will serve as a guide for further studies exploring the impact of motility on shaping of the human oral microbiota.

microbiology↗

Network expansion of genetic associations defines a pleiotropy map of human cell biology

Proteins that interact within molecular networks tend to have similar functions and when perturbed influence the same organismal traits. Interaction networks can be used to expand the list of likely trait associated genes from genome-wide association studies (GWAS). Here, we used improvements in SNP-to-gene mapping to perform network based expansion of trait associated genes for 1,002 human traits showing that this recovers known disease genes or drug targets. The similarity of network expansion scores identifies groups of traits likely to share a common genetic basis as well as the biological processes underlying this. We identified 73 pleiotropic gene modules linked to multiple traits that are enriched in genes involved in processes such as protein ubiquitination and RNA processing. We show examples of modules linked to human diseases enriched in genes with pathogenic variants found in patients or relevant mouse knock-out phenotypes and can be used to map targets of approved drugs for repurposing opportunities. Finally, we illustrate the use of the network expansion scores to study genes at inflammatory bowel disease (IBD) GWAS loci, and implicate IBD-relevant genes with strong functional and genetic support.

genetics↗

Swarm-mediated phage transport disrupts a biofilm inherently protected from phage penetration

The treatment of chronic bacterial infections by phages has shown promise in combating antimicrobial resistance. A typical phage particle is at least an order of magnitude larger than an antibiotic molecule. Hence, phages diffuse slower than antibiotics, and can also get trapped in the polymeric mesh of biofilm matrix. By tracking fluorescently labeled lambda phages that do not infect Capnocytophaga gingivalis, a bacterium abundant in the human oral microbiota, we demonstrate active phage transportation by a C. gingivalis swarm. As a result, the rate of disruption of the prey of lambda phage i.e., an Escherichia coli colony, increases 10 times. C. gingivalis drills tunnels within a curli fiber containing E. coli biofilm and increase the efficiency of phage penetration. This provides evidence for a novel mechanism of phage-bacterial warfare.

microbiology↗

Ultra-compact Dual-band Smart NEMS Magnetoelectric Antennas for Simultaneous Wireless Energy Harvesting and Magnetic Field Sensing

Ultra-compact wireless implantable medical devices (IMDs) are in great demand for healthcare applications, in particular for neural recording and stimulation. Current implantable technologies based on miniaturized micro-coils suffer from low wireless power transfer efficiency (PTE) and are not always compliant with the specific absorption rate imposed by the Federal Communications Commission, particularly for deep brain implantation where field attenuation and tissue loss are significant. Moreover, current implantable devices are reliant on recordings of voltage or current. This has two major weaknesses: 1) the necessary direct contact between electrode and tissue degrades over time due to electrochemical fouling and tissue reactions, and 2) the necessity for differential recordings across space. Here, we report, for the first time, an ultra-compact dual-band smart nanoelectromechanical systems magnetoelectric (ME) antenna with a size of 250×174 µm2 that can efficiently perform wireless energy harvesting and sense ultra-small magnetic fields such as those arising from neural activities. The proposed smart ME antenna has a wireless PTE 1∼2 orders of magnitude higher than any other reported miniaturized micro-coil, allowing the wireless IMDs to be compliant with the specific absorption rate (SAR) limit and to operate under safe exposure of radio frequency energy. Furthermore, the magnetic sensing capability of the proposed smart ME antenna, with a limit of detection of 300∼500pT at > 200Hz, should allow the IMDs to record neural magnetic fields from the brain without requiring differential recording.Competing Interest StatementThe authors have declared no competing interest.View Full Text

bioengineering↗

The IMEx Coronavirus interactome: an evolving map of Coronaviridae-Host molecular interactions

The current Coronavirus Disease 2019 (COVID-19) pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has spurred a wave of research of nearly unprecedented scale. Among the different strategies that are being used to understand the disease and develop effective treatments, the study of physical molecular interactions enables studying fine-grained resolution of the mechanisms behind the virus biology and the human organism response. Here we present a curated dataset of physical molecular interactions, manually extracted by IMEx Consortium curators focused on proteins from SARS-CoV-2, SARS-CoV-1 and other members of the Coronaviridae family. Currently, the dataset comprises over 2,200 binarized interactions extracted from 86 publications. The dataset can be accessed in the standard formats recommended by the Proteomics Standards Initiative (HUPO-PSI) at the IntAct database website (www.ebi.ac.uk/intact), and will be continuously updated as research on COVID-19 progresses.

bioinformatics↗

Reversing age: dual species measurement of epigenetic age with a single clock

Young blood plasma is known to confer beneficial effects on various organs in mice. However, it was not known whether young plasma rejuvenates cells and tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly-accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=593 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=850 human tissue samples to the training data. We employed these six clocks to investigate the rejuvenation effects of a plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. Cellular senescence, which is not associated with epigenetic aging, was also considerably reduced in vital organs. Overall, this study demonstrates that a plasma-derived treatment markedly reverses aging according to epigenetic clocks and benchmark biomarkers of aging.

developmental biology↗

Diversified RACE Sampling on Data Streams Applied to Metagenomic Sequence Analysis

The rise of whole-genome shotgun sequencing (WGS) has enabled numerous breakthroughs in large-scale comparative genomics research. However, the size of genomic datasets has grown exponentially over the last few years, leading to new challenges for traditional streaming algorithms. Modern petabyte-sized genomic datasets are difficult to process because they are delivered by high-throughput data streams and are difficult to store. As a result, many traditional streaming problems are becoming increasingly relevant. One such problem is the task of constructing a maximally diverse sample over a data stream. In this regime, complex sampling procedures are not possible due to the overwhelming data generation rate. In theory, the best diversity sampling methods are based on a simple greedy algorithm that compares the current sequence with a large pool of sampled sequences and decides whether to accept or reject the sequence. While these methods are elegant and optimal, they are largely confined to the theoretical realm because the greedy procedure is too slow in practice. While there are many methods to identify common elements in data streams efficiently, fast and memory-efficient diversity sampling remains a challenging and fundamental data streaming problem with few satisfactory solutions. In this work, we bridge the gap with RACE sampling, an online algorithm for diversified sampling. Unlike random sampling, which samples uniformly, RACE selectively accepts samples from streams that lead to higher sequence diversity. At the same time, RACE is as computationally efficient as random sampling and avoids pairwise similarity comparisons between sequences. At the heart of RACE lies an efficient lookup array constructed using locality-sensitive hashing (LSH). Our theory indicates that an accept/reject procedure based on LSH lookups is sufficient to obtain a highly diverse subsample. We provide rigorous theoretical guarantees for well-known biodiversity indices and show that RACE can nearly double the Shannon and Simpson indices of a genetic sample in practice, all while using the same resources as random sampling. We also compare RACE against Diginorm and coreset-based diversity sampling methods and find that RACE is faster and more memory efficient. Our algorithm is straightforward to implement, easy to parallelize, and fast enough to keep pace with the overwhelming data generation rates. We expect that as DNA sequence data streams become more mainstream and faster, RACE will become an essential component for many applications.1

bioinformatics↗

Capturing variation impact on molecular interactions: the IMEx Consortium mutations data set

The current wealth of genomic variation data identified at the nucleotide level has provided us with the challenge of understanding by which mechanisms amino acid variation affects cellular processes. These effects may manifest as distinct phenotypic differences between individuals or result in the development of disease. Physical interactions between molecules are the linking steps underlying most, if not all, cellular processes. Understanding the effects that amino acid variation of a molecules sequence has on its molecular interactions is a key step towards connecting a full mechanistic characterization of nonsynonymous variation to cellular phenotype. Here we present an open access resource created by IMEx database curators over 14 years, featuring 28,000 annotations fully describing the effect of individual point sequence changes on physical protein interactions. We describe how this resource was built, the formats in which the data content is provided and offer a descriptive analysis of the data set. The data set is publicly available through the IntAct website at www.ebi.ac.uk/intact/resources/datasets#mutationDs and is being enhanced with every monthly release.

bioinformatics↗

Cargo Transport Shapes the Spatial Organization of a Microbial Community

The human microbiome is an assemblage of diverse bacteria that interact with one another to form communities. Bacteria in a given community are arranged in a three-dimensional matrix with many degrees of freedom. Snapshots of the community display well-defined structures, but the steps required for their assembly are not understood. Here, we show that this construction is carried out with the help of gliding bacteria. Gliding is defined as the motion of cells over a solid or semi-solid surface without the necessity of growth or the aid of pili or flagella. Genomic analysis suggests that gliding bacteria are present in human microbial communities. We focus on Capnocytophaga gingivalis which is present in abundance in the human oral microbiome. Tracking of fluorescently-labeled single cells and of gas bubbles carried by fluid flow shows that swarms of C. gingivalis are layered, with cells in the upper layers moving more rapidly than those in the lower layers. Thus, cells also glide on top of one another. Cells of non-motile bacterial species attach to the surface of C. gingivalis and are propelled as cargo. The cargo cell moves along the length of a C. gingivalis cell, looping from one pole to the other. Multi-color fluorescent spectral imaging of cells of different live but non-motile bacterial species reveals their long-range transport in a polymicrobial community. A swarm of C. gingivalis transports some non-motile bacterial species more efficiently than others and helps shape the spatial organization of a polymicrobial community.\n\nSignificanceWe describe a situation in which bacteria typical of the human oral microbiome are organized spatially by gliding cells, species of Capnocytophaga, that move backwards and forwards over the substratum. The mobile adhesins that pull the cells over the substratum also attach to cells of non-motile bacterial species, which are carried up and down the motile cells as cargo. The synchronized transport of non-motile cargo bacteria helps shape a polymicrobial community.

microbiology↗

A molecular rack and pinion actuates a cell-surface adhesin and enables bacterial gliding motility

The mechanism for bacterial gliding is not understood. The gliding bacterium Flavobacterium johnsoniae is known to have an adhesin, SprB, that moves along the cell surface on a spiral track. When cells are sheared by passage of a suspension through thin tubing, they stop gliding but can be tethered by addition of an anti-SprB antibody. Tethered cells spin about 3 Hz. We labeled the Type 9 secretion system (T9SS) with a yellow-fluorescent-protein (YFP) fusion of GldL. When labeled cells were tethered, a yellow fluorescent spot was found near the rotation axis, which shows that the motor that drives the rotation localizes with the T9SS. The spiral track was labeled by following the motion of Cy3 attached to SprB via an antibody. The distance between the rotation axis and the track was determined by a measurement involving both labels, YFP and Cy3, yielding 90 nm. If a rotary motor spins a pinion of radius 90 nm 3 Hz, a spot on its periphery will move 1.5 m/s, the speed at which cells glide. We suggest that the pinion drives a flexible tread that carries SprB along a track fixed to the cell surface. Cells glide when such an adhesin adheres to the solid substratum.

microbiology↗