Biology subjects

Bose, T.

Publications and source records attributed to Bose, T..

10 recordsLinked to original sources

bioRxiv2025

Overexpression of DnaJ chaperones in ameliorating toxicities associated with FUS and TDP-43

Amyotrophic Lateral Sclerosis (ALS) is an adult-onset neurodegenerative disease. It primarily affects the motor neurons, leading to muscle weakness and eventually death of the patients. Various factors, such as genetics, environment, age, etc, are involved in the etiopathogenesis of ALS. As ALS is a highly challenging and complex disease involving various pathogeneses linked with progressive motor neuron degeneration, it is difficult to have a single therapeutic target against this disease. ALS mutants of TDP-43 and FUS are showing slow growth as well as protein aggregation in the cytoplasm in yeast. Our study involves cloning of 38 Drosophila DnaJ domain chaperones and overexpressing them in a yeast ALS model. After the interaction of mutants TDP-43 and FUS with the DnaJ domain chaperones, they were categorized into suppressors and enhancers. The major hits on our screen were CG7872, Hsc70-4, and Mrj, which rescued TDP-43 toxicity by reducing protein aggregation and slow growth in yeast cells. In FUS, slow growth and protein aggregation are reduced with the chaperones CG32641 and CG6693, resulting in a lowering of FUS toxicity. On the other hand, chaperones CG2911, CG2790, and CG8476 in presence of TDP-43 overexpression, grows slower with an increase in the number of aggregates in yeast cells. These chaperones increase the toxicity of TDP-43. Similarly, in FUS, Hsc20, CG7130, CG2911, and JdpC also showed slow growth phenotype and an increase in protein aggregation in yeast cells. These chaperones enhance the toxicity of FUS. This screening will enhance our understanding of the ALS pathology, and the chaperones identified in this study can serve as neuroprotective agents for ALS. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/656528v2_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@16ed84dorg.highwire.dtl.DTLVardef@3ad413org.highwire.dtl.DTLVardef@39431borg.highwire.dtl.DTLVardef@164ae09_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Evidence from metagenomic study indicate that subclinical mastitis may have a different pathological origin than clinical mastitis

Bovine mastitis is one of the main causes of low milk production, resulting in significant economic losses for the dairy industry. Therefore, the industry will benefit from the development of strategies for the timely diagnosis of bovine mastitis, especially the sub-clinical sub-type. Here, we analysed the milk metagenome of healthy cows and cows suffering from various forms of mastitis, viz. clinical, sub-clinical and chronic/ recurrent sub-types. We identified Neisseria, Eubacterium and Streptococcus as the key drivers of the change in microbial community structure from a healthy state to a clinical mastitis state. Our results also indicate that the microbiota composition and the probable cause of clinical and recurrent bovine mastitis may not be the same as that of sub-clinical mastitis. Further, the sensory protein load in the sub-clinical mastitis sub-group differed significantly from the other studied categories, wherein Achromobacter, Dickeya, Pectobacterium and Raoultella were identified as the discriminatory features. We also propose ML-based classifiers to screen for bovine mastitis using milk metagenomic samples. The principles elucidated here through the study of mastitis in cows can be applied to other animals and hopefully will benefit the entire dairy industry.

microbiology↗

bioRxiv2023

Identification of two novel DnaJ chaperone family proteins as modifiers of Huntingtin aggregates

Huntingtons disease (HD) is a rare neurodegenerative disease. It is caused due to aggregation of Huntingtin (HTT) protein containing Q repeats more than 40. Similar protein aggregation is also a hallmark of several other neurodegenerative diseases related to loss of cognitive function. In search of modifiers of HTT aggregation, we have screened putative chaperone proteins from Drosophila in both fly and yeast model of HD. DnaJ chaperones were screened by evaluating HTT protein aggregation related phenotypes using growth assays for studying the growth rate of the cells, imaging studies, and gel-based approaches like semi-denaturing detergent agarose gel electrophoresis (SDD-AGE). Our screening led us to categorize several proteins as suppressors and enhancers of the HTT associated phenotypes. Out of the 40 chaperones and co-chaperones, two chaperones that came up strikingly were CG5001 and P58IPK. Protein aggregation was found to be reduced in both S2 cells and Drosophila transgenic lines with HTT103Q in presence of these class of chaperones. As these DnaJ chaperones have protein sequence similarity across species, these might be used as possible tools to combat the effects of neurodegenerative diseases, as evidenced specifically in Huntingtons disease and Amyotrophic Lateral Sclerosis (ALS).

genetics↗

bioRxiv2023

Composition of nasopharyngeal microbiota in individuals with SARS-COV-2 infection across three COVID-19 waves in India

Multiple variants of the SARS-CoV-2 virus have been plaguing the world through successive waves of infection over the past three years. Studies by independent research groups across geographies have shown that the microbiome composition in COVID-19 patients (CP) differ from that of healthy individuals (CN). However, such observations were based on limited-sized sample-sets collected primarily from the early days of the pandemic. Here, we study the nasopharyngeal microbiota in COVID-19 patients, wherein the samples have been collected across the three COVID-19 waves witnessed in India, which were driven by different variants of concern. We also present the variations in microbiota of symptomatic vs asymptomatic COVID-19 patients. The nasopharyngeal swabs were collected from 589 subjects providing samples for diagnostics purposes at Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India. CP showed a marked shift in the microbial diversity and composition compared to CN, in a wave-dependent manner. Rickettsiaceae was the only family that was noted to be consistently depleted in CP samples across the waves. The genera Staphylococcus, Anhydrobacter, Thermus, and Aerococcus were observed to be highly abundant in the symptomatic CP patients when compared to the asymptomatic group. In general, we observed a decrease in the burden of opportunistic pathogens in the host microbiota during the later waves of infection. To our knowledge, this is the first longitudinal study which was designed to understand the relation between the evolving nature of the virus and the changes in the human nasopharyngeal microbiota. Such studies not only pave way for better understanding of the disease pathophysiology but also help gather preliminary evidence on whether interventions to the host microbiota can help in better protection or faster recovery.

microbiology↗

bioRxiv2022

Mrj an Hsp40 family chaperone regulates oligomerization of Orb2 and long-term memory

Orb2 the Drosophila homolog of Cytoplasmic polyadenylation element binding protein (CPEB) forms prion-like oligomers. These oligomers consist of Orb2A and Orb2B isoforms and their formation are dependent on the oligomerization of the Orb2A isoform. Drosophila with a mutation diminishing Orb2As prion-like oligomerization forms long-term memory but fails to maintain it over time. Since, this prion-like oligomerization of Orb2A plays a crucial role in the maintenance of memory, here we aim to find what regulates this oligomerization. In an immunoprecipitation-based screen, we identify interactors of Orb2A in the Hsp40 and Hsp70 families of proteins. Amongst these, we find an Hsp40 family protein Mrj as a regulator of the conversion of Orb2A to its prion-like form. Mrj interacts with Hsp70 proteins and acts as a chaperone by interfering with the aggregation of pathogenic Huntingtin. Unlike its mammalian homolog, we find Drosophila Mrj is neither an essential gene nor causes any gross neurodevelopmental defect. We observe a loss of Mrj results in a reduction in Orb2 oligomers. Further, the knockdown of Mrj in the mushroom body neurons results in a deficit in long-term memory. Our work implicates a chaperone Mrj in mechanisms of memory regulation through controlling the oligomerization of Orb2A and its association with the translating polysomes.

neuroscience↗

bioRxiv2022

Asynchrony rescues statistically-optimal group decisions from information cascades through emergent leaders

It is usually assumed that information cascades are most likely to occur when an early but incorrect opinion spreads through the group. Here we analyse models of confidence-sharing in groups and reveal the opposite result: simple but plausible models of naive Bayesian decision-making exhibit information cascades when group decisions are synchronous; however, when group decisions are asynchronous, the early decisions reached by Bayesian decision makers tend to be correct, and dominate the group consensus dynamics. Thus early decisions actually rescue the group from making errors, rather than contribute to it. We explore the likely realism of our assumed decision-making rule with reference to the evolution of mechanisms for aggregating social information, and known psychological and neuroscientific mechanisms.

animal behavior and cognition↗

bioRxiv2021

A compendium of predicted growths and derived symbiotic relationships between 803 gut microbes in 13 different diets

Gut health is intimately linked to dietary habits and the microbial community (microbiota) that flourishes within. The delicate dependency of the latter on nutritional availability is also strongly influenced by symbiotic relationships (such as, parasitic or mutualistic) between the resident microbes, often affecting their growth rate and ability to produce key metabolites. Since, cultivating the entire repertoire of gut microbes is an infeasible task, metabolic models (genome-based metabolic reconstructions) could be employed to predict their growth patterns and interactions. Here, we have used 803 gut microbial metabolic models from the Virtual Metabolic Human repository, and subsequently optimized and simulated them to grow on 13 dietary compositions. The presented pairwise interaction data (https://osf.io/ay8bq/) and the associated bacterial growth rates are expected to be useful for (a) deducing microbial association patterns, (b) diet-based inference of personalised gut profiles, and (c) as a steppingstone for studying multi-species metabolic interactions.

systems biology↗

bioRxiv2020

Chaperonin Abundance Boosts Bacterial Fitness

The ability of chaperonins to buffer mutations that affect protein folding pathways suggests that their abundance should be evolutionarily advantageous. Here, we investigate the effect of chaperonin overproduction on cellular fitness in Escherichia coli. We demonstrate that chaperonin abundance confers (a) an ability to tolerate higher temperatures, (b) improved cellular fitness and (c) enhanced folding of metabolic enzymes, which is expected to lead to enhanced energy harvesting potential.

biochemistry↗

bioRxiv2019

A role of cellular translation regulation associated with toxic Huntingtin protein

Huntingtons disease (HD) is a severe neurodegenerative disorder caused by poly Q repeat expansion in the Huntingtin (Htt) gene. While the Htt amyloid aggregates are known to affect many cellular processes, its role in translation is not addressed. Here we report pathogenic Htt expression causes protein synthesis deficit in cells. We find a functional prion-like protein, the translation regulator Orb2 to be sequestered by Htt aggregates. Coexpression of Orb2 can partially rescue the lethality associated with poly Q expanded Htt. These findings can be relevant for HD as human homologs of Orb2 also can be sequestered by pathogenic Htt aggregates. Our work suggests that translation dysfunction could be one of the contributors in the pathogenesis of HD and new therapies targeting protein synthesis pathways might help alleviate disease symptoms.

cell biology↗

bioRxiv2018

Inhibition and excitation shape activity selection: effect of oscillations in a decision-making circuit

Decision-making is a complex task and requires adaptive mechanisms that facilitate efficient behaviour. Here, we consider a neural circuit that guides the behaviour of an animal in ongoing binary choice tasks. We adopt an inhibition motif from neural network theory and propose a dynamical system characterized by nonlinear feedback, which links mechanism (the implementation of the neural circuit) and function (increasing reproductive value). A central inhibitory unit influences evidence-integrating excitatory units, which in our terms correspond to motivations competing for selection. We determine the parameter regime where the animal exhibits improved decision-making behaviour, and explain different behavioural outcomes by making the link between bifurcation analysis of the nonlinear neural circuit model and decision-making performance. We find that the animal performs best if it tunes internal parameters of the neural circuit in accordance with the underlying bifurcation structure. In particular, variation of inhibition strength and excitation-over-inhibition ratio have a crucial effect on the decision outcome, by allowing the animal to break decision deadlock and to enter an oscillatory phase that describes its internal motivational state. Our findings indicate that this oscillatory phase may improve the overall performance of the animal in an ongoing foraging task. Our results underpin the importance of an integrated functional and mechanistic study of animal activity selection.\n\nAuthor summaryOrganisms frequently select activities, which relate to economic, social and perceptual decision-making problems. The choices made may have substantial impact on their lives. In foraging decisions, for example, animals aim at reaching a target intake of nutrients; it is generally believed that a balanced diet improves reproductive success, yet little is known about the underlying mechanisms that integrate nutritional needs within the brain. In our study, we address this coupling between physiological states and a decision-making circuit in the context of foraging decisions. We consider a model animal that has the drive to eat or drink. The motivation to select and perform one of these activities (i.e. eating or drinking), is processed in artificial neuronal units that have access to information on how hungry and thirsty the animal is at the point it makes the decision. We show that inhibitory and excitatory mechanisms in the neural circuit shape ongoing binary decisions, and we reveal under which conditions oscillating motivations may improve the overall performance of the animal. Our results indicate that inefficient or pathological decision-making may originate from suboptimal modulation of excitation and inhibition in the neurobiological network.

neuroscience↗