Biology subjects

Dey, A.

Publications and source records attributed to Dey, A..

63 records · Page 4Linked to original sources

bioRxiv2020

CoRhythMo: A Computational Framework for Modeling Biobehavioral Rhythms from Mobile and Wearable Data Streams

This paper presents CoRhythMo, the first computational framework for modeling biobehavioral rhythms - the repeating cycles of physiological, psychological, social, and environmental events - from mobile and wearable data streams. The framework incorporates four main components: mobile data processing, rhythm discovery, rhythm modeling, and machine learning. We use a dataset of smartphone and Fitbit data collected from 138 college students over a semester to evaluate the frameworks ability to 1) model biobehavioral rhythms of students, 2) measure the stability of their rhythms over the course of the semester, 3) model differences between rhythms of students with different health status, and 4) predict the mental health status in students using the model of their biobehavioral rhythms. Our evaluation provides evidence for the feasibility of using CoRhythMo for modeling and discovering human rhythms and using them to assess and predict different life and health outcomes.

bioinformatics↗

bioRxiv2020

Receptor-independent membrane mediated pathways of serotonin action

Serotonin is a neurotransmitter as well as a somatic signaling molecule, and the serotonergic system is a major target for psychotropic drugs. Serotonin, together with a few related neurotransmitters, has recently been found to exhibit an unexpectedly high lipid membrane affinity1–3. It has been conjectured that extrasynaptic serotonin can diffuse in the lipid membrane to efficiently reach remote receptors (and receptors with buried ligand-binding sites)4, providing a mechanism for the diffuse ‘volume’ neurotransmission that serotonin is capable of5–10. Here we show that membrane binding by serotonin can directly modulate membrane properties and cellular function, independent of its receptor-mediated actions. Atomic force microscopy shows that serotonin binding makes artificial lipid bilayers softer. It induces nucleation of liquid disordered domains inside the raft-like liquid-ordered domains in a ternary bilayer displaying phase separation. Solid-state NMR spectroscopy corroborates this data, revealing a rather homogeneous decrease in the order parameter of the lipid chains in the presence of serotonin. In the RN46A immortalized serotonergic neuronal cell line, extracellular serotonin enhances transferrin receptor endocytosis, an action exerted even in the presence of both broad-spectrum serotonin receptor and transporter inhibitors. Similarly, it increases the binding and internalization of Islet Amyloid Polypeptide (IAPP) oligomers, suggesting a connection between serotonin, which is co-secreted with IAPP by pancreatic beta cells, and the cellular effects of IAPP. Our results uncover a hitherto unknown serotonin-bilayer interaction that can potentiate key cellular processes in a receptor-independent fashion. Therefore, some pathways of serotonergic action may escape potent pharmaceutical agents designed for serotonin transporters or receptors. Conversely, bio-orthogonal serotonin-mimetics may provide a new class of cell-membrane modulators.Competing Interest StatementThe authors have declared no competing interest.View Full Text

biophysics↗

bioRxiv2020

A Novel Therapeutic Approach to Corneal Alkaline Burn Model by Targeting Fidgetin-like 2, a Microtubule Regulator

Purpose To determine the efficacy of nanoparticle-encapsulated FL2 siRNA (FL2-NPsi), a novel therapeutic agent targeting the Fidgetin-like 2 (FL2) gene, for the treatment of corneal alkaline chemical injury.Methods Eighty 12-week-old, male Sprague-Dawley rats were divided evenly into 8 treatment groups: prednisolone, empty nanoparticles, control-NPsi (1 μM, 10 μM, 20 μM) and FL2-NPsi (1 μM, 10 μM, 20 μM). An alkaline burn was induced onto the cornea of each rat, which was then treated for 14 days according to group assignment. Clinical (N=10 per group), histopathologic (N=6 per group), and immunohistochemical (N=4 per group) analyses were conducted to assess for wound healing. FL2-NPsi-mediated knockdown of FL2 was confirmed by in vitro qPCR. Toxicity assays were performed to assess for apoptosis (TUNEL assay, N=3 per group) and nerve damage (whole mount immunochemical staining, N=2 per group). Statistical analyses were performed using student’s t-test and ANOVA.Results Compared to controls, FL2-NPsi-treated groups demonstrated enhanced corneal wound healing, with the 10 and 20 μM FL2-NPsi-treated groups demonstrating maximum rates of corneal re-epithelialization (p=0.0003 at Day 4 and p<0.0001 at Day 8) as assessed by ImageJ software, enhanced corneal transparency, and improved stromal organization on histology. Immunohistochemical analysis of vascular endothelial cells, macrophages, and neutrophils did not show significant differences between treatment groups. FL2-NPsi was not found to be toxic to nerves or induce apoptosis (p=0.917).Conclusion Dose-response studies found both 10 and 20 μM FL2-NPsi to be efficacious in this rat model. FL2-NPsi may offer a novel treatment for corneal alkaline chemical injuries.Competing Interest StatementDr. Wang, Dr. Kramer, Dr. Baker, and Dr. Dey are employees of MicroCures, Inc. Dr. Sharp is co-founder and Chief Scientific Officer for MicroCures, Inc and is the inventor of U.S. Patent #20130022667 entitled "Fidgetin-like 2 as a target to enhance wound healing,” which has been licensed by MicroCures. Dr. Chuck is a scientific advisor for MicroCures, Inc. Dr. Friedman holds stock in MicroCures. No other author has a conflict of interest.View Full Text

physiology↗

bioRxiv2020

On the theory of condensin mediated loop extrusion in genomes

Condensation of hundreds of mega-base-pair-long human chromosomes in a small nuclear volume is a spectacular biological phenomenon. This process is driven by the formation of chromosome loops. The ATP consuming motor, condensin, interacts with chromatin segments to actively extrude loops. Motivated by real-time imaging of loop extrusion (LE), we created an analytically solvable model, predicting the LE velocity and step size distribution as a function of external load. The theory fits the available experimental data quantitatively, and suggests that condensin must undergo a large conformational change, induced by ATP binding, bringing distant parts of the motor to proximity. Simulations using a simple model confirm that the motor transitions between an open and a closed state in order to extrude loops by a scrunching mechanism, similar to that proposed in DNA bubble formation during bacterial transcription. Changes in the orientation of the motor domains are transmitted over ~ 50 nm, connecting the motor head and the hinge, thus providing an allosteric basis for LE.

biophysics↗

bioRxiv2020

BACTERIAL GROWTH INDUCED BIOCEMENTATION TECHNOLOGY, 'SPACE BRICK' - A PROPOSAL FOR EXPERIMENT AT MICROGRAVITY AND PLANETARY ENVIRONMENTS

We present results of our investigation of microbial induced calcite precipitation for manufacturing space bricks and a proposal for study of this activity in low-earth orbit (LEO). Sporosarcina pasteurii, a urease producing bacterial strain was used to consolidate lunar simulant soil (LSS) in the form of a brick with non-trivial strength properties. Potential of a naturally occurring polymer namely, guar gum, as an additive was investigated for enhancement in compressive strength of bio-consolidated samples. Experimental results of bio-brick exhibited an approximate 10-fold increase in compressive strength with guar gum supplementation in soil. We present results of microstructural analysis of the space bricks and also propose a payload design for related experiments in LEO.

bioengineering↗

bioRxiv2019

Studying POU2F1 to Unveil the Structural Facet for Pan-Cancer Analysis Considering the Functional Annotations and Sequence-Structure Space Paradigm

POU domain class 2 homebox 1 (POU2F1) is largely known for its transcription factor(TF) activity. Due to its association with different types of malignancies, POU2F1 becomes one of the key factors in pan-cancer analysis. However, in spite of understanding it as a potential drug target, none of the drug has been designed till date due to its extreme dynamicity. In this article, we have proposed a three fold comprehensive framework for understanding the structural conservation and co-variation of POU2F1. Firstly, a gene regulatory network based non-pathogenic and pathogenic study have been performed to understand the strong association between cancers and POU2F1. After that, based on evolutionary sequence space study, the comparative sequential dynamicity of the protein members of POU domain family has been observed mostly between non-human and human samples. Subsequently, the reciprocity effect of the residual co-variation has been identified through direct coupling analysis. Along with that, the structure of POU2F1 has been analysed depending on quality assessment and normal mode based structure network. Comparing the sequence and structure space information, the most significant set of residue viz., 3, 9, 13, 17, 20, 21, 28, 35, 36 have been identified as structural facet for stable binding. It is observed that targeting these residues can help to prevent the monomeric aggregations. This study demonstrates-the observed malleability of POU2F1 is one of the prime reason behind its functional multiplicity in terms of protein moonlighting.\n\nSIGNIFICANCEPOU2F1 is one of the important TFs associated with several malignancies. In spite of orderly stable structure in primitive family proteins, this protein is highly unstable at the monomeric stage. Previous studies show that POU2F1 has a clear association with 121 different diseases. Therefore, it becomes one of the important links in the pan-cancer study. Interestingly, TFs can be considered as a potential drug target. However, it is hardly possible to control the extreme dynamicity of TFs. In this regard, protein moonlighting plays an important role. We have tried to provide a theoretical frame to build understanding on POU2F1. The study provides pathogenic and non-pathogenic connections of the protein in terms of comprehensive and precise Gene Regulatory Network. Subsequently, the instability has been unveiled and the structural facet has been identified. Finally, the specified set of function for a suitable session to target the protein is analyzed based on protein moonlighting properties.

bioinformatics↗

bioRxiv2019

Microbially induced calcite precipitation using Bacillus velezensis with guar gum

The present study was performed to explore the efficiency of microbially induced calcite precipitation (MICP) via locally isolated bacterial strains. Strains were isolated from soil and were screened for urease activity as well as microbial precipitation. Among all screened isolates, a carbonate precipitating soil bacterium was subjected for 16S rRNA gene sequencing. This strain was identified as Bacillus velezensis. The MICP characteristics of this strain were explored under three different media compositions and significant amount of precipitation in all cases was observed. Highest amount of precipitation was seen with guar as a biopolymer additive medium under experimented conditions. Activity of isolated strain with reference to pH profile, and ammonia concentration and total reducing sugar was further explored under media supplemented with four concentrations of guar (0.25%, 0.5%, 0.75% and 1% w/v). Microstructural analysis of microbial precipitation was performed with the help of scanning electron microscopy (SEM) and X-ray powder diffraction (XRD) analysis, which confirmed the presence of calcium carbonate in different phases. The strain was subjected to bio-cementation and locally available sand was successfully consolidated. XRD results confirmed the presence of calcium carbonate on consolidated samples.

microbiology↗

bioRxiv2018

Sequence variation of rare outer membrane protein β-barrel domains in clinical strains provides insights into the evolution of Treponema pallidum subsp. pallidum, the syphilis spirochete.

In recent years, considerable progress has been made in topologically and functionally characterizing integral outer membrane proteins (OMPs) of Treponema pallidum subspecies pallidum (TPA), the syphilis spirochete, and identifying its surface-exposed {beta}-barrel domains. Extracellular loops in OMPs of Gram-negative bacteria are known to be highly variable. We examined the sequence diversity of {beta}-barrel-encoding regions of tprC, tprD, and bamA, in 31 specimens from Cali, Colombia; San Francisco, California; and the Czech Republic and compared them to allelic variants in the 41 reference genomes in the NCBI database. To establish a phylogenetic framework, we used tp0548 genotyping and tp0558 sequences to assign strains to the Nichols or SS14 clades. We found that (i) {beta}-barrels in clinical strains could be grouped according to allelic variants in TPA reference genomes; (ii) for all three OMP loci, clinical strains within the Nichols or SS14 clades often harbored {beta}-barrel variants that differed from the Nichols and SS14 reference strains; and (iii) OMP variable regions often reside in predicted extracellular loops containing B-cell epitopes. Based upon structural models, non-conservative amino acid substitutions in predicted transmembrane {beta}-strands of TprC and TprD2 could give rise to functional differences in their porin channels. OMP profiles of some clinical strains were mosaics of different reference strains and did not correlate with results from enhanced molecular typing. Our observations suggest that human host selection pressures drive TPA OMP diversity and that genetic exchange contributes to the evolutionary biology of TPA. They also set the stage for topology-based analysis of antibody responses against OMPs and help frame strategies for syphilis vaccine development.\n\nIMPORTANCEDespite recent progress characterizing outer membrane proteins (OMPs) of Treponema pallidum (TPA), little is known about how their surface-exposed, {beta}-barrel-forming domains vary among strains circulating within high-risk populations. In this study, sequences for the {beta}-barrel-encoding regions of three OMP loci, tprC, tprD, and bamA, in TPA from a large number of patient specimens from geographically disparate sites were examined. Structural models predict that sequence variation within {beta}-barrel domains occurred predominantly within predicted extracellular loops. Amino acid substitutions in predicted transmembrane strands that could potentially affect porin channel function also were noted. Our findings suggest that selection pressures exerted by human populations drive TPA OMP diversity and that recombination at OMP loci contributes to the evolutionary biology of syphilis spirochetes. These results also set the stage for topology-based analysis of antibody responses that promote clearance of TPA and frame strategies for vaccine development based upon conserved OMP extracellular loops.

microbiology↗

bioRxiv2018

BRD4 Deficiency Selectively Affects a Unique Developmental Subpopulation in Thymocytes

The bromodomain protein BRD4 is a driver in both inflammatory diseases and cancers. It has multiple functions, contributing to chromatin structure and transcription through its intrinsic HAT and kinase activities. Despite the wide-ranging characterization of BRD4, little is known about its in vivo function. In the present study, we have examined the role of BRD4 in T cell development by conditional deletion at various stages of thymocyte differentiation. We found that BRD4 is critical for normal T cell development. Surprisingly, BRD4 selectively regulates the progression of immature CD8 single positive (ISP) thymocytes into quiescent DP thymocytes. In striking contrast, BRD4 deletion does not affect the extensive proliferation associated with the differentiation of double negative (DN) into ISP cells. Nor does it affect the maturation of double positive (DP) into conventional CD4+ and CD8+ thymocytes. These studies lead to the unexpected conclusion that BRD4 selectively regulates preselection ISP thymocytes.\n\nOn-line SummaryImmature CD8 single-positive (ISP) thymocytes are identified as a molecularly-distinct thymocyte subpopulation, dependent on BRD4 for progression to the DP stage. DN and DP are BRD4-independent. These findings provide new insights into BRD4, a therapeutic target in inflammation and cancer.

immunology↗