Biology subjects

Mandal, S.

Publications and source records attributed to Mandal, S..

At least 55 records · Page 3Linked to original sources

bioRxiv2022

ASTF1, an AP2/ERF-family transcription factor and ortholog of cultivated tomato LEAFLESS, is required for acylsugar biosynthesis

Acylsugars, specialized metabolites produced by solanaceous trichomes, provide protection against biotic and abiotic stresses. Here, we report ACYLSUGAR TRANSCRIPTION FACTOR1 (ASTF1/Sopen05g008450; AP2/ERF-family member) positively regulates acylsugar biosynthesis. Virus-induced gene silencing (VIGS) of ASTF1 in Solanum pennellii reduced acylsugar production by 65%. Most acylsugar (and several flavonoid) metabolic genes were downregulated in ASTF1-silenced plants, and these genes showed strong co-expression with ASTF1. In promoters of potential ASTF1-targets, we identified three enriched motifs, and one motif showed similarity with binding sites of other AP2/ERFs. Phylogenetic analysis and data mining indicated trichome-enriched expression of ASTF1 orthologs in several acylsugar-producing solanaceous species, suggesting a conserved role in acylsugar biosynthesis. This was supported by VIGS of ASTF1 orthologs in Nicotiana benthamiana. Broader phylogenetic analysis revealed relationships among specialized metabolic AP2/ERFs in several asterid species and provided clues about evolutionary emergence of acylsugar phenotype. Cultivated tomato ortholog (LEAFLESS/Solyc05g013540) has been reported to coordinate leaf initiation with transient expression at incipient primordia, and data mining revealed downregulation of trichome-preferentially-expressed genes, including acylsugar (and flavonoid) metabolic genes, in leafless mutants shoot apices, indicating remarkable spatiotemporal functional diversity. Our work will pave a way to disentangle acylsugar regulatory network and holds promise for future metabolic engineering of acylsugar production.

plant biology↗

bioRxiv2022

Estimating the overall fraction of phenotypic variance attributed to high-dimensional predictors measured with error

In prospective genomic studies (e.g., DNA methylation, metagenomics, and transcriptomics), it is crucial to estimate the overall fraction of phenotypic variance (OFPV) attributed to the high-dimensional genomic variables, a concept similar to heritability analyses in genome-wide association studies (GWAS). Unlike genetic variants in GWAS, these genomic variables are typically measured with error due to technical limitation and temporal instability. While the existing methods developed for GWAS can be used, ignoring measurement error may severely underestimate OFPV and mislead the design of future studies. Assuming that measurement error variances are distributed similarly between causal and noncausal variables, we show that the asymptotic attenuation factor equals to the average intraclass correlation coefficients of all genomic variables, which can be estimated based on a pilot study with repeated measurements. We illustrate the method by estimating the contribution of microbiome taxa to body mass index and multiple allergy traits in the American Gut Project. Finally, we show that measurement error does not cause meaningful bias when estimating the correlation of effect sizes for two traits.

genetics↗

bioRxiv2021

Immune escape facilitation by mutations of epitope residues in RdRp of SARS-CoV-2

SARS-CoV-2 has considerably higher mutation rate. SARS-CoV-2 possesses a RNA dependent RNA polymerase (RdRp) which helps to replicate its genome. The mutation P323L in RdRp is associated with the loss of a particular epitope (321-327) from this protein which may influence the pathogenesis of the concern SARS-CoV-2 through the development of antibody escape variants. We consider the effect of mutations in some of the epitope regions including the naturally occurring mutation P323L on the structure of the epitope and their interface with paratope using all-atom molecular dynamics (MD) simulation studies. P323L mutations cause conformational changes in the epitope region by opening up the region associated with increase in the radius of gyration and intramolecular hydrogen bonds, making the region less accessible. Moreover, the fluctuations in the dihedral angles in the epitope:paratope (IgG) interface increase which destabilize the interface. Such mutations may help in escaping antibody mediated immunity of the host.

bioinformatics↗

bioRxiv2021

Transcriptomic-based quantification of the epithelial-hybrid-mesenchymal spectrum across biological contexts

Epithelial-mesenchymal plasticity (EMP) underlies embryonic development, wound healing, and cancer metastasis and fibrosis. Cancer cells exhibiting EMP often have more aggressive behavior, characterized by drug resistance, and tumor-initiating and immuno-evasive traits. Thus, the EMP status of cancer cells can be a critical indicator of patient prognosis. Here, we compare three distinct transcriptomic-based metrics - each derived using a different gene list and algorithm - that quantify the EMP spectrum. Our results for 96 cancer-related RNA-seq datasets reveal a high degree of concordance among these metrics in quantifying the extent of EMP. Moreover, each metric, despite being trained on cancer expression profiles, recapitulates the expected changes in EMP scores for non-cancer contexts such as lung fibrosis and cellular reprogramming into induced pluripotent stem cells. Thus, we offer a scoring platform to quantify the extent of EMP in vitro and in vivo for diverse biological applications including cancer.

bioinformatics↗

bioRxiv2021

Dynamic analysis and control of a rice-pest system under transcritical bifurcations

Cultural methods were widely applied at an early stage of agricultural pest management but then replaced over time through pesticides with adverse effects on crop quality and the environment due to extensive and long-term use. In this study, we have reformulated a rice-pest-control model by first modelling a rice-pest system rigorously to then extend it to become an optimal control problem. We consider both, cultural methods and pesticides, and minimize thereby the density of agricultural pests, to increase the production of rice and to reduce gross annual losses. Pesticides have been applied only in an emergency scenario, which reduces environmental pollution and damage to nearby ecosystems. For the emergency case, we have developed a decision model to mitigate potential risks. The formulated models are verified by stability analysis at equilibrium points and investigated through transcritical bifurcations. Moreover, we have extensively confirmed our main results by numerical investigations and discussed the biological implications in more detail.

systems biology↗

bioRxiv2021

Cooperative escape in ants and robots

The solution of complex problems by the collective action of simple agents in both biologically evolved and synthetically engineered systems involves cooperative action. Understanding the resulting emergent solutions requires integrating across the organismal behaviors of many individuals. Here we investigate an ecologically relevant collective task in black carpenter ants Camponotus pennsylvanicus: escape from a soft, erodible confining corral. Individual ants show a transition from individual exploratory excavation at random locations to spatially localized collective exploitative excavation and escape from the corral. A minimal continuum theory that coarse-grains over individual actions and considers their integrated influence on the environment leads to the emergence of an effective phase space of behaviors in terms of excavation strength and cooperation intensity. To test the theory over the range of predicted behaviors, we used custom-built robots (RAnts) that respond to stimuli and show the emergence (and failure) of cooperative excavation and escape. Overall, our approach shows how the cooperative completion of tasks can arise from relatively simple rules that involve the interaction of simple agents with a dynamically changing environment that serves as an enabler and modulator of behavior.

animal behavior and cognition↗

bioRxiv2021

Immunosuppressive traits of the hybrid epithelial/mesenchymal phenotype

Recent preclinical and clinical data suggests enhanced metastatic fitness of hybrid epithelial/ mesenchymal (E/M) phenotypes, but mechanistic details regarding their survival strategies during metastasis remain unclear. Here, we investigate immune-evasive strategies of hybrid E/M states. We construct and simulate the dynamics of a minimalistic regulatory network encompassing the known associations among regulators of EMT (epithelial-mesenchymal transition) and PD-L1, an established immune-suppressor. Our model simulations, integrated with single-cell and bulk RNA-seq data analysis, elucidate that hybrid E/M cells can have high levels of PD-L1, similar to those seen in cells with a full EMT phenotype, thus obviating the need for cancer cells to undergo a full EMT to be immune-evasive. Specifically, in breast cancer, we show the co-existence of hybrid E/M phenotypes, enhanced resistance to anti-estrogen therapy and increased PD-L1 levels. Our results underscore how the emergent dynamics of interconnected regulatory networks can coordinate different axes of cellular fitness during metastasis.

cancer biology↗

bioRxiv2021

Integrative systems biology approach identified crucial genes and transcription factors associated with gallbladder cancer pathogenesis

Gallbladder cancer (GBC) has a lower incidence rate among the population relative to other cancer types but majorly contributes to the total cancer cases of the biliary tract system. GBC is distinguished from other malignancies due to its high mortality, marked geographical variation and poor prognosis. To date no systemic targeted therapy is available for GBC. The main objective of this study is to determine the molecular signatures correlated with GBC development using integrative system level approaches. We performed analysis of publicly available transcriptomic data to identify differentially regulated genes and pathways. Co-expression network analysis and differential regulatory network analysis identified hub genes and hub transcription factors (TFs) associated with GBC pathogenesis and progression. We then assessed the epithelial-mesenchymal transition (EMT) status of the hub genes using a combination of three scoring methods. The hub genes such as; CDC6, MAPK15, CCNB2, BIRC7, L3MBTL1 identified are regulators of cell cycle components which suggests that cell cycle regulatory genes are significantly linked to GBC pathogenesis and progression.

systems biology↗

bioRxiv2021

Rapid Kinetic Fingerprinting of Single Nucleic Acid Molecules by a FRET-based Dynamic Nanosensor

Biofluids contain cell-free nucleic acids such as microRNAs (miRNAs) and circulating tumor-derived DNAs (ctDNAs) that have emerged as promising disease biomarkers. Conventional detection of these biomarkers by digital PCR and next generation sequencing, although highly sensitive, requires time-consuming extraction and amplification steps that increase the risk of sample loss and cross-contamination, respectively. To achieve the direct, rapid detection of miRNAs and ctDNAs with near-perfect specificity and single-molecule level sensitivity, we herein describe an accelerated amplification-free single-molecule kinetic fingerprinting. This approach, termed intramolecular single-molecule recognition through equilibrium Poisson sampling (iSiMREPS), exploits a dynamic DNA nanosensor comprising a surface anchor and a pair of fluorescent detection probes: one probe captures individual target molecules onto the surface, while the other transiently interrogates them to generate kinetic fingerprints by intramolecular single-molecule Forster resonance energy transfer (smFRET). Formamide is used to further accelerate the kinetics of probe-target interactions and fingerprinting, while background signals are reduced by removing non-target-bound probes from the surface using toehold-mediated strand displacement. We show that iSiMREPS can detect in as little as 10 seconds two distinct, promising cancer biomarkers--miR-141 and a common EGFR exon 19 deletion--reaching a limit of detection (LOD) of ~3 fM and a mutant allele fraction among excess wild-type as low as 1 in 1 million, or 0.0001%. We anticipate that iSiMREPS will find utility in research and clinical diagnostics based on its features of rapid detection, high specificity, sensitivity, and generalizability.

biophysics↗

bioRxiv2021

Relish plays a dynamic role in the niche to modulate Drosophila bloodprogenitor homeostasis in development and infection.

Immune challenges demand the gearing up of basal hematopoiesis to combat infection. Little is known about how during development, this switch is achieved to take care of the insult. Here, we show that the hematopoietic niche of the larval lymph gland of Drosophila senses immune challenge and reacts to it quickly through the nuclear factor-{kappa}B (NF-{kappa}B), Relish, a component of the immune deficiency (Imd) pathway. During development, Relish is triggered by ecdysone signaling in the hematopoietic niche to maintain the blood progenitors. Loss of Relish causes an alteration in the cytoskeletal architecture of the niche cells in a Jun Kinase dependent manner, resulting in the trapping of Hh implicated in progenitor maintenance. Notably, during infection, downregulation of Relish in the niche tilts the maintenance program towards precocious differentiation, thereby bolstering the cellular arm of the immune response.

developmental biology↗

bioRxiv2021

A mechanistic model captures the emergence and implications of non-genetic heterogeneity and reversible drug resistance in ER+ breast cancer cells

Resistance to anti-estrogen therapy is an unsolved clinical challenge in successfully treating ER+ breast cancer patients. Acquisition of mutations can confer heritable resistance to cancer cells, enabling their clonal selection to establish a drug-resistant population. Recent studies have demonstrated that cells can tolerate drug treatment without any genetic alterations too; however, the mechanisms and dynamics of such non-genetic adaptation remain elusive. Here, we investigate coupled dynamics of epithelial-mesenchymal transition (EMT) in breast cancer cells and emergence of reversible drug resistance. Our mechanism-based model for the underlying regulatory network reveals that these two axes can drive one another, thus conferring bidirectional plasticity. This network can also enable non-genetic heterogeneity in a population of cells by allowing for six co-existing phenotypes: epithelial-sensitive, mesenchymal-resistant, hybrid E/M-sensitive, hybrid E/M-resistant, mesenchymal-sensitive and epithelial-resistant, with the first two ones being most dominant. Next, in a population dynamics framework, we exemplify the implications of phenotypic plasticity (both drug-induced and intrinsic stochastic switching) and/or non-genetic heterogeneity in promoting population survival in a mixture of sensitive and resistant cells, even in the absence of any cell-cell cooperation. Finally, we propose the potential therapeutic use of MET (mesenchymal-epithelial transition) inducers besides canonical anti-estrogen therapy to limit the emergence of reversible drug resistance. Our results offer mechanistic insights into empirical observations on EMT and drug resistance and illustrate how such dynamical insights can be exploited for better therapeutic designs.

cancer biology↗

bioRxiv2021

In-Vitro Fluorescence Microscopy Studies Show Retention of Spike-Protein (SARS-Cov-2) on Cell Membrane in the Presence of Amodiaquin Dihydrochloride Dihydrate Drug

The ability of S-glycoprotein (S-protein) in SARS-Cov-2 to bind to the host cell receptor protein (angiotensin-converting enzyme 2 (ACE2)) leading to its entry in the cellular system determines its contagious index and global spread. Three available drugs (Riboflavin, Amodiaquin dihydrochloride dihydrate (ADD), and Remidesivir) were investigated to understand the kinetics of S-protein and its entry inside a cellular environment. Optical microscopy and fluorescence-based assays on 293T cells (transfected with ACE2 plasmid) were used as the preamble for assessing the behavior of S-protein in the presence of these drugs for the first 12 hours post-S-protein - ACE2 binding. Preliminary results suggest relatively long retention of S-protein on the cell membrane in the presence of ADD drug. Evident from the %-overlap and colocalization of S-protein with endosome studies, a significant fraction of S-protein entering the cell escape endosomal degradation process, suggesting S-protein takes non-endocytic mediated entry in the presence of ADD. In contrast, in the presence of Riboflavin, S-protein carries out a normal endocytic pathway, comparable to the control (no drug) group. Therefore, the present study indicates ADD potentially affects S-proteins entry mechanism (endocytic pathway) in addition to its reported target action mechanism. Hence, ADD substantially interferes with S-protein cellular entrance mechanism. This is further strengthened by 24 hrs study. However, detailed studies at the molecular scale are necessary to clarify our understanding of exact intermediate molecular processes. The present study (based on limited data) reveals ADD could be a potential candidate to manage Covid-19 functions through the yet unknown molecular mechanism.

biophysics↗

bioRxiv2020

A novel benzoxaborole works by targeting FabI in Escherichia coli

To combat the looming crisis of antimicrobial-resistant infections, there is an urgent need for novel antimicrobial discovery and drug target identification. The benzoxaborole series were previously identified as inhibitors of mycobacterial growth. Here, we demonstrate that a benzoxaborole is also active against the Gram negative bacterium, Escherichia coli in vitro. We isolated resistant mutants of E. coli and subjected them to whole genome sequencing. We found mutations in the enoyl acyl carrier protein FabI. Mutations mapped around the active center site located close to the co-factor binding site. This site partially overlaps with the binding pocket of triclosan, a known FabI inhibitor. Similar to triclosan, the interaction of the benzoxaborole with FabI was dependent on the co-factor NAD+. Identification of the target of this compound in E. coli provides scope for further development and optimization of this series for Gram negative pathogens.

microbiology↗

bioRxiv2020

Investigating epithelial-mesenchymal heterogeneity of tumors and circulating tumor cells with transcriptomic analysis and biophysical modeling

IntroductionCellular heterogeneity along the Epithelial-Mesenchymal Plasticity (EMP) spectrum is a paramount feature observed in tumors and circulating tumor cells (CTCs). High-throughput techniques now offer unprecedented details on this variability at a single-cell resolution. Yet, there is no current consensus about how EMP in tumors propagates to that in CTCs. To investigate the relationship between EMP associated heterogeneity of tumors and that of CTCs, we integrated transcriptomic analysis and biophysical modeling. MethodsWe apply three EMT (Epithelial-Mesenchymal Transition) scoring metrics to multiple tumor samples and CTC datasets from several cancer types. Moreover, we develop a biophysical model that couples EMT associated phenotypic switching in a primary tumor with cell migration. Finally, we integrate EMT transcriptomic analysis and in silico modeling to evaluate the predictive power of several measurements of tumor aggressiveness, including tumor EMT score, CTC EMT score, fraction of CTC clusters found in circulation, and CTC cluster size distribution. ResultsAnalysis of high-throughput datasets reveals a pronounced heterogeneity without a well-defined relation between EMT traits in tumors and CTCs. Moreover, mathematical modeling predicts different phases where CTCs can be less, equally, or more mesenchymal than primary tumor depending on the dynamics of phenotypic transition and cell migration. Consistently, various datasets of CTC cluster size distribution from different cancer types are fitted onto different regimes of the model. By further constraining the model with experimental measurements of tumor EMT score, CTC EMT score, and fraction of CTC cluster in bloodstream, we show that none of these assays alone can provide sufficient information to predict the other variables. ConclusionsBy integrating analysis of single cell gene expression and in silico modeling, we propose that the relationship between EMT progression in tumors and CTCs can be variable, and in general, predicting one from the other may not be as straightforward as tacitly assumed.

cancer biology↗

bioRxiv2020

SplineDist: Automated Cell Segmentation with Spline Curves

We present SplineDist, an instance segmentation convolutional neural network for bioimages extending the popular StarDist method. While StarDist describes objects as star-convex polygons, SplineDist uses a more flexible and general representation by modelling objects as planar parametric spline curves. Based on a new loss formulation that exploits the properties of spline constructions, we can incorporate our new object model in StarDists architecture with minimal changes. We demonstrate in synthetic and real images that SplineDist produces segmentation outlines of equal quality than StarDist with smaller network size and accurately captures non-star-convex objects that cannot be segmented with StarDist.

bioinformatics↗

bioRxiv2020

Sedimentation rate and organic matter dynamics shape microbiomes across a continental margin

Marine sedimentation rate and bottom-water O2 concentration control the remineralization/sequestration of organic carbon across continental margins; but whether/how they shape microbiome architecture (the ultimate effector of all biogeochemical phenomena), across shelf/slope sediments, is unknown. Here we reveal distinct microbiome structures and functions, amidst comparable pore-fluid chemistries, along ~3 m sediment-horizons underlying the seasonal (shallow coastal) and perennial (deep sea) oxygen minimum zones (OMZs) of the Arabian Sea, situated across the western-Indian margin (water-depths: 31 m and, 530 and 580 m, respectively). Along the perennial- and seasonal-OMZ sediment-cores microbial communities were predominated by Gammaproteobacteria/Alphaproteobacteria and Euryarchaeota/Firmicutes respectively. As a perennial-OMZ signature, a cryptic methane production-consumption cycle was found to operate near the sediment-surface; overall diversity, as well as the relative abundances of simple-fatty-acids-requiring anaerobes (methanogens, anaerobic methane-oxidizers, sulfate-reducers and acetogens), peaked in the topmost sediment-layer and then declined via synchronized fluctuations until the sulfate-methane transition zone was reached. The entire microbiome profile was reverse in the seasonal-OMZ sediment-horizon. We discerned that in the perennial-OMZ sediments organic carbon deposited was higher in concentration, and marine components-rich, so it potentially degraded readily to simple fatty acids; lower sedimentation rate afforded higher O2 exposure time for organic matter degradation despite perennial hypoxia in the bottom-water; thus, the resultant abundance of reduced metabolites sustained multiple inter-competing microbial processes in the upper sediment-layers. Remarkably, the whole geomicrobial scenario was opposite in the sediments of the seasonal/shallow-water OMZ. Our findings create a microbiological baseline for understanding carbon-sulfur cycling across distinct marine depositional settings and water-colum n oxygenation regimes.

microbiology↗

bioRxiv2020

Transcriptional bursting shape autosomal dynamic random monoallelic expression inpre-gastrulation embryos

In recent years, allele-specific single-cell RNA-seq (scRNA-seq) analysis has demonstrated wide-spread dynamic random monoallelic expression of autosomal genes (aRME) in different cell types. However, the prevalence of dynamic aRME during pre-gastrulation development remains unknown. Here, we show that dynamic aRME is wide-spread in different lineages of pre-gastrulation embryos. Additionally, the origin of dynamic aRME remains poorly understood. Theoretically, it is believed that independent transcriptional bursting from each allele leads to the dynamic aRME. However, based on analysis of allele-specific burst kinetics of autosomal genes, we found that allelic burst is not perfectly independent, rather it happens in semi-coordinated fashion. Importantly, we show that semi-coordinated allelic bursting of the genes; particularly with low burst frequency, leads to frequent asynchronous allelic bursting, thereby shaping the landscape of dynamic aRME in pre-gastrulation embryos. Altogether, our study provides significant insight into the prevalence and origin of dynamic aRME and cell to cell expression heterogeneity during early mammalian development. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

genetics↗

bioRxiv2020

Dynamics of the COVID -19 Related Publications

BackgroundThis study aims to analyze the dynamics of the published articles and preprints of Covid-19 related literature from different scientific databases and sharing platforms. MethodsThe PubMed, Elsevier, and Research Gate (RG) databases were under consideration in this study over a specific time. Analyses were carried out on the number of publications as (a) function of time (day), (b) journals and (c) authors. Doubling time of the number of publications was analyzed for PubMed "all articles" and Elsevier published articles. Analyzed databases were (1A) PubMed "all articles" (01/12/2019-12/06/2020) (1B) PubMed Review articles (01/12/2019-2/5/2020) and (1C) PubMed Clinical Trials (01/01/2020-30/06/2020) (2) Elsevier all publications (01/12/2019-25/05/2020) (3) RG (Article, Pre Print, Technical Report) (15/04/2020-30/4/2020). FindingsTotal publications in the observation period for PubMed, Elsevier, and RG were 23000, 5898 and 5393 respectively. The average number of publications/day for PubMed, Elsevier and RG were 70.0 {+/-}128.6, 77.6{+/-}125.3 and 255.6{+/-}205.8 respectively. PubMed shows an avalanche in the number of publication around May 10, number of publications jumped from 6.0{+/-}8.4/day to 282.5{+/-}110.3/day. The average doubling time for PubMed, Elsevier, and RG was 10.3{+/-}4 days, 20.6 days, and 2.3{+/-}2.0 days respectively. In PubMed average articles/journal was 5.2{+/-}10.3 and top 20 authors representing 935 articles are of Chinese descent. The average number of publications per author for PubMed, Elsevier, and RG was 1.2{+/-}1.4, 1.3{+/-}0.9, and 1.1{+/-}0.4 respectively. Subgroup analysis, PubMed review articles mean and median review time for each article were <0|17{+/-}17|77> and 13.9 days respectively; and reducing at a rate of-0.21 days (count)/day. InterpretationAlthough the disease has been known for around 6 months, the number of publications related to the Covid-19 until now is huge and growing very fast with time. It is essential to rationalize the publications scientifically by the researchers, authors, reviewers, and publishing houses. FundingNone

scientific communication and education↗