Biology subjects

Bhattacharya, D.

Publications and source records attributed to Bhattacharya, D..

At least 73 records · Page 4Linked to original sources

bioRxiv2022

Whole-genome duplication in an algal symbiont serendipitously confers thermal tolerance to corals

The algal endosymbiont Durusdinium trenchii enhances the resilience of coral reefs under thermal stress1,2. As an endosymbiont, D. trenchii is generally expected to have a reduced genome compared to its free-living relatives, due in part to the lack of selective pressure for maintaining redundant gene functions in a stable intracellular environment within the host3. However, D. trenchii can live freely or in endosymbiosis, and the analysis of genetic markers4 suggests that this species has undergone whole-genome duplication (WGD). Here we present genome assemblies for two D. trenchii isolates, confirm WGD in these taxa, and examine how selection has shaped the duplicated genome regions. We assess how the competing free-living versus endosymbiotic lifestyles of D. trenchii have contributed to the retention and divergence of duplicated genes, and how these processes have enhanced thermotolerance of corals hosting these symbionts. We find that lifestyle is the driver of post-WGD evolution in D. trenchii, with the free-living phase being most important, followed by endosymbiosis. Adaptations to both lifestyles collectively result in increased cellular fitness for D. trenchii, which provides enhanced thermal stress protection to the host coral. Beyond corals, this polyploid alga is a valuable model for understanding how genome-wide selective forces act to balance the often, divergent constraints imposed by competing lifestyles.

genomics↗

bioRxiv2022

Accurate self-assessment in 2D: protein contact map quality estimation by deep evolutionary reconciliation

Protein contact maps have proven to be a valuable tool in the deep learning revolution of protein structure prediction, ushering in the recent breakthrough by AlphaFold2. However, self-assessment of the quality of predicted structures are typically performed at the granularity of 3D coordinates as opposed to directly exploiting the rotation- and translation-invariant 2D contact maps. Here we present rrQNet, a deep learning method for self-assessment in 2D by contact map quality estimation. Our approach is based on the intuition that for a contact map to be of high quality, the residue pairs predicted to be in contact should be mutually consistent with the evolutionary context of the protein. The deep neural network architecture of rrQNet implements this intuition by cascading two deep modules--one encoding the evolutionary context and the other performing evolutionary reconciliation. The penultimate stage of rrQNet estimates the quality scores at the interacting residue-pair level, which are then aggregated for estimating the quality of a contact map. This design choice offers versatility at varied resolutions from individual residue pairs to full-fledged contact maps. Trained on multiple complementary sources of contact predictors, rrQNet facilitates generalizability across various contact maps. By rigorously testing using publicly available datasets and comparing against several in-house baseline approaches, we show that rrQNet accurately reproduces the true quality score of a predicted contact map and successfully distinguishes between accurate and inaccurate contact maps predicted by a wide variety of contact predictors. The open-source rrQNet software package is freely available at https://github.com/Bhattacharya-Lab/rrQNet.

bioinformatics↗

bioRxiv2021

Genetic evidence that uptake of the fluorescent analog 2NBDG occurs independently of known glucose transporters

The fluorescent derivative of glucose, 2-Deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)-amino]-D-glucose (2NBDG), is a widely used surrogate reagent to visualize glucose uptake in live cells at single cell resolution. Using a model of CRISPR-Cas9 gene editing in 5TGM1 myeloma cells, we demonstrate that ablation of the glucose transporter gene Slc2a1 abrogates radioactive glucose uptake but has no effect on the magnitude or kinetics of 2NBDG import. Extracellular 2NBDG, but not NBD-fructose was transported by plasma cells into the cytoplasm suggesting specific activity that is unlinked to glucose import and that of chemically similar compounds. RNA-Seq analysis of primary plasma cells and the 5TGM1 myeloma cell line revealed expression of other candidate glucose transporters. Yet, deletion of these transporters individually or in combination with one another also had no impact on 2NBDG uptake. Ablation of the genes in the Slc29 and Slc35 families of nucleoside and nucleoside sugar transporters as well as the ATP-binding cassette (ABC) transporter family also failed to impact 2NBDG import. Thus, cellular uptake of 2NBDG is promoted by an unknown mechanism and is not a faithful indicator of glucose transport.

immunology↗

bioRxiv2021

Ploidy variation and its implications for reproduction and population dynamics in two sympatric Hawaiian coral species

Standing genetic variation is a major driver of fitness and resilience, and therefore of fundamental importance for threatened species such as stony corals. We analyzed RNA- seq data generated from 132 Montipora capitata and 119 Pocillopora acuta coral colonies collected from K[a]neohe Bay, Oahu, Hawaii. Our goals were to determine the extent of colony genetic variation and to study reproductive strategies in these two sympatric species. Surprisingly, we found that 63% of the P. acuta colonies were triploid, with putative independent origins of the different triploid clades. These corals have spread primarily via asexual reproduction and are descended from a small number of genotypes, whose diploid ancestor invaded the bay. In contrast, all M. capitata colonies are diploid, outbreeding, with almost all colonies genetically distinct. Only two cases of asexual reproduction, likely via fragmentation, were identified in this species. We report two distinct strategies in sympatric coral species that inhabit the largest sheltered body of water in the main Hawaiian Islands. These data highlight divergence in reproductive behavior and genome biology, both of which contribute to coral resilience and persistence. Significance StatementGiven the threat posed to coral reef ecosystems by human caused climate change, there is a growing focus on developing strategies for the protection and restoration of these critical marine habitats. These efforts are however limited by our understanding of the diversity of coral survival and reproductive strategies. Our analysis of data from two coral species inhabiting the same Hawaiian bay found that one is a strict sexual outbreeder, whereas the other reproduces predominantly asexually (i.e., clonally) and includes both diploids and triploids. These results broaden our understanding of coral biology, adaptability, and evolution, and underpin future research into the mechanisms of coral resilience that can inform restoration activities.

genomics↗

bioRxiv2021

Progenitor-intrinsic Metabolic Sensing Promotes Hematopoietic Homeostasis

Hematopoietic homeostasis is maintained by stem and progenitor cells in part by extrinsic feedback cues triggered by mature cell loss. We demonstrate a different mechanism by which hematopoietic progenitors intrinsically anticipate and prevent the loss of mature progeny through metabolic switches. We examined hematopoiesis in mice conditionally deficient in long-chain fatty acid oxidation (carnitine palmitoyltransferase 2, Cpt2), glutaminolysis (glutaminase, Gls), or mitochondrial pyruvate import (mitochondrial pyruvate carrier 2, Mpc2). While genetic ablation of Cpt2 or Gls minimally impacted most blood lineages, deletion of Mpc2 led to a sharp decline in mature myeloid cells. However, MPC2-deficient myeloid cells rapidly recovered due to a transient increase in myeloid progenitor proliferation. Competitive bone marrow chimera and stable isotope tracing experiments demonstrated that this proliferative burst was intrinsic to MPC2-deficient progenitors and accompanied by a metabolic switch to glutaminolysis. Thus, hematopoietic progenitors intrinsically adjust to metabolic perturbations independently of feedback from downstream mature cells to maintain homeostasis.

developmental biology↗

bioRxiv2021

The peroxisomal transporter ABCD3 plays a major role in dicarboxylic fatty acid metabolism

Peroxisomes metabolize a specific subset of fatty acids, which include dicarboxylic fatty acids (DCAs) generated by {omega}-oxidation. Data obtained in vitro suggest that the peroxisomal transporter ABCD3 (also known as PMP70) mediates the transport of DCAs into the peroxisome, but in vivo evidence to support this role is lacking. In this study, we studied an Abcd3 KO mouse model generated by CRISPR-Cas9 technology using targeted and untargeted metabolomics, histology, immunoblotting, and stable isotope tracing technology. We show that ABCD3 functions in DCA metabolism and uncover a novel role for this peroxisomal transporter in lipid metabolic homeostasis. The Abcd3 KO mouse presents with lipodystrophy, increased circulating free fatty acids, decreased ketone bodies, enhanced hepatic cholesterol synthesis and decreased hepatic de novo lipogenesis. Moreover, our study suggests that DCAs are metabolized by mitochondrial {beta}-oxidation when ABCD3 is not functional, reflecting the importance of the metabolic compartmentalization and communication between peroxisomes and mitochondria. In summary, this study provides data on the role of the peroxisomal transporter ABCD3 in hepatic lipid homeostasis and DCA metabolism, and the consequences of peroxisomal dysfunction for the liver.

physiology↗

bioRxiv2021

Competent immune responses to SARS-CoV-2 variants in older adults following mRNA vaccination

Aging is associated with a reduced magnitude of primary immune responses to vaccination and constriction of immune receptor repertoire diversity. Clinical trials demonstrated high efficacy of mRNA based SARS-CoV-2 vaccines in older adults but concerns about virus variant escape have not been well addressed. We have conducted an in-depth analysis of humoral and cellular immunity against an early-pandemic viral isolate and compared that to the P.1. (Gamma) and B.1.617.2 (Delta) variants in <50 and >55 age cohorts of mRNA vaccine recipients. We have further measured neutralizing antibody titers for B.1.617.1 (Kappa) and B.1.595; a SARS-CoV-2 isolate bearing Spike mutation E484Q. As reported, robust immunity required the second dose of vaccine. Older vaccinees manifested robust cellular immunity against early-pandemic SARS-CoV-2 and more recent variants, which remained statistically comparable to the adult group. The older cohort had lower neutralizing capacity at the first time point following the second dose, but at later time points immunity was indistinguishable between them. While the duration of these immune responses remains to be determined over longer periods of time, these results provide reasons for optimism regarding vaccine protection of older adults against SARS-CoV-2 variants and inform thinking about boost vaccination with variant vaccines. eTOC summaryVaccine responses are often diminished with aging, but we found strong responses to SARS-CoV-2 in older adults following mRNA vaccination. T cell responses were not diminished when confronted by SARS-CoV-2 variants. Neutralizing Ab were reduced but not more than those in adults. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=73 SRC="FIGDIR/small/453287v2_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@1091655org.highwire.dtl.DTLVardef@1996173org.highwire.dtl.DTLVardef@ccf2f9org.highwire.dtl.DTLVardef@163ed22_HPS_FORMAT_FIGEXP M_FIG C_FIG Created with BioRender.com

immunology↗

bioRxiv2021

Tightly constrained genome reduction and relaxation of purifying selection during secondary plastid endosymbiosis

Endosymbiosis, the establishment of a former free-living prokaryotic or eukaryotic cell as an organelle inside a host cell, can dramatically alter the genomic architecture of the endosymbiont. Plastids, the light harvesting organelles of photosynthetic eukaryotes, are excellent models to study this phenomenon because plastid origin has occurred multiple times in evolution. Here, we investigate the genomic signature of molecular processes acting through secondary plastid endosymbiosis - the origination of a new plastid from a free-living eukaryotic alga. We used phylogenetic comparative methods to study gene loss and changes in selective regimes on plastid genomes, focusing on the green lineage that has given rise to three independent lineages with secondary plastids (euglenophytes, chlorarachniophytes, Lepidodinium). Our results show an overall increase in gene loss associated with secondary endosymbiosis, but this loss is tightly constrained by retention of genes essential for plastid function. The data show that secondary plastids have experienced temporary relaxation of purifying selection during secondary endosymbiosis. However, this process is tightly constrained as well, with selection relaxed only relative to the background in primary plastids, but purifying selection remaining strong in absolute terms even during the endosymbiosis events. Selection intensity rebounds to pre-endosymbiosis levels following endosymbiosis events, demonstrating the changes in selection efficiency during different phases of secondary plastid origin. Independent endosymbiosis events in the euglenophytes, chlorarachniophytes, and Lepidodinium differ in their degree of relaxation of selection, highlighting the different evolutionary contexts of these events. This study reveals the selection-drift interplay during secondary endosymbiosis, and evolutionary parallels during the process of organelle origination.

evolutionary biology↗

bioRxiv2021

Invertebrate methylomes provide insight into mechanisms of environmental tolerance and reveal methodological biases

There is a growing focus on the role of DNA methylation in the ability of marine invertebrates to rapidly respond to changing environmental factors and anthropogenic impacts. However, genome-wide DNA methylation studies in non-model organisms are currently hampered by limited understanding of methodological biases. Here we compare three methods for quantifying DNA methylation at single base-pair resolution -- Whole Genome Bisulfite Sequencing (WGBS), Reduced Representation Bisulfite Sequencing (RRBS), and Methyl-CpG Binding Domain Bisulfite Sequencing (MBDBS) -- using multiple individuals from two reef-building coral species with contrasting environmental sensitivity. All methods reveal substantially greater methylation in Montipora capitata (11.4%) than the more sensitive Pocillopora acuta (2.9%). The majority of CpG methylation in both species occurs in gene bodies and flanking regions. In both species, MBDBS has the greatest capacity for detecting CpGs in coding regions at our sequencing depth, however MBDBS may be influenced by intra-sample methylation heterogeneity. RRBS yields robust information for specific loci albeit without enrichment of any particular genome feature and with significantly reduced genome coverage. Relative genome size strongly influences the number and location of CpGs detected by each method when sequencing depth is limited, illuminating nuances in cross-species comparisons. As genome-wide methylation differences, supported by data across bisulfite sequencing methods, may contribute to environmental sensitivity phenotypes in critical marine invertebrate taxa, these data provide a genomic resource for investigating the functional role of DNA methylation in environmental tolerance.

genomics↗

bioRxiv2021

Murine deficiency of peroxisomal L-bifunctional protein (EHHADH) causes medium-chain 3-hydroxydicarboxylic aciduria and perturbs hepatic cholesterol homeostasis

Peroxisomes play an essential role in the {beta}-oxidation of dicarboxylic acids (DCAs), which are metabolites formed upon {omega}-oxidation of fatty acids. Genetic evidence linking transporters and enzymes to specific DCA {beta}-oxidation steps is generally lacking. Moreover, the physiological functions of DCA metabolism remain largely unknown. In this study, we aimed to characterize the DCA {beta}-oxidation pathway in human cells, and to evaluate the biological role of DCA metabolism using mice deficient in the peroxisomal L-bifunctional protein (Ehhadh KO mice). In vitro experiments using HEK-293 KO cell lines demonstrate that ABCD3 and ACOX1 are essential in DCA {beta}-oxidation, whereas both the bifunctional proteins (EHHADH and HSD17B4) and the thiolases (ACAA1 and SCPx) have overlapping functions and their contribution may depend on expression level. We also show that medium-chain 3-hydroxydicarboxylic aciduria is a prominent feature of EHHADH deficiency in mice most notably upon inhibition of mitochondrial fatty acid oxidation. Using stable isotope tracing methodology, we confirmed that products of peroxisomal DCA {beta}-oxidation can be transported to mitochondria for further metabolism. Finally, we show that, in liver, Ehhadh KO mice have increased mRNA and protein expression of cholesterol biosynthesis enzymes with decreased (in females) or similar (in males) rate of cholesterol synthesis. We conclude that EHHADH plays an essential role in the metabolism of medium-chain DCAs and postulate that peroxisomal DCA {beta}-oxidation is a regulator of hepatic cholesterol biosynthesis.

physiology↗

bioRxiv2021

Multi-omic characterization of the thermal stress phenome in the stony coral Montipora capitata

We used network methods to analyze transcriptomic and polar metabolomic data generated from the stress resistant stony coral Montipora capitata. Corals were exposed to ambient or thermal stress conditions over a five-week period that coincided with a mass spawning event of this species. Gene co-expression networks showed that the early thermal stress response involves downregulation of growth and DNA replication, whereas signaling and the immune response are strongly upregulated. Later stages are dominated by suppression of metabolite transport and biomineralization and enhanced expression of transcriptional regulators. Integration of gene-metabolite data demonstrates that the major outcome of the thermal treatment is activation of animal redox stress pathways with detoxification of reactive oxygen species being dominant. Differential regulation of the highly conserved cytochrome P450 gene family was of particular interest with downregulation of CYP1A1, involved in progesterone metabolism, potentially explaining the attenuated mass spawning observed during the sampling period.

genomics↗

bioRxiv2020

Sirt1 mediated regulation of p107 mitochondrial function controls muscle stem cell proliferative fates

Muscle wasting diseases and aging are associated with impaired myogenic stem cell selfrenewal and a diminished number of their proliferating progenitors (MPs). Importantly, distinct metabolic states govern MP proliferation and differentiation. Central to this is the regulation between glycolysis and oxidative phosphorylation (Oxphos). However, the mechanisms that connect these energy provisioning centers to control cell behaviour remain obscure. Herein, our results reveal a mechanism by which mitochondrial-localized transcriptional co-repressor p107 governs MP proliferation. We found p107 directly interacts at the mitochondrial DNA promoter, repressing mitochondrial-encoded genes. This reduces mitochondrial ATP generation, by limiting the electron transport chain complex formation. Importantly, the amount of ATP generated by the mitochondrial function of p107 is directly associated to the cell cycle rate. Sirt1, whose activity is dependent on the cytoplasmic by-product of glycolysis, NAD+, directly interacts with p107 impeding its mitochondrial localization and function. The metabolic control of cell cycle, driven by differential p107 mitochondrial function, establishes a new paradigm to manipulate muscle cell proliferative fates that is likely to extend to most other dividing cell types.

cell biology↗

bioRxiv2020

Sequence analysis of Indian SARS-CoV-2 isolates shows a stronger interaction of mutated receptor binding domain with ACE2 receptor

SARS-CoV-2 is a RNA Coronavirus responsible for the pandemic of the Severe Acute Respiratory Syndrome (COVID-19). It has affected the whole world including Odisha, a state in eastern India. Many people migrated in the state from different countries as well as states during this SARS-CoV-2 pandemic. As per the protocol laid by ICMR and Health & Family welfare of India, all the suspected cases were tested for SARS-CoV-2 infection. The aim of this study was to analyze the RNA binding domain (RBD) sequence of spike protein from the isolates collected from the throat swab samples of COVID-19 positive cases and further to assess the RBD affinity with ACE2 of different species including human. Whole genome sequencing for 35 clinical SARS-CoV-2 isolates from COVID-19 positive patients was performed using ARTIC amplicon based sequencing. Sequence analysis and phylogenetic analysis was carried out for the Spike and RBD region of all isolates. The interaction between the RBD and ACE2 receptor of five different species was also analysed. Except three isolates, spike region of 32 isolates showed one/multiple alterations in nucleotide bases in comparison to the Wuhan reference strain. One of the identified mutation at 1204 (Ref A, RMRC 22 C) in the RBD of spike protein was identified which depicted a stronger binding affinity with human ACE2 receptor compared to the wild type RBD. Furthermore, RBDs of all the Indian isolates are capable of binding to ACE2 of human, bat, hamster and pangolin. As mutated RBD showed stronger interaction with human ACE2, it could potentially result in higher infectivity. The study shows that RBDs of all the studied isolates have binding affinity for all the five species, which suggests that the virus can infect a wide variety of animals which could also act as natural reservoir for SARS-CoV-2.

microbiology↗

bioRxiv2020

SARS-CoV2 genome analysis of Indian isolates and molecular modelling of D614G mutated spike protein with TMPRSS2 depicted its enhanced interaction and virus infectivity

COVID-19 that emerged as a global pandemic is caused by SARS-CoV-2 virus. The virus genome analysis during disease spread reveals about its evolution and transmission. We did whole genome sequencing of 225 clinical strains from the state of Odisha in eastern India using ARTIC protocol-based amplicon sequencing. Phylogenetic analysis identified the presence of all five reported clades 19A, 19B, 20A, 20B and 20C in the population. The analyses revealed two major routes for the introduction of the disease in India i.e. Europe and South-east Asia followed by local transmission. Interestingly, 19B clade was found to be much more prevalent in our sequenced genomes (17%) as compared to other genomes reported so far from India. The haplogroup analysis for clades showed evolution of 19A and 19B in parallel whereas the 20B and 20C appeared to evolve from 20A. Majority of the 19A and 19B clades were present in cases that migrated from Gujarat state in India suggesting it to be one of the major initial points of disease transmission in India during month of March and April. We found that with the time 20A and 20B clades evolved drastically that originated from central Europe. At the same time, it has been observed that 20A and 20B clades depicted selection of four common mutations i.e. 241 C>T (5UTR), P323L in RdRP, F942F in NSP3 and D614G in the spike protein. We found an increase in the concordance of G614 mutation evolution with the viral load in clinical samples as evident from decreased Ct value of spike and Orf1ab gene in qPCR. Molecular modelling and docking analysis identified that D614G mutation enhanced interaction of spike with TMPRSS2 protease, which could impact the shedding of S1 domain and infectivity of the virus in host cells.

genomics↗

bioRxiv2020

Hybridized distance- and contact-based hierarchical structure modeling for folding soluble and membrane proteins

Crystallography and NMR system (CNS) is currently the de facto standard for fragment-free ab initio protein folding from inter-residue distance or contact maps. Despite its widespread use in protein structure prediction, CNS is a decade-old macromolecular structure determination system that was originally developed for solving macromolecular geometry from experimental restraints as opposed to predictive modeling driven by interaction map data. As such, the adaptation of the CNS experimental structure determination protocol for ab initio protein folding is intrinsically anomalous that may undermine the folding accuracy of computational protein structure prediction. In this paper, we propose a new CNS-free hierarchical structure modeling method called DConStruct for folding both soluble and membrane proteins driven by distance and contact information. Rigorous experimental validation shows that DConStruct attains much better reconstruction accuracy than CNS when tested with the same input contact map at varying contact thresholds. The hierarchical modeling with iterative self-correction employed in DConStruct scales at a much higher degree of folding accuracy than CNS with the increase in contact thresholds, ultimately approaching near-optimal reconstruction accuracy at higher-thresholded contact maps. The folding accuracy of DConStruct can be further improved by exploiting distance-based hybrid interaction maps at tri-level thresholding, as demonstrated by the better performance of our method in folding difficult free modeling targets from the 12th and 13th rounds of the Critical Assessment of techniques for protein Structure Prediction (CASP) experiments compared to several popular CNS- and fragment-based approaches, some of which even using much finer-grained distance maps than ours. Additional large-scale benchmarking shows that DConStruct can significantly improve the folding accuracy of membrane proteins compared to a CNS-based approach. These results collectively demonstrate the feasibility of greatly improving the accuracy of ab initio protein folding by optimally exploiting the information encoded in inter-residue interaction maps beyond what is possible by CNS.Author summary Predicting the folded and functional 3-dimensional structure of a protein molecule from its amino acid sequence is of central importance to structural biology. Recently, promising advances have been made in ab initio protein folding due to the reasonably accurate estimation of inter-residue interaction maps at increasingly higher resolutions that range from binary contacts to finer-grained distances. Despite the progress in predicting the interaction maps, approaches for turning the residue-residue interactions projected in these maps into their precise spatial positioning heavily rely on a decade-old experimental structure determination protocol that is not suitable for predictive modeling. This paper presents a new hierarchical structure modeling method, DConStruct, which can better exploit the information encoded in the interaction maps at multiple granularities, from binary contact maps to distance-based hybrid maps at tri-level thresholding, for improved ab initio folding. Multiple large-scale benchmarking experiments show that our proposed method can substantially improve the folding accuracy for both soluble and membrane proteins compared to state-of-the-art approaches. DConStruct is licensed under the GNU General Public License v3 and freely available at https://github.com/Bhattacharya-Lab/DConStruct.Competing Interest StatementThe authors have declared no competing interest.View Full Text

bioinformatics↗

bioRxiv2020

ZBTB38 is dispensable for hematopoiesis and antibody responses.

Members of the broad complex, tram track, bric-a-brac and zinc finger (BTB-ZF) family of transcription factors, such as BCL-6, ZBTB20, and ZBTB32, regulate antigen-specific B cell differentiation, plasma cell longevity, and the duration of antibody production. We found that ZBTB38, a different member of the BTB-ZF family that binds methylated DNA at CpG motifs, is highly expressed by germinal center B cells and plasma cells. To define the functional role of ZBTB38 in B cell responses, we generated mice conditionally deficient in this transcription factor. Germinal center B cells lacking ZBTB38 dysregulated very few genes relative to wild-type and heterozygous littermate controls. Accordingly, mice with hematopoietic-specific deletion of Zbtb38 showed normal germinal center B cell numbers and antibody responses following immunization with hapten-protein conjugates. Memory B cells from these animals functioned normally in secondary recall responses. Despite expression of ZBTB38 in hematopoietic stem cells, progenitors and mature myeloid and lymphoid lineages were also present in normal numbers in mutant mice. These data demonstrate that ZBTB38 is dispensable for hematopoiesis and antibody responses. These conditional knockout mice may instead be useful in defining the functional importance of ZBTB38 in other cell types and contexts.

immunology↗

bioRxiv2020

Metabolome shift associated with thermal stress in coral holobionts

Coral reef systems are under global threat due to warming and acidifying oceans1. Understanding the response of the coral holobiont to environmental change is crucial to aid conservation efforts. The most pressing problem is "coral bleaching", usually precipitated by prolonged thermal stress that disrupts the algal symbiosis sustaining the holobiont2,3. We used metabolomics to understand how the coral holobiont metabolome responds to heat stress with the goal of identifying diagnostic markers prior to bleaching onset. We studied the heat tolerant Montipora capitata and heat sensitive Pocillopora acuta coral species from the Hawaiian reef system in K[a]neohe Bay, Oahu. Untargeted LC-MS analysis uncovered both known and novel metabolites that accumulate during heat stress. Among those showing the highest differential accumulation were a variety of co-regulated dipeptides present in both species. The structures of four of these compounds were determined (Arginine-Glutamine, Lysine-Glutamine, Arginine-Valine, and Arginine-Alanine). These dipeptides also showed differential accumulation in symbiotic and aposymbiotic (alga free) individuals of the sea anemone model Aiptasia4, suggesting their animal provenance and algal symbiont related function. Our results identify a suite of metabolites associated with thermal stress that can be used to diagnose coral health in wild samples.

evolutionary biology↗

bioRxiv2020

DisCovER: distance-based covariational threading for weakly homologous proteins

MotivationThreading a query protein sequence onto a library of weakly homologous structural templates remains challenging, even when sequence-based predicted contact or distance information is used. Contact- or distance-assisted threading methods utilize only the spatial proximity of the interacting residue pairs for template selection and alignment, ignoring their orientation. Moreover, existing threading methods fail to consider the neighborhood effect induced by the query-template alignment. ResultsWe present a new distance- and orientation-based covariational threading method called DisCovER by effectively integrating information from inter-residue distance and orientation along with the topological network neighborhood of a query-template alignment. Our method first selects a subset of templates using standard profile-based threading coupled with topological network similarity terms to account for the neighborhood effect and subsequently performs distance- and orientation-based query-template alignment using an iterative double dynamic programming framework. Multiple large-scale benchmarking results on query proteins classified as hard targets from the Continuous Automated Model Evaluation (CAMEO) experiment and from the current literature show that our method outperforms several existing state-of-the-art threading approaches; and that the integration of the neighborhood effect with the inter-residue distance and orientation information synergistically contributes to the improved performance of DisCovER. Availabilityhttps://github.com/Bhattacharya-Lab/DisCovER Contactbhattacharyad@auburn.edu

bioinformatics↗