Biology subjects

Kundu, S.

Publications and source records attributed to Kundu, S..

83 records · Page 5Linked to original sources

bioRxiv2020

Modulation of proteasome activity by curcumin and didemethylcurcumin

Modulation of proteasome function by pharmacological interventions and molecular biology tools is an active area of research in cancer biology and neurodegenerative diseases. Curcumin (diferuloylmethane) is a naturally occurring polyphenol that affects multiple signaling pathways and known to modulate PKC activities. The therapeutic significance of curcumin is often considered to reside in its anti-inflammatory, antioxidant, anti-angiogenic, or anti-apoptotic properties. However, recent research suggests that the therapeutic efficacy of curcumin may be due to its activity as a potent inhibitor of the proteasome. In this study, we show that both curcumin and its synthetic polyphenolic derivative (didemethylcurcumin), CUIII modulated proteasome activity in a biphasic manner. Curcumin and CUIII increased proteasome activity at nanomolar concentrations but inhibited proteasome activity at micromolar concentrations. Curcumin was more effective than CUIII in relative proteasome activity increase at nanomolar concentrations. Also, curcumin was more effective than CUIII in relative proteasome activity inhibition at micromolar concentration. The docking study was conducted on the 20S proteasome catalytic subunit. Estimated Kd values for curcumin and didemethylcurcumin are 0.0054M and 1.3167M, respectively. These values correlate well with the results of the effectiveness of modulation by curcumin compare to CUIII. The small size of CUIII makes its dock to the narrow cavity of the active site, but the binding interaction is not strong compare to curcumin. This study suggests that curcumin and its didemethyl derivative can be used to modulate proteasome activity. This communication implicates the reason why curcumin and its didemethyl derivative can be used to two different disease mechanisms, neurodegeneration, and cancer.

neuroscience↗

bioRxiv2020

On Inferring Additive and Replacing Horizontal Gene Transfers Through Phylogenetic Reconciliation

Horizontal gene transfer is one of the most important mechanisms for microbial evolution and adaptation. It is well known that horizontal gene transfer can be either additive or replacing depending on whether the transferred gene adds itself as a new gene in the recipient genome or replaces an existing homologous gene. Yet, all existing phylogenetic techniques for the inference of horizontal gene transfer assume either that all transfers are additive or that all transfers are replacing. This limitation not only affects the applicability and accuracy of these methods but also makes it difficult to distinguish between additive and replacing transfers. Here, we address this important problem by formalizing a phylogenetic reconciliation framework that simultaneously models both additive and replacing transfer events. Specifically, we (1) introduce the DTRL reconciliation framework that explicitly models both additive and replacing transfer events, along with gene duplications and losses, (2) prove that the underlying computational problem is NP-hard, (3) perform the first experimental study to assess the impact of replacing transfer events on the accuracy of the traditional DTL reconciliation model (which assumes that all transfers are additive) and demonstrate that traditional DTL reconciliation remains highly robust to the presence of replacing transfers, (4) propose a simple heuristic algorithm for DTRL reconciliation based on classifying transfer events inferred through DTL reconciliation as being replacing or additive, and (5) evaluate the classification accuracy of the heuristic under a range of evolutionary conditions. Thus, this work lays the methodological and algorithmic foundations for estimating DTRL reconciliations and distinguishing between additive and replacing transfers. An implementation of our heuristic for DTRL reconciliation is freely available open-source as part of the RANGER-DTL software package from https://compbio.engr.uconn.edu/software/ranger-dtl/.

bioinformatics↗

bioRxiv2020

Genome-scale conserved molecular principles of mRNA half-life regulation

Precise control of protein and mRNA degradation is essential for cellular metabolism and homeostasis. Controlled and specific degradation of both molecular species necessitates their engagements with the respective degradation machineries; this engagement involves a disordered/unstructured segment of the substrate traversing the degradation tunnel of the machinery and accessing the catalytic sites. Here, we report that mRNAs comprising longer terminal and/or internal unstructured segments have significantly shorter half-lives; the lengths of the 5' terminal, 3' terminal and internal unstructured segments that affect mRNA half-life are compatible with molecular structures of the 5' exo- 3' exo- and endo-ribonuclease machineries. Sequestration into ribonucleoprotein complexes elongates mRNA half-life, presumably by burying ribonuclease engagement sites under oligomeric interfaces. After gene duplication, differences in terminal unstructured lengths, proportions of internal unstructured segments and oligomerization modes result in significantly altered half-lives of paralogous mRNAs. Side-by-side comparison of molecular principles underlying controlled protein and mRNA degradation unravels their remarkable mechanistic similarities, and suggests how the intrinsic structural features of the two molecular species regulate their half-lives on genome-scale and during evolution.

systems biology↗

bioRxiv2020

Single-cell epigenomic identification of inherited risk loci in Alzheimer's and Parkinson's disease

Genome-wide association studies (GWAS) have identified thousands of variants associated with disease phenotypes. However, the majority of these variants do not alter coding sequences, making it difficult to assign their function. To this end, we present a multi-omic epigenetic atlas of the adult human brain through profiling of the chromatin accessibility landscapes and three-dimensional chromatin interactions of seven brain regions across a cohort of 39 cognitively healthy individuals. Single-cell chromatin accessibility profiling of 70,631 cells from six of these brain regions identifies 24 distinct cell clusters and 359,022 cell type-specific regulatory elements, capturing the regulatory diversity of the adult brain. We develop a machine learning classifier to integrate this multi-omic framework and predict dozens of functional single nucleotide polymorphisms (SNPs), nominating gene and cellular targets for previously orphaned GWAS loci. These predictions both inform well-studied disease-relevant genes, such as BIN1 in microglia for Alzheimers disease (AD) and reveal novel gene-disease associations, such as STAB1 in microglia and MAL in oligodendrocytes for Parkinsons disease (PD). Moreover, we dissect the complex inverted haplotype of the MAPT (encoding tau) PD risk locus, identifying ectopic enhancer-gene contacts in neurons that increase MAPT expression and may mediate this disease association. This work greatly expands our understanding of inherited variation in AD and PD and provides a roadmap for the epigenomic dissection of noncoding regulatory variation in disease.

genomics↗

bioRxiv2019

Changing the Waddington landscape to control mesendoderm competence

As pluripotent human embryonic stem cells progress towards one germ layer fate, they lose the ability to adopt alternative fates. It is unknown how the cells competence for these alternative fates changes along their developmental trajectory or if this competence can be modulated. Here, we show that a differentiating stem cells probability of adopting a mesendodermal fate when given the appropriate signal falls sharply at a specific point along the ectodermal trajectory, and we further demonstrate that this point can be moved using genetic perturbations. Using a low-dimensional reaction coordinate to monitor progression towards ectoderm, we can determine the probability that individual cells at different points along this path can transition to the mesendodermal fate upon BMP4 and Activin A signal exposure. Knowing this probability allows us to prospectively isolate and profile differentiating cells based on their mesendoderm competence. Analysis and validation of these RNA-seq and ATAC-seq profiles identified transcription factors that can independently control the cells mesendoderm competence and its progression along the ectodermal developmental trajectory. In the classical picture of a Waddington landscape, these effects correspond to altering the barrier between fates and changing the cells location on the landscape, respectively. The ability of the underlying gene regulatory network to modulate these two aspects of the developmental landscape could allow separate control of the dynamics of differentiation and tissue size proportions.

developmental biology↗

bioRxiv2019

The complete mitochondrial genome of endangered Assam Roofed Turtle, Pangshura sylhetensis (Testudines: Geoemydidae): Genomic features and Phylogeny

Assam Roofed Turtle, Pangshura sylhetensis is an endangered and least studied species endemic to India and Bangladesh. The genomic feature of P. sylhetensis mitogenome is still anonymous to the scientific community. The present study decodes the first complete mitochondrial genome of P. sylhetensis (16,568 bp) by using next-generation sequencing. This de novo assembly encodes 13 Protein-coding genes (PCGs), 22 transfer RNAs (tRNAs), two ribosomal RNAs (rRNAs), and one control region (CR). Most of the genes were encoded on the majority strand, except NADH dehydrogenase subunit 6 (nad6) and eight tRNAs. Most of the PCGs were started with an ATG initiation codon, except for Cytochrome oxidase subunit 1 (cox1) and NADH dehydrogenase subunit 5 (nad5) with GTG. The study also found the typical cloverleaf secondary structure in most of the tRNA genes, except for serine (trnS1) with lack of conventional DHU arm and loop. Both, Bayesian and Maximum-likelihood topologies showed distinct clustering of all the Testudines species with their respective taxonomic ranks and congruent with the previous phylogenetic hypotheses (Pangshura and Batagur sister taxa). Nevertheless, the mitogenomic phylogeny with other amniotes corroborated the sister relationship of Testudines with Archosaurians (Birds and Crocodilians). Additionally, the mitochondrial Gene Order (GO) analysis indicated that, most of the Testudines species showed plesiomorphy with typical vertebrate GO.

genomics↗

bioRxiv2019

Down-regulated GDF9 and BMP15 mRNAs are the important determining factors for the unexplained female infertility cases advised for assisted reproductive technology

BackgroundIn India, the potential risk factors influencing female infertility are not well-characterized. Hence, this study was initially aimed to determine the multi-factor risk-predictive models for the infertile females from different Indian ethnics. Afterwards, when treatment was performed for correcting the abnormal demographic and clinical parameters obtained from our initial findings, some of the patients were observed to be treatment-non-responsive. This further recommended assessing the expression pattern of GDF9 and BMP15 mRNAs in those unexplained infertile females. MethodologyThis study included 470 Primary, 209 Secondary infertile and 419 age-matched Healthy females, where baseline demographic and clinicopathological factors were assessed. Additionally, from the treatment-non-responsive patients, laparoscopy and trans-vaginal ultrasound-guided collection of ovarian follicular fluid were done for studying the expression pattern of GDF9 and BMP15 mRNAs using q-PCR. Principal FindingsMid-education level, no contraception usage and duration of infertility for >2 years were the critical risk factors for female infertility (OR>>1; p<0.05), whereas elevated platelet count showed ~10-fold more risk of having secondary infertility and high ESR showed 3.33-fold increased threat of primary infertility. Besides, abnormal MCV, LH/FSH ratio, mild-anaemia and hypothyroidism were the best risk-predictive multi-factor model. After correcting these abnormal clinical factors, 6.8% of the patients were treatment-non-responsive, where elevated ESR, hypothyroidism and anaemia remained uncorrected. Interestingly, in those unexplained cases, GDF9 and BMP15 mRNAs were significantly down-regulated (2-4 fold) irrespective of age groups. Additionally, for predicting female infertility, the cut-off for the expression level of GDF9 and BMP15 mRNAs were estimated -2.09 and -2.75, respectively, with a relatively high sensitivity ([≥]62.5%) and specificity (75%). ConclusionsGDF9 and BMP15 mRNAs may be considered as molecular markers for predicting female infertility. Their down-regulation along with hypothyroidism and anaemia probably led to the treatment-non-responsiveness, thus, those patients may be advised to assisted reproductive technology with supplementation of exogenous GDF9 and/or BMP15.

epidemiology↗

bioRxiv2018

The first complete mitochondrial genome of marigold pest thrips, Neohydatothrips samayunkur (Sericothripinae) and comparative analysis

The complete mitogenomes in order Thysanoptera is limited to subfamily Thripinae heretofore. In the present study, we sequenced the first mitochondrial genome of Neohydatothrips samayunkur (15,295 bp), a member of subfamily Sericothripinae. The genome was characterized by 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), two ribosomal RNA genes (rRNAs) and three control regions (CRs). This mitogenome had two overlapping regions of 4 bp and twenty four intergenic spacers accounting for 165 bp. All the tRNA had typical cloverleaf secondary structures, except for trnV and trnS which lacked DHU stem and loop. The mitogenomes of N. samayunkur was highly rearranged with many unique features as compared to other thrips mitogenomes, atp6 and nad1 were terminated with TAG and TGA stop codons respectively; location of trnL2, trnA, trnC, and trnV was rearranged; and the first control region (CR1) was upstream of nad6. The phylogenetic analysis of 13 PCGs implementing maximum likelihood and Bayesian inference showed the clustering of N. samayunkur with Scirtothrips dorsalis supporting the Scirtothrips genus-group and Sericothripinae morphology based relationships. Generation of more mitogenomes from different hierarchical level in the order Thysanoptera is required to understand the gene rearrangements, phylogeny and evolutionary relationships.

genomics↗

bioRxiv2018

Sequencing and characterization of the complete mitochondrial genome of Critically Endangered Black Soft-shell Turtle (Nilssonia nigricans)

The complete mitochondrial genome (16796 bp) of an endangered freshwater turtle, Nilssonia nigricans was firstly sequenced and annotated. The mitogenome was encoded by 37 genes and a major non-coding Control Region (CR). The mitogenome was A+T biased (62.16%) and spread with six overlapping and 19 intergenic spacer regions. The initiation codons were exceptionally changed as ATA, ATT, and ATC in three Protein-coding genes (PCGs) and a single base (A, T, and C) incomplete termination codons in nine PCGs. The Relative synonymous codon usage (RSCU) value was consistent among all the studied species; exception with significant reduction of Serine (S) frequency in N. nigricans, N. formosa, and R. swinhoei. The secondary structure of N. nigricans showed a lack of conventional dihydrouridine (DHU) arm in trnS (GCT), as well as formed a small loop structure in the acceptor stem of both trnR (TCG) and trnH (GTG). The mitogenome of N. nigricans also revealed two unique tandem repeats (ATTAT)8, and (TATTA)20 in CR. Further, the average Ka/Ks values of 13 PCGs were indicating a strong natural selection in the studied Trionychidae species. The constructed Maximum Likelihood (ML) phylogeny by PCGs shows cohesive clustering of N. nigricans with N. formosa. The resulted phylogeny illustrated the similar topology by all studied species from different taxonomic ranks and supported the previous taxonomic classification. Moreover, further taxon sampling from different taxonomic hierarchy, and their mitogenomics study is vital to reconcile the Testudines phylogeny and assure their evolutionary relationship.

genomics↗

bioRxiv2018

The complete mitochondrial genome of Melon thrips, Thrips palmi (Thripinae) and comparative analysis: A vector for Tospoviruses

The melon thrips, Thrips palmi is a serious pest and vector for plant viruses on a wide range of economically important crops. DNA barcoding evidenced the presence of cryptic diversity in T. palmi and that warrants exhaustive molecular data. Our present study is on decoding the first complete mitochondrial genome of T. palmi (15,333 bp) through NGS technology. The mitogenome contains 37 genes, including 13 PCGs, two rRNAs, 22 tRNAs, and two control regions. The comparative analyses were conducted for gene arrangements, nucleotide composition, codon usage and phylogenetic relationship with other thrips mitogenomes. The nucleotide composition was 78.29% AT, and 21.72% GC with positive AT skewness (0.09) and negative GC skewness (-0.06). The ATN initiation codons were observed in 12 PCGs except cox1 with unique start codon (TTG). The RSCU analysis revealed Phe, Leu, Ile, Tyr, Asn, Lys and Met were the most frequently used amino acids in all PCGs. The codon CGG (Arg) was absent in T. palmi as compared to other thrips mitogenomes. The Ka/Ks ratio ranges from 0.078 in cox1 to 0.913 in atp8. We observed the typical cloverleaf secondary structure in most of the tRNA genes with a few exceptions; absence of DHU stem and loop in trnV and trnS, absence of DHU loop in trnE, lack of T-arm and loop in trnN. The position of trnS1 (between cox3 and CR2) is unique in T. palmi among all the studied thrips mitogenomes. The mitogenome contained 24 intergenic spacer regions and 12 overlapping regions. The CR2 is 63.77% similar to CR1, indicating a possible duplication and translocation in control region. Both the ML and BI phylogenetic trees revealed the close relationships of Thrips with Scirtothrips as compared to Frankliniella. Thus, more mitogenomes on the diverse thrips species is required to understand the in-depth phylogenetic and evolutionary relationships.

genomics↗

bioRxiv2017

Topology and cooperative stability: the two master regulators of protein half-life in the cell

In a quest for finding additional structural constraints, apart from disordered segments, regulating protein half-life in the cell (and during evolution), here we recognize and assess the influence of native topology of biological proteins and their sequestration into multimeric complexes. Native topology acts as a molecular marker of proteins mechanical resistance and consequently captures their half-life variations on genome-scale, irrespective of the enormous sequence, structural and functional diversity of the proteins. Cooperative stability (slower degradation upon sequestration into complexes) is a master regulator of oligomeric protein half-life that involves at least three mechanisms. (i) Association with multiple complexes results longer protein half-life; (ii) hierarchy of complex self-assembly involves short-living proteins binding late in the assembly order and (iii) binding with larger buried surface area leads to slower subunit dissociation and thereby longer half-life. Altered half-lives of paralog proteins refer to their structural divergence and oligomerization with non-identical set of complexes.

biophysics↗