Biology subjects

Mandal, A.

Publications and source records attributed to Mandal, A..

23 records · Page 2Linked to original sources

bioRxiv2021

Transmission of pre-XDR and XDR-TB in the Mumbai Metropolitan Region, India

Multidrug-resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis complex (MTBC) strains are a great challenge for tuberculosis (TB) control in India. Still, factors driving the MDR/XDR epidemic in India are not well defined. To address this, whole genome sequencing (WGS) data from 1 852 MTBC strains obtained from patients from a tertiary care hospital laboratory in Mumbai were used for phylogenetic strain classification, resistance prediction, and cluster analysis (12 allele distance threshold). Factors associated with pre-XDR/XDR-TB were defined by odds ratios and a multivariate logistic regression model. Overall, 1 017 MTBC strains were MDR, out of which 57.8 % (n=591) were pre-XDR, and 17.9 % (n=183) were XDR. Lineage 2 (L2) strains represented 41.7 % of the MDR, 77.2 % of the pre-XDR, and 86.3 % of the XDR strains, and were significantly associated with pre-XDR/XDR-TB (P < 0.001). Cluster rates were high among MDR (78 %) and pre-XDR/XDR (85 %) strains with three dominant L2 strain clusters (Cl 1-3) representing half of the pre-XDR and two thirds of the XDR-TB cases. Cl 1 strains accounted for 52.5 % of the XDR MTBC strains. Transmission could be confirmed by identical mutation patterns of particular pre-XDR/XDR strains. As a conclusion high rates of pre-XDR/XDR strains among MDR-TB patients require rapid changes in treatment and control strategies. Transmission of particular pre-XDR/XDR L2 strains is the main driver of the pre-XDR/XDR-TB epidemic. Accordingly, control of the epidemic in the region requires measures with stopping transmission especially of pre-XDR/XDR L2 strains.

molecular biology↗

bioRxiv2021

Molecular analysis of prostate cancer: prostate tissue and urine proteomics based approach

Benign prostatic hyperplasia (BPH) and prostate cancer are the most frequently diagnosed conditions in men above 60 years. BPH manifests as benign enlargement of the prostate gland causing pain and difficulty in micturition, often associated with other lower urinary tract symptoms. On the other hand, prostate cancer might initially set in as a tumor of no clinical significance, but can ultimately develop into an aggressively metastatic cancer at later stages. Due to overlapping symptomatic manifestations with BPH, it might be difficult to diagnose prostate cancer and differentiate it from BPH. Screening for prostate cancer is based on examining the levels of prostate specific antigen (PSA), a clinical biomarker for prostate cancer in blood. However, several reported cases indicate that PSA might lack the sensitivity and specificity required to differentiate between the cancerous and benign conditions of prostate. Therefore, in the absence of non-invasive biomarkers in a diagnostic setup, an intensely invasive surgical removal of a part of the tissue and subsequent histopathologial examination is the only available procedure to confirm the cancer. In this study, we used tissue and urine proteomics platforms to profile respective proteomes in both clinical conditions. We observed that latent transforming growth factor binding protein was significantly under-expressed in the both tissue and urine proteome of prostate cancer. We propose that the down-regulation of the latent transforming growth factor binding protein 4 might be explored in a large set of patients with prostate cancer to develop a non-invasive urine based biomarker for the diagnosis of prostate cancer.

cancer biology↗

bioRxiv2020

Differential expression of proteins in human prostate cancer tissues probed by MALDI imaging mass spectrometry

Histopathology, the gold-standard method for diagnosis of human prostate cancer, is based on the analysis of changes in cellular morphology and tissue architecture in chemically stained tissue sections. Even at the very early stages of cancer with minimal phenotypic changes in cellular morphologies, there might be detectable changes in the expression profiles of proteins. Over the last decade, imaging mass spectrometry has been used to explore the spatial distribution and expression profiles of several molecules with their twodimensional heterogeneity retained across the tissue section. In the present study, using MALDI mass spectrometry based tissue imaging, we report the differential expression of three proteins, vinculin, ribonuclease T2 and 60 kDa heat shock protein across human prostate tissue sections in regions pathologically demarcated as frankly malignant. In an independent analysis, quantitative proteomics revealed that in cancerous prostate tissues, ribonuclease T2 and 60 kDa heat shock protein were significantly overexpressed by 22.26- and 6 folds respectively compared to benign condition. Our results show the utility of this approach to probe differential protein expression in architecturally intact cancer tissues. In addition, we propose that ribonuclease T2 and 60 kDa heat shock protein might be developed as diagnostic biomarkers for prostate cancer in future.

biophysics↗

bioRxiv2019

Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control.

Serum urate is the end-product of purine metabolism. Elevated serum urate is causal of gout and a predictor of renal disease, cardiovascular disease and other metabolic conditions. Genome-wide association studies (GWAS) have reported dozens of loci associated with serum urate control, however there has been little progress in understanding the molecular basis of the associated loci. Here we employed trans-ancestral meta-analysis using data from European and East Asian populations to identify ten new loci for serum urate levels. Genome-wide colocalization with cis-expression quantitative trait loci (eQTL) identified a further five new loci. By cis- and trans-eQTL colocalization analysis we identified 24 and 20 genes respectively where the causal eQTL variant has a high likelihood that it is shared with the serum urate-associated locus. One new locus identified was SLC22A9 that encodes organic anion transporter 7 (OAT7). We demonstrate that OAT7 is a very weak urate-butyrate exchanger. Newly implicated genes identified in the eQTL analysis include those encoding proteins that make up the dystrophin complex, a scaffold for signaling proteins and transporters at the cell membrane; MLXIP that, with the previously identified MLXIPL, is a transcription factor that may regulate serum urate via the pentose-phosphate pathway; and MRPS7 and IDH2 that encode proteins necessary for mitochondrial function. Trans-ancestral functional fine-mapping identified six loci (RREB1, INHBC, HLF, UBE2Q2, SFMBT1, HNF4G) with colocalized eQTL that contained putative causal SNPs (posterior probability of causality > 0.8). This systematic analysis of serum urate GWAS loci has identified candidate causal genes at 19 loci and a network of previously unidentified genes likely involved in control of serum urate levels, further illuminating the molecular mechanisms of urate control.\n\nAuthor SummaryHigh serum urate is a prerequisite for gout and a risk factor for metabolic disease. Previous GWAS have identified numerous loci that are associated with serum urate control, however, only a small handful of these loci have known molecular consequences. The majority of loci are within the non-coding regions of the genome and therefore it is difficult to ascertain how these variants might influence serum urate levels without tangible links to gene expression and / or protein function. We have applied a novel bioinformatic pipeline where we combined population-specific GWAS data with gene expression and genome connectivity information to identify putative causal genes for serum urate associated loci. Overall, we identified 15 novel serum urate loci and show that these loci along with previously identified loci are linked to the expression of 44 genes. We show that some of the variants within these loci have strong predicted regulatory function which can be further tested in functional analyses. This study expands on previous GWAS by identifying further loci implicated in serum urate control and new causal mechanisms supported by gene expression changes.

genetics↗

bioRxiv2019

Retrograde mitochondrial transport is essential for mitochondrial homeostasis in neurons

Mitochondrial transport in neurons is essential for forming and maintaining axonal projections. While much is known about anterograde mitochondrial movement, the function of retrograde mitochondrial motility in neurons was unknown. We investigated the dynamics and utility of retrograde mitochondrial transport. Using long-term tracking of mitochondria in vivo, we found mitochondria in axon terminals turnover within hours via retrograde transport. Mitochondria do not return to the cell body solely for degradation; rather, mitochondria use bidirectional transport to redistribute themselves throughout the neuron. Disruption of retrograde mitochondrial transport severely depletes the cell body of mitochondria and impacts mitochondrial health throughout the cell. Altered mitochondrial health correlates with decreased synaptic activity. Using proteomics, we provide evidence that retrograde mitochondrial movement functions to maintain the organelles proteome. Together, our work demonstrates that mitochondrial retrograde transport is essential for the maintenance of a homeostatic population of mitochondria in neurons and consequently effective synaptic activity through promoting mitochondrial protein turnover.

neuroscience↗