Biology subjects

Karmakar, M.

Publications and source records attributed to Karmakar, M..

6 recordsLinked to original sources

bioRxiv2025

Conservation of non-consensus nucleotides in transcription factor binding sites

Transcription factors (TFs) affect gene expression by binding to their sites (TFBSs) in the genome. As regulation of transcription is essential for the optimization of metabolism, evolution of TFBSs is thought to be restricted by the TF binding preferences. This means that nucleotides important for binding (consensus nucleotides, CNs) experience the pressure of negative selection and, therefore, are highly conserved. However, for some regulated genes, the strongest possible repression or activation may not necessarily be optimal (i.e. provide the highest fitness). Here, we show that, along with CNs, nucleotides causing relatively weaker binding (non-consensus nucleotides, NCNs) are sometimes preserved by negative selection. We then consider several possible reasons for the conservation of NCNs and demonstrate that NCNs depend epistatically on other loci of the same TFBS for a substantial fraction of TFBSs.

bioinformatics↗

bioRxiv2024

Targeting the menopause transition with metformin improves breast cancer outcomes, but discontinuation has deleterious effects on metabolic health: Findings from a preclinical model of postmenopausal breast cancer.

BackgroundWomen with obesity and/or type-II-diabetes have an increased breast cancer risk, increased metastasis, and poorer prognosis, especially after menopause. In a rat model of high-fat-diet and menopause-induced weight gain, we previously reported that treatment with the anti-diabetic drug metformin for 8-weeks after ovariectomy (OVX; modeling menopause) reduced growth of existing mammary tumors and inhibited new tumor formation. This identified the menopause transition as a potential window-of-opportunity for interventions to decrease obesity-associated breast cancer incidence and disease progression. Here, we extend these findings to determine if limiting metformin to the peak window of OVX-induced weight gain would have similar anti-cancer effects. FindingsMetformin during the first four weeks following OVX is critical to reducing tumor burden, as rats treated with metformin early (weeks0-4-postOVX) had reduced tumor burden. Conversely, initiating metformin later in the postOVX period (weeks 4-8postOVX) did not reduce cancer burden. Despite improved tumor outcomes, metformin withdrawal after the early postOVX time had detrimental metabolic effects, including weight gain and increased adiposity, insulin, IGF1, and HOMA-IR, which correlate with increased cancer risk. ConclusionsThese data reveal early-postmenopause as a critical window when metformin decreases progression of existing disease and highlights the importance of maintaining treatment to prevent metabolic dysregulation, which could promote secondary tumors/metastasis. These findings also help explain the disconnect between epidemiological studies reporting anticancer benefits of metformin and more recent clinical trials that failed to see similar efficacy, potentially due to issues of timing and/or inclusion of women outside the early postmenopausal window and/or without underlying metabolic dysfunction.

cancer biology↗

bioRxiv2024

Concepts and methods for predicting viral evolution

The seasonal human influenza virus undergoes rapid evolution, leading to significant changes in circulating viral strains from year to year. These changes are typically driven by adaptive mutations, particularly in the antigenic epitopes, the regions of the viral surface protein haemagglutinin targeted by human antibodies. Here we describe a consistent set of methods for data-driven predictive analysis of viral evolution. Our pipeline integrates four types of data: (1) sequence data of viral isolates collected on a worldwide scale, (2) epidemiological data on incidences, (3) antigenic characterization of circulating viruses, and (4) intrinsic viral phenotypes. From the combined analysis of these data, we obtain estimates of relative fitness for circulating strains and predictions of clade frequencies for periods of up to one year. Furthermore, we obtain comparative estimates of protection against future viral populations for candidate vaccine strains, providing a basis for pre-emptive vaccine strain selection. Continuously updated predictions obtained from the prediction pipeline for influenza and SARS-CoV-2 are available on the website previr.app.

biophysics↗

bioRxiv2021

HGDiscovery: an online tool providing functional and phenotypic information on novel variants of homogentisate 1,2- dioxigenase

Alkaptonuria (AKU), a rare genetic disorder, is characterized by the accumulation of homogentisic acid (HGA) in the body. Affected individuals lack enough functional levels of an enzyme required to breakdown HGA. Mutations in the HGD gene cause AKU and they are responsible for deficient levels of functional homogentisate 1,2-dioxygenase (HGD), which, in turn, leads to excess levels of HGA. Although HGA is rapidly cleared from the body by the kidneys, in the long term it starts accumulating in various tissues, especially cartilage. Over time (rarely before adulthood), it eventually changes the color of affected tissue to slate blue or black. Here we report a comprehensive mutation analysis of 111 pathogenic and 190 non-pathogenic HGD missense mutations using protein structural information. Using our comprehensive suite of graph-based signature methods, mCSM complemented with sequence-based tools, we studied the functional and molecular consequences of each mutation on protein stability, interaction and evolutionary conservation. The scores generated from the structure and sequence-based tools were used to train a supervised machine learning algorithm with 84% accuracy. The empirical classifier was used to generate the variant phenotype for novel HGD missense mutations. All this information is deployed as a user friendly freely available web server called HGDiscovery (http://biosig.unimelb.edu.au/hgdiscovery/).

bioinformatics↗

bioRxiv2021

Modelling tuberculosis drug resistance amplification rates in high-burden settings

BackgroundAntimicrobial resistance develops following the accrual of mutations in the bacterial genome, and may variably impact organism fitness and hence, transmission risk. Classical representation of tuberculosis (TB) dynamics using a single or two strain (DS/MDR-TB) model typically does not capture elements of this important aspect of TB epidemiology. To understand and estimate the likelihood of resistance spreading in high drug-resistant TB incidence settings, we used molecular understanding to develop a compartmental epidemiological model of Mycobacterium tuberculosis (Mtb) transmission. MethodsA four-strain (drug-susceptible (DS), isoniazid mono-resistant (INH-R), rifampicin mono-resistant (RIF-R) and multidrug-resistant (MDR)) compartmental deterministic Mtb transmission model was developed to explore the progression from DS-to MDR-TB. The model incorporated strain-specific fitness costs and was calibrated using data from national tuberculosis prevalence surveys and drug resistance surveys from Philippines and Viet Nam. Using an adaptive Metropolis algorithm, we estimated drug resistance amplification and transmission rates. ResultsThe posterior estimates for the proportion of isoniazid mono-resistant amplification among treatment failure was 0.75 (0.64 - 0.85) for Philippines and 0.55 (0.39 - 0.63) for Viet Nam. The proportion of rifampicin mono-resistant amplification among treatment failure was 0.05 (0.04 - 0.06) for Philippines and 0.011 (0.010 - 0.012) for Viet Nam. In Philippines, the estimated proportion of primary resistance resulting from transmission was 56% (42 - 68) for INH-R, 48% (34 - 62) for RIF-R and 42% (34 - 50) for MDR-TB. For Viet Nam, the estimated proportion of drug resistance due to transmission was 79% (70 - 86) for INH-R, 68% (58 - 75) for RIF-R and 50% (45 - 53) for MDR-TB. DiscussionRIF-R strains were more likely to be transmitted than acquired through amplification, while both mechanisms of acquisition were important contributors in the case of INH-R. These findings highlight the complexity of drug resistance dynamics in high-incidence settings, and emphasize the importance of prioritizing testing algorithms which also allow for early detection of INH-R.

microbiology↗

bioRxiv2019

Enhanced biodegradation of naphthalene by Pseudomonas sp. consortium immobilized in calcium alginate beads

Polycyclic aromatic hydrocarbons (PAHs) belong to a large group of organic pollutant which considers as a potential health hazard to living beings. Herein, naphthalene biodegradation potential by free and immobilized Pseudomonas putida strain KD10 and Pseudomonas sp. consortium were studied. Additionally, naphthalene 1, 2-dioxygenase (nahAc) was sequenced and analyzed, which reveals two altered amino acid residues. However, the altered amino acid residues are not present in the vicinity of the active site. The gas-phase binding free energy ({Delta}GLondon) of the mutant variant of naphthalene 1, 2-dioxygenase was -7.10 kcal mol-1 which closely resembles the wild type variant. Naphthalene biodegradation rate by Pseudomonas putida strain KD10 was 79.12 mg L-1 day-1 and it was significantly elevated up to 123 mg L-1 day-1 by the immobilized Pseudomonas sp. consortium. The half-life (t1/2) for naphthalene biodegradation was 3.1 days with the inhibition constant (ki), substrate saturation constant (ks) and maximum specific degradation rate constant (qmax) of 1268 mg L-1, 395.5 mg L-1 and 0.65 h-1, respectively, for the Pseudomonas putida strain KD10. However, the t1/2 value was significantly reduced to 2 days along with ki, ks and qmaxvalues of 1475 mg L-1, 298.8 mg L-1 and 0.71 h-1, respectively, by the immobilized Pseudomonas sp. consortium. The GC-MS data suggest that KD10 might follow D-gluconic acid mediated meta-cleavage pathway of catechol biodegradation. It is concluded that naphthalene biodegradation performance by immobilized Pseudomonas sp. consortium was superior to free or immobilized Pseudomonas putida KD10. Microbial consortium immobilization could be a useful tool for water quality management and environmental remediation.\n\nHighlightsO_LISuperior naphthalene biodegradation by Pseudomonas sp. consortium immobilized in calcium alginate beads.\nC_LIO_LIA common mutation prone amino acid stretch inside chain A of naphthalene 1, 2-dioxygenase has been identified.\nC_LIO_LIA new naphthalene biodegradation pathway by Pseudomonas putida strain KD10 has been proposed.\nC_LI

microbiology↗