Biology subjects

Alam, M. S.

Publications and source records attributed to Alam, M. S..

26 records · Page 2Linked to original sources

bioRxiv2022

A high-quality chromosome-level genome assembly of rohu carp, Labeo rohita, and its utilization in SNP-based exploration of gene flow and sex determination

Labeo rohita (rohu) is a carp important to aquaculture in South Asia, with a production volume close to Atlantic salmon. While genetic improvements to rohu are ongoing, the genomic methods commonly used in other aquaculture improvement programs have historically been precluded in rohu, partially due to the lack of a high quality reference genome. Here we present a high-quality de novo genome produced using a combination of next-generation sequencing technologies, resulting in a 946 Mb genome consisting of 25 chromosomes and 2,844 unplaced scaffolds. Notably, while approximately half the size of the existing genome sequence, our genome represents 97.9% of the genome size newly estimated here using flow cytometry. Sequencing from 120 individuals was used in conjunction with this genome to predict the population structure, diversity, and divergence in three major rivers (Jamuna, Padma, and Halda), in addition to infer a likely sex determination mechanism in rohu. These results demonstrate the utility of the new rohu genome in modernizing some aspects of rohu genetic improvement programs.

genomics↗

bioRxiv2022

A new demethylase gene OsDML4 involved in high temperature induced floury endosperm formation in rice

High temperature (HT) can affect the accumulation of seed storage materials and cause adverse effects on the yield and quality in rice. DNA methylation plays an important role in plant growth and development. However, the temperature and DNA methylation interaction on rice seed development has not been studied yet. Here, we identified a new demethylase gene OsDML4 and discovered its function on cytosine demethylation to affect the endosperm formation during the grain filling. Knockout of OsDML4 induced floury endosperm only under HT, which resulted from dramatically reduced the transcription and accumulation of glutelins and 16-kDa prolamin. The expression of two important transcription factors RISBZ1 and RPBF was significantly declined in the osdml4 mutants. The absence of OsDML4 also caused adverse effects on the formation of protein bodies (PBs), the number of PB-II was greatly decreased and incomplete PB-II with empty space and abnormally shaped PB-II were observed in the osdml4 mutants. Whole-genome bisulfite sequencing analysis of seeds at 15 days after pollination revealed much higher global methylation levels of CG, CHG and CHH contexts in the osdml4 mutants compared to wild type (WT). Moreover, the methylation status of RISBZ1 promoter was hypermethylated but RPBF promoter was nearly unchanged. No significant difference was detected between WT and the osdml4 mutants under room temperature. In conclusion, our study demonstrates a novel OsDML4-mediated epigenetic regulatory mechanism involving in the formation of floury endosperm, which will provide a new perspective in regulating endosperm development and the accumulation of SSPs in rice.

plant biology↗

bioRxiv2021

Sterilizing Effects of Novel Regimens Containing TB47, Clofazimine and Linezolid in a Murine Model of Tuberculosis.

Toxicity and inconvenience associated with the use of injectable drug-containing regimens for tuberculosis (TB) have made all-oral regimens a preferred alternative. Widespread resistance to fluoroquinolones and pyrazinamide makes it essential to identify new drug candidates and study their effects on current regimens for TB. TB47 is a pyrazolo[1,5-a]pyridine-3-carboxamide with powerful synergistic in vitro and in vivo activities against mycobacteria, especially with clofazimine. Here, we investigated the bactericidal and sterilizing activities of novel oral regimens containing TB47 + clofazimine + linezolid, and the potential roles of levofloxacin and/or pyrazinamide in such drug combinations. Using a well-established mouse model, we assessed the effect of these regimens on bacterial burden in the lung during treatment and relapse (4 months after stopping treatment + immunosuppression). Our findings indicate that the TB47 + clofazimine + linezolid + pyrazinamide, with/without levofloxacin, regimens had fast-acting (4 months) sterilizing activity and no relapse was observed. When pyrazinamide was excluded from the regimen, treatment times were longer (5-6 months) to achieve sterilizing conditions. We propose that TB47 + clofazimine + linezolid can form a highly sterilizing block for use as an alternative pan-TB regimen.

microbiology↗

bioRxiv2020

Insecticide resistance status of Aedes aegypti in Bangladesh

BackgroundArboviral diseases including dengue and chikungunya are major public health concern in Bangladesh, with unprecedented levels of transmission reported in recent years. The primary approach to control these diseases is control of Aedes aegypti using pyrethroid insecticides. Although chemical control is long-practiced, no comprehensive analysis of Ae. aegypti susceptibility to insecticides has previously been conducted. This study aimed to determine the insecticide resistance status of Ae. aegypti in Bangladesh and investigate the role of detoxification enzymes and altered target site sensitivity as resistance mechanisms. MethodsAedes eggs were collected using ovitraps from five districts across the country and in eight neighborhoods of the capital city Dhaka from August to November 2017. CDC bottle bioassays were conducted for permethrin, deltamethrin, malathion, and bendiocarb using 3-5-day old F0-F2 non-blood fed female mosquitoes. Biochemical assays were conducted to detect metabolic resistance mechanisms and real-time PCR was performed to determine the frequencies of the knockdown resistance (kdr) mutations Gly1016, Cys1534, and Leu410. ResultsHigh levels of resistance to permethrin were detected in all Ae. aegypti populations, with mortality ranging from 0 - 14.8% at the diagnostic dose. Substantial resistance continued to be detected against higher (2X) doses of permethrin (5.1 - 44.4% mortality). Susceptibility to deltamethrin and malathion varied between populations while complete susceptibility to bendiocarb was observed in all populations. Significantly higher levels of esterase and oxidase activity were detected in most of the test populations as compared to the susceptible reference Rockefeller strain. A significant association was detected between permethrin resistance and the presence of Gly1016 and Cys1534 homozygotes. The frequency of kdr alleles varied across the Dhaka populations, and Leu410 was not detected in any of the tested populations. ConclusionsThe detection of widespread pyrethroid resistance and multiple mechanisms highlights the urgency for implementing alternate Ae. aegypti control strategies. In addition, implementing routine monitoring of insecticide resistance in Ae. aegypti in Bangladesh will lead to a greater understanding of susceptibility trends over space and time, thereby enabling the development of improved control strategies.

microbiology↗

bioRxiv2020

Genomic analyses of glycine decarboxylase neurogenic mutations yield a large scale prediction model for prenatal disease.

Glycine decarboxylase (GLDC) is a mitochondrial protein, hundreds of mutations in which cause a neurometabolic disorder Non-ketotic Hyperglycinemia (NKH), associated with elevation of plasma glycine. But why a mutation induces severe or attenuated neurological disease is poorly understood. We combined a human multiparametric mutation scale that separates severe from attenuated clinical, neurological disease, with new in silico tools to assess 238 of 255 NKH mutations in murine GLDC. We unified novel murine and human genome level-analyses across a linear scale of neurological severity, with in vivo evidence from mice engineered with a top-ranking attenuated mutation and another mutation >10 times more pathogenic and integrated the data in a model of pre- and post-natal disease outcomes, relevant for over a hundred major and minor neurogenic mutations. Our findings suggest that highly severe neurogenic mutations predict fatal, prenatal disease that can be remedied by metabolic supplementation of dams, in absence of amelioration of persistent and age-dependent elevation of plasma glycine.

bioinformatics↗

bioRxiv2019

Large scale analyses of genotype-phenotype relationships of glycine decarboxylase mutations and neurological disease severity.

Monogenetic diseases provide unique opportunity for studying complex, clinical states that underlie neurological severity. Loss of glycine decarboxylase (GLDC) can severely impact neurological development as seen in non-ketotic hyperglycinemia (NKH). NKH is a neuro-metabolic disorder lacking quantitative predictors of disease states. It is characterized by elevation of glycine, seizures and failure to thrive, but glycine reduction often fails to confer neurological benefit, suggesting need for alternate tools to distinguish severe from attenuated disease. A major challenge has been that there are 255 unique disease-causing missense mutations in GLDC, of which 206 remain entirely uncharacterized. Here we report a Multiparametric Mutation Score (MMS) developed by combining in silico predictions of stability, evolutionary conservation and protein interaction models and suitable to assess 251 of 255 mutations. In addition, we created a quantitative scale of clinical disease severity comprising of four major disease domains (seizure, cognitive failure, muscular and motor control and brain-malformation) to comprehensively score patient symptoms identified in 131 clinical reports published over the last 15 years. The resulting patient Clinical Outcomes Scores (COS) were used to optimize the MMS for biological and clinical relevance and yield a patient Weighted Multiparametric Mutation Score (WMMS) that separates severe from attenuated neurological disease (p < 3.5e-5). Our study provides understanding for developing quantitative tools to predict clinical severity of neurological disease and a clinical scale that advances monitoring disease progression needed to evaluate new treatments for NKH.

bioinformatics↗

bioRxiv2019

A molecular barcode and online tool to identify and map imported infection with Plasmodium vivax

Imported cases present a considerable challenge to the elimination of malaria. Traditionally, patient travel history has been used to identify imported cases, but the long-latency liver stages confound this approach in Plasmodium vivax. Molecular tools to identify and map imported cases offer a more robust approach, that can be combined with drug resistance and other surveillance markers in high-throughput, population-based genotyping frameworks. Using a machine learning approach incorporating hierarchical FST (HFST) and decision tree (DT) analysis applied to 831 P. vivax genomes from 20 countries, we identified a 28-Single Nucleotide Polymorphism (SNP) barcode with high capacity to predict the country of origin. The Matthews correlation coefficient (MCC), which provides a measure of the quality of the classifications, ranging from -1 (total disagreement) to 1 (perfect prediction), exceeded 0.9 in 15 countries in cross-validation evaluations. When combined with an existing 37-SNP P. vivax barcode, the 65-SNP panel exhibits MCC scores exceeding 0.9 in 17 countries with up to 30% missing data. As a secondary objective, several genes were identified with moderate MCC scores (median MCC range from 0.54-0.68), amenable as markers for rapid testing using low-throughput genotyping approaches. A likelihood-based classifier framework was established, that supports analysis of missing data and polyclonal infections. To facilitate investigator-lead analyses, the likelihood framework is provided as a web-based, open-access platform (vivaxGEN-geo) to support the analysis and interpretation of data produced either at the 28-SNP core or full 65-SNP barcode. These tools can be used by malaria control programs to identify the main reservoirs of infection so that resources can be focused to where they are needed most.

molecular biology↗

bioRxiv2017

Tolerance of chronic HDACi-administration used for treatment of neurological and visceral disease including lung pathogenesis.

Histone deacetylase (HDAC) inhibitors are of significant interest as drugs. However, their use in neurological disorders has raised concern because HDACs are required for brain function. We have previously shown that a triple combination formulation (TCF) of the pan HDACi vorinostat (Vo) improves pharmacokinetic exposure and entry of Vo into the brain. TCF treatment significantly delayed both neurodegeneration and death in the Npc1nmf164 murine model of Niemann Pick Type C (NPC) disease. The TCF induces no metabolic toxicity, but its risk to normal brain functions and potential utility in treating lung disease, a major NPC clinical complication, remain unknown. Here we report that TCF administered for 8-10 months was not detrimental to brain or neuromuscular functions of healthy mice, based on quantitative analyses of major Purkinje neurons in the cerebellum, inflammation in the hippocampus and symptoms of progressive neurocognitive/muscular disease. The TCF was also not injurious to lung tissue but rather improved delivery of Vo to lungs and reduced accumulation of foamy macrophages in Npc1nmf164 mice. Together these data support feasibility of tolerable, chronic administration of an HDACi formulation to treat brain and systemic disease including lung pathology, a frequent cause of death in NPC and possibly other neurological diseases.

neuroscience↗