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Amin, M. A.

Publications and source records attributed to Amin, M. A..

7 recordsLinked to original sources
bioRxiv2024

Limited O-specific polysaccharide (OSP)-specific functional antibody responses in young children with Shigella infection in Bangladesh

Shigellosis is the second leading cause of diarrheal death in children younger than five years of age globally. At present, there is no broadly licensed vaccine against shigella infection. Previous vaccine candidates have failed at providing protection for young children in endemic settings. Improved understanding of correlates of protection against Shigella infection and severe shigellosis in young children living in endemic settings is needed. Here, we applied a functional antibody profiling approach to define Shigella-specific antibody responses in young children versus older individuals with culture-confirmed shigellosis in Bangladesh, a Shigella endemic area. We analyzed Shigella-specific antibody isotypes, FcR binding and antibody-mediated innate immune cell activation in longitudinal serum samples collected at clinical presentation and up to 1 year later. We found that higher initial Shigella O-specific polysaccharide (OSP)-specific and protein-specific IgG and Fc{gamma}R binding levels correlated with less severe disease regardless of patient age, but that individuals under 5 years of age developed a less prominent class switched, FcR-binding, functional and durable antibody response against both OSP and protein Shigella antigens than older individuals. Focusing on the largest cohort, we found that functional S. flexneri 2a OSP-specific responses were significantly induced only in individuals over age 5 years, and that these responses promoted monocyte phagocytosis and activation. Our findings suggest that in a Shigella endemic region, young children with shigellosis harbor a functional antibody response that fails to maximally activate monocytes; such a response may be important in facilitating subsequent innate cell clearance of Shigella, especially via recruitment and activation of polymorphonuclear cells capable of directly killing Shigella.

immunology↗
bioRxiv2022

The Ndc80 complex is essential for the initial kinetochore-microtubule capture during early mitosis

Mitotic kinetochores are initially captured by dynamic microtubules via a search-and-capture mechanism. The microtubule motor, dynein, is critical for kinetochore capture as it has been shown to transport microtubule-attached chromosomes towards the spindle pole during early mitosis. In metaphase, the kinetochore localized, microtubule-binding complex, Ndc80, plays a central role in stabilizing kinetochore-microtubule (kMT) attachments. It is not yet clear, however, if Ndc80, which is recruited to kinetochores very early during mitosis contributes to initial kMT capture. Here, by combining CRISPR/Cas9-mediated knockout and RNAi technology with assays specifically targeted to study kMT capture, we show that mitotic cells lacking Ndc80 exhibit severe defects in this function during prometaphase. Rescue experiments show that Ndc80 mutants deficient in microtubule-binding are unable to execute proper kMT capture. While cells inhibited of dynein alone are predominantly able to make initial kMT attachments, cells co-depleted of Ndc80 and dynein show severe defects in kMT capture. Further, we demonstrate a novel physical interaction between Ndc80 and dynein during prometaphase. Thus, our studies, for the first time, identify a distinct event in the formation of initial kMT attachments, which is directly mediated by Ndc80 followed by a coordinated function with dynein, both of which are required for efficient kMT capture and proper chromosome alignment.

cell biology↗
bioRxiv2020

Inhibition of histone readers bromodomain extra-terminal proteins alleviates scleroderma fibrosis

Binding of the bromodomain and extra-terminal domain proteins (BETs) to acetylated histone residues is critical for gene transcription. This study sought to determine the anti-fibrotic efficacy and potential mechanisms of BET inhibition in systemic sclerosis (SSc). Blockade of BETs was done using a pan BET inhibitor JQ1, BRD2 inhibitor BIC1, or BRD4 inhibitors AZD5153 or ARV825. BET inhibition, specifically BRD4 blockade, showed anti-fibrotic effects in an animal model of scleroderma and in patient-derived diffuse cutaneous (dc)SSc fibroblasts. Transcriptome analysis of JQ1-treated dcSSc fibroblasts revealed differentially expressed genes related to extracellular matrix, cell cycle, and calcium signaling. The anti-fibrotic effect of BRD4 inhibition was at least in part mediated by downregulation of Ca2+/calmodulin-dependent protein kinase II (CaMKII-) and reduction of intracellular calcium concentrations. These results suggest that targeting calcium pathways or BRD4 might be novel therapeutic approaches for progressive tissue fibrosis.

pharmacology and toxicology↗
bioRxiv2019

Cost implications of a nationwide survey of schistosomiasis and other intestinal helminthiases in Sudan

BackgroundIt is vital to share details of concrete experiences of conducting a nationwide survey, so that the global health community could adapt it to expand geographic mapping programs, eventually contributing to the development of control and elimination strategies with limited resources. A nationwide survey of schistosomiasis and nine other intestinal helminthiases was conducted from December 2016 to March 2017 in Sudan. ObjectivesWe aimed to describe details of the key activities and components required for the nationwide survey of schistosomiasis and other intestinal helminthiases and to analyze its costs. MethodsWe estimated financial and economic costs from the providers perspective. Cash expenditures incurred to implement the survey were defined as financial costs. We took into account all of the resources invested in the survey for economic costs, including the components that were not paid for, such as vehicles and survey equipment provided by the Ministry of Health, Sudan and the opportunity costs of primary school teachers time spent on the survey. We ran one-way sensitivity and probabilistic analyses using Monte-Carlo methods with 10,000 draws to examine the robustness of the primary analysis results. ResultsA total of USD 1,465,902 and USD 1,516,238 was incurred for the financial and economic costs, respectively. The key cost drivers of the nationwide survey were personnel and transportation, for both financial and economic costs. Personnel and transportation accounted for around 64% and 18% of financial costs, respectively. ConclusionsThe cost is expected to vary depending on the quantity and quality of existing laboratory facilities, equipment, and consumables, and the capability of laboratory technicians and sample collectors. Establishing central-level and independent supervision mechanisms to ensure the quality of the survey is equally important. We expect the global health community to draw on this study when developing nationwide surveys of schistosomiasis and other intestinal helminthiases. Author SummaryAlthough large-scale mapping of schistosomiasis and other intestinal helminthiases has been conducted in some countries, little is known about the details of nationwide surveys, such as the necessary scale of the workforce, logistics, and the cost of conducting a nationwide survey. A nationwide survey of schistosomiasis and nine other intestinal helminthiases was conducted from December 2016 to March 2017 in Sudan. A total of 105,167 students participated in the survey from 1,772 primary schools in 183 districts of all 18 states of Sudan. Herein, we present the activities that were necessary to prepare and conduct a nationwide neglected tropical disease survey, along with details on the types and amounts of personnel, survey equipment, and consumables that are required. In addition, through an analysis of the costs of the nationwide survey, we generated average costs at the district and sub-district level. The key cost drivers were personnel and transportation, both of which were recurrent costs. Establishing a steering committee to develop and reach consensus on a survey protocol, assessing the capacities of potential staff (particularly laboratory technicians), and training laboratory technicians and data collectors were key components required to prepare a nationwide survey. If a government finds a way to mobilize existing government officials with no additional payment using the health system already in place, the cost of a nationwide survey would be remarkably lower. We expect the global health community to draw on this study to develop nationwide surveys for schistosomiasis and other intestinal helminthiases.

microbiology↗
bioRxiv2019

First Complete Genome Sequence of the Novel Lineage G-IX (BD-18) of FMDV Serotype Asia1

Foot-and-Mouth Disease (FMD) has been a major threat to livestock worldwide, and is caused by FMD Virus (FMDV) existing as seven serotypes (A, O, C, Asia1 and SAT 1-3), each having variability into topotypes, genetic lineages, sublineages, and strains. Three serotypes are circulating in Indian subcontinent with the widespread distribution of serotype O, whereas serotype A and Asia1 are restricted to certain geographical regions. During 2017-2018, the Sindh-08 lineages of Asia1 serotype was reported from Pakistan, however, in 2018, a novel circulatory foot-and-mouth disease virus serotype Asia1 BD-18 (G-IX) lineage containing a unique mutation has emerged in Bangladesh. The first complete genome of the Asia1/ASIA/G-IX novel lineage strain, isolated from Bangladesh, is reported here. Amino acid substitutions at critical antigenic sites of capsid were identified compared to genome of existing vaccine strain (IND/63/72), and contemporary FMDV serotype A isolate of Bangladesh.

molecular biology↗
bioRxiv2018

Antagonism between the dynein and Ndc80 complexes at kinetochores controls the stability of kinetochore-microtubule attachments during mitosis

Chromosome alignment and segregation during mitosis depends critically on kinetochoremicrotubule (kMT) attachments that are mediated by the function of the molecular motor cytoplasmic dynein, and the kinetochore microtubule (MT) binding complex, Ndc80. The RZZ (Rod-ZW10-Zwilch) complex is central to this coordination as it has an important role in dynein recruitment and has recently been reported to have a key function in the regulation of stable kMT attachment formation in C. elegans. However, the mechanism by which kMT attachments are controlled by the coordinated function of these protein complexes to drive chromosome motility during early mitosis is still unclear. In this manuscript, we provide evidence to show that Ndc80 and dynein directly antagonize each others MT-binding. We also find that severe chromosome alignment defects induced by depletion of dynein, or the dynein adapter spindly, are rescued by codepletion of the RZZ component, Rod, in human cells. Interestingly, the rescue of chromosome alignments defects was independent of Rod function in activation of the spindle assembly checkpoint and was accompanied by a remarkable restoration of stable kMT attachments. Furthermore, rescue of chromosome alignment was critically dependent on the plus-end-directed motility of CENP-E, as cells codepleted of CENP-E along with Rod and dynein were unable to establish stable kMT attachments or align their chromosomes properly. Taken together, our findings support the idea that the dynein motor may control the function of the Ndc80 complex in stabilizing kMT attachments either directly by interfering with Ndc80-MT binding, and/or indirectly by modulating the Rod-mediated inhibition of Ndc80.

cell biology↗