Biology subjects

Islam, M. J.

Publications and source records attributed to Islam, M. J..

7 recordsLinked to original sources

bioRxiv2026

Melanin regulates mitochondrial dynamics, metabolism and inflammatory signaling to protect the retina

Albino individuals are clinically recognized to exhibit heightened susceptibility to light-induced retinal injury, yet the cellular and metabolic mechanisms underlying this vulnerability remain poorly defined. Here, we investigated whether retinal pigment epithelium (RPE) pigmentation governs mitochondrial structure, metabolism, and inflammatory responses that ultimately determine retinal resilience to blue light stress. Using pigmented (C57BL/6J) and albino (Balb/c) mice, we demonstrate that albino animals exhibit markedly increased retinal phototoxicity following blue light exposure, manifested by fundus lesions, outer nuclear layer (ONL) disruption, and structural degeneration evident by OCT. Primary RPE cultures derived from albino mice exhibited profound difference in mitochondrial morphology, characterized by increased mitochondrial number, reduced size, and enhanced fragmentation, accompanied by elevated mitochondrial DNA copy number. These structural changes correlated with transcriptional skewing toward mitochondrial fission (increased Drp1) and suppression of mitochondrial fusion (Mfn1, Mfn2, OPA1). Functionally, albino and depigmented RPE displayed impaired oxidative phosphorylation, reduced ATP production, and diminished reliance on mitochondrial pyruvate carrier (MPC)-dependent metabolism. In parallel, albino RPE demonstrated cell-cycle accumulation at G2/M and heightened basal and blue light-induced secretion of pro-inflammatory cytokines, particularly IFN-{beta}1, IL-6, and TNF-. Importantly, exogenous melanin supplementation partially restored mitochondrial fusion gene expression, pyruvate-dependent respiration, and inflammatory restraint. Together, these findings identify melanin as a critical regulator of RPE mitochondrial architecture, metabolic substrate utilization, and inflammatory signaling, providing a mechanistic framework to explain enhanced photo-vulnerability in the albino retina. These insights establish pigmentation-dependent mitochondrial metabolism as a determinant of retinal resilience and suggest mitochondrial bioenergetics as a therapeutic target.

cell biology↗

bioRxiv2026

Structure-Guided Design and Dynamic Evaluation of VP4-Targeting siRNAs Against Rotavirus A

Rotavirus is a major cause of severe diarrheal disease in children under the age of five, with reduced vaccine effectiveness in low-resource settings causing substantial morbidity and mortality. In the absence of approved antiviral therapeutics, treatment is largely supportive, urging the need for targeted and precision-based interventions. VP4 protein plays an essential role in viral attachment, entry, and infectivity, making it a suitable target for targeted therapy. In this context, RNA interference is a specific method for inhibiting viral gene expression with its efficacy depending on sequence conservation, target accessibility, and compatibility with the RISC-loading machinery. In the present study, an integrative in silico approach was employed to design and evaluate siRNAs targeting conserved regions of the VP4 gene across six geographically diverse countries. Candidate siRNAs were screened using established design rules and regression-based scoring with off-target filtering. Three optimized siRNAs were further assessed through structural modeling, molecular docking, and molecular dynamics simulations to examine interactions with human Dicer, TRBP, and Argonaute-2. Comparative dynamic analyses identified one siRNA with enhanced structural compatibility, reduced conformational fluctuations, and stable interactions with RISC-loading proteins. These findings provide a rational computational basis for VP4-targeted siRNA development, facilitating experimental validation.

bioinformatics↗

bioRxiv2025

Computational investigation unveils pathogenic LIG3 non-synonymous mutations and therapeutic targets in acute myeloid leukemia

Single nucleotide polymorphisms (SNPs) in DNA repair genes can impair protein structure and function, contributing to disease development, including cancer. Non-synonymous SNPs (nsSNPs) in the LIG3 gene are linked to genomic instability and increased cancer risk, particularly acute myeloid leukemia (AML). This study aims to identify the most deleterious nsSNPs in the LIG3 gene and potential therapeutic targets for DNA repair restoration in AML. We employed in-silico computational methods to analyze LIG3 nsSNPs, using PredictSNP and Mutation3D to assess pathogenicity. Subsequently, molecular docking and dynamics simulations were conducted to evaluate ligand-binding affinities and protein stability. Out of the 12,191 mapped SNPs, 132 were nsSNPs located in the coding region. Among these, 18 nsSNPs were identified as detrimental including 12 destabilizing and 6 stabilizing nsSNPs. Nine cancer-associated nsSNPs, including L381R and R528C, were predicted due to their structural and functional impacts. Further analysis revealed key phosphorylation and methylation sites, such as 529S and 224R. Molecular dynamics simulations highlighted stable interactions of compounds AHP-MPC and DM-BFC with wild-type and R528C mutant LIG3 proteins, while R671G and V781M mutants showed instability. Protein-protein interaction networks and functional enrichment linked LIG3 to DNA repair pathways. Kaplan-Meier analysis associated high LIG3 expression with improved survival in breast cancer and AML, suggesting its role as a prognostic biomarker. This study emphasizes the mutation-specific effects of LIG3 nsSNPs on protein stability and ligand interactions. We recommend identifying DM-BFC to advance personalized medicine approaches for targeting deleterious variants, following in vitro and in vivo validation for AML treatment.

cancer biology↗

bioRxiv2023

Development and qualification of a high-yield recombinant human Erythropoietin biosimilar

Recombinant human erythropoietin (rhEPO) has been saving millions of lives worldwide as a potent and safe treatment for the lack of erythrocyte, which is caused by chronic kidney disease (CKD) and other issues. Several biosimilars of rhEPO have been approved since the expiry of the relevant patents to provide cost-effective options but the price of rhEPO is still high for the affordability of global community. Therefore, development of biosimilar of rhEPO at a lower price is highly necessary. Here we report the development and characterization of a biosimilar of rhEPO with high-yield satisfying regulatory requirements. The hEPO-expressing cDNA was stably expressed in CHO cells with successive transfection. The master cell bank (MCB) and working cell bank (WCB) were established from the best selected clone and characterized for 50 passages. The rhEPO was expressed from the WCB in single-use suspension culture system with a high-titer (1.24{+/-}0.16 g/L). To the best of our knowledge this is the highest reported rhEPO titer to date. The rhEPO was purified using a series of validated chromatography unit processes including virus inactivation and filtration. The purified EPO was formulated in serum-free buffer, sterile filtered, and analyzed as the biosimilar of reference product Eprex(R). Physicochemical analysis strongly suggested similarities between the developed rhEPO (GBPD002) and the reference. The in vitro and in vivo functional assays confirmed the similar biofunctionality of the GBPD002 and Eprex(R). GBPD002 could provide a less-expensive solution to the needful communities as an effective and safe biosimilar where rhEPO treatment is necessary.

bioengineering↗

bioRxiv2023

A Cost-effective Purification Process for Erythropoietin Biosimilar through Downstream Process Engineering

Well-characterized and scalable downstream process for purification of biologics is extremely demanding for delivering quality therapeutics to patients at a reasonable price. Erythropoietin (EPO) is a blockbuster biologic with diverse clinical applications but its application is limited to financially well-off societies due to high price. The high price of EPO is associated with the technical difficulties related to the purification challenge to obtain qualified product with a cost-effective defined process. Though there are reports for purification of EPO but there is no report of well-characterized downstream process with critical process parameters (CPPs) that can deliver EPO consistently satisfying the quality target product profile (QTPP), which is a critical regulatory requirement. To advance the field, we applied quality by design (QbD) principle and design of experiment (DoE) protocol to establish an effective process, which is scalable up to 100x batch size satisfying QTPP. We have successfully transformed the process from static mode to dynamic mode and validated. Insignificant variation (p> 0.05) within and between 1x, 10x and 100x batches showed that the process is reproducible and seamlessly scalable. The biochemical analysis along with the biofunctionality data ensures that the products from different-scale batches were indifferent and comparable to a reference product. Our study thereby established a robust and scalable downstream process of EPO biosimilar satisfying QTPP. The technological scheme presented here can speed-up the production of not only EPO but many other life-saving biologics and make them available to mass population at a reduced cost.

bioengineering↗

bioRxiv2021

Glycosuria alters uropathogenic Escherichia coli global gene expression and virulence

Uropathogenic Escherichia coli (UPEC) is the principal etiology of more than half of urinary tract infections (UTI) in humans with diabetes mellitus. Epidemiological data and studies in mouse model of ascending UTI have elucidated various host factors responsible for increasing the susceptibility of diabetic hosts to UPEC-UTI. In contrast, the nature of alterations in UPEC physiology mediated by diabetic urinary microenvironment and the contributions of altered UPEC physiology in shaping UPEC-UTI pathogenesis in diabetes have not been examined. Our central hypothesis is that glycosuria directly induces urinary virulence of UPEC. We compared virulence characteristics and gene expression in human UPEC strains UTI89 (cystitis) and CFT073 (pyelonephritis) exposed for 2h, in vitro to human urine either in the presence or absence of glycosuria (600mg/dl glucose). Compared to control UPEC exposed to nutrient-rich culture medium LB, glycosuria-exposed UPEC exhibited significant increase in biofilm formation and reduction in the hemagglutination of Guinea pig erythrocytes (a surrogate measure of type 1 piliation). In addition, analysis of UTI89 transcriptome by RNA sequencing revealed that 2h-long, in vitro exposure to glycosuria also significantly alters expression of virulence and metabolic genes central to urinary virulence of UPEC. In summary, our results provide novel insights into how glycosuria-mediated early changes in UPEC fitness may facilitate UTI pathogenesis in the diabetic urinary microenvironment. IMPORTANCEUropathogenic Escherichia coli (UPEC) is an important causative agent of urinary tract infections in diabetic humans. We examined the effects of in vitro exposure to glycosuria (presence of glucose in urine) on the virulence and gene expression by UPEC. Our results show that glycosuria rapidly (in 2h) alters UPEC gene expression, induces biofilm formation, and suppresses hemagglutination. These results offer a novel insight into the pathogenesis of UPEC in the urinary tract.

microbiology↗

bioRxiv2020

BANCOVID, the first D614G variant mRNA-based vaccine candidate against SARS-CoV-2 elicits neutralizing antibody and balanced cellular immune response

Effective vaccine against SARS-CoV-2 is the utmost importance in the current world. More than 1 million deaths are accounted for relevant pandemic disease COVID-19. Recent data showed that D614G genotype of the virus is highly infectious and responsible for almost all infection for 2nd wave. Despite of multiple vaccine development initiatives, there are currently no report that has addressed this critical variant D614G as vaccine candidate. Here we report the development of an mRNA-LNP vaccine considering the D614G variant and characterization of the vaccine in preclinical trial. The surface plasmon resonance (SPR) data with spike protein as probe and competitive neutralization with RBD and S2 domain revealed that immunization generated specific antibody pools against the whole extracellular domain (RBD and S2) of the spike protein. The anti-sera and purified IgGs from immunized mice on day 7 and 14 neutralized SARS-CoV-2 pseudovirus in ACE2-expressing HEK293 cells in a dose dependent manner. Importantly, immunization protected mice lungs from pseudovirus entry and cytopathy. The immunologic responses have been implicated by a balanced and stable population of CD4+ cells with a Th1 bias. The IgG2a to IgG1 and (IgG2a+IgG2b) to (IgG1+IgG3) ratios were found 1{+/-}0.2 and 1.24{+/-}0.1, respectively. These values are comparatively higher than relevant values for other published SARS-CoV-2 vaccine in development,1, 2 and suggesting higher viral clearance capacity for our vaccine. The data suggested great promise for immediate translation of the technology to the clinic.

immunology↗