Biology subjects

Islam, K.

Publications and source records attributed to Islam, K..

8 recordsLinked to original sources

bioRxiv2026

Anthracyclines inhibit -1 programmed ribosomal frameshifting and restrict HCoV-OC43 infection

Human coronavirus OC43 (HCoV-OC43) constitutes one of the most common causes of the seasonal cold but can also cause severe disease among elderly and immuno-compromised. Currently, there are no approved antiviral drugs to combat HCoV-OC43 infection. Coronaviruses are positive-sense single-stranded RNA (+ssRNA) viruses and utilize -1 programmed ribosomal frameshifting (-1 PRF) to produce the correct stoichiometry of viral protein components. Due to its high conservation, the ribosomal frameshifting stimulation element (FSE) is a promising target for antiviral drug discovery. Aminoglycosides and anthracyclines interact with structured nucleic acids and some of these compounds affect -1 PRF in SARS-CoV-2. To get a comprehensive view of their putative efficacy, we examined all commercially available aminoglycosides and anthracyclines for their ability to affect -1 PRF in HCoV-OC43 and their potential to reduce HCoV-OC43 infection. Of 25 candidates tested, we identified 3 anthracyclines (Idarubicin, Nogalamycin and Daunorubicin) to reduce HCoV-OC43 -1 PRF using in vitro assays. We further demonstrate that the active anthracyclines, but not the inactive anthracycline, bind to the HCoV-OC43 FSE. The active anthracyclines did not significantly affect -1 PRF in SARS-CoV-2, suggesting differences in the interactions of the anthracyclines and FSEs, despite being relatively conserved in HCoV-OC43 and SARS-CoV-2 RNAs. Interestingly, these potent anthracyclines also significantly reduced HCoV-OC43 infection in human host cells. Although, the anthracyclines show some toxicity and introduce lesions in cellular DNA they could constitute an important scaffold for further antiviral development, with the aim to increase efficacy and reduce toxicity. Author summaryThe recent Covid-19 pandemic caused by SARS-CoV-2 showed the need for functional antivirals to immediately combat infections at the onset of future pandemics. In addition to SARS-CoV-2, four other human coronaviruses can cause mild to severe infection. Among those is HCoV-OC43, a coronavirus particularly troublesome for immunocompromised patients. Despite this clinical relevance, no approved antiviral therapies are currently available for the prevention or treatment of HCoV-OC43 infections. In this work, we have identified a subset of anthracyclines (Idarubicin, Nogalamycin and Daunorubicin) that selectively and significantly reduce HCoV-OC43 infection. In contrast to a non-active anthracycline, the same anthracyclines that reduce infection also reduce ribosomal frameshifting and interact with a structured RNA in the viral RNA-genome. Interestingly, Idarubicin, a clinically used anticancer drug, shows selectivity for HCoV-OC43, but not for SARS-CoV-2 RNA. Our work demonstrates that anthracyclines could be important for pandemic preparedness and serve as attractive scaffolds when developing new antivirals targeting coronaviruses.

microbiology↗

bioRxiv2025

Rete Ovarii Epithelial Cells as an Unappreciated Cell of Origin for Pelvic and Ovarian High-Grade Serous Carcinoma

Over the past two decades, converging clinicopathologic, molecular, and evolutionary evidence has established that pelvic and ovarian high-grade serous carcinoma (HGSC) originates predominantly from tubal-type epithelia rather than the ovarian surface epithelium. Consequently, Fallopian tube secretory epithelial cells are widely recognized as the principal cell of origin for HGSC. However, the female reproductive tract contains additional tubular epithelial networks whose potential contributions to HGSC pathogenesis remain unexplored. Here, we identify the rete ovarii (RO), a complex network of intra- and extra-ovarian tubules located within the ovarian hilus and mesovarium, as an alternative candidate tissue of origin for HGSC. We demonstrate that genetic and genomic alterations in rete ovarii epithelial cells (ROECs) can drive their malignant transformation, giving rise to tumors that closely recapitulate the histologic and molecular characteristics of human HGSC. Spatially resolved single-cell transcriptomic analyses of tumors derived from Brca/Trp53/Pten-deficient ROECs (BTP-RO) reveal distinct invasive and immunosuppressive molecular programs. These findings establish ROECs as a previously unrecognized cell of origin for HGSC, expanding the landscape of potential precursor populations beyond the Fallopian tube. The RO-based HGSC model provides a powerful framework for developing origin-informed prevention strategies, early detection approaches, and targeted therapeutics.

cancer biology↗

bioRxiv2024

Vibrio cholerae lineage and pangenome diversity varies geographically across Bangladesh over one year

Cholera is a diarrhoeal disease caused by Vibrio cholerae. It remains a major public health challenge in the endemic region around the Bay of Bengal. Over decadal time scales, one lineage typically dominates the others and spreads in global pandemic waves. However, it remains unclear to what extent diverse lineages co-circulate during a single outbreak season. Defining the pool of diversity during finer time scales is important because the selective pressures that impact V. cholerae - namely antibiotics and phages - are dynamic on these time scales. To study the nationwide diversity of V. cholerae, we long-read sequenced 273 V. cholerae genomes from seven hospitals over one year (2018) in Bangladesh. Four major V. cholerae lineages were identified: known lineages BD-1, BD-2a, and BD-2b, and a novel lineage that we call BD-3. In 2022, BD-1 caused a large cholera outbreak in Dhaka, apparently outcompeting BD-2 lineages. We show that, in 2018, BD-1 was already dominant in the five northern regions, including Dhaka, consistent with an origin from India in the north. By contrast, we observed a higher diversity of lineages in the two southern regions near the coast. The four lineages differed in pangenome content, including integrative and conjugative elements (ICEs) and genes involved in resistance to bacteriophages and antibiotics. Notably, BD-2a lacked an ICE and is predicted to be more sensitive to phages and antibiotics, but nevertheless persisted throughout the year-long sampling period. Genes associated with antibiotic resistance in V. cholerae from Bangladesh in 2006 were entirely absent from all lineages in 2018-19, suggesting shifting costs and benefits of encoding these genes. Together, our results highlight the dynamic nature of the V. cholerae pangenome and the geographic structure of its lineage diversity.

microbiology↗

bioRxiv2023

Phage predation and antibiotic exposure are inversely associated with disease severity and shape pathogen genetic diversity in cholera patients

Despite an increasingly detailed picture of the molecular mechanisms of phage-bacterial interactions, we lack an understanding of how these interactions evolve and impact disease within patients. Here we report a year-long, nation-wide study of diarrheal disease patients in Bangladesh. Among cholera patients, we quantified Vibrio cholerae (prey) and its virulent phages (predators) using metagenomics and quantitative PCR, while accounting for antibiotic exposure using quantitative mass spectrometry. Virulent phage (ICP1) and antibiotics suppressed V. cholerae to varying degrees and were inversely associated with severe dehydration depending on resistance mechanisms. In the absence of anti-phage defenses, predation was effective, with a high predator:prey ratio that correlated with increased genetic diversity among the prey. In the presence of anti-phage defenses, predation was ineffective, with a lower predator:prey ratio that correlated with increased genetic diversity among the predators. Phage-bacteria coevolution within patients should therefore be considered in the deployment of phage-based therapies and diagnostics. One Sentence SummaryA survey of cholera patients in Bangladesh identifies phage predation as a biomarker of disease severity and driver of coevolution within patients.

microbiology↗

bioRxiv2023

Cardiomyocyte Targeting Peptide to Deliver Amiodarone

BackgroundAmiodarone is underutilized due to significant off-target toxicities. We hypothesized that targeted delivery to the heart would lead to lowering of dose by utilizing a cardiomyocyte targeting peptide (CTP), a cell penetrating peptide identified by our prior phage display work. MethodsCTP was synthesized thiolated at the N-terminus, conjugated to amiodarone via Schiff base chemistry, HPLC purified and confirmed with MALDI/TOF. Stability of the conjugate was assessed using serial HPLCs. Guinea pigs (GP) were injected intraperitoneally daily with vehicle (7 days), amiodarone (7 days; 80mg/Kg), CTP-amiodarone (5 days;26.3mg/Kg), or CTP (5 days; 17.8mg/Kg), after which GPs were euthanized, hearts excised, perfused on a Langendorff apparatus with Tyrodes solution and blebbistatin (5M) to minimize contractions. Voltage (RH237) and Ca2+-indicator dye (Rhod-2/AM) were injected, fluorescence from the epicardium split and focused on two cameras capturing at 570-595nm for cytosolic Ca2+ and 610-750nm wavelengths for voltage. Subsequently, hearts were paced at 250ms with programmed stimulation to measure changes in conduction velocities (CV), action potential duration (APD) and Ca2+ transient durations at 90% recovery (CaTD90). mRNA was extracted from all hearts and RNA sequencing performed with results compared to control hearts. ResultsCTP-amiodarone remained stable for up to 21 days at 37{degrees}C. At [~]1/15th of the dose of amiodarone, CTP-amiodarone decreased CV in hearts significantly compared to control GPs (0.92{+/-}0.05 vs. 1.00{+/-}0.03m/s, p=0.0007), equivalent to amiodarone alone (0.87{+/-}0.08ms, p=0.0003). Amiodarone increased APD (192{+/-}5ms vs. 175{+/-}8ms for vehicle, p=0.0025), while CTP-amiodarone decreased it significantly (157{+/-}16ms, p=0.0136) similar to CTP alone (155{+/-}13ms, p=0.0039). Both amiodarone and CTP-amiodarone significantly decreased calcium transients compared to controls. CTP-amiodarone and CTP decreased CaTD90 to an extent greater than amiodarone alone (p<0.001). RNA-seq showed that CTP alone increased the expression of DHPR and SERCA2a, while decreasing expression of proinflammatory genes NF-kappa B, TNF-, IL-1{beta}, and IL-6. ConclusionsOur data suggests that CTP can deliver amiodarone to cardiomyocytes at [~]1/15th the total molar dose of amiodarone needed to produce comparable slowing of CVs. The ability of CTP to decrease AP durations and CaTD90 may be related to its increase in expression of Ca-handling genes, and merits further study.

molecular biology↗

bioRxiv2021

Uncovering the Bromodomain Interactome using Site-Specific Azide-Acetyllysine Photochemistry, Proteomic Profiling and Structural Characterization

Protein-protein interactions mediated by acetyllysines and bromodomains are essential for the regulation of eukaryotic gene expression. Diagramming the bromodomain interactome network and molecular characterization of these interactions are key to unraveling context-dependent signaling pathways. Herein, we employ a chemoproteomic platform, called interaction-based protein profiling (IBPP), to map the acetylome of the bromodomain and extra terminal domain (BET) family of bromodomains. We developed photo-responsive bromodomain analogues to carry out UV light-induced azide-acetyllysine crosslinking within the recognition cavity of the domain to capture transient interacting partners present in human cells. Subsequent proteomic and biochemical analyses lead to the identification of an array of acetylated interacting factors, which extend the potential function of BET family proteins beyond transcription. We present here eight high-resolution crystal structures of interactome-bound bromodomains that underscore the atypical binding modes and sequence motifs by which BET members recognize an expanded repertoire of acetylated proteins. In addition, we report an acetyllysine-dependent interaction between BRD4 and interleukin enhancer binding factor 3 (ILF3) in human cells, and uncover its role in recruiting transcriptional regulators to the promoter of the Survivin gene, an anti-apoptotic factor overexpressed in a wide range of human neoplasia. Collectively, our work provides a blueprint for engineering bromodomains, establishes IBPP as a robust chemoproteomic tool to characterize bromodomain interactome, and reveals distinctive recognition modes by which such associations may take place in order to modulate signaling pathways. Furthermore, these structural snapshots offer clues to design specific small-molecule inhibitors against the novel BET interactions and paves the path for exploring the biological significance of this newly identified signaling network.

biochemistry↗

bioRxiv2020

Humans surviving cholera develop antibodies against Vibrio cholerae O-specific polysaccharide that inhibit pathogen motility

The mechanism of protection against cholera afforded by previous illness or vaccination is currently unknown. We have recently shown that antibodies targeting O-specific polysaccharide (OSP) of Vibrio cholerae correlate highly with protection against cholera. V. cholerae is highly motile and possesses a flagellum sheathed in O-specific polysaccharide (OSP), and motility of V. cholerae correlates with virulence. Using high speed video microscopy, and building upon previous animal-related work, we demonstrate that sera, polyclonal antibody fractions, and OSP-specific monoclonal antibodies recovered from humans surviving cholera block V. cholerae motility at both subagglutinating and agglutinating concentrations. This anti-motility effect is reversed by pre-adsorbing sera and polyclonal antibody fractions with purified OSP; and is associated with OSP-specific but not flagellin-specific monoclonal antibodies. F[ab] fragments of OSP-specific polyclonal antibodies do not inhibit motility, suggesting a requirement for antibody-mediated crosslinking in motility inhibition. We show that OSP-specific antibodies do not directly affect V. cholerae viability, but that OSP-specific monoclonal antibody highly protects against death in the murine cholera model. We used in vivo competitive index studies to demonstrate that OSP-specific antibodies impede colonization and survival of V. cholerae in intestinal tissues, and that this impact is motility-dependent. Our findings suggest that the impedance of motility by antibodies targeting V. cholerae OSP contributes to protection against cholera. IMPORTANCECholera is a severe dehydrating illness of humans caused by Vibrio cholerae. V. cholerae is a highly motile bacterium that has a single flagellum covered in lipopolysaccharide (LPS) displaying O-specific polysaccharide (OSP), and V. cholerae motility correlates with its ability to cause disease. The mechanisms of protection against cholera are not well understood; however, since V. cholerae is a non-invasive intestinal pathogen, it is likely that antibodies that bind the pathogen or its products in the intestinal lumen contribute to protection from infection. Here, we demonstrate that OSP-specific antibodies isolated from humans surviving cholera in Bangladesh inhibit V. cholerae motility and are associated with protection against challenge in a motility-dependent manner.

microbiology↗

bioRxiv2020

Ancestral function of Inhibitors-of-kappaB regulates Caenorhabditis elegans development

Mammalian I{kappa}B proteins (I{kappa}Bs) exert their main function as negative regulators of NF-{kappa}B, a central signaling pathway controlling immunity and inflammation. An alternative chromatin role for I{kappa}Bs has been shown to affect stemness and cell differentiation. However, the involvement of NF-{kappa}B in this function has not been excluded. NFKI-1 and IKB-1 are I{kappa}B homologs in Caenorhabditis elegans, which lacks NF-{kappa}B nuclear effectors. We found that nfki-1 and ikb-1 mutants display developmental defects that phenocopy mutations in Polycomb and UTX-1 histone demethylase, suggesting a role for C. elegans I{kappa}Bs in chromatin regulation. Further supporting this possibility (i) we detected NFKI-1 in the nucleus of cells; (ii) NFKI-1 and IKB-1 bind to histones and Polycomb proteins, (iii) and associate with chromatin in vivo, and (iv) mutations in nfki-1 and ikb-1 alter chromatin marks. Based on these results, we propose that ancestral I{kappa}B inhibitors modulate Polycomb activity at specific gene subsets with an impact on development.

developmental biology↗