Biology subjects

Mehmood, S.

Publications and source records attributed to Mehmood, S..

5 recordsLinked to original sources

bioRxiv2026

Human skin fibrosis with iPSC-derived organoids reveals RUNX2-mediated fibroblast reprogramming

Fibrotic skin diseases are characterized by persistent fibroblast activation and extracellular matrix remodeling, yet the mechanisms governing fibroblast state transitions remain incompletely understood. Here, we established a human iPSC-derived skin organoid model of fibrosis through chronic TGF-{beta} stimulation. Single-cell RNA sequencing combined with immunofluorescence-based spatial analysis revealed dynamic fibroblast state transitions, spatial reorganization, and expansion of activated fibroblast populations during fibrotic remodeling. Integration with human scleroderma single-cell datasets demonstrated conserved fibroblast states and transcriptional programs between organoids and patient tissues. We further identified broad induction of RUNX2 in the dermal compartment during fibrosis, and RUNX2 depletion attenuated fibrotic marker expression. CUT&RUN profiling revealed RUNX2 occupancy at fibrosis-associated loci, including RUNX1 and LOXL2. Using a machine learning-guided screening approach, we identified F0565-0303, a small molecule that suppressed RUNX2-dependent fibrotic programs in vitro and reduced fibrosis in a bleomycin-induced mouse model. Together, these findings establish human skin organoids as a platform for modeling fibrosis and nominate RUNX2 as a potential therapeutic target.

bioengineering↗

bioRxiv2026

Otoprotective effect of MnTBAP in cisplatin-induced hearing loss

ObjectiveCisplatin, a life-saving chemotherapeutic drug, causes ototoxicity. Although sodium thiosulfate is used to prevent ototoxicity in pediatric patients, no other intervention has been approved for clinical use against cisplatin-induced hearing loss. Hence, there is an urgent need to identify drugs that prevent cisplatin ototoxicity. MethodsCBA/J mice were treated with cisplatin (3 mg/kg, i.p., daily for 5 days), and MnTBAP (10 mg/kg, i.p., daily for 8 days) was used to inhibit cisplatin-induced ototoxicity. Auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) were recorded before and after treatment to assess hearing loss, while immunohistochemistry was performed to examine hair cells and spiral ganglion neuron (SGN) loss. ResultsCisplatin treatment elevated the nitrotyrosine levels in hair cells and SGNs and increased the loss of these cells in the middle and basal cochlear regions. A negative correlation was observed between cisplatin-induced changes in the hair cell count or SGN density and nitrotyrosine levels. Cisplatin elevated the hearing thresholds and lowered the DPOAE amplitudes. However, MnTBAP cotreatment prevented the cisplatin-induced changes in the hearing sensitivity and reversed the morphological changes. ConclusionThe otoprotection observed with MnTBAP cotreatment indicates its potential as a therapeutic drug against cisplatin-induced ototoxicity.

neuroscience↗

bioRxiv2021

Structural dynamics of the β-coronavirus Mpro protease ligand binding sites

{beta}-coronaviruses alone have been responsible for three major global outbreaks in the 21st century. The current crisis has led to an urgent requirement to develop therapeutics. Even though a number of vaccines are available, alternative strategies targeting essential viral components are required as a back-up against the emergence of lethal viral variants. One such target is the main protease (Mpro) that plays an indispensible role in viral replication. The availability of over 270 Mpro X-ray structures in complex with inhibitors provides unique insights into ligand-protein interactions. Herein, we provide a comprehensive comparison of all non-redundant ligand-binding sites available for SARS-CoV2, SARS-CoV and MERS-CoV Mpro. Extensive adaptive sampling has been used to explore conformational dynamics employing convolutional variational auto encoder-based deep learning, and investigates structural conservation of the ligand binding sites using Markov state models across {beta}-coronavirus homologs. Our results indicate that not all ligand-binding sites are dynamically conserved despite high sequence and structural conservation across {beta}-coronavirus homologs. This highlights the complexity in targeting all three Mpro enzymes with a single pan inhibitor.

biophysics↗

bioRxiv2020

Structure of the cysteine-rich domain of Plasmodium falciparum P113 identifies the location of the RH5 binding site

Plasmodium falciparum RH5 is a secreted parasite ligand that is essential for erythrocyte invasion through direct interaction with the host erythrocyte receptor basigin. RH5 forms a tripartite complex with two other secreted parasite proteins: CyRPA and RIPR, and is tethered to the surface of the parasite through membrane-anchored P113. Antibodies against RH5, CyRPA and RIPR inhibit parasite invasion, suggesting that vaccines containing these three components have the potential to prevent blood-stage malaria. To further explore the role of the P113-RH5 interaction, we selected monoclonal antibodies against P113 that were either inhibitory or non-inhibitory for RH5 binding. Using a Fab fragment as a crystallisation chaperone, we determined the crystal structure of the RH5-binding region of P113 and showed that it is composed of two domains with structural similarities to rhamnose-binding lectins. We identified the RH5 binding site on P113 by using a combination of hydrogen-deuterium exchange mass spectrometry and site directed mutagenesis. We found that a monoclonal antibody to P113 that bound to this interface and inhibited the RH5-P113 interaction did not inhibit parasite blood-stage growth. These findings provide further structural information on the protein interactions of RH5 and will be helpful in the development of blood-stage malaria vaccines that target RH5. ImportanceMalaria is a deadly infectious disease primarily caused by the parasite Plasmodium falciparum. It remains a major global health problem and there is no highly effective vaccine. A parasite protein called RH5 is centrally involved in the invasion of host red blood cells, making it - and the other parasite proteins it interacts with - promising vaccine targets. We recently identified a protein called P113 that binds RH5 suggesting that it anchors RH5 to the parasite surface. In this paper, we use structural biology to locate and characterize the RH5 binding region on P113. These findings will be important to guide the development of new anti-malarial vaccines to ultimately prevent this disease which affects some of the poorest people on the planet.

microbiology↗

bioRxiv2018

Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design

Protein glycosylation is a widespread post-translational modification. The first committed step to the lipid-linked glycan used for this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. 2.7.8.15). Missense DPAGT1 variants cause congenital myasthenic syndrome and congenital disorders of glycosylation. In addition, naturally-occurring bactericidal nucleoside analogues such as tunicamycin are toxic to eukaryotes due to DPAGT1 inhibition, preventing their clinical use as antibiotics. However, little is known about the mechanism or the effects of disease-associated mutations in this essential enzyme. Our structures of DPAGT1 with the substrate UDP-GlcNAc and tunicamycin reveal substrate binding modes, suggest a mechanism of catalysis, provide an understanding of how mutations modulate activity (and thus cause disease) and allow design of non-toxic lipid-altered tunicamycins. The structure-tuned activity of these analogues against several bacterial targets allowed design of potent antibiotics for Mycobacterium tuberculosis, enabling treatment in vitro, in cellulo and in vivo thereby providing a promising new class of antimicrobial drug.\n\nHighlightsO_LIStructures of DPAGT1 with UDP-GlcNAc and tunicamycin reveal mechanisms of catalysis\nC_LIO_LIDPAGT1 mutants in patients with glycosylation disorders modulate DPAGT1 activity\nC_LIO_LIStructures, kinetics and biosynthesis reveal role of lipid in tunicamycin\nC_LIO_LILipid-altered, tunicamycin analogues give non-toxic antibiotics against TB\nC_LI

biochemistry↗