Biology subjects

Gosh, S.

Publications and source records attributed to Gosh, S..

4 recordsLinked to original sources

bioRxiv2025

Rapid elicitation of a new class of neutralizing N332-glycan independent V3-glycan antibodies against HIV-1 in nonhuman primates.

Sequential immunization is a promising approach to elicit broadly neutralizing antibodies (bNAbs) against the HIV-1 Envelope (Env). However, available protocols are inefficient and involve multiple immunizations over long periods of time. Here, we present WIN332, a new engineered Env-immunogen that induces a new class of neutralizing N332-glycan-independent antibodies to the conserved V3-glycan epitope of Env after a single bolus immunization in nonhuman primates. WIN332 binds to precursors of canonical human N332-glycan-dependent (Type-I) V3-glycan bNAbs but also of a first-of-its-class N332-glycan-independent (Type-II) V3-glycan bNAb. A single immunization elicits neutralizing serum and monoclonal antibodies that are boosted and affinity matured with a heterologous immunogen. EMPEM analysis of serum antibodies, antibody cloning and cryo-EM analysis reveal that WIN332 elicits N332-glycan-independent antibodies with remarkable sequence and binding similarities with the most potent human type-I and type-II V3-glycan bNAbs. Thus, WIN332 is a promising vaccine candidate to streamline V3-glycan bNAb elicitation.

immunology↗

bioRxiv2024

Genetic Diversity of Zymoseptoria tritici Populations in Central and South-eastern Ethiopia

Septoria tritici blotch (STB), caused by the hemibiotrophic fungus Zymoseptoria tritici, is a serious threat to global wheat production, and a major bottleneck to wheat production in Ethiopia. Accurate identification and analysis of the pathogens genetic structure helps inform robust STB management. This study analyzed the molecular identity and genetic structure of 200 Z. tritici isolates retrieved from diseased crops in central and south-eastern regions of Ethiopia. Allelic diversity at 12 simple sequence repeat (SSR) loci was examined for all 200 isolates, and 165 isolates were identified by Sanger sequencing of the internal transcribed spacer (ITS) region of nuclear DNA (rDNA) region. The microsatellites were highly polymorphic, with mean number of alleles (Na) = 6.23, effective alleles (Ne) =2.90, Neis gene diversity (H) =0.57, and polymorphic information content (PIC) =0.59, and an analysis of molecular variance confirmed the presence of low population differentiation (Fixation Index (FST) = 0.02, Gene Flow (Nm) = 14.7), with 95% of the total genetic variation residing within populations, and only 5% residing between populations. The highest genetic diversity (Number of allele (Na) = 9.33, Effective number of allele (Ne) = 3.41 and Neis gene diversity (H) = 0.68) was observed in the Oromia special zone surrounding Finfinnee (OSZ) Z. tritici populations, followed by Arsi and North Shewa populations, indicating that these areas are ideal for multi-location germplasm resistance screening, and also pathogen genetic and genomic analyses. Cluster analyses did not clearly divide the populations into genetically separate clusters according to their geographic sampling areas, probably because of high gene flow. All individual samples showed genetic admixture, and shared genomic backgrounds from two subgroups (K=2). Overall, the SSR markers proved to be highly informative and effective genetic tools for unlocking the pathogens genetic structure. The Z. tritici populations of central and southeast Ethiopia exhibit high genetic diversity, indicating the need to deploy durable and diverse disease management strategies. North Shewa, OSZ, Arsi and West Arsi administrative zones represent hotspots for genetic and genomic analyses of Z. tritici. Moreover, these areas would be excellent locations for host-pathogen interaction studies, and wheat germplasm screening for STB resistance.

plant biology↗

bioRxiv2023

A Computational Approach for Structural and Functional Analyses of Disease-associated Mutations in the Human CYLD Gene

Tumor suppressor Cylindromatosis protein (CYLD) regulates NF- {kappa}B and JNK signaling pathway by cleaving K63 linked poly-ubiquitin chain from its substrate molecules and thus preventing the progression of tumorigenesis and metastasis of the cancer cells. Mutations in CYLD can cause aberrant structure and abnormal functionality leading to tumor formation. In this study, we utilized several computational tools such as PANTHER, PROVEAN, PREDICT- SNP, POLYPHEN 2, PHD SNP, PON P2, and SIFT to find out deleterious nsSNPs. We also highlighted the damaging impact of those deleterious nsSNPs on the structure and function of the CYLD utilizing Consurf, I-Mutant, SDM, Phyre2, HOPE, Swiss PDB Viewer, and Mutation 3D. We shortlisted 18 high-risk nsSNPs from a total of 446 nsSNPs recorded in the NCBI database. Based on the conservation profile, stability status, and structural impact analysis we finalized 13nsSNPs. Molecular docking analysis and molecular dynamic simulation concluded the study with the findings of two significant nsSNPs (R830K, H827R) which have a remarkable impact on binding affinity, RMSD, RMSF, Radius of gyration, and hydrogen bond formation during CYLD-ubiquitin interaction. The principal component analysis compared native and two mutants R830K, H827R of CYLD that signifies structural and energy profile fluctuations during molecular dynamic (MD) simulation. Finally, the Protein-protein interaction network showed CYLD interacts with 20 proteins involved in several biological pathways that mutations can impair. Considering all these in silico analyses, our study recommended conducting large-scale association studies of nsSNPs of CYLD with cancer as well as designing precise medications against diseases associated with these polymorphisms.

bioinformatics↗

bioRxiv2020

Structural and Functional Implications of Non-synonymous Mutations in the Spike protein of 2,954 SARS-CoV-2 Genomes

Protein-protein interactions between virus and host are crucial for infection. SARS-CoV-2, the causative agent of COVID-19 pandemic is an RNA virus prone to mutations. Formation of a stable binding interface between the Spike (S) protein Receptor Binding Domain (RBD) of SARS-CoV-2 and Angiotensin-Converting Enzyme 2 (ACE2) of host actuates viral entry. Yet, how this binding interface evolves as virus acquires mutations during pandemic remains elusive. Here, using a high fidelity bioinformatics pipeline, we analysed 31,403 SARS-CoV-2 genomes across the globe, and identified 444 non-synonymous mutations that cause 49 distinct amino acid substitutions in the RBD. Molecular phylogenetic analysis suggested independent emergence of these RBD mutants during pandemic. In silico structure modelling of interfaces induced by mutations on residues which directly engage ACE2 or lie in the near vicinity revealed molecular rearrangements and binding energies unique to each RBD mutant. Comparative structure analysis using binding interface from mouse that prevents SARS-CoV-2 entry uncovered minimal molecular determinants in RBD necessary for the formation of stable interface. We identified that interfacial interaction involving amino acid residues N487 and G496 on either ends of the binding scaffold are indispensable to anchor RBD and are well conserved in all SARS-like corona viruses. All other interactions appear to be required to locally remodel binding interface with varying affinities and thus may decide extent of viral transmission and disease outcome. Together, our findings propose the modalities and variations in RBD-ACE2 interface formation exploited by SARS-CoV-2 for endurance. ImportanceCOVID-19, so far the worst hit pandemic to mankind, started in January 2020 and is still prevailing globally. Our study identified key molecular arrangements in RBD-ACE2 interface that help virus to tolerate mutations and prevail. In addition, RBD mutations identified in this study can serve as a molecular directory for experimental biologists to perform functional validation experiments. The minimal molecular requirements for the formation of RBD-ACE2 interface predicted using in silico structure models may help precisely design neutralizing antibodies, vaccines and therapeutics. Our study also proposes the significance of understanding evolution of protein interfaces during pandemic.

evolutionary biology↗