Person: KHAN, MOHAMMAD ASİF
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Publication Metadata only T3SEdb: data warehousing of virulence effectors secreted by the bacterial Type III Secretion System(2010-10-01T00:00:00Z) Tay, Daniel Ming Ming; Govindarajan, Kunde Ramamoorthy; KHAN, MOHAMMAD ASİF; Ong, Terenze Yao Rui; Samad, Hanif M.; Soh, Wei Wei; Tong, Minyan; Zhang, Fan; Tan, Tin Wee; KHAN, MOHAMMAD ASİFBackground: Effectors of Type III Secretion System (T3SS) play a pivotal role in establishing and maintaining pathogenicity in the host and therefore the identification of these effectors is important in understanding virulence. However, the effectors display high level of sequence diversity, therefore making the identification a difficult process. There is a need to collate and annotate existing effector sequences in public databases to enable systematic analyses of these sequences for development of models for screening and selection of putative novel effectors from bacterial genomes that can be validated by a smaller number of key experiments.Publication Metadata only Dissecting the Dynamics of HIV-1 Protein Sequence Diversity(2013-04-01T00:00:00Z) Hu, Yongli; Tan, Paul ThiamJoo; Tan, Tin Wee; August, J. Thomas; KHAN, MOHAMMAD ASİF; KHAN, MOHAMMAD ASİFThe rapid mutation of human immunodeficiency virus-type 1 (HIV-1) and the limited characterization of the composition and incidence of the variant population are major obstacles to the development of an effective HIV-1 vaccine. This issue was addressed by a comprehensive analysis of over 58,000 clade B HIV-1 protein sequences reported over at least 26 years. The sequences were aligned and the 2,874 overlapping nonamer amino acid positions of the viral proteome, each a possible core binding domain for human leukocyte antigen molecules and T-cell receptors, were quantitatively analyzed for four patterns of sequence motifs: (1) -index-, the most prevalent sequence; (2) -major- variant, the most common variant sequence; (3) -minor- variants, multiple different sequences, each with an incidence less than that of the major variant; and (4) -unique- variants, each observed only once in the alignment. The collective incidence of the major, minor, and unique variants at each nonamer position represented the total variant population for the position. Positions with more than 50% total variants contained correspondingly reduced incidences of index and major variant sequences and increased minor and unique variants. Highly diverse positions, with 80 to 98% variant nonamer sequences, were present in each protein, including 5% of Gag, and 27% of Env and Nef, each. The multitude of different variant nonamer sequences (i.e. nonatypes; up to 68%) at the highly diverse positions, represented by the major, multiple minor, and multiple unique variants likely supported variants function both in immune escape and as altered peptide ligands with deleterious T-cell responses. The patterns of mutational change were consistent with the sequences of individual HXB2 and C1P viruses and can be considered applicable to all HIV-1 viruses. This characterization of HIV-1 protein mutation provides a foundation for the design of peptide-based vaccines and therapeutics.Publication Metadata only West Nile Virus T-Cell Ligand Sequences Shared with Other Flaviviruses: a Multitude of Variant Sequences as Potential Altered Peptide Ligands(2012-07-01T00:00:00Z) Jung, Keun-Ok; KHAN, MOHAMMAD ASİF; Tan, Benjamin Yong Liang; Hu, Yongli; Simon, Gregory G.; Nascimento, Eduardo J. M.; Lemonnier, Francois; Brusic, Vladimir; Miotto, Olivo; Tan, Tin Wee; Marques, Ernesto T. A.; Dhalia, Rafael; Salmon, Jerome; August, J. Thomas; KHAN, MOHAMMAD ASİFPhylogenetic relatedness and cocirculation of several major human pathogen flaviviruses are recognized as a possible cause of deleterious immune responses to mixed infection or immunization and call for a greater understanding of the inter-Flavivirus protein homologies. This study focused on the identification of human leukocyte antigen (HLA)-restricted West Nile virus (WNV) T-cell ligands and characterization of their distribution in reported sequence data of WNV and other flaviviruses. H-2-deficient mice transgenic for either A2, A24, B7, DR2, DR3, or DR4 HLA alleles were immunized with overlapping peptides of the WNV proteome, and peptide-specific T-cell activation was measured by gamma interferon (IFN-gamma) enzyme-linked immunosorbent spot (ELISpot) assays. Approximately 30% (137) of the WNV proteome peptides were identified as HLA-restricted T-cell ligands. The majority of these ligands were conserved in similar to >= 88% of analyzed WNV sequences. Notably, only 51 were WNV specific, and the remaining 86, chiefly of E, NS3, and NS5, shared an identity of nine or more consecutive amino acids with sequences of 64 other flaviviruses, including several major human pathogens. Many of the shared ligands had an incidence of >50% in the analyzed sequences of one or more of six major flaviviruses. The multitude of WNV sequences shared with other flaviviruses as interspecies variants highlights the possible hazard of defective T-cell activation by altered peptide ligands in the event of dual exposure to WNV and other flaviviruses, by either infection or immunization. The data suggest the possible preferred use of sequences that are pathogen specific with minimum interspecies sequence homology for the design of Flavivirus vaccines.Publication Metadata only STATdb: A Specialised Resource for the STATome(2014-08-01T00:00:00Z) Patro, C. Pawan K.; Khan, Asif M.; Tan, Tin Wee; Fu, Xin-Yuan; KHAN, MOHAMMAD ASİFSignal transducers and activators of transcription (STAT) proteins are key signalling molecules in metazoans, implicated in various cellular processes. Increased research in the field has resulted in the accumulation of STAT sequence and structure data, which are scattered across various public databases, missing extensive functional annotations, and prone to effort redundancy because of the dearth of community sharing. Therefore, there is a need to integrate the existing sequence, structure and functional data into a central repository, one that is enriched with annotations and provides a platform for community contributions. Herein, we present STATdb (publicly available at http://statdb.bic.nus.edu.sg/), the first integrated resource for STAT sequences comprising 1540 records representing the known STATome, enriched with existing structural and functional information from various databases and literature and including manual annotations. STATdb provides advanced features for data visualization, analysis and prediction, and community contributions. A key feature is a meta-predictor to characterise STAT sequences based on a novel classification that integrates STAT domain architecture, lineage and function. A curation policy workflow has been devised for regulated and structured community contributions, with an update policy for the seamless integration of new data and annotations.Publication Metadata only Identification of highly conserved, serotype-specific dengue virus sequences: implications for vaccine design(2019-12-01T00:00:00Z) Chong, Li Chuin; Khan, Asif M.; KHAN, MOHAMMAD ASİFBackground: The sequence diversity of dengue virus (DENV) is one of the challenges in developing an effective vaccine against the virus. Highly conserved, serotype-specific (HCSS), immune-relevant DENV sequences are attractive candidates for vaccine design, and represent an alternative to the approach of selecting pan-DENV conserved sequences. The former aims to limit the number of possible cross-reactive epitope variants in the population, while the latter aims to limit the cross-reactivity between the serotypes to favour a serotype-specific response. Herein, we performed a large-scale systematic study to map and characterise HCSS sequences in the DENV proteome.Publication Metadata only Cytokine Expression Profile of Dengue Patients at Different Phases of Illness(2012-12-01T00:00:00Z) Rathakrishnan, Anusyah; Wang, Seok Mui; Hu, Yongli; KHAN, MOHAMMAD ASİF; Ponnampalavanar, Sasheela; Lum, Lucy Chai See; Manikam, Rishya; Sekaran, Shamala Devi; KHAN, MOHAMMAD ASİFBackground: Dengue is an important medical problem, with symptoms ranging from mild dengue fever to severe forms of the disease, where vascular leakage leads to hypovolemic shock. Cytokines have been implicated to play a role in the progression of severe dengue disease; however, their profile in dengue patients and the synergy that leads to continued plasma leakage is not clearly understood. Herein, we investigated the cytokine kinetics and profiles of dengue patients at different phases of illness to further understand the role of cytokines in dengue disease.Publication Metadata only Mapping HLA-A2,-A3 and-B7 supertype-restricted T-cell epitopes in the ebolavirus proteome(2018-01-01T00:00:00Z) Lim, Wan Ching; Khan, Asif M.; KHAN, MOHAMMAD ASİFBackground: Ebolavirus (EBOV) is responsible for one of the most fatal diseases encountered by mankind. Cellular T-cell responses have been implicated to be important in providing protection against the virus. Antigenic variation can result in viral escape from immune recognition. Mapping targets of immune responses among the sequence of viral proteins is, thus, an important first step towards understanding the immune responses to viral variants and can aid in the identification of vaccine targets. Herein, we performed a large-scale, proteome-wide mapping and diversity analyses of putative HLA supertype-restricted T-cell epitopes of Zaire ebolavirus (ZEBOV), the most pathogenic species among the EBOV family.Publication Metadata only African Trypanosome-Induced Blood-Brain Barrier Dysfunction under Shear Stress May Not Require ERK Activation(2015-03-01T00:00:00Z) Sumpio, Brandon J.; Chitragari, Gautham; Moriguchi, Takeshi; Shalaby, Sherif; Pappas-Brown, Valeria; Khan, Asif M.; Sekaran, Shamala Devi; Sumpio, Bauer E.; Grab, Dennis J.; KHAN, MOHAMMAD ASİFAfrican trypanosomes are tsetse fly transmitted protozoan parasites responsible for human African trypanosomiasis, a disease characterized by a plethora of neurological symptoms and death. How the parasites under microvascular shear stress (SS) flow conditions in the brain cross the blood-brain barrier (BBB) is not known. In vitro studies using static models comprised of human brain microvascular endothelial cells (BMEC) show that BBB activation and crossing by trypanosomes requires the orchestration of parasite cysteine proteases and host calcium-mediated cell signaling. Here, we examine BMEC barrier function and the activation of extracellular signal-regulated kinase (ERK) 1/2 and ERK5, mitogen-activated protein kinase family regulators of microvascular permeability, under static and laminar SS flow and in the context of trypanosome infection. Confluent human BMEC were cultured in electric cell-substrate impedance sensing (ECIS) and parallel-plate glass slide chambers. The human BMEC were exposed to 2 or 14 dyn/cm(2) SS in the presence or absence of trypanosomes. Real-time changes in transendothelial electrical resistance (TEER) were monitored and phosphorylation of ERK1/2 and ERK5 analyzed by immunoblot assay. After reaching confluence under static conditions human BMEC TEER was found to rapidly increase when exposed to 2 dyn/cm2 SS, a condition that mimics SS in brain postcapillary venules. Addition of African trypanosomes caused a rapid drop in human BMEC TEER. Increasing SS to 14 dyn/cm2, a condition mimicking SS in brain capillaries, led to a transient increase in TEER in both control and infected human BMEC. However, no differences in ERK1/2 and ERK5 activation were found under any condition tested. African trypanosomiasis alters BBB permeability under low shear conditions through an ERK1/2 and ERK5 independent pathway.Publication Metadata only Classification of Dengue Fever Patients Based on Gene Expression Data Using Support Vector Machines(2010-06-01T00:00:00Z) Gomes, Ana Lisa V.; Wee, Lawrence J. K.; KHAN, MOHAMMAD ASİF; Gil, Laura H. V. G.; Marques, Ernesto T. A.; Calzavara-Silva, Carlos E.; Tan, Tin Wee; KHAN, MOHAMMAD ASİFBackground: Symptomatic infection by dengue virus (DENV) can range from dengue fever (DF) to dengue haemorrhagic fever (DHF), however, the determinants of DF or DHF progression are not completely understood. It is hypothesised that host innate immune response factors are involved in modulating the disease outcome and the expression levels of genes involved in this response could be used as early prognostic markers for disease severity.Publication Metadata only Cheminformatics-Based Drug Design Approach for Identification of Inhibitors Targeting the Characteristic Residues of MMP-13 Hemopexin Domain(2010-08-01T00:00:00Z) Kothapalli, Roopa; KHAN, MOHAMMAD ASİF; Basappa, Basappa; Gopalsamy, Anupriya; Chong, Yap Seng; Annamalai, Loganath; KHAN, MOHAMMAD ASİFBackground: MMP-13, a zinc dependent protease which catalyses the cleavage of type II collagen, is expressed in osteoarthritis (OA) and rheumatoid arthritis (RA) patients, but not in normal adult tissues. Therefore, the protease has been intensively studied as a target for the inhibition of progression of OA and RA. Recent reports suggest that selective inhibition of MMP-13 may be achieved by targeting the hemopexin (Hpx) domain of the protease, which is critical for substrate specificity. In this study, we applied a cheminformatics-based drug design approach for the identification and characterization of inhibitors targeting the amino acid residues characteristic to Hpx domain of MMP-13; these inhibitors may potentially be employed in the treatment of OA and RA.