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  • 1
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    Online Resource
    Variability in the Responses of Hepatitis B Virus D-Subgenotypes to Antiviral Therapy: Designing Pan-D-Subgenotypic Reverse Transcriptase Inhibitors
    American Society for Microbiology ; 2022
    In:  Journal of Virology Vol. 96, No. 2 ( 2022-01-26)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 96, No. 2 ( 2022-01-26)
    Abstract: Nucleos(t)ide analogues entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are recommended as first-line monotherapies for chronic hepatitis B (CHB). Multiple HBV genotypes/subgenotypes have been described, but their impact on treatment response remains largely elusive. We investigated the effectiveness of ETV/TDF on HBV/D-subgenotypes, D1/D2/D3/D5, studied the structural/functional differences in subgenotype-specific reverse transcriptase (RT) domains of viral polymerase, and identified novel molecules with robust inhibitory activity on various D-subgenotypes. Transfection of Huh7 cells with full-length D1/D2/D3/D5 and in vitro TDF/ETV susceptibility assays demonstrated that D1/D2 had greater susceptibility to TDF/ETV while D3/D5 exhibited poorer response. Additionally, HBV load was substantially reduced in TDF-treated CHB patients carrying D1/D2 but minimally reduced in D3/D5-infected patients. Comparison of RT sequences of D-subgenotypes led to identification of unique subgenotype-specific residues, and molecular modeling/docking/simulation studies depicted differential bindings of TDF/ETV to the active site of their respective RTs. Replacement of signature residues in D3/D5 HBV clones with corresponding amino acids seen in D1/D2 improved their susceptibility to TDF/ETV. Using high throughput virtual screening, we identified N(9)-[3-fluoro-2-(phosphonomethoxy)propyl] (FPMP) derivatives of purine bases, including N 6 -substituted ( S )-FPMP derivative of 2,6-diaminopurine (DAP) (OB-123-VK), as potential binders of RT of different D-subgenotypes. We synthesized ( S )-FPMPG prodrugs (FK-381-FEE/FK-381-SEE/FK-382) and tested their effectiveness along with OB-123-VK. Both OB-123-VK and FK-381-FEE exerted similar antiviral activities against all D-subgenotypes, although FK-381-FEE was more potent. Our study highlighted the natural variation in therapeutic response of D1/D2/D3/D5 and emphasized the need for HBV subgenotype determination before treatment. Novel molecules described here could benefit future design/discovery of pan-D-subgenotypic inhibitors. IMPORTANCE Current treatment of chronic hepatitis B relies heavily on nucleotide/nucleoside analogs in particular, tenofovir disoproxil fumarate (TDF) and entecavir (ETV) to keep HBV replication under control and prevent end-stage liver diseases. However, it was unclear whether the therapeutic effects of TDF/ETV differ among patients infected with different HBV genotypes and subgenotypes. HBV genotype D is the most widespread of all HBV genotypes and multiple D-subgenotypes have been described. We here report that different subgenotypes of HBV genotype-D exhibit variable response toward TDF and ETV and this could be attributed to naturally occurring amino acid changes in the reverse transcriptase domain of the subgenotype-specific polymerase. Further, we identified novel molecules and also synthesized prodrugs that are equally effective on different D-subgenotypes and could facilitate management of HBV/D-infected patients irrespective of D-subgenotype.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.01800-21
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2022
    detail.hit.zdb_id: 1495529-5
    detail.hit.zdb_id: 80174-4
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  • 2
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    Distinctiveness in virological features and pathogenic potentials of subgenotypes D1, D2, D3 and D5 of Hepatitis B virus
    Springer Science and Business Media LLC ; 2018
    In:  Scientific Reports Vol. 8, No. 1 ( 2018-05-23)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2018-05-23)
    Abstract: Distinct clinical features of HBV infection have been associated with different viral genotype/subgenotype. HBV Genotype-D comprised of 10 subgenotypes, D1–D10, whose clinical implications still remain elusive. We investigated for the first-time, the virologic characteristics and cytopathic effects of four non-recombinant D-subgenotypes, D1/D2/D3/D5. Expressions of viral/host genes were evaluated in Huh7 cells transfected with full-length, linear-monomers of HBV/D-subgenotypes or pGL3-Basic vector carrying subgenotype-specific HBx. Intracellular HBV-DNA and pregenomic-RNA levels were high in D1/D2 than D3/D5. Expressions of PreC-mRNA and HBx were highest for D2 and D1 respectively, whereas PreS2/S-transcript was significantly reduced in D5. Increased apoptotic cell death and marked upregulation in caspase-3/Bax/TNF-R1/FasR/TRAIL-R1/ROS/MCP-1/IP-10/MIP-1β expression were noticed specifically in D2- and also in D3-transfected cells, while D5 resulted in over-expression of ER-stress-markers. D-subgenotype-transfected Huh7 cells were co-cultured with PBMC of healthy-donors or LX-2 cells and significant increase in pro-inflammatory cytokines in PBMC and fibrogenic-markers in LX-2 were noticed in presence of D2/D3. Further, Huh7 cells transfected with D1, in particular and also D5, displayed remarkable induction of EMT-markers and high proliferative/migratory abilities. Collectively, our results demonstrated that D2/D3 were more associated with hepatic apoptosis/inflammation/fibrosis and D1/D5 with increased risk of hepatocarcinogenesis and emphasize the need for determining HBV-subgenotype in clinical practice.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-018-26414-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2615211-3
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  • 3
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    Mutations in SARS-CoV-2 viral RNA identified in Eastern India: Possible implications for the ongoing outbreak in India and impact on viral structure and host susceptibility
    Springer Science and Business Media LLC ; 2020
    In:  Journal of Biosciences Vol. 45, No. 1 ( 2020-12)
    Details
    In: Journal of Biosciences, Springer Science and Business Media LLC, Vol. 45, No. 1 ( 2020-12)
    Type of Medium: Online Resource
    ISSN: 0250-5991 , 0973-7138
    URL: Article
    DOI: 10.1007/s12038-020-00046-1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2071290-X
    detail.hit.zdb_id: 756157-X
    SSG: 12
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  • 4
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    Studies on comparison of nano-urea and prilled urea for enhancing maize (Zea mays) growth and productivity
    Indian Council of Agricultural Research, Directorate of Knowledge Management in Agriculture ; 2024
    In:  The Indian Journal of Agricultural Sciences Vol. 94, No. 3 ( 2024-03-12), p. 325-328
    Details
    In: The Indian Journal of Agricultural Sciences, Indian Council of Agricultural Research, Directorate of Knowledge Management in Agriculture, Vol. 94, No. 3 ( 2024-03-12), p. 325-328
    Abstract: An experiment was conducted during the rainy (kharif) season of 2022–23 at the ICAR-Indian Agricultural Research Institute, Hazaribagh, Jharkhand to assess how well nano- urea performs in maize under different field conditions and investigate its compatibility with other N sources. Results showed that root weight (fresh and dry), partial factor productivity (N, P2O5 and K2O), N concentration (grain and stover), grain yield, biological yield and harvest index of maize were all significantly affected by the application of various N rates and nano-fertilizers. The grain yield of maize was comparable to the yield obtained under RDF and 75% of the recommended N + two nano-urea sprays. These findings indicate that the concurrent use of these nano-fertilizers has the potential to reduce N fertilization by as much as 25%. Furthermore, the results highlight the prospect of augmenting biological yield of maize by incorporating 2 nano-urea sprays alongside the prescribed N quantity from prilled urea, as well as full applications of P2O5 and K2O.
    Type of Medium: Online Resource
    ISSN: 2394-3319 , 0019-5022
    URL: Article
    DOI: 10.56093/ijas.v94i3.143292
    Language: English
    Publisher: Indian Council of Agricultural Research, Directorate of Knowledge Management in Agriculture
    Publication Date: 2024
    detail.hit.zdb_id: 413627-5
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  • 5
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    Synergistic impact of mutations in Hepatitis B Virus genome contribute to its occult phenotype in chronic Hepatitis C Virus carriers
    Springer Science and Business Media LLC ; 2017
    In:  Scientific Reports Vol. 7, No. 1 ( 2017-08-29)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 7, No. 1 ( 2017-08-29)
    Abstract: We characterized occult HBV (OHBV) from hepatitis B surface antigen (HBsAg)-negative chronic HCV carriers of Eastern India to explore the impact of genomic variability of HBV in causing undetectability of HBsAg and low viremia that define the occult phenomenon. Screening of sera samples revealed the presence of OHBV in 17.8% of HCV-infected patients. Determination of full-length OHBV sequences and comparison with that from HBsAg-positive carriers led to the detection of distinct substitutions/mutations in PreS2, S, P and X ORFs and in X-promoter and Enhancer-II of OHBV. These mutations were introduced in wild-type HBV and their effects were evaluated by transfection in Huh7 cells. In vitro assays demonstrated that S-substitutions resulted in antigenically modified HBsAg that escaped detection by immunoassays whereas those in ORF-P caused significant decline in viral replication. Impairment in Enhancer-II and X-promoter activities were noted due to occult-associated mutations that generated reduced pregenomic RNA and intracellular HBV-DNA. Additionally, Enhancer-II mutations altered the small to large surface protein ratio and diminished extracellular HBV-DNA and HBsAg secretion. Further, mutations in PreS2, X and enhancer-II increased Grp78-promoter activity, suggesting that OHBV could trigger endoplasmic reticulum stress. Thus viral mutations contribute synergistically towards the genesis of occult phenotype and disease progression.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-017-09965-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2615211-3
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  • 6
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    Spatial variability assessment of soil available phosphorus using geostatistical approach
    Indian Council of Agricultural Research, Directorate of Knowledge Management in Agriculture ; 2020
    In:  The Indian Journal of Agricultural Sciences Vol. 90, No. 6 ( 2020-09-14), p. 1170-1175
    Details
    In: The Indian Journal of Agricultural Sciences, Indian Council of Agricultural Research, Directorate of Knowledge Management in Agriculture, Vol. 90, No. 6 ( 2020-09-14), p. 1170-1175
    Abstract: Soil available phosphorus (P), a major plant nutrient, exhibits a high degree of spatial variability. Spatial variability assessment of P is necessary for its precise management using geostatistics. Therefore, the present study was conducted in an intensely cropped region of Ladian village of Ludhiana, Punjab during 2014-2016 to assess the spatial variability status of P under three prevalent land use systems, viz. berseem-based land use, rice-wheat system and poplar-wheat based agroforestry system. The classical statistics showed the variability of available-P in terms of percent coefficient of variation (%CV), but unable to distinguish variability between rice-wheat (CV=38.79%) and poplar-wheat system (CV=38.58%). Lower variability was observed in berseem-based land use (CV=15.21%), though the mean available-P content (46 kg/ha) was higher in this land use. However, the geostatistical techniques successfully demonstrated the spatial dependence of P within and in between land uses using nugget-sill (NS) ratio. Gaussian model was found suitable for describing the spatial structure of available-P under berseem-based land use; while, Exponential models were found suitable for rice-wheat and poplar-wheat systems. The value of NS ratio of available-P was 0.17 for poplar-wheat based land use, suggesting strong spatial dependence, whereas the rest other land uses exhibited moderate (NS=0.74) to weak (NS=0.82) spatial dependence of available P. The spatial variability maps of P were generated using ordinary kriging technique, demonstrated significantly the higher variability of P in poplar-wheat system than other systems. This variability should be considered before applying phosphatic fertilizers to this land use to get optimum response. The generated maps would assist the farmers for site-specific P management in the study area.
    Type of Medium: Online Resource
    ISSN: 2394-3319 , 0019-5022
    URL: Article
    DOI: 10.56093/ijas.v90i6.104795
    Language: Unknown
    Publisher: Indian Council of Agricultural Research, Directorate of Knowledge Management in Agriculture
    Publication Date: 2020
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  • 7
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    Integrated nutrient management with cow urine foliar application in wheat (Triticum aestivum)
    Indian Council of Agricultural Research, Directorate of Knowledge Management in Agriculture ; 2022
    In:  The Indian Journal of Agricultural Sciences Vol. 90, No. 3 ( 2022-11-14), p. 666-668
    Details
    In: The Indian Journal of Agricultural Sciences, Indian Council of Agricultural Research, Directorate of Knowledge Management in Agriculture, Vol. 90, No. 3 ( 2022-11-14), p. 666-668
    Abstract: The combination of inorganic fertilizers (100% RDF) with foliar application of 100% concentration of cow urine as organic source of nutrients enhanced growth and yield parameters of wheat. Hence, cow urine application with variable RDF levels could be an effective combination as integrated nutrient management tool for enhancing yields of field crops.
    Type of Medium: Online Resource
    ISSN: 2394-3319 , 0019-5022
    URL: Article
    DOI: 10.56093/ijas.v90i3.101513
    Language: Unknown
    Publisher: Indian Council of Agricultural Research, Directorate of Knowledge Management in Agriculture
    Publication Date: 2022
    detail.hit.zdb_id: 413627-5
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  • 8
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    Hepatitis B virus suppresses complement C9 synthesis by limiting the availability of transcription factor USF-1 and inhibits formation of membrane attack complex: implications in disease pathogenesis
    Springer Science and Business Media LLC ; 2022
    In:  Journal of Biomedical Science Vol. 29, No. 1 ( 2022-11-14)
    Details
    In: Journal of Biomedical Science, Springer Science and Business Media LLC, Vol. 29, No. 1 ( 2022-11-14)
    Abstract: The complement system functions primarily as a first-line host defense against invading microbes, including viruses. However, the interaction of Hepatitis B virus (HBV) with the complement-components during chronic HBV infection remains largely unknown. We investigated the mechanism by which HBV inhibits the formation of cytolytic complement membrane-attack complex (MAC) and studied its impact on MAC-mediated microbicidal activity and disease pathogenesis. Methods Blood/liver tissues were collected from chronically HBV-infected patients and controls. HepG2 hNTCP cells were infected with HBV particles and Huh7 cells were transfected with full-length linear HBV-monomer or plasmids containing different HBV-ORFs and expression of complement components or other host genes were evaluated. Additionally, ELISA, Real-time PCR, Western blot, bioinformatics analysis, gene overexpression/knock-down, mutagenesis, chromatin immunoprecipitation, epigenetic studies, immunofluorescence, and quantification of serum HBV-DNA, bacterial-DNA and endotoxin were performed. Results Among the MAC components (C5b-C9), significant reduction was noted in the expression of C9, the major constituent of MAC, in HBV-infected HepG2 hNTCP cells and in Huh7 cells transfected with full-length HBV as well as HBX. C9 level was also marked low in sera/liver of chronic hepatitis B (CHB) and Immune-tolerant (IT) patients than inactive carriers and healthy controls. HBX strongly repressed C9-promoter activity in Huh7 cells but CpG-island was not detected in C9-promoter. We identified USF-1 as the key transcription factor that drives C9 expression and demonstrated that HBX-induced hypermethylation of USF-1-promoter is the leading cause of USF-1 downregulation that in turn diminished C9 transcription. Reduced MAC formation and impaired lysis of HBV-transfected Huh7 and bacterial cells were observed following incubation of these cells with C9-deficient CHB sera but was reversed upon C9 supplementation. Significant inverse correlation was noted between C9 concentration and HBV-DNA, bacterial-DNA and endotoxin content in HBV-infected patients. One-year Tenofovir therapy resulted in improvement in C9 level and decline in viral/bacterial/endotoxin load in CHB patients. Conclusion Collectively, HBX suppressed C9 transcription by restricting the availability of USF-1 through hypermethylation of USF-1-promoter and consequently hinder the formation and lytic functions of MAC. Early therapy is needed for both CHB and IT to normalize the aberrant complement profile and contain viral and bacterial infection and limit disease progression.
    Type of Medium: Online Resource
    ISSN: 1423-0127
    URL: Article
    DOI: 10.1186/s12929-022-00876-1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 1482918-6
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  • 9
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    Contrasting Distribution of SARS-CoV-2 Lineages across Multiple Rounds of Pandemic Waves in West Bengal, the Gateway of East and North-East States of India
    American Society for Microbiology ; 2022
    In:  Microbiology Spectrum Vol. 10, No. 4 ( 2022-08-31)
    Details
    In: Microbiology Spectrum, American Society for Microbiology, Vol. 10, No. 4 ( 2022-08-31)
    Abstract: The evolution of viral variants and their impact on viral transmission have been an area of considerable importance in this pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We analyzed the viral variants in different phases of the pandemic in West Bengal, a state in India that is important geographically, and compared the variants with other states like Delhi, Maharashtra, and Karnataka, located in other regions of the country. We have identified 57 pango-lineages in 3,198 SARS-CoV-2 genomes, alteration in their distribution, as well as contrasting profiles of amino acid mutational dynamics across different waves in different states. The evolving characteristics of Delta (B.1.617.2) sublineages and alterations in hydrophobicity profiles of the viral proteins caused by these mutations were also studied. Additionally, implications of predictive host miRNA binding/unbinding to emerging spike or nucleocapsid mutations were highlighted. Our results throw considerable light on interesting aspects of the viral genomic variation and provide valuable information for improved understanding of wave-defining mutations in unfolding the pandemic. IMPORTANCE Multiple waves of infection were observed in many states in India during the coronavirus disease 2019 (COVID19) pandemic. Fine-scale evolution of major SARS-CoV-2 lineages and sublineages during four wave-window categories: Pre-Wave 1, Wave 1, Pre-Wave 2, and Wave 2 in four major states of India: Delhi (North), Maharashtra (West), Karnataka (South), and West Bengal (East) was studied using large-scale virus genome sequencing data. Our comprehensive analysis reveals contrasting molecular profiles of the wave-defining mutations and their implications in host miRNA binding/unbinding of the lineages in the major states of India.
    Type of Medium: Online Resource
    ISSN: 2165-0497
    URL: Article
    DOI: 10.1128/spectrum.00914-22
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2022
    detail.hit.zdb_id: 2807133-5
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  • 10
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    HBV quasispecies composition in Lamivudine-failed chronic hepatitis B patients and its influence on virological response to Tenofovir-based rescue therapy
    Springer Science and Business Media LLC ; 2017
    In:  Scientific Reports Vol. 7, No. 1 ( 2017-03-17)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 7, No. 1 ( 2017-03-17)
    Abstract: The present study sought to evaluate the structure of HBV quasispecies in Lamivudine (LMV)-failed chronic hepatitis B (CHB) patients and its impact in defining the subsequent virological responses to Tenofovir (TDF)-based rescue-therapy. By analyzing HBV clones encompassing reverse transcriptase (RT) and surface (S) region from LMV-failed and treatment-naïve CHB patients, we identified 5 classical and 12 novel substitutions in HBV/RT and 9 substitutions in immune-epitopes of HBV/S that were significantly associated with LMV failure. In silico analysis showed spatial proximity of some of the newly-identified, mutated RT residues to the RT catalytic centre while most S-substitutions caused alteration in epitope hydrophobicity. TDF administration resulted in virological response in 60% of LMV-failed patients at 24-week but non-response in 40% of patients even after 48-weeks. Significantly high frequencies of 6 S-substitutions and one novel RT-substitution, rtH124N with 6.5-fold-reduced susceptibility to TDF in vitro , were noted at baseline in TDF non-responders than responders. Follow-up studies depicted greater evolutionary drift of HBV quasispecies and significant decline in frequencies of 3 RT and 6 S-substitutions in responder-subgroup after 24-week TDF-therapy while most variants persisted in non-responders. Thus, we identified the HBV-RT/S variants that could potentially predict unfavorable response to LMV/TDF-therapy and impede immune-mediated viral clearance.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/srep44742
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2615211-3
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