cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.20394/2kkeoyfd
title: Adzuna panel dataset series: local authority and travel to work areas

description: This Adzuna data product is comprised of two series of panel datasets, one at the Local Authority level and the other at the Travel to Work Area level. Both series cover Great Britain and contain weekly counts of the number of Adzuna vacancies between April 2016 and December 2023. Disaggregated counts of the number of vacancies by pay frequency - hourly, daily, weekly and annual salaries – are also provided, as are breakdowns by sector, advert seniority and occupation. 

Since not all Adzuna vacancies can be assigned to a local authority or travel to work area, a supplementary dataset on panel sample sizes has been provided. This dataset can assist researchers in understanding the trade-off they face when choosing between panels with more granular breakdowns (with smaller vacancy coverages) and more aggregate panels (with larger vacancy coverages).
DOI: 10.6084/m9.figshare.24886903
title: High-throughput screening and <i>in vitro</i> evaluation of CSB-0914; a novel small molecule NF-κB inhibitor attenuating inflammatory responses through NF-κB, Nrf2 and HO-1 cross-talk

description: Unpleasant side effects of standard inflammatory drugs urges search for novel therapeutic candidates. This study aims in identifying novel anti-inflammatory NF-κB inhibitor by high-throughput computational and in-vitro pre-clinical approaches. Lead candidate selection was conducted by the use of computational docking molecular-dynamic simulations. The RBL-2H3 cell line, derived from rat basophils, was used to evaluate the release of cytokines and degranulation. The study focused on the study of neutrophil elastase and its role in cellular motility. Flow cytometry was utilized to evaluate the activation of basophils and the expression of critical signaling proteins. High throughput screening identified CSB-0914 to stably bind NF-κB-p50 subunit. Dose based loss in T NF-α and IL-2 release were observed in RBL-2H3 cells in addition to degranulation inhibition by CSB-0914. The compound demonstrated significant efficacy in reducing basophil activation assay induced by FcεRI receptors, with an IC50 value of 98.41 nM.. A dose dependent decrease in neutrophil migration and elastase were observed when treated with CSB- 0914. The compound was effective in decreasing. Upon stimulation, RBL-2H3 cells exhibited phosphorylation of NF-κB p-65 as well as upregulation of the Nrf2 and HO-1 signaling pathways. Collectively, our study has successfully identified a novel inhibitor called CSB-0914 that effectively regulates inflammatory responses. These reactions are primarily mediated by the interplay between NF-κB, Nrf2, and HO-1. The findings of this study provide support for the need to conduct more research on CSB-0914 with the aim of its development as a pharmaceutical agent for anti-inflammatory purposes.
DOI: 10.6084/m9.figshare.24886903.v1
title: High-throughput screening and <i>in vitro</i> evaluation of CSB-0914; a novel small molecule NF-κB inhibitor attenuating inflammatory responses through NF-κB, Nrf2 and HO-1 cross-talk

description: Unpleasant side effects of standard inflammatory drugs urges search for novel therapeutic candidates. This study aims in identifying novel anti-inflammatory NF-κB inhibitor by high-throughput computational and in-vitro pre-clinical approaches. Lead candidate selection was conducted by the use of computational docking molecular-dynamic simulations. The RBL-2H3 cell line, derived from rat basophils, was used to evaluate the release of cytokines and degranulation. The study focused on the study of neutrophil elastase and its role in cellular motility. Flow cytometry was utilized to evaluate the activation of basophils and the expression of critical signaling proteins. High throughput screening identified CSB-0914 to stably bind NF-κB-p50 subunit. Dose based loss in T NF-α and IL-2 release were observed in RBL-2H3 cells in addition to degranulation inhibition by CSB-0914. The compound demonstrated significant efficacy in reducing basophil activation assay induced by FcεRI receptors, with an IC50 value of 98.41 nM.. A dose dependent decrease in neutrophil migration and elastase were observed when treated with CSB- 0914. The compound was effective in decreasing. Upon stimulation, RBL-2H3 cells exhibited phosphorylation of NF-κB p-65 as well as upregulation of the Nrf2 and HO-1 signaling pathways. Collectively, our study has successfully identified a novel inhibitor called CSB-0914 that effectively regulates inflammatory responses. These reactions are primarily mediated by the interplay between NF-κB, Nrf2, and HO-1. The findings of this study provide support for the need to conduct more research on CSB-0914 with the aim of its development as a pharmaceutical agent for anti-inflammatory purposes.
DOI: 10.6084/m9.figshare.24972935
title: A computational strategy for systematic virtual screening of plasmodium falciparum heme detoxification protein inhibitors from the Drugbank database

description: Antimalarial drug resistance poses one of the greatest threats to malaria treatment, resulting in increased morbidity and mortality. Heme Detoxification Protein (HDP) is among the essential hemoglobinases of P. falciparum (Pf), a vital molecular target for the treatment of malaria. In this study, we utilized the virtual screening workflow tool of the Schrodinger suite to find the best hits for the PfHDP from the DrugBank library. A total of 14,942 compounds were identified against the PfHDP. The top compounds with the highest docking scores and least energy scores were subjected to molecular simulations for 500 nanosecond to check the stability of the protein-drug complexes. The top three DrugBank compounds were found to be stable over 500 ns, namely DB09298 (silibinin), DB07426 (1-Hydroxy-2-(1,1':3',1''-Terphenyl-3-Yloxy) Ethane-1,1-Diyl] Bis (Phosphonic Acid), and DB07410 [(2-(3-Dibenzofuran-4-yl-Phenyl)-1-Hydroxy-1-Phosphono-Ethyl]-Phosphonic Acid). Overall analysis suggests that the top three compounds, DB09298, DB07426, and DB07410, have good stability for 500 ns. Their scaffolds can be used to design and develop new analogs of the target HDP protein. Silibinin, the anti-cancer drug, was found to be highly stable for the entire simulation period as compared to the other compounds. DB07426 shows its therapeutic effect on bones, especially in the treatment of osteoporosis, and DB07410 has anti-tumor, antibacterial, anti-oxidative, and anti-viral activities. All three compounds can be considered for repurposing as antimalarial drugs to evaluate the binding capacity or inhibition potential of these compounds. Further in-vivo and in-vitro analysis against the PfHDP protein should be conducted.
DOI: 10.6084/m9.figshare.24972935.v1
title: A computational strategy for systematic virtual screening of plasmodium falciparum heme detoxification protein inhibitors from the Drugbank database

description: Antimalarial drug resistance poses one of the greatest threats to malaria treatment, resulting in increased morbidity and mortality. Heme Detoxification Protein (HDP) is among the essential hemoglobinases of P. falciparum (Pf), a vital molecular target for the treatment of malaria. In this study, we utilized the virtual screening workflow tool of the Schrodinger suite to find the best hits for the PfHDP from the DrugBank library. A total of 14,942 compounds were identified against the PfHDP. The top compounds with the highest docking scores and least energy scores were subjected to molecular simulations for 500 nanosecond to check the stability of the protein-drug complexes. The top three DrugBank compounds were found to be stable over 500 ns, namely DB09298 (silibinin), DB07426 (1-Hydroxy-2-(1,1':3',1''-Terphenyl-3-Yloxy) Ethane-1,1-Diyl] Bis (Phosphonic Acid), and DB07410 [(2-(3-Dibenzofuran-4-yl-Phenyl)-1-Hydroxy-1-Phosphono-Ethyl]-Phosphonic Acid). Overall analysis suggests that the top three compounds, DB09298, DB07426, and DB07410, have good stability for 500 ns. Their scaffolds can be used to design and develop new analogs of the target HDP protein. Silibinin, the anti-cancer drug, was found to be highly stable for the entire simulation period as compared to the other compounds. DB07426 shows its therapeutic effect on bones, especially in the treatment of osteoporosis, and DB07410 has anti-tumor, antibacterial, anti-oxidative, and anti-viral activities. All three compounds can be considered for repurposing as antimalarial drugs to evaluate the binding capacity or inhibition potential of these compounds. Further in-vivo and in-vitro analysis against the PfHDP protein should be conducted.
DOI: 10.6084/m9.figshare.24877832
title: <i>In-silico</i> development of multi-epitope subunit vaccine against lymphatic filariasis

description: The World Health Organization in 2022 reported that more than 863 million people in 50 countries are at risk of developing lymphatic filariasis (LF), a disease caused by parasitic infection. Immune responses to parasites suggest that the development of a prophylactic vaccine against LF is possible. Using a reverse vaccinology approach, the current study identified Trehalose-6-phosphatase (TPP) as a potential vaccine candidate among 15 reported vaccine antigens for <i>B. malayi</i>. High-ranking B and T-cell epitopes in the Trehalose-6-phosphatase (TPP) were shortlisted using online servers for subsequent analysis. We selected these peptides to construct a vaccine model using I-TASSER and GalaxyRefine server. The vaccine construct showed favorable physicochemical properties, high antigenicity, no allergenicity, no toxicity, and high stability. Structural validation using the Ramachandran plot showed that 98% of the residues were in favorable or mostly allowed regions. Molecular docking and simulation showed a strong binding affinity and stability of the subunit vaccine with toll-like receptor 4 (TLR4). Furthermore, the subunit vaccine showed a strong IgG/IgM response, with the disappearance of the antigen. We propose that our vaccine construct should be further evaluated using cellular and animal models to develop a vaccine that is safe and effective against LF.
DOI: 10.6084/m9.figshare.24877832.v1
title: <i>In-silico</i> development of multi-epitope subunit vaccine against lymphatic filariasis

description: The World Health Organization in 2022 reported that more than 863 million people in 50 countries are at risk of developing lymphatic filariasis (LF), a disease caused by parasitic infection. Immune responses to parasites suggest that the development of a prophylactic vaccine against LF is possible. Using a reverse vaccinology approach, the current study identified Trehalose-6-phosphatase (TPP) as a potential vaccine candidate among 15 reported vaccine antigens for <i>B. malayi</i>. High-ranking B and T-cell epitopes in the Trehalose-6-phosphatase (TPP) were shortlisted using online servers for subsequent analysis. We selected these peptides to construct a vaccine model using I-TASSER and GalaxyRefine server. The vaccine construct showed favorable physicochemical properties, high antigenicity, no allergenicity, no toxicity, and high stability. Structural validation using the Ramachandran plot showed that 98% of the residues were in favorable or mostly allowed regions. Molecular docking and simulation showed a strong binding affinity and stability of the subunit vaccine with toll-like receptor 4 (TLR4). Furthermore, the subunit vaccine showed a strong IgG/IgM response, with the disappearance of the antigen. We propose that our vaccine construct should be further evaluated using cellular and animal models to develop a vaccine that is safe and effective against LF.
DOI: 10.6084/m9.figshare.25196047.v1
title: A comprehensive bioinformatics analysis identifies mitophagy biomarkers and potential Molecular mechanisms in hypertensive nephropathy

description: Mitophagy, the selective removal of damaged mitochondria, plays a critical role in kidney diseases, but its involvement in hypertensive nephropathy (HTN) is not well understood. To address this gap, we investigated mitophagy-related genes in HTN, identifying potential biomarkers for diagnosis and treatment. Transcriptome datasets from the Gene Expression Omnibus database were analyzed, resulting in the identification of seven mitophagy related differentially expressed genes (MR-DEGs), namely PINK1, ULK1, SQSTM1, ATG5, ATG12, MFN2, and UBA52. Further, we explored the correlation between MR-DEGs, immune cells, and inflammatory factors. The identified genes demonstrated a strong correlation with Mast cells, T-cells, TGFβ3, IL13, and CSF3. Machine learning techniques were employed to screen important genes, construct diagnostic models, and evaluate their accuracy. Consensus clustering divided the HTN patients into two mitophagy subgroups, with Subgroup 2 showing higher levels of immune cell infiltration and inflammatory factors. The functions of their proteins primarily involve complement, coagulation, lipids, and vascular smooth muscle contraction. Single-cell RNA sequencing revealed that mitophagy was most significant in proximal tubule cells (PTC) in HTN patients. Pseudotime analysis of PTC confirmed the expression changes observed in the transcriptome. Intercellular communication analysis suggested that mitophagy might regulate PTC's participation in intercellular crosstalk. Notably, specific transcription factors such as HNF4A, PPARA, and STAT3 showed strong correlations with mitophagy-related genes in PTC, indicating their potential role in modulating PTC function and influencing the onset and progression of HTN. This study offers a comprehensive analysis of mitophagy in HTN, enhancing our understanding of the pathogenesis, diagnosis, and treatment of HTN.
DOI: 10.6084/m9.figshare.24885046
title: Evaluation of substrate specificity and catalytic promiscuity of <i>Bacillus albus</i> cellulase: an insight into <i>in silico</i> proteomic study aiming at enhanced production of renewable energy

description: Cellulases are enzymes that aid in the hydrolysis of cellulosic fibers and have a wide range of industrial uses. In the present <i>in silico</i> study, sequence alignment between cellulases from different <i>Bacillus</i> species revealed that most of the residues are conserved in those aligned enzymes. Three dimensional structures of cellulase enzymes from 23 different <i>Bacillus</i> species have been predicted and based on the alignment between the modeled structures, those enzymes have been categorized into 7 different groups according to the homology in their conformational folds. There are two structural contents in Gr-I cellulase namely β1-α2 and β3-α5 loops which varies greatly according to their static position. Molecular docking study between the <i>B. albus</i> cellulase and its various cellulosic substrates including xylanoglucan oligosaccharides revealed that residues <i>viz.</i> Phe154, Tyr258, Tyr282, Tyr285, and Tyr376 of <i>B. albus</i> cellulase are significantly involved in formation stacking interaction during enzyme-substrate binding. Residue interaction network and binding energy analysis for the <i>B. albus</i> cellulase with different cellulosic substrates depicted the strong affinity of XylGlc3 substrate with the receptor enzyme. Molecular interaction and molecular dynamics simulation studies exhibited structural stability of enzyme-substrate complexes which are greatly influenced by the presence of catalytic promiscuity in their substrate binding sites. Screening of <i>B. albus</i> in carboxymethylcellulose (CMC) and xylan supplemented agar media revealed the capability of the bacterium in degrading both cellulose and xylan. Overall, the study demonstrated <i>B. albus</i> cellulase as an effective biocatalyst candidate with the potential role of catalytic promiscuity for possible applications in biofuel industries.
DOI: 10.6084/m9.figshare.24885046.v1
title: Evaluation of substrate specificity and catalytic promiscuity of <i>Bacillus albus</i> cellulase: an insight into <i>in silico</i> proteomic study aiming at enhanced production of renewable energy

description: Cellulases are enzymes that aid in the hydrolysis of cellulosic fibers and have a wide range of industrial uses. In the present <i>in silico</i> study, sequence alignment between cellulases from different <i>Bacillus</i> species revealed that most of the residues are conserved in those aligned enzymes. Three dimensional structures of cellulase enzymes from 23 different <i>Bacillus</i> species have been predicted and based on the alignment between the modeled structures, those enzymes have been categorized into 7 different groups according to the homology in their conformational folds. There are two structural contents in Gr-I cellulase namely β1-α2 and β3-α5 loops which varies greatly according to their static position. Molecular docking study between the <i>B. albus</i> cellulase and its various cellulosic substrates including xylanoglucan oligosaccharides revealed that residues <i>viz.</i> Phe154, Tyr258, Tyr282, Tyr285, and Tyr376 of <i>B. albus</i> cellulase are significantly involved in formation stacking interaction during enzyme-substrate binding. Residue interaction network and binding energy analysis for the <i>B. albus</i> cellulase with different cellulosic substrates depicted the strong affinity of XylGlc3 substrate with the receptor enzyme. Molecular interaction and molecular dynamics simulation studies exhibited structural stability of enzyme-substrate complexes which are greatly influenced by the presence of catalytic promiscuity in their substrate binding sites. Screening of <i>B. albus</i> in carboxymethylcellulose (CMC) and xylan supplemented agar media revealed the capability of the bacterium in degrading both cellulose and xylan. Overall, the study demonstrated <i>B. albus</i> cellulase as an effective biocatalyst candidate with the potential role of catalytic promiscuity for possible applications in biofuel industries.
DOI: 10.6084/m9.figshare.25196047
title: A comprehensive bioinformatics analysis identifies mitophagy biomarkers and potential Molecular mechanisms in hypertensive nephropathy

description: Mitophagy, the selective removal of damaged mitochondria, plays a critical role in kidney diseases, but its involvement in hypertensive nephropathy (HTN) is not well understood. To address this gap, we investigated mitophagy-related genes in HTN, identifying potential biomarkers for diagnosis and treatment. Transcriptome datasets from the Gene Expression Omnibus database were analyzed, resulting in the identification of seven mitophagy related differentially expressed genes (MR-DEGs), namely PINK1, ULK1, SQSTM1, ATG5, ATG12, MFN2, and UBA52. Further, we explored the correlation between MR-DEGs, immune cells, and inflammatory factors. The identified genes demonstrated a strong correlation with Mast cells, T-cells, TGFβ3, IL13, and CSF3. Machine learning techniques were employed to screen important genes, construct diagnostic models, and evaluate their accuracy. Consensus clustering divided the HTN patients into two mitophagy subgroups, with Subgroup 2 showing higher levels of immune cell infiltration and inflammatory factors. The functions of their proteins primarily involve complement, coagulation, lipids, and vascular smooth muscle contraction. Single-cell RNA sequencing revealed that mitophagy was most significant in proximal tubule cells (PTC) in HTN patients. Pseudotime analysis of PTC confirmed the expression changes observed in the transcriptome. Intercellular communication analysis suggested that mitophagy might regulate PTC's participation in intercellular crosstalk. Notably, specific transcription factors such as HNF4A, PPARA, and STAT3 showed strong correlations with mitophagy-related genes in PTC, indicating their potential role in modulating PTC function and influencing the onset and progression of HTN. This study offers a comprehensive analysis of mitophagy in HTN, enhancing our understanding of the pathogenesis, diagnosis, and treatment of HTN.
DOI: 10.6084/m9.figshare.24864342
title: Molecular dynamics simulations show how antibodies may rescue HIV-1 mutants incapable of infecting host cells

description: High mutation and replication rates of HIV-1 result in the continuous generation of variants, allowing it to adapt to changing host environments. Mutations often have deleterious effects, but variants carrying them are rapidly purged. Surprisingly, a particular variant incapable of entering host cells was found to be rescued by host antibodies targeting HIV-1. Understanding the molecular mechanism of this rescue is important to develop and improve antibody-based therapies. To unravel the underlying mechanisms, we performed fully atomistic molecular dynamics simulations of the HIV-1 gp41 trimer responsible for viral entry into host cells, its entry-deficient variant, and its complex with the rescuing antibody. We find that the Q563R mutation, which the entry-deficient variant carries, prevents the native conformation of the gp41 6-helix bundle required for entry and stabilizes an alternative conformation instead. This is the consequence of substantial changes in the secondary structure and interactions between the domains of gp41. Binding of the antibody F240 to gp41 reverses these changes and re-establishes the native conformation, resulting in rescue. To test the generality of this mechanism, we performed simulations with the entry-deficient L565A variant and antibody 3D6. We find that 3D6 binding was able to reverse structural and interaction changes introduced by the mutation and restore the native gp41 conformation. Viral variants may not only escape antibodies but be aided by them in their survival, potentially compromising antibody-based therapies, including vaccination and passive immunization. Our simulation framework could serve as a tool to assess the likelihood of such resistance against specific antibodies.
DOI: 10.6084/m9.figshare.24864342.v1
title: Molecular dynamics simulations show how antibodies may rescue HIV-1 mutants incapable of infecting host cells

description: High mutation and replication rates of HIV-1 result in the continuous generation of variants, allowing it to adapt to changing host environments. Mutations often have deleterious effects, but variants carrying them are rapidly purged. Surprisingly, a particular variant incapable of entering host cells was found to be rescued by host antibodies targeting HIV-1. Understanding the molecular mechanism of this rescue is important to develop and improve antibody-based therapies. To unravel the underlying mechanisms, we performed fully atomistic molecular dynamics simulations of the HIV-1 gp41 trimer responsible for viral entry into host cells, its entry-deficient variant, and its complex with the rescuing antibody. We find that the Q563R mutation, which the entry-deficient variant carries, prevents the native conformation of the gp41 6-helix bundle required for entry and stabilizes an alternative conformation instead. This is the consequence of substantial changes in the secondary structure and interactions between the domains of gp41. Binding of the antibody F240 to gp41 reverses these changes and re-establishes the native conformation, resulting in rescue. To test the generality of this mechanism, we performed simulations with the entry-deficient L565A variant and antibody 3D6. We find that 3D6 binding was able to reverse structural and interaction changes introduced by the mutation and restore the native gp41 conformation. Viral variants may not only escape antibodies but be aided by them in their survival, potentially compromising antibody-based therapies, including vaccination and passive immunization. Our simulation framework could serve as a tool to assess the likelihood of such resistance against specific antibodies.