Binding Pattern Determination Of Class of Antifungal Drugs

Crystal Structure of cytochrome p450 2B4 has 476 amino acids, through docking approach we have attempted to explain the specificity of CYP2B4, total 28 imidazole drug were used for the studies as antifungal drugs in which bound bifonazole (reference) shows the binding energy of -8.67 kcal/mol .Compound Miconazole shows the minimum binding energy of -10.45 kcal/mol. The 2B4-bifonazole structure identified 10 residues (ALA 298, GLY 299, GLU 301, THR 302, ILE 363, VAL 292) within 6.5 Å of the active site of bifonazole. GLU 301, THR 302 are also located in 6.5 Å of the bound ligand in 2B4 structure. Due to the presence of the multiple binding substrates in cytochrome p450, it acts as the major target of many drugs in xenobiotic metabolism.
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BRCA1 and BRCA2 Variation in Taiwanese General Population and the Cancer Cohort

BRCA1 and BRCA2 (BRCA) play essential roles in maintaining genome stability. Rapidly evolving human BRCA generates oncogenic variants causing high cancer risk. BRCA variation is ethnic-specific in reflecting adaptation and/or effects of genetic drift. Taiwanese population of 23.8 million is an admixture of multiple ethnic origins; Taiwan’s subtropical and tropical climate and geographically islandic location provide a unique natural environment. Therefore, Taiwanese population provides a unique model to study human BRCA variation. Through collecting, standardizing, annotating, and classifying publicly available BRCA variants derived from Taiwanese general population and the cancer cohort, we identified 335 BRCA variants, of which 164 were from 1,517 non-cancer individuals, 126 from 2,665 cancer individuals, and 45 from both types of individuals. We compared the variant data with those from other ethnic populations such as mainland Chinese, Macau Chinese, Japanese, Korean, Indian, and non-Asians. We observed that the sharing rates with other Asian ethnic populations were correlated with its genetic relationship. Over 60% of the 335 Taiwanese BRCA variants were VUS, unclassified variants, or novel variants, reflecting the ethnic-specific features of Taiwanese BRCA variation. While it remains challenging to classify these variants, our structural and in silico analyses predicted their enrichment of BRCA deleterious variants. We further determined the 3.8% prevalence of BRCA pathogenic variants in the Taiwanese breast cancer cohort, and determined 0.53% prevalence of the BRCA pathogenic variants in Taiwanese general population, with the estimated 126,140 BRCA pathogenic variant carriers. We identified BRCA2 c.5164_5165delAG at BRCA2 BRC6 motif as a potential founder mutation in Taiwanese population. Our study on BRCA variation in Taiwanese and other East Asian populations demonstrates that ethnic specificity is a common phenomenon for BRCA variation in East Asian population; the data generated from the study provide a reference for clinical applications in BRCA-related cancer in Taiwanese population

Annotated Speech Corpus for Low Resource Indian Languages: Awadhi, Bhojpuri, Braj and Magahi

In this paper we discuss an in-progress work on the development of a speech corpus for four low-resource Indo-Aryan languages -- Awadhi, Bhojpuri, Braj and Magahi using the field methods of linguistic data collection. The total size of the corpus currently stands at approximately 18 hours (approx. 4-5 hours each language) and it is transcribed and annotated with grammatical information such as part-of-speech tags, morphological features and Universal dependency relationships. We discuss our methodology for data collection in these languages, most of which was done in the middle of the COVID-19 pandemic, with one of the aims being to generate some additional income for low-income groups speaking these languages. In the paper, we also discuss the results of the baseline experiments for automatic speech recognition system in these languages.Comment: Speech for Social Good Workshop, 2022, Interspeech 202

Using Portuguese BRCA pathogenic variation as a model to study the impact of human admixture on human health

This study was supported by grants from the Macau Science and Technology Development Fund (085/2017/A2, 0077/2019/AMJ) (SMW), 0032/2022/A1 (SMW, XD), the University of Macau (SRG2017-00097-FHS, MYRG2019-00018-FHS, MYRG2020-00094-FHS) (SMW), SRG2023-00007-FHS (XD), the Faculty of Health Sciences, University of Macau (FHSIG/SW/0007/2020P, MOE Frontiers Science Center for Precision Oncology pilot grant, and a startup fund) (SMW); Lisbon Polytechnic Institute research grant (MB). Stephanie Andaluz is supported by a fellowship from the International Affairs Office of the University of Macau.Background: Admixture occurs between different ethnic human populations. The global colonization in recent centuries by Europeans led to the most significant admixture in human history. While admixture may enhance genetic diversity for better fitness, it may also impact on human health by transmitting genetic variants for disease susceptibility in the admixture population. The admixture by Portuguese global exploration initiated in the 15th century has reached over 20 million of Portuguese-heritage population worldwide. It provides a valuable model to study the impact of admixture on human health. BRCA1 and BRCA2 (BRCA) are two of the important tumor suppressor genes. The pathogenic variation (PV) in BRCA is well determined to cause a high risk of hereditary breast and ovarian cancer. Tracing the distribution of Portuguese BRCA PV in the Portuguese-heritage population will help to understand the impact of admixture on cancer susceptibility in modern humans. In this study, we analyzed the distribution of the Portuguese-originated BRCA variation in the Brazilian population, which has a high degree of Portuguese heritage. Methods: By comprehensive data mining, standardization, and annotation, we generated a Portuguese-derived BRCA variation dataset and a Brazilian-derived BRCA variation dataset. We compared the two BRCA variation datasets to identify the BRCA variants shared between the two populations. Results: The Portuguese-derived BRCA variation dataset consists of 220 BRCA variants including 78 PVs from 11,482 Portuguese cancer patients, 93 (42.2%) in BRCA1 and 127 (57.7%) in BRCA2. Of the 556 Portuguese BRCA PV carriers carrying the 78 PVs, 331 (59.5%) carried the three Portuguese-BRCA founder PVs of BRCA1 c.2037delinsCC, BRCA1 c.3331_3334del and BRCA2 c.156_157insAlu. The Brazilian-derived BRCA variation dataset consists of 255 BRCA PVs from 7,711 cancer patients, 136 (53.3%) in BRCA1 and 119 (46.6%) in BRCA2. We developed an open database named dbBRCA-Portuguese (https://genemutation.fhs.um.edu.mo/dbbrca-portuguese/) and an open database named dbBRCA-Brazilian (https://genemutation.fhs.um.edu.mo/dbbrca-brazilian) to host the BRCA variation data from Portuguese and Brazilian populations. We compared the BRCA PV datasets between Portuguese and Brazilian populations and identified 29 Portuguese-specific BRCA PVs shared between Portuguese and Brazilian populations, 14 in BRCA1 including the Portuguese founder BRCA1 c.3331_3334del and BRCA1 c.2037delinsCC, and 15 in BRCA2 including the Portuguese founder BRCA2 c.156_157insAlu. Searching the 78 Portuguese BRCA PVs in over 5,000 ancient human genomes identified evolution origin for only 8 PVs in Europeans dated between 37,470 and 3,818 years before the present, confirming the Portuguese-specificity of Portuguese BRCA PVs; comparing the 78 Portuguese BRCA PVs Portuguese, 255 Brazilian BRCA PVs, and 134 African BRCA PVs showed little overlapping, ruling out the possibility that the BRCA PVs shared between Portuguese and Brazilian may also be contributed by African. Conclusion: Our study provides evidence that the admixture in recent human history contributed to cancer susceptibility in modern humans.info:eu-repo/semantics/publishedVersio

High fidelity simulation of the endoscopic transsphenoidal approach: Validation of the UpSurgeOn TNS Box

Objective: Endoscopic endonasal transsphenoidal surgery is an established technique for the resection of sellar and suprasellar lesions. The approach is technically challenging and has a steep learning curve. Simulation is a growing training tool, allowing the acquisition of technical skills pre-clinically and potentially resulting in a shorter clinical learning curve. We sought validation of the UpSurgeOn Transsphenoidal (TNS) Box for the endoscopic endonasal transsphenoidal approach to the pituitary fossa./ Methods: Novice, intermediate and expert neurosurgeons were recruited from multiple centres. Participants were asked to perform a sphenoidotomy using the TNS model. Face and content validity were evaluated using a post-task questionnaire. Construct validity was assessed through post-hoc blinded scoring of operative videos using a Modified Objective Structured Assessment of Technical Skills (mOSAT) and a Task-Specific Technical Skill scoring system./ Results: Fifteen participants were recruited of which n = 10 (66.6%) were novices and n = 5 (33.3%) were intermediate and expert neurosurgeons. Three intermediate and experts (60%) agreed that the model was realistic. All intermediate and experts (n = 5) strongly agreed or agreed that the TNS model was useful for teaching the endonasal transsphenoidal approach to the pituitary fossa. The consensus-derived mOSAT score was 16/30 (IQR 14–16.75) for novices and 29/30 (IQR 27–29) for intermediate and experts (p < 0.001, Mann–Whitney U). The median Task-Specific Technical Skill score was 10/20 (IQR 8.25–13) for novices and 18/20 (IQR 17.75–19) for intermediate and experts (p < 0.001, Mann-Whitney U). Interrater reliability was 0.949 (CI 0.983–0.853) for OSATS and 0.945 (CI 0.981–0.842) for Task-Specific Technical Skills. Suggested improvements for the model included the addition of neuro-vascular anatomy and arachnoid mater to simulate bleeding vessels and CSF leak, respectively, as well as improvement in materials to reproduce the consistency closer to that of human tissue and bone./ Conclusion: The TNS Box simulation model has demonstrated face, content, and construct validity as a simulator for the endoscopic endonasal transsphenoidal approach. With the steep learning curve associated with endoscopic approaches, this simulation model has the potential as a valuable training tool in neurosurgery with further improvements including advancing simulation materials, dynamic models (e.g., with blood flow) and synergy with complementary technologies (e.g., artificial intelligence and augmented reality)