Unveiling the structural features of CysE: a novel target for therapeutic interventions against persistent mycobacteria

World Health Organization (WHO) reports that one-third of the world’s population is infected with a persistent form of Mycobacterium tuberculosis (M.tb), the causative bacterium responsible for causing the dreaded tuberculosis disease. Targeting mycobacterial persisters is important for achieving WHO’s End TB target. The de-novo cysteine biosynthetic pathway is a novel target for addressing M.tb persistence.  The two-step pathway comprises of serine acetyltransferase/CysE and O-acetyl-serine-sulfhydrylase/OASS/CysK. The present study is an attempt to understand the structural features of mycobacterial CysE by investigating the divergence amongst orthologous through phylogenetic analysis. Mapping of mycobacterial CysE sequences on the whole orthologous (COG1045) tree segregated the species into four clusters and several isoforms leading to their descendants identification. Interestingly the analysis revealed that the extended C-terminal α-helix believed unique to M.tb is also present in other organisms such as: Campylobacter ureolyticus, Bacillus cereus, Geminocystis herdmanii and Paenibacillus borealis. Further, the Hidden Markov model search against the whole Uniprot database suggests a plausible role of C-terminal α-helix of CysE in strengthening the substrate and/or co-factor binding. In addition, phylogenetic analysis of CysE sequences from the Mycobacteriaceae family facilitates grouping them under ten well-formed and six monophyletic clades, each based on characteristic features with respect to domain architecture, oligomeric assembly, C-terminal tetra-peptide tail, regulatory and feedback mechanism etc. Employing molecular phylogeny in conjunction with structural analysis has provided detailed insights for mycobacterial CysEs as drug target

PGP Implementation with modified 3DE

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Design de fiabilidade bidimensional do software de múltiplos lançamentos tendo em conta o fator de redução de falhas na depuração imperfeita

Introduction: The present research was conducted at the University of Delhi, India in 2017. Methods: We develop a software reliability growth model to assess the reliability of software products released in multiple versions under limited availability of resources and time. The Fault Reduction Factor (frf) is considered to be constant in imperfect debugging environments while the rate of fault removal is given by Delayed S-Shaped model. Results: The proposed model has been validated on a real life four-release dataset by carrying out goodness of fit analysis. Laplace trend analysis was also conducted to judge the trend exhibited by data with respect to change in the system’s reliability. Conclusions: A number of comparison criteria have been calculated to evaluate the performance of the proposed model relative to only time-based multi-release Software Reliability Growth Model (srgm). Originality: In general, the number of faults removed is not the same as the number of failures experienced in given time intervals, so the inclusion of frf in the model makes it better and more realistic. A paradigm shift has been observed in software development from single release to multi release platform. Limitations: The proposed model can be used by software developers to take decisions regarding the release time for different versions, by either minimizing the development cost or maximizing the reliability and determining the warranty policies.Introducción: la presente investigación se realizó en la Universidad de Delhi, India en 2017. Métodos: desarrollamos un modelo de crecimiento de confiabilidad de software para evaluar la confiabilidad de los productos de software lanzados en múltiples versiones bajo disponibilidad limitada de recursos y tiempo. El factor de reducción de fallas (frf) se considera una constante en entornos de depuración imperfecta, mientras que la tasa de eliminación de fallas está dada por el modelo de forma retardada en S. Resultados: se valida el modelo propuesto en un conjunto de datos de cuatro lanzamientos de la vida real mediante un análisis de bondad de ajuste. También se aplicó el análisis de tendencia de Laplace para juzgar la tendencia que presentan los datos con respecto al cambio en la confiabilidad del sistema. Conclusiones: se calculó una serie de criterios de comparación para evaluar el rendimiento del modelo propuesto en relación con el modelo de crecimiento de confiabilidad del software (srgm) de múltiples lanzamientos basado únicamente en el tiempo. Originalidad: en general, el número de fallas eliminadas no es el mismo que el número de fallas experimentadas en intervalos de tiempo determinados, por lo que la inclusión de frf en el modelo lo mejora y lo hace más realista. Se ha observado un cambio de paradigma en el desarrollo de software, que pasa de un lanzamiento único a una plataforma múltiples lanzamientos. Limitaciones: los desarrolladores de software pueden emplear el modelo propuesto para tomar decisiones con respecto al tiempo de lanzar diferentes versiones, ya sea minimizando el costo de desarrollo o maximizando la confiabilidad y determinando las políticas de la garantía.Introdução: esta pesquisa foi realizada na Universidade de Deli, na Índia, em 2017. Métodos: desenvolvemos um modelo de crescimento de confiabilidade de software para avaliar a confiabilidade dos produtos de software lançados em múltiplas versões sob disponibilidade limitada de recursos e tempo. O fator de redução de falhas (frf) é considerado uma constante em contextos de depuração imperfeita, enquanto a taxa de eliminação de falhas é dada pelo modelo de forma retardada em S.Resultados: o modelo proposto é avaliado em um conjunto de dados de quatro lançamentos da vida real mediante uma análise de bondade de ajuste. Também foi utilizada a análise de tendência de Laplace para avaliar a tendência apresentada pelos dados com respeito à mudança na confiabilidade do sistema.Conclusões: uma série de critérios de comparação foi calculada para avaliar o rendimento do modelo proposto em relação com o modelo de crescimento de confiabilidade do software (srgm) de múltiplos lançamentos baseado unicamente no tempo.Originalidade: em geral, o número de falhas eliminadas não é o mesmo que o número de falhas existentes em intervalos de tempo determinados, sendo assim, a inclusão do frf no modelo o torna melhor e mais realista. Foi observada uma mudança de paradigma no desenvolvimento de software, que passa de um lançamento único a uma plataforma de múltiplos lançamentos.Limitações: o modelo proposto pode ser utilizado pelos desenvolvedores de software para tomar decisões com respeito ao tempo de lançar diferentes versões, seja para minimizar o custo de desenvolvimento ou maximizar a confiabilidade e determinar as políticas de garantia

ScripTONES: Sentiment-Conditioned Music Generation for Movie Scripts

Film scores are considered an essential part of the film cinematic experience, but the process of film score generation is often expensive and infeasible for small-scale creators. Automating the process of film score composition would provide useful starting points for music in small projects. In this paper, we propose a two-stage pipeline for generating music from a movie script. The first phase is the Sentiment Analysis phase where the sentiment of a scene from the film script is encoded into the valence-arousal continuous space. The second phase is the Conditional Music Generation phase which takes as input the valence-arousal vector and conditionally generates piano MIDI music to match the sentiment. We study the efficacy of various music generation architectures by performing a qualitative user survey and propose methods to improve sentiment-conditioning in VAE architectures.Comment: Presented at NeurIPS 2023 - ML For Audio workshop. To appear in proceedings of AIML Systems 2023 - Generative A

Dissecting the Role of Critical Residues and Substrate Preference of a Fatty Acyl-CoA Synthetase (FadD13) of Mycobacterium tuberculosis

Newly emerging multi-drug resistant strains of Mycobacterium tuberculosis (M.tb) severely limit the treatment options for tuberculosis (TB); hence, new antitubercular drugs are urgently needed. The mymA operon is essential for the virulence and intracellular survival of M.tb and thus represents an attractive target for the development of new antitubercular drugs. This study is focused on the structure-function relationship of Fatty Acyl-CoA Synthetase (FadD13, Rv3089) belonging to the mymA operon. Eight site-directed mutants of FadD13 were designed, constructed and analyzed for the structural-functional integrity of the enzyme. The study revealed that mutation of Lys487 resulted in ∼95% loss of the activity thus demonstrating its crucial requirement for the enzymatic activity. Comparison of the kinetic parameters showed the residues Lys172 and Ala302 to be involved in the binding of ATP and Ser404 in the binding of CoenzymeA. The influence of mutations of the residues Val209 and Trp377 emphasized their importance in maintaining the structural integrity of FadD13. Besides, we show a synergistic influence of fatty acid and ATP binding on the conformation and rigidity of FadD13. FadD13 represents the first Fatty Acyl-CoA Synthetase to display biphasic kinetics for fatty acids. FadD13 exhibits a distinct preference for C26/C24 fatty acids, which in the light of earlier reported observations further substantiates the role of the mymA operon in remodeling the cell envelope of intracellular M.tb under acidic conditions. A three-dimensional model of FadD13 was generated; the docking of ATP to the active site verified its interaction with Lys172, Ala302 and Lys487 and corresponded well with the results of the mutational studies. Our study provides a significant understanding of the FadD13 protein including the identification of residues important for its activity as well as in the maintenance of structural integrity. We believe that the findings of this study will provide valuable inputs in the development of inhibitors against the mymA operon, an important target for the development of antitubercular drugs

A rare coexistence of concurrent breast hemangioma with fibroadenoma: a case report

We report the case of a 38-year-old Asian, Indian female with capillary hemangioma breast in coexistence with the commonly occurring fibroadenoma. Clinical examination of the breast revealed a 4 cm diameter lump. Mammography revealed a well defined slightly hypoechoic lesion with smooth contours. A lumpectomy was performed. Histopathology confirmed the diagnosis of a completely encapsulated fibroadenoma coexistent with a capillary hemangioma in the adjacent breast tissue. The rarity of literature on breast hemangioma especially capillary type with coexisting fibroadenoma deserves mention

Acute post-disaster medical needs of patients with diabetes: emergency department use in New York City by diabetic adults after Hurricane Sandy.

OBJECTIVE: To evaluate the acute impact of disasters on diabetic patients, we performed a geospatial analysis of emergency department (ED) use by New York City diabetic adults in the week after Hurricane Sandy. RESEARCH DESIGN AND METHODS: Using an all-payer claims database, we retrospectively analyzed the demographics, insurance status, and medical comorbidities of post-disaster ED patients with diabetes who lived in the most geographically vulnerable areas. We compared the patterns of ED use among diabetic adults in the first week after Hurricane Sandy\u27s landfall to utilization before the disaster in 2012. RESULTS: In the highest level evacuation zone in New York City, postdisaster increases in ED visits for a primary or secondary diagnosis of diabetes were attributable to a significantly higher proportion of Medicare patients. Emergency visits for a primary diagnosis of diabetes had an increased frequency of certain comorbidities, including hypertension, recent procedure, and chronic skin ulcers. Patients with a history of diabetes visited EDs in increased numbers after Hurricane Sandy for a primary diagnosis of myocardial infarction, prescription refills, drug dependence, dialysis, among other conditions. CONCLUSIONS: We found that diabetic adults aged 65 years and older are especially at risk for requiring postdisaster emergency care compared to other vulnerable populations. Our findings also suggest that there is a need to support diabetic adults particularly in the week after a disaster by ensuring access to medications, aftercare for patients who had a recent procedure, and optimize their cardiovascular health to reduce the risk of heart attacks

Awareness, knowledge, and barriers to low vision services among eye care practitioners in Maharashtra

Background: Visual impairment is an important global health issue. 90% of the world's blind people reside in underdeveloped countries. According to population-based statistics, India has the most visually impaired persons (about 9 million). The world health organization (WHO) estimates that 285 million people worldwide are blind or have impaired eyesight. Hence it is necessary to have information about knowledge and awareness of low vision services among eye care practitioners to improve the low vision care in the world.Methods: A prospective cross-sectional survey was done at Dr. D. Y. Patil medical college and research centre (Ophthalmology department) between eye care practitioners practicing in Maharashtra, India, through a pre-tested standardized questionnaire.Results: In this study, retinal problems (76.1%) and glaucoma (11.1%) were reported as two major causes of low vision. Provision of best spectacle correction, rehabilitation, and referral to other hospitals/specialized centers was considered by 31.7%, 4.7%, and 23.8% practitioners, respectively. Magnifiers were found to be the most commonly prescribed low vision device (73%).Conclusions: Low eyesight is a big health issue all over the world. Low vision services assist patients in improving and maintain their functional vision. It also enhances the quality of life and everyday living skills. There are many barriers and a lack of understanding about low vision services. They assess eye care providers' awareness, knowledge, and challenges to poor vision services in Maharashtra. This study results showed a lack of awareness (33.3%) and training (33.3%) among the practitioners were the significant barriers restricting low vision services