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Aberrant activation of the cell cycle of terminally-differentiated neurons results in their apoptosis and is known to contribute to neuronal loss in various neurodegenerative disorders like Alzheimer's Disease. However, the mechanisms that regulate Cell Cycle Related Neuronal Apoptosis (CRNA) are poorly understood. We identified several miRNA that are dysregulated in neurons from a transgenic APP/PS1 mouse model for AD (TgAD). Several of these miRNA are known to and/or are predicted to target cell cycle-related genes. Detailed investigation on miR-449a revealed: a. it promotes neuronal differentiation by suppressing the neuronal cell cycle; b. its expression in cortical neurons was impaired in response to amyloid peptide Aß42; c. loss of its expression resulted in aberrant activation of the cell cycle leading to apoptosis. miR-449a may prevent CRNA by targeting cyclin D1 and protein phosphatase CDC25A, which are important for G1-S transition. Importantly, the lentiviral mediated delivery of miR-449a in TgAD mouse brain significantly reverted the defects in learning and memory, which are associated with AD.
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Besides its functions in the skeletomuscular system, vitamin D is known to alleviate viral-inflicted pathologies. However, the mechanism underlying protective vitamin D function remains unclear. We examined the role of vitamin D in controlling cellular infections by Chandipura virus, an RNA virus implicated in human epidemics. How immune signaling pathways, including those regulating NF-κB and IFN regulatory factors (IRFs), are activated in virus-infected cells has been well studied. Our investigation involving human- and mouse-derived cells revealed that vitamin D instructs the homeostatic state of these antiviral pathways, leading to cellular resilience to subsequent viral infections. In particular, vitamin D provoked autoregulatory type 1 IFN-IRF7 signaling even in the absence of virus infection by downmodulating the expression of the IFN-inhibitory NF-κB subunit RelB. Indeed, RelB deficiency rendered vitamin D treatment redundant, whereas IRF7 depletion abrogated antiviral vitamin D action. In sum, immune signaling homeostasis appears to connect micronutrients to antiviral immunity at the cellular level. The proposed link may have a bearing on shaping public health policy during an outbreak.
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Mycobacterium tuberculosis encodes ~200 transcription factors that modulate gene expression under different microenvironments in the host. Even though high-throughput chromatin immunoprecipitation sequencing and transcriptome sequencing (RNA-seq) studies have identified the regulatory network for ~80% of transcription factors, many transcription factors remain uncharacterized. EmbR is one such transcription factor whose in vivo regulon and biological function are yet to be elucidated. Previous in vitro studies suggested that phosphorylation of EmbR by PknH upregulates the embCAB operon. Using a gene replacement mutant of embR, we investigated its role in modulating cellular morphology, antibiotic resistance, and survival in the host. Contrary to the prevailing hypothesis, under normal growth conditions, EmbR is neither phosphorylated nor impacted by ethambutol resistance through the regulation of the embCAB operon. The embR deletion mutant displayed attenuated M. tuberculosis survival in vivo. RNA-seq analysis suggested that EmbR regulates operons involved in the secretion pathway, lipid metabolism, virulence, and hypoxia, including well-known hypoxia-inducible genes devS and hspX. Lipidome analysis revealed that EmbR modulates levels of all lysophospholipids, several phospholipids, and M. tuberculosis-specific lipids, which is more pronounced under hypoxic conditions. We found that the EmbR mutant is hypersusceptible to hypoxic stress, and RNA sequencing performed under hypoxic conditions indicated that EmbR majorly regulates genes involved in response to acidic pH, hypoxia, and fatty acid metabolism. We observed condition-specific phosphorylation of EmbR, which contributes to EmbR-mediated transcription of several essential genes, ensuring enhanced survival. Collectively, the study establishes EmbR as a key modulator of hypoxic response that facilitates mycobacterial survival in the host. IMPORTANCE Mycobacterium tuberculosis modulates its transcriptional machinery in response to dynamic microenvironments encountered within the host. In this study, we identified that EmbR, a transcription factor, plays important roles in modulating cellular morphology, antibiotic resistance, and survival in the host. We found that EmbR undergoes condition-specific phosphorylation for its activation. Together, the study establishes a key role of EmbR as a transcriptional activator of genes belonging to multiple pathways, viz., virulence, secretion, or polyketide synthesis, that aid in mycobacterial survival during hypoxia and within the host.
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Proteínas Bacterianas , Mycobacterium tuberculosis , Factores de Transcripción , Factores de Virulencia , Proteínas Bacterianas/metabolismo , Regulación Bacteriana de la Expresión Génica , Hipoxia , Mycobacterium tuberculosis/metabolismo , Factores de Transcripción/metabolismo , Factores de Virulencia/genética , Factores de Virulencia/metabolismoRESUMEN
All approved coronavirus disease 2019 (COVID-19) vaccines in current use are safe, effective, and reduce the risk of severe illness. Although data on the immunological presentation of patients with COVID-19 is limited, increasing experimental evidence supports the significant contribution of B and T cells towards the resolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Despite the availability of several COVID-19 vaccines with high efficacy, more effective vaccines are still needed to protect against the new variants of SARS-CoV-2. Employing a comprehensive immunoinformatic prediction algorithm and leveraging the genetic closeness with SARS-CoV, we have predicted potential immune epitopes in the structural proteins of SARS-CoV-2. The S and N proteins of SARS-CoV-2 and SARS-CoVs are main targets of antibody detection and have motivated us to design four multi-epitope vaccines which were based on our predicted B- and T-cell epitopes of SARS-CoV-2 structural proteins. The cardinal epitopes selected for the vaccine constructs are predicted to possess antigenic, non-allergenic, and cytokine-inducing properties. Additionally, some of the predicted epitopes have been experimentally validated in published papers. Furthermore, we used the C-ImmSim server to predict effective immune responses induced by the epitope-based vaccines. Taken together, the immune epitopes predicted in this study provide a platform for future experimental validations which may facilitate the development of effective vaccine candidates and epitope-based serological diagnostic assays.
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Biología Computacional , Mapeo Epitopo , SARS-CoV-2/inmunología , Proteínas Estructurales Virales/inmunología , Secuencia de Aminoácidos , Vacunas contra la COVID-19/química , Vacunas contra la COVID-19/inmunología , Bases de Datos como Asunto , Epítopos de Linfocito B/química , Epítopos de Linfocito B/inmunología , Epítopos de Linfocito T/química , Epítopos de Linfocito T/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Modelos Moleculares , Conformación Proteica , Reproducibilidad de los Resultados , Proteínas Estructurales Virales/químicaRESUMEN
Background: Neuropsychiatric disorders such as Schizophrenia (SCZ) and Bipolar disorder (BPD) pose a broad range of problems with different symptoms mainly characterized by some combination of abnormal thoughts, emotions, behaviour, etc. However, in depth molecular and pathophysiological mechanisms among different neuropsychiatric disorders have not been clearly understood yet. We have used RNA-seq data to investigate unique and overlapping molecular signatures between SCZ and BPD using an integrative network biology approach. Methods: RNA-seq count data were collected from NCBI-GEO database generated on post-mortem brain tissues of controls (n = 24) and patients of BPD (n = 24) and SCZ (n = 24). Differentially expressed genes (DEGs) were identified using the consensus of DESeq2 and edgeR tools and used for downstream analysis. Weighted gene correlation networks were constructed to find non-preserved (NP) modules for SCZ, BPD and control conditions. Topological analysis and functional enrichment analysis were performed on NP modules to identify unique and overlapping expression signatures during SCZ and BPD conditions. Results: We have identified four NP modules from the DEGs of BPD and SCZ. Eleven overlapping genes have been identified between SCZ and BPD networks, and they were found to be highly enriched in inflammatory responses. Among these eleven genes, TNIP2, TNFRSF1A and AC005840.1 had higher sum of connectivity exclusively in BPD network. In addition, we observed that top five genes of NP module from SCZ network were downregulated which may be a key factor for SCZ disorder. Conclusions: Differential activation of the immune system components and pathways may drive the common and unique pathogenesis of the BPD and SCZ.