Structural Requirements for Sterol Regulatory Element-Binding Protein Cleavage in Fission Yeast

Cells can respond rapidly to changes in their cellular environments such as oxygen levels, and transcription factors play a critical role in response to such changes to achieve homeostasis. Sterol regulatory element-binding proteins (SREBPs) are membrane-bound transcription factors that serve as master regulators of cholesterol and fatty acid homeostasis. Mammalian SREBPs are proteolytically activated and liberated from the membrane by Golgi Site-1 and Site-2 proteases. However, fission yeast SREBPs, Sre1 and Sre2, employ a different mechanism that genetically requires the Golgi defective for SREBP cleavage (Dsc) E3 ligase complex for cleavage activation. In this thesis, I defined structural requirements for fission yeast SREBP cleavage. I isolated a collection of cleavage mutants in Sre2 C-terminus and identified a novel SREBP cleavage motif, the glycine-leucine motif. I revealed an extensive conservation of this motif in at least 20 SREBP homologs of ascomycete fungi using defined bioinformatic criteria, including the human opportunistic pathogen Aspergillus fumigatus and Candida albicans where SREBPs are required for fungal pathogenesis. I also demonstrated functional conservation of this motif in Sre1 as required for adaptation to low oxygen. Further, I identified potential mechanisms for degradation of Sre2 C-terminus by the Dsc E3 ligase and the proteasome. Importantly, I have established Sre2 as the first physiological substrate for dissecting Golgi E3 ligase-dependent protein processing. Therefore, Sre2 can serve as a model substrate and gateway for understanding Golgi protein degradation and processing. Further study into the mechanism of Dsc E3 ligase-dependent SREBP processing entails broad implications for cellular adaptation to low oxygen and sterol conditions and may enable the development of novel antifungal therapeutics

Nap1-Regulated Neuronal Cytoskeletal Dynamics Is Essential for the Final Differentiation of Neurons in Cerebral Cortex

SummaryThe cytoskeletal regulators that mediate the change in the neuronal cytoskeletal machinery from one that promotes oriented motility to one that facilitates differentiation at the appropriate locations in the developing neocortex remain unknown. We found that Nck-associated protein 1 (Nap1), an adaptor protein thought to modulate actin nucleation, is selectively expressed in the developing cortical plate, where neurons terminate their migration and initiate laminar-specific differentiation. Loss of Nap1 function disrupts neuronal differentiation. Premature expression of Nap1 in migrating neurons retards migration and promotes postmigratory differentiation. Nap1 gene mutation in mice leads to neural tube and neuronal differentiation defects. Disruption of Nap1 retards the ability to localize key actin cytoskeletal regulators such as WAVE1 to the protrusive edges where they are needed to elaborate process outgrowth. Thus, Nap1 plays an essential role in facilitating neuronal cytoskeletal changes underlying the postmigratory differentiation of cortical neurons, a critical step in functional wiring of the cortex

Publication trend of TMPRSS2 as SARS-CoV-2 receptor during the COVID-19 pandemic

The Coronavirus Disease 2019 (COVID-19) pandemic has not yet been fully under public health control, which is still currently impacting a large number of people worldwide in 2023. Since the pandemic emerged, the growing number of publications related to TMPRSS2 as a SARS-CoV-2 receptor worldwide has increased rapidly with various findings and qualities. It is important to determine the trend of TMPRSS2 publication as no such studies currently exist that represent the publication trend related to this critical field of study. Here, we employed a bibliometric-based approach to evaluate the research trends of TMPRSS2 mechanistically as the SARS-CoV-2 receptor. We identified 1012 research documents published between 2020 and 2022 for this study. The most common document category was "Research Article" (646 articles, 63.84%) followed by "Review Article" (261 articles, 25.79%), and letters to editors (57 articles, 5.63%). Germany was the most cited country with a total of citations (9400 citations), followed by the USA (6409 citations) and China (1788 citations), respectively. In conclusion, given the impact of COVID-19, this study indicated TMPRSS2 as a SARS-CoV-2 receptor as a timely and highly relevant research topic

Integration of genomic variants and bioinformatic-based approach to drive drug repurposing for multiple sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease in the central nervous system (CNS) marked by inflammation, demyelination, and axonal loss. Currently available MS medication is limited, thereby calling for a strategy to accelerate new drug discovery. One of the strategies to discover new drugs is to utilize old drugs for new indications, an approach known as drug repurposing. Herein, we first identified 421 MS-associated SNPs from the Genome-Wide Association Study (GWAS) catalog (p-value 0.8. MS risk genes were then prioritized using bioinformatics analysis to identify biological MS risk genes. The prioritization was performed based on six defined categories of functional annotations, namely missense mutation, cis-expression quantitative trait locus (cis-eQTL), molecular pathway analysis, protein-protein interaction (PPI), genes overlap with knockout mouse phenotype, and primary immunodeficiency (PID). A total of 144 biological MS risk genes were found and mapped into 194 genes within an expanded PPI network. According to the DrugBank and the Therapeutic Target. Database, 27 genes within the list targeted by 68 new candidate drugs were identified. Importantly, the power of our approach is confirmed with the identification of a known approved drug (dimethyl fumarate) for MS. Based on additional data from ClinicalTrials.gov, eight drugs targeting eight distinct genes are prioritized with clinical evidence for MS disease treatment. Notably, CD80 and CD86 pathways are promising targets for MS drug repurposing. Using in silico drug repurposing, we identified belatacept as a promising MS drug candidate. Overall, this study emphasized the integration of functional genomic variants and bioinformatic-based approach that reveal important biological insights for MS and drive drug repurposing efforts for the treatment of this devastating disease

Hasil cek similarity "Integration of genomic databases and bioinformatic approach to identify genomic variants for sjogren’s syndrome on multiple continents"

An autoimmune disorder is an abnormality that causes a disease. It is caused by a weakened immune system. One of the autoimmune diseases is Sjogren’s syndrome, which affects the salivary and lacrimal glands and causes dry mouth, dry eyes, and dry skin. Sjogren’s syndrome influences humans of every age, with the symptoms occurring at the age of 45–55 years and rarely in children. One of the factors causing Sjogren’s syndrome is genetic disorders. To identify genes that can influence Sjogren’s syndrome in this study, we used several databases, including GWAS Catalog, HaploReg Version 4.1, GTEX portal, and Ensembl, particularly to identify the gene expression profiles of TNIP1, TNFAIP3, and IRF5 and the quantitative properties of locus’ expression. This research showed that the missense variants and splice donor rs2233290, rs2230926, and rs2004640 influenced the susceptibility of autoimmune diseases, especially Sjogren’s syndrome, in the fibroblast tissue, sigmoid tissue, sigmoid colon, skin, esophagus, and adrenal glands. The allele frequency of each variant was then assessed in African, American, European, and Asian populations. Our data showed that TNIP1, TNFAIP3, and IRF5 genes in African and American populations had higher frequencies than in the Asian population. This implies that the last of the aforementioned populations might be relatively susceptible to the autoimmune disease Sjogren’s syndrome

The use of genomic variants to drive drug repurposing for chronic hepatitis B

Background: One of the main challenges in personalized medicine is to establish and apply a large number of variants from genomic databases into clinical diagnostics and further facilitate genome-driven drug repurposing. By utilizing biological chronic hepatitis B infection (CHB) risk genes, our study proposed a systematic approach to use genomic variants to drive drug repurposing for CHB. Method: The genomic variants were retrieved from the Genome-Wide Association Study (GWAS) and Phenome- Wide Association Study (PheWAS) databases. Then, the biological CHB risk genes crucial for CHB progression were prioritized based on the scoring system devised with five strict functional annotation criteria. A score of ≥ 2 were categorized as the biological CHB risk genes and further shed light on drug target genes for CHB treatments. Overlapping druggable targets were identified using two drug databases (DrugBank and Drug-Gene Interaction Database (DGIdb)). Results: A total of 44 biological CHB risk genes were screened based on the scoring system from five functional annotation criteria. Interestingly, we found 6 druggable targets that overlapped with 18 drugs with status of undergoing clinical trials for CHB, and 9 druggable targets that overlapped with 20 drugs undergoing preclinical investigations for CHB. Eight druggable targets were identified, overlapping with 25 drugs that can potentially be repurposed for CHB. Notably, CD40 and HLA-DPB1 were identified as promising targets for CHB drug repur- posing based on the target scores. Conclusion: Through the integration of genomic variants and a bioinformatic approach, our findings suggested the plausibility of CHB genomic variant-driven drug repurposing for CH

Integration of genomic databases and bioinformatic approach to identify genomic variants for sjogren’s syndrome on multiple continents

An autoimmune disorder is an abnormality that causes a disease. It is caused by a weakened immune system. One of the autoimmune diseases is Sjogren’s syndrome, which affects the salivary and lacrimal glands and causes dry mouth, dry eyes, and dry skin. Sjogren’s syndrome influences humans of every age, with the symptoms occurring at the age of 45–55 years and rarely in children. One of the factors causing Sjogren’s syndrome is genetic disorders. To identify genes that can influence Sjogren’s syndrome in this study, we used several databases, including GWAS Catalog, HaploReg Version 4.1, GTEX portal, and Ensembl, particularly to identify the gene expression profiles of TNIP1, TNFAIP3, and IRF5 and the quantitative properties of locus’ expression. This research showed that the missense variants and splice donor rs2233290, rs2230926, and rs2004640 influenced the susceptibility of autoimmune diseases, especially Sjogren’s syndrome, in the fibroblast tissue, sigmoid tissue, sigmoid colon, skin, esophagus, and adrenal glands. The allele frequency of each variant was then assessed in African, American, European, and Asian populations. Our data showed that TNIP1, TNFAIP3, and IRF5 genes in African and American populations had higher frequencies than in the Asian population. This implies that the last of the aforementioned populations might be relatively susceptible to the autoimmune disease Sjogren’s syndrome

Investigation of susceptibility genes for chickenpox disease across multiple continents

Chickenpox (varicella) is caused by infection with the varicella-zoster virus (VZV), a neurotropic alpha herpes virus with a double-stranded DNA genome. Chickenpox can cause life-threatening complications, including subsequent bacterial infections, central nervous system symptoms, and even death without any risk factors. Few studies have been reported to investigate genetic susceptibility implicated in chickenpox. Herein, our study identified global genetic variants that potentially contributed to chickenpox susceptibility by utilizing the established bioinformatic-based approach. We integrated several databases, such as genome-wide association studies (GWAS) catalog, GTEx portal, HaploReg version 4.1, and Ensembl databases analyses to investigate susceptibility genes associated with chickenpox. Notably, increased expression of HLA-S, HCG4P5, and ABHD16A genes underlie enhanced chickenpox susceptibility in the European, American, and African populations. As compared to the Asian population, Europeans, Americans, and Africans have higher allele frequencies of the extant variants rs9266089, rs10947050, and rs79501286 from the susceptibility genes. Our study suggested that these susceptibility genes and associated genetic variants might play a critical role in chickenpox progression based on host genetics with clinical implications

Remote ischemic conditioning: from experimental observation to clinical application: report from the 8th Biennial Hatter Cardiovascular Institute Workshop

In 1993, Przyklenk and colleagues made the intriguing experimental observation that 'brief ischemia in one vascular bed also protects remote, virgin myocardium from subsequent sustained coronary artery occlusion' and that this effect '.... may be mediated by factor(s) activated, produced, or transported throughout the heart during brief ischemia/reperfusion'. This seminal study laid the foundation for the discovery of 'remote ischemic conditioning' (RIC), a phenomenon in which the heart is protected from the detrimental effects of acute ischemia/reperfusion injury (IRI), by applying cycles of brief ischemia and reperfusion to an organ or tissue remote from the heart. The concept of RIC quickly evolved to extend beyond the heart, encompassing inter-organ protection against acute IRI. The crucial discovery that the protective RIC stimulus could be applied non-invasively, by simply inflating and deflating a blood pressure cuff placed on the upper arm to induce cycles of brief ischemia and reperfusion, has facilitated the translation of RIC into the clinical setting. Despite intensive investigation over the last 20 years, the underlying mechanisms continue to elude researchers. In the 8th Biennial Hatter Cardiovascular Institute Workshop, recent developments in the field of RIC were discussed with a focus on new insights into the underlying mechanisms, the diversity of non-cardiac protection, new clinical applications, and large outcome studies. The scientific advances made in this field of research highlight the journey that RIC has made from being an intriguing experimental observation to a clinical application with patient benefit

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis