Effects of Exercise Training on Immune-Related Genes and Pathways in the Cortex of Animal Models of Alzheimer's Disease: A Systematic Review.

Background: Alzheimer's disease (AD) is a chronic neurodegenerative disease that affects the immune system due to the accumulation of amyloid-ß (Aß) and tau associated molecular pathology and other pathogenic processes. To address AD pathogenesis, various approaches had been conducted from drug development to lifestyle modification to reduce the prevalence of AD. Exercise is considered a prominent lifestyle modification to combat AD. Objective: This observation prompted us to review the literature on exercise related to immune genes in the cortex of animal models of AD. We focused on animal model studies due to their prevalence in this domain. Methods: The systematic review was conducted according to PRISMA standards using Web of Science (WoS) and PubMed databases. Any kind of genes, proteins, and molecular molecules were included in this systematic review. The list of these immune-related molecules was analyzed in the STRING database for functional enrichment analysis. Results: We found that 17 research studies discussed immune-related molecules and 30 immune proteins. These studies showed that exercise had the ability to ameliorate dysfunction in AD-related pathways, which led to decreasing the expression of microglia-related pathways and Th17-related immune pathways. As a result of decreasing the expression of immune-related pathways, the expression of apoptosis-related pathways was also decreasing, and neuronal survival was increased by exercise activity. Conclusions: Based on functional enrichment analysis, exercise not only could reduce apoptotic factors and immune components but also could increase cell survival and Aß clearance in cortex samples. PROSPERO ID: CRD42022326093.

Transcriptomics Meta-Analysis Reveals Phagosome and Innate Immune System Dysfunction as Potential Mechanisms in the Cortex of Alzheimer's Disease Mouse Strains.

Immune-related pathways can affect the immune system directly, such as the chemokine signaling pathway, or indirectly, such as the phagosome pathway. Alzheimer's disease (AD) is reportedly associated with several immune-related pathways. However, exploring its underlying mechanism is challenging in animal studies because AD mouse strains differentially express immune-related pathway characteristics. To overcome this problem, we performed a meta-analysis to identify significant and consistent immune-related AD pathways that are expressed in different AD mouse strains. Next-generation RNA sequencing (RNA-seq) and microarray datasets for the cortex of AD mice from different strains such as APP/PSEN1, APP/PS2, 3xTg, TREM, and 5xFAD were collected from the NCBI GEO database. Each dataset's quality control and normalization were already processed from each original study source using various methods depending on the high-throughput analysis platform (FastQC, median of ratios, RMA, between array normalization). Datasets were analyzed using DESeq2 for RNA-seq and GEO2R for microarray to identify differentially expressed (DE) genes. Significantly DE genes were meta-analyzed using Stouffer's method, with significant genes further analyzed for functional enrichment. Ten datasets representing 20 conditions were obtained from the NCBI GEO database, comprising 116 control and 120 AD samples. The DE analysis identified 284 significant DE genes. The meta-analysis identified three significantly enriched immune-related AD pathways: phagosome, the complement and coagulation cascade, and chemokine signaling. Phagosomes-related genes correlated with complement and immune system. Meanwhile, phagosomes and chemokine signaling genes overlapped with B cells receptors pathway genes indicating potential correlation between phagosome, chemokines, and adaptive immune system as well. The transcriptomic meta-analysis showed that AD is associated with immune-related pathways in the brain's cortex through the phagosome, complement and coagulation cascade, and chemokine signaling pathways. Interestingly, phagosome and chemokine signaling pathways had potential correlation with B cells receptors pathway.

Transcriptomic Analyses of Exercise Training in Alzheimer's Disease Cerebral Cortex.

BACKGROUND: Research reported exercise could reduce Alzheimer's disease (AD) symptoms in human and animals. However, the molecular mechanism of exercise training via transcriptomic analysis was unclear especially in AD in the cortex area. OBJECTIVE: Investigate potential significant pathways in the cortex area that were affected by exercise during AD. METHODS: RNA-seq analysis, differential expressed genes, functional enrichment analysis, and GSOAP clustering analysis were performed in the isolated cerebral cortex from eight 3xTg AD mice (12 weeks old) randomly and equally divided into control (AD) and exercise training (AD-EX) group. Swimming exercise training in AD-EX group was conducted 30 min/day for 1 month. RESULTS: There were 412 genes significant differentially expressed in AD-EX group compared to AD group. Top 10 upregulated genes in AD-EX group against AD group mostly correlated with neuroinflammation, while top 10 downregulated genes mostly had connection with vascularization, membrane transport, learning memory, and chemokine signal. Pathway analysis revealed the upregulated interferon alpha beta signaling in AD-EX had association with cytokines delivery in microglia cells compared to AD and top 10 upregulated genes involved in interferon alpha beta were Usp18, Isg15, Mx1, Mx2, Stat1, Oas1a, and Irf9; The downregulated extracellular matrix organization in AD-EX had correlation with Aß and neuron cells interaction and Vtn was one of the top 10 downregulated genes involved in this pathway. CONCLUSION: Exercise training influenced 3xTg mice cortex through interferon alpha beta signaling upregulation and extracellular matrix organization downregulation based on transcriptomics analysis.

CRISPR-Edited Stem Cell Transplantation for HIV-Related Gene Modification In Vivo: A Systematic Review.

BACKGROUND: CRISPR is a novel genomic editing technology which can be useful for the treatment of immune diseases such as HIV. However, the application of CRISPR in stem cells for HIV-related research was not effective, and most of the research was done in vivo. This systematic review is to identify a new research idea about increase CRISPR-editing efficiencies in stem cell transplantation for HIV treatment, as well as its future perspective. METHOD: Four databases were searched for articles published during 1952 to 2020. PRISMA method was used to select appropriate research papers. CAMARADES was used to identify the paper quality. The outcome was engraftment efficiency, gene disruption percentage, differentiation ability, HIV-resistant efficiency. RESULT: Screening method showed 196 papers mentioned the topic. However, only 5 studies were reliable with the research objective. We found that (1) Two research ideas which was double gene knockout and knockout-knockin method to provide HIV-resistant cells, engraftment support and avoid cardiac disease as an HIV disease side effect. (2) Ribonucleoprotein (RNP) delivery was the best way to deliver the CRISPR/Cas9 and Adeno-Associated Virus (AAV) would be effective for knockin purpose. (3) CRISPR/SaCas9 could replace CRISPR/Cas9 role in editing HIV-related gene. CONCLUSION: Potential genes to increase HIV resistance and stem cell engraftment should be explored more in the future. Double knockout and knock-in procedures should be applied to set up a better engraftment for improving HIV treatment or resistance of patients. CRISPR/SaCas9 and RNP delivery should be explored more in the future. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020203312.

Impactful factors and research design in CRISPR-edited stem cell research from top 10 highly cited articles.

Our objective in this review was to determine (1) impactful research articles about CRISPR-edited stem cells, (2) factors that affected CRISPR method performance in stem cell, and (3) research design related to CRISPR-edited stem cells. Screening research papers of related topic was carried out by using the Science Citation Index Expanded (SCIE) database of the Clarivate Analytics Web of Science Core Collection updated. We screened impactful CRISPR/Cas9-edited stem cells based on total citation until 2020. The result showed the title "RNA-guided human genome engineering via Cas9" was the highest citation in stem cell research using the CRISPR method with total citation 4789 from Web of Science Core Collection until 2020. It became the most influenced paper because this was the first research using CRISPR method for modifying human cells. On the other hand, cell type, CRISPR/Cas9 delivery, and gene target affected CRISPR/Cas9 performance in stem cells. The more complex the cell structure, the more difficult for CRISPR/Cas9 to mutate the host cells. This problem could be solved by modifying the CRISPR/Cas9 delivery by liposome and SaCas9 modification. Another way was using ribonucleoprotein (RNP) as a delivery method. Then, double gene target was more difficult to execute than single gene target. Although it is difficult, CRISPR/Cas9 had the capability to target any genome region from promoter until intron. Research design used a combination of dry lab and wet lab. The dry lab is usually used for sequence analysis and gRNA design. The wet lab which consisted of in vitro and in vivo was used for gene characterization. In particular, colony selection, DNA analysis, and sequencing were important parts for in vitro research design, while DNA analysis and sequencing were crucial parts for in vivo research design. We hoped these findings could give researchers, investor, and students a guideline to conduct CRISPR-edited stem cells in the future.

Indonesians Human Leukocyte Antigen (HLA) Distributions and Correlations with Global Diseases.

In Human, Major Histocompatibility Complex known as Human Leukocyte Antigen (HLA). The HLA grouped into three subclasses regions: the class I region, the class II region, and the class III region. There are thousands of polymorphic HLAs, many of them are proven to have correlations with diseases. Indonesia consists of diverse ethnicity people and populations. It carries a unique genetic diversity between one and another geographical positions. This paper aims to extract Indonesians HLA allele data, mapping the data, and correlating them with global diseases. From the study, it is found that global diseases, like Crohn's disease, rheumatoid arthritis, Graves' disease, gelatin allergy, T1D, HIV, systemic lupus erythematosus, juvenile chronic arthritis, and Mycobacterial disease (tuberculosis and leprosy) suspected associated with the Indonesian HLA profiles.