BACKGROUND: Atrial fibrillation (AF), the most common atrial arrhythmia, presents varied clinical manifestations. Despite the identification of genetic loci associated with AF, particularly in specific populations, research within Asian ethnicities remains limited. This study aimed to develop predictive models for AF using AF-associated single-nucleotide polymorphisms (SNPs) from a Genome-Wide Association Study (GWAS) on a substantial cohort of Taiwanese individuals, evaluating the models\' predictive efficacy.
METHODS: Involving 75,121 subjects, including 5,694 AF patients and 69,427 normal controls with GWAS data, the study merged polygenic risk scores (PRS) from AF-associated SNPs with Phenome-wide association study (PheWAS)-derived risk factors. Advanced statistical and machine learning techniques were employed to develop and evaluate AF predictive models for discrimination and calibration.
RESULTS: The study identified the top 30 significant SNPs associated with AF, predominantly on chromosomes 10 and 16, implicating genes like NEURL1, SH3PXD2A, INA, NT5C2, STN1, and ZFHX3. Notably, INA, NT5C2, and STN1 were newly linked to AF. The GWAS predictive power using PRS-CS analysis for AF exhibited an area under the curve (AUC) of 0.600 (P < 0.001), improving to 0.855 (P < 0.001) after adjusting for age and gender. PheWAS analysis showed the top 10 diseases associated with these genes were circulatory system diseases.
CONCLUSIONS: Integrating genetic and phenotypic data enhanced the accuracy and clinical relevance of AF predictive models. The findings suggest promise for refining AF risk assessment, enabling personalized interventions, and reducing AF-related morbidity and mortality burdens.

The purpose of the current study was to elucidate the physiological roles of intraocularly present fatty acid-binding protein 4 (FABP4). Using four representative intraocular tissue-derived cell types, including human non-pigmented ciliary epithelium (HNPCE) cells, retinoblastoma (RB) cells, adult retinal pigment epithelial19 (ARPE19) cells and human ocular choroidal fibroblast (HOCF) cells, the intraocular origins of FABP4 were determined by qPCR analysis, and the intracellular functions of FABP4 were investigated by seahorse cellular metabolic measurements and RNA sequencing analysis using a specific inhibitor for FABP4, BMS309403. Among these four different cell types, FABP4 was exclusively expressed in HOCF cells. In HOCF cells, both mitochondrial and glycolytic functions were significantly decreased to trace levels by BMS309403 in a dose-dependent manner. In the RNA sequencing analysis, 67 substantially up-regulated and 94 significantly down-regulated differentially expressed genes (DEGs) were identified in HOCF cells treated with BMS309403 and those not treated with BMS309403. The results of Gene Ontology enrichment analysis and ingenuity pathway analysis (IPA) revealed that the DEGs were most likely involved in G-alpha (i) signaling, cAMP-response element-binding protein (CREB) signaling in neurons, the S100 family signaling pathway, visual phototransduction and adrenergic receptor signaling. Furthermore, upstream analysis using IPA suggested that NKX2-1 (thyroid transcription factor1), HOXA10 (homeobox A10), GATA2 (gata2 protein), and CCAAT enhancer-binding protein A (CEBPA) were upstream regulators and that NKX homeobox-1 (NKX2-1), SFRP1 (Secreted frizzled-related protein 1) and TREM2 (triggering receptor expressed on myeloid cells 2) were causal network master regulators. The findings in this study suggest that intraocularly present FABP4 originates from the ocular choroid and may be a critical regulator for the cellular homeostasis of non-adipocyte HOCF cells.

To elucidate the currently unknown molecular mechanisms responsible for the similarity and difference during the acquirement of resistance against gemcitabine (GEM) and paclitaxel (PTX) in patients with pancreatic carcinoma, we examined two-dimensional (2D) and three-dimensional (3D) cultures of parent MIA PaCa-2 cells (MIA PaCa-2-PA) and their GEM resistance cell line (MIA PaCa-2-GR) and PTX resistance (MIA PaCa-2-PR). Using these cells, we examined 3D spheroid configurations and cellular metabolism, including mitochondrial and glycolytic functions, with a Seahorse bio-analyzer and RNA sequencing analysis. Compared to the MIA PaCa-2-PA, (1) the formation of the 3D spheroids of MIA PaCa-2-GR or -PR was much slower, and (2) their mitochondrial and glycolytic functions were greatly modulated in MIA PaCa-2-GR or -PR, and such metabolic changes were also different between their 2D and 3D culture conditions. RNA sequencing and bioinformatic analyses of the differentially expressed genes (DEGs) using an ingenuity pathway analysis (IPA) suggested that various modulatory factors related to epithelial -mesenchymal transition (EMT) including STAT3, GLI1, ZNF367, NKX3-2, ZIC2, IFIT2, HEY1 and FBLX, may be the possible upstream regulators and/or causal network master regulators responsible for the acquirement of drug resistance in MIA PaCa-2-GR and -PR. In addition, among the prominently altered DEGs (Log2 fold changes more than 6 or less than -6), FABP5, IQSEC3, and GASK1B were identified as unique genes associated with their antisense RNA or pseudogenes, and among these, FABP5 and GASK1B are known to function as modulators of cancerous EMT. Therefore, the observations reported herein suggest that modulations of cancerous EMT may be key molecular mechanisms that are responsible for inducing chemoresistance against GEM or PTX in MIA PaCa-2 cells.

Mycobacterium avium complex (MAC) is a non-tuberculous mycobacterium widely distributed in the environment. Even though MAC infection is increasing in older women and immunocompromised patients, to our knowledge there has been no comprehensive analysis of the MAC-infected host-cell transcriptome-and particularly of long non-coding RNAs (lncRNAs). By using in vitro-cultured primary mouse bone-marrow-derived macrophages (BMDMs) and Cap analysis of gene expression, we analyzed the transcriptional and kinetic landscape of macrophage genes, with a focus on lncRNAs, during MAC infection. MAC infection of macrophages induced the expression of immune/inflammatory response genes and other genes similar to those involved in M1 macrophage activation, consistent with previous reports, although Nos2 (M1 activation) and Arg1 (M2 activation) had distinct expression profiles. We identified 31 upregulated and 30 downregulated lncRNA promoters corresponding respectively to 18 and 26 lncRNAs. Upregulated lncRNAs were clustered into two groups-early and late upregulated-predicted to be associated with immune activation and the immune response to infection, respectively. Furthermore, an Ingenuity Pathway Analysis revealed canonical pathways and upstream transcription regulators associated with differentially expressed lncRNAs. Several differentially expressed lncRNAs reported elsewhere underwent expressional changes upon M1 or M2 preactivation and subsequent MAC infection. Finally, we showed that expressional change of lncRNAs in MAC-infected BMDMs was mediated by toll-like receptor 2, although there may be other mechanisms that sense MAC infection. We identified differentially expressed lncRNAs in MAC-infected BMDMs, revealing diverse features that imply the distinct roles of these lncRNAs in MAC infection and macrophage polarization.

UNASSIGNED: Collagen triple helix repeat containing 1 (CTHRC1) is a protein that has been implicated in pro-migratory pathways, arterial tissue-repair processes, and inhibition of collagen deposition via the regulation of multiple signaling cascades. Studies have also demonstrated an upregulation of CTHRC1 in multiple cancers where it has been linked to enhanced proliferation, invasion, and metastasis. However, the understanding of the exact role and mechanisms of CTHRC1 in cancer is far from complete.
UNASSIGNED: This review focuses on analyzing the role of CTHRC1 in cancer as well as its associations with clinicopathologies and cancer-related processes and signaling. We have also summarized the available literature information regarding the role of CTHRC1 in tumor microenvironment and immune signaling. Finally, we have discussed the mechanisms associated with CTHRC1 regulations, and opportunities and challenges regarding the development of CTHRC1 as a potential target for cancer management.
UNASSIGNED: CTHRC1 is a multifaceted protein with critical roles in cancer progression and other pathological conditions. Its association with lower overall survival in various cancers, and impact on the tumor immune microenvironment make it an intriguing target for further research and potential therapeutic interventions in cancer.

Adipose tissues are closely related to physiological functions and pathological conditions in most organs. Although differentiated 3T3-L1 preadipocytes have been used for in vitro adipose studies, the difference in cellular characteristics of adipogenic differentiation in two-dimensional (2D) culture and three-dimensional (3D) culture remain unclear. In this study, we evaluated gene expression patterns using RNA sequencing and metabolic functions using an extracellular flux analyzer in 3T3-L1 preadipocytes with and without adipogenic induction in 2D culture and 3D culture. In 2D culture, 565 up-regulated genes and 391 down-regulated genes were identified as differentially expressed genes (DEGs) by adipogenic induction of 3T3-L1 preadipocytes, whereas only 69 up-regulated genes and 59 down-regulated genes were identified as DEGs in 3D culture. Ingenuity Pathway Analysis (IPA) revealed that genes associated with lipid metabolism were identified as 2 out of the top 3 causal networks related to diseases and function in 3D spheroids, whereas only one network related to lipid metabolism was identified within the top 9 of these causal networks in the 2D planar cells, suggesting that adipogenic induction in the 3D culture condition exhibits a more adipocyte-specific gene expression pattern in 3T3-L1 preadipocytes. Real-time metabolic analysis revealed that the metabolic capacity shifted from glycolysis to mitochondrial respiration in differentiated 3T3-L1 cells in the 3D culture condition but not in those in the 2D cultured condition, suggesting that adipogenic differentiation in 3D culture induces a metabolic phenotype of well-differentiated adipocytes. Consistently, expression levels of mitochondria-encoded genes including mt-Nd6, mt-Cytb, and mt-Co1 were significantly increased by adipogenic induction of 3T3-L1 preadipocytes in 3D culture compared with those in 2D culture. Taken together, the findings suggest that induction of adipogenesis in 3D culture provides a more adipocyte-specific gene expression pattern and enhances mitochondrial respiration, resulting in more adipocyte-like cellular properties.

Coronavirus disease-19 (COVID-19) is caused by the infection of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The virus enters host cells through receptor-mediated endocytosis of angiotensin-converting enzyme-2 (ACE2), leading to systemic inflammation, also known as a \"cytokine storm\", and neuroinflammation. COVID-19\'s upstream regulator, interferon-gamma (IFNG), is downregulated upon the infection of SARS-CoV-2, which leads to the downregulation of ACE2. The neuroinflammation signaling pathway (NISP) can lead to neurodegenerative diseases, such as Parkinson\'s disease (PD), which is characterized by the formation of Lewy bodies made primarily of the α-synuclein protein encoded by the synuclein alpha (SNCA) gene. We hypothesize that COVID-19 may modulate PD progression through neuroinflammation induced by cytokine storms. This study aimed to elucidate the possible mechanisms and signaling pathways involved in COVID-19-triggered pathology associated with neurodegenerative diseases like PD. This study presents the analysis of the pathways involved in the downregulation of ACE2 following SARS-CoV-2 infection and its effect on PD progression. Through QIAGEN\'s Ingenuity Pathway Analysis (IPA), the study identified the NISP as a top-five canonical pathway/signaling pathway and SNCA as a top-five upstream regulator. Core Analysis was also conducted on the associated molecules between COVID-19 and SNCA to construct a network connectivity map. The Molecule Activity Predictor tool was used to simulate the infection of SARS-CoV-2 by downregulating IFNG, which leads to the predicted activation of SNCA, and subsequently PD, through a dataset of intermediary molecules. Downstream effect analysis was further used to quantify the downregulation of ACE2 on SNCA activation.

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To elucidate the currently unknown molecular mechanisms responsible for the aberrant expression of recoverin (Rec) within cancerous cells, we examined two-dimensional (2D) and three-dimensional (3D) cultures of Rec-negative lung adenocarcinoma A549 cells which had been transfected with a plasmid containing human recoverin cDNA (A549 Rec) or an empty plasmid as a mock control (A549 MOCK). Using these cells, we measured cytotoxicity by several anti-tumor agents (2D), cellular metabolism including mitochondrial and glycolytic functions by a Seahorse bio-analyzer (2D), the physical properties, size and stiffness of the 3D spheroids, trypsin sensitivities (2D and 3D), and RNA sequencing analysis (2D). Compared with the A549 MOCK, the A549 Rec cells showed (1) more sensitivity toward anti-tumor agents (2D) and a 0.25% solution of trypsin (3D); (2) a metabolic shift from glycolysis to oxidative phosphorylation; and (3) the formation of larger and stiffer 3D spheroids. RNA sequencing analysis and bioinformatic analyses of the differentially expressed genes (DEGs) using Gene Ontology (GO) enrichment analysis suggested that aberrantly expressed Rec is most likely associated with several canonical pathways including G-protein-coupled receptor (GPCR)-mediated signaling and signaling by the cAMP response element binding protein (CREB). The findings reported here indicate that the aberrantly expressed Rec-induced modulation of the cell viability and drug sensitivity may be GPCR mediated.

Polyhexamethylene guanidine phosphate (PHMG-p), the main ingredient of humidifier disinfectants, circulates systemically through the lungs; however, its toxicological assessment has been primarily limited to pulmonary disease. Herein, we investigated the possible abnormalities in hematopoietic function 20 weeks after intratracheal instillation of PHMG-p in a rat model. Notable abnormalities were found out in the peripheral blood cell count and bone marrow (BM) biopsy, while RNA sequencing of BM tissue revealed markedly altered gene expression. Furthermore, signaling involved in hematopoietic dysfunction was predicted by analyzing candidate genes through Ingenuity Pathway Analysis (IPA) program. Respiratory PHMG-p exposure significantly decreased monocyte and platelet (PLT) counts and total protein, while significantly increasing hemoglobin and hematocrit levels in peripheral blood. Histopathological analysis of the BM revealed a reduced number of megakaryocytes, with no significant differences in spleen and liver weight to body weight. Moreover, PHMG-p exposure significantly activated estrogen receptor signaling and RHOA signaling, and inhibited RHOGDI signaling. In IPA analysis, candidate genes were found to be strongly related to \'hematological system development and function\' and \'hematological disease.\' Accordingly, our results suggest that PHMG-p could affect hematopoiesis, which participates in monocyte differentiation and PLT production, and may induce hematologic diseases via the respiratory tract.