Cytomegalovirus Infection Causes an Increase of Arterial Blood Pressure

Cytomegalovirus (CMV) infection is a common infection in adults (seropositive 60–99% globally), and is associated with cardiovascular diseases, in line with risk factors such as hypertension and atherosclerosis. Several viral infections are linked to hypertension, including human herpes virus 8 (HHV-8) and HIV-1. The mechanisms of how viral infection contributes to hypertension or increased blood pressure are not defined. In this report, the role of CMV infection as a cause of increased blood pressure and in forming aortic atherosclerotic plaques is examined. Using in vivo mouse model and in vitro molecular biology analyses, we find that CMV infection alone caused a significant increase in arterial blood pressure (ABp) (p<0.01 $\sim$0.05), measured by microtip catheter technique. This increase in blood pressure by mouse CMV (MCMV) was independent of atherosclerotic plaque formation in the aorta, defined by histological analyses. MCMV DNA was detected in blood vessel samples of viral infected mice but not in the control mice by nested PCR assay. MCMV significantly increased expression of pro-inflammatory cytokines IL-6, TNF-$\alpha$, and MCP-1 in mouse serum by enzyme-linked immunosorbent assay (ELISA). Using quantitative real time reverse transcriptase PCR (Q-RT-PCR) and Western blot, we find that CMV stimulated expression of renin in mouse and human cells in an infectious dose-dependent manner. Co-staining and immunofluorescent microscopy analyses showed that MCMV infection stimulated renin expression at a single cell level. Further examination of angiotensin-II (Ang II) in mouse serum and arterial tissues with ELISA showed an increased expression of Ang II by MCMV infection. Consistent with the findings of the mouse trial, human CMV (HCMV) infection of blood vessel endothelial cells (EC) induced renin expression in a non-lytic infection manner. Viral replication kinetics and plaque formation assay showed that an active, CMV persistent infection in EC and expression of viral genes might underpin the molecular mechanism. These results show that CMV infection is a risk factor for increased arterial blood pressure, and is a co-factor in aortic atherosclerosis. Viral persistent infection of EC may underlie the mechanism. Control of CMV infection can be developed to restrict hypertension and atherosclerosis in the cardiovascular system

Semantics-Consistent Cross-domain Summarization via Optimal Transport Alignment

Multimedia summarization with multimodal output (MSMO) is a recently explored application in language grounding. It plays an essential role in real-world applications, i.e., automatically generating cover images and titles for news articles or providing introductions to online videos. However, existing methods extract features from the whole video and article and use fusion methods to select the representative one, thus usually ignoring the critical structure and varying semantics. In this work, we propose a Semantics-Consistent Cross-domain Summarization (SCCS) model based on optimal transport alignment with visual and textual segmentation. In specific, our method first decomposes both video and article into segments in order to capture the structural semantics, respectively. Then SCCS follows a cross-domain alignment objective with optimal transport distance, which leverages multimodal interaction to match and select the visual and textual summary. We evaluated our method on three recent multimodal datasets and demonstrated the effectiveness of our method in producing high-quality multimodal summaries

MMSum: A Dataset for Multimodal Summarization and Thumbnail Generation of Videos

Multimodal summarization with multimodal output (MSMO) has emerged as a promising research direction. Nonetheless, numerous limitations exist within existing public MSMO datasets, including insufficient maintenance, data inaccessibility, limited size, and the absence of proper categorization, which pose significant challenges. To address these challenges and provide a comprehensive dataset for this new direction, we have meticulously curated the \textbf{MMSum} dataset. Our new dataset features (1) Human-validated summaries for both video and textual content, providing superior human instruction and labels for multimodal learning. (2) Comprehensively and meticulously arranged categorization, spanning 17 principal categories and 170 subcategories to encapsulate a diverse array of real-world scenarios. (3) Benchmark tests performed on the proposed dataset to assess various tasks and methods, including \textit{video summarization}, \textit{text summarization}, and \textit{multimodal summarization}. To champion accessibility and collaboration, we will release the \textbf{MMSum} dataset and the data collection tool as fully open-source resources, fostering transparency and accelerating future developments. Our project website can be found at~\url{https://mmsum-dataset.github.io/}Comment: Project website: https://mmsum-dataset.github.io

Alpha-Adducin Gly460Trp Polymorphism and Hypertension Risk: A Meta-Analysis of 22 Studies Including 14303 Cases and 15961 Controls

BACKGROUND: No clear consensus has been reached on the alpha-adducin polymorphism (Gly460Trp) and essential hypertension risk. We performed a meta-analysis in an effort to systematically summarize the possible association. METHODOLOGY/PRINCIPAL FINDINGS: Studies were identified by searching MEDLINE and EMBASE databases complemented with perusal of bibliographies of retrieved articles and correspondence with original authors. The fixed-effects model and the random-effects model were applied for dichotomous outcomes to combine the results of the individual studies. We selected 22 studies that met the inclusion criteria including a total of 14303 hypertensive patients and 15961 normotensive controls. Overall, the 460Trp allele showed no statistically significant association with hypertension risk compared to Gly460 allele (P = 0.69, OR = 1.02, 95% CI 0.94-1.10, P(heterogeneity)<0.0001) in all subjects. Meta-analysis under other genetic contrasts still did not reveal any significant association in all subjects, Caucasians, East Asians and others. The results were similar but heterogeneity did not persist when sensitivity analyses were limited to these studies. CONCLUSIONS/SIGNIFICANCE: Our meta-analysis failed to provide evidence for the genetic association of α-adducin gene Gly460Trp polymorphism with hypertension. Further studies investigating the effect of genetic networks, environmental factors, individual biological characteristics and their mutual interactions are needed to elucidate the possible mechanism for hypertension in humans

Artificial Intelligence Framework Identifies Candidate Targets for Drug Repurposing in Alzheimer’s Disease

Background: Genome-wide association studies (GWAS) have identified numerous susceptibility loci for Alzheimer’s disease (AD). However, utilizing GWAS and multi-omics data to identify high-confidence AD risk genes (ARGs) and druggable targets that can guide development of new therapeutics for patients suffering from AD has heretofore not been successful. Methods: To address this critical problem in the field, we have developed a network-based artificial intelligence framework that is capable of integrating multi-omics data along with human protein–protein interactome networks to accurately infer accurate drug targets impacted by GWAS-identified variants to identify new therapeutics. When applied to AD, this approach integrates GWAS findings, multi-omics data from brain samples of AD patients and AD transgenic animal models, drug-target networks, and the human protein–protein interactome, along with large-scale patient database validation and in vitro mechanistic observations in human microglia cells. Results: Through this approach, we identified 103 ARGs validated by various levels of pathobiological evidence in AD. Via network-based prediction and population-based validation, we then showed that three drugs (pioglitazone, febuxostat, and atenolol) are significantly associated with decreased risk of AD compared with matched control populations. Pioglitazone usage is significantly associated with decreased risk of AD (hazard ratio (HR) = 0.916, 95% confidence interval [CI] 0.861–0.974, P = 0.005) in a retrospective case-control validation. Pioglitazone is a peroxisome proliferator-activated receptor (PPAR) agonist used to treat type 2 diabetes, and propensity score matching cohort studies confirmed its association with reduced risk of AD in comparison to glipizide (HR = 0.921, 95% CI 0.862–0.984, P = 0.0159), an insulin secretagogue that is also used to treat type 2 diabetes. In vitro experiments showed that pioglitazone downregulated glycogen synthase kinase 3 beta (GSK3β) and cyclin-dependent kinase (CDK5) in human microglia cells, supporting a possible mechanism-of-action for its beneficial effect in AD. Conclusions: In summary, we present an integrated, network-based artificial intelligence methodology to rapidly translate GWAS findings and multi-omics data to genotype-informed therapeutic discovery in AD

Decoding the spermatogonial stem cell niche under physiological and recovery conditions in adult mice and humans

The intricate interaction between spermatogonial stem cell (SSC) and testicular niche is essential for maintaining SSC homeostasis; however, this interaction remains largely uncharacterized. In this study, to characterize the underlying signaling pathways and related paracrine factors, we delineated the intercellular interactions between SSC and niche cell in both adult mice and humans under physiological conditions and dissected the niche-derived regulation of SSC maintenance under recovery conditions, thus uncovering the essential role of C-C motif chemokine ligand 24 and insulin-like growth factor binding protein 7 in SSC maintenance. We also established the clinical relevance of specific paracrine factors in human fertility. Collectively, our work on decoding the adult SSC niche serves as a valuable reference for future studies on the aetiology, diagnosis, and treatment of male infertility.</p

Histone demethylase KDM5D drives sex-specific differences in colorectal cancer

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A-6G and A-20C Polymorphisms in the Angiotensinogen Promoter and Hypertension Risk in Chinese: A Meta-Analysis

BACKGROUND: Numerous studies in Chinese populations have evaluated the association between the A-6G and A-20C polymorphisms in the promoter region of angiotensinogen gene and hypertension. However, the results remain conflicting. We carried out a meta-analysis for these associations. METHODS AND RESULTS: Case-control studies in Chinese and English publications were identified by searching the MEDLINE, EMBASE, CNKI, Wanfang, CBM, and VIP databases. The random-effects model was applied for dichotomous outcomes to combine the results of the individual studies. We finally selected 24 studies containing 5932 hypertensive patients and 5231 normotensive controls. Overall, we found significant association between the A-6G polymorphism and the decreased risk of hypertension in the dominant genetic model (AA+AG vs. GG: P=0.001, OR=0.71, 95%CI 0.57-0.87, P(heterogeneity)=0.96). The A-20C polymorphism was significantly associated with the increased risk for hypertension in the allele comparison (C vs. A: P=0.03, OR=1.14, 95%CI 1.02-1.27, P(heterogeneity)=0.92) and recessive genetic model (CC vs. CA+AA: P=0.005, OR=1.71, 95%CI 1.18-2.48, P(heterogeneity)=0.99). In the subgroup analysis by ethnicity, significant association was also found among Han Chinese for both A-6G and A-20C polymorphisms. A borderline significantly decreased risk of hypertension between A-6G and Chinese Mongolian was seen in the allele comparison (A vs. G: P=0.05, OR=0.79, 95%CI 0.62-1.00, P(heterogeneity)=0.84). CONCLUSION: Our meta-analysis indicated significant association between angiotensinogen promoter polymorphisms and hypertension in the Chinese populations, especially in Han Chinese