Effect of severe acute respiratory syndrome coronavirus 2 infection during pregnancy in K18-hACE2 transgenic mice.

OBJECTIVE: This study aimed to examine the influence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on pregnancy in cytokeratin-18 (K18)-hACE2 transgenic mice. METHODS: To determine the expression of hACE2 mRNA in the female reproductive tract of K18-hACE2 mice, real-time polymerase chain reaction (RT-PCR) was performed using the ovary, oviduct, uterus, umbilical cord, and placenta. SARS-CoV-2 was inoculated intranasally (30 µL/mouse, 1×104 TCID50/mL) to plug-checked K18-hACE2 homozygous female mice at the pre-and post-implantation stages at 2.5 days post-coitum (dpc) and 15.5 dpc, respectively. The number of implantation sites was checked at 7.5 dpc, and the number of normally born pups was investigated at 20.5 dpc. Pregnancy outcomes, including implantation and childbirth, were confirmed by comparison with the non-infected group. Tissues of infected mice were collected at 7.5 dpc and 19.5 dpc to confirm the SARS-CoV-2 infection. The infection was identified by performing RT-PCR on the infected tissues and comparing them to the non-infected tissues. RESULTS: hACE2 mRNA expression was confirmed in the female reproductive tract of the K18-hACE2 mice. Compared to the non-infected group, no significant difference in the number of implantation sites or normally born pups was found in the infected group. SARS-CoV-2 infection was detected in the lungs but not in the female reproductive system of infected K18-hACE2 mice. CONCLUSION: In K18-hACE2 mice, intranasal infection with SARS-CoV-2 did not induce implantation failure, preterm labor, or miscarriage. Although the viral infection was not detected in the uterus, placenta, or fetus, the infection of the lungs could induce problems in the reproductive system. However, lung infections were not related to pregnancy outcomes.

Estrogen Regulates the Expression and Localization of YAP in the Uterus of Mice.

The dynamics of uterine endometrium is important for successful establishment and maintenance of embryonic implantation and development, along with extensive cell differentiation and proliferation. The tissue event is precisely and complicatedly regulated as several signaling pathways are involved including two main hormones, estrogen and progesterone signaling. We previously showed a novel signaling molecule, Serine/threonine protein kinase 3/4 (STK3/4), which is responded to hormone in the mouse uterine epithelium. However, the role and regulation of its target, YES-associated protein (YAP) remains unknown. In this study, we investigated the expression and regulation of YAP in mouse endometrium. We found that YAP was periodically expressed in the endometrium during the estrous cycle. Furthermore, periodic expression of YAP was shown to be related to the pathway under hormone treatment. Interestingly, estrogen was shown to positively modulate YAP via endometrial epithelial receptors. In addition, the knockdown of YAP showed that YAP regulated various target genes in endometrial cells. The knockdown of YAP down-regulated numerous targets including ADAMTS1, AMOT, AMOTL1, ANKRD1, CTNNA1, MCL1. On the other hand, the expressions of AREG and AXL were increased by its knockdown. These findings imply that YAP responds via Hippo signaling under various intrauterine signals and is considered to play a role in the expression of factors important for uterine endometrium dynamic regulation.

Hippo Signaling in the Endometrium.

The uterus is essential for embryo implantation and fetal development. During the estrous cycle, the uterine endometrium undergoes dramatic remodeling to prepare for pregnancy. Angiogenesis is an essential biological process in endometrial remodeling. Steroid hormones regulate the series of events that occur during such remodeling. Researchers have investigated the potential factors, including angiofactors, involved in endometrial remodeling. The Hippo signaling pathway discovered in the 21st century, plays important roles in various cellular functions, including cell proliferation and cell death. However, its role in the endometrium remains unclear. In this review, we describe the female reproductive system and its association with the Hippo signaling pathway, as well as novel Hippo pathway genes and potential target genes.

Generation of a B2M homozygous knockout human somatic cell nuclear transfer-derived embryonic stem cell line using the CRISPR/Cas9 system.

Beta2-microglobulin (B2M) is a subunit of human leukocyte antigen class-I (HLA-I) heterodimer that mediates immune rejection through activation of cytotoxic T cells. B2M binding to HLA-I proteins is essential for functional HLA-I on the cell surface. Here, we generated a B2M homozygous knockout somatic cell nuclear transfer-induced embryonic stem cell (SCNT-ESC) line using CRISPR/Cas9-mediated gene targeting. B2M KO cell line, which does not express HLA-I molecules on cell surface, has pluripotency and differentiation ability to three germ layers. This cell line provides a useful cell source for investigating immunogenicity of allogeneic ESCs and their derivatives for tissue regeneration.

Genetic Risk, Muscle Strength, and Incident Stroke: Findings From the UK Biobank Study.

OBJECTIVE: To examine the associations of muscle strength and genetic risk for stroke with stroke incidence. PARTICIPANTS AND METHODS: We included 284,767 white British participants of UK Biobank without genetic relatedness and stroke or myocardial infarction at baseline between March 13, 2006, and October 1, 2010. Genetic risk was assessed with polygenic risk scores, calculated by summing the risk-increasing alleles, weighted by the effect estimates. Muscle strength was assessed through grip strength tests by hand dynamometers. Incidence of overall (n= 4008), ischemic (n= 3031), and hemorrhagic (n=1073) stroke was adjudicated during 11.5-year follow-up. RESULTS: Compared with the bottom muscle strength tertile, hazard ratios (95% CI) of stroke were 0.81 (0.75 to 0.87) and 0.76 (0.71 to 0.82) for the middle and top muscle strength tertiles, respectively, after adjustment for confounders and genetic risk; higher genetic risk was independently associated with higher stroke incidence. Stroke hazards for the top muscle strength tertile were consistently lower across genetic risk strata, with no evidence of interaction. Compared with individuals with high muscle strength and low genetic risk, stroke hazards were higher for individuals who had medium or high genetic risk combined with low or medium muscle strength but not for those who had medium genetic risk but high muscle strength. Associations were similar for ischemic and hemorrhagic stroke (although CIs were inconclusive for some of the associations). CONCLUSION: Higher muscle strength was associated with lower stroke incidence in all individuals, including those with high genetic susceptibility. The increased genetic risk of overall and ischemic stroke was partly attenuated through increased muscle strength.

Exercise and incidence of myocardial infarction, stroke, hypertension, type 2 diabetes and site-specific cancers: prospective cohort study of 257 854 adults in South Korea.

OBJECTIVE: The objective of this study was to examine the longitudinal associations of exercise frequency with the incidence of myocardial infarction, stroke, hypertension, type 2 diabetes and 10 different cancer outcomes. DESIGN: A prospective cohort study. SETTING: Physical examination data linked with the entire South Korean population's health insurance system: from 2002 to 2015. PARTICIPANTS: 257 854 South Korean adults who provided up to 7 repeat measures of exercise (defined as exercises causing sweat) and confounders. PRIMARY OUTCOME MEASURES: Each disease incidence was defined using both fatal and non-fatal health records (a median follow-up period of 13 years). RESULTS: Compared with no exercise category, the middle categories of exercise frequency (3-4 or 5-6 times/week) showed the lowest risk of myocardial infarction (HR 0.79; 95% CI 0.70 to 0.90), stroke (HR 0.80; 95% CI 0.73 to 0.89), hypertension (HR 0.86; 95% CI 0.85 to 0.88), type 2 diabetes (HR 0.87; 95% CI 0.84 to 0.89), stomach (HR 0.87; 95% CI 0.79 to 0.96), lung (HR 0.80; 95% CI 0.71 to 0.91), liver (HR 0.85; 95% CI 0.75 to 0.98) and head and neck cancers (HR 0.76; 95% CI 0.63 to 0.93; for 1-2 times/week), exhibiting J-shaped associations. There was, in general, little evidence of effect modification by body mass index, smoking, alcohol consumption, family history of disease and sex in these associations. CONCLUSIONS: Moderate levels of sweat-inducing exercise showed the lowest risk of myocardial infarction, stroke, hypertension, type 2 diabetes, stomach, lung, liver and head and neck cancers. Public health and lifestyle interventions should, therefore, promote moderate levels of sweat-causing exercise as a behavioural prevention strategy for non-communicable diseases in a wider population of East Asians.

Bisphenol A exposure and type 2 diabetes mellitus risk: a meta-analysis.

BACKGROUND: This meta-analytic study explored the relationship between the risk of type 2 diabetes mellitus (T2DM) and bisphenol A concentrations. METHODS: The Embase and Medline (PubMed) databases were searched, using relevant keywords, for studies published between 1980 and 2018. A total of 16 studies, twelve cross-sectional, two case-control and one prospective, were included in the meta-analysis. The odds ratio (OR) and its 95% confidence interval (CI) were determined across the sixteen studies. The OR and its 95% CI of diabetes associated with bisphenol A were estimated using both fixed-effects and random-effects models. RESULTS: A total of 41,320 subjects were included. Fourteen of the sixteen studies included in the analysis provided measurements of urine bisphenol A levels and two study provided serum bisphenol A levels. Bisphenol A concentrations in human bio-specimens showed positive associations with T2DM risk (OR 1.28, 95% CI 1.14, 1.44). A sensitivity analysis indicated that urine bisphenol A concentrations were positively associated with T2DM risk (OR 1.20, 95% CI 1.09, 1.31). CONCLUSIONS: This meta-analysis indicated that Bisphenol A exposure is positively associated with T2DM risk in humans.

Traditional and Genetic Risk Score and Stroke Risk Prediction in Korea.

BACKGROUND AND OBJECTIVES: Whether using both traditional risk factors and genetic variants for stroke as opposed to using either of the 2 alone improves the prediction of stroke risk remains unclear. The purpose of this study was to compare the predictability of stroke risk between models using traditional risk score (TRS) and genetic risk score (GRS). METHODS: We used a case-cohort study from the Korean Cancer Prevention Study-II (KCPS-II) Biobank (n=156,701). We genotyped 72 single nucleotide polymorphisms (SNPs) identified in genome-wide association study (GWAS) on the KCPS-II sub-cohort members and stroke cases. We calculated GRS by summing the number of risk alleles. Prediction models with or without GRS were evaluated in terms of the area under the receiver operating characteristic curve (AUROC). RESULTS: Sixteen out of 72 SNPs identified in GWAS showed significant associations with stroke, with an odds ratio greater than 2.0. For participants aged <40 years, AUROCs for incident stroke were 0.58, 0.65, and 0.67 in models using modifiable TRS only, GRS only, and TRS plus GRS, respectively, showing that GRS only model had better prediction than TRS only. For participants aged ≥40 years, however, TRS only model had better prediction than GRS only model. Favorable levels of traditional risk were associated with significantly lower stroke risks within each genetic risk category. CONCLUSIONS: TRS and GRS were both independently associated with stroke risk. Using genetic variants in addition to traditional risk factors may be the most accurate way of predicting stroke risk, particularly in relatively younger individuals.

Analysis of metabolites and metabolic pathways in breast cancer in a Korean prospective cohort: the Korean Cancer Prevention Study-II.

INTRODUCTION: Since blood is in contact with all tissues in the body and is considered to dynamically reflect the body's pathophysiological status, serum metabolomics changes are important and have diagnostic value in early cancer detection. OBJECTIVES: In this prospective study, we investigated the application of metabolomics to differentiate subjects with incident breast cancer (BC) from subjects who remained free of cancer during a mean follow-up period of 7 years with the aim of identifying valuable biomarkers for BC. METHODS: Baseline serum samples from 84 female subjects with incident BC (BC group) and 88 cancer-free female subjects (control group) were used. Metabolic alterations associated with BC were investigated via metabolomics analysis of the baseline serum samples using ultra-performance liquid chromatography-linear-trap quadrupole-Orbitrap mass spectrometry. RESULTS: A total of 57 metabolites were identified through the metabolic analysis. Among them, 20 metabolite levels were significantly higher and 22 metabolite levels were significantly lower in the BC group than in the control group at baseline. Ten metabolic pathways, including amino acid metabolism, arachidonic acid (AA) metabolism, fatty acid metabolism, linoleic acid metabolism, and retinol metabolism, showed significant differences between the BC group and the control group. Logistic regression revealed that the incidence of BC was affected by leucine, AA, prostaglandin (PG)J2, PGE2, and γ-linolenic acid (GLA). CONCLUSIONS: This prospective study showed the clinical relevance of dysregulation of various metabolisms on the incidence of BC. Additionally, leucine, AA, PGJ2, PGE2, and GLA were identified as independent variables affecting the incidence of BC.

On Constructing Seminal Paper Genealogy.

Let us consider that someone is starting a research on a topic that is unfamiliar to them. Which seminal papers have influenced the topic the most? What is the genealogy of the seminal papers in this topic? These are the questions that they can raise, which we try to answer in this paper. First, we propose an algorithm that finds a set of seminal papers on a given topic. We also address the performance and scalability issues of this sophisticated algorithm. Next, we discuss the measures to decide how much a paper is influenced by another paper. Then, we propose an algorithm that constructs a genealogy of the seminal papers by using the influence measure and citation information. Finally, through extensive experiments with a large volume of a real-world academic literature data, we show the effectiveness and efficiency of our approach.