Two duplicated gsdf homeologs cooperatively regulate male differentiation by inhibiting cyp19a1a transcription in a hexaploid fish.

Although evolutionary fates and expression patterns of duplicated genes have been extensively investigated, how duplicated genes co-regulate a biological process in polyploids remains largely unknown. Here, we identified two gsdf (gonadal somatic cell-derived factor) homeologous genes (gsdf-A and gsdf-B) in hexaploid gibel carp (Carassius gibelio), wherein each homeolog contained three highly conserved alleles. Interestingly, gsdf-A and gsdf-B transcription were mainly activated by dmrt1-A (dsx- and mab-3-related transcription factor 1) and dmrt1-B, respectively. Loss of either gsdf-A or gsdf-B alone resulted in partial male-to-female sex reversal and loss of both caused complete sex reversal, which could be rescued by a nonsteroidal aromatase inhibitor. Compensatory expression of gsdf-A and gsdf-B was observed in gsdf-B and gsdf-A mutants, respectively. Subsequently, we determined that in tissue culture cells, Gsdf-A and Gsdf-B both interacted with Ncoa5 (nuclear receptor coactivator 5) and blocked Ncoa5 interaction with Rora (retinoic acid-related orphan receptor-alpha) to repress Rora/Ncoa5-induced activation of cyp19a1a (cytochrome P450, family 19, subfamily A, polypeptide 1a). These findings illustrate that Gsdf-A and Gsdf-B can regulate male differentiation by inhibiting cyp19a1a transcription in hexaploid gibel carp and also reveal that Gsdf-A and Gsdf-B can interact with Ncoa5 to suppress cyp19a1a transcription in vitro. This study provides a typical case of cooperative mechanism of duplicated genes in polyploids and also sheds light on the conserved evolution of sex differentiation.

Association of Lung Ultrasound B-Lines with Left Ventricular Diastolic Function in Clinically Euvolemic Haemodialysis Patients.

INTRODUCTION: Left ventricular diastolic dysfunction (LVDD) frequently occurs in haemodialysis patients and is associated with adverse outcomes. Lung ultrasound (LUS) has been recently proposed for the quantification of extravascular lung water through assessment of B-lines. LUS findings and their relationship with LVDD in clinically euvolemic haemodialysis patients were investigated in this study. METHODS: Echocardiography and LUS examinations were performed on each patient. Multivariate linear regression and forward stepwise logistic regression were performed to determine the relationship between B-lines and LVDD. A receiver operating characteristic (ROC) curve with area under the curve (AUC) was calculated to determine the accuracy of B-lines for evaluating LVDD. RESULTS: A total of 119 patients were enrolled. The number of B-lines was statistically related to echocardiographic parameters (LAVI, LVEDVI, E/A, and E/e') of diastolic function, while the relationship between B-lines and LVEF disappeared after adjusting for potential confounding factors. Additionally, compared with the mild B-line group (B-lines: <14), the moderate (B-lines: 14-30) and severe B-line groups (B-lines: >30) were associated with an increased risk of LVDD (OR 24.344, 95% CI 4.854-122.084, p < 0.001, and OR 94.552, 95% CI 9.617-929.022, p < 0.001, respectively). Furthermore, the AUC of the ROC curve for B-lines predicting LVDD was 0.845, and the cut-off of B-lines was 14.5 (sensitivity 64.91%, specificity 93.55%). CONCLUSION: LUS B-lines were closely associated with left ventricular diastolic function in clinically euvolemic haemodialysis patients. Moreover, our findings suggested a B-line ≥14.5 as a reliable cut-off value for identifying patients with LVDD. LUS B-lines may be used as a novel indicator for evaluating LVDD.

Genomic anatomy of male-specific microchromosomes in a gynogenetic fish.

Unisexual taxa are commonly considered short-lived as the absence of meiotic recombination is supposed to accumulate deleterious mutations and hinder the creation of genetic diversity. However, the gynogenetic gibel carp (Carassius gibelio) with high genetic diversity and wide ecological distribution has outlived its predicted extinction time of a strict unisexual reproduction population. Unlike other unisexual vertebrates, males associated with supernumerary microchromosomes have been observed in gibel carp, which provides a unique system to explore the rationales underlying male occurrence in unisexual lineage and evolution of unisexual reproduction. Here, we identified a massively expanded satellite DNA cluster on microchromosomes of hexaploid gibel carp via comparing with the ancestral tetraploid crucian carp (Carassius auratus). Based on the satellite cluster, we developed a method for single chromosomal fluorescence microdissection and isolated three male-specific microchromosomes in a male metaphase cell. Genomic anatomy revealed that these male-specific microchromosomes contained homologous sequences of autosomes and abundant repetitive elements. Significantly, several potential male-specific genes with transcriptional activity were identified, among which four and five genes displayed male-specific and male-biased expression in gonads, respectively, during the developmental period of sex determination. Therefore, the male-specific microchromosomes resembling common features of sex chromosomes may be the main driving force for male occurrence in gynogenetic gibel carp, which sheds new light on the evolution of unisexual reproduction.

Clinical and metabolic characteristics of endometrial lesions in polycystic ovary syndrome at reproductive age.

BACKGROUND: We aimed to explore the clinical and metabolic characteristics in polycystic ovary syndrome (PCOS) patients with different endometrial lesions. METHODS: 234 PCOS patients who underwent hysteroscopy and endometrial biopsy were categorized into four groups: (1) normal endometrium (control group, n = 98), (2) endometrial polyp (EP group, n = 92), (3) endometrial hyperplasia (EH group, n = 33), (4) endometrial cancer (EC group, n = 11). Serum sex hormone levels, 75 g oral glucose tolerance test, insulin release test, fasting plasma lipid, complete blood count and coagulation parameters were measured and analyzed. RESULTS: Body mass index and triglyceride level of the EH group were higher while average menstrual cycle length was longer in comparison with the control and EP group. Sex hormone-binding globulin (SHBG) and high density lipoprotein were lower in the EH group than that in the control group. 36% of the patients in the EH group suggested obesity, higher than the other three groups. Using multivariant regression analysis, patients with free androgen index > 5 had higher risk of EH (OR 5.70; 95% CI 1.05-31.01), while metformin appeared to be a protective factor for EH (OR 0.12; 95% CI 0.02-0.80). Metformin and hormones (oral contraceptives or progestogen) were shown to be protective factors for EP (OR 0.09; 95% CI 0.02-0.42; OR 0.10; 95% CI 0.02-0.56). Hormones therapy appeared to be a protective factor for EC (OR 0.05; 95% CI 0.01-0.39). CONCLUSION: Obesity, prolonged menstrual cycle, decreased SHBG, and dyslipidemia are risk factors for EH in patients with PCOS. Oral contraceptives, progestogen and metformin are recommended for prevention and treatment of endometrial lesions in PCOS patients.

The impact of SARS-COV-2 infection on menstruation.

BACKGROUND: Recent study has demonstrated that the GnRH system in patients with post-COVID syndrome may be influenced by SARS-CoV-2. However, the impact of COVID-19 infection on women's menstruation is still unknown. OBJECTIVE: We aimed to investigate the the relationship between coronavirus disease 2019 (COVID-19) and menstruation in premenopausal women. METHODS: This was a retrospective cohort study. Pre-menopausal women were invited to participate in the online questionnaire on wechat. Participants were divided into four groups according to whether they were infected with severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) and whether they had menstrual changes during the pandemic. Sociodemographic characteristics, history of COVID-19, menstruation and menstrual changes of the participants were collected. Statistical analyses were performed using SPSS, version 25.0 (SPSS Inc., Chicago, IL, USA). RESULTS: A total of 1946 women were included in the study. 1800 participants had been or were currently infected with SARS-COV-2, and 146 people had not been infected. Among 1800 patients with COVID-19, 666 (37.0%) had changes in menstruation, and 1134 (63.0%) did not, which was significantly higher than the uninfected participants (c2 = 12.161, P = 0.000). The proportion of participants with menstrual cycle changes (450/67.6%) is larger than that of uninfected participants (c2 = 6.904, P = 0.009). COVID-19 vaccination was associated with lower odds of menstrual cycle change (OR, 0.855; 95% CI, 0.750-0.976). Participants who reported chest pain (OR, 1.750, 95% CI, 1.209-2.533) and dyspnea (OR, 1.446; 95% CI, 1.052-1.988) during infection had greater odds of changes to their menstrual cycle compared with the participants who did not. CONCLUSIONS: The association between the COVID-19 and increased prevalence of menstrual cycle irregularity. COVID-19 vaccination is a protective factor in the long term, and participants with chest pain and dyspnea are more likely to develop AUB.

Cloning, expression, and bioinformatics analysis of heavy metal resistance-related genes fd-I and fd-II from Acidithiobacillus ferrooxidans.

Five heavy metals were introduced into the bacterial heavy metal resistance tests. The results showed that apparent inhibition effects of Cd2+ and Cu2+ on the growth of Acidithiobacillus ferrooxidans BYSW1 occurred at high concentrations (>0.04 mol l-1). Significant differences (P < 0.001) were both noticed in the expression of two ferredoxin-encoding genes (fd-I and fd-II) related to heavy metal resistance in the presence of Cd2+ and Cu2+ . When exposed to 0.06 mol l-1 Cd2+, the relative expression levels of fd-I and fd-II were about 11 and 13 times as much as those of the control, respectively. Similarly, exposure to 0.04 mol l-1 Cu2+ caused approximate 8 and 4 times higher than those of the control, respectively. These two genes were cloned and expressed in Escherichia coli, and the structures, functions of two corresponding target proteins, i.e. Ferredoxin-I (Fd-I) and Ferredoxin-II (Fd-II), were predicted. The recombinant cells inserted by fd-I or fd-II were more resistant to Cd2+ and Cu2+ compared with wild-type cells. This study was the first investigation regarding the contribution of fd-I and fd-II to enhancing heavy metal resistance of this bioleaching bacterium, and laid a foundation for further elucidation of heavy metal resistance mechanisms caused by Fd.

Superresolution imaging reveals spatiotemporal propagation of human replication foci mediated by CTCF-organized chromatin structures.

Mammalian DNA replication is initiated at numerous replication origins, which are clustered into thousands of replication domains (RDs) across the genome. However, it remains unclear whether the replication origins within each RD are activated stochastically or preferentially near certain chromatin features. To understand how DNA replication in single human cells is regulated at the sub-RD level, we directly visualized and quantitatively characterized the spatiotemporal organization, morphology, and in situ epigenetic signatures of individual replication foci (RFi) across S-phase at superresolution using stochastic optical reconstruction microscopy. Importantly, we revealed a hierarchical radial pattern of RFi propagation dynamics that reverses directionality from early to late S-phase and is diminished upon caffeine treatment or CTCF knockdown. Together with simulation and bioinformatic analyses, our findings point to a "CTCF-organized REplication Propagation" (CoREP) model, which suggests a nonrandom selection mechanism for replication activation at the sub-RD level during early S-phase, mediated by CTCF-organized chromatin structures. Collectively, these findings offer critical insights into the key involvement of local epigenetic environment in coordinating DNA replication across the genome and have broad implications for our conceptualization of the role of multiscale chromatin architecture in regulating diverse cell nuclear dynamics in space and time.

IL-27 improves adoptive CD8+ T cells' antitumor activity via enhancing cell survival and memory T cell differentiation.

IL-27 is an anti-inflammatory cytokine that triggers enhanced antitumor immunity, particularly cytotoxic T lymphocyte responses. In the present study, we sought to develop IL-27 into a therapeutic adjutant for adoptive T cell therapy using our well-established models. We have found that IL-27 directly improved the survival status and cytotoxicity of adoptive OT-1 CD8+ T cells in vitro and in vivo. Meanwhile, IL-27 treatment programs memory T cell differentiation in CD8+ T cells, characterized by upregulation of genes associated with T cell memory differentiation (T-bet, Eomes, Blimp1, and Ly6C). Additionally, we engineered the adoptive OT-1 CD8+ T cells to deliver IL-27. In mice, the established tumors treated with OT-1 CD8+ T-IL-27 were completely rejected, which demonstrated that IL-27 delivered via tumor antigen-specific T cells enhances adoptive T cells' cancer immunity. To our knowledge, this is the first application of CD8+ T cells as a vehicle to deliver IL-27 to treat tumors. Thus, this study demonstrates IL-27 is a feasible approach for enhancing CD8+ T cells' antitumor immunity and can be used as a therapeutic adjutant for T cell adoptive transfer to treat cancer.

Identifying psychiatric disorder-associated gut microbiota using microbiota-related gene set enrichment analysis.

Psychiatric disorders are a group of complex psychological syndromes with high prevalence. It has been reported that gut microbiota has a dominant influence on the risks of psychiatric disorders through gut microbiota-brain axis. We extended the classic gene set enrichment analysis (GSEA) approach to detect the association between gut microbiota and complex diseases using published genome-wide association study (GWAS) and GWAS of gut microbiota summary data. We applied our approach to real GWAS data sets of five psychiatric disorders, including attention deficiency/hyperactive disorder (ADHD), autism spectrum disorder (AUT), bipolar disorder (BD), schizophrenia (SCZ) and major depressive disorder (MDD). To evaluate the performance of our approach, we also tested the genetic correlations of obesity and type 2 diabetes with gut microbiota. We identified several significant associations between psychiatric disorders and gut microbiota, such as ADHD and genus Desulfovibrio (P = 0.031), order Clostridiales (P = 0.034). For AUT, association signals were observed for genera Bacteroides (P = 0.012) and Desulfovibrio (P = 0.033). Genus Desulfovibrio (P = 0.005) appeared to be associated with BD. For MDD, association signals were observed for genus Desulfovibrio (P = 0.003), order Clostridiales (P = 0.004), family Lachnospiraceae (P = 0.007) and genus Bacteroides (P = 0.007). Genus Desulfovibrio (P = 0.012) and genus Bacteroides (P = 0.038) appeared to be associated with SCZ. Our study results provide novel clues for revealing the roles of gut microbiota in psychiatric disorders. This study also illustrated the good performance of GSEA approach for exploring the relationships between gut microbiota and complex diseases.

Intranasal Dexmedetomidine in Elderly Patients (Aged > 65 Years) During Maxillofacial Surgery: Sedative Properties and Safety Analysis.

PURPOSE: Light sedation rather than intravenous sedation is preferred when patients have a low heart rate and blood pressure during maxillofacial surgery. Intranasal administration of dexmedetomidine is reported to be efficacious and safe in adults. However, dexmedetomidine could be unsuitable for routine clinical use in elderly patients because many of these patients take ß-blockers, which increase the cardiovascular effects of dexmedetomidine. The objectives of the study were to evaluate the sedative properties and safety of intranasal dexmedetomidine, regardless of concurrent ß-blocker treatment, in elderly patients who underwent maxillofacial surgery. METHODS: This study was a retrospective analysis of 535 patients aged > 65 years (American Society of Anesthesiologists physical status I or II) who were undergoing maxillofacial surgery. Very anxious patients and those with hypertension received intranasal 1 µg/kg dexmedetomidine through an intranasal mucosal atomization device before anesthesia (local ropivacaine). RESULTS: Intranasal administration of dexmedetomidine decreased the requirement for midazolam before surgery (18 of 252 vs 63 of 283, P < .0001), but increased the requirement for norepinephrine (102 of 252 vs 8 of 283, P < .0001) during or after the surgery. A combination of a ß-blocker and intranasal administration of dexmedetomidine reduced the hemodynamic parameters for an extended period. Intranasal administration of dexmedetomidine resulted in bradycardia and hypotension, regardless of concurrent ß-blocker treatment. CONCLUSIONS: Intranasal 1 µg/kg dexmedetomidine was associated with a high sedation score during the operation, but also with bradycardia and hypotension.

[Anti-photoaging effects and mechanisms of active ingredients of Chinese medicine: a review].

Skin photoaging is exogenous aging caused by long-term ultraviolet radiation, which not only affects skin appearance, but also has a close relationship with the development of skin cancer. Saponins, flavonoids, polyphenols, polysaccharides, and extracts of Chinese medicine have been found to have anti-skin photoaging effects in recent studies. Various mechanisms such as anti-oxidative stress damage, inhibition of matrix metalloproteinase expression, promotion of collagen synthesis, inhibition of inflammatory response, DNA damage repair, enhancement of cell autophagy, and inhibition of melanin synthesis can improve the symptoms of skin photoaging and delay the photoaging process. With the active ingredients of Chinese medicine for anti-skin photoaging as the entry point, the study systematically discussed the research progress of the mechanisms underlying the anti-photoaging effects of active ingredients of Chinese medicine in recent years, in order to provide theoretical reference for the development of new anti-photoaging drugs and methods.

PCA-based GRS analysis enhances the effectiveness for genetic correlation detection.

Genetic risk score (GRS, also known as polygenic risk score) analysis is an increasingly popular method for exploring genetic architectures and relationships of complex diseases. However, complex diseases are usually measured by multiple correlated phenotypes. Analyzing each disease phenotype individually is likely to reduce statistical power due to multiple testing correction. In order to conquer the disadvantage, we proposed a principal component analysis (PCA)-based GRS analysis approach. Extensive simulation studies were conducted to compare the performance of PCA-based GRS analysis and traditional GRS analysis approach. Simulation results observed significantly improved performance of PCA-based GRS analysis compared to traditional GRS analysis under various scenarios. For the sake of verification, we also applied both PCA-based GRS analysis and traditional GRS analysis to a real Caucasian genome-wide association study (GWAS) data of bone geometry. Real data analysis results further confirmed the improved performance of PCA-based GRS analysis. Given that GWAS have flourished in the past decades, our approach may help researchers to explore the genetic architectures and relationships of complex diseases or traits.

Comparison of outcomes between neoadjuvant imatinib and upfront surgery in patients with localized rectal GIST: An inverse probability of treatment weighting analysis.

BACKGROUND AND OBJECTIVES: This study aimed to compare outcomes between neoadjuvant imatinib and upfront surgery in patients with localized rectal gastrointestinal stromal tumors (GIST) patients. METHODS: Eighty-five patients with localized rectal GIST were divided into two groups: upfront surgery ± adjuvant imatinib (Group A, n = 33) and the neoadjuvant imatinib + surgery + adjuvant imatinib (Group B, n = 52). Baseline characteristics between groups were controlled for with inverse probability of treatment weighting (IPTW) adjusted analysis. RESULTS: The response rate to neoadjuvant imatinib was 65.9%. After the IPTW-adjusted analysis, patients who underwent neoadjuvant therapy had better distant recurrence-free survival (DRFS) and disease-specific survival (DSS) compared with those who underwent upfront surgery (5-year DRFS 97.8 vs. 71.9%, hazard ratio [HR], 0.15; 95% CI, 0.03-0.87; p = 0.03; 5-year DSS 100 vs. 77.1%; HR, 0.11; 95% CI, 0.01-0.92; p = 0.04). While no significant association was found between overall survival (OS) and treatment groups (p = 0.07), 5-year OS was higher for the neoadjuvant group than upfront surgery group (97.8% vs. 71.9%; HR, 0.2; 95% CI, 0.03-1.15). CONCLUSIONS: In patients with localized rectal GIST, neoadjuvant imatinib not only shrunk the tumor size but also decreased the risk of metastasis and tumor-related deaths when compared to upfront surgery and adjuvant imatinib alone.

Quantitative CT for detecting COVID­19 pneumonia in suspected cases.

BACKGROUND: Corona Virus Disease 2019 (COVID-19) is currently a worldwide pandemic and has a huge impact on public health and socio-economic development. The purpose of this study is to explore the diagnostic value of the quantitative computed tomography (CT) method by using different threshold segmentation techniques to distinguish between patients with or without COVID-19 pneumonia. METHODS: A total of 47 patients with suspected COVID-19 were retrospectively analyzed, including nine patients with positive real-time fluorescence reverse transcription polymerase chain reaction (RT-PCR) test (confirmed case group) and 38 patients with negative RT-PCR test (excluded case group). An improved 3D convolutional neural network (VB-Net) was used to automatically extract lung lesions. Eight different threshold segmentation methods were used to define the ground glass opacity (GGO) and consolidation. The receiver operating characteristic (ROC) curves were used to compare the performance of various parameters with different thresholds for diagnosing COVID-19 pneumonia. RESULTS: The volume of GGO (VOGGO) and GGO percentage in the whole lung (GGOPITWL) were the most effective values for diagnosing COVID-19 at a threshold of - 300 HU, with areas under the curve (AUCs) of 0.769 and 0.769, sensitivity of 66.67 and 66.67%, specificity of 94.74 and 86.84%. Compared with VOGGO or GGOPITWL at a threshold of - 300 Hounsfield units (HU), the consolidation percentage in the whole lung (CPITWL) with thresholds at - 400 HU, - 350 HU, and - 250 HU were statistically different. There were statistical differences in the infection volume and percentage of the whole lung, right lung, and lobes between the two groups. VOGGO, GGOPITWL, and volume of consolidation (VOC) were also statistically different at the threshold of - 300 HU. CONCLUSIONS: Quantitative CT provides an image quantification method for the auxiliary diagnosis of COVID-19 and is expected to assist in confirming patients with COVID-19 pneumonia in suspected cases.

High-Sensitive Cardiac Troponin T for Prediction of Cardiovascular Outcomes in Stable Maintenance Hemodialysis Patients: A 3-Year Prospective Study.

BACKGROUND: Hemodialysis patients, who are often excluded from cardiovascular (CV) clinical trials, are associated with higher CV morbidity and mortality. The risk stratification scheme for these patients is lacking. Therefore, this investigation examined the independent CV prognostic value of high-sensitive cardiac troponin T (hs-cTnT) and added prognostic value over echocardiographic parameters and other clinical risk predictors in asymptomatic stable maintenance hemodialysis (MHD) patients. METHODS: 181 patients with end-stage renal disease undergoing MHD were eligible from the dialysis center of Tongren Hospital, Shanghai Jiao Tong University School of Medicine between October 2017 and September 2018. These patients were followed until September 2020 or until death. The median follow-up was 31 (IQR: 21-33) months. Outcome measures were all-cause mortality, first fatal or nonfatal CV events (CVEs), and 4-point composite major adverse CVEs (MACE). We performed multivariable Cox regression analysis using demographic, clinical, laboratory, and echocardiographic data to identify predictors of CV outcomes. We also evaluated the increased discriminative value associated with the addition of echocardiographic parameters and hs-cTnT using net reclassification improvement (NRI) and integrated discrimination improvement (IDI). RESULTS: During follow-up, 37 patients died, 84 patients suffered one or more CVEs, and 78 patients developed 4-point MACE. In univariable analyses, age, dialysis vintage, diastolic blood pressure, parathyroid hormone concentrations, hs-cTnT, B-type natriuretic peptide, left ventricular mass index (LVMI), and E/E' predicted all end points. hs-cTnT remained a strong predictor for each end point in multivariate analysis, whereas LVMI and E/E' did not. The addition of hs-cTnT on top of clinical and echocardiographic variables was associated with improvements in reclassification for CVEs (NRI = 44.6% [15.9-74.3%], IDI = 15.9% [5.7-31.0%], all p < 0.001), all-cause mortality (NRI = 35.5% [10.1-50.2%], p < 0.001, IDI = 4.4% [1.3-8.5%], p = 0.005), and 4-point MACE (NRI = 47.2% [16.1-64.9%], p < 0.001, IDI = 16.9% [5.5-37.3%], p = 0.005). Adding echocardiographic variables on top of clinical variables and hs-cTnT was not associated with significant improvements in NRI and IDI (all p > 0.05). CONCLUSIONS: Our data suggest that hs-cTnT is a powerful independent predictor of CV outcome and all-cause mortality in stable MHD patients. The additional use of echocardiography for improvement of risk stratification is not supported by our results.

Risk factors of endometrial cancer in patients with endometrial hyperplasia: implication for clinical treatments.

BACKGROUND: Endometrial hyperplasia (EH) is commonly-seen in the patients with endometrial cancer (EC), we aimed to evaluated the risk factors of EC in patients with EH, to provide evidence to the clinical prevention and treatment of EC. METHODS: This study was a retrospective study design. EH patients confirmed by pathological examinations and treated with hysterectomy in our hospital from June 1, 2018 to February 28, 2021 were included. The clinical characteristics of EC and no-EC patients were compared and analyzed. Logistics regression analyses were conducted to evaluate the risk factors of EC in patients with EH. RESULTS: A total of 228 EH patients were included, the incidence of EC in the EH patients was 31.58%. There were significant differences in the age, BMI, diabetes, hypertension and pathology of EH between EC and no EC groups (all P < 0.05), no significant differences in the hyperlipidemia, preoperative CA125, number of deliveries, menopause and endometrial thickness between EC and no EC groups were found (all P > 0.05). Logistic regression analyses indicated that age > 50 y (OR 3.064, 95% CI 1.945-5.931), BMI ≥ 25 kg/m2 (OR 2.705, 95% CI 1.121-3.889), diabetes (OR 3.049, 95% CI 1.781-5.114), hypertension (OR 2.725, 95% CI 1.108-3.431) and severe hyperplasia (OR 3.181, 95% CI 1.496-4.228) were the risk factors of EC in patients with EH (all P < 0.05). CONCLUSIONS: The risk of EC in EH patients is high, especially for those patients with age > 50 y, BMI ≥ 25 kg/m2, diabetes, hypertension and severe hyperplasia, special attentions should be paid for occurrence of EC and early diagnosis and early treatment are needed for those patients.

Genetic Correlation Analysis and Transcriptome-wide Association Study Suggest the Overlapped Genetic Mechanism between Gout and Attention-deficit Hyperactivity Disorder.

OBJECTIVES: Gout is a common inflammatory arthritis, which is caused by hyperuricemia. Limited efforts have been paid to systematically explore the relationships between gout and common psychiatric disorders. METHODS: Genome-wide association study summary data of gout were obtained from the GeneATLAS, which contained 452,264 participants including 3,528 gout cases. Linkage disequilibrium score regression (LDSC) was first conducted to evaluate the genetic relationships between gout and 5 common psychiatric disorders. Transcriptome-wide association studies (TWAS) was then conducted to explore the potential biological mechanism underlying the observed genetic correlation between gout and attention-deficit hyperactivity disorder (ADHD). The Database for Annotation, Visualization and Integrated Discovery online functional annotation system was applied for pathway enrichment analysis and gene ontology enrichment analysis. RESULTS: LDSC analysis observed significant genetic correlation between gout and ADHD (genetic correlation coefficients = 0.29, standard error = 0.09 and P value = 0.0015). Further TWAS of gout identified 105 genes with P value < 0.05 in muscle skeleton and 228 genes with P value < 0.05 in blood. TWAS of ADHD also detected 300 genes with P value < 0.05 in blood. Further comparing the TWAS results identified 9 common candidate genes shared by gout and ADHD, such as CD300C (Pgout = 0.0040; PADHD = 0.0226), KDM6B (Pgout = 0.0074; PADHD = 0.0460), and BST1 (Pgout = 0.0349; PADHD = 0.03560). CONCLUSION: We observed genetic correlation between gout and ADHD and identified multiple candidate genes for gout and ADHD.

Evaluating the Correlations Between Osteoporosis and Lifestyle-Related Factors Using Transcriptome-Wide Association Study.

Osteoporosis (OP) is a multi-factorial bone disease influenced by genetic factors, age, and lifestyles. The aim of this study is to evaluate the genetic correlations between OP and multiple lifestyle-related factors, and explore the genes underlying the detected genetic correlations. Linkage disequilibrium score regression (LDSC) analysis was applied to evaluate the genetic correlations of total body bone mineral density (TB-BMD) of different ages (including 15-30 years, 30-45 years, 45-60 years, and over 60 years) with four common lifestyle/environment-related factors (including serum 25-hydroxyvitamin D, cigarette smoking, alcohol dependence, and caffeine metabolites). Transcriptome-wide association studies (TWAS) of TB-BMD (30-45 years) and smoking were conducted in peripheral blood (PB), whole blood (WB), and adipose tissues. The identified candidate genes were also subjected to gene set enrichment analysis (GSEA). Genetic correlation was only observed between TB-BMD (30-45 years) and cigarette smoking status (P = 0.01, LD score = 0.11 ± 0.04). No significant genetic correlation was detected for other lifestyle/environmental factors, including serum 25-hydroxyvitamin D, alcohol dependence, and caffeine metabolites for TB-BMD within all of the four age groups. TWAS identified 85 genes in PB and 163 genes in WB for TB-BMD, as well as 123 genes in PB and 257 genes in WB for smoking. Multiple common candidate genes shared by both TB-BMD and smoking were detected, such as MAP1LC3B (PTB-BMD-PB = 1.00 × 10-3, Psmoking-PB = 9.62 × 10-3, PTB-BMD-WB = 2.99 × 10-2) and SLC23A3 (PTB-BMD-WB = 1.48 × 10-2, Psmoking-WB = 8.76 × 10-3). GSEA detected one GO terms for TB-BMD (cytosol) in WB, one GO term for smoking (mitochondrion) in PB, and one pathway (oocyte meiosis) for smoking in WB.

EA15, MIR22, LINC00472 as diagnostic markers for diabetic kidney disease.

This study aimed to investigate the molecular mechanisms of diabetic kidney disease (DKD) and to explore new potential therapeutic strategies and biomarkers for DKD. First we analyzed the differentially expressed changes between patients with DKD and the control group using the chip data in Gene Expression Omnibus (GEO) database. Then the gene chip was subjected to be annotated again, so as to screen long noncoding RNAs (lncRNAs) and study expression differences of these lncRNAs in DKD and controlled samples. At last, the function of the differential lncRNAs was analyzed. A total of 252 lncRNAs were identified, and 14 were differentially expressed. In addition, there were 1,629 differentially expressed messenger RNAs (mRNAs) genes, and proliferation and apoptosis adapter protein 15 (PEA15), MIR22, and long intergenic nonprotein coding RNA 472 ( LINC00472) were significantly differentially expressed in DKD samples. Through functional analysis of the encoding genes coexpressed by the three lncRNAs, we found these genes were mainly enriched in type 1 diabetes and autoimmune thyroid disease pathways, whereas in Gene Ontology (GO) function classification, they were also mainly enriched in the immune response, type I interferon signaling pathways, interferon-γ mediated signaling pathways, and so forth. To summary, we identified EA15, MIR22, and LINC00472 may serve as the potential diagnostic markers of DKD.

Integrative analysis of transcriptome-wide association study data and messenger RNA expression profiles identified candidate genes and pathways for inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a complex disease, resulting from abnormal immune response to intestinal tract microbiota in genetically susceptible individuals. Crohn's disease and ulcerative colitis (UC) are the two major types of IBD. Transcriptome-wide association study (TWAS) of IBD was first performed using a large-scale genome-wide association study summary data sets of IBD. The FUSION software was applied for TWAS, considering various tissues and cells. The genes identified by TWAS were then validated by the gene expression profiling data sets of IBD. The functional annotation and potential pathways of common differentially expressed genes were further subjected to gene ontology (GO) and pathway enrichment analysis. Integrative analysis of TWAS and messenger RNA (mRNA) expression data detected several tissues related common genes for UC, such as HLA-DRB1 (PTWAS = 0.024; mRNA expression ratio = 1.700) and TAP2 in colon (P TWAS = 0.047; mRNA expression ratio = 2.170). Further comparing the GO enrichment analysis results of TWAS and mRNA expression data, we identified 11 common GO terms for UC, such as plasma membrane (P value = 5.08 × 10-10 ) in intestinal tissues and immune response (P = 0.001) in peripheral blood. We also detected several common pathways for UC, including cell adhesion molecules (P = 0.003) in intestinal tissues, IBD (P = 0.049) in whole blood and phagosome (P = 0.0003) in peripheral blood. Our study results provide novel clues for understanding the genetic mechanism of IBD.