Genome-wide association and Mendelian randomization analysis provide insights into the shared genetic architecture between high-dimensional electrocardiographic features and ischemic heart disease.

Observational studies have revealed that ischemic heart disease (IHD) has a unique manifestation on electrocardiographic (ECG). However, the genetic relationships between IHD and ECG remain unclear. We took 12-lead ECG as phenotypes to conduct genome-wide association studies (GWAS) for 41,960 samples from UK-Biobank (UKB). By leveraging large-scale GWAS summary of ECG and IHD (downloaded from FinnGen database), we performed LD score regression (LDSC), Mendelian randomization (MR), and polygenic risk score (PRS) regression to explore genetic relationships between IHD and ECG. Finally, we constructed an XGBoost model to predict IHD by integrating PRS and ECG. The GWAS identified 114 independent SNPs significantly (P value < 5 × 10-8/800, where 800 denotes the number of ECG features) associated with ECG. LDSC analysis indicated significant (P value < 0.05) genetic correlations between 39 ECG features and IHD. MR analysis performed by five approaches showed a putative causal effect of IHD on four S wave related ECG features at lead III. Integrating PRS for these ECG features with age and gender, the XGBoost model achieved Area Under Curve (AUC) 0.72 in predicting IHD. Here, we provide genetic evidence supporting S wave related ECG features at lead III to monitor the IHD risk, and open up a unique approach to integrate ECG with genetic factors for pre-warning IHD.

Genetic evidence for T-wave area from 12-lead electrocardiograms to monitor cardiovascular diseases in patients taking diabetes medications.

Aims Many studies indicated use of diabetes medications can influence the electrocardiogram (ECG), which remains the simplest and fastest tool for assessing cardiac functions. However, few studies have explored the role of genetic factors in determining the relationship between the use of diabetes medications and ECG trace characteristics (ETC). Methods Genome-wide association studies (GWAS) were performed for 168 ETCs extracted from the 12-lead ECGs of 42,340 Europeans in the UK Biobank. The genetic correlations, causal relationships, and phenotypic relationships of these ETCs with medication usage, as well as the risk of cardiovascular diseases (CVDs), were estimated by linkage disequilibrium score regression (LDSC), Mendelian randomization (MR), and regression model, respectively. Results The GWAS identified 124 independent single nucleotide polymorphisms (SNPs) that were study-wise and genome-wide significantly associated with at least one ETC. Regression model and LDSC identified significant phenotypic and genetic correlations of T-wave area in lead aVR (aVR_T-area) with usage of diabetes medications (ATC code: A10 drugs, and metformin), and the risks of ischemic heart disease (IHD) and coronary atherosclerosis (CA). MR analyses support a putative causal effect of the use of diabetes medications on decreasing aVR_T-area, and on increasing risk of IHD and CA. ConclusionPatients taking diabetes medications are prone to have decreased aVR_T-area and an increased risk of IHD and CA. The aVR_T-area is therefore a potential ECG marker for pre-clinical prediction of IHD and CA in patients taking diabetes medications.

Optimal dose and type of non-pharmacological treatments to improve cognitive function in people with Alzheimer's disease: a systematic review and network meta-analysis.

OBJECTIVES: To evaluate and rank the effectiveness of specific non-pharmacological treatments (NPTs) in improving the global cognitive function in individuals with Alzheimer's disease (AD) and to examine the dose-response relationship. METHOD: We conducted a systematic search in PubMed, MEDLINE, Embase, PsycINFO, CENTRAL, WOS, and CNKI from their inception to 15 February 2023. Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated for outcomes using random effects models. RESULTS: We included 68 studies involving 5053 participants in this meta-analysis. The treatments with the highest cumulative probabilities for improving global cognitive function were transcranial direct current stimulation (tDCS), followed by physical exercise (PE), and repetitive transcranial magnetic stimulation (rTMS). Additionally, cognitive stimulation (CS), cognitive training CT), multidisciplinary program (MD), and reminiscence treatment (RT) also significantly improve the global cognitive function of people with AD. A non-linear dose-response association was observed for tDCS, PE, rTMS, CS, and CT with global cognitive improvement. Notably, no minimal threshold was identified for the beneficial effects of PE on cognition. The estimated minimal doses for clinically relevant changes in cognition were 33 min per week for tDCS, 330 MET-min per week for PE, and 8000 pulses per week for rTMS. CONCLUSION: tDCS, PE, and rTMS are the better effective NPTs for enhancing global cognitive function in individuals with AD. Properly dosing these treatments can yield significant clinical benefits. Our findings support the clinical utility of low-dose exercise in improving cognition in people with AD.

The effect of home-based exercise on motor and non-motor symptoms with Parkinson's disease patients: A systematic review and network meta-analysis.

OBJECTIVE: To evaluate the effects of home-based exercise in Parkinson's disease (PD) patients. DESIGN: A network meta-analysis of randomized controlled trials. METHODS: This study systematically searched PubMed, MEDLINE, Embase, Cochrane library and Web of Science. The quality of the literature was assessed using the Cochrane Risk of Bias 2.0 criteria. The data were pooled using R software. Results are presented as pooled standardized mean difference (SMD) with 95% confidence interval (CI). RESULTS: Thirty studies involving 2264 PD patients were included. Meta-analysis results showed that home-based exercise had a small effect in relieving overall motor symptoms in PD patients (SMD: -.28, 95% Crl [-.43; -.14]), improving quality of life (SMD = .15 [.03, .26]), walking speed (SMD = .30 [.04, .56]), balance ability (SMD = .18 [.04, .33]; p < .0001) and finger dexterity (SMD = .28 [.10, .46]). Mixed exercise (Mix) had better effects on improving motor symptoms and quality of life. In addition, the results of dose analysis showed that only mixed exercise exceeding 850 METs-min per week and more than 18 weeks can significantly alleviate the overall motor symptoms of PD patients. CONCLUSION: Home-based exercise was an effective form of therapy for alleviating motor symptoms. In addition, Mix appeared to be more suitable for PD patients engaging in home-based exercise. Existing evidence suggested that significant therapeutic effects were achieved with a Mix, with a weekly exercise volume exceeding 850 METs and a duration of more than 18 weeks. RELEVANCE TO CLINICAL PRACTICE: Home-based exercise had a small effect in relieving overall motor symptoms in PD patients, improving quality of life, walking speed, balance ability and finger dexterity. In terms of exercise dosage, we recommend the exercise period is no less than 18 weeks and the dose per is no less than 850 METs-min. No Patient or Public Contribution.

Inferring the genetic relationship between brain imaging-derived phenotypes and risk of complex diseases by Mendelian randomization and genome-wide colocalization.

Observational studies consistently disclose brain imaging-derived phenotypes (IDPs) as critical markers for early diagnosis of both brain disorders and cardiovascular diseases. However, it remains unclear about the shared genetic landscape between brain IDPs and the risk of brain disorders and cardiovascular diseases, restricting the applications of potential diagnostic techniques through brain IDPs. Here, we reported genetic correlations and putative causal relationships between 921 brain IDPs, 20 brain disorders and six cardiovascular diseases by leveraging their large-scale genome-wide association study (GWAS) summary statistics. Applications of Mendelian randomization (MR) identified significant putative causal effects of multiple region-specific brain IDPs in relation to the increased risks for amyotrophic lateral sclerosis (ALS), major depressive disorder (MDD), autism spectrum disorder (ASD) and schizophrenia (SCZ). We also found brain IDPs specifically from temporal lobe as a putatively causal consequence of hypertension. The genome-wide colocalization analysis identified three genomic regions in which MDD, ASD and SCZ colocalized with the brain IDPs, and two novel SNPs to be associated with ASD, SCZ, and multiple brain IDPs. Furthermore, we identified a list of candidate genes involved in the shared genetics underlying pairs of brain IDPs and MDD, ASD, SCZ, ALS and hypertension. Our results provide novel insights into the genetic relationships between brain disorders and cardiovascular diseases and brain IDP, which may server as clues for using brain IDPs to predict risks of diseases.

Hepatic steatosis aggravates atherosclerosis via small extracellular vesicle-mediated inhibition of cellular cholesterol efflux.

BACKGROUND & AIMS: While it is recognized that non-alcoholic fatty liver disease (NAFLD) is associated with cardiovascular disease (CVD), how NAFLD affects the development and progression of CVD remains unclear and debatable. Hence, we aimed to determine the role of steatotic hepatocyte-derived small extracellular vesicles (sEVs) in foam cell formation and atherosclerosis progression. METHODS: sEVs from steatotic hepatocytes were isolated and characterized. MicroRNA (miRNA) deep sequencing was utilized to identify functional miRNA in sEVs. Lastly, we conducted a cross-sectional study on patients with NAFLD to validate these findings. RESULTS: Treatment of sEVs from steatotic hepatocytes promoted macrophage-derived foam cell formation and atherosclerosis progression via inhibition of ABCA1-mediated cholesterol efflux. Macrophage-specific deletion of Abca1 in ApoE-/- mice abolished the role of steatotic hepatocyte-derived sEVs in atherosclerosis progression. In addition, hepatocyte-specific deletion of Rab27a, which is the key GTPase regulating sEV release, significantly ameliorated high-fat, high-cholesterol diet-induced atherosclerosis progression in ApoE-/- mice. The miRNA deep sequencing results showed that miR-30a-3p was enriched in sEVs from steatotic hepatocytes. miR-30a-3p directly targeted the 3' untranslated region of ABCA1 to inhibit ABCA1 expression and cholesterol efflux. Treatment with antagomiR-30a-3p significantly attenuated atherosclerosis progression in high-fat, high-cholesterol diet-fed ApoE-/- mice. Moreover, serum sEVs from patients with NAFLD and sEV-miR-30a-3p expression were associated with decreased cholesterol efflux levels in foam cells. CONCLUSION: Steatotic hepatocyte-derived sEVs promote foam cell formation and facilitate atherogenesis via the miR-30a-3p/ABCA1 axis. Reducing sEV secretion by steatotic hepatocytes or targeting miR-30a-3p may be potential therapeutic approaches to slow the progression of NAFLD-driven atherosclerosis. IMPACT AND IMPLICATIONS: The presence of hepatic steatosis is strongly correlated with the risk of cardiovascular disease and cardiovascular events, yet the molecular mechanisms linking steatosis to progression of atherosclerosis are unclear. Herein, we identified small extracellular vesicles from steatotic hepatocytes as a trigger that accelerated the progression of atherosclerosis. Steatotic hepatocyte-derived small extracellular vesicles promoted foam cell formation via the miR-30a-3p/ABCA1 axis. Our findings not only provide mechanistic insight into non-alcoholic fatty liver disease-driven atherosclerosis but also provide potential therapeutic targets for patients with atherosclerosis.

Sex differences of the shared genetic landscapes between type 2 diabetes and peripheral artery disease in East Asians and Europeans.

Type 2 diabetes (T2D) is a critical risk factor for peripheral artery disease (PAD). However, the sex differences in genetic basis, causality, and underlying mechanisms of the two diseases are still unclear. Using sex-stratified and ethnic-based GWAS summary, we explored the genetic correlation and causal relationship between T2D and PAD in both ethnicities and sexes by linkage disequilibrium score regression, LAVA and six Mendelian Randomization approaches. We observed stronger genetic correlations between T2D and PAD in females than males in East Asians and Europeans. East Asian females exhibit higher causal effects of T2D on PAD than males. The gene-level analysis found KCNJ11 and ANK1 genes associated with the cross-trait of T2D and PAD in both sexes. Our study provides genetic evidence for the sex difference of genetic correlations and causal relationships between PAD and T2D, indicating the importance of using sex-specific strategies for monitoring PAD in T2D patients.

Symptom profiles and vaccination status for COVID-19 after the adjustment of the dynamic zero-COVID policy in China: An observational study.

There has been a substantial rise in coronavirus disease 2019 (COVID-19) cases after adjusting the dynamic zero-COVID policy in China. We conducted a survey to investigate the self-perceived symptom profile and its association with vaccination status during this outbreak. There were 552 individuals in this survey. The infected individuals displayed various symptoms associated with different factors. The three most common symptoms were fatigue (92.21%), phlegm (91.49%), and cough (89.31%). Two typical clusters of COVID-19 symptoms were identified through hierarchical clustering: one was the symptoms with a high probability of co-occurrence that primarily involved the upper respiratory tract, and the other was the symptoms with a high prevalence of severe cases that affected multiple systems. Symptoms exhibited distinct across regions. Hebei Province reported the most severe respiratory symptoms, and Chongqing City reported the worst neurological and digestive symptoms. Cough and fatigue occurred together in most regions. Nevertheless, the cough severity of Zhejiang, Liaoning, and Yunnan provinces was lower than in other areas (t-test p < 0.001). Regression analysis suggested a potential protective effect of recent vaccination on some symptoms. Compared with people who had been vaccinated within half a year, those for more than 1 year had a higher risk of developing phlegm, cough, vertigo, and nausea (all p < 0.05). Our study illustrated the characteristics and symptom profiles of COVID-19 during this wave and provided data supporting its relationship with multiple factors. These findings offered new insights into the recent COVID-19 pandemic in China.

Mendelian randomization suggests a potential causal effect of eosinophil count on influenza vaccination responsiveness.

Currently, the clinical factors affecting immune responses to influenza vaccines have not been systematically explored. The mechanism of low responsiveness to influenza vaccination (LRIV) is complicated and not thoroughly elucidated. Thus, we integrate our in-house genome-wide association studies (GWAS) analysis result of LRIV (N = 111, Ncase [Low Responders] = 34, Ncontrol [Responders] = 77) with the GWAS summary of 10 blood-based biomarkers (sample size ranging from 62 076-108 794) deposited in BioBank Japan (BBJ) to comprehensively explore the shared genetics between LRIV and blood-based biomarkers to investigate the causal relationships between blood-based biomarkers and LRIV by Mendelian randomization (MR). The applications of four MR approaches (inverse-variance-weighted [IVW], weighted median, weighted mode, and generalized summary-data-based MR [GSMR]) suggested that the genetically instrumented LRIV was associated with decreased eosinophil count (ß = -5.517 to -4.422, p = 0.004-0.039). Finally, we conclude that the low level of eosinophil count is a suggestive risk factor for LRIV.

Fourier convolution-parallel neural network framework with library matching for multi-tool processing decision-making in optical fabrication.

Intelligent manufacturing of ultra-precision optical surfaces is urgently desired but rather difficult to achieve due to the complex physical interactions involved. The development of data-oriented neural networks provides a new pathway, but existing networks cannot be adapted for optical fabrication with a high number of feature dimensions and a small specific dataset. In this Letter, for the first time to the best of our knowledge, a novel Fourier convolution-parallel neural network (FCPNN) framework with library matching was proposed to realize multi-tool processing decision-making, including basically all combination processing parameters (tool size and material, slurry type and removal rate). The number of feature dimensions required to achieve supervised learning with a hundred-level dataset is reduced by 3-5 orders of magnitude. Under the guidance of the proposed network model, a 260 mm × 260 mm off-axis parabolic (OAP) fused silica mirror successfully achieved error convergence after a multi-process involving grinding, figuring, and smoothing. The peak valley (PV) of the form error for the OAP fused silica mirror decreased from 15.153λ to 0.42λ and the root mean square (RMS) decreased from 2.944λ to 0.064λ in only 25.34 hours. This network framework has the potential to push the intelligence level of optical manufacturing to a new extreme.

Development and application of a dual ERA method for the detection of Feline Calicivirus and Feline Herpesvirus Type I.

Feline calicivirus (FCV) and feline herpesvirus type I (FHV-1) are the most common viral pathogens responsible for cat respiratory diseases, and coinfection with these two pathogens is often found. In veterinary clinics, the main diagnostic methods for FCV and FHV-1 are test strips and polymerase chain reaction (PCR). However, the sensitivity of test strips are not sufficient, and PCR is time-consuming. Therefore, developing a rapid and high-performance clinical diagnostic test is imperative for the prevention and treatment of these diseases. Enzymatic recombinase amplification (ERA) is an automated isothermal nucleic acid amplification technique that maintains a constant temperature, and is both rapid and highly accurate. In this study, a dual ERA method was developed using the Exo probe for a differential detection of FCV and FHV-1. This dual ERA method demonstrated high performance with the detection limit of 101 copies for both viruses, and no cross-reactions with feline parvovirus virus and F81 cells. To test the utility of the method for clinical applications, 50 nasopharyngeal swabs from cats with respiratory symptoms were collected and tested. The positive rates of FCV and FHV-1 were 40% (20/50, 95% confidence interval [CI], 26.4 to 54.8%) and 14% (7/50, 95% CI, 5.8 to 26.7%), respectively. The rate of coinfection with FCV and FHV-1 was 10% (5/50, 95% CI, 3.3 to 21.8%). These results were in agreement with those found using quantitative real-time PCR. Therefore, this dual ERA method is a novel and efficient clinical diagnostic tool for FCV and FHV-1 detection.

Comparative efficacy of 24 exercise types on postural instability in adults with Parkinson's disease: a systematic review and network meta-analysis.

OBJECTIVE: To compare, rank and evaluate the 24 exercise types that improve postural instability in patients with Parkinson's disease (PD). METHODS: We searched the data in PubMed, MEDLINE, Embase, PsycINFO, Cochrane library, and Web of Science from their inception date to January 23, 2023. Randomized controlled trials (RCTs) that aimed at determining the effectiveness of physical activity interventions on postural instability in adults with PD. This review focused on different balance outcome categories: (a) balance test batteries (BBS); (b) static steady-state balance (sSSB); (c) dynamic steady-state balance (dSSB); (d) proactive balance (PB); (e) reactive balance (RB). RESULTS: Among 10,474 records, 199 studies (patients = 9523) were eligible for qualitative synthesis. The random-effects NMA model revealed that the following exercise training modalities had the highest p score of being best when compared with control group: body-weight support treadmill training (BWS_TT) for BBS (p score = 0.97; pooled standardised mean difference (95% CI): 1.56 (0.72 to 2.39)) and dSSB (1.00; 1.53 (1.07 to 2.00)), aquatic exercise (AQE) for sSSB (0.85; 0.94 (0.33 to 1.54)), Pilates for PB (0.95; 1.42 (0.59 to 2.26)). Balance and gait training with the external cue or attention (BGT_ECA) and robotic assisted gait balance (RA_GT) had similar superior effects in improving RB. The confidence in evidence was often low according to Confidence in Network Meta-Analysis. CONCLUSIONS: There is low quality evidence that BWS_TT, AQE, Pilates, BGT_ECA and RA_GT are possibly the most effective treatments, pending outcome of interest, for adults with PD.

The effect of home-based exercise on motor symptoms, quality of life and functional performance in Parkinson's disease: a systematic review and meta-analysis.

BACKGROUND: Faced with the lack of physical activity caused by mandatory home isolation during special periods and patients' inconvenience in carrying out professionally supervised exercise, many home-based exercise programs have been developed. This systematic review and meta-analysis aimed to examine the effects of home-based exercise on measures of motor symptoms, quality of life and functional performance in Parkinson's disease (PD) patients. METHODS: We performed a systematic review and meta-analysis, and searched PubMed, MEDLINE, Embase, Cochrane library, and Web of Science from their inception date to April 1, 2023. The quality of the literature was assessed using PEDro's quality scale. The data was pooled using R software. Results are presented as pooled standardized mean difference (SMD) with 95% confidence interval (CI). RESULTS: A total of 20 studies involving 1885 PD patients were included. Meta-analysis results showed that home-based exercise had a small effect in relieving overall motor symptoms in PD patients (SMD = -0.29 [-0.45, -0.13]; P < 0.0001), improving quality of life (SMD = 0.20 [0.08, 0.32]; P < 0.0001), walking speed (SMD = 0.26 [0.05, 0.48]; P = 0.005), balance ability (SMD = 0.23 [0.10, 0.36]; P < 0.0001), finger dexterity (SMD = 0.28 [0.10, 0.46]; P = 0.003) and decreasing fear of falling (SMD = -0.29 [-0.49, -0.08]; P = 0.001). However, home-based exercise did not significantly relieve the overall motor symptoms of PD patients when the training period was less than 8 weeks and the total number of sessions was less than 30. CONCLUSION: During times of limited physical activity due to pandemics such as COVID-19, home-based exercise is an alternative to maintain and improve motor symptoms in PD patients. In addition, for the minimum dose of home-based exercise, we recommend that the exercise period is no less than 8 weeks and the total number of sessions is no less than 30 times. TRIAL REGISTRATION: PROSPERO registration number: CRD42022329780.

Mitochondrial dysfunction and endoplasmic reticulum stress induced by activation of PPARα leaded testicular to apoptosis in SD rats explored to di-(2-ethylhexyl) phthalate (DEHP).

Di-2-ethylhexyl phthalate (DEHP), as a common endocrine disrupting chemicals, can induce toxicity to reproductive system. However, the mechanism remains to be explored. In our study, DEHP exposure induced testicular injury in rats. The high throughput transcriptional sequencing was performed to identify differentially expressed genes (DEGs) between the treatment and control groups. KEGG analysis revealed that DEGs were enriched in apoptosis, PPARα, and ER stress pathway. DEHP up-regulated the expression of PPARα, Bax, Bim, caspase-4. GRP78, PERK, p-PERK, eIF2α, p-eIF2α, ATF4 and CHOP. This view has also been confirmed in TM3 and TM4 cells. In vitro, after pre-treatment with GW6471 (an inhibitor of PPARα) or GSK (an inhibitor of PERK), the apoptosis was inhibited and mitochondrial dysfunction was improved. Moreover, the improvement of mitochondrial dysfunction decreased the expression of PERK pathway by using SS-31(a protective agent for mitochondrial function). Interestingly, ER stress promoted the accumulation of ROS by ERO1L (the downstream of CHOP during ER stress), and the ROS further aggravated the ER stress, thus forming a feedback loop during the apoptosis. In this process, a vicious cycle consisting of PERK, eIF2α, ATF4, CHOP, ERO1L, ROS was involved. Taken together, our results suggested that mitochondrial dysfunction and ER stress-ROS feedback loop caused by PPARα activation played a crucial role in DEHP-induced apoptosis. This work provides insight into the mechanism of DEHP-induced reproductive toxicity.

Identification of Putative Causal Relationships Between Type 2 Diabetes and Blood-Based Biomarkers in East Asians by Mendelian Randomization.

Observational studies have revealed phenotypic associations between type 2 diabetes (T2D) and many biomarkers. However, causality between these conditions in East Asians is unclear. We leveraged genome-wide association study (GWAS) summary statistics on T2D (n = 77,418 cases; n = 356,122 controls) from the Asian Genetic Epidemiology Network (sample recruited during 2001-2011) and GWAS summary statistics on 42 biomarkers (n = 12,303-143,658) from BioBank Japan (sample recruited during 2003-2008) to investigate causal relationships between T2D and biomarkers. Applications of Mendelian randomization approaches consistently revealed genetically instrumented associations of T2D with increased serum potassium levels (liability-scale ß = 0.04-0.10; P = 6.41 × 10-17-9.85 × 10-5) and decreased serum chloride levels (liability-scale ß = -0.16 to -0.06; P = 5.22 × 10-27-3.14 × 10-5), whereas these 2 biomarkers showed no causal effects on T2D. Heritability Estimation Using Summary Statistics (ρ-HESS) and summary-data-based Mendelian randomization highlighted 27 genomic regions and 3 genes (α-1,3-mannosyl-glycoprotein 2-ß-N-acetylglucosaminyltransferase (MGAT1), transducing-like enhancer (TLE) family member 1, transcriptional corepressor (TLE1), and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)) that interactively associated with the shared genetics underlying T2D and the 2 biomarkers. Thus, T2D may causally affect serum potassium and chloride levels among East Asians. In contrast, the relationships of potassium and chloride with T2D are not causal, suggesting the importance of monitoring electrolyte disorders for T2D patients.

Genetic evidence for a causal relationship between type 2 diabetes and peripheral artery disease in both Europeans and East Asians.

BACKGROUND: Observational studies have revealed that type 2 diabetes (T2D) is associated with an increased risk of peripheral artery disease (PAD). However, whether the two diseases share a genetic basis and whether the relationship is causal remain unclear. It is also unclear as to whether these relationships differ between ethnic groups. METHODS: By leveraging large-scale genome-wide association study (GWAS) summary statistics of T2D (European-based: Ncase = 21,926, Ncontrol = 342,747; East Asian-based: Ncase = 36,614, Ncontrol = 155,150) and PAD (European-based: Ncase = 5673, Ncontrol = 359,551; East Asian-based: Ncase = 3593, Ncontrol = 208,860), we explored the genetic correlation and putative causal relationship between T2D and PAD in both Europeans and East Asians using linkage disequilibrium score regression and seven Mendelian randomization (MR) models. We also performed multi-trait analysis of GWAS and two gene-based analyses to reveal candidate variants and risk genes involved in the shared genetic basis between T2D and PAD. RESULTS: We observed a strong genetic correlation (rg) between T2D and PAD in both Europeans (rg = 0.51; p-value = 9.34 × 10-15) and East Asians (rg = 0.46; p-value = 1.67 × 10-12). The MR analyses provided consistent evidence for a causal effect of T2D on PAD in both ethnicities (odds ratio [OR] = 1.05 to 1.28 for Europeans and 1.15 to 1.27 for East Asians) but not PAD on T2D. This putative causal effect was not influenced by total cholesterol, body mass index, systolic blood pressure, or smoking initiation according to multivariable MR analysis, and the genetic overlap between T2D and PAD was further explored employing an independent European sample through polygenic risk score regression. Multi-trait analysis of GWAS revealed two novel European-specific single nucleotide polymorphisms (rs927742 and rs1734409) associated with the shared genetic basis of T2D and PAD. Gene-based analyses consistently identified one gene ANKFY1 and gene-gene interactions (e.g., STARD10 [European-specific] to AP3S2 [East Asian-specific]; KCNJ11 [European-specific] to KCNQ1 [East Asian-specific]) associated with the trans-ethnic genetic overlap between T2D and PAD, reflecting a common genetic basis for the co-occurrence of T2D and PAD in both Europeans and East Asians. CONCLUSIONS: Our study provides the first evidence for a genetically causal effect of T2D on PAD in both Europeans and East Asians. Several candidate variants and risk genes were identified as being associated with this genetic overlap. Our findings emphasize the importance of monitoring PAD status in T2D patients and suggest new genetic biomarkers for screening PAD risk among patients with T2D.

Associations between ambient air pollution and IVF outcomes in a heavily polluted city in China.

RESEARCH QUESTION: Is air pollution related to IVF outcomes in a heavily polluted city in China? DESIGN: A retrospective cohort study of 8628 fresh, autologous IVF cycles was conducted for the first time at the Reproductive Medicine Center of The Third Affiliated Hospital of Zhengzhou University between May 2014 and December 2018 (oocyte retrieval date). The exposure was divided into four periods (gonadotrophin injection to oocyte retrieval [P1], oocyte retrieval to embryo transfer [P2], 1 day after embryo transfer to embryo transfer +14 days [P3] and gonadotrophin injection to embryo transfer +14 days [P4]) and four levels (Q1-Q4 according to their 25th, 50th and 75th percentiles). RESULTS: An interquartile range increase (Q2 versus Q1) in particulate matter ≤10 µm (PM10) during P3 and P4 and sulphur dioxide (SO2) during P3 significantly decreased the clinical pregnancy rate (adjusted odds ratio [aOR] 0.81, 95% confidence interval [CI] 0.71-0.92 for PM10 of P3; aOR 0.87, 95% CI 0.76-1.00 for PM10 of P4; aOR 0.82, 95% CI 0.73-0.93 for SO2 of P3). In addition, PM10 was associated with an increased biochemical pregnancy rate (Q3 versus Q1: aOR 1.55, 95% CI 1.09-2.19 for PM10 of P1) and decreased live birth rate (Q2 versus Q1: aOR 0.88, 95% CI 0.77-0.99 for PM10 of P3). The multivariate regression results were consistent with that of multiple treatments propensity score method (PSM) for SO2 pollutants in P3 and PM10 pollutants in P4. CONCLUSION: From the early follicular stage to the pregnancy test period, high concentrations of PM10 and SO2 may have a negative impact on IVF treatment outcomes in the study area.

Eupalinolide B inhibits hepatic carcinoma by inducing ferroptosis and ROS-ER-JNK pathway.

Primary hepatic carcinoma is a common malignant tumor. The classic molecular targeted drug sorafenib is costly and is only effective for some patients. Therefore, it is of great clinical significance to search for new molecular targeted drugs. Eupalinolide B (EB) from Eupatorium lindleyanum DC. is used to treat chronic tracheitis in clinical practice. However, the role of EB in hepatic carcinoma is unknown. In this study, we first measure the effect of EB on tumor growth in a xenograft model and PDX model. The cell proliferation and migration are also detected in human hepatocarcinoma cell lines (SMMC-7721 and HCCLM3). Then, we investigate cell cycle, cell apoptosis, cell necrosis, cell autophagy, and ferroptosis by flow cytometry, western blot analysis and electron microscopy. The results demonstrate that EB exerts anti-proliferative activity in hepatic carcinoma by blocking cell cycle arrest at S phase and inducing ferroptosis mediated by endoplasmic reticulum (ER) stress, as well as HO-1 activation. When HO-1 is inhibited, EB-induced cell death and ER protein expression are rescued. The migration-related mechanism consists of activation of the ROS-ER-JNK signaling pathway and is not connected to ferroptosis. In summary, we first discover that EB inhibits cell proliferation and migration in hepatic carcinoma, and thus EB is a promising anti-tumor compound that can be used for hepatic carcinoma.

Discovery of novel tripeptide propylene oxide proteasome inhibitors for the treatment of multiple myeloma.

The ubiquitin proteasome pathway (UPP) plays a critical role in the maintenance of cell homeostasis and the development of diseases, such as cancer and neurodegenerative disease. A series of novel tripeptide propylene oxide compounds as proteasome inhibitors were designed, synthesized and biologically investigated in this manuscript. The enzymatic activities of final compounds against 20S human proteasome were investigated and structure-activity relationship (SAR) was summarized. Some potent compounds were further evaluated to inhibit the proliferation of multiple myeloma (MM) cancer cell lines RPMI8226 and U266B. The results showed that some compounds were active against MM cancer cell lines with IC50 values of less than 50 nM. The microsomal metabolic stabilities in human, rat and mice species were carried out and the results showed that compounds 30 and 31 were stable enough to be in vivo investigated. The in vivo pharmacokinetic results showed that compounds 30 and 31 had acceptable biological parameters for both ig and iv administrations. In vivo antitumor activities of compounds 30 and 31 with the doses of 100 mg/kg and 50 mg/kg BIW were performed by using RPMI8226 xenograft nude mouse model. Toxicities of compounds 30 and 31 were not observed during the experiment and dose dependent effect was obvious and the tumor volume was greatly inhibited.

The HSD17B13 rs72613567 variant is associated with lower levels of albuminuria in patients with biopsy-proven nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Several susceptibility gene variants predisposing to nonalcoholic fatty liver disease (NAFLD) have been identified in chronic kidney disease (CKD). Evidence supports that 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) rs72613567 plays a role in NAFLD development by affecting lipid homeostasis. Since lipid droplets may accumulate in the kidneys and contribute to renal injury, we investigated the association between the HSD17B13 rs72613567 variant and markers of renal function/injury in NAFLD. METHODS AND RESULTS: We measured estimated glomerular filtration rate (eGFR), urinary/serum neutrophil gelatinase-associated lipocalin (NGAL), and urinary albumin-to-creatinine ratio (u-ACR) in individuals with biopsy-proven NAFLD. Multivariable regression analyses were undertaken to examine the associations between the HSD17B13 rs72613567 variant and markers of renal function/injury. Individuals were stratified by HSD17B13 rs72613567 genotypes into -/-, A/- and A/A groups. HSD17B13 rs72613567 genotypes were not significantly associated with eGFR and urinary/serum NGAL levels. Conversely, the prevalence of abnormal albuminuria in the A/- + A/A group was lower than in the -/- group (4.92% vs. 19.35%, p = 0.001). Additionally, the mean u-ACR levels were lower among carriers of the A/- or A/A genotypes with coexisting hypertension or diabetes, than among those with the -/- genotype. The risk of abnormal albuminuria (adjusted-odds ratio 0.16, p = 0.001) remained significantly lower in the A/- + A/A group after adjustment for established renal risk factors and histologic severity of NAFLD. CONCLUSION: HSD17B13 rs72613567: A allele is associated with a lower risk of having abnormal albuminuria, but not with lower eGFR or urinary/serum NGAL levels, in patients with biopsy-proven NAFLD.