SIRT7 promotes Hippo/YAP activation and cancer cell proliferation in hepatocellular carcinoma via suppressing MST1.

Abnormal activation of the oncogene YAP in the Hippo pathway is a major feature in liver cancer and inactivation of MST1/2 has been shown to be responsible for the overactivation of YAP that led to tumorigenesis. However, mechanisms underlying MST1/2 dysregulation remain poorly understood. RNA-seq analysis and genome (KEGG) pathway enrichment analysis were used to identify genes and pathways that were regulated by SIRT7. qRT-PCR, ChIP, and luciferase assay were used to investigate transcriptional regulation. Mass spectrometry, co-immunoprecipitation and immunoprecipitation were used to exam protein-protein interaction and post-transcriptional modification. A xenograft mouse model was used to confirm the effect of SIRT7 and SIRT7 inhibitors on hepatocellular carcinoma (HCC) proliferation in vivo. We found that SIRT7 suppresses MST1 by both transcriptional regulation and post-transcriptional modification, which in turn promotes YAP nuclear localization and transcriptional activation in liver cancer. Mechanistically, we revealed that SIRT7 suppresses MST1 transcription by binding to the MST1 promoter and inducing H3K18 deacetylation in its promoter region. In addition, SIRT7 directly binds to and deacetylates MST1, which primes acetylation-dependent MST1 ubiquitination and protein degradation. In clinical samples, we confirmed a negative correlation between SIRT7 and MST1 protein levels, and high SIRT7 expression correlated with elevated YAP expression and nuclear localization. In addition, SIRT7 specific inhibitor 2800Z sufficiently inhibited HCC growth by disrupting the SIRT7/MST1/YAP axis. Our data thus revealed the previously undescribed function of SIRT7 in regulating the Hippo pathway in HCC and further proved that targeting SIRT7 might provide novel therapeutic options for the treatment of liver cancer.

Bisphenol C Induces Cardiac Developmental Defects by Disrupting m6A Homeostasis.

Bisphenol A (BPA) is a commonly used plastic additive. Since BPA has been banned in maternal and infant food containers in many countries, BPA substitutes have been widely introduced to replace it. By systematically assessing the potential developmental toxicity of BPA substitutes, we observed that the 41-150 nM in vivo BPC exposure (around the reported concentration detected in infant urine: 6-186 nM) induced cardiac defects in zebrafish. Mechanistically, BPC disrupted m6A homeostasis by downregulation of the key m6A methyltransferase, Mettl3, thereby causing the m6A reader, Igf2bp2b, to fail in recognizing and stabilizing the inefficiently m6A-modified acox1 and tnnt2d mRNA. Then, downregulation of Acox1 (a regulator in cardiac fatty acid metabolism) and Tnnt2d (a component of cardiac troponin for muscle contraction) led to cardiac defects. Indeed, the dual cardiac functional axes regulated by the same m6A reader in response to BPC provided new insight into the regulatory mechanisms of epitranscriptomics and cardiac development. Collectively, our study not only presented evidence showing that the internal exposure levels of BPC in humans could lead to cardiac developmental defects but also demonstrated the underlying mechanism of BPC-mediated defects by disrupting the Mettl3-m6A-Igf2bp2b-Acox1/Tnnt2d pathways, which provided potential molecular markers associated with BPC exposure.

The Prognostic Value of Advanced Lung Cancer Inflammation Index in Elderly Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

This study aimed to investigate the predictive value of advanced lung cancer inflammation index (ALI) for major adverse cardiovascular events (MACEs) in elderly patients with acute coronary syndrome (ACS).A total of 586 ACS patients undergoing percutaneous coronary intervention (PCI) over 65 years old between January 2017 and December 2018 were retrospectively collected. The patients were divided into two groups by the optimal cutoff value of ALI. Spearman rank correlation coefficient was used to evaluate the correlation between ALI and the Global Registry of Acute Coronary Events (GRACE). Time-dependent receiver operating characteristic (ROC) curves, Cox survival analysis, and Kaplan Meier curves were used to assess the predictive value of ALI for MACEs.Spearman's nonparametric test revealed a moderate correlation between ALI and the GRACE (r: -0.417, P < 0.001). Time-dependent ROC curves showed that the area under the curve for ALI was 0.751 (95% CI, 0.699-0.798) in predicting MACEs, higher than Geriatric Nutritional Risk Index (0.531, 95% CI 0.435-0.627) and Prognostic Nutritional Index (0.590, 95% CI 0.505-0.676), and for combined diagnostic models (ALI + GRACE) was 0.913, (95% CI 0.875 - 0.942, P < 0.001). Multivariate Cox analysis demonstrated that ALI (HR: 0.974, 95% CI: 0.952-0.996, P = 0.017) was an independent risk factor for MACEs. Kaplan Meier survival analysis showed that the cumulative incidence of MACEs was significantly higher in elderly ACS patients with lower ALI (log-rank test, P < 0.001).ALI could be a nutrition-inflammation indicator with independent predictive value for long-term MACEs of elderly ACS patients after PCI.

Ferroptosis: An Emerging Target for Bladder Cancer Therapy.

Bladder cancer (BC), as one of the main urological cancers in the world, possesses the abilities of multiple-drug resistance and metastasis. However, there remains a significant gap in the understanding and advancement of prognosis and therapeutic strategies for BC. Ferroptosis, a novel type of iron-dependent regulated cell death, depends on lipid peroxidation, which has been proven to have a strong correlation with the development and treatment of BC. Its mechanism mainly includes three pathways, namely, lipid peroxidation, the antioxidant system, and the iron overload pathway. In this review, we reviewed the mechanism of ferroptosis, along with the related therapeutic targets and drugs for BC, as it might become a new anticancer treatment in the future.

Elevation of LncRNA ENST00000453774.1 Prevents Renal Fibrosis by Upregulating FBN1, IGF1R, and KLF7.

INTRODUCTION: Transforming growth factor-ß (TGF-ß), a common outcome of various progressive chronic kidney diseases, can regulate and induce fibrosis. OBJECTIVE: The study aimed to identify downstream targets of lncRNA ENST00000453774.1 (lnc453774.1) and outline their functions on the development of renal fibrosis. METHODS: HK-2 cells were induced with 5 ng/mL TGF-ß1 for 24 h to construct a renal fibrosis cell model. Differentially expressed genes (DEGs) targeted by lnc453774.1 in TGF-ß1-induced renal fibrosis were identified using RNA sequencing. The dataset GSE23338 was employed to identify DEGs in 48-h TGF-ß1-stimulated human kidney epithelial cells, and these DEGs were intersected with genes in the key module using weighted gene co-expression network analysis to generate key genes associated with renal fibrosis. MicroRNAs (miRs) that had targeting relationship with keys genes and lnc453774.1 were predicted by using Miranda software, and important genes were intersected with key genes that had targeting relationship with these miRs. Key target genes by lnc453774.1 were identified in a protein-protein interaction network among lnc453774.1, important genes, and reported genes related to autophagy, oxidative stress, and cell adhesion. RESULTS: Key genes in the key module (turquoise) were intersected with DEGs in the dataset GSE23338 and yielded 20 key genes regulated by lnc453774.1 involved in renal fibrosis. Fourteen miRs had targeting relationship with lnc453774.1 and key genes, and 8 important genes targeted by these 14 miRs were identified. Fibrillin-1 (FBN1), insulin-like growth factor 1 receptor (IGF1R), and Kruppel-like factor 7 (KLF7) were identified to be involved in autophagy, oxidative stress, and cell adhesion and were elevated in the lnc453774.1-overexpressing TGF-ß1-induced cells. CONCLUSION: These results show FBN1, IGF1R, and KLF7 serve as downstream targets of lnc453774.1, and that lnc453774.1 may protect against renal fibrosis through competing endogenous miRs which target FBN1, IGF1R, and KLF7 mRNAs.

Role of Artificial Intelligence in Kidney Disease.

Artificial intelligence (AI), as an advanced science technology, has been widely used in medical fields to promote medical development, mainly applied to early detections, disease diagnoses, and management. Owing to the huge number of patients, kidney disease remains a global health problem. Challenges remain in its diagnosis and treatment. AI could take individual conditions into account, produce suitable decisions and promise to make great strides in kidney disease management. Here, we review the current studies of AI applications in kidney disease in alerting systems, diagnostic assistance, guiding treatment and evaluating prognosis. Although the number of studies related to AI applications in kidney disease is small, the potential of AI in the management of kidney disease is well recognized by clinicians; AI will greatly enhance clinicians' capacity in their clinical practice in the future.

Retrospective Analysis of Clinical Outcomes in Patients with Immunoglobulin A Nephropathy and Persistent Hematuria Following Renin-Angiotensin System Blockade.

BACKGROUND Recent guidelines recommend that patients with immunoglobulin A nephropathy (IgAN) and proteinuria 0.5-1 g/d and >1 g/d be treated with long-term renin-angiotensin system blockade (RASB). This study investigated whether patients with IgAN and persistent hematuria, but without proteinuria, can benefit from RASB. MATERIAL AND METHODS IgAN patients with persistent hematuria at four centers were recruited from January 2013 to December 2018. Patients were divided into those who did and did not receive long-term RASB. The primary outcome was the appearance of proteinuria, and the secondary outcomes were the decreased percentage of hematuria, rate of decline in estimated glomerular filtration rate (eGFR) and final blood pressure. The effects of RASB on these outcomes were assessed by multivariate Cox regression models and propensity score matching. RESULTS Of the 110 eligible patients, 44 (40.0%) received RASB and 66 (60.0%) did not. Treated patients had higher diastolic pressure. The unadjusted primary outcome, the appearance of proteinuria, was significantly less frequent in individuals who were than who were not treated with RASB. Multivariate Cox regression showed that RASB reduced the risk of the primary outcome and the levels of hematuria. The rate of eGFR decline and final blood pressure did not differ in the two groups. CONCLUSIONS RASB reduced the risk of proteinuria development and increased the remission of hematuria in patients with IgAN who presented with persistent hematuria alone. RASB, however, did not affect blood pressure in patients without hypertension and did not affect the rate of eGFR decline.

Neutrophil-to-lymphocyte ratio and incident end-stage renal disease in Chinese patients with chronic kidney disease: results from the Chinese Cohort Study of Chronic Kidney Disease (C-STRIDE).

BACKGROUND: Chronic kidney disease (CKD) leads to end-stage renal failure and cardiovascular events. An attribute to these progressions is abnormalities in inflammation, which can be evaluated using the neutrophil-to-lymphocyte ratio (NLR). We aimed to investigate the association of NLR with the progression of end stage of renal disease (ESRD), cardiovascular disease (CVD) and all-cause mortality in Chinese patients with stages 1-4 CKD. METHODS: Patients with stages 1-4 CKD (18-74 years of age) were recruited at 39 centers in 28 cities across 22 provinces in China since 2011. A total of 938 patients with complete NLR and other relevant clinical variables were included in the current analysis. Cox regression analysis was used to estimate the association between NLR and the outcomes including ESRD, CVD events or all-cause mortality. RESULTS: Baseline NLR was related to age, hypertension, serum triglycerides, total serum cholesterol, CVD history, urine albumin to creatinine ratio (ACR), chronic kidney disease-mineral and bone disorder (CKD-MBD), hyperlipidemia rate, diabetes, and estimated glomerular filtration rate (eGFR). The study duration was 4.55 years (IQR 3.52-5.28). Cox regression analysis revealed an association of NLR and the risk of ESRD only in patients with stage 4 CKD. We did not observe any significant associations between abnormal NLR and the risk of either CVD or all-cause mortality in CKD patients in general and CKD patients grouped according to the disease stages in particular. CONCLUSION: Our results suggest that NLR is associated with the risk of ESRD in Chinese patients with stage 4 CKD. NLR can be used in risk assessment for ESRD among patients with advanced CKD; this application is appealing considering NLR being a routine test. Trial registration ClinicalTrials.gov Identifier NCT03041987. Registered January 1, 2012. (retrospectively registered) ( https://www.clinicaltrials.gov/ct2/show/NCT03041987?term=Chinese+Cohort+Study+of+Chronic+Kidney+Disease+%28C-STRIDE%29&rank=1 ).

Survival Benefit of Germline BRCA Mutation is Associated with Residual Disease in Ovarian Cancer.

BACKGROUND/AIMS: Prognostic value of germline BRCA1 or BRCA2 (gBRCA1/2) mutations in epithelial ovarian cancer (EOC) remains controversial, especially in the estimation of long-term survival. We previously reported the largest study of gBRCA1/2 mutation prevalence in Chinese EOC patients. The aim of this study is to further illustrate the correlation of residual disease and survival in BRCA-associated EOC in China. METHODS: In the current cohort consisting of 615 cases from the Chinese EOC genome-wide association study, we evaluated the association between gBRCA1/2 mutation and clinical outcomes. RESULTS: Overall, we did not find any significant difference between gBRCA1/2 mutation carriers and non-carriers in both progression-free survival (PFS) and overall survival (OS) (19.3 vs. 18.1 months and 77.2 vs. 73.2 months, P=0.528 and 0.147, HR 0.93 and 0.79, 95%CI 0.74-1.17 and 0.57-1.09, respectively). However, within three years after diagnosis, mutation carriers showed a longer OS than non-carriers (P=0.018, HR 0.53, 95%CI 0.31-0.90). Such a survival advantage decreased along with the extension of follow-up time. Quite interestingly, in the subgroup of patients with gross residual disease, mutation carriers had a longer survival than non-carriers (18.5 vs. 15.1 months and 68.5 vs. 54.3 months, P=0.046 and 0.038, HR 0.74 and 0.65, 95% CI 0.55-1.00 and 0.43-0.98, for PFS and OS respectively). CONCLUSIONS: Our findings provided the evidence that gBRCA1/2 mutation was not associated with survival in Chinese EOC patients, which possibly attributed to more than 37% of the patients without gross residual disease. Survival benefit of gBRCA1/2 mutation was prominent in ovarian cancer patients with gross residual disease.

Hydrogen postconditioning promotes survival of rat retinal ganglion cells against ischemia/reperfusion injury through the PI3K/Akt pathway.

Retinal ischemia/reperfusion injury (IRI) plays a crucial role in the pathophysiology of various ocular diseases. Our previous study have shown that postconditioning with inhaled hydrogen (H2) (HPC) can protect retinal ganglion cells (RGCs) in a rat model of retinal IRI. Our further study aims to investigate potential mechanisms underlying HPC-induced protection. Retinal IRI was performed on the right eyes of rats and was followed by inhalation of 67% H2 mixed with 33% oxygen immediately after ischemia for 1 h daily for one week. RGC density was counted using haematoxylin and eosin (HE) staining, retrograde labelling with cholera toxin beta (CTB) and TUNEL staining, respectively. Visual function was assessed using flash visual evoked potentials (FVEP) and pupillary light reflex (PLR). The phosphorylated Akt was analysed by RT-PCR and western blot. The results showed that administration of HPC significantly inhibited the apoptosis of RGCs and protected the visual function. Simultaneously, HPC treatment markedly increased the phosphorylations of Akt. Blockade of PI3K activity by inhibitors (LY294002) dramatically abolished its anti-apoptotic effect and lowered both visual function and Akt phosphorylation levels. Taken together, our results demonstrate that HPC appears to confer neuroprotection against retinal IRI via the PI3K/Akt pathway.

Correction to: Fine mapping of powdery mildew resistance gene Pm4e in bread wheat (Triticum aestivum L.).

Unfortunately, the style of the units was incorrectly published ("cm" instead of "cM") throughout the original article.

Fine mapping of powdery mildew resistance gene Pm4e in bread wheat (Triticum aestivum L.).

MAIN CONCLUSION: Fine mapping of wheat powdery mildew-resistance gene Pm4e to a 0.19 cM interval with sequence-based markers provides the foundation for map-based cloning and marker-assisted selection with breeder-friendly markers. Powdery mildew caused by Blumeria graminis f. sp. tritici is a wheat foliar disease that poses a serious threat to global wheat production. Pm4 is a resistance gene locus that has played a key role in controlling this disease in wheat production and a few resistance alleles of this locus have been identified. We have previously mapped the Pm4e allele to a 6.7 cM interval on chromosome 2AL. In this study, Pm4e was delimited to a 0.19 cM interval flanked by Xwgrc763 and Xwgrc865, through employment of a larger segregating population, derived from the cross of resistant parent D29 with susceptible parent Yangmai 158 (Y158), and enrichment of the genetic interval with markers developed on Chinese Spring (C.S.) survey sequence. In this interval, Pm4e co-segregated with a few markers, some of which were either D29-dominant or Y158-dominant, implying great sequence variation in the interval between D29 and Y158. Most of these co-segregation markers could not differentiate the Pm4 alleles from each other. Survey of 55 wheat cultivars with four co-dominant markers showed that the Pm4e-co-segregating loci always co-exist. Annotation of the Pm4e interval-corresponding C.S. sequence revealed more than a dozen resistance gene analogs clustered in a 2.4 Mb region, although C.S. is susceptible to the Pm4e-avirulent isolate Bgt2. This study has established the foundation for map-based cloning of Pm4e. Moreover, some of the co-dominant markers developed in this study could help in marker-assisted transfer of Pm4e into elite cultivars.

BRCA1 and BRCA2 mutations in ovarian cancer patients from China: ethnic-related mutations in BRCA1 associated with an increased risk of ovarian cancer.

BRCA1/2 are cancer predisposition genes involved in hereditary breast and ovarian cancer (HBOC). Mutation carriers display an increased sensitivity to inhibitors of poly(ADP-ribose) polymerase (PARP). Despite a number of small-size hospital-based studies being previously reported, there is not yet, to our knowledge, precise data of BRCA1/2 mutations among Chinese ovarian cancer patients. We performed a multicenter cohort study including 916 unselected consecutive epithelial ovarian cancer (EOC) patients from eastern China to screen for BRCA1/2 mutations using the next-generation sequencing approach. A total of 153 EOC patients were found to carry pathogenic germline mutations in BRCA1/2, accounting for an overall mutation incidence of 16.7% with the predominance in BRCA1 (13.1%) compared with BRCA2 (3.9%). We identified 53 novel pathogenic mutations, among which the c.283_286delCTTG and the c.4573C > T of BRCA1 were both found in two unrelated patients. More importantly, the most common mutation found in this study, c.5470_5477del8 was most likely to be Chinese population-related without an apparent founder origin. This hot-spot mutation was presumably associated with an increased risk of ovarian cancer. Taken together, germline BRCA1/2 mutations were common in Chinese EOC patients with distinct mutational spectrum compared to Western populations. Our study contributes to the current understanding of BRCA1/2 mutation prevalence worldwide. We recommend BRCA1/2 genetic testing to all Chinese women diagnosed with EOC to identify HBOC families, to provide genetic counseling and clinical management for at-risk relatives. Mutation carriers may also benefit from PARP-targeted therapies.

Expression Profiles of Endometrial Carcinoma by Integrative Analysis of TCGA Data.

BACKGROUND: This study was to explore the expression profile of endometrial carcinoma (EC) and identify the potential molecular mechanism and therapeutic targets. METHODS: Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were identified in EC using mRNA and miRNA sequencing data released by the Cancer Genome Atlas database; then, gene function and pathway of DEGs were analyzed based on the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway databases; finally, the transcription factors (TFs) latently regulating the DEGs and DEMs were predicted and a TF-miRNA-Gene network was then established to summarize the regulatory links between TFs, DEMs and DEGs. RESULTS: One thousand five hundred and forty two upregulated and 1,885 downregulated DEGs, 34 upregulated and 12 downregulated DEMs were identified. The principal DEGs-enriched functions were cell differentiation, cell migration, and cell surface receptor signaling pathway. The DEGs-enriched cell signaling pathways including the MAPK, Wnt signaling pathway, and the p53 signaling pathway. As shown in the TF-miRNA-Gene network, TFs such as CPBP and GKLF, miRNAs such as miR-141-3p and miR-130b-3p, regulated most of DEGs and DEMs. CONCLUSION: These results may contribute to the study of the molecular mechanism and therapeutic targets in EC, and facilitate the discovery of new biomarkers for screening, diagnosis and monitoring.

Non-negligible clear-sky biases of satellite thermal infrared observations for analyzing surface urban heat island intensity: A case study in China.

Surface urban heat island (SUHI) intensity generally determined by satellite-derived clear-sky land surface temperature (LST) has ignored the impacts of cloud coverage and cannot reflect the real SUHI intensity. Only a few studies focus on the effects of this issue based on short-time LST datasets, which could contain non-negligible uncertainties to summarize reliable rules. To investigate the influence, the SUHI intensity (SUHII) clear-sky bias (CSB), which is defined as the SUHII difference between clear-sky and all-weather conditions, was investigated in 35 cities in China, based on clear-sky and all-weather LST datasets from 2003 to 2022. Results show that the two SUHIIs show similar spatial distribution patterns, with stronger SUHIs in southern China at daytime and weaker at nighttime. However, a non-negligible difference can be found between these two SUHIIs, with a SUHII CSB range of -1.43 to 2.27 °C at daytime and - 2.17 to 0.91 °C at nighttime. In terms of intra-annual variation, SUHII CSBs in similar climate regions exhibit similar patterns but different ranges due to their different natural properties. Generally, intra-annual variations of SUHII CSB can be divided into three groups, i.e., "Table Mountain", single peak, and single valley, varying across climate regions and years. The main reason for SUHII CSB was analyzed, i.e., spatial gaps of the data directly caused the SUHII CSB, and the thermal properties and meteorological conditions of the missing pixels affect the magnitude of the SUHII CSB. Taking the urban system as an example, this study has provided evidence of the non-negligible SUHII clear-sky bias to emphasize the importance of using all-weather LST for relevant studies.

Advanced Planar Projection Contour (PPC): A Novel Algorithm for Local Feature Description in Point Clouds.

Local feature description of point clouds is essential in 3D computer vision. However, many local feature descriptors for point clouds struggle with inadequate robustness, excessive dimensionality, and poor computational efficiency. To address these issues, we propose a novel descriptor based on Planar Projection Contours, characterized by convex packet contour information. We construct the Local Reference Frame (LRF) through covariance analysis of the query point and its neighboring points. Neighboring points are projected onto three orthogonal planes defined by the LRF. These projection points on the planes are fitted into convex hull contours and encoded as local features. These planar features are then concatenated to create the Planar Projection Contour (PPC) descriptor. We evaluated the performance of the PPC descriptor against classical descriptors using the B3R, UWAOR, and Kinect datasets. Experimental results demonstrate that the PPC descriptor achieves an accuracy exceeding 80% across all recall levels, even under high-noise and point density variation conditions, underscoring its effectiveness and robustness.

Disitamab Vedotin Alone or in Combination With Immune Checkpoint Inhibitors in Bladder-Sparing Treatment of Muscle-Invasive Bladder Cancer: A Real-World Study.

PURPOSE: To evaluate the efficacy and safety of a novel humanized anti-HER2 antibody, RC48-ADC (Disitamab vedotin, DV), the combination of RC48-ADC with PD-1 inhibitors was used to treat muscle-invasive bladder cancer (MIBC). This combination therapy has potential applications in both bladder preservation and neoadjuvant therapy for MIBC. METHODS: Patients with MIBC underwent transurethral resection of bladder tumors followed by RC48-ADC alone or in combination with PD-1 inhibitors. Radiological and endoscopic evaluations were conducted 3 months later. The primary endpoint was objective response rate (ORR), with secondary endpoints including complete response rate (CR), partial response rate (PR), and bladder preservation rate. Treatment safety was assessed according to RECIST v1.1 criteria. RESULTS: Eleven patients were enrolled, with a median follow-up of 19.0 months. Nine patients achieved objective response, including 6 CR and 3 PR cases. The pathological ORR was 81.8%. Eight patients continued combined treatment after 3 months, maintaining a 72.7% bladder preservation rate at 16 months. One elderly patient progressed from ypT2N0M0 to ypT3N0M0 and underwent radical cystectomy but had no recurrence or metastasis 12 months postoperation. All patients reported varying degrees of treatment-related adverse reactions, which were largely manageable. CONCLUSION: The combination of RC48-ADC and PD-1 inhibitors proves to be a viable and safe option for bladder-sparing therapy, particularly for T2-stage MIBC patients who are ineligible for surgery and chemotherapy. This approach offers a promising new direction for bladder preservation or neoadjuvant therapy in MIBC patients.

Causal relationship between neuroticism and frailty: A bidirectional Mendelian randomization study.

BACKGROUND: Observational studies have shown that neuroticism is associated with frailty, but the causal relationship between them remains unclear. METHODS: A two-sample Mendelian randomization (MR) study was conducted to explore the bidirectional causal relationship between neuroticism (n = 380,506 for the primary analysis, n = 79,004 for the validation) and frailty (n = 175,226) using publicly available genome-wide association study data. The inverse variance weighted (IVW), weighted median, and MR-Egger were used to obtain the causal estimates. Findings were verified through extensive sensitivity analyses and validated using another dataset. Multivariable MR (MVMR) analysis was performed to estimate the direct causal effects with adjustment of potential confounders. Two-step MR technique was then conducted to explore the mediators in the causal effects of neuroticism on frailty. RESULTS: Genetically-predicted higher neuroticism score was significantly correlated with higher frailty index (IVW beta: 0.53, 95%CI: 0.48 to 0.59, P = 9.3E-83), and genetically-determined higher frailty index was significantly associated with higher neuroticism score (IVW beta: 0.28, 95%CI: 0.21 to 0.35, P = 1.3E-16). These results remained robust across sensitivity analyses and were reproducible using another dataset. The MVMR analysis indicated that the causal relationships remained significant after adjusting for the potential confounding factors. Mediation analysis revealed that depression, years of schooling, and smoking were significantly mediated the causal effects of neuroticism on frailty. CONCLUSIONS: A bidirectional causal relationship existed between neuroticism and frailty. Our findings suggested that early intervention and behavioral changes might be helpful to reduce the neuroticism levels and prevent the development of frailty.

Liproxstatin-1 Alleviated Ischemia/Reperfusion-Induced Acute Kidney Injury via Inhibiting Ferroptosis.

Ferroptosis, as a novel regulable cell death, is characterized by iron overload, glutathione depletion, and an accumulation of lipid peroxides. Recently, it has been discovered that ferroptosis is involved in ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) and plays a crucial role in renal tubular cell death. In this study, we tried to investigate the effect and mechanism of liproxstatin-1 (Lip-1) in I/R-induced AKI and seek the key regulator of ferroptosis in I/R-induced AKI. Mice were administrated with clamping bilateral renal pedicles for 30 min. We found that early growth response 1 (EGR1) might be a key regulator of ferroptosis, and Lip-1 could suppress ferroptosis via EGR1. Meanwhile, Lip-1 could reduce macrophage recruitment and the release of inflammatory cytokines. These findings indicated that Lip-1 alleviated I/R-induced AKI via regulating EGR1, and it might pave the theoretical basis of a new therapeutic strategy for I/R-induced AKI.

In-situ direct seawater electrolysis using floating platform in ocean with uncontrollable wave motion.

Direct hydrogen production from inexhaustible seawater using abundant offshore wind power offers a promising pathway for achieving a sustainable energy industry and fuel economy. Various direct seawater electrolysis methods have been demonstrated to be effective at the laboratory scale. However, larger-scale in situ demonstrations that are completely free of corrosion and side reactions in fluctuating oceans are lacking. Here, fluctuating conditions of the ocean were considered for the first time, and seawater electrolysis in wave motion environment was achieved. We present the successful scaling of a floating seawater electrolysis system that employed wind power in Xinghua Bay and the integration of a 1.2 Nm3 h-1-scale pilot system. Stable electrolysis operation was achieved for over 240 h with an electrolytic energy consumption of 5 kWh Nm-3 H2 and a high purity (>99.9%) of hydrogen under fluctuating ocean conditions (0~0.9 m wave height, 0~15 m s-1 wind speed), which is comparable to that during onshore water electrolysis. The concentration of impurity ions in the electrolyte was low and stable over a long period of time under complex and changing scenarios. We identified the technological challenges and performances of the key system components and examined the future outlook for this emerging technology.