Maternal inheritance of glucose intolerance via oocyte TET3 insufficiency.

Diabetes mellitus is prevalent among women of reproductive age, and many women are left undiagnosed or untreated1. Gestational diabetes has profound and enduring effects on the long-term health of the offspring2,3. However, the link between pregestational diabetes and disease risk into adulthood in the next generation has not been sufficiently investigated. Here we show that pregestational hyperglycaemia renders the offspring more vulnerable to glucose intolerance. The expression of TET3 dioxygenase, responsible for 5-methylcytosine oxidation and DNA demethylation in the zygote4, is reduced in oocytes from a mouse model of hyperglycaemia (HG mice) and humans with diabetes. Insufficient demethylation by oocyte TET3 contributes to hypermethylation at the paternal alleles of several insulin secretion genes, including the glucokinase gene (Gck), that persists from zygote to adult, promoting impaired glucose homeostasis largely owing to the defect in glucose-stimulated insulin secretion. Consistent with these findings, mouse progenies derived from the oocytes of maternal heterozygous and homozygous Tet3 deletion display glucose intolerance and epigenetic abnormalities similar to those from the oocytes of HG mice. Moreover, the expression of exogenous Tet3 mRNA in oocytes from HG mice ameliorates the maternal effect in offspring. Thus, our observations suggest an environment-sensitive window in oocyte development that confers predisposition to glucose intolerance in the next generation through TET3 insufficiency rather than through a direct perturbation of the oocyte epigenome. This finding suggests a potential benefit of pre-conception interventions in mothers to protect the health of offspring.

BRCA1 safeguards genome integrity by activating chromosome asynapsis checkpoint to eliminate recombination-defective oocytes.

In the meiotic prophase, programmed DNA double-strand breaks are repaired by meiotic recombination. Recombination-defective meiocytes are eliminated to preserve genome integrity in gametes. BRCA1 is a critical protein in somatic homologous recombination, but studies have suggested that BRCA1 is dispensable for meiotic recombination. Here we show that BRCA1 is essential for meiotic recombination. Interestingly, BRCA1 also has a function in eliminating recombination-defective oocytes. Brca1 knockout (KO) rescues the survival of Dmc1 KO oocytes far more efficiently than removing CHK2, a vital component of the DNA damage checkpoint in oocytes. Mechanistically, BRCA1 activates chromosome asynapsis checkpoint by promoting ATR activity at unsynapsed chromosome axes in Dmc1 KO oocytes. Moreover, Brca1 KO also rescues the survival of asynaptic Spo11 KO oocytes. Collectively, our study not only unveils an unappreciated role of chromosome asynapsis in eliminating recombination-defective oocytes but also reveals the dual functions of BRCA1 in safeguarding oocyte genome integrity.

Intracytoplasmic sperm injection versus conventional in-vitro fertilisation for couples with infertility with non-severe male factor: a multicentre, open-label, randomised controlled trial.

BACKGROUND: Introduced in 1992, intracytoplasmic sperm injection (ICSI) was initially indicated for severe male infertility; however, its use has since been expanded to non-severe male infertility. We aimed to compare the efficacy and safety of ICSI versus conventional in-vitro fertilisation (IVF) in couples with infertility with non-severe male factor. METHODS: We conducted an investigator-initiated, multicentre, open-label, randomised controlled trial in ten reproductive medicine centres across China. Couples with infertility with non-severe male factor without a history of poor fertilisation were randomly assigned (1:1) to undergo either ICSI or conventional IVF. The primary outcome was live birth after first embryo transfer. We performed the primary analysis in the intention-to-treat population using log-binomial regression models for categorical outcomes or linear regression models for continuous outcomes, adjusting for centre. This trial is registered with Clinicaltrials.gov, NCT03298633, and is completed. FINDINGS: Between April 4, 2018, and Nov 15, 2021, 3879 couples were screened, of whom 2387 (61·5%) couples were randomly assigned (1184 [49·6%] to the ICSI group and 1203 [50·4%] to the conventional IVF group). After excluding couples who were ineligible, randomised twice, or withdrew consent, 1154 (97·5%) in the ICSI group and 1175 (97·7%) in the conventional IVF group were included in the primary analysis. Live birth after first embryo transfer occurred in 390 (33·8%) couples in the ICSI group and in 430 (36·6%) couples in the conventional IVF group (adjusted risk ratio [RR] 0·92 [95% CI 0·83-1·03]; p=0·16). Two (0·2%) neonatal deaths were reported in the ICSI group and one (0·1%) in the conventional IVF group. INTERPRETATION: In couples with infertility with non-severe male factor, ICSI did not improve live birth rate compared with conventional IVF. Given that ICSI is an invasive procedure associated with additional costs and potential increased risks to offspring health, routine use is not recommended in this population. FUNDING: National Natural Science Foundation of China, National Key Research and Development Program, Beijing Municipal Science & Technology Commission, and Peking University Third Hospital.

Changes in frailty and incident cardiovascular disease in three prospective cohorts.

BACKGROUND AND AIMS: Previous studies found that frailty was an important risk factor for cardiovascular disease (CVD). However, previous studies only focused on baseline frailty status, not taking into consideration the changes in frailty status during follow-up. The aim of this study was to investigate the associations of changes in frailty status with incident CVD. METHODS: This study used data of three prospective cohorts: China Health and Retirement Longitudinal Study (CHARLS), English Longitudinal Study of Ageing (ELSA), and Health and Retirement Study (HRS). Frailty status was evaluated by the Rockwood frailty index and classified as robust, pre-frail, or frail. Changes in frailty status were assessed by frailty status at baseline and the second survey which was two years after the baseline. Cardiovascular disease was ascertained by self-reported physician-diagnosed heart disease (including angina, heart attack, congestive heart failure, and other heart problems) or stroke. Cox proportional hazard models were used to calculate the hazard ratio (HR) and 95% confidence interval (95% CI) after adjusting for potential confounders. RESULTS: A total of 7116 participants from CHARLS (female: 48.6%, mean age: 57.4 years), 5303 from ELSA (female: 57.7%, mean age: 63.7 years), and 7266 from HRS (female: 64.9%, mean age: 65.1 years) were included according to inclusion and exclusion criteria. The median follow-up periods were 5.0 years in the CHARLS, 10.7 years in the ELSA, and 9.5 years in the HRS. Compared with stable robust participants, robust participants who progressed to pre-frail or frail status had increased risks of incident CVD (CHARLS, HR = 1.84, 95% CI: 1.54-2.21; ELSA, HR = 1.53, 95% CI: 1.25-1.86; HRS, HR = 1.59, 95% CI: 1.31-1.92). In contrast, frail participants who recovered to robust or pre-frail status presented decreased risks of incident CVD (CHARLS, HR = 0.62, 95% CI: 0.47-0.81; ELSA, HR = 0.49, 95% CI: 0.34-0.69; HRS, HR = 0.70, 95% CI: 0.55-0.89) when compared with stable frail participants. These decreased risks of incident CVD were also observed in pre-frail participants who recovered to robust status (CHARLS, HR = 0.66, 95% CI: 0.52-0.83; ELSA, HR = 0.65, 95% CI: 0.49-0.85; HRS, HR = 0.71, 95% CI: 0.56-0.91) when compared with stable pre-frail participants. CONCLUSIONS: Different changes in frailty status are associated with different risks of incident CVD. Progression of frailty status increases incident CVD risks, while recovery of frailty status decreases incident CVD risks.

MHC-Fine: Fine-tuned AlphaFold for precise MHC-peptide complex prediction.

The precise prediction of major histocompatibility complex (MHC)-peptide complex structures is pivotal for understanding cellular immune responses and advancing vaccine design. In this study, we enhanced AlphaFold's capabilities by fine-tuning it with a specialized dataset consisting of exclusively high-resolution class I MHC-peptide crystal structures. This tailored approach aimed to address the generalist nature of AlphaFold's original training, which, while broad-ranging, lacked the granularity necessary for the high-precision demands of class I MHC-peptide interaction prediction. A comparative analysis was conducted against the homology-modeling-based method Pandora as well as the AlphaFold multimer model. Our results demonstrate that our fine-tuned model outperforms others in terms of root-mean-square deviation (median value for Cα atoms for peptides is 0.66 Å) and also provides enhanced predicted local distance difference test scores, offering a more reliable assessment of the predicted structures. These advances have substantial implications for computational immunology, potentially accelerating the development of novel therapeutics and vaccines by providing a more precise computational lens through which to view MHC-peptide interactions.

Healthy lifestyle and cancer survival: A multinational cohort study.

Lifestyle factors after a cancer diagnosis could influence the survival of cancer 60 survivors. To examine the independent and joint associations of healthy lifestyle factors with mortality outcomes among cancer survivors, four prospective cohorts (National Health and Nutrition Examination Survey [NHANES], National Health Interview Survey [NHIS], UK Biobank [UKB] and Kailuan study) across three countries. A healthy lifestyle score (HLS) was defined based on five common lifestyle factors (smoking, alcohol drinking, diet, physical activity and body mass index) that related to cancer survival. We used Cox proportional hazards regression to estimate the hazard ratios (HRs) for the associations of individual lifestyle factors and HLS with all-cause and cancer mortality among cancer survivors. During the follow-up period of 37,095 cancer survivors, 8927 all-cause mortality events were accrued in four cohorts and 4449 cancer death events were documented in the UK and US cohorts. Never smoking (adjusted HR = 0.77, 95% CI: 0.69-0.86), light alcohol consumption (adjusted HR = 0.86, 95% CI: 0.82-0.90), adequate physical activity (adjusted HR = 0.90, 95% CI: 0.85-0.94), a healthy diet (adjusted HR = 0.69, 95% CI: 0.61-0.78) and optimal BMI (adjusted HR = 0.89, 95% CI: 0.85-0.93) were significantly associated with a lower risk of all-cause mortality. In the joint analyses of HLS, the HR of all-cause and cancer mortality for cancer survivors with a favorable HLS (4 and 5 healthy lifestyle factors) were 0.55 (95% CI 0.42-0.64) and 0.57 (95% CI 0.44-0.72), respectively. This multicohort study of cancer survivors from the United States, the United Kingdom and China found that greater adherence to a healthy lifestyle might be beneficial in improving cancer prognosis.

Live Birth with or without Preimplantation Genetic Testing for Aneuploidy.

BACKGROUND: Embryo selection with preimplantation genetic testing for aneuploidy (PGT-A) may improve pregnancy outcomes after initial embryo transfer. However, it remains uncertain whether PGT-A improves the cumulative live-birth rate as compared with conventional in vitro fertilization (IVF). METHODS: In this multicenter, randomized, controlled trial, we randomly assigned subfertile women with three or more good-quality blastocysts to undergo either PGT-A or conventional IVF; all the women were between 20 and 37 years of age. Three blastocysts were screened by next-generation sequencing in the PGT-A group or were chosen by morphologic criteria in the conventional-IVF group and then were successively transferred one by one. The primary outcome was the cumulative live-birth rate after up to three embryo-transfer procedures within 1 year after randomization. We hypothesized that the use of PGT-A would result in a cumulative live-birth rate that was no more than 7 percentage points higher than the rate after conventional IVF, which would constitute the noninferiority margin for conventional IVF as compared with PGT-A. RESULTS: A total of 1212 patients underwent randomization, and 606 were assigned to each trial group. Live births occurred in 468 women (77.2%) in the PGT-A group and in 496 (81.8%) in the conventional-IVF group (absolute difference, -4.6 percentage points; 95% confidence interval [CI], -9.2 to -0.0; P<0.001). The cumulative frequency of clinical pregnancy loss was 8.7% and 12.6%, respectively (absolute difference, -3.9 percentage points; 95% CI, -7.5 to -0.2). The incidences of obstetrical or neonatal complications and other adverse events were similar in the two groups. CONCLUSIONS: Among women with three or more good-quality blastocysts, conventional IVF resulted in a cumulative live-birth rate that was noninferior to the rate with PGT-A. (Funded by the National Natural Science Foundation of China and others; ClinicalTrials.gov number, NCT03118141.).

Selectively Extending the Curved Side of N-Doped Hexa-peri-hexabenzocoronene.

A curved nanographene, conceptually by insertion of nitrogen into a trapezoidal planar nanographene at the edge was synthesized by π-extension of the nitrogen-doped hexa-peri-hexabenzocoronene. This aza-doped nanographene exhibited a π-electronic concave face containing a nonaromatic azepine ring in the middle with a size of 14.0 Å length and 4.0 Å depth, which represents an unprecedented half-side concave geometry of curved nanographene. The bent π-extension exhibited a low degree of conjugation suggested by calculation results. Due to the unique 3D structure and electron-rich property, this nanographene showed pronounced intermolecular charge transfer with C60.

Weight-adjusted waist index as a practical predictor for diabetes, cardiovascular disease, and non-accidental mortality risk.

BACKGROUND AND AIM: Identifying a more suitable marker among various measures of adiposity, demonstrating strong associations and predictive ability for clinical use, remains a topic of debate. Weight-adjusted waist index (WWI) has been proposed as a novel index of adiposity, yet its exploration is limited, especially in Chinese populations. This study seeks to examine the associations between body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHTR), weight-adjusted waist index (WWI), waist circumference divided by body mass to the power of 0.333 (WC/M0.333), visceral adiposity index (VAI), lipid accumulation product (LAP), and the incidence of diabetes, cardiovascular disease, and non-accidental mortality in Chinese populations. Furthermore, our goal is to compare the respective predictive values of these measures for these health outcomes. METHODS AND RESULTS: This prospective cohort study included 21,750 subjects with a 9-year follow-up period. Cox proportional hazard models were used to investigate the relationship between eight anthropometric indexes and the incidence of diabetes, cardiovascular disease, and non-accidental mortality. The predictive value of these eight indexes was compared using the area under the curve metric. Significant positive associations were found between WWI and the risk of diabetes. Using the first quartile (Q1) of WWI as the reference group, hazard ratios with 95% confidence intervals for the risk of diabetes were 1.58 (0.98-2.55) for Q2, 2.18 (1.34-3.35) for Q3, and 2.27 (1.41-3.67) for Q4. Significant associations were observed with the highest quartile of WWI for the risk of cardiovascular disease [Q2: HR 1.45 (95% CI 1.06-1.98); Q3: 1.33 (0.97-1.83); Q4: 1.55 (1.13-2.14)] and risk of non-accidental mortality [Q2: 0.94 (0.80-1.11); Q3: 1.24 (1.04-1.48); Q4: 1.44 (1.16-1.79)]. Receiver operating characteristic analysis revealed that WWI exhibited superior discrimination and accuracy in predicting cardiovascular disease and non-accidental mortality compared to other adiposity indexes (BMI, WC, WHR, WHTR, WC/M0.333, VAI, and LAP). CONCLUSION: WWI exhibited the most robust and consistent association with the incidence of cardiovascular disease and non-accidental mortality. Given its simplicity and widespread use, WWI emerges as a novel and practical predictor of diabetes, cardiovascular disease, and non-accidental mortality among the eight adiposity indexes investigated in this study.

Opposite effects of soil pH on bacteria and fungi ß diversity in forests at a continental scale.

Soil microbial diversity is crucial for regulating biogeochemical cycles, including soil carbon (C) dynamics and nutrient cycling. However, how climate, plants, and soil properties influence the microbiome in forests remains unclear, especially at the continental scale, hindering us to better understand forest C-climate change feedback. Here, we investigated the spatial patterns of microbial diversity across China's forests and explored the controlling factors of microbial ß diversity and network complexity. Our results showed that soil pH strongly influenced bacterial and fungal ß diversity compared to climate, soil nutrient and plant properties. To further investigate the environmental preference of the microbial networks, we classified the amplicon sequence variants (ASVs) into five groups ranging from acidic to alkaline soils. Co-occurrence network analysis revealed that the topological structure of the bacterial network (e.g., edge and degree) increased with pH and was negatively correlated with ß diversity but not for fungal diversity. Soil fungi exhibited higher ß diversity and network complexity (i.e., degree and betweenness) than bacteria in acidic soils (pH < 5.1), and vice versa in neutral and alkaline soils (pH > 5.5). Within the pH range of 5.1-5.5, the bacterial-fungal network displayed the highest network complexity with the lowest fungal ß diversity, and significant positive correlations were found between fungal ß diversity and soil properties. In addition, bacterial growth in acidic soil (pH < 5.5) showed positive correlations with acid phosphatase (AP), but negative ones with ß-1,4-glucosidase (BG), and vice versa in neutral and alkaline soils (pH > 5.5). Furthermore, 46 bacterial core species were identified, and their abundance had significant correlation with soil pH. These findings highlight the critical role of soil pH in driving soil microbial ß diversity across China's forests and reveal the effects of pH thresholds on changes in the soil microbial network and core species.

Association between factors in life course and physiological disorders among the middle-aged and older population in Zhoushan city of Zhejiang province. / æµ™æ±ŸçœèˆŸå±±å¸‚ä¸­è€å¹´äººç¾¤ç”Ÿå‘½åŽ†ç¨‹å› ç´ ä¸Žç”Ÿç†å¤±è°ƒçš„å ³è”ç ”ç©¶.

OBJECTIVES: To analyze the associations between factors in life course and physiological disorders in the middle-aged and elderly population of Zhoushan city of Zhejiang province, and the mediating roles of lifestyle and mental health. METHODS: A total of 1553 island residents aged ≥45 years were enrolled from the Zhejiang Metabolic Syndrome Cohort Zhoushan Liuheng Sub-cohort. The demographic information, life-course information, lifestyle, and mental health information of participants were documented, and blood samples of were collected. The status of aging was evaluated by physiological disorders calculation model developed by authors previously. The Shapley value decomposition method was used to assess the cumulative and relative contribution of multiple factors in life course to the aging. Principal component analysis and hierarchical cluster analysis were used to classify subgroups. General linear regression model was used to assess the associations between the life-course subgroups and physiological disorders. Five key factors associated with aging were finally identified. Logistic regression model, general linear regression model, and mediation analysis model were used to assess the complex associations between life-course subgroups, key factors, unhealthy lifestyle, mental health, and aging. RESULTS: Shapley value decomposition method indicated that eight types of life-course factors explained 6.63% (SE=0.0008) of the individual physiological disorders variance, with the greatest relative contribution (2.78%) from adversity experiences in adulthood. The study participants were clustered into 4 subgroups, and subgroups experiencing more adversity in adulthood and having low educational attainment or experiencing more trauma and having poorer relationships in childhood had significantly higher levels of physiological disorders. Life-course subgroups and key factors (childhood trauma and health, adversity experience in adulthood, and lower education) were positively associated with unhealthy lifestyles (ß=0.12-0.41, P<0.05). In addition, life-course subgroups and key factors (adversity experience in adulthood) were positively associated with psychological problems (OR=2.14-4.68, P<0.05). Unhealthy lifestyle scores showed a marginal significant association with physiological disorders (ß=0.03, P=0.055). However, no significant association was found between psychological problems and physiological disorders (ß=0.03, P=0.748). The results of the mediation analysis model suggested that unhealthy lifestyles partially mediated the associations between life-course subgroups, adversity experience in adulthood and physiological disorders. CONCLUSIONS: Multiple life-course factors contribute about 6% of the variance in physiological disorders in the middle aged and elderly population of the study area; subgroups with adverse life course experiences have higher levels of aging; and the association may be partially mediated by unhealthy lifestyles.

Cross-talks between gut microbiota and tobacco smoking: a two-sample Mendelian randomization study.

BACKGROUND: Considerable evidence has been reported that tobacco use could cause alterations in gut microbiota composition. The microbiota-gut-brain axis also in turn hinted at a possible contribution of the gut microbiota to smoking. However, population-level studies with a higher evidence level for causality are lacking. METHODS: This study utilized the summary-level data of respective genome-wide association study (GWAS) for 211 gut microbial taxa and five smoking phenotypes to reveal the causal association between the gut microbiota and tobacco smoking. Two-sample bidirectional Mendelian randomization (MR) design was deployed and comprehensively sensitive analyses were followed to validate the robustness of results. We further performed multivariable MR to evaluate the effect of neurotransmitter-associated metabolites on observed associations. RESULTS: Our univariable MR results confirmed the effects of smoking on three taxa (Intestinimonas, Catenibacterium, and Ruminococcaceae, observed from previous studies) with boosted evidence level and identified another 13 taxa which may be causally affected by tobacco smoking. As for the other direction, we revealed that smoking behaviors could be potential consequence of specific taxa abundance. Combining with existing observational evidence, we provided novel insights regarding a positive feedback loop of smoking through Actinobacteria and indicated a potential mechanism for the link between parental smoking and early smoking initiation of their children driven by Bifidobacterium. The multivariable MR results suggested that neurotransmitter-associated metabolites (tryptophan and tyrosine, also supported by previous studies) probably played a role in the action pathway from the gut microbiota to smoking, especially for Actinobacteria and Peptococcus. CONCLUSIONS: In summary, the current study suggested the role of the specific gut microbes on the risk for cigarette smoking (likely involving alterations in metabolites) and in turn smoking on specific gut microbes. Our findings highlighted the hazards of tobacco use for gut flora dysbiosis and shed light on the potential role of specific gut microbiota for smoking behaviors.

LncRNA landscape and associated ceRNA network in placental villus of unexplained recurrent spontaneous abortion.

BACKGROUND: Unexplained recurrent spontaneous abortion (URSA) is one of the most challenging conditions frustrates women of childbearing age profoundly. The gene expression patterns and biological characteristics of placental villus in patients with URSA remain largely unknown. The aim of our study was to identify potential lncRNAs as well as their action mechanisms in URSA. METHOD: The ceRNA microarray was used to identify the mRNA and lncRNA expression profiles of URSA patients and normal pregnancy. Functional enrichment analyses for differentially expressed mRNAs in URSA were performed. Protein-protein interaction analysis of differentially expressed mRNAs was performed to identify hub genes and key modules. Subsequently, the co-dysregulated ceRNA network of URSA was established, and the enrichment analyses for the mRNAs in the ceRNA network was implemented. qRT-PCR was performed to validated the expression of key ENST00000429019 and mRNAs in URSA. RESULTS: We found that URSA placental villus have distinct mRNA and lncRNA expression profiles through ceRNA microarray, with a total of 347 mRNAs and 361 lncRNAs differentially expressed compared with controls. The functional enrichment analysis revealed that ncRNA processing, DNA replication, cell cycle, apoptosis, cytokine-mediated signaling pathway, ECM-receptor interaction were the potentially disrupted pathways in URSA patients. Then we constructed a co-dysregulated ceRNA network and found differentially expressed mRNAs were regulated by a small fraction of hub lncRNAs. Finally, we found a key network of ENST00000429019 and three cell proliferation or apoptosis related key mRNAs (CDCA3, KIFC1, NCAPH), and validated their expression and regulation in tissue and cellular levels. CONCLUSIONS: This study identified a key ceRNA network, which might take part in URSA and correlate with cell proliferation and apoptosis. Optimistically, this study may deepen our apprehensions about the underlying molecular and biological causes of URSA and provide an important theoretical basis for future therapeutic strategies for patients with URSA.

Exploring the potential mechanism of Xuebijing injection against sepsis based on metabolomics and network pharmacology.

Sepsis is a major contributor to the death of critically ill patients globally, in which metabolic disturbance is observed. Xuebijing injection (XBJ), a well-known traditional Chinese medicine, has received approval by the State Food and Drug Administration (SFDA) of China owing to its satisfactory clinical therapeutic effect. Nowadays, it has been applied clinically to the treatment of sepsis, but its effect on metabolic disorders remains unclear. In the present study, we sought to explore its underlying mechanism by employing a combination of network pharmacology and metabolomics. Initially, its protective effects were validated using a sepsis rat model created through cecal ligation puncture (CLP). Subsequently, the metabonomic strategy was utilized to discriminate the differential metabolic markers. Meanwhile, a comprehensive view of the potential ingredient-target-disease network was constructed based on a network pharmacology analysis. Next, the network diagram was constructed by integrating the results of network pharmacology and metabonomics. Finally, qRT-PCR together with Western blot was used to validate the expression levels of the associated genes. Based on our findings, we identified 34 differential metabolites in the sepsis group and 26 distinct metabolites in the XBJ group, with 8 common biological metabolites predominantly associated with arginine and proline metabolism. Through comprehensive analysis, we identified 21 genes that regulate metabolites, and qRT-PCR validation was conducted on six of these genes in both liver and kidney tissues. Additionally, XBJ demonstrated the capability to inhibit the activation of the NF-kB signaling pathway in both liver and kidney tissues, leading to a reduction in the occurrence of inflammatory responses. In summary, our study has validated the complexity of the natural compounds within XBJ and elucidated their potential mechanisms for addressing CLP-induced metabolic disturbances. This work contributes to our understanding of the bioactive compounds and their associated targets, providing insights into the potential molecular mechanisms involved.

Identifying pyroptosis- and inflammation-related genes in intracranial aneurysms based on bioinformatics analysis.

BACKGROUND: Intracranial aneurysm (IA) is the most common cerebrovascular disease, and subarachnoid hemorrhage caused by its rupture can seriously impede nerve function. Pyroptosis is an inflammatory mode of cell death whose underlying mechanisms involving the occurrence and rupture of IAs remain unclear. In this study, using bioinformatics analysis, we identified the potential pyroptosis-related genes (PRGs) and performed their inflammatory response mechanisms in IAs. METHODS: The mRNA expression matrix of the IA tissue was obtained from the Gene Expression Omnibus database, and 51 PRGs were obtained from previous articles collected from PubMed. The differentially expressed PRGs (DEPRGs) were performed using R software. Subsequently, we performed enrichment analysis, constructed a protein-protein interaction network, performed weighted gene coexpression network analysis (WGCNA) and external validation using another dataset, and identified a correlation between hub genes and immune cell infiltration. Finally, the expression and tissue distribution of these hub genes in IA tissues were detected using Western blotting and immunohistochemical (IHC) staining. RESULTS: In total, 12 DEPRGs associated with IA were identified in our analysis, which included 11 up-regulated and one down-regulated genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that the DEPRGs were mostly enriched in the NOD-like receptor signaling pathway, interleukin-1 beta production, and the inflammasome complex. Three hub genes, NLRP3, IL1B and IL18, were identified using Cytoscape software and the WGCNA correlation module, and external validation revealed statistically significant differences between the expression of these hub genes in the ruptured and unruptured aneurysm groups (p < 0.05). Furthermore, all AUC values were > 0.75. Immune cell infiltration analysis suggested that the hub genes are related to CD8 T cell, macrophages and mast cells. Finally, IHC staining revealed that the protein levels of these hub genes were higher in ruptured and unruptured IA tissues than in normal tissues (p < 0.05). CONCLUSION: The results of bioinformatics analysis showed that pyroptosis is closely related to the formation and rupture of IA, and identified three potential hub genes involved in the pyroptosis and infiltration ofcells. Our findings may improve the understanding of the mechanisms underlying pyroptosis in IA.

An in-hospital stroke system to optimize emergency management of acute ischemic stroke by reducing door-to-needle time.

BACKGROUND: Door-to-needle time (DNT) is a critical consideration in emergency management of acute ischemic stroke (AIS). Deficiencies in the widely applied standard hospital workflow process, based on international guidelines, impede rapid treatment of AIS patients. We developed an in-hospital stroke system to reduce DNT and optimize hospitals' emergency procedures. OBJECTIVES: To investigate the effect of the in-hospital stroke system on the hospital workflow for AIS patients. METHODS: We performed a retrospective study on AIS patients between June 2017 and December 2021. AIS cases were assigned to a pre-intervention group (before the in-hospital stroke system was established) and a post-intervention group (after the system's establishment). We compared the two groups' demographic features, clinical characteristics, treatments and outcomes, and time metrics data. RESULTS: We analyzed 1031 cases, comprising 474 and 557 cases in the pre-intervention and post-intervention groups, respectively. Baseline data were similar for both groups. Significantly more patients in the post-intervention group (41.11%) were treated with intravenous thrombolysis (IVT) or endovascular therapy (ET) compared with those in the pre-intervention group (8.65%) (p < 0.001). DNT was markedly improved (decreasing from 118 (80.5-137) min to 26 (21-38) min among patients in the post-intervention group treated with IVT or bridging ET. Consequently, a much higher proportion of these patients (92.64%) received IVT within 60 min compared with those in the pre-intervention group (17.39%) (p < 0.001). Consequently, their hospital stays were shorter (8 [6-11] days vs. 10 [8-12] days for the pre-intervention group; p < 0.001), and they showed improved National Institutes of Health Stroke Scale (NIHSS) scores at discharge (-2 [-5-0] vs. -1 [-2-0], p < 0.001). CONCLUSION: DNT was significantly reduced following implementation of the in-hospital stroke system, which contributed to improved patient outcomes measured by the length of hospital stay and NIHSS scores.

Ablation of Mto1 in zebrafish exhibited hypertrophic cardiomyopathy manifested by mitochondrion RNA maturation deficiency.

Deficient maturations of mitochondrial transcripts are linked to clinical abnormalities but their pathophysiology remains elusive. Previous investigations showed that pathogenic variants in MTO1 for the biosynthesis of τm5U of tRNAGlu, tRNAGln, tRNALys, tRNATrp and tRNALeu(UUR) were associated with hypertrophic cardiomyopathy (HCM). Using mto1 knock-out(KO) zebrafish generated by CRISPR/Cas9 system, we demonstrated the pleiotropic effects of Mto1 deficiency on mitochondrial RNA maturations. The perturbed structure and stability of tRNAs caused by mto1 deletion were evidenced by conformation changes and sensitivity to S1-mediated digestion of tRNAGln, tRNALys, tRNATrp and tRNALeu(UUR). Notably, mto1KO zebrafish exhibited the global decreases in the aminoacylation of mitochondrial tRNAs with the taurine modification. Strikingly, ablated mto1 mediated the expression of MTPAP and caused the altered polyadenylation of cox1, cox3, and nd1 mRNAs. Immunoprecipitation assay indicated the interaction of MTO1 with MTPAP related to mRNA polyadenylation. These alterations impaired mitochondrial translation and reduced activities of oxidative phosphorylation complexes. These mitochondria dysfunctions caused heart development defects and hypertrophy of cardiomyocytes and myocardial fiber disarray in ventricles. These cardiac defects in the mto1KO zebrafish recapitulated the clinical phenotypes in HCM patients carrying the MTO1 mutation(s). Our findings highlighted the critical role of MTO1 in mitochondrial transcript maturation and their pathological consequences in hypertrophic cardiomyopathy.

Estimated cardiorespiratory fitness and incident risk of cardiovascular disease in China.

BACKGROUND: Limited evidence is available on the association between estimated cardiorespiratory fitness (e-CRF) and incidence of cardiovascular disease (CVD) in Chinese population. METHODS: A total of 10,507 adults including 5084 men (48.4%) and 5423 (51.6%) women with a median age of 56.0 (25% quantile: 49, 75% quantile 63) years from the China Health and Retirement Longitudinal Study (CHARLS) was recruited in 2011 as baseline. The CVD incident events were followed-up until 2018. e-CRF was calculated from sex-specific longitudinal non-exercise equations and further grouped into quartiles. Cox proportional models were used to calculate hazard ratio (HR) and 95% confidence interval (CI) for incidence risks of CVD, heart disease and stroke. RESULTS: During a median follow-up of 7 years, a total of 1862 CVD, 1409 heart disease and 612 stroke events occurred. In fully adjusted models, each one MET increment of e-CRF was associated with lower risk of CVD (HR = 0.91, 95%CI = 0.85-0.96 for males, HR = 0.87, 95%CI = 0.81-0.94 for females). Compared with the Quartile (Q)1 group, the HRs (95%CI) of the Q2, Q3 and Q4 groups were 0.84 (0.63-1.03), 0.72 (0.57-0.91) and 0.66 (0.51-0.87) for CVD in males. Females had HRs of 0.79 (0.66-0.96) in Q2, 0.71 (0.57-0.88) in Q3 and 0.58 (0.45-0.75) in Q4 for CVD. The associations between e-CRF and heart disease and stroke were slightly weaker than that for CVD in both males and females. CONCLUSIONS: Higher e-CRF decreases the incident risk of CVD, heart disease and stroke.

ß-CD-Induced Precipitation of Eriochrome Black T Recovered via CTAB-Assisted Foam Fractionation for Adsorption of Trace Cu(II).

In order to remove and reuse the ecotoxic dye Eriochrome black T (EBT) from dyeing wastewater, we used a process called cetyltrimethylammonium bromide (CTAB)-assisted foam fractionation. By optimizing this process with response surface methodology, we achieved an enrichment ratio of 110.3 ± 3.8 and a recovery rate of 99.1 ± 0.3%. Next, we prepared composite particles by adding ß-cyclodextrin (ß-CD) to the foamate obtained through foam fractionation. These particles had an average diameter of 80.9 µm, an irregular shape, and a specific surface area of 0.15 m2/g. Using these ß-CD-CTAB-EBT particles, we were able to effectively remove trace amounts of Cu2+ ions (4 mg/L) from the wastewater. The adsorption of these ions followed pseudo-second-order kinetics and Langmuir isotherm models, and the maximal adsorption capacities at different temperatures were 141.4 mg/g at 298.15 K, 143.1 mg/g at 308.15 K, and 144.5 mg/g at 318.15 K. Thermodynamic analysis showed that the mechanism of Cu2+ removal via ß-CD-CTAB-EBT was spontaneous and endothermic physisorption. Under the optimized conditions, we achieved a removal ratio of 95.3 ± 3.0% for Cu2+ ions, and the adsorption capacity remained at 78.3% after four reuse cycles. Overall, these results demonstrate the potential of ß-CD-CTAB-EBT particles for the recovery and reuse of EBT in dyeing wastewater.

Research progress and challenges of preimplantation genetic testing for polygenic diseases. / å¤šåŸºå› ç–¾ç— èƒšèƒŽæ¤å ¥å‰é—ä¼ å­¦æ£€æµ‹çš„ç ”ç©¶è¿›å±•åŠæŒ‘æˆ˜.

Preimplantation genetic testing is an important part in assisted reproductive technology, which can block the intergenerational inheritance of single gene or chromosomal diseases. Preimplantation genetic testing for polygenic disease risk (PGT-P) is the latest development in the field. It is known that polygenic diseases usually have the characteristics of high incidence, late onset, affecting the quality of life and mental health of patients. On the basis of the development of artificial intelligence and genetic detection technology, PGT-P can analyze genetic material, calculate polygenic risk score turning into incidence probability. Embryos with relatively low incidence probability can be screened for transfer, so as to reduce the possibility of offspring suffering from the disease in the future, which has significant clinical and social significance. At present, PGT-P has been applied clinically and made phased progress at home and abroad. At the same time, as a developing technology, PGT-P still has some technical defects, unstable results, environmental influences and racial differences cannot be ruled out. From the perspective of ethics, if the screening indications are not strictly regulated, it is likely to cause new social problems. In this paper, we review the technical composition and recent progress of PGT-P, and put forward the prospect of its future development, especially how to establish a complete and suitable screening model for Chinese population.