Off-label use of Baricitinib improves moderate and severe atopic dermatitis in China through inhibiting MAPK and PI3K/Akt/mTOR pathway via targeting JAK-STAT signaling of CD4+ cells.

As an inflammatory disease with a disrupted immune system, cytokine disorders in atopic dermatitis (AD) are closely related to the abnormal activation of JAK-STAT signal pathway. The critical relevance of the JAK-STAT signaling pathway to the pathogenesis of AD provides a strong rationale for JAK inhibitor research. Baricitinib, a small-molecule oral JAK inhibitor, has been proven to inhibit JAK-STAT signaling in a variety of diseases, including AD. It is currently available in China for off-label use. However, its efficacy in China and its mechanism are rarely reported. In our study, we found that the immune status of patients with moderate and severe AD was hyperactive. Among the 49 known immunotherapy targets, JAK1 and JAK2 genes on lymphocytes of AD patients were significantly upregulated, which was closely related to the symptom severity in moderate and severe AD patients. Baricitinib can improve immune hyperresponsiveness and clinical symptoms in moderate and severe AD by inhibiting the activation of Th2 cell subsets and the secretion of Th2-type cytokines through MAPK, mTOR and PI3K-Akt signaling pathways, providing an important theoretical basis for clinical off-label use of Baricitinib to treat moderate and severe AD.

Association of high-density lipoprotein cholesterol with all-cause and cause-specific mortality in a Chinese population of 3.3 million adults: a prospective cohort study.

Background: High-density lipoprotein cholesterol (HDL-C) has been inversely associated with cardiovascular disease (CVD) risk, but recent evidence suggests that extremely high levels of HDL-C are paradoxically related to increased CVD incidence and mortality. This study aimed to comprehensively examine the associations of HDL-C with all-cause and cause-specific mortality in a Chinese population. Methods: The China Health Evaluation And risk Reduction through nationwide Teamwork (ChinaHEART) project included 3,397,547 participants aged 35-75 years with a median follow-up of 3.9 years. Baseline HDL-C levels were measured, and mortality data was ascertained from the National Mortality Surveillance System and Vital Registration of Chinese Center for Disease Control and Prevention. Findings: This study found U-shaped associations of HDL-C with all-cause, cardiovascular and cancer mortality. When compared with the groups with the lowest risk, the adjusted hazard ratios (95% CIs) for HDL-C <30 mg/dL was 1.23 (1.17-1.29), 1.33 (1.23-1.45) and 1.18 (1.09-1.28) for all-cause, CVD and cancer mortality, respectively. For HDL-C >90 mg/dL, the corresponding HR (95% CIs) was 1.10 (1.05-1.15), 1.09 (1.01-1.18) and 1.11 (1.03-1.19). Similar U-shaped patterns were also found in associations of HDL-C with ischemic heart disease, ischemic stroke, and liver cancer. About 3.25% of all-cause mortality could be attributed to abnormal levels of HDL-C. The major contributor to mortality was ischemic heart disease (16.06 deaths per 100,000 persons, 95% UI: 10.30-22.67) for HDL-C <40 mg/dL and esophageal cancer (2.29 deaths per 100,000 persons, 95% UI: 0.57-4.77) for HDL-C >70 mg/dL. Interpretation: Both low and high HDL-C were associated with increased mortality risk. We recommended 50-79 mg/dL as the optimal range of HDL-C among Chinese adults. Individuals with dyslipidemia might benefit from proper management of both low and high HDL-C. Funding: The CAMS Innovation Fund for Medical Science (2021-1-I2M-011), the National High Level Hospital Clinical Research Funding (2022-GSP-GG-4), the Ministry of Finance of China and National Health Commission of China, and the 111 Project from the Ministry of Education of China (B16005), the Program for Guangdong Introducing Innovative and Enterpreneurial Teams (2019ZT08Y481), Sanming Project of Medicine in Shenzhen (SZSM201811096), the Young Talent Program of the Academician Fund, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen (YS-2022-006) and Guangdong Basic and Applied Basic Research Foundation (2023A1515010076 & 2021A1515220173).

APOE from patient-derived astrocytic extracellular vesicles alleviates neuromyelitis optica spectrum disorder in a mouse model.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system, mediated by antibodies against aquaporin-4 water channel protein (AQP4-Abs), resulting in damage of astrocytes with subsequent demyelination and axonal damage. Extracellular communication through astrocyte-derived extracellular vesicles (ADEVs) has received growing interest in association with astrocytopathies. However, to what extent ADEVs contribute to NMOSD pathogenesis remains unclear. Here, through proteomic screening of patient-derived ADEVs, we observed an increase in apolipoprotein E (APOE)-rich ADEVs in patients with AQP4-Abs-positive NMOSD. Intracerebral injection of the APOE-mimetic peptide APOE130-149 attenuated microglial reactivity, neuroinflammation, and brain lesions in a mouse model of NMOSD. The protective effect of APOE in NMOSD pathogenesis was further established by the exacerbated lesion volume in APOE-deficient mice, which could be rescued by exogenous APOE administration. Genetic knockdown of the APOE receptor lipoprotein receptor-related protein 1 (LRP1) could block the restorative effects of APOE130-149 administration. The transfusion ADEVs derived from patients with NMOSD and healthy controls also alleviated astrocyte loss, reactive microgliosis, and demyelination in NMOSD mice. The slightly larger beneficial effect of patient-derived ADEVs as compared to ADEVs from healthy controls was further augmented in APOE-/- mice. These results indicate that APOE from astrocyte-derived extracellular vesicles could mediate disease-modifying astrocyte-microglia cross-talk in NMOSD.

Healthy lifestyle, statin, and mortality in people with high CVD risk: A nationwide population-based cohort study.

Objective: To examine the joint association of healthy lifestyles and statin use with all-cause and cardiovascular mortality in high-risk individuals, and evaluate the survival benefits by life expectancy. Methods: During 2015-2021, participants aged 35-75 years were recruited by the China Health Evaluation And risk Reduction through nationwide Teamwork. Based on number of healthy lifestyles related to smoking, alcohol drinking, physical activity, and diet, we categorized them into: very healthy (3-4), healthy (2), and unhealthy (0-1). Statin use was determined by self-report taking statin in last two weeks. Results: Among the 265,209 included participants at high risk, 6979 deaths were observed, including 3236 CVD deaths during a median 3.6 years of follow-up. Individuals taking statin and with a very healthy lifestyle had the lowest risk of all-cause (HR: 0.70; 95 %CI: 0.57-0.87) and cardiovascular mortality (0.56; 0.40-0.79), compared with statin non-users with an unhealthy lifestyle. High-risk participants taking statin and with a very healthy lifestyle had the highest years of life gained (5.90 years at 35-year-old [4.14-7.67; P < 0.001]) compared with statin non-users with an unhealthy lifestyle among high-risk people. And their life expectancy was comparable with those without high risk but with a very healthy lifestyle (4.49 vs. 4.68 years). Conclusion: The combination of preventive medication and multiple healthy lifestyles was associated with lower risk of all-cause and cardiovascular mortality and largest survival benefits. Integrated strategy to improve long-term health for high-risk people was urgently needed.

Deubiquitinase Mysm1 regulates neural stem cell proliferation and differentiation by controlling Id4 expression.

Neural stem cells (NSCs) are critical for brain development and maintenance of neurogenesis. However, the molecular mechanisms that regulate NSC proliferation and differentiation remain unclear. Mysm1 is a deubiquitinase and is essential for the self-renewal and differentiation of several stem cells. It is unknown whether Mysm1 plays an important role in NSCs. Here, we found that Mysm1 was expressed in NSCs and its expression was increased with age in mice. Mice with Mysm1 knockdown by crossing Mysm1 floxed mice with Nestin-Cre mice exhibited abnormal brain development with microcephaly. Mysm1 deletion promoted NSC proliferation and apoptosis, resulting in depletion of the stem cell pool. In addition, Mysm1-deficient NSCs skewed toward neurogenesis instead of astrogliogenesis. Mechanistic investigations with RNA sequencing and genome-wide CUT&Tag analysis revealed that Mysm1 epigenetically regulated Id4 transcription by regulating histone modification at the promoter region. After rescuing the expression of Id4, the hyperproliferation and imbalance differentiation of Mysm1-deficient NSCs was reversed. Additionally, knockdown Mysm1 in aged mice could promote NSC proliferation. Collectively, the present study identified a new factor Mysm1 which is essential for NSC homeostasis and Mysm1-Id4 axis may be an ideal target for proper NSC proliferation and differentiation.

Associations between Chinese visceral adiposity index and risks of all-cause and cause-specific mortality: A population-based cohort study.

AIM: To determine the associations between the Chinese visceral adiposity index (CVAI) and the risks of all-cause and cause-specific mortality. MATERIALS AND METHODS: A total of 3 916 214 Chinese adults were enrolled in a nationwide population cohort covering all 31 provinces of mainland China. The CVAI was calculated based on age, body mass index, waist circumference, and triglyceride and high-density lipoprotein cholesterol concentrations. We used a Cox proportional hazards regression model to determine the hazard ratios and 95% confidence intervals (CIs) for risk of mortality associated with different CVAI levels. RESULTS: The median follow-up duration was 3.8 years. A total of 86 158 deaths (34 867 cardiovascular disease [CVD] deaths, 29 884 cancer deaths, and 21 407 deaths due to other causes) were identified. In general, after adjusting for potential confounding factors, a U-shaped relationship between CVAI and all-cause mortality was observed by restricted cubic spline (RCS). Compared with participants in CVAI quartile 1, those in CVAI quartile 4 had a 23.0% (95% CI 20.0%-25.0%) lower risk of cancer death, but a 23.0% (95% CI 19.0-27.0) higher risk of CVD death. In subgroup analysis, a J-shaped and inverted U-shaped relationship for all-cause mortality and cancer mortality was observed in the group aged < 60 years. CONCLUSIONS: The CVAI, an accessible indicator reflecting visceral obesity among Chinese adults, has predictive value for all-cause, CVD, and cancer mortality risks. Moreover, the CVAI carries significance in the field of health economics and secondary prevention. In the future, it could be used for early screening purposes.

Associations of remnant cholesterol with cardiovascular and cancer mortality in a nationwide cohort.

The health significance of triglyceride-rich lipoproteins, also known as remnant cholesterol, has been increasingly recognized. However, evidence of their associations with cause-specific mortality in the general population was previously insufficient. To explore these associations and their heterogeneities across subgroups, a prospective cohort study was conducted including 3,403,414 community-based participants from ChinaHEART, an ongoing government-funded public health program throughout China, from November 2014 through December 2022. The study assessed mortality risk of all-cause mortality, cardiovascular disease (CVD) mortality (including mortality from ischemic heart diseases (IHD), ischemic stroke (IS), and hemorrhagic stroke (HS), separately), and cancer mortality (including lung cancer, stomach cancer, and liver cancer, separately). During the 4-year follow-up, 23,646 individuals died from CVD (including 8807 from IHD, 3067 from IS, and 5190 from HS), and 20,318 from cancer (including 6208 from lung cancer, 3013 from liver cancer, and 2174 from stomach cancer). Compared with individuals with remnant cholesterol <17.9 mg/dL, multivariable-adjusted mortality hazard ratios (HRs) for individuals with remnant cholesterol ≥27.7 mg/dL were 1.03 (1.00-1.05) for all-cause mortality, 1.17 (1.12-1.21) for CVD (1.19 (1.12-1.27) for IHD mortality, and 1.22 (1.09-1.36) for IS mortality), and 0.90 (0.87-0.94) for all-cancer mortality (0.94 (0.87-1.02) for lung cancer, 0.59 (0.53-0.66) for liver cancer, and 0.73 (0.64-0.83) for stomach cancer). In summary, this study revealed a correlation between increased remnant cholesterol levels and an elevated risk of cardiovascular disease mortality, as well as a reduced risk of mortality for certain types of cancer.

Plasma Reference Ranges for Brain Injury Biomarkers (NfL, NfH, MCP-1, and MMP-9) in Healthy Chinese.

BACKGROUND: Brain injury triggers neuroaxonal injury and neural death, that leads to the development of secondary sequelae. Throughout this process, brain injury factors released into circulation via the injured neurovascular unit are important prognostic parameters. Plasma NfL, NfH, MCP-1, and MMP-9 have been identified as potential indicators in this regard. METHODS: Using a microfluidic ELISA platform, we measured plasma from 273 healthy subjects that underwent quantifications of NfL, NfH, MCP-1, and MMP-9 levels. We investigated the possible associations between biomarkers and basic demographics. RESULTS: The median concentration of plasma NfL was 10.40 (IQR = 6.73 - 16.60) pg/mL, NfH was 70.70 (IQR = 39.75 - 125.50) pg/mL, MCP-1 was 191.0 (IQR = 162.0 - 237.5) pg/mL, and MMP-9 was 169,255 (IQR = 107,657 - 231,276) pg/mL. Among all four biomarkers, plasma NfL and NfH levels were positively correlated with age (r = 0.557, p < 0.001, r = 0.364, p = 0.003). NfL was also correlated with NfH (r = 0.391, p = 0.002). CONCLUSIONS: These data provide a basis for the potential application of a brain-injury biomarker panel in routine clinical practice. It lays a significant foundation in supporting circulating CNS-biomarkers as noninvasive biomarkers for neurological disorders.

Function and regulation of miR-186-5p, miR-125b-5p and miR-1260a in chordoma.

BACKGROUND: The function and regulation of miRNAs in progression of chordoma were unclear. METHODS: Five miRNAs were identified by the machine learning method from the miRNA expression array. CCk-8 assay, EDU assay, wound healing migration assay, and trans-well assay were used to reveal the effect of the miRNAs in chordoma cell lines. Moreover, bioinformation analysis and the mRNA expression array between the primary chordomas and recurrent chordomas were used to find the target protein genes of miRNAs. Furthermore, qRT-PCR and luciferase reporter assay were used to verify the result. RESULTS: miR-186-5p, miR-30c-5p, miR-151b, and miR-125b-5p could inhibit proliferation, migration, and invasion of chordoma while miR-1260a enhances proliferation, migration, and invasion of chordoma. Recurrent chordoma has a worse disease-free outcome than the primary chordoma patients. AMOT, NPTX1, RYR3, and P2RX5 were the target protein mRNAs of miR-186-5p; NPTX1 was the target protein mRNAs of miR-125b-5p; and AMOT and TNFSF14 were the target protein mRNAs of miR-1260a. CONCLUSIONS: miR-186-5p, miR-125b-5p, miR-1260a, and their target protein mRNAs including AMOT, NPTX1, RYR3, P2RX5, TNFSF14 may be the basement of chordoma research.

Human neural stem cells.

'Human neural stem cells' jointly drafted and agreed upon by experts from the Chinese Society for Stem Cell Research, is the first guideline for human neural stem cells (hNSCs) in China. This standard specifies the technical requirements, test methods, test regulations, instructions for use, labelling requirements, packaging requirements, storage requirements, transportation requirements and waste disposal requirements for hNSCs, which is applicable to the quality control for hNSCs. It was originally released by the China Society for Cell Biology on 30 August 2022. We hope that publication of the guideline will facilitate institutional establishment, acceptance and execution of proper protocols, and accelerate the international standardization of hNSCs for clinical development and therapeutic applications.

A mathematical model to simulate the release of Fe and Mn from sediments in a drinking water reservoir.

Fe and Mn release from sediments promotes the release of other chemicals and jointly affects downstream water safety, especially in drinking water reservoirs. Quantitative research on release processes and flux estimation methods for endogenous Fe and Mn in reservoirs is still limited. Static incubation experiments were designed to systematically explore the effects of water temperature (WT), dissolved oxygen (DO), pH, carbon sources, and microbial activity on Fe and Mn release. The results showed that increased WT and carbon source addition promoted the release of acid-extractable Fe and Mn from the sediments; hypoxia and acidification promoted the dissolution of reducible sediment Fe and Mn; and microorganisms participated in the cycling of Fe and Mn. Based on the experimental results, first-order kinetic equations for sediment Fe and Mn release to overlying water were proposed, and the relationships between release rate and environmental factors were mathematically represented by a surface equation (R2 = 0.88 and 0.86, respectively). A diffusion gradients in thin films (DGT) device based on the diffusion model was used in situ to obtain the diffusion fluxes of Fe (JFe = 13.93 mg m-2 d-1) and Mn (JMn = 3.48 mg m-2 d-1). When environmental factors obtained in the field were introduced into the established mathematical model, the modeled release fluxes of Fe and Mn were RFe = 20.92 mg m-2 d-1 and RMn = 13.12 mg m-2 d-1, respectively. The established model filled gaps in the diffusion model, which does not account for differences in release fluxes under changing physicochemical water conditions. This work serves as a reference for studying the release fluxes of endogenous chemicals in sediments.

Platelet activation: a promoter for psoriasis and its comorbidity, cardiovascular disease.

Psoriasis is a chronic inflammatory skin disease with a prevalence of 0.14% to 1.99%. The underlying pathology is mainly driven by the abnormal immune responses including activation of Th1, Th17, Th22 cells and secretion of cytokines. Patients with psoriasis are more likely to develop cardiovascular disease (CVD) which has been well recognized as a comorbidity of psoriasis. As mediators of hemostasis and thromboinflammation, platelets play an important part in CVD. However, less is known about their pathophysiological contribution to psoriasis and psoriasis-associated CVD. A comprehensive understanding of the role of platelet activation in psoriasis might pave the path for more accurate prediction of cardiovascular (CV) risk and provide new strategies for psoriasis management, which alleviates the increased CV burden associated with psoriasis. Here we review the available evidence about the biomarkers and mechanisms of platelet activation in psoriasis and the role of platelet activation in intriguing the common comorbidity, CVD. We further discussed the implications and efficacy of antiplatelet therapies in the treatment of psoriasis and prevention of psoriasis-associated CVD.

Development of a CRISPR/Cas9D10A Nickase (nCas9)-Mediated Genome Editing Tool in Streptomyces.

Streptomycetes have a strong ability to produce a vast array of bioactive natural products (NPs) widely used in agriculture and veterinary/human medicine. The recently developed CRISPR/Cas9-based genome editing tools have greatly facilitated strain improvement for target NP overproduction as well as novel NP discovery in Streptomyces. However, CRISPR/Cas9 shows high toxicity to the host, limiting its application in many Streptomyces strains with a low DNA transformation efficiency. In this study, we developed a low-toxicity CRISPR/Cas9D10A nickase (nCas9)-based genome editing tool in the model strain Streptomyces coelicolor M145. We showed that in the presence of both targeting sgRNA and Cas proteins, utilization of nCas9 instead of Cas9 significantly reduced the toxicity to the host and greatly enhanced cell survival. Using this tool, we achieved deletion of single genes and gene clusters with efficiencies of 87-100 and 63-87%, and simultaneous deletion of two genes or gene clusters with efficiencies of 47 and 43%, respectively. The editing efficiency of nCas9 is comparable to that of the Cas9-mediated editing tool. Finally, the nCas9-based editing tool was successfully applied for genome editing in the industrial rapamycin-producing strain Streptomyces rapamycinicus, in which CRISPR/Cas9 cannot work well. We achieved the deletion of three tested genes with an efficiency of 27.2-30%. Collectively, the CRISPR/nCas9-based editing tool offers a convenient and efficient genetic modification system for the engineering of streptomycetes, particularly those with low DNA transformation efficiency.

Associations of long-term fine particulate matter exposure with all-cause and cause-specific mortality: results from the ChinaHEART project.

Background: The chronic effects of fine particulate matter (PM2.5) at high concentrations remains uncertain. We aimed to examine the relationship of long-term PM2.5 exposure with all-cause and the top three causes of death (cardiovascular disease [CVD], cancer, and respiratory disease), and to analyze their concentration-response functions over a wide range of concentrations. Methods: We enrolled community residents aged 35-75 years from 2014 to 2017 from all 31 provinces of the Chinese Mainland, and followed them up until 2021. We used a long-term estimation dataset for both PM2.5 and O3 concentrations with a high spatiotemporal resolution to assess the individual exposure, and used Cox proportional hazards models to estimate the associations between PM2.5 and mortalities. Findings: We included 1,910,923 participants, whose mean age was 55.6 ± 9.8 years and 59.4% were female. A 10 µg/m3 increment in PM2.5 exposure was associated with increased risk for all-cause death (hazard ratio 1.02 [95% confidence interval 1.012-1.028]), CVD death (1.024 [1.011-1.037]), cancer death (1.037 [1.023-1.052]), and respiratory disease death (1.083 [1.049-1.117]), respectively. Long-term PM2.5 exposure nonlinearly related with all-cause, CVD, and cancer mortalities, while linearly related with respiratory disease mortality. Interpretation: The overall effects of long-term PM2.5 exposure on mortality in the high concentration settings are weaker than previous reports from settings of PM2.5 concentrations < 35 µg/m³. The distinct concentration-response relationships of CVD, cancer, and respiratory disease mortalities could facilitate targeted public health efforts to prevent death caused by air pollution. Funding: The Chinese Academy of Medical Sciences Innovation Fund for Medical Science, the National High Level Hospital Clinical Research Funding, the Ministry of Finance of China and National Health Commission of China, the 111 Project from the Ministry of Education of China.

CD22 blockade modulates microglia activity to suppress neuroinflammation following intracerebral hemorrhage.

Microglia are first responders to acute brain insults and initiate neuroinflammation to drive secondary tissue injury. Yet the key molecular switches in control of the inflammatory activity of microglia remain poorly understood. Intracerebral hemorrhage (ICH) is a devastating stroke subtype whereby a hematoma is formed within the brain parenchyma and associated with high mortality. Using a mouse model of ICH, we found upregulation of CD22 that predominantly occurred in microglia. Antibody blockade of CD22 led to a reduction in neurological deficits, brain lesion and hematoma volume. This was accompanied by reduced inflammatory activity, increased expression of alternative activation markers (CD206 and IL-10) and enhanced phagocytosis activity in microglia after ICH. CD22 blockade also led to an increase of phosphorylated SYK and AKT after ICH. Notably, the benefits of CD22 blockade were ablated in ICH mice subjected to microglial depletion with a colony-stimulating factor 1 receptor inhibitor PLX5622. Additionally, the protective effects of CD22 blockade was diminished in ICH mice receiving a SYK inhibitor R406. Together, our findings highlight CD22 as a key molecular switch to control the detrimental effects of microglia after acute brain injury, and provide a novel strategy to improve the outcome of ICH injury.

HSPA8 acts as an amyloidase to suppress necroptosis by inhibiting and reversing functional amyloid formation.

Ultra-stable fibrous structure is a hallmark of amyloids. In contrast to canonical disease-related amyloids, emerging research indicates that a significant number of cellular amyloids, termed 'functional amyloids', contribute to signal transduction as temporal signaling hubs in humans. However, it is unclear how these functional amyloids are effectively disassembled to terminate signal transduction. RHIM motif-containing amyloids, the largest functional amyloid family discovered thus far, play an important role in mediating necroptosis signal transduction in mammalian cells. Here, we identify heat shock protein family A member 8 (HSPA8) as a new type of enzyme - which we name as 'amyloidase' - that directly disassembles RHIM-amyloids to inhibit necroptosis signaling in cells and mice. Different from its role in chaperone-mediated autophagy where it selects substrates containing a KFERQ-like motif, HSPA8 specifically recognizes RHIM-containing proteins through a hydrophobic hexapeptide motif N(X1)φ(X3). The SBD domain of HSPA8 interacts with RHIM-containing proteins, preventing proximate RHIM monomers from stacking into functional fibrils; furthermore, with the NBD domain supplying energy via ATP hydrolysis, HSPA8 breaks down pre-formed RHIM-amyloids into non-functional monomers. Notably, HSPA8's amyloidase activity in disassembling functional RHIM-amyloids does not require its co-chaperone system. Using this amyloidase activity, HSPA8 reverses the initiator RHIM-amyloids (formed by RIP1, ZBP1, and TRIF) to prevent necroptosis initiation, and reverses RIP3-amyloid to prevent necroptosis execution, thus eliminating multi-level RHIM-amyloids to effectively prevent spontaneous necroptosis activation. The discovery that HSPA8 acts as an amyloidase dismantling functional amyloids provides a fundamental understanding of the reversibility nature of functional amyloids, a property distinguishing them from disease-related amyloids that are unbreakable in vivo.

Educational inequalities in mortality and their mediators among generations across four decades: nationwide, population based, prospective cohort study based on the ChinaHEART project.

OBJECTIVES: To assess the different educational inequalities in mortality among generations born between 1940 and 1979 in China, and to investigate the role of socioeconomic, behavioural, and metabolic factors as potential contributors to the reduction of educational inequalities. DESIGN: Nationwide, population based, prospective cohort study. SETTING: The ChinaHEART (China Health Evaluation And risk Reduction through nationwide Teamwork) project in all 31 provinces in the mainland of China. PARTICIPANTS: 1 283 774 residents aged 35-75 years, divided into four separate cohorts born in 1940s, 1950s, 1960s, and 1970s. MAIN OUTCOME MEASURES: Relative index of inequality and all cause mortality. RESULTS: During a median follow-up of 3.5 years (interquartile range 2.1-4.7), 22 552 deaths were recorded. Among the four generations, lower education levels were found to be associated with a higher risk of all cause death: Compared with participants with college level education or above, the hazard ratio for people with primary school education and below was 1.4 (95% confidence interval 1.2 to 1.7) in the 1940s cohort, 1.8 (1.5 to 2.1) in the 1950s cohort, 2.0 (1.7 to 2.4) in the 1960s cohort, and 1.8 (1.4 to 2.4) in the 1970s cohort. Educational relative index of inequality in mortality increased from 2.1 (95% confidence interval 1.9 to 2.3) in the 1940s cohort to 2.6 (2.1 to 3.3) in the 1970s cohort. Overall, the mediation proportions were 37.5% (95% confidence interval 32.6% to 42.8%) for socioeconomic factors, 13.9% (12.0% to 16.0%) for behavioural factors, and 4.7% (3.7% to 5.8%) for metabolic factors. Except for socioeconomic measurements, the mediating effects by behavioural and metabolic factors decreased in younger generations. CONCLUSION: Educational inequalities in mortality increased over generations in China. Improving healthy lifestyles and metabolic risk control for less educated people, especially for younger generations, is essential to reduce health inequalities.

Total Syntheses of Kopsaporine, Kopsinol and Kopsiloscine†A.

Kopsia alkaloids represent a complex class of natural products bearing a polycyclic ring system with two or three consecutive quaternary carbon centers. In this article, we report the first total synthesis of Kopsaporine related alkaloids. Features of our structure-unit-based strategy are an intramolecular Pummerer rearrangement induced nucleophilic cyclization/aza-Prins cyclization to construct the highly functional hexahydrocarbazole skeleton, an olefin migration vinylogous alkylation to establish the C20 all-carbon quaternary center, an iridium complex mediated radical addition to fuse the aspidofractine framework, an unprecedented IBX oxidation to introduce the α-hydroxyketone moiety, and a bioinspired retro-Aldol/Aldol reaction to convert kopsaporine to kopsiloscine A.

Calcium isotopic geochemistry of geothermal systems in the tectonically active southeastern Tibetan Plateau.

The global Calcium (Ca) cycle is closely coupled to the carbon cycle, and Ca isotopes have potential in tracing it. Even though groundwater is one of the main reservoirs of Ca at the Earth's surface, few data are available for groundwater, and the behavior of Ca and its isotopes in geothermal systems remains unknown. Here we analysed the stable Ca and radiogenic Sr isotope compositions of thermal waters distributed along the Jinsha and Yalong river valleys in the southeastern Tibetan Plateau. The Ca isotopic composition of the thermal water ranges from 0.45 to 2.16 ‰ (δ44/40Ca values relative to SRM 915a). The thermal waters collected from carbonate aquifers have higher δ44/40Ca values than bedrocks, which was attributed to secondary carbonate precipitation accompanied by CO2 degassing. In contrast, δ44/40Ca values in thermal waters collected from clastic and igneous rocks are similar to bedrock. Despite some thermal waters undergoing secondary silicates formation and CaNa ion exchange, such processes maybe not play a significant role in governing the Ca isotopic composition of these thermal waters. This suggests that Ca isotopes can be used to trace secondary carbonate precipitation driven by CO2 degassing (e.g. travertine) in geothermal systems located in tectonically active areas.