Microwave ablation combined with PD-L1 blockade synergistically promotes Cxcl9-mediated antitumor immunity.

Although microwave ablation (MWA) is an important curative therapy in colorectal cancer liver metastasis, recurrence still occurs clinically. Our previous studies have shown that the expression of programmed cell death 1 ligand 1 (PD-L1) is upregulated following MWA, suggesting that MWA combined with anti-PD-L1 treatment can serve as a promising clinical therapeutic strategy against cancer. Using MWA-treated preclinical mice models, MWA combined with αPD-L1 treatment decreased tumor growth and prolonged overall survival (OS). Furthermore, through flow cytometry and single-cell RNA sequencing analysis, we determined that the MWA plus αPD-L1 therapy significantly suppressed CD8+ T cell exhaustion and enhanced their effector function. A significant increase in γ-interferon (IFN-γ) stimulated transcription factors, specifically Irf8, was observed. This enhancement facilitated the polarization of tumor-associated macrophages (TAM1s and TAM2s) through the nuclear factor-κB/JAK-STAT1 signaling pathway. Furthermore, the combination therapy stimulated the production of CXC motif chemokine ligand (CXCL9) by TAM1s and tumor cells, potentially increasing the chemotaxis of CD8 T cells and Th1 cells. Knocking out Cxcl9 in MC38 tumor cells or using CXCL9 blockade enhanced tumor growth of untreated tumors and shortened OS. Taken together, our study showed that blocking the IFN-γ-Cxcl9-CD8+ T axis promoted tumor progression and discovered a potential involvement of IRF8-regulated TAMs in preventing T cell exhaustion. Collectively, we identified that the combination of MWA with anti-PD-L1 treatment holds promise as a therapeutic strategy to rejuvenate the immune response against tumors. This merits further exploration in clinical studies.

Ferredoxin 1: a gatekeeper in halting lung adenocarcinoma progression through activation of the GPRIN2 signaling pathway.

BACKGROUND: Lung adenocarcinoma (LUAD) is a highly lethal form of lung cancer. Despite advancements in treatments, managing LUAD is still challenging due to its aggressive behavior. Recent studies indicate that various molecular pathways, including the dysregulation of ferredoxin 1 (FDX1), play roles in LUAD progression. FDX1, a crucial protein in cellular redox reactions and energy metabolism, has been linked to several cancers. However, its exact role in the development of LUAD is not yet fully understood. METHODS: We investigated the role of ferredoxin 1 (FDX1) in LUAD progression through analysis of its expression in LUAD tissues and its impact on patient survival. Functional assays were performed to assess the effects of FDX1 overexpression on LUAD cell proliferation, migration, and invasion. A xenograft model was employed to evaluate the tumorigenesis potential of LUAD cells with FDX1 overexpression. Mechanistic insights into FDX1 regulation were gained through depletion experiments targeting the G protein-regulated inducer of neurite outgrowth 2 (GPRIN2)/PI3K signaling pathway. RESULTS: FDX1 expression was down-regulated in LUAD tissues, correlating with shorter patient survival. Overexpression of FDX1 suppressed LUAD cell proliferation, migration, and invasion in vitro, and inhibited tumorigenesis in vivo. Mechanistically, the GPRIN2/PI3K signaling pathway was implicated in FDX1 regulation, as depletion of GPRIN2 reversed the effects of FDX1 overexpression on cellular functions. CONCLUSIONS: Our findings highlight FDX1 as a potential tumor suppressor in LUAD, acting through modulation of the GPRIN2/PI3K signaling pathway. These results suggest FDX1 as a promising therapeutic target for LUAD treatment, warranting further investigation into its clinical relevance.

Sulforaphane Attenuates AOM/DSS-Induced Colorectal Tumorigenesis in Mice via Inhibition of Intestinal Inflammation.

Sulforaphane (SFN) is a compound derived from cruciferous plants. It has received considerable attention in recent years due to its effectiveness in cancer prevention and anti-inflammatory properties. The purpose of this study was to evaluate the antitumor potential of sulforaphane on colitis-associated carcinogenesis (CAC) through the establishment of a mouse model with AOM/DSS. First, AOM/DSS and DSS-induced model were established and administered SFN for 10 wk, and then the severity of colitis-associated colon cancer was examined macroscopically and histologically. Subsequently, immune cells and cytokines in the tumor microenvironment (TME) were quantified. Finally, the influence of sulforaphane was also investigated using different colon cell lines. We found that sulforaphane treatment decreased tumor volume, myeloid-derived suppressor cells (MDSC) expansion, the expression of the proinflammatory cytokine IL-1ß, and the level of IL-10 in serum. Also, it enhanced the antitumor activities of CD8+ T cells and significantly reduced tumorigenesis as induced by AOM/DSS. SFN also attenuated intestinal inflammation in DSS-induced chronic colitis by reshaping the inflammatory microenvironment. This work demonstrates that sulforaphane suppresses carcinogenesis-associated intestinal inflammation and prevents AOM/DSS-induced intestinal tumorigenesis and progression.

Primary care providers' preferences for pay-for-performance programs: a discrete choice experiment study in Shandong China.

BACKGROUND: Pay-for-performance (P4P) schemes are commonly used to incentivize primary healthcare (PHC) providers to improve the quality of care they deliver. However, the effectiveness of P4P schemes can vary depending on their design. In this study, we aimed to investigate the preferences of PHC providers for participating in P4P programs in a city in Shandong province, China. METHOD: We conducted a discrete choice experiment (DCE) with 882 PHC providers, using six attributes: type of incentive, whom to incentivize, frequency of incentive, size of incentive, the domain of performance measurement, and release of performance results. Mixed logit models and latent class models were used for the statistical analyses. RESULTS: Our results showed that PHC providers had a strong negative preference for fines compared to bonuses (- 1.91; 95%CI - 2.13 to - 1.69) and for annual incentive payments compared to monthly (- 1.37; 95%CI - 1.59 to - 1.14). Providers also showed negative preferences for incentive size of 60% of monthly income, group incentives, and non-release of performance results. On the other hand, an incentive size of 20% of monthly income and including quality of care in performance measures were preferred. We identified four distinct classes of providers with different preferences for P4P schemes. Class 2 and Class 3 valued most of the attributes differently, while Class 1 and Class 4 had a relatively small influence from most attributes. CONCLUSION: P4P schemes that offer bonuses rather than fines, monthly rather than annual payments, incentive size of 20% of monthly income, paid to individuals, including quality of care in performance measures, and release of performance results are likely to be more effective in improving PHC performance. Our findings also highlight the importance of considering preference heterogeneity when designing P4P schemes.

The role of primary health care in improving health status, financial protection and health equity in the context of China's health system reform.

BACKGROUND: Stronger primary health care (PHC) is critical to achieving the United Nations' Sustainable Development Goals. However, there is scarce evidence on the impact of PHC on health system performance in developing countries. Since 2009, China has implemented an ambitious health system reform, among which PHC has received unprecedented attention. This study investigates the role of PHC resource in improving health status, financial protection and health equity. METHODS: We obtained province-level and individual-level data to conduct a longitudinal study across the period of China's health system reform. The dependent variables included health outcomes and financial protection. The independent variables were the number of PHC physicians and share of PHC physicians in all physicians. Mixed-effect models were used for adjusted associations. RESULTS: From 2003 to 2017, the number of PHC physicians slightly increased by 31.75 per 100,000 persons and the share of PHC physicians in all physicians increased by 3.62 percentage points. At the province level, greater PHC physician density was positively associated with life expectancy, negatively associated with age-standardized excess mortality, infectious disease mortality, perinatal mortality low birth weight, as well as the share of health expenses in total consumption expenses. At the individual and household level, greater PHC physician density was positively associated with self-assessed health, and negatively associated with incidence of catastrophic health expenditures. Compared to other quintiles, the poorest quintile benefited more from PHC physician density. CONCLUSIONS: In China, an increased PHC physician supply was associated with improved health system performance. While China's PHC system has been strengthened in the context of China's health system reforms, further effective incentives should be developed to attract more qualified PHC workers.

ALDH2 ameliorates ethanol-induced gastric ulcer through suppressing NLPR3 inflammasome activation and ferroptosis.

Gastric ulcer (GU) is a prevalent and life-threating gastrointestinal disorder. Aldehyde dehydrogenase 2 (ALDH2) is a pivotal component of alcohol metabolism which has been supported to suppress oxidative stress-elicited DNA damage in gastric mucosa cells. Nonetheless, whether ALDH2 is also involved in GU remains indistinct. Firstly, HCl/ethanol-induced experimental rat GU model was successfully established. RT-qPCR and Western blot tested ALDH2 expression in rat tissues. Following the addition of ALDH2 activator Alda-1, gastric lesion area and index were measured. H&E staining detected the histopathology of gastric tissues. ELISA examined the levels of inflammatory mediators. Alcian blue staining evaluated mucus production of gastric mucosa. Oxidative stress levels were estimated by corresponding kits and Western blot. Western blot examined the expression of NLRP3 inflammasome- and ferroptosis-related proteins. Prussian blue staining and corresponding assay kits measured ferroptosis. In ethanol-treated GES-1 cells, NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, iron content, ferroptosis, inflammation and oxidative stress were detected as aforementioned above. In addition to that, DCFH-DA staining examined ROS generation. The experimental data corroborated that ALDH2 expression was declined in the tissues of HCl/ethanol-treated rats. Alda-1 ameliorated HCl/ethanol-stimulated gastric mucosal damage, inflammatory response, oxidative stress, NLRP3 inflammasome activation and ferroptosis in rats. Also, the suppressive role of ALDH2 in inflammatory response and oxidative stress was reversed by ferroptosis activator erastin or NLRP3 activator nigericin in HCl/ethanol-challenged GES-1 cells. To be summarized, ALDH2 might play the protective role in the process of GU.

Data envelopment analysis on the efficiency of vaccination services and its influencing factors in Beijing, China.

OBJECTIVES: Vaccination is an important part of public health services. We aim to assess the efficiency of vaccination services in Beijing, the capital of China, and to further study the influencing factors of efficiency. METHODS: Using the immunization service data of Beijing, China in 2020, we firstly developed a data envelopment analysis (DEA) model to calculate the score of vaccination efficiency. Secondly, we used DEA model scenario simulations with different combinations of input-output factors to derive the magnitude of the effect of each input factor on the efficiency. Finally, combined with the data from the Beijing Regional Statistical Yearbook 2021, we developed the Tobit model to examine the effect of external social environmental factors on efficiency. RESULTS: The average scores of efficiency of POVs (Point of Vaccination) in different areas of Beijing vary greatly. Different input factors had different degrees of positive effects on the efficiency score. In addition, the number of populations served by POV was positively associated with efficiency, the GDP and financial allocation of the POVs' district was also positively associated with efficiency score, while the total dependency ratio of the POVs' district was negatively associated with efficiency score. CONCLUSION: The efficiency of vaccination services varied considerably across POVs. Constrained by limited resources, efficiency scores can be increased by increasing input factors that have a larger impact on efficiency score and reducing those that have a smaller impact on efficiency. In addition, the social environment should be considered in allocating vaccination resources, and more resources should be invested in areas with low levels of economic development, low financial allocation, and high population.

Effect of storage time on chemical compositions, physiological and cooking quality characteristics of different rice types.

BACKGROUND: Storage affects rice quality significantly. The aim of this study was to investigate the changes in the chemical composition and in the physiological and cooking quality characteristics of three rice types after 1 year storage at 25 °C. RESULTS: Two japonica, two indica, and two indica-japonica hybrid rice varieties were selected. After storage, the total starch content decreased. The amylose content of japonica, indica, and indica-japonica hybrid rice increased by 9.63%-11.65%, 2.99%-4.67%, and 8.07%-8.97%, respectively, and the fat content decreased by 60.00%-65.00%, 37.21%-46.51%, and 41.67%-42.42%, respectively. The abscisic acid (ABA) and raffinose content decreased after 1 year's storage; the former decreased gradually during the storage and the latter increased by 19.35%-45.45%, 7.02%-10.77%, and 16.13%-28.13%, respectively, after 4 months' storage and then decreased to the lowest level after 1 year's storage. The activity of antioxidant enzymes deceased, which resulted in the increases in fatty acid value and malondialdehyde (MDA). The changes in chemical composition after 1 year storage led to the deterioration of rice cooking quality, which was reflected in the decrease in viscosity and increases in gelatinization temperature and cooked rice hardness. CONCLUSION: After 1 year's storage, the rice chemical composition changed and physiological and cooking quality characteristics decreased. Compared with japonica and indica-japonica hybrid rice, indica rice was more stable during 1 year storage. This may be due to the higher content of ABA and raffinose in fresh rice. Our findings will provide information for the identification and breeding of storable rice cultivars. © 2022 Society of Chemical Industry.

Effectiveness of Community-Based Rehabilitation Interventions on Symptoms and Functioning for People with Schizophrenia: A Systematic Review and Meta-Analysis.

Schizophrenia is a serious mental illness that imposes huge burden of illness on the society. We aimed to conduct a meta-analytic and systematic review of literature on the effectiveness of community-based rehabilitation interventions on symptoms and functioning for people with schizophrenia. The PubMed, Embase, the Cochrane Library, Web of Science, and CINAHL databases were searched through April 16 and 17, 2021, including clinical trial registries and previous Cochrane reviews. We included 24 randomized controlled trials in this review. The content of interventions varied from single-faceted rehabilitation intervention or cognitive retraining, to multi-component rehabilitation interventions or case management. Among 20 studies that reported effects of community-based rehabilitation interventions on symptoms, the pooled SMDs across all interventions was 0.94 (95% CI = 0.11, 1.76; P < 0.001; I2 = 99.1%; n = 3694), representing a strong effect. 21 included studies showed that community-based rehabilitation interventions also had beneficial impacts on functioning (SMD = 1.65; 95% CI = 0.88, 2.43; P < 0.001; I2 = 98.9%; n = 3734). Overall quality of evidence was moderate with a high level of heterogeneity. Community-based rehabilitation interventions have positive effectiveness in improving patients' symptoms and functioning. Community-based rehabilitation interventions should therefore be provided as an adjuvant service in addition to facility-based care for people with schizophrenia.

Effects of providing free hearing aids on multiple health outcomes among middle-aged and older adults with hearing loss in rural China: a randomized controlled trial.

BACKGROUND: Hearing loss has been associated with serious health problems around the globe. Previous studies have found the positive effects of fitting hearing aids on health, but few studies were conducted in developing countries. The aim of this study is to examine the effects of hearing aids on multiple health outcomes among middle-aged and older adults with hearing loss in rural China. METHODS: In this randomized controlled trial (RCT), participants aged 45 and above were randomly assigned to the treatment group prescribing with hearing aids or to the control group with no intervention. Trial outcomes for 385 participants were collected during the 20-month follow-up study. Using the difference-in-difference approach, our primary outcomes were hearing-related quality of life (QoL) and generic QoL. RESULTS: The intervention led to improvements in hearing-related QoL, presenting as the reduction in Hearing Handicap Inventory for the Elderly Screening Version (HHIE-S) scores (interaction coefficient = - 2.86, p = 0.005), HHIE-S-Emotional scores (interaction coefficient = - 1.42, p = 0.029), and HHIE-S-Situational scores (interaction coefficient = - 1.43, p = 0.007). The intervention was also effective in alleviating the increase in depressive symptoms (interaction coefficient = - 0.14, p = 0.042). Subgroup analysis revealed that the effects were only shown among people with social activities or active social networks. CONCLUSIONS: Our study is the first RCT in China to measure the health effects and heterogeneity of hearing aid interventions. Wearing hearing aids can help improve hearing-related QoL and alleviate the increase in depressive symptoms. The intervention is expected to be applicable to similar settings in other developing countries to combat hearing-related health problems. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900024739 . Registered on 26 July 2019.

The methyltransferase METTL3 promotes tumorigenesis via mediating HHLA2 mRNA m6A modification in human renal cell carcinoma.

BACKGROUND: As an important N6-methyladenosine (m6A) regulator, abnormal expression of methyltransferase-like protein 3 (METTL3) has been reported in certain human cancers. Although some data have shown that METTL3 plays an essential role in the progression of clear-cell renal cell carcinoma RCC (ccRCC), the detailed mechanism still remains largely undetermined. METHODS: Immunohistochemistry (IHC) assay was used to examine the expression of METTL3 and its clinical implications in human ccRCC by using tissue-microarray (TMA). The cellular models based on ccRCC cell lines such as 786-O and ACHN, were established by operating METTL3 and HHLA2 via knockdown or overexpression, followed by in vitro cellular function studies and in vivo subcutaneous transplantation tumor model. RESULTS: We found that METTL3 expression in ccRCC tissues was significantly higher compared with adjacent normal tissues. We also found the overall survival (OS) of the patients with low METTL3 expression was significantly better compared with the patients with high METTL3 expression. Furthermore, HHLA2highMETTL3high could serve as a better prognostic predictor for ccRCC patients. Depletion of METTL3 could significantly inhibit the cell viability, migration, and invasion abilities in ccRCC cell lines. Cellular studies further revealed that METTL3 could regulate HHLA2 expression via m6A modification of HHLA2 mRNA. In vitro studies revealed that HHLA2 overexpression could reverse the inhibition of cellular functions mediated by METTL3 depletion. The subcutaneous transplantation tumor model confirmed that HHLA2 overexpression could reverse the inhibition of tumor growth mediated by METTL3 depletion. CONCLUSION: Our study indicated that METTL3 served as an important prognostic predictor for ccRCC patients, and we demonstrated a novel regulatory mechanism of HHLA2 by mRNA epigenetic modification via METTL3. Moreover, we found that the METTL3/HHLA2 axis could promote tumorigenesis of ccRCC. Collectively, our current findings provided new insights into the therapeutic strategy against this malignancy targeting METTL3.

LAG3 blockade coordinates with microwave ablation to promote CD8+ T cell-mediated anti-tumor immunity.

BACKGROUND: The immune checkpoint inhibitors (ICIs) combined with other therapeutic strategies have shown exciting results in various malignancies, and ICIs have now become the gold standard for current cancer treatment. In several preclinical and clinical investigations, ablation coupled with immunotherapy has proved to be quite effective. Our previous studies have shown that ablation coupled with ICI is a potential anti-cancer regimen for colorectal cancer liver metastases (CRLM). Furthermore, we have reported that following microwave ablation (MWA), the expression of LAG3 is up-regulated in tumor microenvironment (TME), indicating that LAG3 is implicated in the regulation of immunosuppressive immune response, and combination therapy of MWA and LAG3 blockade can serve as a promising therapeutic strategy against cancer. METHODS: The expression of LAG3 was investigated in this study utilizing a preclinical mouse model treated with MWA. Moreover, we monitored the tumor development and survival in mice to assess the anti-cancer effects of MWA alone or in combination with LAG3 blockade. Flow cytometry was also used to phenotype the tumor-infiltrating lymphocytes (TILs) and CD8+ T cell effector molecules. We finally analyzed the single-cell RNA sequencing (scRNA-seq) data of infiltrating CD45+ immune cells in the tumors from the MWA alone and MWA combined with LAG3 blockade groups. RESULTS: After MWA, the expression of LAG3 was up-regulated on sub-populations of TILs, and introducing LAG3 blockade to MWA postponed tumor development and extended survival in the MC38 tumor model. Flow cytometry and scRNA-seq revealed that LAG3 blockade in combination with MWA markedly boosted the proliferation and the function of CD8+ TILs, leading to altered myeloid cells in the TME. CONCLUSION: Combination therapy of LAG3 blockade and MWA was a unique therapeutic regimen for some solid tumors, and such combination therapy might reprogram the TME to an anti-tumor manner.

Does self-perceived income priority matter? The association between income inequality and allostatic load in China.

There is a scarcity of evidence about the association between income inequality and allostatic load (AL) across diverse population, which is critical to identify the downstream biological pathway of the inequality-health linkage. This study aimed to determine the association of income inequality with AL, and assess whether there are differences in such association between people with different perception of income priority. We utilized data from the 2006 and 2009 wave of China Health and Nutrition Survey (CHNS). Multilevel linear regression analyses were conducted to examine the association between AL score and community Gini coefficient. Additionally, to investigate whether the association of income inequality and AL score would vary among individuals with different perception of income priority, a cross-level interaction term for Gini coefficient and self-perceived income priority was applied. Both the cross-sectional analysis in 2009 (coefficient = 0.081, p = .016) and the time-lagged analysis (0.106, 0.008) suggested that community-level Gini coefficient was positively associated with AL. Similar result was only found among individuals from low median income communities in subsample analysis. Additionally, the cross-level interaction between Gini coefficient and self-perceived income priority was significantly associated with AL among respondents from low-median income communities. There is a positive association between income inequality and AL among Chinese adults, with individual who perceived income as a higher priority in their life suffering more from income inequality. This study contributes to the increasing efforts and new perspective to understand the inner mechanism of both the detrimental effect of income inequality and the accumulation of AL.

Hearing impairment, family financial support, and depressive symptoms among Chinese middle-aged and older adults.

AIMS: Hearing impairment (HI) is prevalent among middle-aged and older adults, but few studies have examined its mental health consequences in China. This study investigated the association of HI with depressive symptoms and whether family financial support moderated the association among adults aged 45 in China. METHODS: Data were obtained from three waves of the China Health and Retirement Longitudinal Study (2011, 2013 and 2015). Hearing impairment was defined as a self-reported hearing problem in one or both ears. Depressive symptoms were measured with CESD-10. Associations between HI and depressive symptoms were modeled using fixed-effect models. RESULTS: People with self-reported hearing loss were more likely than those without hearing loss to have depressive symptoms, with an odds ratio of 1.25 [1.07-1.47]. The association remained significant after adjusting for socio-demographic characteristics, lifestyle behaviors, and health conditions. Family financial support moderated this association. Among those with HI, adults with a higher level of family financial support tend to have better performance on symptoms of depression. CONCLUSIONS: HI was positively associated with depressive symptoms among adults aged ≥45 in China, and family financial support played a buffering role in the relationship between HI and depressive symptoms.

Changes in health care utilization and financial protection after integration of the rural and urban social health insurance schemes in Beijing, China.

BACKGROUND: China expanded health coverage to residents in informal economic sectors by the rural new cooperative medical scheme (NCMS) for rural population and urban resident basic medical insurance scheme (URBMI) for non-working urban residents. Fragmentation of resident social health insurance schemes exacerbated the health inequity and China started the integration of urban and rural resident medical insurance schemes since 2016. Beijing finished the insurance integration in 2017 and has been implementing a unified urban and rural resident basic medical insurance scheme (URRBMI) since the beginning of 2018. This study aims to examine changes in health care utilization and financial protection after integration of the rural and urban social health insurance schemes. METHODS: We used household survey data from Beijing Health Services Survey in 2013 and 2018. Respondents who were 15 or older and covered by URBMI, NCMS or URRBMI were included in this study. Our study finally included 8,554 individuals in 2013 and 6,973 individuals in 2018, about 70% of which were rural residents in each year. Descriptive analysis was used to compare the healthcare utilization, healthcare expenditure and incidence of catastrophic health expenditure between different groups. A series of two-part regression models were used to analyze the changes of healthcare utilization, healthcare expenditure and incidence of catastrophic health expenditure. RESULTS: From 2013 to 2018, urban-rural disparity in outpatient care utilization seemed widened because urban residents' utilization of outpatient care increased 131% while rural residents' utilization only increased 72%; both rural and urban residents' spending on outpatient care increased about 50%. Utilization of inpatient care changed little and poor residents still used significantly less inpatient care compared with the rich residents. Poor residents still suffered heavily catastrophic health expenditures. CONCLUSION: From 2013 to 2018, residents' utilization of healthcare, especially outpatient care, increased in Beijing. Health insurance reforms increased residents' utilization of healthcare but failed to reduce their healthcare financial burden, especially for poor people. Our study advocates more pro-poor insurance policies and more efforts on the efficiency of health system.

Prenatal di-(2-ethylhexyl) phthalate exposure induced myocardial cytotoxicity via the regulation of the NRG1-dependent ErbB2/ErbB4-PI3K/AKT signaling pathway in fetal mice.

Environmental sanitation of maternal contact during pregnancy is extremely important for the development of different fetal tissues and organs. In particular, during early pregnancy, any adverse exposure may cause abnormal fetal growth or inhibit the development of embryogenic organs. The potential risks of phthalate exposure, which affects the development of humans and animals, are becoming a serious concern worldwide. However, the specific molecular mechanism of di-(2-ethylhexyl) phthalate (DEHP)-induced cardiotoxicity in fetal mice remains unclear. In this study, animal models of DEHP gavage at concentrations of 250, 500, and 1000 mg/kg/day within 8.5-18.5 days of pregnancy were established. The cell proliferation, survival, and apoptosis rates were evaluated using CCK8, EdU, TUNEL and flow cytometry. The molecular mechanism was assessed via transcriptome sequencing, immunohistochemistry, immunofluorescence, reverse transcription-quantitative polymerase chain reaction, and Western blot analysis. In vivo, DEHP increased apoptosis, decreased Ki67 and CD31 expression, reduced heart weight and area, slowed down myocardial sarcomere development, and caused cardiac septal defect in fetal mice heart. Transcriptome sequencing showed that DEHP decreased NRG1 expression and downregulated the ErbB2/ErbB4-PI3K/AKT signaling pathway-related target genes. In vitro, primary cardiomyocytes were cultured with DEHP at a concentration of 150 µg/mL combined with ErbB inhibitor (AG1478, 10 µmol/L) and/or NRG1 protein (100 ng/mL) for 72 h. After DEHP intervention, the expression of NRG1 and the phosphorylation level of ErbB2, ErbB4, PI3K, and AKT decreased, and the apoptosis-related protein levels increased. Moreover, the apoptosis rate increased. After adding exogenous NRG1, the phosphorylation level of the NRG1/ERbB2/ERbB4-PI3K/AKT pathway increased, and the apoptosis-related protein levels decreased. Further, the apoptosis rate reduced. Interestingly, after exposure to DEHP and AG1478 + NRG1, the anti-apoptotic effect of NRG1 and cardiomyocyte proliferation decreased by inhibiting the NRG1/ERbB2/ERbB4-PI3K/AKT pathway. Hence, the NRG1-dependent regulation of the ERbB2/ERbB4-PI3K/AKT signaling pathway may be a key mechanism of DEHP-induced myocardial cytotoxicity.

Direct and indirect associations between childhood socioeconomic status and cognitive function in the middle-aged and older adults in China.

OBJECTIVES: To investigate whether childhood socioeconomic status (SES) is associated with cognitive function, and what factors might mediate the associations. METHOD: Using data from the China Health and Retirement Longitudinal Study (CHARLS) and within frameworks of the latency model, the pathway model and the accumulation model, we quantified direct and indirect pathways between childhood SES and cognitive function for Chinese middle-aged and older adults aged 45+ by structural equations modeling. RESULTS: We found significant direct, indirect and total effects of childhood SES on cognitive function at baseline. The indirect effects were mediated through educational attainment, household consumption, smoking behaviors and social engagement. At follow-ups, cognitive enhancement can be made by indirect pathways through educational attainment, improvement of household consumption and social engagement. CONCLUSION: Our results supported the latency model, the pathway model and the accumulation model when considering pathways linking childhood SES to cognitive function. The findings underscored the value of taking early interventions to improve SES and cognitive function, especially among those with low childhood SES.

Earlier migration, better cognition? The role of urbanization in bridging the urban-rural cognition gaps in middle and older age.

OBJECTIVES: With the process of population aging and urbanization, a vast amount of studies have confirmed the increasing urban-rural cognition gaps, while less is known about the extent to which cognition gaps can be explained by urban-rural difference and urbanization status. This study aimed to examine the role of urbanization in bridging the cognition gaps for Chinese middle-aged and older adults. METHOD: Based on the national representative China Health and Retirement Longitudinal Study (CHARLS) 2015, the Blinder-Oaxaca decomposition method was employed. The method uses stratified linear regression to disaggregate cognition gaps into explained and unexplained differences, as well as the absolute and relative attribution of explanatory factors. RESULTS: There were significant cognitive differences between urban and rural samples. Migrating to the urban predicts better cognition among the rural-born. A larger environment-related explained gap existed for those fully urbanized and those migrating earlier, indicating that migration can operate through a beneficial and cumulative change in the environment and bridge the urban-rural cognition gap. CONCLUSION: Public health actions targeting cognitive disparities can benefit from focusing on the unequal distribution in urban-rural social and economic recourses. Areas of priority include promoting their socioeconomic status, physical functioning, social support, and lifestyles.

Development of Certified Reference Materials for the Determination of Apparent Amylose Content in Rice.

Apparent amylose content (AAC) is one of the most important parameters in rice quality evaluation. In this study, four rice reference materials used to test rice AAC were developed. The AAC of rice reference materials were measured by a spectrophotometric method with a defatting procedure, calibrated from potato amylose and waxy rice amylopectin at the absorption wavelengths of 620 and 720 nm. Homogeneity test (n = 20) was judged by F-test based on the mean squares of among and within bottles, and short- and long-term stability monitoring was performed by T-test to check if there was significant degradation at the delivery temperature of under 40 °C (14 days) and at 0-4 °C storage condition (18 months), respectively. After joint evaluation by ten laboratories, Dixion and Cochran statistical analyses were presented. The expanded uncertainties were calculated based on the uncertainty of homogeneity, short- and long-term stability, and inter-laboratory validation containing factor k = 2. It found that the four reference materials were homogenous and stable, and had the AAC (g/100 g, k = 2) of 2.96 ± 1.01, 10.68 ± 0.66, 17.18 ± 1.04, and 16.09 ± 1.29, respectively, at 620 nm, and 1.46 ± 0.49, 10.44 ± 0.56, 16.82 ± 0.75, and 24.33 ± 0.52, respectively, at 720 nm. It was indicated that 720 nm was more suitable for the determination of rice AAC with lower uncertainties. The determinations of the AAC of 11 rice varieties were carried out by two methods, the method without defatting and with calibration from the four rice reference materials and the method with a defatting procedure and calibrating from potato amylose and waxy rice amylopectin. It confirmed that the undefatted rice reference materials could achieve satisfactory results to test the rice samples with the AAC ranging from 1 to 25 g/100 g. It would greatly reduce the time cost and improve testing efficiency and applicability, and provide technical support for the high-quality development of the rice industry.

Involvement of the BNP/NPR-A/BKCa pathway in rat trigeminal ganglia following chronic constriction injury.

Accumulating evidence indicates that the brain natriuretic peptide (BNP) and its receptor (natriuretic peptide receptor, NPR) are widely distributed in a variety of tissues including trigeminal ganglion (TG). Furthermore, recent studies support the involvement of the BNP-NPR-A pathway in acute and chronic pain. To investigate the role of this pathway in chronic pain, an infraorbital nerve-chronic constriction injury (ION-CCI) model of trigeminal neuralgia (TN) was produced in the rat. The time course of changes in mechanical pain threshold was examined. We observed an upregulation of BNP and NPR-A and a downregulation of large-conductance Ca2+-activated K+ (BKCa) mRNA and protein in rats subjected to ION-CCI. Patch clamping experiments in vitro found that BKCa currents were significantly reduced in rats subjected to ION-CCI. BNP increased BKCa currents in ION-CCI rats. These results suggest that BNP and NPR-A might serve as endogenous pain relievers in ION-CCI rats. Modulation of the BNP/NPR-A/BKCa channel pathway in TG may be a viable strategy for the treatment of TN.NEW & NOTEWORTHY BNP has been known to activate its receptor, NPR-A, to modulate inflammatory pain. However, the potential modulatory roles of BNP in TN have not been investigated in detail. We established an ION-CCI model of TN in the rat and observed an upregulation of BNP and NPR-A and a downregulation of BKCa in rats subjected to ION-CCI. Moreover, BNP can increase BKCa currents in ION-CCI rats. Thus, BNP and NPR-A might have inhibitory effects on trigeminal neuralgia through activating the BNP/NPR-A/BKCa channel pathway.