Efficient Lead Removal by Assembly of Bio-Derived Ellagate Framework, Which Enables Electrocatalytic Reduction of CO2 to Formate.

Lead (Pb) poisoning and CO2-induced global warming represent two exemplary environmental and energy issues threatening humanity. Various biomass-derived materials are reported to take up Pb and convert CO2 electrochemically into low-valent carbon species, but these works address the problems separately rather than settle the issues simultaneously. In this work, cheap, natural ellagic acid (EA) extracted from common plants is adopted to assemble a stable metal-organic framework (MOF), EA-Pb, by effective capture of Pb2+ ions in an aqueous medium (removal rate close to 99%). EA-Pb represents the first structurally well-defined Pb-based MOF showing selective electrocatalytic CO2-to-HCOO- conversion with Faradaic efficiency (FE) of 95.37% at -1.08 V versus RHE. The catalytic mechanism is studied by 13CO2 labeling, in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), and theoretical calculation. The use of EA-Pb as an electrocatalyst for CO2 reduction represents a 2-in-1 solution of converting detrimental wastes (Pb2+) as well as natural resources (EA) into wealth (electrocatalytic EA-Pb) for addressing the global warming issue.

Association between concurrence of multiple risk factors and under-5 mortality: a pooled analysis of data from Demographic and Health Survey in 61 low-and-middle-income countries.

Background: Exposure to multiple risk factors is prevalent in low-and middle-income countries (LMICs), challenging one-directional strategies to address preventable under-5 mortality (U5M). This study aims to assess the associations between concurrence of multiple risk factors and U5M in LMICs. Methods: We extracted data from the Demographic and Health Surveys conducted between 2010 and 2021 across 61 LMICs. Our primary outcome was U5M, defined as deaths from birth to 59 months. Binary logistic regression model was applied to ascertain the association between U5M and a total of 20 critical risk factors. Upon identifying the risk factors demonstrating the strongest associations, we investigated the simultaneous presence of multiple risk factors in each individual and assessed their combined effects on U5M with logistic regression models. Findings: Of the 604,372 under-5 children, 18,166 (3.0%) died at the time of the survey. Unsatisfied family planning needs was the strongest risk factor for U5M (odds ratio [OR]: 2.0, 95% confidence interval [CI]: 1.9-2.1), followed by short birth interval (<18 months; OR: 2.0, 95% CI: 1.9-2.1), small birth size (OR: 2.0, 95% CI: 1.8-2.1), never breastfed or delayed breastfeeding (OR: 2.0, 95% CI: 1.9-2.0), and low maternal education (OR: 1.6, 95% CI: 1.4-1.8). 66.7% (66.6%-66.8%) of the children had 2 or more leading risk factors simultaneously. Simultaneous presence of multiple leading risk factors was significantly associated with elevated risk of U5M and children presenting with all 5 leading risk factors exhibited an exceedingly high risk of U5M (OR: 5.2, 95% CI: 4.3-6.3); a dose-response relationship between the number of risk factors and U5M was also observed-with the increment of numbers of leading risk factors, the U5M showed an increasing trend (p-trend < 0.001). Interpretation: Exposure to multiple risk factors is very common in LMICs and underscores the necessity of developing multisectoral and integrated approaches to accelerate progress in reducing U5M in line with the SDG 3.2. Funding: This research is funded by Research Fund, Vanke School of Public Health, Tsinghua University.

Prevalence, trend, and inequality of prolonged exclusive breastfeeding among children aged 6-23 months old in India from 1992-2021: A cross-sectional study of nationally representative, individual-level data.

Background: Prolonged exclusive breastfeeding (PEB) for children older than six months old is a threat to appropriate complementary feeding practices. This study aims to examine the trend of PEB among children aged 6-23 months in India. Methods: We adopted five waves of National Family Health Survey (NFHS) data between 1992-93 and 2019-21. PEB was defined as children aged six months and above currently consuming breastmilk as the only source of energy, protein and micronutrients. We generated descriptive statistics and a series of multivariable logistic regressions to estimate the prevalence and trend in the PEB rate. Moreover, we assessed how child age and socioeconomic factors (i.e. child gender and age, place of residence, household wealth, and maternal education) were related with PEB using mutually and single-adjusted model. Results: There were 184 891 Indian children aged 6-23 months old included in this study with 48.0% being female. We found that the proportion of PEB increased from 4.3% in 1992 to 7.7% in 2021, of which the rate for children aged six-eight months rose from 14.0 to 20.1%. Our results showed that children who were from poorer households or with lower-educated mothers were more likely to experience prolonged exclusive breastfed. Take the year of 2019-21 as an example, compared to the households of the richest quintile, children from households of the poorer quintile were significantly more likely to experience PEB, with odds ratio (OR) of 1.33 (95% confidence interval (CI) = 1.09-1.61). Moreover, children with illiterate mothers had 21% higher odds of having prolonged exclusively breastfeeding (OR = 1.21; 95% CI = 1.01-1.44) compared with children with mothers who have college and above education. Conclusions: PEB among children over six months old is prevalent in India, particularly among children from disadvantaged households. Poverty reduction and maternal education are of great potential importance for policymakers to promote appropriate complementary feeding practice.

The association of a disability-targeted cash transfer programme with disability status and health-care access: a quasi-experimental study using a nationwide cohort of 4·3 million Chinese adults living with severe disabilities.

BACKGROUND: Cash transfer is a crucial policy tool to address inequality. The objective of this study was to investigate the association between China's disability-targeted cash transfer programme and disability status, as well as equitable access to rehabilitation and medical services. METHODS: For this quasi-experimental study, we drew data from the nationwide administrative cohort of individuals with disabilities between Jan 1, 2015, and Dec 31, 2019. Individuals were enrolled in the cohort if they were aged 18 years or older, had severe disabilities as defined by the Chinese Government, and had available cash transfer information for at least 4 consecutive years, without having started receiving cash transfer benefits at the time of enrolment. We used a quasi-experimental design with propensity score matching to estimate the effects of cash transfers on disability status, access to rehabilitation services, and access to medical treatment. The primary outcomes were development of new disability and reduction of existing disabilities. Secondary outcomes were use of rehabilitation services, financial barriers as a major obstacle to accessing rehabilitation services, use of medical services by individuals who had an illness in the previous 2 weeks, and financial barriers as a major obstacle to accessing medical services. FINDINGS: From an initial pool of 51 356 125 individuals with disabilities registered in the administrative system, 2 686 024 individuals were eligible for analysis, of whom 2 165 335 (80·6%) were cash transfer beneficiaries and 520 689 (19·4%) non-beneficiaries. After propensity score matching, the cohort included 4 330 122 adults with severe disabilities. Cash transfer beneficiaries had significantly lower odds of developing new disabilities over time than non-beneficiaries (odds ratio [OR] 0·90, 95% CI 0·86-0·94; p<0·0001) and higher odds of having a reduced number of disabilities over time (1·17, 1·10-1·25; p<0·0001). Compared with non-beneficiaries, cash transfer beneficiaries were more likely to use rehabilitation services (2·12, 2·11-2·13; p<0·0001) and medical services (1·74, 1·69-1·78; p<0·0001), and less likely to report financial hardship to access rehabilitation services (0·53, 0·52-0·54; p<0·0001) and medical services (0·88, 0·84-0·93; p<0·0001) at the study endpoint. INTERPRETATION: The receipt of cash transfers was associated with improved disability status and increased access to disability-related services. The findings suggest that cash transfers could be a potential method for promoting universal health coverage among individuals living with disabilities. FUNDING: China National Natural Science Foundation.

Prevalence and changes of intimate partner violence against women aged 15 to 49 years in 53 low-income and middle-income countries from 2000 to 2021: a secondary analysis of population-based surveys.

BACKGROUND: In low-income and middle-income countries (LMICs), intimate partner violence poses a substantial barrier to accomplishing target 5.2 of the Sustainable Development Goals: to eliminate all forms of violence against women and girls. Our study aimed to assess the prevalence and changes of intimate partner violence against women in LMICs. We also explored the association between women's empowerment and intimate partner violence. METHODS: In this secondary analysis of population-based surveys, we obtained data from the nationally representative Demographic and Health Surveys conducted in LMICs between 2000 and 2021. We selected countries with available data on the domestic violence module, and women aged 15 to 49 years who currently or formerly had a husband or partner, and who had provided information about intimate partner violence, were included in the analysis. We first estimated the weighted prevalence of intimate partner violence in LMICs with available data, and then we assessed the average annual rate of change using Poisson regression with robust error variance in a subset of countries with at least two surveys. We used multilevel analysis to investigate the association between intimate partner violence and women's empowerment measured at both the country and individual levels. Country-level empowerment was measured by gender inequality index, while individual-level empowerment considered social independence, decision making, and attitude to violence. FINDINGS: A total of 359 479 women aged 15 to 49 years were included from 53 LMICs. 336 811 women from 21 countries with two surveys provided data for assessing the trends of intimate partner violence. The weighted prevalence of any type of intimate partner violence was 37·2% (95% CI 36·6 to 37·8). A significant overall decline in the prevalence of any type of intimate partner violence was observed with an average annual rate of change of -0·2% (95% CI -0·4 to -0·03); however six countries showed significant increasing trends, with average annual rates of change ranging from 1·2% (95% CI 0·7 to 1·7) in Nigeria to 6·6% (5·3 to 7·8) in Sierra Leone. Notably, the prevalence of psychological intimate partner violence has risen (average annual rate of change, 2·3% [95% CI 2·1 to 2·6]), reflected in increased rates across eight countries. Higher levels of country-level women's empowerment were associated with a lower risk of intimate partner violence: women from countries with the highest tertile of gender inequality index had an increased odds of any type of intimate partner violence (odds ratio 1·58 [95% CI 1·12 to 2·23]). Similarly, better individual-level women's empowerment also showed significant associations with a lower risk of intimate partner violence. INTERPRETATION: The prevalence of intimate partner violence remains high, and some countries have shown an increasing trend. The strong relationship between both country-level and individual-level women's empowerment and the prevalence of intimate partner violence suggests that accelerating women's empowerment could be one strategy to further reduce intimate partner violence against women. FUNDING: National Natural Science Foundation; Vanke School of Public Health, Tsinghua University; and Sanming Project of Medicine in Shenzhen.

DFT Study on the Oxidation Mechanism of Common Cyclic Carbonates in the Presence of BF4- Anions.

Oxidative decomposition reactions of common cyclic carbonates in the presence of BF4- anions were investigated using density functional theory. A polarized continuum model was utilized to model solvent effects in the oxidation of ethylene carbonate (EC) and propylene carbonate (PC) clusters. We have found that the presence of BF4- significantly reduces EC and PC oxidation stability, from 7.11 to 6.17 and from 7.10 to 6.06 V (vs Li+/Li), respectively. The sequence of EC and PC oxidative decomposition paths and the oxidative products were affected by the BF4- anion. The decomposition products of the oxidized EC-BF4- contained CO2, vinyl alcohol, and acetaldehyde, while the decomposition products of the oxidized PC-BF4- contained CO2, acetone, and propanal, in agreement with the previous experimental studies. The oxidative decomposition reactions for PC-BF4- are compared with those for the isolated PC, PC2, PC-ClO4-, and PC-PF6-.

Global determination of reaction rates and lipid turnover kinetics in Mus musculus.

Metabolism is fundamental to life, but measuring metabolic reaction rates remains challenging. Here, we applied C13 fluxomics to monitor the metabolism of dietary glucose carbon in 12 tissues, 9 brain compartments, and over 1,000 metabolite isotopologues over a 4-day period. The rates of 85 reactions surrounding central carbon metabolism are determined with elementary metabolite unit (EMU) modeling. Lactate oxidation, not glycolysis, occurs at a comparable pace with the tricarboxylic acid cycle (TCA), supporting lactate as the primary fuel. We expand the EMU framework to track and quantify metabolite flows across tissues. Specifically, multi-organ EMU simulation of uridine metabolism shows that tissue-blood exchange, not synthesis, controls nucleotide homeostasis. In contrast, isotopologue fingerprinting and kinetic analyses reveal the brown adipose tissue (BAT) having the highest palmitate synthesis activity but no apparent contribution to circulation, suggesting a tissue-autonomous synthesis-to-burn mechanism. Together, this study demonstrates the utility of dietary fluxomics for kinetic mapping in vivo and provides a rich resource for elucidating inter-organ metabolic cross talk.

Celastrol attenuates hepatitis C virus translation and inflammatory response in mice by suppressing heat shock protein 90ß.

Hepatitis C virus (HCV) infection is one of the major factors to trigger a sustained hepatic inflammatory response and hence hepatocellular carcinoma (HCC), but direct-acting-antiviral (DAAs) was not efficient to suppress HCC development. Heat shock protein 90 kDa (HSP90) is highly abundant in different types of cancers, and especially controls protein translation, endoplasmic reticulum stress, and viral replication. In this study we investigated the correlation between the expression levels of HSP90 isoforms and inflammatory response marker NLRP3 in different types of HCC patients as well as the effect of a natural product celastrol in suppression of HCV translation and associated inflammatory response in vivo. We identified that the expression level of HSP90ß isoform was correlated with that of NLRP3 in the liver tissues of HCV positive HCC patients (R2 = 0.3867, P < 0.0101), but not in hepatitis B virus-associated HCC or cirrhosis patients. We demonstrated that celastrol (3, 10, 30 µM) dose-dependently suppressed the ATPase activity of both HSP90α and HSP90ß, while its anti-HCV activity was dependent on the Ala47 residue in the ATPase pocket of HSP90ß. Celastrol (200 nM) halted HCV internal ribosomal entry site (IRES)-mediated translation at the initial step by disrupting the association between HSP90ß and 4EBP1. The inhibitory activity of celastrol on HCV RNA-dependent RNA polymerase (RdRp)-triggered inflammatory response also depended on the Ala47 residue of HSP90ß. Intravenous injection of adenovirus expressing HCV NS5B (pAde-NS5B) in mice induced severe hepatic inflammatory response characterized by significantly increased infiltration of immune cells and hepatic expression level of Nlrp3, which was dose-dependently ameliorated by pretreatment with celastrol (0.2, 0.5 mg/kg, i.p.). This study reveals a fundamental role of HSP90ß in governing HCV IRES-mediated translation as well as hepatic inflammation, and celastrol as a novel inhibitor of HCV translation and associated inflammation by specifically targeting HSP90ß, which could be developed as a lead for the treatment of HSP90ß positive HCV-associated HCC.

The effect of a disability-targeted cash transfer program on universal health coverage and universal access to education: a nationwide cohort study of Chinese children and adolescents with disabilities.

Background: To achieve improved outcomes for children and adolescents with disabilities, it is central to have universal health coverage (UHC) and universal access to education. This study investigates whether a disability-targeted cash transfer (CT) program is associated with improved access to healthcare and education for children and adolescents with disabilities. Methods: We used nationwide survey data of two million children and adolescents living with disabilities, who aged 8-15 years when entering the cohort between January 1, 2015, and December 31, 2019. With a quasi-experimental study design, we compared the outcomes between CT beneficiaries who newly received CT benefits during the study period and non-beneficiaries who were disabled but never received CT using logistic regressions after propensity score matching with a 1:1 ratio. Outcomes of interest were utilization of rehabilitation services in the past year, medical treatment if the individual had illness in the past two weeks, school attendance if not in school at the start of the study, and reported financial hardship to access these services. Findings: Of the total cohort, 368,595 children and adolescents fit the inclusion criteria, including 157,707 new CT beneficiaries and 210,888 non-beneficiaries. After matching, CT beneficiaries showed 2.27 (95% confidence interval [CI]: 2.23, 2.31) higher odds of utilizing rehabilitation services and 1.34 (95% CI: 1.23, 1.46) higher odds of getting medical treatment compared to non-beneficiaries. CT benefits were also significantly associated with less report of financial barrier to access rehabilitation services (odds ratio [OR]: 0.63, 95% CI: 0.60, 0.66) and medical treatment (OR: 0.66, 95% CI: 0.57, 0.78). Moreover, CT program was associated with higher odds of school attendance (OR: 1.99, 95% CI: 1.85, 2.15) and lower odds of reporting financial difficult to access education (OR: 0.41, 95% CI: 0.36, 0.47). Interpretation: Our results suggest that the receipt of CT was associated with improved access to health and educational resources. This finding provides supporting evidence for the identification of efficient and feasible interventions to move toward UHC and universal education under the Sustainable Development Goals. Funding: This research was supported by Sanming Project of Medicine in Shenzhen (NO.SZSM202111001), China National Natural Science Foundation (Grant/Award Number: 72274104, 71904099) and Tsinghua University Spring Breeze Fund (20213080028).

Ni(II)-Pyrazolate Framework Bearing a Metalated Schiff-Base Moiety for Electrocatalytic Hydrogen Evolution.

A robust and porous Ni-based metal-organic framework (MOF), NiL1, was assembled from Ni(II) ions and a dipyrazolate linker (L12-). A Ni(II)-anchored MOF catalyst Ni@NiL1-Sal has been successfully prepared by post-synthetic modification (PSM) condensation between NiL1 with salicylaldehyde, followed by chelation of Ni(II) ions by salicylaldimine as a secondary active site. Ni@NiL1-Sal with carbon black was found to exhibit enhanced electrocatalytic hydrogen evolution reaction (HER) performance (the smallest overpotential, 384 mV, and Tafel slope, 87 mV dec-1) when compared with primitive NiL1 and NiL1-Sal. Such improvement in HER highlights the creation of unambiguous secondary active sites as an avenue to the rational design of a functional MOF-based electrocatalyst.

Association Between Parental Education and Simultaneous Malnutrition Among Parents and Children in 45 Low- and Middle-Income Countries.

Importance: Parental education is known to be associated with the health status of parents and their offspring. However, the association between parental education and the simultaneous manifestation of multiple forms of malnutrition within households remains underinvestigated globally. Objective: To assess the association between parental education and the simultaneous manifestation of malnutrition of both parent and child (either overnutrition or undernutrition)-referred to as the double burden of malnutrition (DBM)-at the household level in mother-child and father-child pairs in low- and middle-income countries (LMICs). Design, Setting, and Participants: This cross-sectional study used data from the US Agency for International Development Demographic and Health Surveys (January 1, 2010, to December 31, 2021) to identify mother-child pairs and father-child pairs from LMICs. The eligibility criteria were as follows: (1) children aged 0 to 59 months; (2) nonpregnant mothers at the time of the survey in the sample of mother-child pairs; and (3) valid measures of the weight, height, and hemoglobin level for the child and at least 1 of their parents. Exposures: Highest level of parental education obtained and number of years of education completed. Main Outcomes and Measures: Four sets of multivariable logistic regression models were constructed to assess the association between parental education and DBM, and analysis was performed between March 10 and May 15, 2022. Results: This study included 423 340 mother-child pairs from 45 LMICs and 56 720 father-child pairs from 16 LMICs. The mean (SD) age of the mother-child pairs was 28.2 (6.1) and 1.9 (1.4) years, respectively; 48.8% of the children were female. We observed that 49.0% of mother-child pairs experienced DBM. Compared with mother-child pairs with no maternal education, higher maternal education was associated with a lower risk of DBM. For example, the odds ratio (OR) for tertiary maternal education was 0.71 (95% CI, 0.67-0.74). However, the association differed by DBM subtypes: higher maternal education was associated with a lower risk of both mothers and children being undernourished but with a higher risk of almost all DBM subtypes involving overnutrition. For example, compared with mother-child pairs with no maternal education, those with secondary education were less likely to develop simultaneous maternal and child undernutrition (OR, 0.83 [95% CI, 0.80-0.86]) but were more likely to experience simultaneous maternal and child overnutrition (OR, 2.20 [95% CI, 1.61-3.00]); similar results were observed for pairs with primary and tertiary education. The results in mother-child pairs remained consistent after controlling for paternal education. Among the father-child pairs, 26.5% had DBM, with fathers with tertiary education significantly more likely to experience simultaneous paternal overnutrition and child undernutrition (OR, 1.55 [95% CI, 1.23-1.95]) compared with pairs with no paternal education; they were also less likely to have both paternal and child undernutrition (OR, 0.70 [95% CI, 0.59-0.84]). Conclusions and Relevance: In this study, maternal education and paternal education were independently associated with DBM, and the associations differed by DBM subtypes. These findings suggest that the different risks of malnutrition faced by households with various levels of education should thus be considered in policy evaluation.

High-Quality Genome Resource of Bacillus subtilis N4, a Biological Control Agent Isolated from Phoebe bournei.

Bacillus subtilis strain N4, an endophyte isolated from the healthy leaves of Phoebe bournei, possesses an excellent biocontrol effect against stem canker of P. bournei caused by Lasiodiplodia theobromae. To understand its biocontrol mechanism, we assembled a high-quality genome of N4 using a combination of second- and third-generation sequencing methods. The N4 genome contained one circular DNA chromosome of 4,218,183 bp length with 43.5% GC content and 11 secondary metabolite biosynthesis gene clusters, including genes for subtilomycin synthesis. This high-quality genome assembly and gene annotation resource will provide better insights into the biocontrol potential of B. subtilis strain N4 against stem canker of P. bournei.

Microenvironment Regulation of Metal-Organic Frameworks to Anchor Transition Metal Ions for the Electrocatalytic Hydrogen Evolution Reaction.

Bearing triazine-centered linkers, three primitive metal-organic frameworks (MOFs) with a Zr6O4 cluster have been prepared as ZrL1 (without any branch), ZrL2 (with -F), and ZrL3 (with -SCH3). The electrocatalytic hydrogen evolution reaction (HER) by their pristine and transition metal-loaded (TM-loaded) forms was studied. It was found that the loading of TM ions could enhance the electrocatalytic power of these TM-loaded MOFs in HER, as reflected by their lower overpotentials and smaller Tafel slopes when compared with primitive MOFs. More importantly, the best electrocatalytic HER performance of ZrL3-TM among all TM-loaded MOFs studied in this work highlights the effective housing of TM ions for unambiguous active sites through cooperative coordination by triazinic N and thioether pendants. This work proposes microenvironment regulation of MOFs as an effective strategy to enhance the electrocatalytic activity of MOF materials.

Independent and cumulative effects of risk factors associated with stillbirths in 50 low- and middle-income countries: A multi-country cross-sectional study.

Background: Early identification of high-risk pregnancies could reduce stillbirths, yet remains a challenge in low- and middle-income countries (LMICs). This study aims to estimate the associations between easily observable risk factors and stillbirths, and construct a risk score which could be adopted in LMICs to identify pregnancies with high risk of stillbirths. Methods: Using the most recent Demographic and Health Surveys from 50 low- and middle-income countries (LMICs) with available data between January 1, 2010 and December 31, 2021, we analysed a total of 22 factors associated with stillbirths in a series of single-adjusted and mutually adjusted logistic regression models. Upon identification of the risk factors with the strongest associations, we constructed a risk score on the basis of the magnitude of the ß coefficient to examine the cumulative effects of risk factors on stillbirths. To assess whether the associations between risk scores and stillbirths were moderated by protective factors, we added an interaction term between the identified protective factor and risk scores to the regression model. We also conducted two sets of subgroup analyses for previous history of pregnancy and maternal age at pregnancy and four sets of supplementary analyses to test the robustness of the results. Findings: Among the 795,642 women identified for analysis with at least one pregnancy within the five years before the survey, the most recent pregnancy of 8968 (1.13%) ended as stillbirths. Using a mutually adjusted regression model, we found that the top factors showing the strongest associations with stillbirths were short maternal height (odds ratio [OR]: 1.99, 95% confidence interval [CI]: 1.48-2.67, P < 0.001), interpregnancy interval less than six months (OR: 1.84, 95% CI: 1.42-2.38, P < 0.001), previous stillbirth history (OR: 1.55, 95% CI: 1.07-2.26, P < 0.020), low maternal education (OR: 1.50, 95% CI: 1.01-2.24, P = 0.045), and lowest household wealth (OR: 1.32, 95% CI: 1.08-1.61, P = 0.008). A female household head was a protective factor with an OR of 0.71 (95% CI: 0.55-0.90, P = 0.005). Single-adjusted models, subgroup analyses, and sensitivity analyses showed generally consistent results. We also found that the odds of stillbirths increased with a larger risk score with a P trend <0.001. Compared with women without any risk factors, women with a risk score of 5 or more were 4.11 (95% CI: 2.83-5.97, P < 0.001) times more likely to have their pregnancies ending up as stillbirths. However, these associations were weakened if the head of household was female. Interpretation: Our study suggested that short maternal height, low socioeconomic status, previous stillbirth history, low maternal education, and very short interpregnancy interval had the strongest associations with stillbirths. The construction of risk scores using easily observable risk factors could be an effective way to identify high-risk pregnancies in resource-poor settings. Funding: This research was supported by Sanming Project of Medicine in Shenzhen (NO. SZSM202111001) and China National Natural Science Foundation (NO. 72203119).

Retinoic Acid Receptor Alpha (RARα) in Macrophages Protects from Diet-Induced Atherosclerosis in Mice.

Retinoic acid signaling plays an important role in regulating lipid metabolism and inflammation. However, the role of retinoic acid receptor alpha (RARα) in atherosclerosis remains to be determined. In the current study, we investigated the role of macrophage RARα in the development of atherosclerosis. Macrophages isolated from myeloid-specific Rarα-/- (RarαMac-/-) mice showed increased lipid accumulation and inflammation and reduced cholesterol efflux compared to Rarαfl/fl (control) mice. All-trans retinoic acid (AtRA) induced ATP-binding cassette subfamily A member 1 (Abca1) and Abcg1 expression and cholesterol efflux in both RarαMac-/- mice and Rarαfl/fl mice. In Ldlr-/- mice, myeloid ablation of RARα significantly reduced macrophage Abca1 and Abcg1 expression and cholesterol efflux, induced inflammatory genes, and aggravated Western diet-induced atherosclerosis. Our data demonstrate that macrophage RARα protects against atherosclerosis, likely via inducing cholesterol efflux and inhibiting inflammation.

Analysis of the network pharmacology and the structure-activity relationship of glycyrrhizic acid and glycyrrhetinic acid.

Licorice, a herbal product derived from the root of Glycyrrhiza species, has been used as a sweetening agent and traditional herbal medicine for hundreds of years. Glycyrrhizic acid (GL) and glycyrrhetinic acid (GA) are the most important active ingredients in licorice. Both GL and GA have pharmacological effects against tumors, inflammation, viral infection, liver diseases, neurological diseases, and metabolic diseases. However, they also exhibit differences. KEGG analysis indicated that licorice is involved in neuroactive ligand‒receptor interactions, while 18ß-GA is mostly involved in arrhythmogenic right ventricular cardiomyopathy. In this article, we comprehensively review the therapeutic potential of GL and GA by focusing on their pharmacological effects and working mechanisms. We systemically examine the structure-activity relationship of GL, GA and their isomers. Based on the various pharmacological activities of GL, GA and their isomers, we propose further development of structural derivatives of GA after chemical structure modification, with less cytotoxicity but higher targeting specificity. More research is needed on the clinical applications of licorice and its active ingredients.

Hepatic retinoic acid receptor alpha mediates all-trans retinoic acid's effect on diet-induced hepatosteatosis.

All-trans retinoic acid (AtRA) is an active metabolite of vitamin A that influences many biological processes in development, differentiation, and metabolism. AtRA functions through activation of retinoid acid receptors (RARs). AtRA is shown to ameliorate hepatic steatosis, but the underlying mechanism is not well understood. In this study, we investigated the role of hepatocyte RAR alpha (RARα) in mediating the effect of AtRA on hepatosteatosis in mice. Hepatocyte-specific Rarα-/- (L-Rarα-/- ) mice and their control mice were fed a chow diet, high-fat diet (HFD), or a high-fat/cholesterol/fructose (HFCF) diet. Some of the mice were also treated with AtRA. Loss of hepatocyte RARα-induced hepatosteatosis in chow-fed aged mice and HFD-fed mice. AtRA prevented and reversed HFCF diet-induced obesity and hepatosteatosis in the control mice but not in L-Rarα-/- mice. Furthermore, AtRA reduced hepatocyte fatty acid uptake and lipid droplet formation, dependent on hepatocyte RARα. Our data suggest that hepatocyte RARα plays an important role in preventing hepatosteatosis and mediates AtRA's effects on diet-induced hepatosteatosis.

Analysis of child mortality under 5 years old in Liuyang City from 2013 to 2020. / 浏阳市2013至2020年5岁以下儿童死亡状况分析.

OBJECTIVES: To provide reference basis for reducing the mortality for children under 5 years old and promote the healthy development, the mortality for children under 5 years old and the main causes for death in Liuyang City from 2013 to 2020 are analyzed. METHODS: The data of 725 cases of death for children under 5 years old in Liuyang City from 2013 to 2020 were collected.The causes and difference of death among the children were analyzed retrospectively by descriptive statistic methods. RESULTS: There were a total of 144 516 live births in Liuyang City from 2013 to 2020. The mortality for children under 5 years old was 5.01‰, for infants was 3.39‰, and for newborns was 1.63‰. The male child mortality was 5.28‰, and the female child mortality rate was 4.72‰, with significant difference (P>0.05). The mortality for children under 5 years old was seasonal fluctuation, without significant difference among seasons (P>0.05). For the past 5 years, the top 3 causes for death among children under 5 years old were preterm birth and low birth weight, congenital heart disease, and pneumonia. Before death, 341 cases (47.04%) were treated in provincial hospitals, 198 cases (27.31%) in county-level hospitals, 56 cases (7.72%) in village-level hospitals, and 130 cases (17.93%) were not treated. CONCLUSIONS: The mortality for children under 5 years old in Liuyang City is gradually reduced in the past 5 years. The main causes for death are premature birth and low birth weight, congenital heart disease and pneumonia. We should develop healthy education, improve the rate of prenatal diagnosis, promote the construction of obstetrics and paediatrics, and fundamentally reduce the mortality for children under 5 years old.

Integrated 16S rRNA gene sequencing and LC/MS-based metabolomics ascertained synergistic influences of the combination of acupuncture and NaoMaiTong on ischemic stroke.

ETHNOPHARMACOLOGICAL RELEVANCE: Acupuncture is an effective therapy for ischemic stroke, which has been widely used in China and gradually accepted in more countries and regions recently. In addition, Chinese medicine also plays an important role in stroke treatment, among which NaoMaiTong (NMT) is an example of an effective herbal formula for the treatment of stroke. A therapeutic strategy that combines acupuncture and medicine was widely used in stroke patients. However, the synergistic influences and mechanisms of combined acupuncture and medicine on ischemic stroke have not yet been entirely elucidated. AIM OF THIS STUDY: The purpose of this study is to explore whether acupuncture and medicine combination treatments can produce synergism by using NMT, a clinically effective Chinese medicinal formula for the treatment of ischemic stroke for decades and has been demonstrated to be effective against ischemic brain injury, as a probe. Meanwhile, the potential mechanisms were investigated via cecal microbiome and plasma metabolomics to provide more strategies and basis for acupuncture-medicine combination for stroke. MATERIALS AND METHODS: Adopted middle-cerebral artery occlusion/reperfusion (MCAO/R) rat models, the effect for the stroke of the combination treatment consisting of acupuncture and NMT was evaluated by detecting neurological issues, cerebral infarct dimensions, levels of inflammatory factors (IL-6, IL-1ß, TNF-α) and oxidative stress factors (SOD, MDA) and brain-derived neurotrophic factor (BDNF). Subsequently,16S rRNA gene sequencing and LC/MS-based metabolomic analysis were utilized to explore the characteristics of cecal-contents microecology and plasma metabolic profile, respectively. Finally, the correlation between intestinal microecological characteristics and plasma metabolic characteristics was analyzed to explore the potential mechanism of the acupuncture-NMT combination. RESULTS: The efficacy of acupuncture-NMT therapy was more effective than a single treatment on ischemic stroke, with more effectively reduced infarct sizes, improved neurobehavioral deficits, and alleviated oxidative stress and inflammatory responses. Besides, the combination therapy not only adjusted gut microbiota disturbances by enriching species diversity, reducing the abundance of pathogenic bacteria (such as Escherichia-Shaigella), as well as increasing the abundance of beneficial bacteria (such as Turicibacter, Bifidobacterium), but also improved metabolic disorders by reversing metabolite plasma levels to normality. The results of the correlation analysis demonstrated a significant association between intestinal microbiota and plasma metabolic profile, especially the strong correlation of Turicibacter and isoflavones phyto-estrogens metabolites. CONCLUSION: The combination of acupuncture and NMT could produce synergism, suggesting acupuncture-medicine combination therapy might be more conducive to the recovery of ischemic stroke. And the potential mechanism was probably related to the mediation of intestinal microecology and plasma metabolism. Turicibacter and isoflavones phyto-estrogens metabolites might be the targets for acupuncture-NMT combination for stroke. Our current findings could provide a potential therapeutic strategy against ischemic stroke.

Hepatocyte ATF3 protects against atherosclerosis by regulating HDL and bile acid metabolism.

Activating transcription factor (ATF)3 is known to have an anti-inflammatory function, yet the role of hepatic ATF3 in lipoprotein metabolism or atherosclerosis remains unknown. Here we show that overexpression of human ATF3 in hepatocytes reduces the development of atherosclerosis in Western-diet-fed Ldlr-/- or Apoe-/- mice, whereas hepatocyte-specific ablation of Atf3 has the opposite effect. We further show that hepatic ATF3 expression is inhibited by hydrocortisone. Mechanistically, hepatocyte ATF3 enhances high-density lipoprotein (HDL) uptake, inhibits intestinal fat and cholesterol absorption and promotes macrophage reverse cholesterol transport by inducing scavenger receptor group B type 1 (SR-BI) and repressing cholesterol 12α-hydroxylase (CYP8B1) in the liver through its interaction with p53 and hepatocyte nuclear factor 4α, respectively. Our data demonstrate that hepatocyte ATF3 is a key regulator of HDL and bile acid metabolism and atherosclerosis.