SMYD2-Methylated PPARγ Facilitates Hypoxia-Induced Pulmonary Hypertension by Activating Mitophagy.

BACKGROUND: Hyperproliferation of pulmonary arterial smooth muscle cells (PASMCs) and consequent pulmonary vascular remodeling are the crucial pathological features of pulmonary hypertension (PH). Protein methylation has been shown to be critically involved in PASMC proliferation and PH, but the underlying mechanism remains largely unknown. METHODS: PH animal models were generated by treating mice/rats with chronic hypoxia for 4 weeks. SMYD2-vTg mice (vascular smooth muscle cell-specific suppressor of variegation, enhancer of zeste, trithorax and myeloid Nervy DEAF-1 (deformed epidural auto-regulatory factor-1) domain-containing protein 2 transgenic) or wild-type rats and mice treated with LLY-507 (3-cyano-5-{2-[4-[2-(3-methylindol-1-yl)ethyl]piperazin-1-yl]-phenyl}-N-[(3-pyrrolidin-1-yl)propyl]benzamide) were used to investigate the function of SMYD2 (suppressor of variegation, enhancer of zeste, trithorax and myeloid Nervy DEAF-1 domain-containing protein 2) on PH development in vivo. Primary cultured rat PASMCs with SMYD2 knockdown or overexpression were used to explore the effects of SMYD2 on proliferation and to decipher the underlying mechanism. RESULTS: We demonstrated that the expression of the lysine methyltransferase SMYD2 was upregulated in the smooth muscle cells of pulmonary arteries from patients with PH and hypoxia-exposed rats/mice and in the cytoplasm of hypoxia-induced rat PASMCs. More importantly, targeted inhibition of SMYD2 by LLY-507 significantly attenuated hypoxia-induced pulmonary vascular remodeling and PH development in both male and female rats in vivo and reduced rat PASMC hyperproliferation in vitro. In contrast, SMYD2-vTg mice exhibited more severe PH phenotypes and related pathological changes than nontransgenic mice after 4 weeks of chronic hypoxia treatment. Furthermore, SMYD2 overexpression promoted, while SMYD2 knockdown suppressed, the proliferation of rat PASMCs by affecting the cell cycle checkpoint between S and G2 phases. Mechanistically, we revealed that SMYD2 directly interacted with and monomethylated PPARγ (peroxisome proliferator-activated receptor gamma) to inhibit the nuclear translocation and transcriptional activity of PPARγ, which further promoted mitophagy to facilitate PASMC proliferation and PH development. Furthermore, rosiglitazone, a PPARγ agonist, largely abolished the detrimental effects of SMYD2 overexpression on PASMC proliferation and PH. CONCLUSIONS: Our results demonstrated that SMYD2 monomethylates nonhistone PPARγ and inhibits its nuclear translocation and activation to accelerate PASMC proliferation and PH by triggering mitophagy, indicating that targeting SMYD2 or activating PPARγ are potential strategies for the prevention of PH.

Protein Kinase A Is a Master Regulator of Physiological and Pathological Cardiac Hypertrophy.

BACKGROUND: The sympathoadrenergic system and its major effector PKA (protein kinase A) are activated to maintain cardiac output coping with physiological or pathological stressors. If and how PKA plays a role in physiological cardiac hypertrophy (PhCH) and pathological CH (PaCH) are not clear. METHODS: Transgenic mouse models expressing the PKA inhibition domain (PKAi) of PKA inhibition peptide alpha (PKIalpha)-green fluorescence protein (GFP) fusion protein (PKAi-GFP) in a cardiac-specific and inducible manner (cPKAi) were used to determine the roles of PKA in physiological CH during postnatal growth or induced by swimming, and in PaCH induced by transaortic constriction (TAC) or augmented Ca2+ influx. Kinase profiling was used to determine cPKAi specificity. Echocardiography was used to determine cardiac morphology and function. Western blotting and immunostaining were used to measure protein abundance and phosphorylation. Protein synthesis was assessed by puromycin incorporation and protein degradation by measuring protein ubiquitination and proteasome activity. Neonatal rat cardiomyocytes (NRCMs) infected with AdGFP (GFP adenovirus) or AdPKAi-GFP (PKAi-GFP adenovirus) were used to determine the effects and mechanisms of cPKAi on myocyte hypertrophy. rAAV9.PKAi-GFP was used to treat TAC mice. RESULTS: (1) cPKAi delayed postnatal cardiac growth and blunted exercise-induced PhCH; (2) PKA was activated in hearts after TAC due to activated sympathoadrenergic system, the loss of endogenous PKIα (PKA inhibition peptide α), and the stimulation by noncanonical PKA activators; (3) cPKAi ameliorated PaCH induced by TAC and increased Ca2+ influxes and blunted neonatal rat cardiomyocyte hypertrophy by isoproterenol and phenylephrine; (4) cPKAi prevented TAC-induced protein synthesis by inhibiting mTOR (mammalian target of rapamycin) signaling through reducing Akt (protein kinase B) activity, but enhancing inhibitory GSK-3α (glycogen synthase kinase-3α) and GSK-3ß signals; (5) cPKAi reduced protein degradation by the ubiquitin-proteasome system via decreasing RPN6 phosphorylation; (6) cPKAi increased the expression of antihypertrophic atrial natriuretic peptide (ANP); (7) cPKAi ameliorated established PaCH and improved animal survival. CONCLUSIONS: Cardiomyocyte PKA is a master regulator of PhCH and PaCH through regulating protein synthesis and degradation. cPKAi can be a novel approach to treat PaCH.

Comparative Genomic Analysis Identifies Great-Ape-Specific Structural Variants and Their Evolutionary Relevance.

During the origin of great apes about 14 million years ago, a series of phenotypic innovations emerged, such as the increased body size, the enlarged brain volume, the improved cognitive skill, and the diversified diet. Yet, the genomic basis of these evolutionary changes remains unclear. Utilizing the high-quality genome assemblies of great apes (including human), gibbon, and macaque, we conducted comparative genome analyses and identified 15,885 great ape-specific structural variants (GSSVs), including eight coding GSSVs resulting in the creation of novel proteins (e.g., ACAN and CMYA5). Functional annotations of the GSSV-related genes revealed the enrichment of genes involved in development and morphogenesis, especially neurogenesis and neural network formation, suggesting the potential role of GSSVs in shaping the great ape-shared traits. Further dissection of the brain-related GSSVs shows great ape-specific changes of enhancer activities and gene expression in the brain, involving a group of GSSV-regulated genes (such as NOL3) that potentially contribute to the altered brain development and function in great apes. The presented data highlight the evolutionary role of structural variants in the phenotypic innovations during the origin of the great ape lineage.

Studies on the Coordination Patterns of Diamine-Bridged Tetraphenoxy Ligands with Group 3 and 4 Metals.

Alkane elimination reactions between the diamino- and dianilino-bridged tetrakis(phenolate) proligands 1a,b-H4 and precursors M(CH2SiMe3)3(THF)2, M(CH2C6H4-o-NMe2)3 (M = Sc and Y), and Hf(CH2Ph)4 were investigated. The diamino-bridged 1a-H4 afforded nonsymmetric complex 2a-Y2 incorporating two metal centers in different coordination environments. This one and other dinuclear compounds 2b-Sc2, 2a-Hf2, and 2b-Hf2 were characterized by NMR spectroscopy, elemental analysis, and X-ray diffraction study (for 2a-Y2 and 2b-Sc2) and turned out to be symmetric in solution. Compound 2a-Y2, upon treatment with 2 equiv of 2-phenylpyridine, afforded symmetric bis(aryl) product 3a-Y2, which was authenticated by NMR spectroscopy and X-ray crystallography. The mechanism of its formation was studied by DFT computations and presumably involves a cooperative reorganization process within the nonsymmetric parent 2a-Y2 to afford a symmetric isomer prior to its reaction with 2-phenylpyridine.

Cognitive benefits of folic acid, docosahexaenoic acid and a combination of both nutrients in mild cognitive impairment; possible alterations though mitochondrial function and DNA damage.

INTRODUCTION: It is uncertain whether folic acid (FA) combined with docosahexaenoic acid (DHA) could improve cognitive performance. This study evaluated the effects of a 12-month FA and DHA supplementation, in combination or alone, on cognitive function, DNA oxidative damage, and mitochondrial function in participants with mild cognitive impairment (MCI). METHODS: This randomized, double-blind, placebo-controlled trial recruited MCI participants aged 60 years and older. Two hundred and eighty participants were randomly divided in equal proportion into four groups: FA+DHA (FA 800µg/d + DHA 800mg/d), FA (800µg/d), DHA (800mg/d), and placebo groups daily orally for 12 months. The primary outcome was cognitive function evaluated by the Wechsler Adult Intelligence Scale-Revised (WAIS-RC). Cognitive tests and blood mechanism-related biomarkers were determined at baseline and 12 months. RESULTS: During the 12-month follow, scores of full intelligence quotient (FIQ) (ßDHA: 1.302, 95%CI: 0.615, 1.990, p < 0.001; ßFA: 1.992, 95%CI: 1.304, 2.679, p < 0.001; ßFA+DHA: 2.777, 95%CI: 2.090, 3.465, p < 0.001), verbal intelligence quotient, and some subtests of the WAIS-RC were significantly improved in FA+DHA and single intervention groups compared to the placebo group. Moreover, the FA and DHA intervention combination was superior to either intervention alone (p < 0.001). Meanwhile, FA, DHA and their combined use significantly decreased 8-OHdG level and increased mitochondrial DNA copy number compared to the placebo (p < 0.05). CONCLUSIONS: Supplementation of FA and DHA, alone or combined, for 12 months can improve cognitive function in MCI participants, possibly through mitigating DNA oxidative damage and enhancing mitochondrial function. Combined supplementation may provide more cognitive benefit than supplementation alone. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000034351. Registered 3 July 2020 - Retrospectively registered, https://www.chictr.org.cn/showproj.html?proj=53345.

Associations of types of grains and lifestyle with all-cause mortality among Chinese adults aged 65 years or older: a prospective cohort study.

BACKGROUND: Little is known on the association of types of grains with mortality and the moderating effect of lifestyle on this association. This study aims to evaluate the single or joint associations of types of grains and lifestyle with all-cause mortality among Chinese older adults. METHODS: Data were derived from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) from 1998 to 2018. Subjects aged ≥ 65 years were eligible. The types of grains included wheat, total rice, and coarse cereals. Lifestyle was derived using smoking, alcohol consumption, physical activity, and dietary pattern. All-cause mortality was the primary outcome. RESULTS: This study included 30275 participants with a mean age 87 ± 11 years and documented 19261 deaths during a mean follow-up of 4.8 years. Compared to wheat, in those with healthy and intermediate lifestyle, total rice was associated with a 13% (HR: 0.87, 95% CI 0.80, 0.93) and 6% (HR: 0.94, 95% CI 0.90, 1.00) lower risk of mortality, respectively, and coarse cereals were associated with a 14% (HR: 0.86, 95% CI 0.74, 1.00) and 12% (HR: 0.88, 95% CI 0.79, 0.97) lower risk of mortality, respectively. Meanwhile, an increase per SD in intakes of wheat and coarse cereals was associated with a 10% (HR: 1.10, 95% CI 1.03, 1.18) and 25% (HR: 1.25, 95% CI 1.08, 1.44) higher mortality rate in those with healthy lifestyle, and a 13% (HR: 1.13, 95% CI 1.08, 1.19) and 29% (HR: 1.29, 95% CI 1.17, 1.44) higher mortality in females but not males. In addition, a U-shaped association of intake of total grains with all- cause mortality was observed (P for non-linearity = 0.002), and a J-shaped association of intake of total rice with all- cause mortality was observed (P for non-linearity = 0.003). CONCLUSIONS: Specific types of grains and lifestyle were separately or jointly associated with all-cause mortality. Compared to wheat, total rice and coarse cereals were advanced grains for participants with a relatively healthy lifestyle. Intake of total rice was related to all-cause mortality in a dose-response manner. Therefore, a combination of intermediate intake of total rice and healthy lifestyle should be encouraged in older adults.

Synthesis of Mono- and Dinuclear Aluminum Complexes Bearing Aromatic Amino-Phenolato Ligands: A Comparative Study in the Ring-Opening Polymerization of Cyclohexene Oxide.

Dinuclear aluminum methyl complexes bearing aromatic diamine-bridged tetra(phenolato) ligands and the mononuclear aluminum methyl complex with the phenylamine-bridged bis(phenolato) ligand have been synthesized and characterized. Structure determination revealed that the Al-Al distances in these dinuclear aluminum complexes are tunable by the choice of the suitable aromatic backbone of the diamine-bridged tetra(phenolato) ligands. The catalytic behaviors of these mono- and dinuclear aluminum complexes for cyclohexene oxide (CHO) polymerization were investigated. The activities of these dinuclear Al complexes were observed to increase with the decrease of Al-Al distances, and the dinuclear Al complexes appeared to have better catalytic activity than the mononuclear Al complex, even if the Al-Al distance is as long as 9.401 Å. Dinuclear aluminum complex 2, with the shortest Al-Al distance (7.236 Å), showed the highest activity toward CHO polymerization with TOFs up to 6460 h-1 in neat CHO at 30 °C. Furthermore, comparative kinetic studies revealed that the polymerization is first-order for CHO concentration, and the reaction orders for initiator concentration are different for the mono- and dinuclear Al complexes. The polymerization mechanism study revealed that both the methyl and phenolate groups were involved in the initiation process.

Folic Acid Inhibits Aging-Induced Telomere Attrition and Apoptosis in Astrocytes In Vivo and In Vitro.

Folic acid (FA) has been reported to inhibit astrocyte apoptosis and improve aging-induced disorders; however, its role in telomere attrition remains unclear. In present study, 4-month-old senescence-accelerated mouse prone 8 (SAMP8) mice were assigned to four treatment groups for the in vivo experiment: FA-deficient diet (FA-D) group, FA-normal diet (FA-N) group, low FA-supplemented diet (FA-L) group, and high FA-supplemented diet (FA-H) group. These mice were euthanized when 10 months old. There was also a young SAMP8 (4 months old) control group (Con-Y) fed with FA-normal diet. In in vitro study, primary cultures of astrocytes from hippocampus and cerebral cortex were incubated for five generations with various concentrations of FA (0-40 µM) and were assigned to five groups: FA 0 µM (generation 5), FA 10 µM (generation 5), FA 20 µM (generation 5), FA 40 µM (generation 5), and FA 10 µM (generation 1). The results showed that FA supplementation inhibited aging-induced astrocytosis, astrocyte apoptosis, neurodegeneration, and prevented telomere attrition in hippocampus and cortex of SAMP8 mice. FA supplementation also decreased apoptosis and telomere attrition, and increased telomerase activity, in primary cultures of astrocytes. These results showed that it may be one of the mechanisms that FA inhibiting aging-induced apoptosis of astrocyte by alleviating telomere attrition.

Association of dietary inflammatory index and leukocyte telomere length with mild cognitive impairment in Chinese older adults.

BACKGROUND: There are minimal data on the relationship between DII and MCI in an elderly Chinese population and no research has assessed the potential effect of LTL. OBJECTIVE: We investigated the association between DII and MCI while taking into account the potential effect of LTL. METHODS: This cross-sectional study included 3,386 participants aged ≥ 60 years of age from the Tianjin Elderly Nutrition and Cognition Cohort study. DII score was constructed based on a validated self-administered food frequency questionnaire was calculated based on the method developed by Shivappa et al. LTL was measured by quantitative real-time polymerase chain reaction. Multivariable logistic regression analysis was used to analyze the association between DII, LTL and MCI. Moreover, mediation analysis was employed to test the mediation effect of LTL on the total effect of DII on MCI. RESULTS: Compared with the participants in the lowest tertiles of LTL and DII score, the odds ratios (ORs) of MCI in the highest tertiles were 0.386(95% CI: 0.281-0.529) and 1.650 (95% CI: 1.232-2.209), respectively. The significant association between DII score and MCI persisted after further adjusting for LTL (OR: 1.595; 95% CI: 1.189-2.140). The link between DII score and MCI was mediated partially by LTL (ßindirect effect= -0.008, P<0.05). CONCLUSION: High DII score was positively associated with MCI prevalence in an elderly Chinese population and the link between DII scores and MCI seemed to be mediated partially by LTL.

Bone-targeting exosome nanoparticles activate Keap1 / Nrf2 / GPX4 signaling pathway to induce ferroptosis in osteosarcoma cells.

BACKGROUND: In recent years, the development of BMSCs-derived exosomes (EXO) for the treatment of osteosarcoma (OS) is a safe and promising modality for OS treatment, which can effectively deliver drugs to tumor cells in vivo. However, the differences in the drugs carried, and the binding of EXOs to other organs limit their therapeutic efficacy. Therefore, improving the OS-targeting ability of BMSCs EXOs and developing new drugs is crucial for the clinical application of targeted therapy for OS. RESULTS: In this study, we constructed a potential therapeutic nano platform by modifying BMSCs EXOs using the bone-targeting peptide SDSSD and encapsulated capreomycin (CAP) within a shell. These constructed nanoparticles (NPs) showed the ability of homologous targeting and bone-targeting exosomes (BT-EXO) significantly promotes cellular endocytosis in vitro and tumor accumulation in vivo. Furthermore, our results revealed that the constructed NPs induced ferroptosis in OS cells by prompting excessive accumulation of reactive oxygen species (ROS), Fe2+ aggregation, and lipid peroxidation and further identified the potential anticancer molecular mechanism of ferroptosis as transduced by the Keap1/Nrf2/GPX4 signaling pathway. Also, these constructed NP-directed ferroptosis showed significant inhibition of tumor growth in vivo with no significant side effects. CONCLUSION: These results suggest that these constructed NPs have superior anticancer activity in mouse models of OS in vitro and in vivo, providing a new and promising strategy for combining ferroptosis-based chemotherapy with targeted therapy for OS.

Telomere and mitochondria mediated the association between dietary inflammatory index and mild cognitive impairment: A prospective cohort study.

BACKGROUND: Diet and chronic inflammation might play a major role in the pathogenesis of mild cognitive impairment (MCI). In addition, peripheral blood leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn) might mediate the relationship between inflammation and MCI risk. The purpose of the present study is to evaluate whether inflammatory potential of diet assessed by dietary inflammatory index (DII), chronic inflammation, peripheral blood LTL, and mtDNAcn were associated with the risk of MCI. RESULTS: A population-based cohort study was conducted with a total of 2944 participants. During a median follow-up of 2 years, 438 (14.90%) individuals were new-onset MCI. After adjustment, a higher score of DII (hazard ratio [HR]: 1.056, 95% CI: 1.005, 1.109), a higher log systemic immune inflammation index (SII) (HR: 1.333, 95% CI: 1.089, 1.633) and log system inflammation response index (SIRI) (HR: 1.487, 95% CI: 1.024, 2.161) predicted elevated risk of MCI. An increased mtDNAcn (HR: 0.843, 95% CI: 0.712, 0.997), but not LTL, predicted a decreased risk of MCI. Negative associations of log SII with LTL (ß:-0.359, 95% CI: -0.445, -0.273) and mtDNAcn (ß:-0.048, 95% CI: -0.090, -0.006) were found. Additionally, negative associations of log SIRI with LTL (ß: -0.035, 95% CI: -0.052, -0.017) and mtDNAcn (ß:-0.136, 95% CI: -0.216, -0.056) were also found. Path analysis suggested that SIRI, LTL, and mtDNAcn, in series, have mediation roles in the association between DII score and MCI risk. CONCLUSIONS: Higher DII, SII, and SIRI might predict a greater risk of MCI, while a longer LTL and an increased mtDNAcn were linked to a reduced risk of MCI among the older population. LTL and mtDNAcn could play mediation roles in the association between DII and MCI risk.

New Monoterpene Glycoside Paeoniflorin Derivatives as NO and IL-1ß Inhibitors: Synthesis and Biological Evaluation.

Several monoterpene glycoside compounds were extracted from Paeonia lactiflora Pall. Among them, paeoniflorin, a water-soluble monoterpene glycoside found in the root of Paeonia lactiflora Pall, exhibits excellent antioxidant pharmacological functions. Initially, Sc(CF3SO3)3 was employed as the catalyst for paeoniflorin's dehydration and rearrangement reactions with alcohols. Subsequently, structural modifications were performed on paeoniflorin through a series of responses, including acetylation, deacetylation, and debenzoylation, ultimately yielding 46 monoterpene glycoside derivatives. The potential inhibitory effects on the pro-inflammatory mediators interleukin-1 beta (IL-1ß) and nitric oxide (NO) were assessed in vitro. The results revealed that compounds 29 and 31 demonstrated notable inhibition of NO production, while eight derivatives (3, 8, 18, 20, 21, 29, 34, and 40) displayed substantial inhibitory effects on the secretion of IL-1ß. Computational research was also undertaken to investigate the binding affinity of the ligands with the target proteins. Interactions between the proteins and substrates were elucidated, and corresponding binding energies were calculated accordingly. The findings of this study could provide valuable insights into the design and development of novel anti-inflammatory agents with enhanced pharmacological properties.

Role of ceRNA network in inflammatory cells of rheumatoid arthritis. / CeRNAç½‘ç»œåœ¨ç±»é£Žæ¹¿å ³èŠ‚ç‚Žçš„ç‚Žç—‡ç»†èƒžä¸­çš„ä½œç”¨.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease caused by inflammatory cells. Various inflammatory cells involved in RA include fibroblast-like synoviocytes, macrophages, CD4+T-lymphocytes, B lymphocytes, osteoclasts and chondrocytes. The close interaction between various inflammatory cells leads to imbalance of immune response and disorder of the expression of mRNA in inflammatory cells. It helps to drive production of pro-inflammatory cytokines and stimulate specific antigen-specific T- and B-lymphocytes to produce autoantibodies which is an important pathogenic factor for RA. Competing endogenous RNA (ceRNA) can regulate the expression of mRNA by competitively binding to miRNA. The related ceRNA network is a new regulatory mechanism for RNA interaction. It has been found to be involved in the regulation of abnormal biological processes such as proliferation, apoptosis, invasion and release of inflammatory factors of RA inflammatory cells. Understanding the ceRNA network in 6 kinds of RA common inflammatory cells provides a new idea for further elucidating the pathogenesis of RA, and provides a theoretical basis for the discovery of new biomarkers and effective therapeutic targets.

TBC1D21 is an essential factor for sperm mitochondrial sheath assembly and male fertility‡.

During spermiogenesis, the formation of the mitochondrial sheath is critical for male fertility. The molecular processes that govern the development of the mitochondrial sheath remain unknown. Whether TBC1D21 serves as a GTPase-activating protein (GAP) for GTP hydrolysis in the testis is unclear, despite recent findings indicating that it collaborates with numerous proteins to regulate the formation of the mitochondrial sheath. To thoroughly examine the property of TBC1D21 in spermiogenesis, we applied the CRISPR/Cas9 technology to generate the Tbc1d21-/- mice, Tbc1d21D125A R128K mice with mutation in the GAP catalytic residues (IxxDxxR), and Tbc1d21-3xFlag mice. Male Tbc1d21-/- mice were infertile due to the curved spermatozoa flagella. In vitro fertilization is ineffective for Tbc1d21-/- sperm, although healthy offspring were obtained by intracytoplasmic sperm injection. Electron microscopy revealed aberrant ultrastructural changes in the mitochondrial sheath. Thirty-four Rab vectors were constructed followed by co-immunoprecipitation, which identified RAB13 as a novel TBC1D21 binding protein. Interestingly, infertility was not observed in Tbc1d21D125A R128K mice harboring the catalytic residue, suggesting that TBC1D21 is not a typical GAP for Rab-GTP hydrolysis. Moreover, TBC1D21 was expressed in the sperm mitochondrial sheath in Tbc1d21-3xFlag mice. Immunoprecipitation-mass spectrometry demonstrated the interactions of TBC1D21 with ACTB, TPM3, SPATA19, and VDAC3 to regulate the architecture of the sperm midpiece. The collective findings suggest that TBC1D21 is a scaffold protein required for the organization and stabilization of the mitochondrial sheath morphology.

Apolipoprotein E polymorphism ε4-stratified longitudinal association between daytime naps, sleep apnea and mild cognitive impairment: A prospective cohort study.

BACKGROUND AND PURPOSE: Sleep characteristics, including taking a nap and sleep apnea, have been proven to have effects on cognitive function, and apolipoprotein E polymorphism ε4 (APOEε4) has been confirmed to be a risk factor for mild cognitive impairment (MCI), but epidemiological studies linking sleep characteristics and APOEε4 are scarce. We aimed to explore the longitudinal association between sleep characteristics and MCI in an overall cohort, in APOEε4 carriers and in APOEε4 non-carriers. METHODS: We included 3053 older adults from the Tianjin Elderly Nutrition and Cognition Cohort (TENCC) study, recruited from March 2018 to June 2019, and followed up from March 2021 to June 2021. All participants underwent detailed neuropsychological evaluation that allowed psychometric MCI classification. Information on self-reported sleep characteristics was gathered via face-to-face interviews. Crude and multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard regression models. RESULTS: In the multivariable-adjusted models, taking a nap at noon was associated with decreased risk of MCI in all participants (yes vs. no: HR 0.723, 95% CI 0.592, 0.883) and in APOEε4 non-carriers (yes vs. no: HR 0.719, 95% CI 0.576, 0.897). Sleep apnea was associated with increased risk of MCI in all participants (vs. good: HR 2.213, 95% CI 1.171, 4.180) and in APOEε4 non-carriers (vs. good: HR 2.217, 95% CI 1.085, 4.529). CONCLUSIONS: This study suggests that taking a nap at noon might be a potential protective factor against development of MCI in APOEε4 non-carriers, and sleep apnea might be associated with increased incidence of MCI in APOEε4 non-carriers.

Circulating folate concentrations and the risk of mild cognitive impairment: A prospective study on the older Chinese population without folic acid fortification.

BACKGROUND: The longitudinal association between serum folate concentrations and the risk of cognitive impairment remains unclear in populations with low folate levels. We examined the association between serum folate concentrations and mild cognitive impairment (MCI) in older adults in China, where mandatory fortification of foods with folic acid has not been implemented. We further explored if homocysteine (Hcy) and leukocyte telomere length (LTL) mediate the association between serum folate and MCI. METHODS: We performed a longitudinal analysis of 3974 participants aged ≥60 years from the Tianjin Elderly Nutrition and Cognition (TENC) cohort study. The associations between serum folate level and the risk of cognitive impairment overall and stratified by apolipoprotein E (APOE) ε4 genotypes were evaluated using multivariable Cox proportional hazards models. The mediating effects of Hcy and LTL on the folate-MCI association were explored via a path analysis approach. RESULTS: Within a 3-year follow-up, we documented 560 incident MCI cases. After multivariable adjustment, higher serum folate concentrations were associated with lower incidence of MCI, with hazard ratios (95% confidence interval) across quartiles of folate (from lowest to highest concentrations) of 1.00 (reference), 0.66 (0.52, 0.83), 0.57 (0.45, 0.73), 0.66 (0.52, 0.84), respectively (p for trend <0.001). In mediation analyses, the status of serum folate deficiency and MCI were correlated via two intermediary pathways, Hcy and Hcy-telomere (p < 0.05). CONCLUSIONS: Lower folate concentrations, independently of APOE genotype, were associated with increased risk of MCI among elderly Chinese people, a population with relatively low folate intake. Our data were compatible with the mediation hypothesis that the association between folate status and MCI was mediated by Hcy and LTL.

Association between methionine cycle metabolite-related diets and mild cognitive impairment in older Chinese adults: a population-based observational study.

BACKGROUND: Homocysteine (Hcy) and folate, involved in a common metabolic pathway supplying essential methyl groups for DNA and protein synthesis, have been found to be associated with cognitive function. Moreover, diet may influence methionine cycle metabolites (MCM) as well as mild cognitive impairment (MCI), but MCM-related dietary patterns are unclear in an older population. OBJECTIVE: The study aimed to identify MCM-related dietary patterns of older Chinese adults, and examine their association with the prevalence of MCI in a large population-based study. METHODS: This study included 4457 participants ≥ 60 years of age from the Tianjin Elderly Nutrition and Cognition Cohort study. Dietary data were collected using a valid self-administered food frequency questionnaire, and factor analysis was used to identify major dietary patterns in the population. MCM-based dietary patterns were derived using reduced rank regression (RRR) based on serum folate and Hcy as response variables. RESULTS: Compared with the participants in the lowest quartile of vegetarian pattern and processed foods pattern, the odds ratios (ORs) of MCI in the highest quartile were 0.72 (95% CI 0.53-0.98) and 1.39 (95% CI 1.03-1.88), respectively. In the MCM-based dietary patterns derived using RRR, the ORs for MCI for the highest quartile of MCM patterns I and II were 0.58 (95% CI 0.44-0.78) and 1.38 (95% CI 1.04-1.83), respectively, compared with participants in the lower quartile. CONCLUSIONS: Findings from this large population-based study suggested that adopting an MCM-related dietary pattern, especially avoiding processed foods, can decrease the occurrence of MCI.

Baseline folic acid status affects the effectiveness of folic acid supplements in cognitively relevant outcomes in older adults: a systematic review.

BACKGROUND: Folic acid was investigated for decreased concentrations of the same type of cysteine (Hcy), which is considered a risk factor for Alzheimer's disease. However, the conclusions are inconsistent, while supplementing elders with different folic acid states. METHOD: The PubMed, Science Network and EMBASE databases were searched for randomized controlled trials published over the past decade; The 11/485 study was included on the basis of pre-defined criteria. Cognitive-related results, including cognitive function and brain atrophy, were measured using cognitive scales and magnetic resonance imaging. RESULTS: Significant cognitive benefits were reported in individuals with incomplete folic acid (n s 4); However, individuals with sufficient folic acid (n s 2) do not benefit from supplements, evaluated by the cognitive scale. On the other hand, a significant positive association was established in the participants of plasma Hcy, but the folic acid state was sufficient (n s 2). One study reported that folic acid supplements did not provide any benefit, but folic acid status data were missing. In addition, folic acid supplementation also improves brain atrophy (n s 2). CONCLUSION: Baseline folic acid status may be a potential factor affecting the results of cognitive function folic acid supplementation in older adults. Older people with insufficient folic acid will benefit from folic acid supplementation.

Research on the governance of campus bullying and prevention mechanism of students' mental health problem.

At present, juvenile campus bullying is seriously threatening their own physical and mental health, campus security and even social security, making social instability factors increase. It is to explore how to reduce and avoid the frequent occurrence of campus bullying and provide effective countermeasures for the governance of campus bullying. The relevant research on the governance of campus bullying and the prevention mechanism of students' mental health problems is conducted from the judicial perspective. The methods of literature survey and questionnaire are employed to investigate and analyze the campus bullying problem governance and the influencing factors of students' mental health. The results show that the causes of campus bullying are not only due to external factors, but also due to internal factors from students themselves. The principle of timely prevention and comprehensive management must be followed in the construction of the multigovernance system of campus bullying. It suggests that there are many factors for the occurrence of campus bullying. Only by finding out the root cause of the problem and taking measures to deal with it can the occurrence of campus bullying be effectively avoided.

Carbon-Bridged 1,2-Bis(2-thienyl)ethylene: An Extremely Electron Rich Dithiophene Building Block Enabling Electron Acceptors with Absorption above 1000 nm for Highly Sensitive NIR Photodetectors.

The emerging donor-acceptor-donor (A-D-A)-type nonfullerene acceptors (NFAs) featuring near-infrared (NIR) photoresponsivity have greatly boosted the development of organic photovoltaics (OPVs) and display great potential for sensitive NIR organic photodetectors (OPDs). However, NIR NFAs with absorption above 1000 nm, which is of great importance for application in NIR OPDs for bioimaging, remote communication, night surveillance, etc., are still rare due to the scarcity of strong electron-rich cores. We report herein a new dithiophene building block, namely PDT, which exhibits the strongest electron-donating ability among the widely used dithiophene building blocks. By applying PDT and PDTT as the electron-donating cores and DFIC as the electron-accepting terminals, we developed two new NIR electron acceptors, PDTIC-4F and PDTTIC-4F, with optical absorptions up to 1030 nm, surpassing that of the well-known O6T-4F acceptor. In comparison with the carbon-oxygen-bridged core COi8 in O6T-4F, the synthetic complexity of PDT and PDTT is significantly reduced. Conventional OPV devices based on PM6:PDTTIC-4F display power conversion efficiencies (PCEs) of up to 10.70% with a broad external quantum efficiency (EQE) response from the ultraviolet-visible to the infrared, leading to a high short-circuit current density (Jsc) of 25.90 mA cm-2. Encouraged by these results, we investigated inverted PM6:PDTTIC-4F-based OPD devices by suppressing the dark current via modulation of the film thickness. The optimal OPD device exhibits compelling performance metrics that can compete with those of commercial silicon photodiodes: a record responsivity of 0.55 A W-1 (900 nm) among photodiode-type OPDs and excellent shot-noise-limited specific detectivity (Dsh*) of over 1013 jones.