No abstract

Background/Aims: Atrazine (ATR) is a broad-spectrum herbicide in wide use around the world. However, ATR is neurotoxic and can cause cell death in dopaminergic neurons, leading to neurodegenerative disorders. Autophagy is the basic cellular catabolic process involving the degradation of proteins and damaged organelles. Studies have shown that certain plant compounds can induce autophagy and prevent neuronal cell death. This prompted us to investigate plant compounds that might reduce the neurotoxic effects of ATR. Methods: By CCK-8 and flow cytometry, we tested the ability of five candidate compounds—isoflavones, resveratrol, quercetin, curcumin, and green tea polyphenols—to protect cells from ATR. Changes in the expression of tyrosine hydroxylase (TH) and brain-expressed X-linked 2 (BEX2), autophagy-related proteins and key factors in mTOR signaling, were detected by Western blotting. Results: Isoflavones had the strongest activity against ATR-induced neuronal apoptosis. ATR reduced the expression of TH and BEX2, whereas isoflavones increased TH and BEX2 expression. In addition, ATR inhibited autophagy, whereas isoflavones induced autophagy through the accumulation of LC3-II and decreased expression of p62; this effect was abolished by 3-methyladenine (3-MA). Furthermore, BEX2 siRNA abolished isoflavone-mediated autophagy and neuroprotection in vitro. Conclusion: Isoflavones activate BEX2-dependent autophagy, protecting against ATR-induced neuronal apoptosis.

Context Adult height is highly heritable, yet no genetic predictor has demonstrated clinical utility compared to mid-parental height. Objective To develop a polygenic risk score for adult height and evaluate its clinical utility. Design A polygenic risk score was constructed based on meta-analysis of genome-wide association studies and evaluated on the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Subjects Participants included 442,599 genotyped White British individuals in the UK Biobank, and 941 genotyped child-parent trios of European ancestry in the ALSPAC cohort. Interventions None. Main Outcome Measures Standing height was measured using stadiometer; Standing height two standard deviations below the sex-specific population average was considered as short stature. Results Combined with sex, a polygenic risk score captured 71.1% of the total variance in adult height in the UK Biobank. In the ALSPAC cohort, the polygenic risk score was able to identify children who developed adulthood short stature with an area under the receiver operating characteristic curve (AUROC) of 0.84, which is close to that of mid-parental height. Combining this polygenic risk score with mid-parental height, or only one of the child’s parent’s height, could improve the AUROC to at most 0.90. The polygenic risk score could also substitute mid-parental height in age-specific Khamis-Roche height predictors and achieve an equally strong discriminative power in identifying children with a short stature in adulthood. Conclusions A polygenic risk score could be considered as an alternative or adjunct to mid-parental height to improve screening for children at risk of developing short stature in adulthood in European ancestry populations.

Atrazine (2-chloro-4-ethytlamino-6-isopropylamine-1,3,5-triazine; ATR) is a broad-spectrum herbicide with a wide range of applications worldwide. However, ATR is neurotoxic; it reduces dopamine levels in the substantia nigra and corpus striatum in the midbrain, affects the absorption of synaptic vesicles and synaptic bodies, and interferes with dopamine storage and uptake in synaptic vesicles, leading to neurodegenerative disorders. Microglia are resident immunocompetent and phagocytic cells that regulate and participate in the microenvironment in the central nervous system. They demonstrate macrophage characteristics after activation by releasing inflammatory cytokines and neurotoxic substances to increase the inflammatory response, and are thus involved in neurodegeneration. The aim of this study was to investigate the neurotoxic effects of ATR-activated microglia-mediated neuronal damage in terms of human dopaminergic neuroblastoma SH-SY5Y cell death. ATR was administered to BV-2 microglial cells at 12.5, 25, and 50 μM for 1, 6, 12, 24 and 48 h, respectively. ATR increased activated-microglia-induced overexpression of reactive oxygen species, inducible nitric oxide synthase, nitric oxide, gp91(phox), p47(phox), and the inflammatory cytokines tumor necrosis factor α and interleukin-1β, thus reducing SH-SY5Y cell viability. These results suggest that activated microglia may play a critical role in inflammation-mediated dopaminergic neuronal death, and provide the basis for further studies on the mechanisms of ATR-induced dopaminergic system toxicity.

Background - The clinical implications of a polygenic risk score (PRS) for low-density lipoprotein cholesterol (LDL-C) are not well understood, both within the general population and individuals with familial hypercholesterolemia (FH). Methods - We developed the LDL-C PRS using LASSO regression in 377,286 white British participants from UK Biobank and tested its association with LDL-C according to FH variant carrier status in another 41,748 whole-exome sequenced individuals. Next, we tested for an enrichment of FH variant carriers amongst individuals with severe hypercholesterolemia and low LDL-C PRS. Last, we contrasted the effect of the LDL-C PRS, measured LDL-C and FH variant carrier status on risk of ischemic heart disease (IHD) amongst 3,010 cases and 38,738 controls. Results - Amongst the 41,748 whole-exome sequenced white British individuals, one SD increase in the LDL-C PRS was associated with elevated LDL-C amongst both FH variant carriers (0.34, 95% CI 0.22 to 0.47 mmol/L) and non-carriers (0.42, 95% CI 0.42 to 0.43 mmol/L). Amongst individuals with severe hypercholesterolemia, FH variant carriers were enriched in those with a low LDL-C PRS (OR 2.20, 95% CI 1.66 to 2.71 per SD). Each SD increase in the LDL-C PRS was associated with risk of IHD to the comparable magnitude as measured LDL-C (OR 1.24, 95% CI 1.20 to 1.29 and OR 1.15, 95% CI 1.09 to 1.23, respectively). The LDL-C PRS was not strongly associated with other traditional IHD risk factors. Conclusions - An LDL-C PRS could be used to identify individuals with a higher probability of harboring FH variants. The association between IHD and the LDL-C PRS was comparable to measured LDL-C, likely because the PRS reflects lifetime exposure to LDL-C levels.

No abstract

Aims This study aimed to compare the efficacy of angiotensin receptor‐neprilysin inhibitor (ARNI) therapy with angiotensin converting enzyme inhibitor or angiotensin receptor blocker (ACEI/ARB) therapy for cardiovascular outcomes in patients with acute myocardial infarction (AMI). Methods and results Data were collected from the Biobank of the First Affiliated Hospital of Xi'an Jiaotong University between January 2016 and December 2020. A total of 7556 AMI patients were screened for eligibility. Propensity score matching based on age, sex, blood pressure, kidney function, baseline left ventricular ejection fraction (LVEF), and cardiovascular medication were conducted, resulting in 291 patients with AMI being assigned to ARNI, ACEI, and ARB group, respectively. Patients receiving ARNI had significantly lower rates of the composite cardiovascular outcome than ACEI {hazard ratio [HR] 0.51, [95% confidence interval (CI), 0.27–0.95], P = 0.02}, and ARB users [HR 0.47, (95%CI, 0.24–0.90), P = 0.02]. Patients receiving ARNI showed lower rates of cardiovascular death than ACEI [HR 0.37, (95%CI, 0.18–0.79), P = 0.01] and ARB users [HR 0.41, (95%CI, 0.18–0.95), P = 0.04]. Subgroup analysis indicated that patients with LVEF no more than 40% tend to benefit more from ARNI as compared with ACEI [HR 0.30, (95%CI, 0.11–0.86), P = 0.01] or ARB [HR 0.21, (95%CI, 0.04–1.1), P = 0.05]. Patients aged no more than 60 years exhibited reduced composite endpoints [HR for ARNI vs. ARB: 0.11, (95%CI, 0.03–0.46), P = 0.002]. Conclusions In patients with AMI, ARNI was superior to ACEI/ARB in reducing the long‐term adverse cardiovascular outcomes. Subgroup analysis further indicates that ARNI is more likely to benefit patients with LVEF less than 40% and aged less than 60 years.

Hot phonon bottleneck (HPB), one of the dominant effects for tuning hot carrier (HC) cooling, has been extensively studied in lead halide perovskites (LHP), and most attention has been devoted to its role in those photovoltaic devices. However, behaviors of HPB in strongly confined systems and its influence on optical gain remain obscure. Herein, by monitoring state-resolved relaxation in strongly confined CsPbBr3 quantum dots (QDs), we discover a discrete cooling process of HCs and demonstrate that their elongation, induced by HPB, primarily occurs during the intraband relaxation from the first excited (1P) to the lowest (1S) states. Moreover, a threshold-like character of HPB in LHP QDs, where the energy dissipation rate significantly drops only beyond a certain carrier density, could be ascribed to the nonadiabatic interaction by coupling with ligand vibrations. Remarkably, HPB has been found to trigger the formation of a giant optical gain (6000 cm–1) near the second absorption peak, and spectral analysis indicates its origin from population inversion at the higher-transition or 1P state. Our findings could strengthen the understanding of photophysics in LHP QDs and guide the development of efficient and broadband lighting applications.