Notes

To prevent conductivity and superconductivity in very overdoped La2-x Ca a CuO4 thin films.
Lymphoid-specific tyrosine phosphatase (LYP), which exclusively exists in immune cells and down-regulates T cell receptor signaling (TCR), has becoming a potent target for various autoimmune diseases. Herein, we designed and synthesized imidazolidine-2,4-dione and 2-thioxothiazolidin-4-one derivatives as new LYP inhibitors. Among them, the cinnamic acids-based inhibitors (9p and 9r) displayed good LYP inhibitory activities (IC50 = 2.85-6.95 μM). Especially, the most potent inhibitor 9r was identified as competitive inhibitor (Ki = 1.09 μM) and bind LYP reversibly. Meanwhile, 9r exhibited better selectivity over other phosphatases than known LYP inhibitor A15. Furthermore, compound 9r could regulate TCR associated signaling pathway in Jurkat T cell.Histone deacetylases (HDACs) have been indicated important roles in neurodegenerative disorders including Alzheimer's disease (AD). Herein, a series of novel compounds that contain a memantine moiety were designed to target HDACs and N-methyl-d-aspartate receptor (NMDAR) which are related to the treatment of AD. Biological characterization established that compound 9d exhibited a balanced inhibitory activity on NMDAR and HDACs. This compound is relatively selective to HDAC6 with IC50 of 0.18 μM and also maintains comparable activity on NMDAR (Ki = 0.59 μM) as memantine. Functionally, treatment with 9d increased the level of AcTubulin in MV4-11 cells and rescued PC-12 cells from H2O2-induced cytotoxicity with EC50 of 0.94 μM. Studies in mice also demonstrated that compound 9d efficiently penetrates the blood brain barrier to reach the brain tissue. Collectively, the results strongly encourage further development of 9d as a potential therapeutic agent for AD.
Early cannabis use is associated with mental health and substance use (MHSU) challenges into adulthood. Given the vulnerability of youth who use cannabis, it is important to understand their clinical profiles and markers of risk. This cross-sectional descriptive study examines youth who began using cannabis during early adolescence compared to those who initiated at an older age.

634 youth and emerging adults (age M=19.5, SD=2.3; 46.5% female) were assessed at intake in a Canadian youth mental health and concurrent disorder out-patient service. Measures of demographic characteristics and MHSU were compared for youth who initiated cannabis use under the age of 14 versus 14 years or over.

Nearly 30% of youth initiated cannabis use before age 14. Those who initiated cannabis early were younger and had distinct psychosocial risk factors. They were more likely to use cannabis (p=.005), tobacco (p=.006), powder cocaine (p=.030), and/or benzodiazepines (p=.033) at a high frequency. If they used other substances, they were more likely to have begun using them younger (all p<.001). Early initiators had more externalizing mental health symptoms (p=.024), crime/violence concerns (p<.001), and past trauma (p=.001).

Distinct, clinically meaningful differences emerged between youth who initiated cannabis use early versus later. Early cannabis use is associated with multiple, overlapping needs. dWIZ-2 chemical Cannabis use and concurrent MHSU should be systematically assessed from an early age, and prevention/promotion efforts should take early onset into account.
Distinct, clinically meaningful differences emerged between youth who initiated cannabis use early versus later. Early cannabis use is associated with multiple, overlapping needs. Cannabis use and concurrent MHSU should be systematically assessed from an early age, and prevention/promotion efforts should take early onset into account.
Several cross-sectional and longitudinal studies have found associations between attitudes about aggression and aggressive behaviors. However, few studies examine all subtypes of Adolescent Dating Aggression (ADA)-physical, psychological/emotional, sexual, and stalking; occurring in person or electronically-and there is a paucity of longitudinal studies that follow adolescents over several years.

Middle school and high school students (N=1240), in the Midwestern United States, participated in surveys one time per year for four years. Data from each year (Y1, Y2, Y3, & Y4) was used to conduct a cross-lagged panel analysis of attitudes about aggression and aggressive behaviors, among both cohorts.

By Y4, approximately 46% of the middle school cohort and 60% of the high school cohort perpetrated some form of ADA. The cross-lagged panel analysis revealed significant cross-sectional associations in the middle school (Y1, Y2, & Y4) and high school (Y1 & Y2) cohorts. Aggressive behaviors were significantly associated with future aggressive behaviors for the middle and high school cohorts each year. Similarly, attitudes about aggression were significantly associated with attitudes in the following years for both cohorts. Among the middle school cohort, there were significant cross-lagged effects between aggressive behaviors in Y2 and attitudes about aggression in Y3, as well as aggressive behaviors in Y3 and attitudes about aggression in Y4. Among the high school cohort, a bidirectional association was found from Y2 to Y3.

These findings suggest prevention programs should be implemented earlier, among middle school aged adolescents, and target factors beyond attitudes supporting aggression.
These findings suggest prevention programs should be implemented earlier, among middle school aged adolescents, and target factors beyond attitudes supporting aggression.The chemokine receptor CXCR4 has been proposed as a drug target based on its important functions in HIV infection, inflammation/autoimmune diseases and cancer metastasis. Herein we report the design, synthesis and evaluation of novel CXCR4 antagonists based on a pyrrolidine scaffold. The structural exploration/optimization identified numerous potent CXCR4 antagonists, represented by compound 46, which displayed potent binding affinity to CXCR4 receptor (IC50 = 79 nM competitively displacing fluorescent 12G5 antibody) and inhibited CXCL12 induced cytosolic calcium flux (IC50 = 0.25 nM). Moreover, in a transwell invasion assay, compound 46 significantly mitigated CXCL12/CXCR4 mediated cell migration. Compound 46 exhibited good physicochemical properties (MW 367, logD7.4 1.12, pKa 8.2) and excellent in vitro safety profiles (e.g., hERG patch clamp IC50 > 30 μM and minimal CYP isozyme inhibition). Importantly, 46 displayed much improved metabolic stability in human and rat liver microsomes. Lastly, 46 demonstrated marked efficacy in a cancer metastasis model in mice.
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