Inhibition of SIRT2 by Targeting GSK3β-Mediated Phosphorylation Alleviates SIRT2 Toxicity in SH-SY5Y Cells

Sirtuin 2 (SIRT2) is thought to be important in the pathogenesis of Parkinson’s disease (PD), and the inhibition of SIRT2 rescues α-synuclein toxicity in a cellular model of PD. Recent studies have focused on identifying inhibitors of SIRT2, but little is known about the processes that directly regulate its function. GSK3β is a serine/threonine protein kinase that affects a wide range of biological functions, and it is localized in Lewy bodies (LBs). Therefore, we investigated whether SIRT2 is regulated by GSK3β and enhances cell death in PD. In the present study, Western blot showed that total SIRT2 levels did not change noticeably in a cellular model of PD but that SIRT2 phosphorylation was increased, and GSK3β activity was elevated. In addition, mass spectrometry (MS) studies indicated that SIRT2 was phosphorylated by GSK3β at three specific sites. Phospho- or dephospho-mimicking studies demonstrated that this postmodification (phosphorylation) increased SIRT2 toxicity in SH-SY5Y cells. Collectively, our findings identify a posttranslational mechanism that controls SIRT2 function in PD and provide evidence for a novel regulatory pathway involving GSK3β, SIRT2, and α-synuclein

Ticagrelor vs Clopidogrel in CYP2C19 loss-of-function carriers with Stroke or TIA

BACKGROUNDComparisons between ticagrelor- aspirin and clopidogrel-aspirin in CYP2C19 loss-of-function carriers have not been well studied for secondary stroke prevention.METHODSWe conducted a randomized, double-blind, placebo-controlled trial of 6,412 patients with a minor ischemic stroke or TIA who carried CYP2C19 LOF alleles determined by point-of-care testing. Patients were randomly assigned within 24 hours after symptom onset, in a 1:1 ratio to receive ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2 through 90) or clopidogrel (300 mg loading dose on day 1 followed by 75 mg per day for days 2 through 90), plus aspirin (75-300 mg loading dose followed by 75 mg daily for 21 days). The primary efficacy outcome was stroke and the primary safety outcome was severe or moderate bleeding, both within 90 days. RESULTSStroke occurred within 90 days in 191 (6.0%) versus 243 (7.6%), respectively (hazard ratio, 0.77; 95% confidence interval, 0.64 to 0.94; P=0.008). Moderate or severe bleeding occurred in 9 patients (0.3%) in the ticagrelor-aspirin group and in 11 patients (0.3%) in the clopidogrel-aspirin group; any bleeding event occurred in 170 patients (5.3%) vs 80 (2.5%), respectively. CONCLUSIONSAmong Chinese patients with minor ischemic stroke or TIA within 24 hours after symptoms onset who were carriers of CYP2C19 loss-of-function alleles, ticagrelor- aspirin was modestly better than clopidogrel-aspirin for reducing the risk of stroke but was associated with more total bleeding events at 90 days. (CHANCE-2 ClinicalTrials.gov number, NCT04078737.

Boundedness of homogeneous fractional integral operator on Morrey space

Abstract For 0 < α < n $0<\alpha<n$ , the homogeneous fractional integral operator T Ω , α $T_{\Omega,\alpha}$ is defined by T Ω , α f ( x ) = ∫ R n Ω ( x − y ) | x − y | n − α f ( y ) d y . $$T_{\Omega,\alpha}f(x)= \int_{{\Bbb {R}}^{n}}\frac{\Omega (x-y)}{\vert x-y\vert ^{n-\alpha}}f(y)\,dy.$$ In this paper we prove that if Ω satisfies some smoothness conditions on S n − 1 $S^{n-1}$ , then T Ω , α $T_{\Omega,\alpha}$ is bounded from L λ α , λ ( R n ) $L^{\frac{\lambda}{\alpha },\lambda}({\Bbb {R}}^{n})$ to BMO ( R n ) $\operatorname {BMO}({\Bbb {R}}^{n})$ , and from L p , λ ( R n ) $L^{p,\lambda}({\Bbb {R}}^{n})$ ( λ α < p < ∞ $\frac{\lambda}{\alpha}< p<\infty$ ) to a class of the Campanato spaces L l , λ ( R n ) $\mathcal{L}_{l,\lambda }({\Bbb {R}}^{n})$ , respectively

Longitudinal Impacts of Religious Profiles on Substance Abuse Among Emerging Adults: A Fusion of Unsupervised and Supervised Learning Approach

This study aims to assess the longitudinal patterns of multifaceted religious profiles and their relationships with illegal substance abuse among young people transitioning from late adolescence to early adulthood. A novel longitudinal approach integrating the cutting-edge unsupervised and supervised learning techniques is proposed to analyze the data from the National Longitudinal Survey of Youth 1997. The results show that emerging adults who are highly religious in either subjective (e.g., religious beliefs) or objective (e.g., religious attendance) domain are much less likely to abuse illegal substances than their religiously disengaged peers. Religiosity, regardless of subjective or objective, tends to be protective, but its effect is most prominent among young people most profoundly devoted to both religious beliefs and behaviors. Nevertheless, possessing strong commitment to religious beliefs without accompanying frequent religious behaviors may put emerging adults at greater risk for illicit substance abuse, compared to those who hold high level of religious beliefs but do not engage in corresponding religious behaviors frequently

The BE COOL Treatments (Batroxobin, oxygEn, Conditioning, and cOOLing): Emerging Adjunct Therapies for Ischemic Cerebrovascular Disease

Ischemic cerebrovascular disease (ICD), the most common neurological disease worldwide, can be classified based on the onset time (acute/chronic) and the type of cerebral blood vessel involved (artery or venous sinus). Classifications include acute ischemic stroke (AIS)/transient ischemic attack (TIA), chronic cerebral circulation insufficiency (CCCI), acute cerebral venous sinus thrombosis (CVST), and chronic cerebrospinal venous insufficiency (CCSVI). The pathogenesis of cerebral arterial ischemia may be correlated with cerebral venous ischemia through decreased cerebral perfusion. The core treatment goals for both arterial and venous ICDs include perfusion recovery, reduction of cerebral ischemic injury, and preservation of the neuronal integrity of the involved region as soon as possible; however, therapy based on the current guidelines for either acute ischemic events or chronic cerebral ischemia is not ideal because the recurrence rate of AIS or CVST is still very high. Therefore, this review discusses the neuroprotective effects of four novel potential ICD treatments with high translation rates, known as the BE COOL treatments (Batroxobin, oxygEn, Conditioning, and cOOLing), and subsequently analyzes how BE COOL treatments are used in clinical settings. The combination of batroxobin, oxygen, conditioning, and cooling may be a promising intervention for preserving ischemic tissues

Stressors and coping at work : what influences how we feel and what we do?

This paper discusses the variables that influence individuals’ cognitive appraisals of the stress process. Specifically, occupational stress research has highlighted the relationship between cognitive appraisal and the perception of stressors and coping strategies employed. However, existing literature remains unclear as to what influences individuals’ cognitive appraisals. Utilizing the transactional model of stress proposed by Lazarus and Folkman (1984), this paper explores and ascertains that individual differences (socioeconomic status, gender, Type A/B, and self-efficacy) and environmental characteristics (situation-dependent control and social support) influence the cognitive appraisal of stressors and coping strategies. Implications of current findings emphasize the need for more research to investigate possible variables which influence cognitive appraisals. Finally, in line with the existing research, individual-focused and workplace-focused interventions are recommended to help employees modify their cognitive appraisals in relation to job stressors.Bachelor of Art

Heat shock protein 70 is involved in polaprezinc driven cell protection against Helicobacter pylori-induced injury

Polaprezinc (PZ) plays a role in the protection of gastric mucosa and inhibiting Helicobacter pylori (H. pylori) growth in vitro. The objective of this study was to determine the protective effects of PZ on human gastric epithelial cells (GES-1) against H. pylori-induced damage, while also examining heat shock protein 70 (HSP70) as a potential underlying factor in this protection. Our findings revealed that PZ exerted bactericidal effects against H. pylori strains. We also observed that PZ mitigated the H. pylori-induced damage to GES-1 cells by increasing cell viability, reducing LDH release, and decreasing the secretion of pro-inflammatory factors such as MCP-1 and IL-6. Co-culturing PZ with GES-1 cells significantly up-regulated the GES-1 HSP70 expression in both a time and dose-dependent manner. Pre-incubating (for 12 h) or co-culturing (for 24 h) GES-1 cells with PZ reversed the down-regulation of HSP70 in GES-1 cells caused by H. pylori infection. However, when quercetin was used to inhibit the up-regulation of HSP70 in GES-1 cells, the protective effect of PZ on GES-1 cells was significantly reduced. Based on the results of this study, PZ exhibits a protective role on GES-1 cells against H. pylori injury, as well as a direct bactericidal effect on H. pylori. HSP70 is involved in the PZ-driven host cell protection against H. pylori injury. These findings provide insight into alternative strategies for H. pylori treatment

Alpha oscillations encode Bayesian belief updating underlying attentional allocation in dynamic environments

In a dynamic environment, expectations of the future constantly change based on updated evidence and affect the dynamic allocation of attention. To further investigate the neural mechanisms underlying attentional expectancies, we employed a modified Central Cue Posner Paradigm in which the probability of cues being valid (that is, accurately indicated the upcoming target location) was manipulated. Attentional deployment to the cued location (α), which was governed by precision of predictions on previous trials, was estimated using a hierarchical Bayesian model and was included as a regressor in the analyses of electrophysiological (EEG) data. Our results revealed that before the target appeared, alpha oscillations (8∼13 Hz) for high-predictability cues (88 % valid) were significantly predicted by precision-dependent attention (α). This relationship was not observed under low-predictability conditions (69 % and 50 % valid cues). After the target appeared, precision-dependent attention (α) correlated with alpha band oscillations only in the valid cue condition and not in the invalid condition. Further analysis under conditions of significant attentional modulation by precision suggested a separate effect of cue orientation. These results provide new insights on how trial-by-trial Bayesian belief updating relates to alpha band encoding of environmentally-sensitive allocation of visual spatial attention

Association between tumor necrosis factor alpha-238G/a polymorphism and tuberculosis susceptibility: a meta-analysis study

Abstract Background Tumor necrosis factor alpha (TNF-α) plays a key role in the containment of tuberculosis. The relationship between the TNF -238G/A polymorphism and tuberculosis susceptibility remains inconclusive. A comprehensive meta-analysis was made to provide a more precise estimate of the relationship between them. Methods Multiple search strategies were used. A fixed effect model was takentook to estimate pooled OR with 95% confidence interval (CI) for the association between the TNF -238G/A polymorphism and tuberculosis susceptibility. The Chi-squared-based Q-test and I-squaredI2 statistic were calculated to examine heterogeneity. Begg’s funnel plot and Egger’s test were used to assess publication bias. Results 9 case-control studies were included in this meta-analysis. No significant heterogeneity was demonstrated, and no obvious publication bias was detected among the included studies. The meta-analysis indicated that there was no significant association between the TNF -238G/A polymorphism and tuberculosis susceptibility (GA+AA versus GG model: OR=1.005, 95% CI: 0.765-1.319; A versus G model: OR=1.000, 95% CI: 0.769-1.300). In the subgroup analyses by ethnicity, types of TB and human immunodeficiency virus (HIV) status, no significant association were identified. Conclusions The meta-analysis involving 2723 subjects did not detect any association between the TNF -238G/A polymorphism and tuberculosis susceptibility.</p