Chronic stress induces Alzheimer's disease-like pathologies through DNA damage-Chk1-CIP2A signaling.

Stress is an important initiating factor in promoting Alzheimer's disease (AD) pathogenesis. However, the mechanism by which stress induces AD-like cognitive impairment remains to be clarified. Here, we demonstrate that DNA damage is increased in stress hormone Corticotropin-releasing factor (CRF)-treated cells and in brains of mice exposed to chronic restraint stress. Accumulation of DNA damage drives activation of cell cycle checkpoint protein kinase 1 (Chk1), upregulation of cancerous inhibitor of PP2A (CIP2A), tau hyperphosphorylation, and Aß overproduction, eventually resulting in synaptic impairment and cognitive deficits. Pharmacological intervention targeting Chk1 by specific inhibitor and DNA damage by vitamin C, suppress DNA damage-Chk1-CIP2A signaling pathway in chronic stress animal model, which in turn attenuate AD-like pathologies, synaptic impairments and cognitive deficits. Our study uncovers a novel molecular mechanism of stress-induced AD-like pathologies and provides effective preventive and therapeutic strategies targeting this signaling pathway.

Tau induces inflammasome activation and microgliosis through acetylating NLRP3.

BACKGROUND: Alzheimer's disease (AD) and related Tauopathies are characterised by the pathologically hyperphosphorylated and aggregated microtubule-associated protein Tau, which is accompanied by neuroinflammation mediated by activated microglia. However, the role of Tau pathology in microglia activation or their causal relationship remains largely elusive. METHODS: The levels of nucleotide-binding oligomerisation domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) acetylation and inflammasome activation in multiple cell models with Tau proteins treatment, transgenic mice with Tauopathy, and AD patients were measured by Western blotting and enzyme-linked immunosorbent assay. In addition, the acetyltransferase activity of Tau and NLRP3 acetylation sites were confirmed using the test-tube acetylation assay, co-immunoprecipitation, immunofluorescence (IF) staining, mass spectrometry and molecular docking. The Tau-overexpressing mouse model was established by overexpression of human Tau proteins in mouse hippocampal CA1 neurons through the adeno-associated virus injection. The cognitive functions of Tau-overexpressing mice were assessed in various behavioural tests, and microglia activation was analysed by Iba-1 IF staining and [18F]-DPA-714 positron emission tomography/computed tomography imaging. A peptide that blocks the interaction between Tau and NLRP3 was synthesised to determine the in vitro and in vivo effects of Tau-NLRP3 interaction blockade on NLRP3 acetylation, inflammasome activation, microglia activation and cognitive function. RESULTS: Excessively elevated NLRP3 acetylation and inflammasome activation were observed in 3xTg-AD mice, microtubule-associated protein Tau P301S (PS19) mice and AD patients. It was further confirmed that mimics of 'early' phosphorylated-Tau proteins which increase at the initial stage of diseases with Tauopathy, including TauT181E, TauS199E, TauT217E and TauS262E, significantly promoted Tau-K18 domain acetyltransferase activity-dependent NLRP3 acetylation and inflammasome activation in HEK293T and BV-2 microglial cells. In addition, Tau protein could directly acetylate NLRP3 at the K21, K22 and K24 sites at its PYD domain and thereby induce inflammasome activation in vitro. Overexpression of human Tau proteins in mouse hippocampal CA1 neurons resulted in impaired cognitive function, Tau transmission to microglia and microgliosis with NLRP3 acetylation and inflammasome activation. As a targeted intervention, competitive binding of a designed Tau-NLRP3-binding blocking (TNB) peptide to block the interaction of Tau protein with NLRP3 inhibited the NLRP3 acetylation and downstream inflammasome activation in microglia, thereby alleviating microglia activation and cognitive impairment in mice. CONCLUSIONS: In conclusion, our findings provide evidence for a novel role of Tau in the regulation of microglia activation through acetylating NLRP3, which has potential implications for early intervention and personalised treatment of AD and related Tauopathies.

The potential of using non-coding RNAs in forensic science applications.

With the continuous development and integration of molecular biology and forensic science, non-coding RNAs (ncRNAs), especially ncRNAs with regulatory functions such as microRNA, long non-coding RNA, and circular RNA, have recently been actively explored by forensic scholars. In this study, we review the literature on these ncRNAs in various fields of forensic science, including postmortem interval determination, wound age estimation, forensic age assessment, cause of death analysis, and body fluid identification, aiming to evaluate the current research and provide a perspective for future applications.

Theoretical Modeling and Experimental Verification of the Bending Deformation of Fiber Metal Laminates.

Fiber metal laminates have been widely used as the primary materials in aircraft panels, and have excellent specific strength. Bending deformation is the most common loading mode of such components. An accurate theoretical predictive model for the bending process for the carbon reinforced aluminum laminates is of great significance for predicting the actual stress response. In this paper, based on the metal-plastic bending theory and the modified classical fiber laminate theory, a modified bending theory model of carbon-fiber-reinforced aluminum laminates was established. The plastic deformation of the thin metal layer in laminates and the interaction between fiber and metal interfaces were considered in this model. The bending strength was predicted analytically. The FMLs were made from 5052 aluminum sheets, with carbon fibers as the reinforcement, and were bonded and cured by locally manufacturers. The accuracy of the theory was verified by three-point bending experiments, and the prediction error was 8.4%. The results show that the fiber metal laminates consisting of three layers of aluminum and two layers of fiber had the best bending properties. The theoretical model could accurately predict the bending deformation behaviors of fiber metal laminates, and has significant value for the theoretical analysis and performance testing of laminates.

Updating Urinary Microbiome Analyses to Enhance Biologic Interpretation.

Objective: An approach for assessing the urinary microbiome is 16S rRNA gene sequencing, where analysis methods are rapidly evolving. This re-analysis of an existing dataset aimed to determine whether updated bioinformatic and statistical techniques affect clinical inferences. Methods: A prior study compared the urinary microbiome in 123 women with mixed urinary incontinence (MUI) and 84 controls. We obtained unprocessed sequencing data from multiple variable regions, processed operational taxonomic unit (OTU) tables from the original analysis, and de-identified clinical data. We re-processed sequencing data with DADA2 to generate amplicon sequence variant (ASV) tables. Taxa from ASV tables were compared to the original OTU tables; taxa from different variable regions after updated processing were also compared. Bayesian graphical compositional regression (BGCR) was used to test for associations between microbial compositions and clinical phenotypes (e.g., MUI versus control) while adjusting for clinical covariates. Several techniques were used to cluster samples into microbial communities. Multivariable regression was used to test for associations between microbial communities and MUI, again while adjusting for potentially confounding variables. Results: Of taxa identified through updated bioinformatic processing, only 40% were identified originally, though taxa identified through both methods represented >99% of the sequencing data in terms of relative abundance. Different 16S rRNA gene regions resulted in different recovered taxa. With BGCR analysis, there was a low (33.7%) probability of an association between overall microbial compositions and clinical phenotype. However, when microbial data are clustered into bacterial communities, we confirmed that bacterial communities are associated with MUI. Contrary to the originally published analysis, we did not identify different associations by age group, which may be due to the incorporation of different covariates in statistical models. Conclusions: Updated bioinformatic processing techniques recover different taxa compared to earlier techniques, though most of these differences exist in low abundance taxa that occupy a small proportion of the overall microbiome. While overall microbial compositions are not associated with MUI, we confirmed associations between certain communities of bacteria and MUI. Incorporation of several covariates that are associated with the urinary microbiome improved inferences when assessing for associations between bacterial communities and MUI in multivariable models.

Quantitative Analysis on NCDs Prevention and Control Policies Based on the Perspective of Policy Instruments - China, 1990-2020.

What is already known about this topic?: Noncommunicable diseases (NCDs) are a major public health problem in the world. NCDs are the leading cause of premature deaths and disabilities among Chinese residents, resulting in heavy economic and health burdens. What is added by this report?: This study conducted a quantitative analysis of the policy texts on NCDs prevention and control in China from 1990 to 2020, based on the perspective of policy instruments. It was discovered that China's NCDs prevention and control policies developed rapidly from the ground up over the 30 years from 1990 to 2020 and that the majority of China's NCDs prevention and control policies were environment-oriented, while supply-oriented and demand-oriented policies were insufficient. What are the implications for public health practice?: The findings of this study suggested that increasing supply-oriented and demand-oriented strategies should be prioritized in the future formulation and revision of NCDs prevention and control policies.

Evaluation of China Healthy Lifestyle for All Interventions Based on RE-AIM Framework - China, 2007-2020.

What is already known about this topic?: Since the launch of China Healthy Lifestyle for All (CHLA), each action area has been evaluated at the local level and effective results have been achieved in most areas. What is added by this report?: Based on the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) model, the study found that there is an imbalance in the development of CHLA, and some of the action goals and indicators are not satisfactory. What are the implications for public health practices?: A national action evaluation index system should be built to ensure the sustainability and scientific nature of this strategy. In addition, the government needs to attach great importance to CHLA to effectively help residents take health actions.

Elevated Th17 cell proportion, related cytokines and mRNA expression level in patients with hypertension-mediated organ damage: a case control study.

BACKGROUND: Immune abnormalities and inflammatory responses play critical roles in progression of hypertension. Basic studies have confirmed that Th17 cell and related cytokines are important in promoting hypertension-mediated organ damage, but few clinical evidences have been published. Therefore, our study aimed to investigate the relationship between Th17 cell and its related cytokines and hypertension-mediated organ damage in human. METHODS: This study enrolled 179 patients with hypertension (including 92 with hypertension-mediated organ damage and 87 without hypertension-mediated organ damage) and 63 healthy participants. The proportion of Th17 cells in peripheral blood mononuclear cells was measured by flow cytometry. The concentrations of interleukin-17 and interleukin-23 were detected by enzyme-linked immunosorbent assay. Real time-polymerase chain reaction was used to detect the mRNA expression levels of interleukin-17, retinoic acid-related orphan receptor (ROR) γt and signal transducer and activator of transcription-3 (STAT-3). RESULTS: The proportion of Th17 cells, the concentration of interleukin-17 and interleukin-23 and the mRNA expression levels of interleukin-17, retinoic acid-related orphan receptor γt and signal transducer and activator of transcription-3 were significantly increased in hypertension-mediated organ damage group compared with those in non-hypertension-mediated organ damage group and control group (P < 0.005). CONCLUSION: Th17 cells and their associated cytokines may be involved in hypertension-mediated organ damage formation and may be able to serve as new biomarkers of hypertension-mediated organ damage and potential therapeutic targets.

Acute toxicity, bioaccumulation and elimination of prometryn in tilapia (Oreochromis niloticus).

Tilapia juvenile (Oreochromis niloticus) (mean weight 50.00 ± 10.00 g) were aqueous exposed to different concentrations of the herbicide prometryn to investigate its acute toxicity, bioaccumulation and uptake and elimination rates. First, a 96-h acute toxicity test was carried out. The resulting 96 h LC50 was 5.49 mg/L, and the 96 h LC10 was 5.02 mg/L. Then, fish were exposed to 0.55 mg/L (1/10 96 h LC50) and 0.055 mg/L (1/100 96 h LC50) of prometryn solution for 28 days, followed by 14 days of elimination in clean groundwater. The result shows that in both water and tissues, prometryn concentrations fluctuated during the exposure period, indicating that steady state was not reached. The bioaccumulation of prometryn was the highest in liver, followed by gill, muscle and blood. The accumulated concentration levels in various tissues were always higher in the high concentration compared to the low concentration. The highest accumulated concentration of prometryn in various tissues in the 0.055 mg/L treatment were for muscle: 0.136 ± 0.0616 mg/kg (1 d), liver: 3.74 ± 2.95 mg/kg (7 d), gill: 0.971 ± 1.45 mg/kg (1 d) and blood: 0.0716 ± 0.0669 mg/kg (22 d). In the 0.55 mg/L treatment, the highest levels were for muscle: 1.27 ± 0.284 mg/kg (1 d), liver: 16.9 ± 12.7 mg/kg (7 d), gill: 8.11 ± 3.02 mg/kg (1 d) and blood: 0.751 ± 0.0775 mg/kg (22 d). The highest bioconcentration factor (BCF) of 93.1 was observed in the liver when exposed to the low concentration. Besides, for other tissues, the highest BCF were for muscle: 5.76, gill: 32.3 and blood: 2.91, all observed in the 0.55 mg/L treatment. Most of the accumulated prometryn was removed from all tissues within 24 h after the organisms were transferred to clean water. However, management of using prometryn in China aquaculture should be improved to prevent possible ecotoxicological effects and ensure food safety.

Relationship between Coronary VH-IVUS Plaque Characteristics and CTRP9, SAA, and Hcy in Patients with Coronary Heart Disease.

Coronary heart disease is a common disease threatening human health. In recent years, the incidence of coronary heart disease in China has only increased. It is the most common type of organ disease caused by coronary atherosclerosis, which is observed in the aorta, carotid artery, and femoral artery. The main clinical treatments for coronary heart disease include coronary artery bypass grafting and drug treatment. To investigate the relationship of serum adipocytokine C1q/tumor necrosis factor-related protein 9 (CTRP9), amyloid A (SAA), and plasma homocysteine (Hcy) with coronary artery plaque characteristics in patients with coronary heart disease. Overall, 143 patients with coronary heart disease admitted to our hospital are selected as research participants. The proportion of plaque necrosis core volume is higher in group A than in group B, and the differences are statistically significant (P < 0.05). In group A, necrotic core volume percentage is negatively correlated with CTRP9 levels and positively correlated with SAA and Hcy levels (P < 0.05). Logistic regression analysis revealed that increased systolic blood pressure, increased number of coronary artery lesions, decreased CTRP9 levels, and increased Hcy levels are independent risk factors for thin fibrous cap atherosclerosis in patients with coronary heart disease (P < 0.05). Decreased CTRP9 levels and increased Hcy levels are independent risk factors for coronary heart disease patients with thin fibrous cap atherosclerosis.

Chk1 Inhibition Ameliorates Alzheimer's Disease Pathogenesis and Cognitive Dysfunction Through CIP2A/PP2A Signaling.

Alzheimer's disease (AD) is the most common neurodegenerative disease with limited therapeutic strategies. Cell cycle checkpoint protein kinase 1 (Chk1) is a Ser/Thr protein kinase which is activated in response to DNA damage, the latter which is an early event in AD. However, whether DNA damage-induced Chk1 activation participates in the development of AD and Chk1 inhibition ameliorates AD-like pathogenesis remain unclarified. Here, we demonstrate that Chk1 activity and the levels of protein phosphatase 2A (PP2A) inhibitory protein CIP2A are elevated in AD human brains, APP/PS1 transgenic mice, and primary neurons with Aß treatment. Chk1 overexpression induces CIP2A upregulation, PP2A inhibition, tau and APP hyperphosphorylation, synaptic impairments, and cognitive memory deficit in mice. Moreover, Chk1 inhibitor (GDC0575) effectively increases PP2A activity, decreases tau phosphorylation, and inhibits Aß overproduction in AD cell models. GDC0575 also reverses AD-like cognitive deficits and prevents neuron loss and synaptic impairments in APP/PS1 mice. In conclusion, our study uncovers a mechanism by which DNA damage-induced Chk1 activation promotes CIP2A-mediated tau and APP hyperphosphorylation and cognitive dysfunction in Alzheimer's disease and highlights the therapeutic potential of Chk1 inhibitors in AD.

Pharmacokinetics and residue elimination of norfloxacin in rainbow trout (Oncorhynchus mykiss).

We studied the metabolism and elimination of norfloxacin in rainbow trout (Oncorhynchus mykiss) following a single oral administration of 50 mg/kg at 15 ± 2°C. Norfloxacin was measured by high-performance liquid chromatography-tandem mass spectrometry in plasma, muscle, liver, kidney, skin and remainder tissues, and the concentrationtime curve was characterized by a double peak. The drug was absorbed rapidly; the first peak appeared within 4 h, and the second peak appeared within 24 h in all substrates tested. The maximal concentrations in plasma, muscle, liver and kidney were 0.468 mg/L, 14.146 mg/kg, 6.445 mg/kg and 0.977 mg/kg, respectively. The distribution half-life was 5.814, 9.026, 17.027 and 1.004 h, respectively. The elimination half-life was 41.205, 41.667, 44.896 and 54.908 h, respectively. Using the kidney as the reference tissue for norfloxacin monitoring in aquaculture and 2 µg/kg as a maximum residue limit standard, it takes 555 temperature-day (°C days) for norfloxacin to be completely eliminated from rainbow trout.

Removal behavior and mechanisms of cadmium and lead by coupled ethylenediaminetetraacetic acid washing and electrochemical reduction: influence of current conditions.

Ethylenediaminetetraacetic acid (EDTA) washing has been used extensively to remediate heavy metal-contaminated soils. Electrochemical reduction treatment of spent washing solution is an effective method of EDTA regeneration. However, at present, these two technologies are usually regarded as two independent treatment processes. This research raised a new heavy metal-contaminated soil treatment strategy-a combination technique of coupled EDTA washing and electrochemical reduction. We speculated that the combination of EDTA washing and electroreduction treatment could improve the efficiency of Cd and Pb removal from contaminated soil. In this study, the removal performance and mechanisms of Cd and Pb under different current conditions were investigated based on a coupling of EDTA washing and electrochemical reduction. The combination technique can increase Cd and Pb removal efficiencies by 13.37-15.24% and 14.91-27.05%, respectively, compared with EDTA washing alone. Sequential extraction analysis showed that the reducible fraction improved metal removal efficiency. The percentage of metal removed increased with an increased current value and EDTA concentration. In addition, pulse current mode removed more Cd and Pb than continuous current, although the difference was not significant (p > 0.05). However, pulse current could effectively eliminate the cathodic hydrogen evolution reaction, resulting in a further heavy metal deposition at the cathode. The combination technique exhibited enhanced removal efficiency due to EDTA regeneration in the suspension and the cathodic reduction reaction. The most cost-effective treatment in 48 h was a pulse current mode of 32 min on/16 min off-32 mA-EDTA-10 mM, where 47.56% of Cd and 77.00% of Pb were removed from the soil with an electric energy consumption of 8.24 Wh.

Pancreatic neuroendocrine tumor producing vasopressin: A case report.

RATIONALE: Functional pancreatic neuroendocrine tumors (pNETs) rarely produce vasopressin. Here, we reported a case of pNET producing vasopressin in a 78-year-old man with hyponatremia. PATIENT CONCERNS: The patient presented with anorexia approximately 4 years ago, and the laboratory test results indicated hyponatremia. He was hospitalized 3 times subsequently due to anorexia in the past 4 years, during which laboratory tests consistently indicated severe hyponatremia. DIAGNOSIS: Upon admission, his serum osmolarity, urine osmolarity, urine sodium level, and 24-hour urine sodium level was 277 mOsm/kg H2O, 465 mOsm/kg H2O, 82.5 mmol/L, and 140.25 mmol, respectively. Gallium-68-labeled tetraazacyclododecanetetraacetic acid-Dphel-Tyr3-octreotate positron emission tomography-computed tomography showed a high uptake lesion measuring approximately 1 cm in diameter in the pancreatic body, and the possibility of pNET was considered. Besides, laboratory tests showed that adrenocorticotropic hormone, follicle-stimulating hormone, and luteinizing hormone released by the pituitary was insufficient in the case of low levels of cortisol, estradiol, progesterone, and testosterone. Thus, the diagnosis of the syndrome of inappropriate antidiuresis (SIAD) was considered along with hypopituitarism. INTERVENTIONS: The patient underwent surgery, and pNET was confirmed by pathology examination. The immunohistochemical study showed that the tumor cells were positive for somatostatin receptors 2 and vasopressin. OUTCOMES: In the last follow-up 17 months after surgery, the patient was in good condition, taking methylprednisolone 4 mg every other day, and had been free of anorexia or hyponatremia episodes. LESSONS: This case illustrated the potential ectopic production of vasopressin resulting in SIAD in pNETs, highlighting the adoption of gallium-68-labeled tetraazacyclododecanetetraacetic acid-Dphel-Tyr3-octreotate positron emission tomography-computed tomography and vasopressin immunohistochemical staining in the evaluation of the etiology of SIAD.

LDL cholesterol levels and in-hospital bleeding in patients on high-intensity antithrombotic therapy: findings from the CCC-ACS project.

AIMS: Emerging evidence has linked cholesterol metabolism with platelet responsiveness. We sought to examine the dose-response relationship between low-density lipoprotein cholesterol (LDL-C) and major in-hospital bleeds in acute coronary syndrome (ACS) patients. METHODS AND RESULTS: Among 42 378 ACS patients treated with percutaneous coronary intervention (PCI) enrolled in 240 hospitals in the Improving Care for Cardiovascular Disease in China-ACS project from 2014 to 2019, a total of 615 major bleeds, 218 ischaemic events, and 337 deaths were recorded. After controlling for baseline variables, a non-linear relationship was observed for major bleeds, with the higher risk at lower LDL-C levels. No dose-response relationship was identified for ischaemic events and mortality. A threshold value of LDL-C <70 mg/dL was associated with an increased risk for major bleeds (adjusted odds ratio: 1.49; 95% confidence interval: 1.21-1.84) in multivariable-adjusted logistic regression models and in propensity score-matched cohorts. The results were consistent in multiple sensitivity analyses. Among ticagrelor-treated patients, the LDL-C threshold for increased bleeding risk was observed at <88 mg/dL, whereas for clopidogrel-treated patients, the threshold was <54 mg/dL. Across a full spectrum of LDL-C levels, the treatment effect size associated with ticagrelor vs. clopidogrel on major bleeds favoured clopidogrel at lower LDL-C levels, but no difference at higher LDL-C levels. CONCLUSIONS: In a nationwide ACS registry, a non-linear association was identified between LDL-C levels and major in-hospital bleeds following PCI, with the higher risk at lower levels. As the potential for confounding may exist, further studies are warranted. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02306616.