Acute high altitude disease (AHAD) is a general term for a series of clinical reactions that occur when the body fails to adapt to the low-pressure hypoxic environment of high altitudes. Mild cases can cause symptoms such as headache, nausea and vomiting, while more severe cases can lead to life-threatening conditions such as pulmonary edema, cerebral edema and other critical conditions that can be fatal. With the increasing demand for high altitudes deployment, understanding the common preventive measures of AHAD can reduce its morbidity or mortality to a certain extent, which is of great benefit to those who reside temporarily at high altitudes. In recent years, as people's health awareness has improved, there has been a growing attention towards non-pharmacological methods of disease prevention. At the same time, non-pharmacological therapy has significant therapeutic effects in preventing and treating high-altitude diseases, which has attracted the attention of researchers in this field. This review summarizes the major non-pharmacological preventive components of modern medicine and outlines the current non-pharmacological approaches to AHAD from the perspective of traditional Chinese medicine, intending to serve clinical purposes and improve the onset and prognosis of AHAD.

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (M^pro) and papain like protease (PL^pro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M^pro inhibitors and 205 PL^pro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M^pro and PL^pro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M^pro inhibitors and over 20% of PL^pro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M^pro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Humans ; Antiviral Agents/chemistry* ; COVID-19 ; COVID-19 Drug Treatment ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Protease Inhibitors/chemistry* ; SARS-CoV-2/enzymology* ; Viral Nonstructural Proteins

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors. Although hundreds of ASD risk genes, implicated in synaptic formation and transcriptional regulation, have been identified through human genetic studies, the East Asian ASD cohorts are still under-represented in genome-wide genetic studies. Here, we applied whole-exome sequencing to 369 ASD trios including probands and unaffected parents of Chinese origin. Using a joint-calling analytical pipeline based on GATK toolkits, we identified numerous de novo mutations including 55 high-impact variants and 165 moderate-impact variants, as well as de novo copy number variations containing known ASD-related genes. Importantly, combined with single-cell sequencing data from the developing human brain, we found that the expression of genes with de novo mutations was specifically enriched in the pre-, post-central gyrus (PRC, PC) and banks of the superior temporal (BST) regions in the human brain. By further analyzing the brain imaging data with ASD and healthy controls, we found that the gray volume of the right BST in ASD patients was significantly decreased compared to healthy controls, suggesting the potential structural deficits associated with ASD. Finally, we found a decrease in the seed-based functional connectivity between BST/PC/PRC and sensory areas, the insula, as well as the frontal lobes in ASD patients. This work indicated that combinatorial analysis with genome-wide screening, single-cell sequencing, and brain imaging data reveal the brain regions contributing to the etiology of ASD.
Humans ; Autism Spectrum Disorder/metabolism* ; Autistic Disorder ; Exome Sequencing ; DNA Copy Number Variations ; East Asian People ; Brain/metabolism* ; Mutation/genetics* ; Genetic Predisposition to Disease/genetics*

Objective To establish an improved type Ⅱ cardio-renal syndrome rat model and evaluate it.Methods Twenty male SD rats were randomly divided into sham and model groups with 7 rats in the sham group and 13 rats in the model group.The model group received the method of squeezing the heart under a small animal anesthesia machine to permanently ligate the left anterior descending branch of the coronary artery to cause myocardial infarction.One week later,unilateral nephrectomy(right nephrectomy)was performed.The rats underwent cardiac echocardiography,pathological staining,and blood and urine tests at 6 weeks to verify model establishment.Results Compared with the sham group,the cardiac function assessed by echocardiography and the endogenous creatinine clearance rate in the model group rats were significantly decreased(P<0.01),and the levels of brain natriuretic peptide,blood creatinine,urea nitrogen,and 24 h urine protein in the model group were significantly increased(P<0.01).HE staining revealed a disordered myocardial arrangement,glomerular atrophy,and inflammatory cell infiltration in model group rats.Picric acid-Sirius red staining showed a significant increase in myocardial collagen fibers,an irregular arrangement of renal tubules,and a large amount of collagen deposition in model group rats.The positive staining area ratio was also significantly increased(P<0.01).Conclusions This improved modeling method provided a typeⅡcardio-renal syndrome rat model with s simple operation,minimal surgical trauma,and low mortality rate.This model simulates the early onset of cardiac and renal function damage and pathological changes in type Ⅱ CRS,laying the foundation for systematic and in-depth research on the pathogenesis and pathological mechanism of type Ⅱ cardio-renal syndrome.

ObjectiveTo investigate the inhibitory effect of hederasaponin B on gastric cancer HGC-27 cell and the mechanism. MethodMethyl thiazolyl tetrazolium （MTT） assay， hematoxylin-eosin （HE） staining， 4'，6-diamidino-2-phenylindote （DAPI） staining， colony formation assay， scratch assay， and flow cytometry were employed for the analysis of apoptosis and cell cycle. Thereby， the inhibitory effect of hederasaponin B on gastric cancer HGC-27 cell was investigated. Then the Pharm Mapper， UniProt， Swissdock， STRING， and Metascape were used for target screening， gene annotation， molecular docking， protein-protein interaction （PPI） network construction， Gene Ontology （GO） term and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway analysis to explore the mechanism. ResultHederasaponin B （15， 30， 60， 120 μmol·L^-1） can significantly reduce the survival rate of HGC-27 cell （P<0.01） in a time-dependent and dose-dependent manner compared with the blank group. It had no significant toxicity to normal GES-1 cell at concentration below 120 μmol·L^-1. Compared with the blank group， hederasaponin B （30， 60， 120 μmol·L^-1） induced cytoplasmic vacuolization， and nuclear deformation and karyopyknosis， inhibited the migration of HGC-27 cell （P<0.01）， and brought about the apoptosis （P<0.05， P<0.01） and cell cycle arrest of HGC-27 cell （P<0.05， P<0.01）. Hederasaponin B （10， 20， 30 μmol·L^-1） also suppressed the independent survival ability and proliferation ability of HGC-27 cell （P<0.01）. The possible action targets were kinesin-like protein KIF11， cGMP-specific 3，5 cyclic phosphodiesterase， caspase-3， serine/threonine protein kinase Chk1， proto-oncogene tyrosine protein kinase， epidermal growth factor receptor， and mitogen-activated protein kinase （MAPK） 8. The mechanism may be related to MAPK signaling pathway （pathways in cancer）， adhesion connection， focal adhesion and proteoglycans in cancer （epithelial cell signaling pathways in Helicobacter pylori infection）. ConclusionHederasaponin B exerts significant inhibitory effect on gastric cancer HGC-27 cell through multiple targets and multiple pathways.

Objective:To analyze clinical characteristics and genetic characteristics of children with ATP sensitive potassium passage (K ATP-HI). Methods:Forty-five children with genetically confirmed K ATP-HI and their families admitted to Beijing Children′s Hospital of Capital Medical University between February 2002 and December 2018 were selected as the study subjects. A detailed retrospective analysis of the patient's clinical characteristics, diagnosis and treatment process, disease-causing gene carrying status and later follow-up data was performed. ABCC8/KCNJ11 gene was sequenced by second-generation sequencing technology. Results:Among 45 children with K ATP-HI, 34 cases (75.6%) were neonatal onset, the first symptoms of 21 cases (46.7%) were convulsions. 39 cases had been treated with diazoxide, including 12 cases (30.8%) with good efficacy, 16 cases (41%) with poor efficacy and 11 cases with uncertain efficacy. Octreotide was further applied in 18 patients with uncertain or ineffective efficacy after diazoxide treatment, and 13 cases (72.2%) were effective, 3 cases were ineffective, and 2 cases were uncertain. 10 CHI patients who were ineffective to drug treatment or had clearly focal lesions confirmed by 18F-dopa positron emission by computed tomography ( 18F-DOPA PET) scans had undergone surgical treatment, 8 of which underwent partial pancreatectomy and blood glucose returned to normal after the operation; the other 2 cases underwent subtotal pancreatectomy and both had secondary diabetes after operation. Among 45 children with K ATP-HI, 1 case carried both ABCC8 and KCNJ11 mutations, 10 cases carried ABCC8 compound heterozygous mutations, and the remaining 34 cases carried ABCC8/KCNJ11 single genetic mutation. Among them, 21 cases had paternal inheritance, and 3 cases had maternal inheritance, 6 cases were identified with de novo mutations. Conclusions:Diazoxide treatment was ineffective for most K ATP-HI children, but octreotide had a higher effective rate. Partial pancreatectomy for focal type patients had a higher cure rate, and there was a risk of secondary diabetes after subproximal pancreatectomy, so it was very important to clarify the histological type of children before surgery. ABCC8 gene mutations and KCNJ11 gene mutations were the main pathogenic genes of K ATP-HI. Among patients carrying mutations in single ABCC8 or KCNJ11 gene mutation, K ATP-HI inherited by paternity were the majority. Some K ATP-HI children can relieve the hypoglycemia symptoms by themselves.

Objective:To explore the effect of group cognitive behavior therapy (GCBT) on anxiety, depression and quality of life in patients with chronic obstructive pulmonary disease (COPD) in community.Methods:From August to November 2019, patients with moderate COPD in 18 communities in Xuzhou City were randomly divided into the intervention group ( n=240) and the control group ( n=223). The control group received routine management and the intervention group received group cognitive behavioral therapy intervention for 8 weeks on the basis of routine management.Before and after the intervention, FEV 1% predicted value and FEV 1/FVC were measured by pulmonary function tester.Hospital Anxiety and Depression Scale (HADS) was used to evaluate the anxiety and depression of patients.St.George's respiratory questionnaire (SGRQ), COPD assessment test (CAT) and modified medical research council dyspnea (mMRC) were used to evaluate the quality of life of patients.SPSS 20.0 software was used for analysis.The χ 2 test, independent sample t-test, paired sample t-test were used for statistical analysis. Results:After 8 weeks of intervention, the anxiety and depression scores of the intervention group were lower than those of the control group (anxiety: (8.23±4.02) vs (10.71±3.60); depression: (7.87±3.73) vs (10.20±3.72)( t=6.415, 6.185, both P<0.01). After the intervention, there was no significant difference in FEV 1%((51.7±12.3)% vs (52.0±12.6)%) predicted value and FEV 1/FVC((57.3±10.8)% vs (56.9±10.7)%) between the two groups( t=-0.259, 0.400, both P>0.05). The scores of CAT, mMRC and SGRQ in the intervention group were lower than those in the control group((17.35±5.78) vs (20.90±8.00), (1.55±0.82) vs (2.30±1.21), (41.78±21.56) vs (57.08±24.46))( t=-5.061, -7.227, -6.580, all P<0.01). Conclusion:Group cognitive behavioral therapy can relieve the anxiety and depression and improve the quality of life of patients with COPD.

Periodontitis patients are at risk of alveolar bone loss during orthodontic treatment. The aim of this study was to investigate whether intermittent parathyroid hormone (1-34) treatment (iPTH) could reduce alveolar bone loss during orthodontic tooth movement (OTM) in individuals with periodontitis and the underlying mechanism. A rat model of OTM in the context of periodontitis was established and alveolar bone loss was observed. The control, iPTH and iPTH + stattic groups received injections of vehicle, PTH and vehicle, or PTH and the signal transducer and activator of transcription 3 (STAT3) inhibitor stattic, respectively. iPTH prevented alveolar bone loss by enhancing osteogenesis and suppressing bone resorption in the alveolar bone during OTM in rats with periodontitis. This effect of iPTH was along with STAT3 activation and reduced by a local injection of stattic. iPTH promoted osteoblastic differentiation and might further regulate the Wnt/β-catenin pathway in a STAT3-dependent manner. The findings of this study suggest that iPTH might reduce alveolar bone loss during OTM in rats with periodontitis through STAT3/β-catenin crosstalk.
Animals ; Homeostasis ; Humans ; Osteogenesis ; Parathyroid Hormone ; Periodontitis/drug therapy* ; Rats ; STAT3 Transcription Factor/metabolism* ; Tooth Movement Techniques ; beta Catenin

Objective:To investigate the prevalence and risk factors of stroke in Xuzhou city.Methods:A total of 41 932 residents aged 18 years and above were selected using the multi-stage stratified cluster sampling method. A questionnaire survey was conducted to investigate the rate of stroke, and a physical examination was performed to investigate height, weight, blood pressure, etc. Univariate analyses of stroke were performed using the Chi square test and trend chi-square test. Logistic regression analysis was performed for multi-factor analysis.Results:A total of 39 854 participants (19 222 males, 10 323 from urban areas) from 41 932 eligible participants were included in the statistical analysis, and their average age was (52.1±16.8). In this study, 885 stroke patients (464 males, 302 from urban areas) were found among 39 854 participants. The prevalence of stroke was 2 220.61/100 000, which was separately 2 413.90/100 000 and 2 040.52/100 000 among males and females. The difference between males and females was significant (χ2=6.22, P=0.013). The prevalence of stroke in urban areas (2 925.51/100 000) was higher than in rural areas (1 974.20/100 000) (χ2 =31.45, P<0.001). The results of univariate analysis revealed that the risk factors for stroke were [ OR(95% CI)] smoking [1.82(1.53-2.08)], drinking [1.22(1.08-1.81)], sleep quality [1.42(1.13-1.96)], physical activities [1.44(1.11-2.14)], hypertension [3.53(2.44-6.02)], heart disease [1.23(1.11-1.75)], diabetes [1.42(1.31-2.05)], family history of hypertension [1.43(1.30-2.37)], family history of diabetes [1.22(1.10-1.65)], and family history of stroke [1.57(1.46-2.06)]. Logistic regression analysis showed that age [3.02(2.14-4.96)], smoking [1.59(1.12-3.85)], poor sleep quality [1.15(1.03-3.23)], lack of physical activity [1.22(1.08-3.38)], hypertension [4.53(3.07-7.36)], diabetes [1.08(1.02-3.23)], and family history of stroke [1.15(1.08-3.31)] were related to stroke. Conclusion:The epidemic of stroke in Xuzhou city was relatively high, and prevention and control measures of stroke should be taken according to the risk factors of stroke in the population distribution.

Objective: To explore the value of baseline geriatric nutritional risk index (GNRI) in evaluating the prognosis of patients with end-stage renal disease (ESRD) who underwent peritoneal dialysis (PD). Methods: The clinical data of patients who underwent PD catheterization and started PD therapy at the First Affiliated Hospital of Zhengzhou University from January 1, 2013 to December 30, 2018 were collected retrospectively. The follow-up endpoint was death or hemodialysis. The follow-up deadline was March 1, 2019. The GNRI cut-off value was determined according to the ROC curve, and the patients were divided into GNRI≤90.5 group and GNRI>90.5 group. The differences of clinical data and laboratory tests were compared between the two groups. Kaplan-Meier survival curves were used to compare the difference in PD rate between the two groups during follow-up, and the factors that affecting patients PD withdrawal were analyzed by Cox regression. Results: The GNRI cut-off value was determined to be 90.5 based on the ROC curve. Until the deadline for follow-up, the drop-out rate of GNRI≤90.5 group was significantly higher than the GNRI>90.5 group (35.88% vs 21.58%, P=0.003). Kaplan-Meier survival curves showed a higher rate of maintaining PD in the GNRI>90.5 group than that in GNRI≤90.5 group during follow-up (P=0.021). Cox univariate regression showed that male, GNRI and serum Alb were protective factors for PD patients, and Scr was a risk factor. After multiple factors correction, male and GNRI were also the protective factors for PD patients. Conclusion As an objective indicator of nutritional evaluation, baseline GNRI can be used as a prognostic indicator for PD patients.