The ongoing outbreak of the coronavirus disease 2019 (COVID-19) as named by the World Health Organization has millions of confirmed cases around the world and has claimed hundreds of thousands of lives. The virus was named SARS-CoV-2 in February by International Committee on Taxonomy of Viruses. COVID-19 presents as fever, dry cough, dyspnea, headache and pneumonia. In a small subset of severe cases, the disease quickly progresses to respiratory failure and even death. Since the 21st century, there have been three major outbreaks caused by human coronaviruses, including the severe acute respiratory syndrome (SARS) that broke out in 2003, the Middle East respiratory syndrome (MERS) in 2012, and the recent pandemic of COVID-19. Since 2003, significant progress has been made in the study of SARS-CoV and MERS-CoV concerning their natural origins, pathogenesis, antiviral development and vaccine design. Since SARS-CoV-2 and SARS-CoV are closely related, previous findings on SARS-CoV are highly relevant to a better understanding as well as diagnosis, treatment, prevention and control of SARS-CoV-2. In this review, we highlight recent progresses in the field; compare the biological characteristics of SARS-CoV and SARS-CoV-2; summarize the urgently-needed diagnostic, treatment, prevention and control options; and provide future perspectives for the outcome of the outbreak and research questions to be answered, including some of the difficulties in vaccine development. Hopefully, our comments and suggestions would prove useful for the control of the SARS-CoV-2 epidemic in China and the world.
Antiviral Agents ; pharmacology ; therapeutic use ; Betacoronavirus ; drug effects ; immunology ; pathogenicity ; Coronavirus Infections ; diagnosis ; prevention & control ; therapy ; virology ; Humans ; Middle East Respiratory Syndrome Coronavirus ; drug effects ; immunology ; pathogenicity ; Pandemics ; prevention & control ; Pneumonia, Viral ; diagnosis ; prevention & control ; therapy ; virology ; SARS Virus ; drug effects ; immunology ; pathogenicity ; Severe Acute Respiratory Syndrome ; diagnosis ; prevention & control ; therapy ; virology ; Viral Vaccines

In consideration of the population aging and growing demands for elderly health care, medical institutions in China are faced with severe challenges. Medical knowledge, given its potential to guide clinical practice, cannot apply to clinical practice directly, and a synergy research network should be built among diversified organizations instead. Authors of this paper described the roadblocks against building a medical synergy network, and presented the experiences of Huashan Hospital, Fudan University in its exploration and development of National Clinical Research Center for Aging and Medicine. In view of major setbacks such as the absence of the following factors, namely the trust towards medical evidences produced in other facilities, a trans-organizational information sharing system, a referral procedure, clear requirements at hospital management level, and a well-functioning reimbursement mechanism. Hence the hospital is required to enhance its functionality of clinical research and play a more active role in the clinical research eco-system.

OBJECTIVETo investigate the effects of cAMP-response element binding protein-1 (CREB-1) on transforming growth factor-b3 (TGF b3) mRNA expression and promoter activity in hepatic stellate cells (HSCs).

METHODSFreshly isolated HSCs from rats were divided into six groups: CREB-1 expression plasmid transfected group (C), siRNA-CREB-1 plasmid transfected group (S), negative control group (N), forskolin treated group (F), H-89 treated group (H), and blank group (B). Rats in each group were further sub-divided according to whether (+) or not (-) they were exposed to exogenous TGF b3. TGF b3 mRNA expression was measured by real time quantitative PCR. HSCs of the C, S, N, F, H and B groups were transfected with the TGF b3 promoter luciferase reporter plasmid (PGL3-TGF b3-P; W group), the TGF b3 promoter luciferase reporter plasmid with CRE mutation (PGL3-basic-TGF b3P-mCRE; M group) and the renilla luciferase control plasmid (pRL-SV40; control group). TGF b3 promoter activity was assessed by luciferase reporter assays.

RESULTSCompared to N(-), the TGF b3 mRNA expression was reduced to 0.69+/-0.15 in S(-) (P less than 0.05) and increased to 4.68+/-2.76 in C(-) (P more than 0.05). Compared to B(-), the TGF b3 mRNA expression was reduced to 0.57+/-0.08 in H(-) (P less than 0.05). The differences between N(+) and N(-), S(+) and S(-), B(+) and B(-), and H(+) and H(-) were all significant (P less than 0.05). The values of TGF b3 promoter activity in S(W), N(W), and C(W) were 0.062+/-0.013, 0.122+/-0.011, and 0.165+/-0.016 (P less than 0.05), but the changes of TGF b3 promoter activity in S(M), N(M), and C(M) were not significant (P more than 0.05). The values of TGF b3 promoter activity in H(W), B(W), and F(W) were 0.154+/-0.010, 0.188+/-0.016, and 0.276+/-0.031 (P less than 0.05), but the changes of TGF b3 promoter activity in H(M), B(M), and F(M) were not significant (P more than 0.05).

CONCLUSIONIncreased levels of CREB-1 mRNA or p-CREB-1 up-regulate the TGF b3 mRNA expression and promoter activity in rat HSCs. The CRE site in the TGF b3 promoter is critical for this effect, and the gene's activity becomes significantly decreased when the site is missing. Exogenous TGF b3 enhances expression of endogenous TGF b3 in rat HSCs.

Animals ; Cells, Cultured ; Cyclic AMP Response Element-Binding Protein ; metabolism ; Hepatic Stellate Cells ; metabolism ; Promoter Regions, Genetic ; RNA, Messenger ; genetics ; Rats ; Transforming Growth Factor beta3 ; genetics

Extracranial carotid artery occlusive disease is a major cause of ischemic stroke in Caucasians. However, intracranial artery occlusive disease, especially middle cerebral artery (MCA) stenosis is more significant in Asians. The underlying mechanisms of ischemic stroke with intracranial artery occlusive lesions is different from that of extracranial artery it is expected to recognize the pathogenesis and epidemiology of intracranial artery occlusive disease. By digital magnetic resonance angiography (MRA) and transcranial doppler (TCD) instead of traumatic subtract angiography methods for screening diagnosis of intracranial artery stenosis that were developed in recent two decades. In current paper, we summarized the results studied with MRA and TCD in Peking Union Medical College Hospital and Chinese University of Hong Kong with literatures reviews in this field. Two aspects are discussed (1) Methods for diagnosis of intracranial artery stenosis; (2) Epidemiology of intracranial artery stenosis.
Angiography, Digital Subtraction ; Carotid Artery, Internal ; diagnostic imaging ; Carotid Stenosis ; diagnosis ; epidemiology ; Cerebral Arteries ; diagnostic imaging ; China ; epidemiology ; Constriction, Pathologic ; diagnosis ; diagnostic imaging ; Humans ; Infarction, Middle Cerebral Artery ; diagnosis ; diagnostic imaging ; Intracranial Arteriosclerosis ; diagnosis ; epidemiology ; Magnetic Resonance Imaging ; Ultrasonography, Doppler, Transcranial

The aim of this study was to investigate the effect of human bone marrow mesenchymal stem cells on human T-cell proliferation resulted from stimulation with PHA and possible immunomodulating mechanism. T cells were positively selected by CD3(+) magnetic beads, and were then co-cultured with irradiated MSCs overnight before the addition of PHA. T-cell proliferation was measured by BrdU assay and the degree of apoptosis was assessed by flow cytometry with Annexin V/PI. T cells co-cultured with or without MSCs were treated with PHA for 72 hours, then harvested. They were labeled with anti-CD4, anti-CD8, anti-CD25 antibodies and analyzed by flow cytometry. The results showed that MSCs inhibited T-cell proliferation, but did not induce T cell apoptosis. There were no significant changes in the ratio of CD4(+) and CD8(+) T cells of MSC-treated group, as compared with the control group. After stimulation with PHA, there was an increase in CD4(+) T cells and decrease of CD4(+)CD25(+) cells in MSC co-cultured group. It is concluded that the MSCs inhibit T-cell proliferation after stimulation with PHA, and show more inhibitive effects on CD8(+) and CD4(+) T cells, but CD25(+) regulatory T cells may not be involved in this process.
Bone Marrow Cells ; cytology ; CD4-CD8 Ratio ; Cell Proliferation ; Cells, Cultured ; Coculture Techniques ; Humans ; Mesenchymal Stromal Cells ; cytology ; physiology ; T-Lymphocyte Subsets ; cytology

Objective To understand the prevailing status of coal-burning endemic fluorosis in Henan, and to provide scientific grounds for endemic fluorosis prevention. Methods Undertook general surveillance on factors such as coal using, living habit, main foods, the structure of the houses and the fluoride content in drinking-water among 1832 historical coal-burning endemic fluorosis villages within 13 counties in 2006 and 2007, and conducted focal point sampling survey on 216 villages which still using local high-fluoride. For all children aged 8-12 years of each village, conducted dental fluorosis examination and collected 30 immediate urinary samples for fluoride content determination. Results The fluoride content in drinking-water of all historical fluorosis villages was below 1.0 mg/L. Households having individual kitchens accounted for 93.7%(241 281/257 393), those with stoves having smoke evacuation devices accounted for 41.9% (107 917/257 393), those using local high-fluoride coal for cooking accounted for 28.6%(73 686/257 393), those using local high-fluoride coal for heating accounted for 24.1%(61 924/257 393). Villages with serf-supply of main foods accounted for 95.7%(1753/1832) of all fluorosis villages. Solar drying food was used in all households. Villages with dental fluorosis detection rate for children aged 8 to 12 years above 30.0% accounted for 16.2%(35/216), which axe all in Luoyang City. Among 77.8%(168/216) of fluorosis villages, children' s urinary fluoride concentrations were no higher than 1.50 mg/L. Conclusions Coal-burning endemic fluorosis areas in Henan Province were decreased greatly and the extent of the health hazard was becoming slightly. The detection rate of dental fluorosis for children aged 8 to 12 years of 8 counties had reached the standard for fluorosis control, whereas the other 5 counties had not yet, all located in Luoyang City.

Objective To determine the value and the optimal cutoff point of waist circumference (WC) in screening diabetes mellitus (DM) and to provide evidence for DM prevention and identifying population at risk in mid-western rural areas of Shandong province.Methods A sample consisting 16 341 rural residents was selected and studied.All participants were physically examined on height,weight,WC and fasting plasma glucose (FPG).Oral glucose tolerance test (OGTT) was performed for subjects with FPG valued from 6.1 to 7.0 mmol/L.DM was defined according to the criteria set by WHO in 1999.Area under the curve (AUC),sensitivity,specificity and Youden index were computed based on the receiver operating characteristic (ROC) curve analysis.Optimal cutoff point was determined by the maximum of Youden index.Results The prevalence rates of DM for males and females increased along with the rise of WC (trend test X2=72.01,122.65,P＜0.01 ).It appeared significantly higher in those with WC 85 cm in females and≥80 cm in males,with those WC ＜85 cm for females and ＜80 cm for males,in particular.AUCs were 0.639 and 0.655 for males and females respectively and both had significant differences (t=7.22,11.07,P ＜0.01 ).However,the AUCs did not show significant difference (t=0.70,P ＞ 0.05) between males and females.The Youden index reached maximum when WC approached 85 cm for females (24.90%) and 80 cm for males (24.39%).The sensitivity and specificity were 58.04%and 66.86%for males,and 67.08%and 57.31%for females.Conclusion WC seemed to be an effective indicator for screening the DM.The optimal cutoff point of WC would be 85 cm for females and 80 cm for males in screening DM and defining the population at risk in this area.

Objective To compare the curative effects ofziprasidone and aripiprazole at acute stage on patients with drug-naive schizophrenia and their effects on metabolism of these patients.Methods Forty-six patients with drug-naive schizophrenia,admitted to our hospital from February 2010 to February 2011,were divided into ziprasidone treatment group (n=24,[165±13.51] mg/d) and aripiprazole treatment group (n=22,[28.86±3.06] mg/d); these patients were given the above treatment for 6 week.The scores of positive and negative syndrome scale (PANSS),body mass index (BMI),insulin resistance index (IRI),and levels of fasting blood glucose (FBG),insulin (INS),C-Peptide (CP),total cholesterol (TC),high density lipoprotein cholesterol (HDL-C),low density lipoprotein cholesterol (LDL-C),triglyceride (TG),apolipoprotein-a (APOA) and apolipoprotein-b (APOB) were obtained before and at the end of treatment.Results At the end of treatment,2 patients (9.1％) were cured,7 (31.8％)achieved obvious improvement,9 (40.9％) achieved improvement,and only 4 (18.2％) did not achieve any improvement in the aripiprazole treatment group.However,at the end of treatment,no patient (0％)was cured,7 (29.2％) achieved obvious improvement,12 (50％) achieved improvement,and 5 (20.8％)did not achieve any improvement in the ziprasidone treatment group.The total scores of PANSS after the treatment in both groups decreased significantly as compared with those before treatment (P＜0.05).The BMI ([20.14±2.63] kg/m2) in the ziprasidone treatment group at the end of treatment was obviously increased as compared with that ([19.68±2.76] kg/m2) before treatment (P＜0.05).The FBG ([4.38±0.59]mmmol/L) at the end of treatment decreased significantly as compared with those before treatment ([4.79±0.59] mmmol/L),and the BMI ([19.65±2.15] kg/m2) was obviously increased as compared with that before treatment ([19.19±2.28] kg/m2) in the aripiprazole treatment group (P＜0.05).The metabolic index in the 2 groups was not significantly different at the end of the treatment (P＞0.05).Conclusion Both ziprasidone and olanzapine are effective in the treatment of patients with drug-naive schizophrenia;both of them have mild effects on weight of patients with drug-naive schizophrenia,but no obvious effects on other metabolic indices.

Objective: To investigate the protective effects of grape seed proanthocyanidin extracts ( GSPE ) against CoCl 2-induced hypoxic injury in cultured RGC-5 cells.Mtehods: CoCl 2( 400 μmol L/) was used to induce hypoxic injury in cultured RGC-5 cells;the cells were pretreated with 0, 100, 200, 400 and 800μmol/L GSPE for 24h. The cell viability was assayed by MTT; the apoptosis was detected by Hoechst 33342 staining;the intracellular reactive oxygen species ( ROS) was measured by H2DCFDA oxidative reaction.The mRNA expression of Bcl-2, caspase 9 and caspase 3 was determined by real-time PCR.Results: Compared to hypoxic control group, pretreatment with GSPE significantly increased viability of RGC-5 cells ( P <0.001 ) , reduced cell apoptosis ( P<0.001 ) and intracellular ROS ( P<0.001 ) .In addition , GSPE significantly increased the mRNA expression of Bcl-2 (P<0.001 ) and decreased mRNA expression of caspase 9 ( P <0.001 ) and caspase 3 ( P<0.001 ) compared to hypoxic control group .Conclusion: GSPE may have a protective effect against CoCl 2-induced hypoxic injury in cultured RGC -5 cells. The decrease of intercellular ROS , up-regulation of Bcl-2 and down-regulation of caspase 9 and caspase 3 may be involved in the mechanism of the protective effect of GSPE .

The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics. Drugging the multi-functional papain-like protease (PLpro) domain of the viral nsp3 holds promise. However, none of the known coronavirus PLpro inhibitors has been shown to be in vivo active. Herein, we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity, including against the Sarbecoviruses (SARS-CoV-1 and SARS-CoV-2), Merbecovirus (MERS-CoV), as well as the Alphacoronavirus (hCoV-229E and hCoV-OC43). Importantly, F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice. F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage, as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity. Despite the significant difference of substrate recognition, mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue, whereas an allosteric inhibitor of MERS-PLpro interacting with its 271E position. Our proof-of-concept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anti-coronavirus agents. The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.
Animals ; Coronavirus Papain-Like Proteases/antagonists & inhibitors* ; Cricetinae ; Humans ; Mice ; Pandemics ; SARS-CoV-2/enzymology* ; COVID-19 Drug Treatment