As a common protease with high similarity among coronavirus species, the main protease (M^pro) of SARS-CoV-2 is responsible for the catalytic hydrolysis of viral precursor proteins into functional proteins, which is essential for coronavirus replication and is one of the ideal targets for the development of broad-spectrum antiviral drugs. This paper reviews the main protease inhibitors of SARS-CoV-2, including their molecular structures, potencies and drug-like profiles, binding modes and structure-activity relationships, etc.

COVID-19 epidemic continues to spread around the world till these days, and it is urgent to develop more safe and effective new drugs. Due to the limited P3 biosafety laboratories for directly screening inhibitors of virulent viruses with high infectivity, it is necessary to develop rapid and efficient screening methods for viral proteases and other related targets. The main protease (M^pro), which plays a key role in the replication cycle of SARS-CoV-2, is highly conserved and has no homologous proteases in humans, making it an ideal target for drug development. From two different levels, namely, molecular level and cellular level, this paper summarizes the reported screening methods of SARS-CoV-2 M^pro inhibitors through a variety of representative examples, expecting to provide references for further development of SARS-CoV-2 M^pro inhibitors.

OBJECTIVEDietary factors that could potentially be related to the risk of birth defects are still unknown in Shanxi province, a region with high prevalence of neural tube defects(NTDs) in China. The main aim of this study was to evaluate the association between NTDs and local dietary factors.

METHODSA population-based case-control study was conducted during 2003-2005 in four selected counties of Shanxi province with 363 NTDs cases ascertained and 523 control babies without any external birth defects.

RESULTSBy multivariate logistic regression analysis, we found the NTDs risk was significantly associated with low consumption of meat and legume, high consumption of pickled vegetables, noncentralized supply of drinking water and drinking tea after adjusting for maternal education level and birth defects history. A significant dose response trend was found between the NTDs risk and the lower frequencies of meat and legume consumption and higher frequency of pickled vegetable consumption, with population attributable risks (PAR) of 69.4%, 22.0% and 18.5%, respectively. Mothers who got their drinking water from river or pond during periconceptional period were more likely to have a NTD-affected pregnancy [OR = 3.42, 95% CI: 1.44-8.09, population attributable risk (PAR) = 4.7%] compared with those who utilized tap or well water. Those who drank tea everyday had an elevated risk of having a NTD-affected pregnancy compared with those who didn't (OR = 4.65, 95% CI: 1.41-15.36, PAR = 2.6%).

CONCLUSIONHigher intake of meat and legume protects a woman from having a NTD-affected pregnancy, and consumption of pickled vegetables, drinking water from river or pond and drinking tea everyday increase the risk of having such a pregnancy in the study population.

Case-Control Studies ; China ; epidemiology ; Diet ; Female ; Humans ; Meat ; Neural Tube Defects ; epidemiology ; Pregnancy ; Risk Factors ; Vegetables ; Water Supply

Objective To explore the associations between cesarean section with different types and intensity of physical activity in the second trimester pregnant women． Methods Six hundred and seventy－two participants from the Chinese pregnant women cohort study ( CPWCS) were analyzed． The pregnancy physical activity questionnaire ( PPAQ) was used to collect the status of physical activities in pregnant women． The participants were followed up and the data of delivery way was collected． Logistic regression model was conducted to analyze the associations． Ｒesults A total of 273 pregnant women ( 40. 63%) were delivered by cesarean section． After adjusting age，pre-pregnancy BMI and history of childbirth，results of Logistic regression model showed that pregnant women with higher levels of exercise had a lower risk of cesarean section than those who did not participate in exercise ( OＲ= 0. 564，95% CI: 0. 338－0. 941) . In terms of physical activity intensity，pregnant women who participated in the higher level of moderate to vigorous physical activity had a lower risk of cesarean section than those who partici- pated in the lower level ( OＲ= 0．642，95% CI: 0．437－0．972) ． Conclusions Exercise and moderate to vigorous physical activity are protective factors for cesarean section． Health education should be further strengthened to encourage pregnant women to carry out appropriate physical activity during pregnancy．

BACKGROUNDThe long term prognosis of unprotected left main coronary artery (LMCA) stenting is controversial. This study was conducted to evaluate the immediate and long term outcomes of LMCA stenting in Chinese patients and to determine which factors affect the outcomes.

METHODSFrom May 1997 to March 2003, 224 patients in 23 hospitals underwent elective unprotected LMCA stenting with bare metal stents. Their clinical records were analysed to ascertain immediate and long term outcomes of LMCA stenting as well as factors influencing the prognosis.

RESULTSStents were implanted into LMCA successfully in 223 cases (99.6 %). One death (0.5%) and one case of non-Q wave nonfatal myocardial infarction (MI) occurred in hospital. The mean follow-up time was (15.6 +/- 12.3) months. Cardiac death developed in 10 cases (4.5%), noncardiac death in 2 cases (0.9%), nonfatal MI in 4 cases (1.8%), target lesion revascularization (TLR) of LMCA in 26 cases (11.7%) and TLR of nonLMCA in 37 cases (16.5%). Univariate analysis showed that cardiac death correlated with left ventricular ejection fraction (LVEF < 40%), female gender and LMCA combined with multivessel disease; that major adverse cardiac events (MACE) correlated with LVEF < 40%, bifurcation lesion and incomplete revascularization. Logistic regression analysis revealed that LVEF < 40% and female gender were independent predictors of cardiac death and MACE. Follow-up angiography was performed in 102 cases (45.7%). The restenosis rate was 31.4%.

CONCLUSIONSLong-term outcomes of stenting for selected patients with unprotected LMCA stenosis is acceptable. It should be performed in inoperable or low risk patients with LVEF > or = 40% and isolated LMCA disease or LMCA combined with multivessel diseases in whom complete revascularization can be obtained.

Adult ; Aged ; Aged, 80 and over ; Coronary Angiography ; Coronary Disease ; therapy ; Coronary Restenosis ; etiology ; Female ; Humans ; Male ; Middle Aged ; Prognosis ; Retrospective Studies ; Stents ; adverse effects ; Treatment Outcome

Objective To explore the influence of reproduction history on depression during pregnancy． Methods Data on 3 792 pregnant women from the Chinese pregnant women cohort study with complete information on reproduction history and depression were used in the present study． The Edinburgh postnatal depression scale was used to assess depression status among pregnant women． A chi-square test was used for univariate analysis，and a Log－binomial regression was used for multivariate analysis． The adjusted relative risks ( ＲＲs) with 95% confidence intervals ( 95% CIs) were calculated，and were presented in a forest plot． Ｒesults The results of Log－binomial regression showed that a history of delivery could increase the risk of depression during the second trimester ( ＲＲ: 1. 04，95% CI: 1. 01 － 1. 08，P= 0. 042) and the third trimester ( ＲＲ: 1. 05，95% CI: 1. 01－1. 10，P= 0. 020) ． There was a 6% increase of risk on depression in women with a history of cesarean delivery compared with women without that during the third trimester ( ＲＲ: 1. 06，95% CI: 1. 01－1. 11，P = 0. 041) ． Conclusions There is asignificant influence of reproduction history on gestational depression． Maternal and child health personnel should focus on these pregnant women，and conduct targeted health education and mental nursing． In addition，medical personnel should also pay attention to the emotional changes of these women and provide them with several adjustment strategies．

Objective To explore the association between unhealthy diets and depression in early pregnancy. Methods 7 976 women in early pregnancy were recruited and analyzed in this study from the Chinese Pregnant Women Cohort Study (CPWCS) from July 25th, 2017 to July 24th, 2018. Differences of baseline characteristics between the two groups were conducted by a chi-square test. The qualitative food frequency questionnaire and the edinburgh postnatal depression scale were used to assess depression status and food intake frequency during the first trimester respectively. Log-binomial regression was used to analyze the relationship between unhealthy diets and depression in early pregnancy. Prevalence ratio (PR) and its 95% confidence interval (95% CI) were calculated. Results Eating regularly (PR=0.45, 95% CI:0.38-0.54，P<0.001) and eating breakfast frequently (PR=0.80, 95% CI:0.72-0.90, P<0.001) were related to the low incidence of depression while frequent consumption of fried food (PR=1.25, 95% CI:1.03-1.53, P=0.027), Western-style fast food (PR=1.36, 95% CI:1.06-1.74, P=0.015) and puffed food (PR=1.37, 95% CI:1.11-1.70, P=0.003) as well as drinking sugar-sweetened beverage (PR=1.37, 95% CI:1.17-1.61, P<0.001),wine (PR=1.60, 95% CI:1.26-2.01, P<0.001) and liqueur (PR=1.26, 95% CI:1.00-1.59, P=0.047) were linked with the high incidence of depression. Conclusions There might be an association between unhealthy diets and depression in early pregnancy. Pregnant women should take the initiative to better understand what are healthy diets and reduce the frequency of unhealthy diets consumption to decrease the incidence of depression during pregnancy.

OBJECTIVETo evaluate the sensitivity and specificity of CD8CD28/CD8CD28T lymphocyte balance in predicting the gastrointestinal hemorrhage (GH) in patients with inflammatory bowel disease (IBD).

METHODSForty-nine IBD patients, including 30 with ulcerous colitis (UC) and 19 with Crohn's disease (CD), were enrolled to test peripheral blood CD8CD28and CD8CD28T cells using flow cytometry. All the patients were followed up for one year. The receiver-operating characteristic (ROC) curves were used to test the efficiency of CD8CD28/CD8CD28T lymphocyte balance to predict GH. The differences in lasting time of remission (LTR) under different factors were compared using Kaplan-Meier survival analysis, and the correlation between CD8T lymphocytes and the factors were analyzed.

RESULTSThe utilization rates of immunosuppressant, steroids, and biological agent (BA) were significantly higher in CD patients than in UC patients (P=0.003, 0.043 and 0.002, respectively). The frequencies of CD8CD28T cells were obviously higher in UC patients than those in CD patients (t=3.022, P=0.004). CD8CD28T cells, CD8CD28T cells, and especially CD8CD28/CD8CD28ratio (area under curve of 0.977, P=0.000; cut-off value of 1.14 [13.95%/12.24%] with a sensitivity of 93.3% and a specificity of 91.2%) showed good efficiencies in predicting GH (P<0.01). The mean and median of LTR of IBD patients who did not receive BA or surgical treatment were significantly longer (Χ=9.730, P=0.002; Χ=15.981, P=0.000). CD8CD28/CD8CD28ratio was significantly related to both BA (P=0.009) and surgery (P=0.038).

CONCLUSIONBoth decreased CD8CD28T cells and elevated CD8CD28T cells are closely correlated with GH, and their ratio can predict the occurrence of GH with a high sensitivity and specificity and is correlated with BA and surgery at the cut-off value of 1.14.

Radiotherapy is widely used in the management of advanced colorectal cancer (CRC). However, the clinical efficacy is limited by the safe irradiated dose. Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation. The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination (HR) DSB repair, and its functions may be affected by HERC2 or BAP1. Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes; however, the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn't been defined. Through activity-based profiling, we identified PT33 as an active entity for HR repair suppression. Subsequently, we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen. Mechanistically, pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, interrupting HR repair. Consequently, PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo. Overall, these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.