Evading host immunity killing is a critical step for virus survival. Inhibiting viral immune escape is crucial for the treatment of viral diseases. Serine/threonine kinase 39 (STK39) was reported to play an essential role in ion homeostasis. However, its potential role and mechanism in viral infection remain unknown. In this study, we found that viral infection promoted STK39 expression. Consequently, overexpressed STK39 inhibited the phosphorylation of interferon regulatory factor 3 (IRF3) and the production of type I interferon, which led to viral replication and immune escape. Genetic ablation or pharmacological inhibition of STK39 significantly protected mice from viral infection. Mechanistically, mass spectrometry and immunoprecipitation assays identified that STK39 interacted with PPP2R1A (a scaffold subunit of protein phosphatase 2A (PP2A)) in a kinase activity-dependent manner. This interaction inhibited DDB1 and CUL4 associated factor 1 (DCAF1)-mediated PPP2R1A degradation, maintained the stabilization and phosphatase activity of PP2A, which, in turn, suppressed the phosphorylation of IRF3, decreased the production of type I interferon, and then strengthened viral replication. Thus, our study provides a novel theoretical basis for viral immune escape, and STK39 may be a potential therapeutic target for viral infectious diseases.

The clinical antiprotozoal drug nitazoxanide has been demonstrated to improve the experimental diabetes mellitus, lipid metabolism disorders, atherosclerosis and inhibit inflammation. Since the pathogenesis of heart failure with preserved ejection (HFpEF) is multifactorial and closely associated with the aforementioned diseases, we aim to study the effect of nitazoxanide on high-fat diet (HFD) plus L-NAME (N ω-nitro-l-arginine methyl ester)-induced HFpEF and metabolic syndrome in mice. We found that oral nitazoxanide improved cardiac hypertrophy, cardiac fibrosis, cardiac diastolic dysfunction, increased blood pressure, impaired exercise tolerance, impaired glucose handling, serum lipid disorders, hepatic steatosis, increased weight of white adipose tissues and kidney fibrosis in HFD + L-NAME-treated mice. In the established HFD + L-NAME-induced HFpEF and metabolic syndrome mouse model, therapeutic treatment with nitazoxanide rescued HFD + L-NAME-induced pathological phenotypes as mentioned above. The in vitro experiments revealed that tizoxanide, the active metabolite of nitazoxanide, increased the basal mitochondria metabolism of cardiomyocytes, inhibited cardiomyocyte hypertrophy and collagen secretion from cardiac fibroblasts, and relaxed phenylephrine- and U46619-induced constriction of rat mesenteric arteries, indicating that the direct effect of tizoxanide might partly contribute to the protective effect of nitazoxanide against HFpEF in vivo. The present study suggests that nitazoxanide might be a potential drug for HFpEF and metabolic syndrome therapy.

Objective To observe the changes of plasma gastrointestinal hormones in motion sickness sensitive and insensitive individuals before and after vertical oscillation stimulation,and to construct a susceptibility prediction model for motion sickness.Methods A total of 60 healthy male volunteers were enrolled to receive sinusoidal vertical oscillation stimulation for 45 min.The motion sickness susceptibility questionnaire(MSSQ)was filled out before the experiment.Immediately after motion,the severity of motion sickness was evaluated by Graybiel scale.The motion sickness sensitive(Graybiel score≥8 and MSSQ susceptibility index＞21,n=15)and insensitive(Graybiel score≤2 and MSSQ susceptibility index＜5,n=15)participants were screened.Plasma levels of glucagon-like peptide-1(GLP-1),cholecystokinin(CCK),leptin,ghrelin,neuropeptide Y(NPY)and orexin A(OXA)were detected by enzyme-linked immunosorbent assay before and after vertical oscillation stimulation.Logistic regression model was used to analyze the predictive effect of plasma gastrointestinal hormone levels on susceptibility to motion sickness,and a combined predictive model was established.Receiver operating characteristic(ROC)curve was used to analyze predictive value of the model.Results Ghrelin and CCK levels were significantly increased in the sensitive group after stimulation compared with those before stimulation(both P＜0.01),while NPY and leptin levels were significantly decreased(both P＜0.01).Similar results were also observed when compared with the insensitive group after stimulation.Multivariate logistic regression analysis showed that plasma ghrelin,CCK and NPY were independent predictors of susceptibility to motion sickness.The established susceptibility prediction model for motion sickness was logit(P)=-0.051 ×ghrelin+0.060× NPY-0.169 ×CCK+33.397.ROC curve analysis showed that area under curve(AUC)value of the prediction model was 0.988,the sensitivity and specificity were 100.0％and 93.3％,respectively,and the prediction effect was better than ghrelin,CCK and NPY alone(AUC=0.792,0.880,0.838).Conclusion The changes of peripheral gastrointestinal appetite regulating hormone levels may be related to the susceptibility to motion sickness.The combined use of these indicators can predict the susceptibility to motion sickness.

Objective To explore the improving effects of motion sickness acclimatization training methods,namely sinusoidal vertical oscillation stimulation and sinusoidal vertical oscillation stimulation combined with visual virtual reality(VR)swell stimulation,on cognitive performance of individuals with extremely severe motion sickness.Methods A total of 90 individuals with extremely severe motion sickness screened by the Graybiel score during 6 h navigation were randomly divided into vertical group,vertical+VR group,and control group(n=30).The abilities of vigilance,memory,rapid calculation,information processing and visual manipulation were evaluated before and after the acclimatization training using a self-developed cognitive performance evaluation software.Results On the 1st day of training,the numbers of missed targets of the vertical group and vertical+VR group were increased in the vigilance test;the reaction time was prolonged in the short-term memory,rapid calculation,information processing and visual manipulation tasks;and the efficiency of rapid calculation was reduced.After acclimatization training,the numbers of missed targets were reduced to the baseline level in the vertical and vertical+VR groups,and the reaction time in the short-term memory,rapid calculation,information processing and visual manipulation tasks and the efficiency of rapid calculation were improved.Conclusion Motion sickness caused by vertical oscillation stimulation or vertical oscillation combined with visual VR swell stimulation can decrease vigilance,short-term memory,rapid calculation,information processing and visual manipulation abilities.Motion sickness acclimatization training can significantly improve the above cognitive abilities.

Objective To study the acclimatization time and effects for preventing motion sickness under sinusoidal vertical oscillation stimulation,visual virtual reality(VR)swell stimulation,and their combined stimulation.Methods Totally 120 individuals with extremely severe motion sickness during 6 h navigation were randomly divided into 4 groups(n=30):vertical group,VR group,vertical+VR group,and control group.The severity of symptoms during the training period was assessed daily by Graybiel scale,and the number of drops from flexible treadmill in the VR group was recorded.The Graybiel score of 0 for 3 d and/or the number of drops for 0 were considered as complete acclimatization.The training effect was validated by navigation under more severe sea conditions.Results The Graybiel scores of the vertical group and vertical+VR group,as well as the number of drops of the VR group were decreased with the increase of training days,and reached the acclimatization level on the 3rd,5th,and 2nd training day,respectively.The longest acclimatization time in the vertical,vertical+VR,and VR groups was 8,8,and 5 d,with an average acclimatization time of 3.6,3.9,and 2.7 d,respectively;the acclimatization rates within 5 d were 93.33％(28/30),76.67％(23/30),and 100.00％(30/30),respectively;the proportions of individuals with effective acclimatization training in the verification voyage were 86.67％(26/30),96.67％(29/30),and 66.67％(20/30),respectively;and the training efficiency was 85.19％,96.30％,and 62.97％,respectively.Conclusion Three training methods all have effects on motion sickness acclimatization,and the acclimatization period is 5-8 d.The acclimatization effects of the vertical oscillation and vertical oscillation+VR training are better than the VR training.

Objective To observe the effect of the supine-posture ripple wood training in preventing motion sickness caused by linear acceleration.Methods Totally 61 motion sickness sensitive males were screened by a vertical oscillation simulator and divided into mildly sensitive group(Graybiel score 1-15,n=28)and severely sensitive group(Graybiel score 16,n=33).The participants in the 2 groups received 5-d ripple wood training,30 min/d.The movement frequency of the ripper wood was maintained at 0.25-0.35 Hz,with an acceleration of 0.15-0.25 g.Graybiel score during the training period was recorded.The static balance function test was conducted before and after training on the 1st and 5th day.Results During the training period,the Graybiel scores and motion sickness incidence in the severely sensitive group were decreased with the increase of training days,and all participants achieved complete acclimatization on the 4th day.The Graybiel scores of the mildly sensitive group were low during the whole period,and the complete acclimatization period was 2 d.There was no significant difference in the sway area of the severely sensitive group in static balance function test before and after training(P＞0.05).The mean velocity of the severely sensitive group in static balance function test was significantly increased after training versus before training on the 1st day(P＜0.01),and there was no significant difference before and after training on the 5th day(P＞0.05).There were no significant differences in the sway area or mean velocity of the mildly sensitive group during the whole training period(all P＞0.05).The validation experiment showed that the motion sickness incidence and the symptom severity were significantly decreased in both groups;the motion sickness incidence of the mildly sensitive group decreased from 100.00％(28/28)to 35.71％(10/28);the incidence of severe symptoms in the severely sensitive group decreased from 100.00％(33/33)to 6.06％(2/33)and the vomiting incidence decreased from 96.97％(32/33)to 6.06％(2/33).Conclusion The supine-posture ripple wood training has great effect in preventing motion sickness,with widespread use and simple operation.

Objective To observe the distribution characteristics of motion sickness susceptibility and compare the efficacy of modified motion sickness susceptibility questionnaire(MSSQ),motion sickness history questionnaire and Graybiel scale in evaluating motion sickness.Methods The susceptibility to motion sickness and historical symptoms were investigated using MSSQ and motion sickness history questionnaire among 1 661 males in navy units A,B,and C.A total of 389 people from the unit C were selected for simulating vertical oscillation stimulation,and the severity of motion sickness was evaluated by Graybiel scale during the stimulation process.The evaluation efficacy of MSSQ,motion sickness history questionnaire and Graybiel scale for motion sickness was analyzed by receiver operating characteristic(ROC)curves.Results The overall distribution of motion sickness susceptibility assessed by MSSQ and motion sickness history questionnaire in this population was right skewed.The distribution characteristics in the units A,B,and C were consistent with the overall distribution,and there was no significant difference among the 3 units.A positive correlation was observed between the MSSQ and the motion sickness history questionnaire in the units A,B,and C(rs=0.565,0.565,0.554),and both of them were comparable in assessing the incidence of motion sickness and severe motion sickness.However,the incidence of motion sickness assessed by Graybiel scale was significantly lower than that assessed by MSSQ and motion sickness history questionnaire(both P＜0.05),and the incidence of severe motion sickness was significantly higher than that assessed by MSSQ and motion sickness history questionnaire(both P＜0.05).ROC curve analysis showed that MSSQ had good predictive value for motion sickness susceptibility and severe motion sickness(area under curve[AUC]=0.736,0.750),while the Graybiel scale had poor predictive ability(AUC=0.559,0.557).Conclusion The right skewed distribution of susceptibility to motion sickness is preliminarily determined.During the acclimatization training for motion sickness,the susceptible individuals can be screened by MSSQ and then subjected to vertical oscillation stimulation to improve the training efficiency.

Objective To explore the effect of Jiawei Liujunzi decoction in improving volume overload and residual renal protection in continuous ambulatory peritoneal dialysis(CAPD)patients with spleen deficiency.Methods A total of 82 patients treated in the Peritoneal Dialysis Center of Dongyang Hospital of Traditional Chinese Medicine of Affiliated to Wenzhou Medical University from July 2022 to April 2023 were selected as study objects.According to random number table method,the patients were divided into control group and treatment group,41 cases in each group.The control group was given basic western medicine treatment,and the treatment group was given supplemented with Jiawei Liujunzi decoction on the basis of control group,and the treatment course was 8 weeks.The percentage of extracellular water to total body water(ECW％),urea clearance index of residual kidney(Kt/V)and brain natriuretic peptide(BNP)of two groups were compared,and safety of the drug was evaluated.Results After treatment,ECW％and BNP in two groups were significantly lower than before treatment(P＜0.05).The urine volume of control group was significantly lower than that before treatment(P＜0.05).After treatment,there were no significant differences in ECW％,BNP,Kt/V and urine volume between two groups(P＞0.05).After treatment,there were no significant differences in alanine aminotransferase,aspartate aminotransferase,albumin,phosphorus,calcium and potassium between two groups(P＞0.05),indicating good safety.After 12 months of follow-up,the survival rate of treatment group was significantly higher than that of control group(P＜0.05).Conclusion Jiawei Liujunzi decoction can improve the volume overload of CAPD patients with spleen deficiency to a certain extent,with good safety,and can improve the long-term survival rate of patients.

Abstract OBJECTIVE To analyze the differences in adverse drug reactions between newborns using medium/long chain fat emulsions and multiple types of oil fat emulsions, and to explore potential risk factors. METHODS A retrospective cohort study was conducted using data from newborns who used medium/long chain fat emulsions or multiple oil fat emulsions from January 2020 to June 2023. The China Hospital Pharmacovigilance System(CHPS) was used to retrieve adverse reaction information and evaluate it. Four hundred and ninety-nine newborns in the medium/long chain fat emulsion group and 1 940 newborns in the multiple oil fat emulsion group were included. Using logistic regression and stratified analysis to explore the safety differences between groups and the risk factors that affect the occurrence of adverse reactions. RESULTS The total incidence of adverse reactions in the medium/long chain fat emulsion group was 19.24%, with common adverse reactions including fever(5.81%), decreased hemoglobin(3.01%), increased blood pressure(2.40%) and hypoglycemia(2.40%); The total incidence of adverse reactions in the group of multiple oil fat emulsions was 36.44%, with a very common adverse reaction being fever(10.57%); common adverse reactions include decreased hemoglobin(8.97%), decreased blood pressure(3.20%), and increased blood pressure(3.09%); rare adverse reactions include liver dysfunction(0.05%), splenomegaly(0.05%) and cyanosis (0.05%). In univariate analysis, the risk of fever, decreased hemoglobin, and increased blood sugar in the group of multiple oil fat emulsions was higher than that in the medium/long chain fat emulsion group(P<0.05), but this association did not show statistical differences in the overall multivariate analysis. Furthermore, a stratified factor analysis based on gestational age found that the risk of fever and decreased hemoglobin in the group of multiple oil fat emulsions was significantly higher than that in the medium/long chain fat emulsion group in extremely premature infants. The corresponding OR(95%CI) were 6.437(1.327, 31.227) and 5.066(1.089, 23.570), respectively, with no significant differences observed in other gestational age stratification. CONCLUSION The risk of using medium/long chain fat emulsions in newborns is similar to that of using multiple types of oil fat emulsions. However, in extremely premature infants, the risk of fever and decreased hemoglobin in multiple types of oil fat emulsions is higher than that in medium/long chain fat emulsions. It is recommended to regularly monitor indicators such as body temperature, hemoglobin, and blood pressure, and do a good job in drug vigilance.

Thimerosal has been widely used as a preservative in drug and vaccine products for decades.Due to the strong propensity to modify thiols in proteins,conformational changes could occur due to covalent bond formation between ethylmercury(a degradant of thimerosal)and thiols.Such a conformational change could lead to partial or even complete loss of desirable protein function.This study aims to investigate the effects of thimerosal on the capsid stability and antigenicity of recombinant human papillomavirus(HPV)18 virus-like particles(VLPs).Dramatic destabilization of the recombinant viral capsid upon thimerosal treatment was observed.Such a negative effect on the thermal stability of VLPs preserved with thimerosal was shown to be dependent on the thimerosal concentration.Two highly neutralizing antibodies,13H12 and 3C3,were found to be the most sensitive to thimerosal treatment.The kinetics of antigenicity loss,when monitored with 13H12 or 3C3 as probes,yielded two distinctly different sets of kinetic parameters,while the data from both monoclonal antibodies(mAbs)followed a biphasic expo-nential decay model.The potential effect of thimerosal on protein function,particularly for thiol-containing proteinaceous active components,needs to be comprehensively characterized during formulation development when a preservative is necessary.