eIF3a is a N ⁶-methyladenosine (m⁶A) reader that regulates mRNA translation by recognizing m⁶A modifications of these mRNAs. It has been suggested that eIF3a may play an important role in regulating translation initiation via m⁶A during infection when canonical cap-dependent initiation is inhibited. However, the death of animal model studies impedes our understanding of the functional significance of eIF3a in immunity and regulation in vivo. In this study, we investigated the in vivo function of eIF3a using eIF3a knockout and knockdown mouse models and found that eIF3a deficiency resulted in splenic tissue structural disruption and multi-organ damage, which contributed to severe sepsis induced by Lipopolysaccharide (LPS). Ectopic eIF3a overexpression in the eIF3a knockdown mice rescued mice from LPS-induced severe sepsis. We further showed that eIF3a maintains a functional and healthy immune system by regulating B cell function and quantity through m⁶A modification of mRNAs. These findings unveil a novel mechanism underlying sepsis, implicating the pivotal role of B cells in this complex disease process regulated by eIF3a. Furthermore, eIF3a may be used to develop a potential strategy for treating sepsis.

ObjectiveTo develop traditional Chinese medicine （TCM） formulae for the treatment of nonsevere coronavirus disease 2019 （COVID-19） and to explore its anti-inflammatory mechanism. MethodsThe dysregulated signaling pathways were determined in macrophages from bronchoalveolar lavage fluid of COVID-19 patients and in lung epithelial cells infected with SARS-CoV-2 in vitro based on transcriptome analysis. A total of 102 TCM formulae for the clinical treatment of nonsevere COVID-19 were collected through literature. The pathway-reversing rates of these formulae in macrophages and lung epithelial cells were evaluated based on signature signaling pathways， and the basic formula was determined in conjunction with TCM theory. The commonly used Chinese materia medica for nonsevere COVID-19 were summarized from the 102 TCM formulae as abovementioned. And together with the screening results from the Pharmacopoeia of the People's Republic of China， a “Chinese materia medica pool” was esta-blished for the development of TCM formulae for COVID-19. The regulatory effects of each herb on signaling pathways were obtained based on targeted transcriptome analysis. Oriented at reversing dysregulated signaling pathways of COVID-19， the calculation was carried out， and the artificial intelligent methods for compositing formulae， that are exhaustive method and parallel computing， were used to obtain candidate compound formulas. Finally， with reference to professional experience， an innovative formula for the treatment of nonsevere COVID-19 was developed. The ethanol extract of the formula was evaluated for its anti-inflammatory effects by detecting the mRNA expression of interleukin 1b （Il1b）， C-X-C motif chemokine ligand 2 （Cxcl2）， C-X-C motif chemokine ligand 10 （Cxcl10）， C-C motif chemokine ligand 2 （Ccl2）， nitric oxide synthase 2 （Nos2）， and prostaglandin-endoperoxide synthase 2 （Ptgs2） using reverse transcription-quantitative polymerase chain reaction （RT-qPCR） in RAW264.7 cells treated with lipopolysaccharide （LPS）. ResultsIn macrophages and lung epithelial cells， 34 dysregulated signaling pathways associated with COVID-19 were identified respectively. The effects of the 102 formulae for clinical treatment of nonsevere COVID-19 were evaluated based on the dysregulated signaling pathways and targeted transcriptome， and the result showed that Yinqiao Powder and Pingwei Powder （银翘散合平胃散， YQPWP） ranked first， reversing 91.18% of the dysregulated signaling pathways in macrophages and 100% of the dysregulated signaling pathways in lung epithelial cells. Additionally， YQPWP had the function of scattering wind and clearing heat， resolving toxins and removing dampness in accordance with the pathogenesis of wind-heat with dampness in COVID-19. It was selected as the basic formula， and was further modified and optimized to develop an innovative fomula Qiaobang Zhupi Yin （翘蒡术皮饮， QBZPY） based on expert experience and artificial intelligence in composing formulae. QBZPY can reverse all the dysregulated signaling pathways associated with COVID-19 in macrophages and lung epithelial cells， with the reversing rates of 100%. The chief medicinal of QBZPY， including Lianqiao （Fructus Forsythiae）， Xixiancao （Herba Siegesbeckiae） and Niubangzi （Fructus Arctii）， can down-regulate multiple signaling pathways related with virus infection， immune response， and epithelial damage. RT-qPCR results indicated that compared with the model group， the QBZPY group down-regulated the mRNA expression of Il1b， tumor necrosis factor （Tnf）， Cxcl2， Cxcl10， Ccl2， Nos2 and Ptgs2 induced by LPS in RAW264.7 cells （P＜0.05 or P＜0.01）. ConclusionBased on targeted transcriptome analysis， expert experience in TCM and artificial intelligence， QBZPY has been developed for the treatment of nonsevere COVID-19. The ethanol extract of QBZPY has been found to inhibit mRNA expression of several pro-inflammatory genes in a cellular inflammation model.

Multiple myeloma(MM)is a malignant proliferative disease of plasma cells,ranking as the second most common hematologic tu-mor.Although the use of proteasome inhibitors and immunotherapeutic regimens has improved the prognosis of patients with MM,it re-mains incurable in most patients,mainly because of the eventual development of drug resistance in MM cells.Myeloid-derived suppressor cells(MDSCs)are a heterogeneous group of cells causing significant suppression of the T-cell immune response.They arise from bone mar-row myeloid progenitor cells that are blocked from differentiation and promote MM development by resisting immune destruction.Recent studies indicate that MDSCs stimulate MM cell proliferation,inducing drug resistance and metastasis.In this paper,we review multiple mechanisms exhibited by MDSCs in MM pathogenesis and discuss the feasibility and challenges of current therapeutic strategies targeting MDSCs,aiming to provide pertinent references regarding MM treatment.

Objective To investigate the clinical value of uric acid(UA)to albumin(Alb)ratio(UAR)in predicting the prognosis of the patients with heart failure.Methods A total of 1 893 patients with heart failure and complete clinical data in the Chinese Heart Failure Database were selected as the clinical research subjects for conducting the retrospective cohort analysis.The general clinical data,coagulation routine,tropo-nin Ⅰ(cTnⅠ),cardiac enzyme profile,liver function,B-type brain natriuretic peptide(BNP),uric acid(UA)and left ventricular ejection fraction in echocardiography in the study subjects were collected to calculate UAR.Ac-cording to the receiver operating characteristic(ROC)curve,the optimal cut-off value of UAR was selected as 17.48.Then the subjects were divided into the low UAR group(UAR＜17.48,n=1 525)and high UAR group(UAR≥17.48,n=368).The clinical data were compared between the two groups,and the effect of UAR on the all-cause mortality in the patients with heart failure was evaluated by the binary logistic regres-sion analysis.Results The follow up time in the patients was 90 d,and 37 cases(2.0％)of all-cause death oc-curred during the follow up period.The proportion of males,proportion of cardiac function grade Ⅳ,propor-tion of myocardial infarction,levels of uric acid,D-dimer,creatine kinase(CK),creatine kinase isoenzyme(CK-MB),lactate dehydrogenase(LDH),alanine aminotransferase(ALT),glutamyl transpeptidase(GGT),alkaline phosphatase(AKP)and BNP in the high UAR group were higher than those in the low UAR group,while the pulse,systolic pressure,diastolic pressure,proportions of heart function grade Ⅱ and grade Ⅲ and ALB level were lower than those in the UAR group,and the differences were statistically significant(P＜0.05).The ROC curve analysis results showed that the area under the curve of UAR for assessing the all-cause death occurrence in heart failure was 0.715(95％CI:0.626-0.804,P＜0.001),the sensitivity was 56.8％and the specificity was 81.4％;the binary logistic regression analysis results showed that the incidence rate of all-cause mortality in the high UAR group was 1.09 times higher than that in the low UAR group(OR=1.09,95％CI:1.02-1.20,P=0.017).Conclusion UAR could serve as an independent predictive fac-tor of all-cause death occurrence in heart failure,which needs clinic to pay attention.

OBJECTIVE: To explore the correlation between altered levels of neurotransmitters in the frontal lobe and hippocampus and behavioral abnormalities in a Clock variant mice modeling bipolar disorder manic disorder. METHODS: Open field test and Elevated plus-maze test were carried out on the Clock mutant and wild-type control groups. The frontal lobe and hippocampus of Clock mutant mice and controls were dissected, and neurotransmitters in tissue extracts were analyzed by high-performance liquid chromatography and mass spectrometry. The concentration of neurotransmitters and behavioral indicators were assessed by t test and Pearson correlation analysis using SPSS 22.0. RESULTS: The Clock mutant mice showed a significant increase in activity, albeit with no difference in the level of anxiety from the wild-type controls, which suggested that the Clock mutant mice can be used as a model for manic attack of bipolar disorder. Altered neurotransmitter levels were detected in the frontal and hippocampal regions, including elevated histamine in the left hippocampus, reduced histamine in the right hippocampus, reduced gamma-aminobutyric acid (GABA) in bilateral hippocampus, elevated dihydroxyphenylalanine (DOPA) in the left frontal lobe and reduced DOPA in the right hippocampus, and decreased glutamine in bilateral frontal lobes. The reduced glutamine in the left frontal lobe and GABA in the right hippocampus correlated with the increased activity of Clock mutant mice. CONCLUSION Clock mutant mice showed abnormal behavior with increased activity. Reduced glutamine in the left frontal lobe and GABA in the right hippocampus were correlated with increased activity.

Objective To observe the expression changes ofmiR-34a and its related target genes sirtuin 1 (Sirtl) and nuclear factor-E2-related factor 2 (Nrf2) in subependymal zone (SVZ) of rats after cerebral ischemia,and to explore the effect of miR-34a on proliferation of endogenous neural stem cells (NSCs) after cerebral ischemia.Methods Forty SD rats were randomly divided into control group,cerebral ischemia one d group,cerebral ischemia three d group and cerebral ischemia 7 d group (n=10).Middle cerebral artery occlusion models were established by thread embolization in the latter three groups,and the SVZs were taken one,three and 7 d after model making,respectively.Immunofluorescence staining was used to detect the expression of nestin,real-time PCR was used to detect the mRNA expressions ofmiR-34a,Sirtl and Nrf2,and Western blotting was used to detect the protein expressions of Sirt1 and Nrf2.Results (1) In SVZs of cerebral ischemia one d group,cerebral ischemia three d group and cerebral ischemia 7 d group,the number of nestin positive cells increased gradually ([2.013±0.526],[4.821 ±1.154],and [6.394±1.027]) cells/filed,with statistical differences (P＜0.05).(2) In SVZs of cerebral ischemia one d group,cerebral ischemia three d group and cerebral ischemia 7 d group,the expression levels of miR-34a mRNA increased gradually (0.295±0.145,0.701 ±0.075,and 1.136±0.018),the Sirt1 mRNA expression levels showed a downward trend (0.835±0.024,0.620±0.133,and 0.278±0.110),the Nrf2 mRNA expression levels obviously decreased (1.032±0.256,0.833±0.187,and 0.630±0.123),the Sirt1 protein expression levels showed a downward trend (0.832±0.018,0.731±0.156,and 0.454±0.132),and the Nrf2 protein expression levels obviously decreased (1.003±0.133,0.813±0.111,and 0.671 ±0.071),with statistically significant differences (P＜0.05).(3)Statistical correlation analysis showed that the number of nestin positive cells was positively correlated with miR-34a mRNA expression level and negatively correlated with Sirt1 and Nrf2 mRNA and protein expression levels after cerebral ischemia (r=0.887,P=0.003;r=-0.746,P=0.005;r=-0.521,P=0.013;r=-0.344,P=0.025;r=-0.863,P=0.000).Conclusions MiR-34a may regulate the proliferation of NSCs through Sirt1/Nrf2 pathway after cerebral ischemia.

Objective: To explore the relationships of neutrophil gelatinase-associated lipocalin (NGAL) with severity of skin lesions in children with psoriasis and peripheral neutrophil count, and to evaluate in vitro effect of NGAL on expression of tumor necrosis factor-α (TNF-α) and interleukin-22 (IL-22) by a human immortalized keratinocyte cell line HaCaT. Methods: From January 1st 2017 to December 31st 2018, 98 children who newly developed psoriasis were enrolled from Department of Dermatology of 6 hospitals in China, including 51 males and 47 females. Their age was 7.00 ± 2.99 years (range: 3-14 years) , and their course of disease was 7.4 ± 5.85 days (range: 3-28 days) . The serum level of NGAL was detected in all the patients before and two weeks after treatment, and the relationships of NGAL with psoriasis area and severity index (PASI) scores and peripheral neutrophil count were evaluated. Western blot analysis and reverse-transcription (RT) -PCR were performed to determine the protein and mRNA expression of TNF-α and IL-22 in HaCaT cells, respectively, after 12-hour treatment with NGAL at concentrations of 0 (control group) , 0.125, 0.25, 0.5, 1 mg/L. Statistical analysis was carried out with SPSS 16 software. by using t test and one-way analysis of variance. Results: After 2-week treatment, the PASI score, neutrophil count and NGAL level in children with psoriasis significantly decreased (1.80 ± 1.19, [6.16 ± 0.76] × 10⁹/L, 90.86 ± 0.75 μg/L, respectively) compared with those before the treatment (10.38 ± 3.42, [11.01 ± 2.85] × 10⁹/L, 113.48 ± 21.26 μg/L, respectively; t = 31.42, 18.34, 16.37 respectively, all P < 0.001) . Before the treatment, the serum level of NGAL in the patients was positively correlated with the PASI score and peripheral neutrophil count (r = 0.918, 0.799 respectively, both P < 0.05) . The mRNA and protein expression of IL-22 in HaCaT cells significantly differed among these groups treated with different concentrations of NGAL (F = 176.31, 296.96 respectively, both P < 0.001) , so did the mRNA and protein expression of TNF-α (F = 193.28, 318.80 respectively, both P < 0.001) . Additionally, the protein and mRNA expression of IL-22 and TNF-α in HaCaT cells was significantly higher in the 0.125-, 0.25-, 0.5- and 1-mg/L NGAL group than in the control group (all P < 0.05) . The NGAL level was positively correlated with the protein and mRNA expression of TNF-α and IL-22 in HaCaT cells (all P < 0.05) . Conclusions The serum level of NGAL was high in children with psoriasis, and positively correlated with severity of skin lesions and peripheral neutrophil count. NGAL can upregulate the expression of TNF-α and IL-22 in HaCaT cells in vitro.

Objective To investigate the efficacy and safety of intravesical instillation with Sufuning (SFN) lotion for prevention of postoperative recurrence of bladder cancer. Methods A total of 240 bladder cancer patients who were diagnosed as bladder cancer and accepted trans-urethral resection of bladder tumor from January 2010 to June 2016 in Shanxi Provincial Cancer Hospital were randomly divided into the experimental group (120 cases) and the control group (120 cases) according to the envelope method. The patients in the experimental group were treated with SFN lotion for immediate intravesical instillation(250 mg for once), and the patients in the control group were treated with pirarubicin (THP) for immediate intravesical instillation (30 mg for once). The patients of two groups were treated with intravesical chemotherapy once a week for 8 times, and the chemotherapy was performed once a month for 1 year. The recurrence rate, progression-free survival (PFS) rate, overall survival (OS) rate and recent side effects were compared between the two groups. Results The patients were followed up for 6 to 60 months. The median follow-up time was 36.5 months.In the experimental group,6 patients were lost and 8 patients were lost in the control group.The experimental group, the total recurrence rate was 26.3 % (30/114). The control group, the overall recurrence rate was 25.0 % (28/112) (χ2= 0.142, P = 0.781). Five years of PFS rate in the experimental group and the control group was 73.7 % (84/114) and 75.0 % (84/112) respectively, and there was no significant difference between the two groups (χ2= 2.011, P= 0.615). Five years of OS rate in the experimental group and the control group was 95.6 % and 92.9 % respectively, and there was no significant difference between the two groups (χ 2= 1.611, P= 0.425). The major side effects included chemical cystitis and hematuria. The incidence of chemical cystitis and hematuria in the experimental group was significantly lower than that in the control group(χ2=5.991,P=0.018;χ2=4.925,P=0.036).There was a statistically significant difference of the hematological side effects (blood routine changes) between the two groups (χ 2= 4.891, P= 0.032). Conclusion It is safe and effective for intravesical instillation of SFN lotion to prevent the recurrence of bladder cancer.

Objective To analyze the etiological characteristics of human Brucella strains isolated, and to improve the precision in control and prevention of brucellosis. Methods In 2016, blood samples were collected from patients in Jingyuan County Gansu Province, and tested via the Rose-Bengal Plate Agglutination Test (RBPT) and the tube agglutination test methods,and serological positive blood samples were inoculated to bidirectional blood culture bottle for culturing, and further identified by traditional biological classification method and the Brucella abortus, Brucella melitensis, Brucella ovis, and Brucella suis species-specific PCR (AMOS-PCR). Multiple-locus variable number tandem repeat sequence analysis (MLVA) -16 was used to detect molecular typing and do cluster analysis. Results The isolated strain was identified by the traditional biological classification method, bacteria could grow in thionine and reddened dye, A and M factors agglutination tests were positive, Bk2phage treatment of bacterial strain cracking, but Tb, Wb phages were not cracked. AMOS-PCR amplification result showed a 731 bp band, which was a strain of Brucella melitensis. The results of MLVA-16 showed that there was a difference in the number of repeats on some Variaable Number of Tandem Repeat(VNTR)sites of the isolated strain. Clustering analysis showed that, the isolated strain was clusted into the same clade with the clustering of Brucella melitensis type 3 from GS-201605 in Gansu. And the clustering was similar compared with that of Zhejiang, Guangdong, Fujian and Yunnan. Conclusion Human brucellosis is a inputting transmission in Gansu Province, there is a genetic variation of genotype 3 sheep Brucella between Gansu Province and other domestic provinces.

Objective To analyze the economic burden and its influencing factors of brucellosis for providing scientific basis to targeted epidemic prevention and control in Gansu Province.Methods A total of 226 outpatients and inpatients treated at different levels of medical institutions in Jingyuan County of Gansu Province during 2013 to 2016 were selected as research subjects.The basic information (sex,age,education level,family income,etc.) of the subjects was collected according to the questionnaire.By consulting the patient's hospital billing settlement list,outpatient billing invoices,and related bills,the information about the cost of visiting the patient due to brucellosis,cost information of the paramedics and the visiting staff was obtained.A Kruskal-Wallis rank-sum test was used for univariate analysis to analyze the direct medical costs and total costs of patients with various diseases,including gender,occupation,age,education level,per capita income,misdiagnosis,medical institution level,different stages,and different types of disease.The generalized multiple linear regression model was used to analyze the relationship between misdiagnosis,different stages,different types of brucellosis,medical institution levels,and the direct medical expenses and total costs of ill patients.Results Of the 226 patients with brucellosis,each person was hospitalized twice a year and stayed in hospital for 28 days.Direct medical expenses of 115 cases with acute brucellosis and 111 cases of chronic patients,direct non-medical expenses,indirect economic losses and total expenses were 11 835,1 850,2 475,16 396 and 16 733,3 240,4 748,24 188 Yuan RMB,respectively.The western medicine fee of direct medical treatment of acute brucellosis was 67.95％ (8 042/11 835),the inspection fee was 16.92％ (2 002/11 835) and the examination fee was 9.02％ (1 068/11 835).The cost of western medicine for chronic and complications was 39.82％ (6 663/16 733),37.50％ (6 339/16 904),the inspection fee was 27.37％ (4 580/16 733),24.30％ (4 108/16 904),the examination fee was 13.32％ (2 229/16 733),15.46％ (2 613/16 904),and the traditional Chinese medicine cost was 9.34％ (1 563/16 733) and 10.11％ (1 709/16 904).The results of univariate analysis showed that there were significant differences in the direct medical expenses and total costs of patients with misdiagnosis,medical institution level,different stages,and different types of brucellosis (P ＜ 0.05).The results of multivariate analysis showed that there was a positive correlation between misdiagnosis and provincial medical institutions and patients' direct medical expenses and total expenses (P ＜ 0.05).Conclusions It should give rise to enough attention that the burden of different types of brucellosis is heavy.Local medical institutions should refer to "Guidelines for the Diagnosis and Treatment of Brucellosis" (2012) to carry out standardized diagnosis and treatment,reduce the complications of brucellosis and chronic brucellosis.Therefore,strengthening the training of medical personnel,standardize diagnosis and treatment of brucellosis in hospitals at all levels is very urgent.