Objective:To investigate the molecular features of hand, foot and mouth disease (HFMD) caused by coxsackievirus A10 (CVA10) in Qingdao and analyze the clinical features of mild and severe cases.Methods:A total of 6 677 cases of HFMD routinely monitored by Qingdao Women and Children Hospital from 2014 to 2021 were enrolled. Throat swab samples were collected. Clinical data of these cases were retrospectively analyzed. Virus nucleic acid was extracted from the samples and the serotypes of enteroviruses were identified. The VP1 genes of CVA10 strains were amplified and sequenced. A phylogenetic tree based on the VP1 gene sequences was constructed using MEGA7. 0 software. SPSS23.0 software was used for statistical analysis.Results:There were 285 cases positive for CVA10, including 183 males and 102 females, and children under five years old accounted for 89.8%. Most of CVA10 infection occurred between the months of April to September. The count of white blood cells, the percentage of neutrophils, the concentration of hemoglobin, and the levels of aspartate aminotransferase and alanine transaminase were significantly higher in severe patients than in mild patients. Besides, chest radiography and brain CT revealed more abnormalities in severe patients, and the duration of ECG monitoring was longer in them. Compared with mild cases, severe cases developed rash early than fever with rash mostly on buttocks ( P<0.05). Phylogenetic analysis showed that most of the CVA10 strains circulating in Qingdao between 2014 and 2021 belonged to clade Ⅰ, and there were two variations A23V and I283V in the amino acid sequence of clade Ⅰ. Conclusions:This study showed that children of all ages were susceptible to CVA10, especially those under five years old. CVA10 showed complex and diverse epidemic trends in different regions and years.

Silicosis is a leading cause of occupational disease-related morbidity and mortality worldwide, but the molecular basis underlying its development remains unclear. An accumulating body of evidence supports gasdermin D (GSDMD)-mediated pyroptosis as a key component in the development of various pulmonary diseases. However, there is little experimental evidence connecting silicosis and GSDMD-driven pyroptosis. In this work, we investigated the role of GSDMD-mediated pyroptosis in silicosis. Single-cell RNA sequencing of healthy and silicosis human and murine lung tissues indicated that GSDMD-induced pyroptosis in macrophages was relevant to silicosis progression. Through microscopy we then observed morphological alterations of pyroptosis in macrophages treated with silica. Measurement of interleukin-1β release, lactic dehydrogenase activity, and real-time propidium iodide staining further revealed that silica induced pyroptosis of macrophages. Additionally, we verified that both canonical (caspase-1-mediated) and non-canonical (caspase-4/5/11-mediated) signaling pathways mediated silica-induced pyroptosis activation, in vivo and in vitro. Notably, Gsdmd knockout mice exhibited dramatically alleviated silicosis phenotypes, which highlighted the pivotal role of pyroptosis in this disease. Taken together, our results demonstrated that macrophages underwent GSDMD-dependent pyroptosis in silicosis and inhibition of this process could serve as a viable clinical strategy for mitigating silicosis.

Objective To investigate the molecular epidemiological characteristics of hemaggluti-nin (HA) and neuraminidase (NA) of influenza B viruses (IBV) isolated in Qingdao from 2011 to 2018. Methods A total of 12236 samples of influenza-like cases in Qingdao from 2011 to 2018 were collected to extract viral RNAs. All samples were screened for influenza A viruses ( IAV) and IBV by one-step multiplex real-time RT-PCR. Lineages of IBV were identified. One hundred and eighty-two strains of IBV were select-ed to amplify HA and NA genes by RT-PCR and then analyzed by sequencing. Phylogenetic analysis and variation analysis of genes and amino acids were carried out. Results IBV was detected almost every year in Qingdao from 2011 to 2018. The positive rate was only slightly lower than that of IAV ( 4. 99％ vs 6. 21％). B/Victoria linkage had two prominent epidemic years (2011-2012, 2015-2016), while B/Yama-gata linkage had three (2013-2014, 2014-2015, 2017-2018). Most of the infected people were children un-der 10 years old, and the people infected with the two lineages had similar age characteristics. Phylogenetic analysis of HA genes showed clusters in Victoria clades of 1A and 1B and Yamagata clades of 2 and 3. IBV of Yamagata lineage had more amino acid mutation sites than those of Victoria lineage in HA genes with grea-ter genetic diversity. The B/Yamagata strains had 12 amino acid mutations and the B/Victoria strains had seven in four major epitopes. In the receptor binding sites, two amino acid mutations were detected in the B/Yamagata strains and three in the B/Victoria strains. In Qingdao, 26 strains of IBV were intra-lineage reas-sortments, mostly of the B/Victoria lineage, and 23 strains were inter-lineage reassortments, mostly between HA-B/Yamagata and NA-B/Victoria strains. A possible resistant strain to NA inhibitor was found. Conclu-sions The significance of IBV in seasonal influenza should not be neglected. Amino acid substitution, in-sertion/deletion and gene reassortment were the main strategies for the natural evolution of IBV. Influenza surveillance was of great importance and influenza vaccine strains needed to be updated in time.

Objective: To analyze the molecular epidemiology of norovirus (NoV) genotype GⅡ.15 in Qingdao City. Methods: One thousand four hundred and twelve stool samples were collected from suspected NoV infected patients and detected by real-time polymerase chain reaction (PCR). Open reading frame (ORF)1-ORF2 and VP1 gene were amplified by reverse transcription (RT)-PCR and sequenced for genotyping, evolutionary analysis and homology modeling. Results: Seven cases of GⅡ.15 type were detected including four sporadic cases and one outbreak.The VP1 gene was highly homologous and had little variation compared with early strain J23/US/1999. The differences of amino acids between strains in Qingdao City were mainly asparagine/asparticacid(N/D)300 and proline/serine(P/S)302.Homology modeling suggested that VP1 of GⅡ.15 strain was composed of S domain and P domain (P1 subdomain included 224-276 and 431-555, P2 subdomain included 277-430). S domain contained eight anti-parallel β-sandwiches and two α-helixes, and P1 subdomain contained one α-helix and seven β-strands, and the P2 subdomain folded into a compact barrel-like structure consisting of six β-strands.Argnine (R)-glycine (G)-valine (V)-motif (289-291) and three specific loci including glutarnine (Q)313, asparagine (N)349 and Q389 were located in the P2 subdomain, with NGR-motif (265-267) located at 22nd upstream of RGV-motif.Site I (SNR-alanine(A)- histidine(H)357-361), Site Ⅱ (D388) and Site Ⅲ (G454, G455) were the main characteristic sites of histo-blood group antigens (HBGA) binding interface, which may be similar to the binding pattern of GⅡ.4 type VA387 and HBGA. Conclusion Although GⅡ.15 type NoV evolves very slowly, it may still have the risk to become an epidemic strain, which needs to be monitored and further studied.

Tumor necrosis factor receptor-associated protein 1 (TRAP1),as one of the main members of the heat shock protein 90 family, resists oxidative stress-induced apoptosis as well as predominantly maintains the integrity of mitochondria and cellu-lar homeostasis. Abnormal expression of TRAP1 was herein closely related to the onset and progression of a wide variety of tumors. As a key regulatory factor mediating energy metabolism within tumor cells, TRAP1 may be able to kill them by interfer-ing with such metabolism. More importantly, the abnormal ex-pression of TRAP1 played a less important role in normal cells, allowing TRAP1 to be a particularly attractive target as it can be used in tumor treatment or interference. The relationship be-tween abnormal expression of TRAP1 protein and tumor onset was reviewed. Besides, the mechanism by which disordered TRAP1 protein expression induced tumor formation was postula-ted, which may provide references for future research and clini-cal treatment.

The abnormal expression (level and status) of the key molecular targets of tumors is related to molecular targeted therapy response, effect, and prognosis. Therefore, the expression level and status of key molecular targets of tumors must be accurately evalu-ated, regardless of the status before, during, and after receiving targeted therapy. Molecular imaging is a non-invasive method used for qualitative and quantitative research on key molecular targets of tumor in vivo and in real-time. This technique is also employed to screen treatment beneficiaries, guide therapy, and evaluate prognosis. This paper reviews the application progress of molecular imag-ing using various probes in cancer targeted therapy. The clinical value of molecular imaging in tumor targeted therapy is further ana-lyzed to promote the development of novel targeted therapy for tumors.

Tumor metastasis is one of the most important biologi-cal characteristics of malignant tumor, and it is also the main factors that cause treatment failure and poor prognosis. Clinical studies have shown that the number of platelets in patients with malignant tumor increased more significantly than that in benign tumor patients and healthy people, which indicate that platelet might be involved in the development process of tumor. Further study found that in the process of cancer spreading to blood, platelet could interact with tumor cells to form tumor emboli, helped tumor cells escape from immune surveillance, thus pro-moted the tumor metastasis. In recent years, related mechanisms on platelets in promoting tumor metastasis were revealed gradual-ly, and several targeted therapies based on platelets were also carried out. This paper reviews the role of platelet in mediating tumor metastasis by hematogenous spread and its mechanisms and discusses the therapy strategies that target platelet, which may provide references for follow-up research and clinical treat-ment.

Aim To observe the effects of the total fla-vonoids of scutellaria barbataon ( TFSB ) on high-fat
feeding ApoE gene deficiency mice in early atheroscle-rosis ( AS ) and its underlying mechanisms. Methods
40 ApoE-/ -male mice were divided into five groups:model group, SIM group and L-TFSB, M-TFSB, H-TFSB group, 5 C57BL/6J mice were selected as nor-mal control group. All mice in experimental group were fed with high-lipid diet for 4 weeks and all mice were killed after 8 weeks. H&E staining was used to observe morphology of aorta. Blood rheometer was used to ex-amine plasm viscosity and whole blood viscosity. Fully automatic biochemical analyser was used to detect the serum levels of TG, TC, LDL-C and HDL-C. The ex-pression levels of PLTP and VE in serum were meas-ured by ELISA. The expression levels of PLTP and FXR in liver were examined by Western blot. Results The model was established successfully. TFSB groups could improve the aorta AS morphology of model mice and significantly reduce the serum levels of TG, TC and LDL-C, while increase the level of HDL-C ( P<0. 05 or P<0. 01 ) . TFSB groups could decrease the
hematocrit value, plasma viscosity and whole blood vis-cosity of AS model mice significantly and had statistical significance when compared with model group ( P <0. 01 ) . The expression levels of PLTP of serum were reduced significantly when compared with model group ( P <0. 01 ) . We also found that the expression of PLTP was in negative correlation with VE ( r = -0. 675,P<0. 01). M-TFSB and H-TFSB group could decrease the expressions of PLTP and FXR of liver when compared with model group ( P <0. 01 ) . Con-clusion TFSB may exert its anti-AS effect partly through inhibiting the levels of FXR and PLTP of ApoE-/ -mice, increasing the level of VE, regulating blood lipids, improving blood rheology and reducing the damage of AS in mice.

Objective To investigate the protective role of Xiongbitong capsule against liver injury in hyperlipemic rats.Methods Sixty Wistar male rats were randomly divided into 5 groups(12 rats in each group): a blank group, a model group, a simvastatin group(10 mg/kg, 2 ml intragastric administration daily), a Xiongbitong capsule high-dose group(25 mg/kg, 2 ml intragastric administration daily), and a Xiongbitong capsule low-dose group(12.5 mg/kg, 2 ml intragastric administration daily). Hyperlipidemia model in rats was indeuced by hyperlipidemic diet. The simvastatin group was intragastric administrated with simvastatin suspension 2 ml(10 mg/kg daily), and the rats in the control group and the model group were intragastric administrated with equal volume of saline. After 10 weeks, the serum leves of total cholesterol(TC), triacylglycerol(TG), low-density lipoprotein cholesterol(LDL-C), high-density lipoprotein cholesterol (HDL-C), nitric oxide(NO), endothelin1(ET-1), and the whole blood viscosities(high-, medium-, low-shear)were measured. Liver injury were evaluated with histopathologic examination by H.E. staining. The expressions of intercellular adhesion molecule-1(ICAM-1), monocyte chemoattractant protein-1(MCP-1)in hepatic tissue were measured by immunohistochemical staining.Results The serum leves of TC(1.47± 0.10 mmol/Lvs. 3.48±0.19 mmol/L), TG(0.38±0.11 mmol/Lvs. 0.95±0.14 mmol/L), LDL-C(1.48± 0.18 mmol/Lvs. 2.39±0.22 mmol/L), ET-1(145.81±18.65 pg/mlvs. 177.70±17.70 pg/ml) in the Xiongbitong capsule high-dose group were significantly lower than those in the model group(allP<0.01), HDL-C(1.21±0.14 mmol/Lvs. 0.65±0.10 mmol/L)and NO(31.28±2.36μmol/Lvs. 19.61±1.28μmol/L) significantly lower than those in the model group(allP<0.01), the expressions of ICAM-1(0.133±0.019vs. 0.187±0.011)and MCP-1(0.153±0.014vs. 0.264±0.020)significantly lower than those in the model group(allP<0.01). The liver injury in the Xiongbitong capsule high-dose group decreased than that in the model group. Conclusions Xiongbitong capsule can protect against liver injury via regulating lipid metabolism, protecting endothelial function and down regulating expressions of MCP-1 and ICAM-1.

MIC.RESULTS The bacteriostatic/bactericidal CFR of 0.5g q8h imipenem/cilastatin and 0.5g q8h meropenem were the highest(100%);that of 3.375g q4h sodium piperacillin/tazobactam sodium against ESBLs-producing E.coli was above 90%;the CFRs of ceftriaxone(1g q24h,2g q24h),ceftazidime(1g q8h,2g q8h),cefepime(1g q8h,1g q12h,2g q8h) and cefoperazone sodium/sulbactam(0.5g q8h,1g q8h,2g q8h) against ESBLs-producing strains were clearly less than those of non-ESBLs-producing ones,and the CFRs could not be effectively improved with the dose and frequency increased.CONCLUSIONS The PK/PD simulation is useful to optimize the regimen of anti-infective treatment,and guide its dosing accurately.