Abstract: Cell death is a fundamental biological phenomenon that is essential for the survival and development of organisms. Cell death can be either a spontaneous programmed process by the host or an accidentally triggered process. According to the different signaling pathway activated by various stimulates, programmed cell death exhibits the lytic or non-lytic morphology. For example, apoptosis, a typical non-lytic form of cell death, exhibits cell shrinkage and induces the formation of apoptotic bodies. Pyroptosis mediated by cysteine-containing aspartate-specific protease-1/11 (caspase-1/11) and necroptosis can induce inflammatory reactions and promote cell lysis to release inflammatory cytokines via triggering the pore-forming mechanism of the cell membrane, representing a typical modes of lytic cell death. In addition, the release of reactive oxygen species caused by the damaged mitochondria may further trigger ferroptosis during the pathogen infection. Programmed cell death can play an immune defensive role by eliminating infected cells and intracellular pathogens and stimulating the innate immune response through the resulting cell corpses. Here, we discuss the molecular mechanisms of five programmed cell death pathways: apoptosis, pyroptosis, ferroptosis, necroptosis and PANoptosis. We describe their roles in the innate immune defense against bacterial infections and give a brief statement of the interactions between the different programmed cell death, hoping to provide new insights for in-depth study of the pathogenic mechanisms of infectious diseases.

Objective To understand the epidemic status quo and influencing factors of Kashin-Beck disease among children in mountain areas of Jilin Province.Methods Two hundred eighty-two severe endemic areas in 18 counties were selected and stratified by random cluster sampling method,and the status quo of KashinBeck disease prevalence was investigated among 7-12 year-old children according to the Diagnostic Criteria of Kashin-Beck Disease (WS/T 207-2010).In the meantime,the annual household income and the proportion of economic crops replanted,grain out-sourced,and returning farmlands to forests and grass were surveyed in the disease affected areas.Results A total of 14 162 children were investigated who had no clinical symptoms.Among them,28 cases were detected positive using X-ray with a detection rate of 1.98‰,while most of the cases were metaphysis positive.The annual household income (≥5 000 Yuan vs.＜ 5 000 Yuan) in the year 2009-2011 had a significant impact on the incidence of Kashin-Beck disease (1.47‰ vs.3.67‰,x2 =6.179,P ＜ 0.05),while the areas of returning farmland to forests and grass which accounted ＞ 1％ had no significant influence on the incidence compared with that ≤ 1％ (3.30‰ vs.1.57‰,x2 =3.876,P ＞ 0.05);the areas of economic crops replanting which accounted ＞ 10％ had no significant influence on the incidence compared with that ≤ 10％ (3.07‰ vs.1.65‰,x2 =2.565,P ＞ 0.05);the proportion of grain out-sourcing which accounted ＞ 50％ had no significant influence on the incidence compared with that ≤50％ (3.07‰ vs.1.65‰,x2 =2.565,P ＞ 0.05).Conehision Up to 2012,the disease among 7-12 year-old children of the mountain areas of Jilin Province have basically met the standard of Kashin-Beck disease elimination and the situation remains stable;furthermore,the household income has a significant impact on the incidence of Kashin-Beck disease.

Objective To investigate the expression of CD127 (interleukin-7 receptor α, IL-7Rα)and its association with apoptosis of CD8 + T lymphocytes in patients with chronic HIV-1 infection. Methods The expression of CD127 on T lymphocytes and spontaneous apoptosis of CD8+ T lymphocytes were measured by flow cytometry in peripheral blood from 24 patients with chronic HIV-1 infections and 12 healthy subjects. The associations of CD127 expression with CD4 +T lymphocytes counts, HIV RNA loads and cell apoptosis were analyzed. Mann-Whitney U test was performed to compare between the groups, and Spearman test was used for correlation analysis. Results The expression of CD127 on CD8 + T lymphocytes was significantly down-regulated in HIV-1 infected subjects (Z = -4.796, P ＜ 0. 01 ), which was positively correlated with CD4 + T lymphocytes (r = 0.817, P ＜ 0.01 ) and negatively correlated with HIV RNA load and CD8+T lymphocytes apoptosis (r= -0.442 and -0.688,P＜0.05 and ＜0.01). Conclusion CD127 down-regulation may play an important role in the descended ability of receiving survival signals and ascended apoptosis of CD8 + T lymphocytes during chronic HIV-1 infection, which indicates that IL-7 might be a novel strategy in treatment of HIV infection.

Human immunodeficiency virus type 1 (HIV-1) infection can damage humoral immunity.The knowledge of B cell perturbations during chronic HIV-1 infection and their recovery after combined antiretroviral therapy (cART) is not complete yet,and thus attempts to further improve humoral immunity are impeded.In this study,an HIV-1 chronically infected cohort with similar demographics,infection history,genetic background,and HIV-1 genotype was established to probe B cell perturbations.Results showed that the B cells from this cohort were highly activated and prone to cell death,and B cell compartments were altered significantly.Notably,although cART partially reversed the hyperactivation and reduced tissue-like memory B cells,other B cell perturbations,including impaired expression of survival factor Bcl-2,costimulatory molecules,and shrunken resting memory B cells,were irreversible.Further functional characterization revealed that the influenza HA-specific antibody-secreting cells were significantly lower during HIV-1 infection,whereas the recalled antibody response to HIV-1-specific antigens was decreased after cART.Finally,CpG plus R848 treatment increased the survival of B cells and memory B cells in vitro from HIV-1-infected patients.In conclusion,this study identified irreversible B cell immune perturbations in chronic HIV-1 infections regardless of cART and proposed the potential strategy to enhance B cell functions through the improvement of cell survival.

The relative bioavailability of roxithromycin dispersive tablet in healthy volunteers was evaluated in this study. Its concentration in plasma was detected by high performance liquid chromatography (HPLC) after twenty healthy male volunteers were given each a single dose of 300 mg roxithromycin. The experiment data were obtained using DAS programme. The values of Cmax were 10.16+/-1.46 and 10.34+/-1.66 microg x ml(-1) at 2.33+/-0.61 and 2.28+/-0.62 h respectively; of t1/2 were 9.00+/-1.58 and 8.68+/-1.66 h respectively; of AUC0-->Tn were 143.32 +/-25. 80 and 138.93+/-22. 49 microg x h x ml(-1) respectively; of AUC0-->infinity were 158.63+/-26.86 and 153.77+/-24.75 microg x h x ml(-1) for test and reference drugs. Relative bioavailability of the tested roxithromycin was 103.63%+/-14.04%. The result showed that the two dispersive tablets are bioequivalent.
Administration, Oral ; Anti-Bacterial Agents ; blood ; pharmacokinetics ; Biological Availability ; Chromatography, High Pressure Liquid ; Humans ; Male ; Roxithromycin ; blood ; pharmacokinetics ; Tablets ; Therapeutic Equivalency ; Young Adult

The original version of this article unfortunately contained a mistake. One of the authors of this article has been misspelled. Xiaoyang Zhang should be Xiaoyan Zhang. The update is also provided here.

To provide new ideas for clinical diagnosis and treatment of coronavirus disease 2019 (COVID-19), this study explore the expression level and prognostic value of platelet parameters in mild, moderate and severe COVID-19. This is a retrospective analysis. From January to May 2020, a total of 69 patients who were diagnosed with COVID-19 in the Third Central Hospital and the Jinnan Hospital (both situated in Tianjin) were enrolled in the disease group. According to the severity, these patients were divided into mild group (15 cases), moderate group (46 cases), and severe group (8 cases). In the same period, 70 non-infected patients were enrolled in control group. The level of white blood cell count (WBC), absolute neutrophil count (NEU#), absolute lymphocyte count (LY#), neutrophil-lymphocyte ratio (NLR), red blood cell count (RBC), hemoglobin (Hb), platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), and platelet-large contrast ratio (P-LCR) before and after treatment were analyzed. Binary logistic regression analysis is used to establish a mathematical model of the relationship between these indexes and the outcome of severe COVID-19 patients. The receiver operating characteristic(ROC) curve is used to further explore the prognosis value of MPV, P-LCR, NLR separately and jointly in COVID-19 patients. Compare to the control group, WBC and NE# increase ( Z=-5.63, P<0.01; Z=-9.19, P<0.01) and LY# decrease ( Z=-9.34, P<0.01) in the severe group; NLR increase with the aggravation of the disease, there is significant difference between groups ( Z=17.61, P<0.01); PLT, PDW, MPV and P-LCR decrease with the aggravation of the disease, there is significant difference between groups ( Z=9.47, P<0.01; Z=11.41, P<0.01; Z =16.76, P<0.01; Z=13.97, P<0.01). Binary logistic regression analysis shows MPV, P-LCR and NLR have predictive value for severe COVID-19 patients. There is a negative correlation between MPV, P-LCR and severe COVID-19 patients ( OR=1.004, P=0.034; OR=1.097, P=0.046). There is a positive correlation between NLR and severe COVID-19 patients ( OR=1.052, P=0.016). MPV and P-LCR of patients with good prognosis after treatment were significantly higher than those before treatment ( Z=-6.47, P<0.01; Z=-5.36, P<0.01). NLR was significantly lower than that before treatment ( Z=-8.13, P<0.01). MPV and P-LCR in poor prognosis group were significantly lower than those before treatment ( Z=-9.46, P<0.01; Z=-6.81, P<0.01). NLR was significantly higher than that before treatment ( Z=-3.24, P<0.01). There were significant differences between good and poor prognosis groups before and after treatment in MPV, P-LCR and NLR ( P<0.01). Combination of these three indexes, ROC shows the AUC is 0.931, the sensitivity is 91.5%, the specificity is 94.1%, the positive predictive value is 88.9%, and the negative predictive value is 87.4%, which is better than any of these indexes separately. Changes in these parameters are closely related to clinical stage of COVID-19 patients. MPV, P-LCR and NLR are of great value in the prediction and prognosis of severe COVID-19 patients.

To provide new ideas for clinical diagnosis and treatment of coronavirus disease 2019 (COVID-19), this study explore the expression level and prognostic value of platelet parameters in mild, moderate and severe COVID-19. This is a retrospective analysis. From January to May 2020, a total of 69 patients who were diagnosed with COVID-19 in the Third Central Hospital and the Jinnan Hospital (both situated in Tianjin) were enrolled in the disease group. According to the severity, these patients were divided into mild group (15 cases), moderate group (46 cases), and severe group (8 cases). In the same period, 70 non-infected patients were enrolled in control group. The level of white blood cell count (WBC), absolute neutrophil count (NEU#), absolute lymphocyte count (LY#), neutrophil-lymphocyte ratio (NLR), red blood cell count (RBC), hemoglobin (Hb), platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), and platelet-large contrast ratio (P-LCR) before and after treatment were analyzed. Binary logistic regression analysis is used to establish a mathematical model of the relationship between these indexes and the outcome of severe COVID-19 patients. The receiver operating characteristic(ROC) curve is used to further explore the prognosis value of MPV, P-LCR, NLR separately and jointly in COVID-19 patients. Compare to the control group, WBC and NE# increase ( Z=-5.63, P<0.01; Z=-9.19, P<0.01) and LY# decrease ( Z=-9.34, P<0.01) in the severe group; NLR increase with the aggravation of the disease, there is significant difference between groups ( Z=17.61, P<0.01); PLT, PDW, MPV and P-LCR decrease with the aggravation of the disease, there is significant difference between groups ( Z=9.47, P<0.01; Z=11.41, P<0.01; Z =16.76, P<0.01; Z=13.97, P<0.01). Binary logistic regression analysis shows MPV, P-LCR and NLR have predictive value for severe COVID-19 patients. There is a negative correlation between MPV, P-LCR and severe COVID-19 patients ( OR=1.004, P=0.034; OR=1.097, P=0.046). There is a positive correlation between NLR and severe COVID-19 patients ( OR=1.052, P=0.016). MPV and P-LCR of patients with good prognosis after treatment were significantly higher than those before treatment ( Z=-6.47, P<0.01; Z=-5.36, P<0.01). NLR was significantly lower than that before treatment ( Z=-8.13, P<0.01). MPV and P-LCR in poor prognosis group were significantly lower than those before treatment ( Z=-9.46, P<0.01; Z=-6.81, P<0.01). NLR was significantly higher than that before treatment ( Z=-3.24, P<0.01). There were significant differences between good and poor prognosis groups before and after treatment in MPV, P-LCR and NLR ( P<0.01). Combination of these three indexes, ROC shows the AUC is 0.931, the sensitivity is 91.5%, the specificity is 94.1%, the positive predictive value is 88.9%, and the negative predictive value is 87.4%, which is better than any of these indexes separately. Changes in these parameters are closely related to clinical stage of COVID-19 patients. MPV, P-LCR and NLR are of great value in the prediction and prognosis of severe COVID-19 patients.

As confusion mounts over RNA isoforms involved in phenotypic plasticity, aberrant CpG methylation-mediated disruption of alternative splicing is increasingly recognized as a driver of intratumor heterogeneity (ITH). Protease serine 3 (PRSS3), possessing four splice variants (PRSS3-SVs; PRSS3-V1-V4), is an indispensable trypsin that shows paradoxical effects on cancer development. Here, we found that PRSS3 transcripts and their isoforms were divergently expressed in lung cancer, exhibiting opposing functions and clinical outcomes, namely, oncogenic PRSS3-V1 and PRSS3-V2 versus tumor-suppressive PRSS3-V3, by targeting different downstream genes. We identified an intragenic CpG island (iCpGI) in PRSS3. Hypermethylation of iCpGI was mediated by UHRF1/DNMT1 complex interference with the binding of myeloid zinc finger 1 (MZF1) to regulate PRSS3 transcription. The garlic-derived compound diallyl trisulfide cooperated with 5-aza-2'-deoxycytidine to exert antitumor effects in lung adenocarcinoma cells through site-specific iCpGI demethylation specifically allowing MZF1 to upregulate PRSS3-V3 expression. Epigenetic silencing of PRSS3-V3 via iCpGI methylation (iCpGIm) in BALF and tumor tissues was associated with early clinical progression in patients with lung cancer but not in those with squamous cell carcinoma or inflammatory disease. Thus, UHRF1/DNMT1-MZF1 axis-modulated site-specific iCpGIm regulates divergent expression of PRSS3-SVs, conferring nongenetic functional ITH, with implications for early detection of lung cancer and targeted therapies.