Tango7 directs cellular remodeling by the Drosophila apoptosome

It is now well appreciated that the apoptosome, which governs caspase-dependent cell death, also drives nonapoptotic caspase activation to remodel cells. However, the determinants that specify whether the apoptosome acts to kill or remodel have yet to be identified. Here we report that Tango7 collaborates with the Drosophila apoptosome to drive a caspase-dependent remodeling process needed to resolve individual sperm from a syncytium. In these cells, Tango7 is required for caspase activity and localizes to the active apoptosome compartment via its C terminus. Furthermore, Tango7 directly stimulates the activity of this complex in vitro. We propose that Tango7 specifies the Drosophila apoptosome as an effector of cellular remodeling.     

Screening and appraisal for immunological adjuvant-active fractions from Platycodon grandiflorum total saponins

In this study, the total saponins from the root of Platycodon grandiflorum (PGS_t) was subjected to D101 macroreticular resin column chromatography to afford four fractions (PGS₃₀, PGS₅₀, PGS₇₅ and PGS₉₅). PGS_t and its four fractions were evaluated and compared for the haemolytic activities and adjuvant potentials on the specific cellular and humoral immune responses of ICR mice against recombinant hepatitis B surface antigen (HBsAg). PGS_t, PGS₃₀, PGS₅₀, PGS₇₅, and PGS₇₅ showed a slight haemolytic effect, with their concentration inducing 50% of the maximum haemolysis (HD₅₀) being 16.13?±?0.81, >200, 17.53?±?0.24, 20.16?±?0.76, 76.31?±?2.20?μg/mL against 0.5% rabbit red blood cell, respectively. PGS_t, PGS₅₀, and PGS₇₅ significantly not only enhanced the Con A-, lipopolysaccharide-, and HBsAg-induced splenocyte proliferation, but promoted the killing activities of natural killer (NK) cells from splenocytes in HBsAg-immunized mice (P?<?0.01 or P?<?0.001). HBsAg-specific IgG, IgG1, IgG2a, and IgG2b antibody levels in serum were also significantly enhanced by PGS_t, PGS₅₀, and PGS₇₅ compared with HBsAg control group (P?<?0.05, P?<?0.01, or P?<?0.001). Moreover, the adjuvant effects of PGS₅₀ and PGS₇₅ on the cellular immune responses and HBsAg-specific IgG2a and IgG2b antibody responses were more significant than those of Alum, PGS₃₀, and PGS₉₅. The results indicated that PGS₅₀ and PGS₇₅ could improve both cellular and humoral immune responses, and elicit a balanced Th1/Th2 response to HBsAg in mice, and that PGS₇₅ may be developed as an ideal candidate adjuvant for hepatitis B vaccine.     

The stress response resolution assay. II. Quantitative assessment of environmental agent/condition effects on cellular stress resolution outcomes in epithelium

Cellular stress responses consist of a complex network of pathways and linked processes that, when perturbed, are postulated to have roles in the pathogenesis of various human diseases. To assess the impact of environmental insults upon this network, we developed a novel stress response resolution (SRR) assay for investigation of cellular stress resolution outcomes and the effects of environmental agents and conditions thereupon. SRR assay‐based criteria identified three distinct groups of surviving cell clones, including those resembling parental cells, those showing Hprt/HPRT mutations, and a third type, “Phenotype‐altered” clones, that occurred predominantly in cells pretreated with a chemical mutagen, was heterogeneous in nature, and expressed significant alterations in cell morphology and/or function compared with parental cells. Further evaluation of Phenotype‐altered clones found evidence of various alterations that resembled epithelial‐to‐mesenchymal transition, phenotype switching, checkpoint dysfunction, senescence barrier bypass, and/or epigenetic reprogramming. Phenotype‐altered clones were found to occur spontaneously in a cell line with a mutator phenotype, to represent the major surviving clone type in a variation of the SRR assay, and to be tumorigenic in nude mice. Assessment of SRR assay final results showed that pretreatment with a chemical mutagen induced significant changes in cellular stress response prosurvival capacity, in damage avoidance versus damage tolerance stress resolution outcomes, and in the damage burden in the final surviving cell populations. Taken together, these results support the conclusion that use of the SRR assay can provide novel insights into the role of environmental insults in the pathogenesis of cancer and other human diseases. Environ. Mol. Mutagen. 54:281–293, 2013. © 2013 Wiley Periodicals, Inc.     

CD19+CD24hiCD38hi B细胞比例预测肝移植术后急性细胞性排斥反应发生的临床研究

目的分析肝移植术后受者外周血CD19⁺CD24^hiCD38^hi B细胞占单个核细胞比例变化情况及其与急性细胞性排斥反应(ACR)之间的关系。 方法回顾性分析2013年12月至2015年12月在浙江大学医学院附属第一医院接受心脏死亡器官捐献肝移植的80例成人受者临床资料,根据术后是否发生ACR,将受者分为ACR组(25例)和非ACR组(55例)。术前、术后各个时间点抽取参加研究者静脉血并分离外周血单个核细胞,加入异硫氰酸荧光素-单克隆鼠抗人CD19抗体、藻红蛋白-单克隆鼠抗人CD24抗体和别藻蓝蛋白-单克隆鼠抗人CD38抗体,流式细胞仪检测各组CD19⁺CD24^hiCD38^hi B细胞百分比。采用t检验和单因素方差分析比较正态分布计量资料,采用χ²检验比较计数资料,采用Kaplan-Meier法绘制受试者工作特征曲线(ROC曲线)。P<0.05为差异有统计学意义。 结果ACR组、非ACR组受者术前外周血平均CD19⁺CD24^hiCD38^hi B细胞比例分别为(3.13±0.91)%、(3.49±0.83)%,差异无统计学意义(t＝1.636,P>0.05)。ACR组术后发生ACR前外周血平均CD19⁺CD24^hiCD38^hi B细胞比例为(1.87±0.70)%。非ACR组受者术后3个月、6个月和1年外周血平均CD19⁺CD24^hiCD38^hi B细胞比例分别为(1.64±0.52)%、(1.63±0.56)%和(2.04±1.24)%,术后3、6个月平均值均低于术前和术后1年,差异均有统计学意义(P均<0.05)。ACR组受者发生ACR时外周血平均CD19⁺CD24^hiCD38^hi B细胞比例为(0.8±0.5)%,低于发生ACR前的平均水平(t＝5.752,P<0.05),且低于非ACR组术后3个月、6个月和1年的平均水平(P<0.05)。ACR组受者接受抗排斥反应治疗后,CD19⁺CD24^hiCD38^hi B细胞比例也逐渐增加,ACR发生后7 d为(0.84±0.08)%,与ACR发生时相比差异无统计学意义(P>0.05);而发生30 d后达(1.65±0.18)%,与ACR发生时相比差异有统计学意义(P<0.05)。当截断值为1.015%时,CD19⁺CD24^hiCD38^hi B细胞比例预测ACR发生的敏感度和特异度分别为0.786和0.702,ROC曲线下面积为0.775(95%CI: 0.671~0.879,P<0.05)。 结论CD19⁺CD24^hiCD38^hi B细胞比例下降与肝移植术后ACR反应发生有关,并可作为预测ACR发生的细胞标志物。     

Fluoxetine-induced hepatic lipid accumulation is mediated by prostaglandin endoperoxide synthase 1 and is linked to elevated 15-deoxy-Δ12,14PGJ2

Major depressive disorder and other neuropsychiatric disorders are often managed with long-term use of antidepressant medication. Fluoxetine, an SSRI antidepressant, is widely used as a first-line treatment for neuropsychiatric disorders. However, fluoxetine has also been shown to increase the risk of metabolic diseases such as non-alcoholic fatty liver disease. Fluoxetine has been shown to increase hepatic lipid accumulation in vivo and in vitro. In addition, fluoxetine has been shown to alter the production of prostaglandins which have also been implicated in the development of non-alcoholic fatty liver disease. The goal of this study was to assess the effect of fluoxetine exposure on the prostaglandin biosynthetic pathway and lipid accumulation in a hepatic cell line (H4-II-E-C3 cells). Fluoxetine treatment increased mRNA expression of prostaglandin biosynthetic enzymes (Ptgs1, Ptgs2, and Ptgds), PPAR gamma (Pparg), and PPAR gamma downstream targets involved in fatty acid uptake (Cd36, Fatp2, and Fatp5) as well as production of 15-deoxy-Δ^12,14PGJ₂ a PPAR gamma ligand. The effects of fluoxetine to induce lipid accumulation were attenuated with a PTGS1 specific inhibitor (SC-560), whereas inhibition of PTGS2 had no effect. Moreover, SC-560 attenuated 15-deoxy-Δ^12,14PGJ₂ production and expression of PPAR gamma downstream target genes. Taken together these results suggest that fluoxetine-induced lipid abnormalities appear to be mediated via PTGS1 and its downstream product 15d-PGJ₂ and suggest a novel therapeutic target to prevent some of the adverse effects of fluoxetine treatment.     

Public Preferences for Policies to Promote COVID-19 Vaccination Uptake: A Discrete Choice Experiment in The Netherlands

ObjectivesThe COVID-19 pandemic forms an unprecedented public health, economic, and social crisis. Uptake of vaccination is critical for controlling the pandemic. Nevertheless, vaccination hesitancy is considerable, requiring policies to promote uptake. We investigate Dutch citizens’ preferences for policies that aim to promote vaccination through facilitating choice of vaccination, profiling it as the norm, making vaccination more attractive through rewards, or punishing people who reject vaccination.MethodsWe conducted a discrete choice experiment in which 747 respondents were asked to choose between policies to promote vaccination uptake and their impacts on the number of deaths, people with permanent health problems, households with income loss, and a tax increase.ResultsRespondents generally had a negative preference for policies that promote vaccination. They particularly disliked policies that punish those who reject the vaccine and were more favorable toward policies that reward vaccination, such as awarding additional rights to vaccinated individuals through vaccination passports. Respondents who reject vaccination were in general much more negative about the policy options than respondents who consider accepting the vaccine. Nevertheless, vaccination passports are supported by both respondents who accept the vaccine, those who reject vaccination, and those who are unsure about vaccination.ConclusionsThis study provides concrete directions for governments attempting to increase the vaccination uptake in ways that are supported by the public. Our results could encourage policy makers to focus on policy options that make vaccination easier and reward people who take the vaccine, as especially the implementation of vaccination passports was supported.