Decoding and rejuvenating human ageing genomes: Lessons from mosaic chromosomal alterations

One of the most curious findings emerged from genome-wide studies over the last decade was that genetic mosaicism is a dominant feature of human ageing genomes. The clonal dominance of genetic mosaicism occurs preceding the physiological and physical ageing and associates with propensity for diseases including cancer, Alzheimer’s disease, cardiovascular disease and diabetes. These findings are revolutionizing the ways biologists thinking about health and disease pathogenesis. Among all mosaic mutations in ageing genomes, mosaic chromosomal alterations (mCAs) have the most significant functional consequences because they can produce intercellular genomic variations simultaneously involving dozens to hundreds or even thousands genes, and therefore have most profound effects in human ageing and disease etiology. Here, we provide a comprehensive picture of the landscapes, causes, consequences and rejuvenation of mCAs at multiple scales, from cell to human population, by reviewing data from cytogenetic, genetic and genomic studies in cells, animal models (fly and mouse) and, more frequently, large-cohort populations. A detailed decoding of ageing genomes with a focus on mCAs may yield important insights into the genomic architecture of human ageing, accelerate the risk stratification of age-related diseases (particularly cancers) and development of novel targets and strategies for delaying or rejuvenating human (genome) ageing.     

Redox imbalance in age-related ovarian dysfunction and perspectives for its prevention

The age at which women have their first child is increasing. This change represents a major health problem to society because advanced maternal age is related with a decay in fertility and an increase in the incidence of a variety of pregnancy complications and offspring health issues. The ovary stands as the main contributor for female reproductive ageing because of the progressive age-related decrease in follicle number and oocyte quality. Loss of redox homeostasis and establishment of an ovarian oxidative microenvironment are seen as major underlying causes for such downfall and impairment of ovarian function. Thus, the use of antioxidants to preserve fertility became an important field of research. In this review, new insights on mechanisms underlying the establishment of oxidative stress and its repercussions on ovarian ageing are addressed, along with the current state of knowledge on antioxidant supplementation and its contribution for healthy ageing and extension of ovarian lifespan.     

Acute toxicity when concentration varies with time: A case study with carbon monoxide inhalation by rats

Exposure to time-varying concentrations of toxic compounds is the norm in both occupational settings and daily human life, but little has been done to investigate the impact of variations in concentration on toxic outcomes; this case study with carbon monoxide helps fill that gap. Median acute lethality of 10-, 20-, 40-, and 60-min continuous exposures of rats to carbon monoxide was well described by the toxic load model (k = Cⁿ × t; k is constant, C = test concentration, n = toxic load exponent, and t = exposure duration) with n = 1.74. Dose response-relationships for 1-h exposures including a recovery period between 10- or 20-min pulses showed greater similarity (in both median lethality and steepness of dose-response curve) to continuous exposures with equivalent pulse duration and concentration, rather than a 60-min exposure with equivalent time-weighted average concentrations or toxic load. When pulses were of unequal concentration (3:1 ratio), only the high concentration pulse contributed to lethality. These findings show that fluctuations or interruptions in exposure over a short time scale (60 min or less) can have a substantial impact on outcomes (when n > 1), and thus high-resolution monitoring data are needed to aid interpretation of resulting outcomes.     

TiO2 nanoparticles tested in a novel screening whole human blood model of toxicity trigger adverse activation of the kallikrein system at low concentrations

There is a compelling need to understand and assess the toxicity of industrially produced nanoparticles (NPs). In order to appreciate the long-term effects of NPs, sensitive human-based screening tests that comprehensively map the NP properties are needed to detect possible toxic mechanisms. Animal models can only be used in a limited number of test applications and are subject to ethical concerns, and the interpretation of experiments in animals is also distorted by the species differences.Here, we present a novel easy-to-perform highly sensitive whole-blood model using fresh non-anticoagulated human blood, which most justly reflects complex biological cross talks in a human system. As a demonstrator of the tests versatility, we evaluated the toxicity of TiO₂ NPs that are widely used in various applications and otherwise considered to have relatively low toxic properties. We show that TiO₂ NPs at very low concentrations (50 ng/mL) induce strong activation of the contact system, which in this model elicits thromboinflammation. These data are in line with the finding of components of the contact system in the protein corona of the TiO₂ NPs after exposure to blood.The contact system activation may lead to both thrombotic reactions and generation of bradykinin, thereby representing fuel for chronic inflammation in vivo and potentially long-term risk of autoimmunity, arteriosclerosis and cancer. These results support the notion that this novel whole-blood model represents an important contribution to testing of NP toxicity.     

8周基础军训对入伍新兵红细胞及其相关指标的影响

目的探讨8周基础军训(basic military training,BMT)对入伍新兵血像中红细胞及其相关指标的影响,为指导科学的军事训练提供参考。方法数据来自新疆边防部队2015年度入伍的50名男性新兵,分别在BMT前后测定并记录受试新兵的红细胞计数、血红蛋白浓度及血清铁蛋白等。结果经过8周的BMT,新兵血液中血红蛋白浓度、红细胞计数及血清铁蛋白均显著下降(P0.05,P0.01)。结论 8周BMT可能导致入伍新兵发生运动性贫血,铁缺乏可能是其主要原因。     

携带小鼠 KLF4 基因重组慢病毒的构建及对 RAW264.7 细胞增殖的影响

目的 构建小鼠 Krüppel 样因子 4（KLF4）慢病毒表达载体,并建立 KLF4 过表达小鼠腹腔巨噬细胞 RAW264.7 细胞株。方法 采用聚合酶链式反应（PCR）技术扩增目的基因 KLF4 后,构建重组质粒 pLVX-KLF4,并 通过 PCR、双酶切和测序方法对其进行鉴定。重组质粒与 pSPAX2、pMD2.G 辅助质粒通过 Lipofectamine® 3000 共转 染 293T 细胞,包装病毒并测定病毒滴度。将获得的慢病毒感染 RAW264.7 细胞,实时定量 PCR 法检测 KLF4 mRNA 的表达。分选流式细胞仪分选 GFP 阳性 RAW264.7 细胞。流式细胞术检测 KLF4 对 RAW264.7 细胞周期的影响。 EdU 法检测 KLF4 对 RAW264.7 细胞增殖的影响。结果 经 PCR、双酶切鉴定和测序证实,成功构建了包含小鼠 KLF4 基因的慢病毒穿梭质粒,RT-PCR 证实 Lenti-KLF4 感染的 RAW264.7 细胞中 KLF4 mRNA 表达高于未感染的 对照组 RAW264.7 细胞（P＜0.05）。初次浓缩后测定小鼠 KLF4 基因重组慢病毒的滴度为 2.05×108 TU/mL。分选出 KLF4 过表达的 RAW264.7 细胞。KLF4 过表达的 RAW264.7 细胞周期变化显示为 S 期延长,G0/G1 期缩短。EdU 检 测显示 KLF4 过表达的 RAW264.7 细胞增殖活性增高。结论 成功构建了 KLF4 的慢病毒表达载体,并建立 KLF4 过表达的 RAW264.7 细胞株,KLF4 过表达促进了 RAW264.7 细胞的增殖。     

Adoptive transfer of IFN-γ-induced M-MDSCs promotes immune tolerance to allografts through iNOS pathway

Inflammation Research - Efficient production of monocytic myeloid-derived suppressor cells (M-MDSCs) with stable immunosuppressive function is crucial for immunomodulatory cell therapy for many...     

抗骨髓炎片对家兔骨髓炎的改善作用研究

目的 探讨抗骨髓炎片对家兔慢性骨髓炎的作用。方法 采用右胫骨骨髓腔内注射金黄色葡萄球菌的方法建立家兔慢性骨髓炎模型,随机分为4组：抗骨髓炎片高、低剂量（480、240 mg/kg）组,庆大霉素（60 mg/kg）组,模型组（等体积0.5% CMC-Na）;另取家兔向骨髓腔内注入生理盐水,作为假手术组（等体积0.5% CMC-Na）,术后当天开始ig给药,每天1次,连续6周。术后第6周对右胫骨行X-线检查并做Laurence评分;术后第2、4、6周采血,血细胞分析仪进行白细胞计数,ELISA法测定血清溶菌酶、肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）含量。结果 模型组家兔均有典型骨髓炎表现,抗骨髓炎片高、低剂量对骨髓炎症状有显著缓解,Laurence评分与模型组比较显著降低（P<0.01）;与模型组比较,抗骨髓炎片高、低剂量组的白细胞计数、血清TNF-α和IL-6含量在术后2、4、6周均明显降低（P<0.01）,高剂量组血清溶菌酶含量在术后2、4、6周均明显升高（P<0.01）,低剂量组血清溶菌酶含量在第4、6周亦明显升高（P<0.05）。结论 抗骨髓炎片对家兔慢性骨髓炎发挥显著改善作用,可能与抑制致病菌、提高机体免疫力、下调炎性因子等途径有关。     

牙科着色氧化钇稳定四方多晶氧化锆陶瓷的制备及颜色性能

目的添加不同着色剂组合配制着色的牙科氧化钇稳定四方多晶氧化锆（3Y-TZP）陶瓷，并测定其颜色性能。方法将TZ-3Y-S粉体与一定组分的着色剂球磨混合后，在200 MPa压力下等静压成型，在1 500 ℃烧结2 h，烧制5种具有一定颜色的氧化锆材料，每个颜色组分别制备10 mm×10 mm×0.5 mm和10 mm×10 mm×1 mm着色氧化锆陶瓷片，在黑色背景下用柯尼卡美能达CM-2600d分光光度计进行颜色测定，并与VITA In-Ceram YZ染色液比色板颜色作比较。结果通过对粉体进行着色，配制出具有一定颜色的本体着色氧化锆陶瓷材料，颜色明度逐级降低，饱和度逐渐增大，2种厚度3Y-TZP陶瓷的颜色片色差较小，颜色空间范围是L*：67.76～77.78；a*：-2.19～3.80；b*：12.13～25.01。与VITA In-Ceram YZ染色液比色板相比，颜色空间近似，但明度的最低值仍较高。结论着色氧化锆陶瓷材料适宜用于临床上与饰面瓷颜色匹配，有必要再进一步研究低明度的着色氧化锆色片。     

珊瑚骨粉复合组织补片进行拔牙位点保存的临床研究

目的探讨使用珊瑚骨粉复合组织补片进行拔牙位点保存的临床效果。方法选取自2012年12月至2014年2月期间在武警总医院口腔种植科门诊采用微创技术拔除磨牙的患者45例,试验组20例,拔牙窝内植入珊瑚骨粉,组织补片覆盖表面关闭拔牙窝;对照组25例,拔牙后常规处理。1、3、6个月复诊,观察拔牙窝愈合情况。拔牙前及拔牙6个月后进行口内取模灌注石膏模型并拍摄X线牙片,分别测量牙槽嵴的高度和宽度,使用配对t检验分别对两组拔牙前至6个月期间牙槽嵴高度、宽度的变化进行统计学分析,使用两独立样本的t检验进行两组间牙槽嵴高度、宽度变化的比较,P〈0.05为差异具有统计学意义。结果临床观察除有一例组织补片脱落外,试验组其他拔牙窝均愈合良好,牙槽骨丰满,牙龈色、形、质与邻牙协调;而对照组牙槽嵴吸收、萎缩,高度降低、宽度显著缩小。统计学分析试验组牙槽嵴高度和宽度的改变无显著的统计学差异（P〉0.05）;对照组的上述改变具有统计学差异（P〈0.05）。两组间牙槽嵴高度、宽度的变化相比,二者间的差异均具有统计学意义（P〈0.05）。结论珊瑚骨粉复合组织补片有效保存了进行种植牙修复所必需的骨量,是进行拔牙后位点保存术的合适材料。