Change in estimated glomerular filtration rate and fracture risk in the Action to Control Cardiovascular Risk in Diabetes Trial

ObjectivePatients with type 2 diabetes (T2DM) are at increased risk of fracture. High prevalence of chronic kidney disease (CKD) in T2DM may contribute to bone fragility, but whether dynamic change in kidney function is associated with fracture risk is unclear.Research design and methodsTo evaluate the association of pre-randomization baseline estimated glomerular filtration (eGFR) and its change over time with subsequent fracture risk in the Bone substudy of Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial, we conducted an observational study of 2262 women and 4737 men with T2DM and with at least 2 eGFR values.ResultsDuring a mean follow-up of 4.40 ± 1.54 years, 235 women and 223 men sustained a new non-vertebral fracture. In multivariable adjusted sex-specific models, pre-randomization baseline eGFR was not a significant predictor of fracture risk in either men or women. However, a steeper decline in eGFR was associated with greater risk of fracture in women (hazard ratio [HR] per standard deviation [SD] decrement in eGFR slope, 1.30; 95%CI 1.17–1.44) but not men (HR per SD decrement in eGFR slope, 0.97; 95%CI 0.82–1.13). Accounting for competing risk of death modestly attenuated the association in women (HR per SD decrement in eGFR slope, 1.19; 95%CI 1.04–1.37), with the relationship in men remaining non-significant (HR per SD decrement in eGFR slope, 0.96; 95%CI 0.77–1.18).ConclusionsDeclining kidney function predicts fracture risk in women but not in men with T2DM. Future studies should investigate the mechanisms for these associations.     

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.     

Selective inhibition of EZH2 by ZLD10A blocks H3K27 methylation and kills mutant lymphoma cells proliferation

EZH2 (Enhancer of zeste homolog 2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2), which is involved in repressing gene expression by methylating lysine 27 of histone H3 (H3K27) and regulates cell proliferation. EZH2 overexpression is implicated in tumorigenesis and has been a candidate oncogene in several tumor types. Recently, point mutations of EZH2 at Tyr641 and Ala677 were identified in diffuse large B cell lymphoma and follicular lymphoma, where they drive H3K27 hypertrimethylation and cancer progression. Here, we reported a novel, highly potent and selective small molecule inhibitor of EZH2, ZLD10A, which inhibited wild-type and mutant versions of EZH2 with nanomolar potency and had greater than 1000-fold selectivity against 10 other histone methyltransferases. Our results have shown that the compound suppressed global H3K27 methylation and cause the anti-proliferation effects in a concentration- and time-dependent manner in DLBCL cell lines. These results demonstrated that ZLD10A, as a novel EZH2 inhibitor, could be a potential promising agent for the treatment of EZH2 mutant lymphoma.     

紫草素药理作用研究进展

紫草素是从传统中药紫草中提取的一类萘醌类化合物,具有多种生物学活性,特别是良好的抗肿瘤作用已被大量研究所证实。文章在文献报道的基础上,对紫草素的相关药理作用及其研究进展进行了综述,重点阐述紫草素的抗炎、抗病毒、抗脂肪生成、抗雌激素、抗肿瘤、免疫调节等方面的药理作用。最后对紫草素的研究现状进行概述,并对以紫草素为先导的临床药物研究加以展望。     

农村妇女主任对当地卫生机构孕产妇保健服务的评价及其影响因素

目的:研究我国贫困农村地区妇女主任对当地不同卫生机构孕产妇保健服务(医疗设备、医务人员技术水平和态度)的满意度评价及影响其评价的相关因素。方法:自行设计问卷,采取整群分层随机调查方法,选取四川、甘肃和云南3省,14县(区),120个乡镇,993个农村的妇女主任作为调查对象,就其对当地不同卫生机构(村卫生室、乡镇卫生院、县妇幼保健站、县医院)孕产妇保健服务评价进行调查,并基于Ordered Logit模型分析影响村妇女主任评价的因素。结果:在医疗设备和医务人员技术水平方面,卫生机构的级别越高,村妇女主任对其评价越好。在医务人员态度方面,卫生机构越基层,村妇女主任对其评价越好。影响村妇女主任对不同卫生机构医疗设备、医务人员技术水平和态度评价的相关因素包括本村孕产妇保健基本情况、村妇女主任个人特征、村级社会经济情况。结论:农村妇女主任对当地不同卫生机构提供的妇幼保健服务总体较为满意,影响村妇女主任对卫生机构医疗设备、医务人员技术水平和态度评价的相关因素因卫生机构的层级而异。通过提高农村基层卫生机构孕产妇保健服务的医疗设备和技术水平、改善县级卫生机构医疗人员的服务态度、加大农村孕产妇保健服务的供给力度、重点扶持农村妇女主任开展孕产妇保健工作、强化农村妇女主任孕产妇保健知识的宣传和培训以提高农村妇女主任对不同卫生机构的满意程度。     

Development and validation of a custom panel including 256 Y-SNPs for Chinese Y-chromosomal haplogroups dissection

Y-chromosomal haplogroups determined by Y-chromosomal single nucleotide polymorphisms (Y-SNPs) allow paternal lineage identification and paternal biogeographic ancestry inference, which has attracted a lot of interest in the forensic community. Recently, a comprehensive Y-SNP tool with dominant markers targeting haplogroups in R, E and I branches has been reported, which allows the inference of 640 Y haplogroups. It had a very good performance and could provide a high level of Y haplogroup resolution in most populations. However, the predominant haplogroups in the Chinese populations are O, C and N, suggesting that more Y-SNPs under these clades are needed to achieve the population-specific high resolution. Herein, aiming at the Chinese population, we presented a largely improved custom Y-SNP MPS panel that contains 256 carefully ascertained Y-SNPs based on our previous studies, and evaluated this panel via a series of tests, including the tests for concordance, repeatability, sensitivity, specificity, and stability, as well as the mixture, degraded and case-type sample analysis. The preliminary developmental validation demonstrated that this panel was highly reliable, sensitive, specific, and robust. In the sensitivity test, even when the DNA input was reduced to as low as 0.5 ng, the sample could still be assigned to the correct Y haplogroup. For mixture analysis, even the 1:99 (Male: Female) mixtures had no effects on the assignation of the Y haplogroup of the male contributor. In summary, this assay has provided a high-resolution Y-chromosomal haplogrouping workflow to determine a male’s paternal lineage and/or paternal biogeographic ancestry and could be widely used for Chinese Y-chromosomal haplogroups dissection.     

Paternal genetic structure of the Qiang ethnic group in China revealed by high-resolution Y-chromosome STRs and SNPs

The Qiang population mainly lived in Beichuan Qiang Autonomous County of Sichuan Province. It is one of the nomads in China, distributed along the Minjiang River. The Qiang population was assumed to have great affinity with the Han, the largest ethnic group in China, when it refers to the genetic origin. Whereas, it is deeply understudied, especially from the Y chromosome. Here in this study, we used validated high-resolution Y-chromosome single nucleotide polymorphisms (Y-SNPs) and short tandem repeats (Y-STRs) panels to study the Qiang ethnic group to unravel their paternal genetic, forensic and phylogenetic characteristics. A total of 422 male samples of the Qiang ethnic group were genotyped by 233 Y-SNPs and 29 Y-STRs. Haplogroup O-M175 (N = 312) was the most predominant haplogroup in the Qiang ethnic group, followed by D-M174 (N = 32) and C-M130 (N = 32), N-M231 (N = 27), and Q-M242 (N = 15). After further subdivision, O2a-M324 (N = 213) accounted for the majority of haplogroup O. Haplogroup C2b-Z1338 (N = 29), D1a-CTS11577 (N = 30). O2a2b1a1a1-F42 (N = 48), O2a1b1a1a1a-F11 (N = 35), and O2a2b1a1-M117 (N = 21) represented other large terminal haplogroups. The results unveiled that Qiang ethnic group was a population with a high percentage of haplogroup O2a2b1a1a1-F42 (48/422) and O2a1b1a1a1a-F11 (35/422), and O2a2b1a1-M117 (21/422), which has never been reported. Its haplogroup distribution pattern was different from any of the Han populations, implying that the Qiang ethnic group had its unique genetic pattern. Mismatch analysis indicated that the biggest mismatch number in haplogroup O2a2b1a1a1-F42 was 21, while that of haplogroup O2a1b1a1a1a-F11 was 20. The haplotype diversity of the Qiang ethnic group equaled 0.999788, with 392 haplotypes observed, of which 367 haplotypes were unique. The haplogroup diversity of the Qiang ethnic group reached 0.9767, and 53 terminal haplogroups were observed (The haplogroup diversity of the Qiang ethnic group was the highest among Qiang and all Han subgroups, indicating the larger genetic diversity of the Qiang ethnic group.). Haplogroup O2a2b1a1a1-F42 was the most predominant haplogroup, including 11.37 % of the Qiang individuals. Median-joining trees showed gene flow between the Qiang and Han individuals. Our results indicated that 1) the highest genetic diversity was observed in the Qiang ethnic group compared to any of the former studied Chinese population, suggesting that the Qiang might be an older paternal branch; 2) the haplogroup D-M174 individuals of Qiang, Tibetans and Japanese distributed in three different subclades, which was unable to identify through low-resolution Y-SNP panel; and 3) the Qiang had lower proportion of haplogroup D compared to Yi and Tibetan ethnic groups, showing that the Qiang had less genetic communication with them than with Han Chinese.     

Effect of ethylparaben on the growth and development of Drosophila melanogaster on preadult

Parabens are esters of p-hydroxybenzoic acid, including methylparaben (MP), ethylparaben (EP), propylparaben (PP), and the like. This substance has estrogenic and antiandrogenic effects, and a putative role in promoting cancer through endocrine disruption. By exposing Drosophila melanogaster to different concentrations of EP (300 mg/L, 700 mg/L, and 1000 mg/L), we investigated the effect of EP on the growth and development of D. melanogaster before emergence. We found that EP prolonged the development cycle of D. melanogaster, and changed the relative expression levels of Met, Gce, EcR, Kr-h1, and Br. In addition, EP reduced the titer of juvenile hormone Ⅲ (JH Ⅲ) and 20-hydroxyecdysone (20E), and delayed the peak of hormone secretion. This study provided a more objective and thorough assessment of safety for the parabens.     

The epigenetically active small chemical N-methyl pyrrolidone (NMP) prevents estrogen depletion induced osteoporosis

Currently, there are several treatments for osteoporosis however; they all display some sort of limitation and/or side effects making the need for new treatments imperative. We have previously demonstrated that NMP is a bioactive drug which enhances bone regeneration in vivo and acts as an enhancer of bone morphogenetic protein (BMP) in vitro. NMP also inhibits osteoclast differentiation and attenuates bone resorption.In the present study, we tested NMP as a bromodomain inhibitor and for osteoporosis prevention on ovariectomized (OVX) induced rats while treated systemically with NMP. Female Sprague–Dawley rats were ovariectomized and weekly NMP treatment was administrated 1 week after surgery for 15 weeks. Bone parameters and related serum biomarkers were analyzed. 15 weeks of NMP treatment decreased ovariectomy-induced gained weight in average by 43% and improved bone mineral density (BMD) and bone volume over total volume (BV/TV) in rat femur on average by 25% and 41% respectively. Moreover, mineral apposition rate and bone biomarkers of bone turnover in the treatment group were at similar levels with those of the Sham group.Due to the function of NMP as a low affinity bromodomain inhibitor and its mechanism of action involving osteoblasts/osteoclasts balance and inhibitory effect on inflammatory cytokines, NMP is a promising therapeutic compound for the prevention of osteoporosis.