Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer

Epimutations in the germline, such as methylation of the MLH1 gene, may contribute to hereditary cancer syndrome in human, but their transmission to offspring has never been documented. Here we report a family with inheritance, in three successive generations, of germline allele-specific and mosaic hypermethylation of the MSH2 gene, without evidence of DNA mismatch repair gene mutation. Three siblings carrying the germline methylation developed early-onset colorectal or endometrial cancers, all with microsatellite instability and MSH2 protein loss. Clonal bisulfite sequencing and pyrosequencing showed different methylation levels in different somatic tissues, with the highest level recorded in rectal mucosa and colon cancer tissue, and the lowest in blood leukocytes. This mosaic state of germline methylation with different tissue distribution could act as the first hit and provide a mechanism for genetic disease inheritance that may deviate from the mendelian pattern and be overlooked in conventional leukocyte-based genetic diagnosis strategy.     

Male-pattern baldness susceptibility locus at 20p11

We conducted a genome-wide association study for androgenic alopecia in 1,125 men and identified a newly associated locus at chromosome 20p11.22, confirmed in three independent cohorts (n = 1,650; OR = 1.60, P = 1.1 x 10(-14) for rs1160312). The one man in seven who harbors risk alleles at both 20p11.22 and AR (encoding the androgen receptor) has a sevenfold-increased odds of androgenic alopecia (OR = 7.12, P = 3.7 x 10(-15)).     

The pathogenesis of cardiac fibrosis

Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium, and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. This review discusses the cellular effectors and molecular pathways implicated in the pathogenesis of cardiac fibrosis. Although activated myofibroblasts are the main effector cells in the fibrotic heart, monocytes/macrophages, lymphocytes, mast cells, vascular cells and cardiomyocytes may also contribute to the fibrotic response by secreting key fibrogenic mediators. Inflammatory cytokines and chemokines, reactive oxygen species, mast cell-derived proteases, endothelin-1, the renin/angiotensin/aldosterone system, matricellular proteins, and growth factors (such as TGF-β and PDGF) are some of the best-studied mediators implicated in cardiac fibrosis. Both experimental and clinical evidence suggests that cardiac fibrotic alterations may be reversible. Understanding the mechanisms responsible for initiation, progression, and resolution of cardiac fibrosis is crucial to design anti-fibrotic treatment strategies for patients with heart disease.     

Identification of low-frequency variants associated with gout and serum uric acid levels

We tested 16 million SNPs, identified through whole-genome sequencing of 457 Icelanders, for association with gout and serum uric acid levels. Genotypes were imputed into 41,675 chip-genotyped Icelanders and their relatives, for effective sample sizes of 968 individuals with gout and 15,506 individuals for whom serum uric acid measurements were available. We identified a low-frequency missense variant (c.1580C>G) in ALDH16A1 associated with gout (OR = 3.12, P = 1.5 × 10(-16), at-risk allele frequency = 0.019) and serum uric acid levels (effect = 0.36 s.d., P = 4.5 × 10(-21)). We confirmed the association with gout by performing Sanger sequencing on 6,017 Icelanders. The association with gout was stronger in males relative to females. We also found a second variant on chromosome 1 associated with gout (OR = 1.92, P = 0.046, at-risk allele frequency = 0.986) and serum uric acid levels (effect = 0.48 s.d., P = 4.5 × 10(-16)). This variant is close to a common variant previously associated with serum uric acid levels. This work illustrates how whole-genome sequencing data allow the detection of associations between low-frequency variants and complex traits.     

英语转移否定句的理解与翻译

在翻译中,英语的否定结构是一个常见的语言现象.由于英汉两种语言在表达方法上存在很大差异,尤其在表达否定概念上,英语在用词、语法和逻辑等方面与汉语都有很大不同.如何将英语否定句的确切含义准确地用汉语表达出来,是一个较为复杂的事.本文就英语转移否定句的理解与翻译从3个方面进行了探讨.     

论侵权法中的损害

在侵权法中，损失包含损害，狭义上的损害由不利益、达到一定程度、否定性评价因素三个要素构成。传统侵权法学说认为侵害结果只是现实损害，这一学说是对客观现实的错误反应，损害与侵害结果并不同质。侵害结果不仅包括现实的实质性损害，还包括实质损害威胁与实质性障碍，不利益性、客观确定性、主观评判性是它最为显著的特征。     

切削用量对刀具耐用度影响的探讨

简述了切削用量对刀具耐用度的影响程度,叙述了在零件加工过程中合理的选取切削用量和合适的刀具耐用度,对于提高机械加工的效率有很大的作用.     

Effect of protein molecules on the photoluminescence properties and stability of water-soluble CdSe/ZnS core-shell quantum dots

The fact that the photoluminescence properties of quantum dots are always strongly influenced by the environment limits the scope of further progress in the field of QD’ bio-applications. In this paper, the effects of immunoglobulin G (IgG) on the photo-luminescence properties and stability of water-soluble CdSe/ZnS core-shell quantum dots coated with amphiphilic poly (acrylic acid) (PAA) are studied. Photoluminescence (PL) spectra, UV-vis spectra and excited state lifetime measurements are used to characterize the influence of different protein molecules, such as IgG (goat anti-human IgG, rabbit anti-human IgG, human IgG, and goat anti-human IgG-human IgG conjugates), avidin and bovine serum albumin (BSA) on the PL properties of QDs. The PL intensity and stability of CdSe/ZnS are largely enhanced compared to that of pure CdSe/ZnS QDs when the IgG molecules are added into the QD solution. The PL intensity increases with increasing the IgG concentration, but there appears no influence on the PL peak and a full width at half maximum (FWHM). The PL evolution of QDs as a function of different protein molecules depends on the structure of protein molecules, which is used as a sensor to recognize human IgG. It is inferred that the interaction between PAA coating layer and IgG molecules results in the enhancement of PL intensity. The study of the effect of pH and ion strength on optical properties of QD-IgG mixed solution, compared with the pure QD solution, suggests that pH value and ion strength do not destroy the interaction between the PAA coating layer and IgG. Excited state lifetime analysis indicates that the PL enhancement comes from the passivation of surface of the QDs with the PAA coating layer. IgG molecules have no effects on the properties of the biological system but can increase the stability and PL intensity of CdSe/ZnS QDs, which will enlarge the application of QDs in biomedicine and other fields.