Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus

Systemic lupus erythematosus (SLE, MIM152700) is an autoimmune disease characterized by self-reactive antibodies resulting in systemic inflammation and organ failure. TNFAIP3, encoding the ubiquitin-modifying enzyme A20, is an established susceptibility locus for SLE. By fine mapping and genomic re-sequencing in ethnically diverse populations, we fully characterized the TNFAIP3 risk haplotype and identified a TT>A polymorphic dinucleotide (deletion T followed by a T to A transversion) associated with SLE in subjects of European (P = 1.58 × 10(-8), odds ratio = 1.70) and Korean (P = 8.33 × 10(-10), odds ratio = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex composed of NF-κB subunits with reduced avidity. Further, compared with the non-risk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. These results establish this TT>A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.     

Germline mutations in RAD51D confer susceptibility to ovarian cancer

Recently, RAD51C mutations were identified in families with breast and ovarian cancer. This observation prompted us to investigate the role of RAD51D in cancer susceptibility. We identified eight inactivating RAD51D mutations in unrelated individuals from 911 breast-ovarian cancer families compared with one inactivating mutation identified in 1,060 controls (P = 0.01). The association found here was principally with ovarian cancer, with three mutations identified in the 59 pedigrees with three or more individuals with ovarian cancer (P = 0.0005). The relative risk of ovarian cancer for RAD51D mutation carriers was estimated to be 6.30 (95% CI 2.86-13.85, P = 4.8 × 10(-6)). By contrast, we estimated the relative risk of breast cancer to be 1.32 (95% CI 0.59-2.96, P = 0.50). These data indicate that RAD51D mutation testing may have clinical utility in individuals with ovarian cancer and their families. Moreover, we show that cells deficient in RAD51D are sensitive to treatment with a PARP inhibitor, suggesting a possible therapeutic approach for cancers arising in RAD51D mutation carriers.     

De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome

Brain malformations are individually rare but collectively common causes of developmental disabilities. Many forms of malformation occur sporadically and are associated with reduced reproductive fitness, pointing to a causative role for de novo mutations. Here, we report a study of Baraitser-Winter syndrome, a well-defined disorder characterized by distinct craniofacial features, ocular colobomata and neuronal migration defect. Using whole-exome sequencing of three proband-parent trios, we identified de novo missense changes in the cytoplasmic actin-encoding genes ACTB and ACTG1 in one and two probands, respectively. Sequencing of both genes in 15 additional affected individuals identified disease-causing mutations in all probands, including two recurrent de novo alterations (ACTB, encoding p.Arg196His, and ACTG1, encoding p.Ser155Phe). Our results confirm that trio-based exome sequencing is a powerful approach to discover genes causing sporadic developmental disorders, emphasize the overlapping roles of cytoplasmic actin proteins in development and suggest that Baraitser-Winter syndrome is the predominant phenotype associated with mutation of these two genes.     

Probabilistic Delay Fault Model for DVFS Circuits

Decreasing the power supply voltage in dynamic voltage frequency scaling to save power consumption may introduce extra delays in CMOS circuits, which may cause errors. This paper presents the probabilistic delay fault model (PDFM), which describes the probability of an error occurring as a function of the power supply voltage and the clock period in synchronous CMOS circuits. In a wide range of applications (graphic, video, digital filtering, etc.), errors occurring with low probability and not remaining for a long time are acceptable. For combinational circuits which have long critical paths with low probability of excitation, a performance increase is achieved with a certain rate of errors determined by the PDFM compared with the traditional design which considers the worst case. The PDFM applied to array multipliers and ripple carry adders shows the agreement of the predicted probabilities with simulated delay histograms to support the practicality of using the PDFM to select power supply voltage and clock period in dynamic voltage frequency scaling circuits with tolerable error rates.     

同性恋与艾滋病防治*

通过介绍中国同性爱社区的现状,特别是艾滋病对社区的影响,强调中国传统文化对该社区的发展既有消极制约作用,又有积极包容作用,从而不同于西方;由于国情,该社区要获得平等权利,仍需较长过程。     

Ploughing the deep sea floor

Bottom trawling is a non-selective commercial fishing technique whereby heavy nets and gear are pulled along the sea floor. The direct impact of this technique on fish populations and benthic communities has received much attention, but trawling can also modify the physical properties of seafloor sediments, water–sediment chemical exchanges and sediment fluxes. Most of the studies addressing the physical disturbances of trawl gear on the seabed have been undertaken in coastal and shelf environments, however, where the capacity of trawling to modify the seafloor morphology coexists with high-energy natural processes driving sediment erosion, transport and deposition. Here we show that on upper continental slopes, the reworking of the deep sea floor by trawling gradually modifies the shape of the submarine landscape over large spatial scales. We found that trawling-induced sediment displacement and removal from fishing grounds causes the morphology of the deep sea floor to become smoother over time, reducing its original complexity as shown by high-resolution seafloor relief maps. Our results suggest that in recent decades, following the industrialization of fishing fleets, bottom trawling has become an important driver of deep seascape evolution. Given the global dimension of this type of fishery, we anticipate that the morphology of the upper continental slope in many parts of the world’s oceans could be altered by intensive bottom trawling, producing comparable effects on the deep sea floor to those generated by agricultural ploughing on land.     

APJ acts as a dual receptor in cardiac hypertrophy

Cardiac hypertrophy is initiated as an adaptive response to sustained overload but progresses pathologically as heart failure ensues. Here we report that genetic loss of APJ, a G-protein-coupled receptor, confers resistance to chronic pressure overload by markedly reducing myocardial hypertrophy and heart failure. In contrast, mice lacking apelin (the endogenous APJ ligand) remain sensitive, suggesting an apelin-independent function of APJ. Freshly isolated APJ-null cardiomyocytes exhibit an attenuated response to stretch, indicating that APJ is a mechanosensor. Activation of APJ by stretch increases cardiomyocyte cell size and induces molecular markers of hypertrophy. Whereas apelin stimulates APJ to activate Gαi and elicits a protective response, stretch signals in an APJ-dependent, G-protein-independent fashion to induce hypertrophy. Stretch-mediated hypertrophy is prevented by knockdown of β-arrestins or by pharmacological doses of apelin acting through Gαi. Taken together, our data indicate that APJ is a bifunctional receptor for both mechanical stretch and the endogenous peptide apelin. By sensing the balance between these stimuli, APJ occupies a pivotal point linking sustained overload to cardiomyocyte hypertrophy.     

All together now: The circular organization in a University Hospital. Part I. Planning and design

During a period of significant change in health care, hospitals are being transformed. This article—part I—reports on one university hospital's experience with a project funded by a Robert Wood Johnson Foundation and Pew Charitable Trusts initiative. The article presents the history and conditions that led to a planning year during which participants defined external and internal conditions contributing to the needs for change. Along with the driving pressures, the article addresses the planning process and the basic design for organization change, Ackoff's idealized design and circular organization. This model had been used in industry, but not in a hospital. Key themes related to the design and start-up are offered. Part II addresses the implementation of the model, the process of change, supports and barriers, and progress to date.     

Methylation of canine cardiac myosin in culture

Summary N, N, N, trimethyllysine and an unidentified methylated amino acid which co-electrophoresed and cochromatographed with the hydrolysis product of S-adenosyl-L-methionine, occur in fetal canine cardiac myosin and are isotopically labeled in vitro with S-adenosyl-L-(methyl³H) methionine between the 10th and the 12th day of culture.