Common variants at CD40 and other loci confer risk of rheumatoid arthritis

To identify rheumatoid arthritis risk loci in European populations, we conducted a meta-analysis of two published genome-wide association (GWA) studies totaling 3,393 cases and 12,462 controls. We genotyped 31 top-ranked SNPs not previously associated with rheumatoid arthritis in an independent replication of 3,929 autoantibody-positive rheumatoid arthritis cases and 5,807 matched controls from eight separate collections. We identified a common variant at the CD40 gene locus (rs4810485, P = 0.0032 replication, P = 8.2 x 10(-9) overall, OR = 0.87). Along with other associations near TRAF1 (refs. 2,3) and TNFAIP3 (refs. 4,5), this implies a central role for the CD40 signaling pathway in rheumatoid arthritis pathogenesis. We also identified association at the CCL21 gene locus (rs2812378, P = 0.00097 replication, P = 2.8 x 10(-7) overall), a gene involved in lymphocyte trafficking. Finally, we identified evidence of association at four additional gene loci: MMEL1-TNFRSF14 (rs3890745, P = 0.0035 replication, P = 1.1 x 10(-7) overall), CDK6 (rs42041, P = 0.010 replication, P = 4.0 x 10(-6) overall), PRKCQ (rs4750316, P = 0.0078 replication, P = 4.4 x 10(-6) overall), and KIF5A-PIP4K2C (rs1678542, P = 0.0026 replication, P = 8.8 x 10(-8) overall).     

PLATFORM SELECTION FOR COMPLEX SYSTEMS:BUILDING AUTOMATION SYSTEMS

Automation systems for buildings interconnect components and technologies from the information technology industry and the telecommunications industry.In these industries,existing platforms and new platforms（that are designed to make building automation systems work） compete for market acceptance and consequently several platform battles among suppliers for building automation networking are being waged.It is unclear what the outcome of these battles will be and also which factors are important in achieving platform dominance.Taking the fuzziness of decision makers＇ judgments into account,a fuzzy multi-criteria decision-making methodology called the Fuzzy Analytic Hierarchy Process is applied to investigate the importance of such factors in platform battles for building automation networking.We present the relative importance of the factors for three types of platforms（subsystem platforms,system platforms,and evolved subsystem platforms）.The results provide a first indication that the set of important factors differs per type of platform.For example,when focusing on other stakeholders,for subsystem platforms,the previous installed base is of importance;for system platforms,the diversity of the network of stakeholders is essential;and for evolved subsystem platforms,the judiciary is an important factor.     

The practical use of a systems approach in large-scale designing

This paper describes in short a new approach to the solution of a practical design problem. The procedures for the approach are based on the use of a systems methodology. The main topics present the development of a project from the external assignment through detailed algorithms of systems modeling to the identification of the solution system.     

How the Venus flytrap snaps

The rapid closure of the Venus flytrap (Dionaea muscipula) leaf in about 100 ms is one of the fastest movements in the plant kingdom. This led Darwin to describe the plant as "one of the most wonderful in the world". The trap closure is initiated by the mechanical stimulation of trigger hairs. Previous studies have focused on the biochemical response of the trigger hairs to stimuli and quantified the propagation of action potentials in the leaves. Here we complement these studies by considering the post-stimulation mechanical aspects of Venus flytrap closure. Using high-speed video imaging, non-invasive microscopy techniques and a simple theoretical model, we show that the fast closure of the trap results from a snap-buckling instability, the onset of which is controlled actively by the plant. Our study identifies an ingenious solution to scaling up movements in non-muscular engines and provides a general framework for understanding nastic motion in plants.     

Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin

Nephronophthisis (NPHP) is the most frequent genetic cause of chronic renal failure in children. Identification of four genes mutated in NPHP subtypes 1-4 (refs. 4-9) has linked the pathogenesis of NPHP to ciliary functions. Ten percent of affected individuals have retinitis pigmentosa, constituting the renal-retinal Senior-Loken syndrome (SLSN). Here we identify, by positional cloning, mutations in an evolutionarily conserved gene, IQCB1 (also called NPHP5), as the most frequent cause of SLSN. IQCB1 encodes an IQ-domain protein, nephrocystin-5. All individuals with IQCB1 mutations have retinitis pigmentosa. Hence, we examined the interaction of nephrocystin-5 with RPGR (retinitis pigmentosa GTPase regulator), which is expressed in photoreceptor cilia and associated with 10-20% of retinitis pigmentosa. We show that nephrocystin-5, RPGR and calmodulin can be coimmunoprecipitated from retinal extracts, and that these proteins localize to connecting cilia of photoreceptors and to primary cilia of renal epithelial cells. Our studies emphasize the central role of ciliary dysfunction in the pathogenesis of SLSN.     

Mutations in SIL1 cause Marinesco-Sjögren syndrome, a cerebellar ataxia with cataract and myopathy

SIL1 (also called BAP) acts as a nucleotide exchange factor for the Hsp70 chaperone BiP (also called GRP78), which is a key regulator of the main functions of the endoplasmic reticulum. We found nine distinct mutations that would disrupt the SIL1 protein in individuals with Marinesco-Sj?gren syndrome, an autosomal recessive cerebellar ataxia complicated by cataracts, developmental delay and myopathy. Identification of SIL1 mutations implicates Marinesco-Sj?gren syndrome as a disease of endoplasmic reticulum dysfunction and suggests a role for this organelle in multisystem disorders.     

Interactions between amphetamine and reserpine in vitro

Resumen Se estudia en el conducto deferente aislado de rata la respuesta a la reserpina después de la estimulación del preparado con anfetamina. En estas condiciones, la reserpina produce una contracción que es proporcional a las concentraciones de anfetamina y reserpina utilizadas, y es máxima para una concentración de reserpina de 2,5×10^–5 g/ml, para ser luego decreciente cualquiera que sea la concentración de anfetamina que se haya empleado previamente. Se discuten los posibles mecanismos que regulan la respuesta a la reserpina después de la anfetamina.     

Twisting the Dollar? On the Consistency of Short‐Run and Long‐Run Exchange Rate Expectations

We examine consistency properties of the exchange rate expectation formation process of short‐run and long‐run forecasts in the dollar/euro and yen/dollar market. Applying nonlinear consistency restrictions we show that in a simple expectation formation structure short‐run forecasts are indeed inconsistent with long‐run predictions. Moreover, we establish a ‘twist’ in the dollar/euro expectation formation process, i.e. market participants expect bandwagon effects in the short run, while they have stabilizing expectations in their long‐run forecasts. Applying a panel probit analysis we find that this twisting behavior is more likely to occur in periods of excess exchange rate volatility. Copyright © 2011 John Wiley & Sons, Ltd.