Evidence of G-protein-coupled receptor and substrate transporter heteromerization at a single molecule level

G-protein-coupled receptors (GPCRs) can constitute complexes with non-GPCR integral membrane proteins, while such interaction has not been demonstrated at a single molecule level so far. We here investigated the potential interaction between the thyrotropin receptor (TSHR) and the monocarboxylate transporter 8 (MCT8), a member of the major facilitator superfamily (MFS), using fluorescence cross-correlation spectroscopy (FCCS). Both the proteins are expressed endogenously on the basolateral plasma membrane of the thyrocytes and are involved in stimulation of thyroid hormone production and release. Indeed, we demonstrate strong interaction between both the proteins which causes a suppressed activation of G_q/11 by TSH-stimulated TSHR. Thus, we provide not only evidence for a novel interaction between the TSHR and MCT8, but could also prove this interaction on a single molecule level. Moreover, this interaction forces biased signaling at the TSHR. These results are of general interest for both the GPCR and the MFS research fields.     

Bias‐corrected bootstrap prediction intervals for autoregressive model: new alternatives with applications to tourism forecasting

This paper proposes the use of the bias‐corrected bootstrap for interval forecasting of an autoregressive time series with an arbitrary number of deterministic components. We use the bias‐corrected bootstrap based on two alternative bias‐correction methods: the bootstrap and an analytic formula based on asymptotic expansion. We also propose a new stationarity‐correction method, based on stable spectral factorization, as an alternative to Kilian's method exclusively used in past studies. A Monte Carlo experiment is conducted to compare small‐sample properties of prediction intervals. The results show that the bias‐corrected bootstrap prediction intervals proposed in this paper exhibit desirable small‐sample properties. It is also found that the bootstrap bias‐corrected prediction intervals based on stable spectral factorization are tighter and more stable than those based on Kilian's stationarity‐correction. The proposed methods are applied to interval forecasting for the number of tourist arrivals in Hong Kong. Copyright © 2010 John Wiley & Sons, Ltd.     

Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis

Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10?1?). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10?3). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10?2?, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV.     

Making the abstract concrete: The role of norms and values in experimental modeling

Experimental modeling is the construction of theoretical models hand in hand with experimental activity. As explained in Section 1, experimental modeling starts with claims about phenomena that use abstract concepts, concepts whose conditions of realization are not yet specified; and it ends with a concrete model of the phenomenon, a model that can be tested against data. This paper argues that this process from abstract concepts to concrete models involves judgments of relevance, which are irreducibly normative. In Section 2, we show, on the basis of several case studies, how these judgments contribute to the determination of the conditions of realization of the abstract concepts and, at the same time, of the quantities that characterize the phenomenon under study. Then, in Section 3, we compare this view on modeling with other approaches that also have acknowledged the role of relevance judgments in science. To conclude, in Section 4, we discuss the possibility of a plurality of relevance judgments and introduce a distinction between locally and generally relevant factors.     

Spectrin-based skeleton as an actor in cell signaling

This review focuses on the recent advances in functions of spectrins in non-erythroid cells. We discuss new data concerning the commonly known role of the spectrin-based skeleton in control of membrane organization, stability and shape, and tethering protein mosaics to the cellular motors and to all major filament systems. Particular effort has been undertaken to highlight recent advances linking spectrin to cell signaling phenomena and its participation in signal transduction pathways in many cell types.     

Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits

We present an approximate conditional and joint association analysis that can use summary-level statistics from a meta-analysis of genome-wide association studies (GWAS) and estimated linkage disequilibrium (LD) from a reference sample with individual-level genotype data. Using this method, we analyzed meta-analysis summary data from the GIANT Consortium for height and body mass index (BMI), with the LD structure estimated from genotype data in two independent cohorts. We identified 36 loci with multiple associated variants for height (38 leading and 49 additional SNPs, 87 in total) via a genome-wide SNP selection procedure. The 49 new SNPs explain approximately 1.3% of variance, nearly doubling the heritability explained at the 36 loci. We did not find any locus showing multiple associated SNPs for BMI. The method we present is computationally fast and is also applicable to case-control data, which we demonstrate in an example from meta-analysis of type 2 diabetes by the DIAGRAM Consortium.