Changes of the intestinal mucosal barrier are considered to play a role in the pathogenesis of inflammatory bowel disease (IBD). Our experiments were designed to identify dysregulation of epithelial junctional molecules in the IBD intestinum and to address whether altered expression of these molecules is a primary event in IBD or a phenomenon secondary to the inflammatory process. Noninflamed and inactively and actively inflamed mucosal tissues from patients with ulcerative colitis or Crohn's disease as well as tissues from control subjects were analyzed for the expression of junctional molecules by different methods. Marked downregulation of junctional proteins and their respective mRNAs was observed in actively inflamed IBD tissues. In IBD tissues with inactive inflammation, only a few junctional molecules such as E-cadherin and α-catenin were affected, whereas expression of desmosomal or tight junction-associated proteins appeared almost unchanged. In noninflamed IBD tissues, junctional protein expression was not different from that seen in normal control subjects. In IBD, downregulation of junctional molecule expression is apparently associated with the inflammatory process and does not likely represent a primary phenomenon.

The composition of skeletal muscle, in terms of the relative number of slow-and fast-twitch fibers, is tightly regulated to enable an organism to respond and adapt to changing physical demands. The phosphatase calcineurin and its downstream targets, transcription factors of the nuclear factor of activated T cells (NFAT) family, play a critical role in this process by promoting the formation of slow-twitch, oxidative fibers. Calcineurin binds to calsarcins, a family of striated muscle-specific proteins of the sarcomeric Z-disc. We show here that mice deficient in calsarcin-2, which is expressed exclusively by fast-twitch muscle and encoded by the myozenin 1 (Myoz1) gene, have substantially reduced body weight and fast-twitch muscle mass in the absence of an overt myopathic phenotype. Additionally, Myoz1 KO mice displayed markedly improved performance and enhanced running distances in exercise studies. Analysis of fiber type composition of calsarcin-2-deficient skeletal muscles showed a switch toward slow-twitch, oxidative fibers. Reporter assays in cultured myoblasts indicated an inhibitory role for calsarcin-2 on calcineurin, and Myoz1 KO mice exhibited both an excess of NFAT activity and an increase in expression of regulator of calcineurin 1-4 (RCAN1-4), indicating enhanced calcineurin signaling in vivo. Taken together, these results suggest that calsarcin-2 modulates exercise performance in vivo through regulation of calcineurin/NFAT activity and subsequent alteration of the fiber type composition of skeletal muscle.

Parasitic flatworm sensitivity to praziquantel is determined by amino acid variation in the binding pocket of a TRP channel.

Rationale: The intercalated disc (ID) is a highly specialized cell-cell contact structure that ensures mechanical and electric coupling of contracting cardiomyocytes. Recently, the ID has been recognized to be a hot spot of cardiac disease, in particular inherited cardiomyopathy. Objective: Given its complex structure and function we hypothesized that important molecular constituents of the ID still remain unknown. Methods and Results: Using a bioinformatics screen, we discovered and cloned a previously uncharacterized 54 kDa cardiac protein which we termed Myozap (Myocardium-enriched zonula occludens-1-associated protein). Myozap is strongly expressed in the heart and lung. In cardiac tissue it localized to the ID and directly binds to desmoplakin and zonula occludens- Key Words: myocytes Ⅲ cardiac Ⅲ cardiomyopathies Ⅲ serum response factor A unique morphological feature of cardiac muscle is the intercalated disc (ID), a highly specialized cell-cell contact structure that connects individual cardiomyocytes. Several independent substructures of the ID have been distinguished, including (1) desmosomes, which link the intermediate filament apparatus of the cell, (2) fasciae adhaerentes, to which the actomyosin filament bundles are attached, and (3) gap junctions, which allow free movement of ions and small molecules between adjacent cardiomyocytes. Together, these structures form a network of proteins which ensure mechanical and electric coupling of contracting cardiomyocytes ("functional syncytium") (reviewed elsewhere 1 ). Recently, immunoelectron microscopy and biochemical studies have revealed that major constituents of the desmosomes such as desmoplakin, plakophilin-2 and the cadherins can also be detected in adherens junctions. 2 Correspondingly, typical components of adherens and gap junctions were found to colocalize with desmosomal molecules. 3 Thus, it has been proposed that in the heart these specialized cell-cell contact structures are merged in an "area composita." 2,4 Given the critical importance of the intercalated disc for cardiac integrity and function, it is perhaps not surprising that the ID has become a hot spot of inherited cardiac disease. In particular, arrhythmogenic right ventricular cardiomyopathy (ARVC), has been coined a "desmosome cardiomyopathy," 5 Original received May 26, 2009; resubmission received November 15, 2009; revised resubmission received December 30, 2009; accepted January 11, 2010. From the Department of Internal Medicine III (T.S.S., D.F., C.R., R.W., S.J., W. MethodsExperimental procedures for cloning and the subsequent bioinformatics, Northern blot analysis and radioactive in situ hybridization, the generation of a Myozap-specific antiserum and western blot analyses, immunofluorescence and immunoelectron microscopy, yeast 2-hybrid assays, tissue culture, immunoprecipitations, reporter gene assays as well as zebrafish injection procedures, and fractional shortening measurement are provided in the expanded Methods section in the Online Data Supplement, avail...