Role of cardiac troponin I phosphorylation in cardiac function: From molecule to mouse

Abstract only availableThe regulation of cardiac muscle contraction involves the interplay between a variety of molecules on the thick and thin filaments. One important regulatory molecule is troponin, which consists of three subunits, troponin C (TnC) that binds calcium, troponin T (TnT) that binds tropomyosin, and troponin I (TnI) that binds actin and tends to inhibit contraction. Following muscle excitation, cytoplasmic calcium rises and binds TnC, which causes a conformational change in TnI that reduces its affinity for actin; this, in turn, allows TnT and tropomyosin to shift positions revealing myosin binding sites on actin, leading to muscle contraction. Interestingly, cardiac troponin I (cTnI) has several phosphorylation sites, which are known to modulate this regulatory process. For example, phosphorylation of serines 23 and 24 on cTnI by protein kinase A (PKA) is known to decrease the calcium binding affinity of cardiac TnC and, thus, thought to speed muscle relaxation. On the other hand, phosphorylation of cTnI on serines 43 and 45 and threonine 144 by protein kinase C (PKC) decreases both force production and calcium sensitivity of force and is thought to contribute to depressed ventricular function in failing hearts. In this study we investigated the effects of chronic cTnI phosphorylation on cardiac function from transgenic animals in which either PKA phosphorylation sites (Ser-23/Ser-24) (PP) or both the PKA and PKC phosphorylation sites (Ser-23/Ser-24/Ser-43/Ser-45/T-144) (All-P) were replaced with aspartic acid to mimic phosphorylation. Left ventricular cardiac myocytes from PP transgenic mice exhibited less calcium sensitivity of force while myocytes from All-P transgenic mice exhibited decreased maximal force, decreased calcium sensitivity of force, and decreased power output, implicating a dominate role of PKC phosphorylation sites on myofilament function. Consistent with these single myocyte studies, left ventricular power output also was depressed in All-P mice compared to both WT and PP transgenic ventricles. We next tested the hypothesis that PP transgenic mice would engage in greater voluntary running compared to WT and All-P transgenic animals. In contrast to this idea, WT and All-P mice ran ~3- and ~4-fold more than the PP transgenic mouse, respectively. Overall, these results indicate that PKC phosphorylation of cTnI plays a dominant role in depressing contractility and may contribute to the maladaptive behavior.NIH grant to K.S. McDonal

A new nodosaurid ankylosaur (Dinosauria: Thyreophora) from the Upper Cretaceous Menefee Formation of New Mexico

Nodosauridae is a clade of armored dinosaurs with a rich fossil record and long history of study in North America. Nodosaurid fossils have been collected throughout the western United States and Canada. Here, we report three new nodosaurid specimens from the Upper Cretaceous (lower Campanian) Allison Member of the Menefee Formation, San Juan Basin, northwestern New Mexico. The three specimens belong to a new genus and species, Invictarx zephyri, characterized by a unique combination of features pertaining to the morphology of the osteoderms. Among the three specimens there are representative cervical/pectoral and thoracic osteoderms, as well as components of a probable co-ossified pelvic shield. The new tax on is most similar to Glyptodontopelta mimus from the Maastrichtian of New Mexico

Quantification of mitral regurgitation by integrated Doppler backscatter power

AbstractObjectives. We attempted to determine whether continuous wave Doppler backscatter power could be used to quantify mitral regurgitation.Background. The power of a Doppler backscatter signal is proportional to the number of scatterers insonated and, hence, to the moving volume of blood. The relative power of the continuous wave Doppler signals from mitral inflow and aortic outflow is therefore proportional to the relative volumes of blood in motion.Methods. Computer postprocessing was used to derive the relative power of the Doppler backscatter signal from the intensity of the pixels within the spectral display of anterograde aortic and mitral flow. The power ratio was used to calculate the regurgitant fraction in 20 patients (mean age 61.4 years) with mitral regurgitation. This Doppler regurgitant fraction was compared with that derived from angiographic left ventricular volume and thermodilution cardiac output. In addition, 12 normal control subjects were studied by the Doppler method.Results. Mean (± SD) catheterization regurgitant fraction was 0.50 ± 0.26, and mean Doppler regurgitant fraction was 0.47 ± 0.25 (r = 0.89). The limits of agreement between the two methods by Bland-Altman analysis were −0.21 to +0.27. In normal control subjects with an expected regurgitant fraction of close to zero, mean Doppler regurgitant fraction was 0.03 ± 0.05.Conclusions. Doppler backscatter power from mitral and aortic inflow provides a new and accurate method for quantifying mitral regurgitation

Topological change of the Fermi surface in ternary iron-pnictides with reduced c/a ratio: A dHvA study of CaFe2P2

We report a de Haas-van Alphen effect study of the Fermi surface of CaFe2P2 using low temperature torque magnetometry up to 45 T. This system is a close structural analogue of the collapsed tetragonal non-magnetic phase of CaFe2As2. We find the Fermi surface of CaFe2P2 to differ from other related ternary phosphides in that its topology is highly dispersive in the c-axis, being three-dimensional in character and with identical mass enhancement on both electron and hole pockets (~1.5). The dramatic change in topology of the Fermi surface suggests that in a state with reduced (c/a) ratio, when bonding between pnictogen layers becomes important, the Fermi surface sheets are unlikely to be nested

Identification, Motivation and Facilitation of Domestic Tourism in a Small Island

This paper presents a case concerning domestic tourism in the Isle of Man, British Isles; a small maritime nation with Norse heritage. Qualitative interviews find the existence of considerable domestic tourism activity conducted by island residents, including daytrips and overnight stays, and explore the motivational and facilitating factors which underpin this. Such behaviour is identified by residents as touristic and distinct from other leisure pursuits. Yet recognition of domestic tourism in small geographic spaces is currently almost entirely absent. This article attempts to highlight the issue and draw attention to attendant benefits of domestic tourism which include economic and social inputs. These may be relevant to a small island community, and in the case of the Isle of Man help to support an otherwise ailing tourism industry

Large hypomethylated blocks as a universal defining epigenetic alteration in human solid tumors

Background: One of the most provocative recent observations in cancer epigenetics is the discovery of large hypomethylated blocks, including single copy genes, in colorectal cancer, that correspond in location to heterochromatic LOCKs (large organized chromatin lysine-modifications) and LADs (lamin-associated domains). Methods: Here we performed a comprehensive genome-scale analysis of 10 breast, 28 colon, nine lung, 38 thyroid, 18 pancreas cancers, and five pancreas neuroendocrine tumors as well as matched normal tissue from most of these cases, as well as 51 premalignant lesions. We used a new statistical approach that allows the identification of large hypomethylated blocks on the Illumina HumanMethylation450 BeadChip platform. Results: We find that hypomethylated blocks are a universal feature of common solid human cancer, and that they occur at the earliest stage of premalignant tumors and progress through clinical stages of thyroid and colon cancer development. We also find that the disrupted CpG islands widely reported previously, including hypermethylated island bodies and hypomethylated shores, are enriched in hypomethylated blocks, with flattening of the methylation signal within and flanking the islands. Finally, we found that genes showing higher between individual gene expression variability are enriched within these hypomethylated blocks. Conclusion: Thus hypomethylated blocks appear to be a universal defining epigenetic alteration in human cancer, at least for common solid tumors. Electronic supplementary material The online version of this article (doi:10.1186/s13073-014-0061-y) contains supplementary material, which is available to authorized users

A new tyrannosaurid (Dinosauria: Theropoda) from the Upper Cretaceous Menefee Formation of New Mexico

The giant tyrannosaurids were the apex predators of western North America and Asia during the close of the Cretaceous Period. Although many tyrannosaurid species are known from numerous skeletons representing multiple growth stages, the early evolution of Tyrannosauridae remains poorly known, with the well-known species temporally restricted to the middle Campanian-latest Maastrichtian (∼77–66 Ma). The recent discovery of a new tyrannosaurid, Lythronax argestes, from the Wahweap Formation of Utah provided new data on early Campanian (∼80 Ma) tyrannosaurids. Nevertheless, the early evolution of Tyrannosauridae is still largely unsampled. We report a new tyrannosaurid represented by an associated skeleton from the lower Campanian Allison Member of the Menefee Formation of New Mexico. Despite fragmentation of much of the axial and appendicular skeleton prior to discovery, the frontals, a metacarpal, and two pedal phalanges are well-preserved. The frontals exhibit an unambiguous autapomorphy and a second potential autapomorphy that distinguish this specimen from all other tyrannosaurids. Therefore, the specimen is made the holotype of the new genus and species Dynamoterror dynastes. A phylogenetic analysis places Dynamoterror dynastes in the tyrannosaurid subclade Tyrannosaurinae. Laser-scanning the frontals and creation of a composite 3-D digital model allows the frontal region of the skull roof of Dynamoterror to be reconstructed

Phylogeny of Basal Iguanodonts (Dinosauria: Ornithischia): An Update

The precise phylogenetic relationships of many non-hadrosaurid members of Iguanodontia, i.e., basal iguanodonts, have been unclear. Therefore, to investigate the global phylogeny of basal iguanodonts a comprehensive data matrix was assembled, including nearly every valid taxon of basal iguanodont. The matrix was analyzed in the program TNT, and the maximum agreement subtree of the resulting most parsimonious trees was then calculated in PAUP. Ordering certain multistate characters and omitting taxa through safe taxonomic reduction did not markedly improve resolution. The results provide some new information on the phylogeny of basal iguanodonts, pertaining especially to obscure or recently described taxa, and support some recent taxonomic revisions, such as the splitting of traditional “Camptosaurus” and “Iguanodon”. The maximum agreement subtree also shows a close relationship between the Asian Probactrosaurus gobiensis and the North American Eolambia, supporting the previous hypothesis of faunal interchange between Asia and North America in the early Late Cretaceous. Nevertheless, the phylogenetic relationships of many basal iguanodonts remain ambiguous due to the high number of taxa removed from the maximum agreement subtree and poor resolution of consensus trees