Gap Junctional Communication via Connexin43 between Purkinje Fibers and Working Myocytes Explains the Epicardial Activation Pattern in the Postnatal Mouse Left Ventricle

The mammalian ventricular myocardium forms a functional syncytium due to flow of electrical current mediated in part by gap junctions localized within intercalated disks. The connexin (Cx) subunit of gap junctions have direct and indirect roles in conduction of electrical impulse from the cardiac pacemaker via the cardiac conduction system (CCS) to working myocytes. Cx43 is the dominant isoform in these channels. We have studied the distribution of Cx43 junctions between the CCS and working myocytes in a transgenic mouse model, which had the His-Purkinje portion of the CCS labeled with green fluorescence protein. The highest number of such connections was found in a region about one-third of ventricular length above the apex, and it correlated with the peak proportion of Purkinje fibers (PFs) to the ventricular myocardium. At this location, on the septal surface of the left ventricle, the insulated left bundle branch split into the uninsulated network of PFs that continued to the free wall anteriorly and posteriorly. The second peak of PF abundance was present in the ventricular apex. Epicardial activation maps correspondingly placed the site of the first activation in the apical region, while some hearts presented more highly located breakthrough sites. Taken together, these results increase our understanding of the physiological pattern of ventricular activation and its morphological underpinning through detailed CCS anatomy and distribution of its gap junctional coupling to the working myocardium.     

Cardiac Oxidative Signaling and Physiological Hypertrophy in the Na/K-ATPase α1s/sα2s/s Mouse Model of High Affinity for Cardiotonic Steroids

The Na/K-ATPase is the specific receptor for cardiotonic steroids (CTS) such as ouabain and digoxin. At pharmacological concentrations used in the treatment of cardiac conditions, CTS inhibit the ion-pumping function of Na/K-ATPase. At much lower concentrations, in the range of those reported for endogenous CTS in the blood, they stimulate hypertrophic growth of cultured cardiac myocytes through initiation of a Na/K-ATPase-mediated and reactive oxygen species (ROS)-dependent signaling. To examine a possible effect of endogenous concentrations of CTS on cardiac structure and function in vivo, we compared mice expressing the naturally resistant Na/K-ATPase α1 and age-matched mice genetically engineered to express a mutated Na/K-ATPase α1 with high affinity for CTS. In this model, total cardiac Na/K-ATPase activity, α1, α2, and β1 protein content remained unchanged, and the cardiac Na/K-ATPase dose–response curve to ouabain shifted to the left as expected. In males aged 3–6 months, increased α1 sensitivity to CTS resulted in a significant increase in cardiac carbonylated protein content, suggesting that ROS production was elevated. A moderate but significant increase of about 15% of the heart-weight-to-tibia-length ratio accompanied by an increase in the myocyte cross-sectional area was detected. Echocardiographic analyses did not reveal any change in cardiac function, and there was no fibrosis or re-expression of the fetal gene program. RNA sequencing analysis indicated that pathways related to energy metabolism were upregulated, while those related to extracellular matrix organization were downregulated. Consistent with a functional role of the latter, an angiotensin-II challenge that triggered fibrosis in the α1^r/rα2^s/s mouse failed to do so in the α1^s/sα2^s/s. Taken together, these results are indicative of a link between circulating CTS, Na/K-ATPase α1, ROS, and physiological cardiac hypertrophy in mice under baseline laboratory conditions.     

Molecular Genetics of Conjunctival Melanoma and Prognostic Value of TERT Promoter Mutation Analysis

The aim of this study was exploration of the genetic background of conjunctival melanoma (CM) and correlation with recurrent and metastatic disease. Twenty-eight CM from the Rotterdam Ocular Melanoma Study group were collected and DNA was isolated from the formalin-fixed paraffin embedded tissue. Targeted next-generation sequencing was performed using a panel covering GNAQ, GNA11, EIF1AX, BAP1, BRAF, NRAS, c-KIT, PTEN, SF3B1, and TERT genes. Recurrences and metastasis were present in eight (29%) and nine (32%) CM cases, respectively. TERT promoter mutations were most common (54%), but BRAF (46%), NRAS (21%), BAP1 (18%), PTEN (14%), c-KIT (7%), and SF3B1 (4%) mutations were also observed. No mutations in GNAQ, GNA11, and EIF1AX were found. None of the mutations was significantly associated with recurrent disease. Presence of a TERT promoter mutation was associated with metastatic disease (p-value = 0.008). Based on our molecular findings, CM comprises a separate entity within melanoma, although there are overlapping molecular features with uveal melanoma, such as the presence of BAP1 and SF3B1 mutations. This warrants careful interpretation of molecular data, in the light of clinical findings. About three quarter of CM contain drug-targetable mutations, and TERT promoter mutations are correlated to metastatic disease in CM.     

Thermal analysis of polymer–water interactions and their relation to gas hydrate inhibition

Gas hydrates formed in oil production pipelines are crystalline solids where hydrocarbon gas molecules such as methane, propane, and their mixtures are trapped in a cagelike structure by hydrogen‐bonded water molecules to form undesirable plugs. Methanol and glycol are currently used to prevent these plugs via thermodynamic inhibition. Small amounts of water‐soluble polymers may provide an alternate approach for preventing gas hydrates. In this study, we expand the fundamental understanding of water–polymer systems with differential scanning calorimetry. Nonfreezable bound water was used to quantify polymer–water interactions and relate them to the chemical structure for a series of polymers, including acrylamides, cyclic lactams, and n‐vinyl amides. For good interactions, the water structure needs to be stabilized through hydrophobic interactions. An increased hydrophobicity of the pendant group also appears to favor polymer performance as a gas hydrate inhibitor. Good inhibitors, such as poly(diethyl acrylamide) and poly(N‐vinyl caprolactam), also show higher heat capacities, which indicate higher hydrophobicity, than poor performers such as polyzwitterions, in which hydrophilicity dominated. The phase behavior and thermodynamic properties of dilute polymer solutions were also evaluated through measurements of the heat of demixing and lower critical solution temperature. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 2642–2653, 2007     

An evaluation of the performance of an automated procedure for comparative modelling of protein tertiary structure

A 3-D model of a protein can be constructed from its amino acidsequence and the 3-D structures of one or more homologues byannealing three sets of fragments: the structurally conservedregions, structurally variable regions and the side chains.The method encoded in the computer program COMPOSER was assessedby generating 3-D models of eight proteins whose crystal structuresare already known and for which 3-D structures of homologuesare available. In the structurally conserved regions, differencesbetween modelled and X-ray structures are smaller than the differencesbetween the X-ray structures of the modelled protein and thehomologues used to build the model. When several homologuesare used, the contributions of the known structures are weighted,preferably by the square of sequence similarity; this is especiallyimportant when the similarities of the homologues to the modelledstructure differ greatly. The ‘collar’ extensionapproach, in which a similar region of different length in ahomologue is used to extend the framework, can result in a moreaccurate model. If known homologues comprise more than one relatedgroup of proteins and they are both distantly related to theunknown, then alignment of the sequence to be modelled witheach group of homologues facilitates identification of structurallyconserved regions of the unknown and leads to an improved model.Models have root mean square differences (r.m.s.d.s) with thestructures defined by X-ray analysis of between 0.73 and 1.56Å for all C atoms, for seven of the eight models. Forthe model of mucor pepsin, where the closest homologue has 33%sequence identity and 20% of the residues are in structurallyvariable regions, the r.m.s.d. for the framework region is 1.71Å and the r.m.s.d. for all C atoms is 3.47 Â.     

Thermal Shock Failure in Thick Epoxy Coatings

In this paper we describe an apparatus for reproducibly measuring thermal shock resistance of thick polymer layers bonded to metals. The thermal shock behavior is discussed in terms of epoxy samples bonded to an aluminum substrate. It was found that both high resin toughness and low resin thermal expansion coefficient improved thermal shock resistance of thick coatings, but only a sample containing 60wt. % glass beads did not develop a failure crack. Effects of sample thickness, temperature gradient, and resin composition on thermal shock behavior are discussed.     

Exploiting Batch Processing on Streaming Architectures to Solve 2D Elliptic Finite Element Problems: A Hybridized Discontinuous Galerkin (HDG) Case Study

Numerical methods for elliptic partial differential equations (PDEs) within both continuous and hybridized discontinuous Galerkin (HDG) frameworks share the same general structure: local (elemental) matrix generation followed by a global linear system assembly and solve. The lack of inter-element communication and easily parallelizable nature of the local matrix generation stage coupled with the parallelization techniques developed for the linear system solvers make a numerical scheme for elliptic PDEs a good candidate for implementation on streaming architectures such as modern graphical processing units (GPUs). We propose an algorithmic pipeline for mapping an elliptic finite element method to the GPU and perform a case study for a particular method within the HDG framework. This study provides comparison between CPU and GPU implementations of the method as well as highlights certain performance-crucial implementation details. The choice of the HDG method for the case study was dictated by the computationally-heavy local matrix generation stage as well as the reduced trace-based communication pattern, which together make the method amenable to the fine-grained parallelism of GPUs. We demonstrate that the HDG method is well-suited for GPU implementation, obtaining total speedups on the order of 30–35 times over a serial CPU implementation for moderately sized problems.     

Simulation of Climate Change Effects on Hydropower Operations in Mountain Headwater Lakes,New Zealand

Future climate change is expected to have wide ranging impacts on the hydrology of mountain rivers because of changes in the magnitudes and timing of rain and snow, as well as the significant spatial variability of topography and other catchment characteristics. In New Zealand, hydropower generation in mountain basins is the primary source of electricity and renewable energy resource in the country. The goal of this study was to simulate and evaluate the potential effects of climate change on hydropower operations in three mountain headwater lakes (lakes Pukaki, Tekapo, and Ohau) in the Upper Waitaki Basin of the central South Island. The TopNet hydrological model was used to estimate catchment runoff and lake inflows based on the 1990s (baseline), 2040s, and 2090s periods. Average temperature and precipitation results from an ensemble of 12 Global Circulation Models based on the IPCC 4th Assessment Report A1B emissions scenario were used as input to TopNet. Linked hydropower lake water balance models were developed and used to simulate hydropower operations including discharge, hydroelectric power generation, and spill based on TopNet future inflow predictions, projected electricity demand, and lake storage and outflow characteristics. Our results indicate that annual lake inflows increase under future climate scenarios, but that there are seasonal effects with increasing flows in winter and early spring, and summer flows decreasing somewhat as a result of increasing temperatures and greater winter rain with less snow. Although overall hydropower generation can increase with the increasing flows and projected electricity demand, the seasonal changes result in demand being met in winter and spring with potential shortfalls in summer and autumn. Maximum annual generation can be achieved for some generating stations, but generation will decrease at other stations and more spill will likely be required through the 2090s because of the seasonal changes. Therefore flood and drought risk could also increase for downstream areas. Results also indicate that by the 2090s electricity demand could exceed generation capacity for these headwater lakes. Copyright © 2016 John Wiley & Sons, Ltd.     

Material specification and the availability and life of desalination equipment in both Saudi Arabia and the Arabian Gulf

The author describes operational experience with various materials of construction in both low temperature polyphosphate treated evaporators and also in high temperature evaporators using acid treatment.The author references the repeated use of unsuitable materials and proposes a solution by the development of more detailed and positive specifications for plant and equipment. A problem faced by many manufacturers is the fact that as a result of broad, open specifications they are forced to use inferior materials in order to remain competitive. The author discusses the use of both corrosion resistant linings and operating experience. In summary, the paper correlates the operating conditions with selection of materials.