Nmrk2 gene is upregulated in dilated cardiomyopathy and required for cardiac function and nad levels during aging

Dilated cardiomyopathy (DCM) is a disease of multifactorial etiologies, the risk of which is increased by male sex and age. There are few therapeutic options for patients with DCM who would benefit from identification of common targetable pathways. We used bioinformatics to identify the Nmrk2 gene involved in nicotinamide adenine dinucleotde (NAD) coenzyme biosynthesis as activated in different mouse models and in hearts of human patients with DCM while the Nampt gene controlling a parallel pathway is repressed. A short NMRK2 protein isoform is also known as muscle integrin binding protein (MIBP) binding the α7β1 integrin complex. We investigated the cardiac phenotype of Nmrk2-KO mice to establish its role in cardiac remodeling and function. Young Nmrk2-KO mice developed an eccentric type of cardiac hypertrophy in response to pressure overload rather than the concentric hypertrophy observed in controls. Nmrk2-KO mice developed a progressive DCM-like phenotype with aging, associating eccentric remodeling of the left ventricle and a decline in ejection fraction and showed a reduction in myocardial NAD levels at 24 months. In agreement with involvement of NMRK2 in integrin signaling, we observed a defect in laminin deposition in the basal lamina of cardiomyocytes leading to increased fibrosis at middle age. The α7 integrin was repressed at both transcript and protein level at 24 months. Nmrk2 gene is required to preserve cardiac structure and function, and becomes an important component of the NAD biosynthetic pathways during aging. Molecular characterization of compounds modulating this pathway may have therapeutic potential

GGC01 cored, seismic monitoring borehole – initial data release

Summary This report gives a short overview of information related to the initial data release for GGC01. The cored, seismic monitoring borehole GGC01 (BGS SOBI number NS66SW BJ 3754) was drilled between 19 November and 12 December 2018 producing a core of 102 mm diameter. The borehole was wireline logged in December 2018 and a string of 5 seismometers were installed in February 2019. Contributions to this report and the data acquired are as follows: Vanessa Starcher: Technical overview, wireline log data acquisition Kirsty Shorter: Fluid and geomicrobiology samples, tracer information, field measurements, photo metadata Hugh Barron: On-site core and data acquisition, initial geological interpretation Joel Burkin; Geomicrobiology samples, on site core management and initial geological interpretation Jack Elsome: Fluid and geomicrobiology samples Mark Fellgett: Wireline log data checking and documentation Andy Kingdon: Wireline log data checking and documentation Megan Barnett: Geomicrobiology samples Alison Monaghan: Coordinating initial data pack, initial geological interpretation IMPORTANT – Note that all borehole depths given in the initial data release are based on the drillers log dataset (excepting wireline data). Borehole depths will be subject to minor change once non-recovery intervals are assigned. Borehole and sample depths will be revised in the final borehole data pack so that core scans, wireline logs and borehole logs/samples are consistent

Special features of high-speed interaction of supercavitating solids in water

Special features of material behavior of a supercavitating projectile are investigated at various initial velocities of entering water on the basis of the developed stress-strain state model with possibility of destruction of solids when moving in water and interacting with various underwater barriers with the use of consistent methodological approach of mechanics of continuous media. The calculation-experimental method was used to study the modes of motion of supercavitating projectiles at sub- and supersonic velocities in water medium after acceleration in the barrelled accelerator, as well as their interaction with barriers. Issues of stabilization of the supercavitating projectile on the initial flight path in water were studied. Microphotographs of state of solids made of various materials, before and after interaction with water, at subsonic and supersonic velocities were presented. Supersonic velocity of the supercavitating projectile motion in water of 1590 m/s was recorded

UK Geoenergy Observatories Glasgow: GGC01 cored, seismic monitoring borehole – intermediate data release

This report gives an overview of information related to an intermediate data release of the borehole information pack for UK Geoenergy Observatories: Glasgow borehole GGC01. The cored, seismic monitoring borehole GGC01 (BGS SOBI number NS66SW BJ 3754, BGS ID 20650619) was drilled between 19 November and 12 December 2018 producing a core of 102 mm diameter. The borehole was wireline logged in December 2018 and a string of 5 seismometers were installed in February 2019. The core was transported to the National Geological Repository (NGR) at BGS Keyworth and was curated into 1 m core boxes. State-of-the-art core scanners are being used to collect radiographic, CT, optical images, geophysical log and XRF along core datasets. Optical images and radiographic images are included in the intermediate release. Also included are sedimentary, discontinuity and engineering log

Improvement of anthropogenic environmental loads assessment methods using modern information technologies

The innovative path of human development is characterized by the active use of information technology in any field. This is due to the rapid development of high technologies and, accordingly, with the advent of new data analysis tools. One of the rapidly developing areas of application of information technology, to which there is great interest in society, the state, commercial organizations, is high-quality forecasting

Theory of differential inclusions and its application in mechanics

The following chapter deals with systems of differential equations with discontinuous right-hand sides. The key question is how to define the solutions of such systems. The most adequate approach is to treat discontinuous systems as systems with multivalued right-hand sides (differential inclusions). In this work three well-known definitions of solution of discontinuous system are considered. We will demonstrate the difference between these definitions and their application to different mechanical problems. Mathematical models of drilling systems with discontinuous friction torque characteristics are considered. Here, opposite to classical Coulomb symmetric friction law, the friction torque characteristic is asymmetrical. Problem of sudden load change is studied. Analytical methods of investigation of systems with such asymmetrical friction based on the use of Lyapunov functions are demonstrated. The Watt governor and Chua system are considered to show different aspects of computer modeling of discontinuous systems

Cell culture-based analysis of postsynaptic membrane assembly in muscle cells

We report a method for studying postsynaptic membrane assembly utilizing the replating of aneural cultures of differentiated skeletal muscle cells onto laminin-coated surfaces. A significant limitation to the current cell culturebased approaches has been their inability to recapitulate the multistage surface acetylcholine receptor (AChR) redistribution events that produce complex AChR clusters found at the intact neuromuscular junction (NMJ). By taking advantage of the ability of substrate laminin to induce advanced maturation of AChR aggregates on the surface of myotubes, we have developed a secondary-plating method that allows more precise analysis of the signaling events connecting substrate laminin stimulation to complex AChR cluster formation. We validate the utility of this method for biochemical and microscopy studies by demonstrating the roles of RhoGTPases in substrate laminin-induced complex cluster assembly

Hidden attractors in fundamental problems and engineering models

Recently a concept of self-excited and hidden attractors was suggested: an attractor is called a self-excited attractor if its basin of attraction overlaps with neighborhood of an equilibrium, otherwise it is called a hidden attractor. For example, hidden attractors are attractors in systems with no equilibria or with only one stable equilibrium (a special case of multistability and coexistence of attractors). While coexisting self-excited attractors can be found using the standard computational procedure, there is no standard way of predicting the existence or coexistence of hidden attractors in a system. In this plenary survey lecture the concept of self-excited and hidden attractors is discussed, and various corresponding examples of self-excited and hidden attractors are considered

Skeletal Muscle-Specific Ablation of γcyto-Actin Does Not Exacerbate the mdx Phenotype

We previously documented a ten-fold increase in γcyto-actin expression in dystrophin-deficient skeletal muscle and hypothesized that increased γcyto-actin expression may participate in an adaptive cytoskeletal remodeling response. To explore whether increased γcyto-actin fortifies the cortical cytoskeleton in dystrophic skeletal muscle, we generated double knockout mice lacking both dystrophin and γcyto-actin specifically in skeletal muscle (ms-DKO). Surprisingly, dystrophin-deficient mdx and ms-DKO mice presented with comparable levels of myofiber necrosis, membrane instability, and deficits in muscle function. The lack of an exacerbated phenotype in ms-DKO mice suggests γcyto-actin and dystrophin function in a common pathway. Finally, because both mdx and ms-DKO skeletal muscle showed similar levels of utrophin expression and presented with identical dystrophies, we conclude utrophin can partially compensate for the loss of dystrophin independent of a γcyto-actin-utrophin interaction

Improving Reproducibility of Phenotypic Assessments in the DyW Mouse Model of Laminin-α2 Related Congenital Muscular Dystrophy

Laminin-α2 related Congenital Muscular Dystrophy (LAMA2-CMD) is a progressive muscle disease caused by partial or complete deficiency of laminin-211, a skeletal muscle extracellular matrix protein. In the last decade, basic science research has queried underlying disease mechanisms in existing LAMA2-CMD murine models and identified possible clinical targets and pharmacological interventions. Experimental rigor in preclinical studies is critical to efficiently and accurately quantify both negative and positive results, degree of efficiency of potential therapeutics and determine whether to move a compound forward for additional preclinical testing. In this review, we compare published available data measured to assess three common parameters in the widely used mouse model DyW, that mimics LAMA2-CMD, we quantify variability and analyse its possible sources. Finally, on the basis of this analysis, we suggest standard set of assessments and the use of available standardized protocols, to reduce variability of outcomes in the future and to improve the value of preclinical research