Impact of Polymorphisms in PTK2 on Intrinsic Muscle Strength

Abstract Title: Impact of Polymorphisms in PTK2 on Intrinsic Muscle Strength Primary Presenter Full Name: Zachary Zeller Co-presenter Full Name(s): Click here to enter text. Co-author Full Name(s): Mohamed Al-Amoodi, Whitney Jones, Danny Lee, Steven Mckenzie, Helen Miller, Seth Stubblefied, Susan Knoblach, Heather Gordish-Dressman, Dustin Hittel, Laura L. Tosi Abstract Text (should not exceed 400 words): Recent studies have begun to search for correlations between genetic variations and muscle strength. One such study by Stebbings et al.1 examined two single nucleotide polymorphisms (SNPs)—rs7843014 and rs7460—on the PTK2 gene. The study found that genetic variation in the PTK2 gene impacts muscle-specific force, which is the force generated per unit of cross-sectional area of muscle. Muscle-specific force ultimately represents the intrinsic strength of a muscle and is a key determinant of functional capacity and mobility. This study sought to expand on prior research by looking for associations between genetic variants of PTK2 and measures of grip strength, as well as general anthropomorphic measures, in a cohort of healthy young adults. Our study assessed phenotypes for height, weight, VO2 max, max grip strength, and body mass index (BMI) using the Assessing Inherited Markers of Metabolic Syndrome in the Young (AIMMY) University of Calgary subset of 190 healthy, primarily Caucasian, individuals between the ages of 18 and 35. DNA samples were genotyped using ThermoFisher Taqman SNP genotype assays, and underwent the Applied Biosystems 7900HT real-time polymerase chain reaction (PCR) process. Analysis of covariance (ANCOVA) models were used to perform statistical analysis to look for genotype-phenotype associations. Unlike the findings by Stebbings et al.1 an association between the PTK2 genotypes and grip strength was not found. This could be due to the lower statistical power in the grip strength test, thus potentially indicating that grip strength and muscle-specific force do not measure similar parameters of muscle strength. Genetic variation in PTK2 has also been previously associated with VO2 max, but no association was found in the current study. Positive associations were found between genetic variants rs7843014 and rs7460 in PTK2 and BMI, and between genetic variant rs7843014 and height. High levels of functioning PTK2 have been found to have increased strength due to increased costamere density, resulting in more muscle myofibrils, and therein larger, presumably heavier muscles. However, this finding was only observed in males, and could be attributed to differential acquisition and maintenance of muscle mass based on sex. We identified a potentially novel association between genetic variants in PTK2 and anthropomorphic phenotypes. However, we were unable to confirm the effects of genetic variants on measures of intrinsic muscle strength, namely max grip strength or VO2 max in terms of functional capacity. Further research is needed to confirm this newly identified role for PTK2

The association of polymorphism rs3736228 within the LRP5 gene with Bone Mineral Density in a Cohort of Caucasian Young Adults

INTRODUCTION: Osteoporosis is a significant burden for our aging population. Developing a better understanding of the genetic underpinnings of poor bone quality may assist in the future development of prevention strategies. Correa-Rodriguez et al. have identified a group of single nucleotide polymorphisms (SNPs) that were associated with bone mineral density (BMD) in a population of Spanish Caucasians. In particular, they found that SNP rs3736228 in the low-density lipoprotein receptor related protein 5 (LRP5) gene had an influence on BMD. While the role of LRP5 in the Wnt canonical pathway has been fairly well characterized, its association with phenotypic BMD and osteoporosis has only been explored in a limited fashion. The aim of this study is to expand on this, and to replicate the findings of previous studies in a cohort of healthy young adults. METHODS: Cohort: The University of Calgary cohort from the Assessing Inherited Metabolic Syndrome Markers in the Young (UC AIMMY) study. Participants included consist of 168 healthy, predominantly Caucasian young adults. Phenotypes: height, weight, BMI, and total BMD. Genotyping: Allelic discrimination was determined. Statistical Analysis: After being tested for Hardy-Weinberg equilibrium (HWE), the data was run through analysis of covariance (ANCOVA). RESULTS: Using a dominant model, we found that females with one or more copies of the risk T allele of SNP rs3736228 had a significant negative association with total BMD (p = 0.0347). However, a similar association was not seen in males in this cohort. We did not find a significant association for this polymorphism and height, weight, or BMI. DISCUSSION: Polymorphisms in rs3736228 alter the codon in position 1330, downregulating the LRP5 cell surface receptor function. The LRP5 gene has now been shown in multiple studies to be associated with bone quality measures like calcaneal Qualitative Ultrasound (QUS) and BMD. Our study suggests that SNP rs3736228 also influences BMD in healthy young females. This supports the work of Correa-Rodriguez et al that found that when stratifying by sex, females only showed a trend towards significance (p = 0.092) in QUS measures. SIGNIFICANCE: This study expands our understanding of the importance of LRP5 rs3736228 polymorphisms in BMD by extending its relationship to a cohort of predominantly Caucasian college students. While the development of BMD is polygenic, this work broadened the role of SNP rs3736228 across the age span, and the sexual dimorphism seen in musculoskeletal traits

CSI 2264: Characterizing Accretion-Burst Dominated Light Curves for Young Stars in NGC 2264

Based on more than four weeks of continuous high cadence photometric monitoring of several hundred members of the young cluster NGC 2264 with two space telescopes, NASA's Spitzer and the CNES CoRoT (Convection, Rotation, and planetary Transits), we provide high quality, multi-wavelength light curves for young stellar objects (YSOs) whose optical variability is dominated by short duration flux bursts, which we infer are due to enhanced mass accretion rates. These light curves show many brief -- several hour to one day -- brightenings at optical and near-infrared (IR) wavelengths with amplitudes generally in the range 5-50% of the quiescent value. Typically, a dozen or more of these bursts occur in a thirty day period. We demonstrate that stars exhibiting this type of variability have large ultraviolet (UV) excesses and dominate the portion of the u-g vs. g-r color-color diagram with the largest UV excesses. These stars also have large Halpha equivalent widths, and either centrally peaked, lumpy Halpha emission profiles or profiles with blue-shifted absorption dips associated with disk or stellar winds. Light curves of this type have been predicted for stars whose accretion is dominated by Rayleigh-Taylor instabilities at the boundary between their magnetosphere and inner circumstellar disk, or where magneto-rotational instabilities modulate the accretion rate from the inner disk. Amongst the stars with the largest UV excesses or largest Halpha equivalent widths, light curves with this type of variability greatly outnumber light curves with relatively smooth sinusoidal variations associated with long-lived hot spots. We provide quantitative statistics for the average duration and strength of the accretion bursts and for the fraction of the accretion luminosity associated with these bursts.Comment: Accepted for publication in AJ. 39 pages; 6 tables; 25 figures, many of which are highly degraded to meet size limits. Please download the regular resolution version at http://web.ipac.caltech.edu/staff/amc/staufferetal2014.pd

A Triple Protostar System Formed via Fragmentation of a Gravitationally Unstable Disk

Binary and multiple star systems are a frequent outcome of the star formation process, and as a result, almost half of all sun-like stars have at least one companion star. Theoretical studies indicate that there are two main pathways that can operate concurrently to form binary/multiple star systems: large scale fragmentation of turbulent gas cores and filaments or smaller scale fragmentation of a massive protostellar disk due to gravitational instability. Observational evidence for turbulent fragmentation on scales of $>$1000~AU has recently emerged. Previous evidence for disk fragmentation was limited to inferences based on the separations of more-evolved pre-main sequence and protostellar multiple systems. The triple protostar system L1448 IRS3B is an ideal candidate to search for evidence of disk fragmentation. L1448 IRS3B is in an early phase of the star formation process, likely less than 150,000 years in age, and all protostars in the system are separated by $<$200~AU. Here we report observations of dust and molecular gas emission that reveal a disk with spiral structure surrounding the three protostars. Two protostars near the center of the disk are separated by 61 AU, and a tertiary protostar is coincident with a spiral arm in the outer disk at a 183 AU separation. The inferred mass of the central pair of protostellar objects is $\sim$1 M$_{sun}$, while the disk surrounding the three protostars has a total mass of $\sim$0.30 M_{\sun}. The tertiary protostar itself has a minimum mass of $\sim$0.085 M$_{sun}$. We demonstrate that the disk around L1448 IRS3B appears susceptible to disk fragmentation at radii between 150~AU and 320~AU, overlapping with the location of the tertiary protostar. This is consistent with models for a protostellar disk that has recently undergone gravitational instability, spawning one or two companion stars.Comment: Published in Nature on Oct. 27th. 24 pages, 8 figure

Organic electrode coatings for next-generation neural interfaces

Traditional neuronal interfaces utilize metallic electrodes which in recent years have reached a plateau in terms of the ability to provide safe stimulation at high resolution or rather with high densities of microelectrodes with improved spatial selectivity. To achieve higher resolution it has become clear that reducing the size of electrodes is required to enable higher electrode counts from the implant device. The limitations of interfacing electrodes including low charge injection limits, mechanical mismatch and foreign body response can be addressed through the use of organic electrode coatings which typically provide a softer, more roughened surface to enable both improved charge transfer and lower mechanical mismatch with neural tissue. Coating electrodes with conductive polymers or carbon nanotubes offers a substantial increase in charge transfer area compared to conventional platinum electrodes. These organic conductors provide safe electrical stimulation of tissue while avoiding undesirable chemical reactions and cell damage. However, the mechanical properties of conductive polymers are not ideal, as they are quite brittle. Hydrogel polymers present a versatile coating option for electrodes as they can be chemically modified to provide a soft and conductive scaffold. However, the in vivo chronic inflammatory response of these conductive hydrogels remains unknown. A more recent approach proposes tissue engineering the electrode interface through the use of encapsulated neurons within hydrogel coatings. This approach may provide a method for activating tissue at the cellular scale, however, several technological challenges must be addressed to demonstrate feasibility of this innovative idea. The review focuses on the various organic coatings which have been investigated to improve neural interface electrodes

A Little Statistical Mechanics for the Graph Theorist

In this survey, we give a friendly introduction from a graph theory perspective to the q-state Potts model, an important statistical mechanics tool for analyzing complex systems in which nearest neighbor interactions determine the aggregate behavior of the system. We present the surprising equivalence of the Potts model partition function and one of the most renowned graph invariants, the Tutte polynomial, a relationship that has resulted in a remarkable synergy between the two fields of study. We highlight some of these interconnections, such as computational complexity results that have alternated between the two fields. The Potts model captures the effect of temperature on the system and plays an important role in the study of thermodynamic phase transitions. We discuss the equivalence of the chromatic polynomial and the zero-temperature antiferromagnetic partition function, and how this has led to the study of the complex zeros of these functions. We also briefly describe Monte Carlo simulations commonly used for Potts model analysis of complex systems. The Potts model has applications as widely varied as magnetism, tumor migration, foam behaviors, and social demographics, and we provide a sampling of these that also demonstrates some variations of the Potts model. We conclude with some current areas of investigation that emphasize graph theoretic approaches. This paper is an elementary general audience survey, intended to popularize the area and provide an accessible first point of entry for further exploration.Comment: 30 pages, 3 figure

Plio-Pleistocene exhumation of the eastern Himalayan syntaxis and its domal ‘pop-up’

The eastern termination of the Himalayan orogen forms a structural syntaxis that is characterised by young (from 10 to &lt; 1 Ma) mineral growth and cooling ages that document Late Miocene to Pleistocene structural, metamorphic, igneous and exhumation events. This region is a steep antiformal and in part domal structure that folds the suture zone between the Indian and Asian plates. It is dissected by the Yarlung Tsangpo, one of the major rivers of the eastern Himalayan–Tibet region, which becomes the Brahmaputra River in the Indian foreland basin before emptying into the Bay of Bengal. Exceptionally high relief and one of the deepest gorges on Earth have developed where the river's tortuous route crosses the Namche Barwa–Gyala Peri massif (&gt; 7 km in elevation) in the core of the syntaxis. Very high erosion rates documented in sediment downstream of the gorge at the foot of the Himalaya contribute ~ 50% of total detritus to the sediment load of the Brahmaputra. The initiation of very high rates of exhumation has been attributed either to the extreme erosive power of a river flowing across a deforming indentor corner and the associated positive feedback, or to the geometry of the Indian plate indentor, with the corner being thrust beneath the Asian plate resulting in buckling which accommodates shortening; both processes may be important. The northern third of the syntaxis corresponds to a steep domal ‘pop-up’ structure bounded by the India–Asia suture on three sides and a thrust zone to the south. Within the dome, Greater Himalaya rocks equilibrated at ~ 800 °C and 25–30 km depth during the Miocene, with these conditions potentially persisting into the latest Miocene and possibly the Pliocene, with modest decompression prior to ~ 4 Ma. This domal ‘pop-up’ corresponds to the area of youngest bedrock ages on a wide variety of thermochronometers and geochronometers. In this paper we review the extensive scientific literature that has focused on the eastern syntaxis and provide new chronological data on its bedrock and erosion products to constrain the age of inception of the very rapid uplift and erosion. We then discuss its cause, with the ultimate aim to reconstruct the exhumation history of the syntaxis and discuss the tectonic context for its genesis. We use zircon and rutile U–Pb, white mica Ar–Ar and zircon fission track dating methods to extract age data from bedrock, Brahmaputra modern sediments (including an extensive compilation of modern detrital chronometry from the eastern Himalaya) and Neogene palaeo-Brahmaputra deposits of the Surma Basin (Bangladesh). Numerical modelling of heat flow and erosion is also used to model the path of rocks from peak metamorphic conditions of ~ 800 °C to &lt; 250 °C. Our new data include U–Pb bedrock rutile ages as young as 1.4 Ma from the Namche Barwa massif and 0.4 Ma from the river downstream of the syntaxis. Combined with existing data, our new data and heat flow modelling show that: i) the detrital age signature of the modern syntaxis is unique within the eastern Himalayan region; ii) the rocks within the domal pop-up were &gt; 575 ± 75 °C only 1–2 Myr ago; iii) the Neogene Surma Basin does not record evidence of the rise and erosion of the domal pop-up until latest Pliocene–Pleistocene time; iv) Pleistocene exhumation of the north-easternmost part of the syntaxis took place at rates of at least 4 km/Myr, with bedrock erosion of 12–21 km during the last 3 Ma; v) the inception of rapid syntaxial exhumation may have started as early as 7 Ma or as late as 3 Ma; and vi) the Yarlung Tsangpo is antecedent and subsequently distorted by the developing antiform. Together our data and modelling demonstrate that the domal pop-up with its exceptional erosion and topographic relief is likely a Pleistocene feature that overprinted earlier structural and metamorphic events typical of Himalayan evolution. Keywords: Eastern Himalayan syntaxis; Namche Barwa; Surma Basin; Yarlung Tsangpo–Brahmaputra; U–Pb rutile dating; Thermal modellin

Subcellular trafficking of the substrate transporters GLUT4 and CD36 in cardiomyocytes

Cardiomyocytes use glucose as well as fatty acids for ATP production. These substrates are transported into the cell by glucose transporter 4 (GLUT4) and the fatty acid transporter CD36. Besides being located at the sarcolemma, GLUT4 and CD36 are stored in intracellular compartments. Raised plasma insulin concentrations and increased cardiac work will stimulate GLUT4 as well as CD36 to translocate to the sarcolemma. As so far studied, signaling pathways that regulate GLUT4 translocation similarly affect CD36 translocation. During the development of insulin resistance and type 2 diabetes, CD36 becomes permanently localized at the sarcolemma, whereas GLUT4 internalizes. This juxtaposed positioning of GLUT4 and CD36 is important for aberrant substrate uptake in the diabetic heart: chronically increased fatty acid uptake at the expense of glucose. To explain the differences in subcellular localization of GLUT4 and CD36 in type 2 diabetes, recent research has focused on the role of proteins involved in trafficking of cargo between subcellular compartments. Several of these proteins appear to be similarly involved in both GLUT4 and CD36 translocation. Others, however, have different roles in either GLUT4 or CD36 translocation. These trafficking components, which are differently involved in GLUT4 or CD36 translocation, may be considered novel targets for the development of therapies to restore the imbalanced substrate utilization that occurs in obesity, insulin resistance and diabetic cardiomyopathy