Evolution of a Non-Abelian Cosmic String Network

We describe a numerical simulation of the evolution of an $S_3$ cosmic string network which takes fully into account the non-commutative nature of the cosmic string fluxes and the topological obstructions which hinder strings from moving past each other or intercommuting. The influence of initial conditions, string tensions, and other parameters on the network's evolution is explored. Contrary to some previous suggestions, we find no strong evidence of the ``freezing'' required for a string-dominated cosmological scenario. Instead, the results in a broad range of regimes are consistent with the familiar scaling law; i.e., a constant number of strings per horizon volume. The size of this number, however, can vary quite a bit, as can other overall features. There is a surprisingly strong dependence on the statistical properties of the initial conditions. We also observe a rich variety of interesting new structures, such as light string webs stretched between heavier strings, which are not seen in Abelian networks.Comment: 89 pages, Tex, figures included, phyzzx macros included. Revised version: minor changes in wording and layout; some errors corrected in Table 2; references added. Animations now available at http://physics.unc.edu/~mcgraw/stringmovies.htm

From high temperature supercondutivity to quantum spin liquid: progress in strong correlation physics

This review gives a rather general discussion of high temperature superconductors as an example of a strongly correlated material. The argument is made that in view of the many examples of unconventional superconductors discovered in the past twenty years, we should no longer be surprised that superconductivity emerges as a highly competitive ground state in systems where Coulomb repulsion plays a dominant role. The physics of the cuprates is discussed, emphasizing the unusual pseudogap phase in the underdoped region. It is argued that the resonating valence bond (RVB) picture, as formulated using gauge theory with fermionic and bosonic matter fields, gives an adequate physical understanding, even though many details are beyond the powers of current calculational tools. The recent discovery of quantum oscillations in a high magnetic field is discussed in this context. Meanwhile, the problem of the quantum spin liquid (a spin system with antiferromagnetic coupling which refuses to order even at zero temperature) is a somewhat simpler version of the high $T_c$ problem where significant progress has been made recently. It is understood that the existence of matter fields can lead to de-confinement of the U(1) gauge theory in 2+1 dimensions, and novel new particles (called fractionalized particles), such as fermionic spinons which carry spin ${1\over 2}$ and no charge, and gapless gauge bosons can emerge to create a new critical state at low energies. We even have a couple of real materials where such a scenario may be realized experimentally. The article ends with answers to questions such as: what limits $T_c$ if pairing is driven by an electronic energy scale? why is the high $T_c$ problem hard? why is there no consensus? and why is the high $T_c$ problem important?Comment: Submitted as "Key Issue" essay for Report of Progress in Physics; v2: References are added and typos correcte

Cyclic strain induces dualmode endothelial-mesenchymal transformation of the cardiac valve

Endothelial-mesenchymal transformation (EMT) is a critical event for the embryonic morphogenesis of cardiac valves. Inducers of EMT during valvulogenesis include VEGF, TGF-β1, and wnt/β-catenin (where wnt refers to the wingless-type mammary tumor virus integration site family of proteins), that are regulated in a spatiotemporal manner. EMT has also been observed in diseased, strain-overloaded valve leaflets, suggesting a regulatory role for mechanical strain. Although the preponderance of studies have focused on the role of soluble mitogens, we asked if the valve tissue microenvironment contributed to EMT. To recapitulate these microenvironments in a controlled, in vitro environment, we engineered 2D valve endothelium from sheep valve endothelial cells, using microcontact printing to mimic the regions of isotropy and anisotropy of the leaflet, and applied cyclic mechanical strain in an attempt to induce EMT. We measured EMT in response to both low (10%) and high strain (20%), where low-strain EMT occurred via increased TGF-β1 signaling and high strain via increased wnt/β-catenin signaling, suggesting dual strain-dependent routes to distinguish EMT in healthy versus diseased valve tissue. The effect was also directionally dependent, where cyclic strain applied orthogonal to axis of the engineered valve endothelium alignment resulted in severe disruption of cell microarchitecture and greater EMT. Once transformed, these tissues exhibited increased contractility in the presence of endothelin-1 and larger basal mechanical tone in a unique assay developed to measure the contractile tone of the engineered valve tissues. This finding is important, because it implies that the functional properties of the valve are sensitive to EMT. Our results suggest that cyclic mechanical strain regulates EMT in a strain magnitude and directionally dependent manner. tight junctions | cytokines | activated myofibroblast C ardiac valves are sophisticated structures that function in a complex mechanical environment, opening and closing more than 3 billion times during the average human lifetime (1). Initially considered passive flaps of tissue, it is now acknowledged that valves contain a highly heterogeneous population of endothelial (VEC) and interstitial (VIC) cells. The VICs exist as synthetic, myofibroblast, or smooth muscle-like phenotypes (2, 3) and alter their tone in response to vasoactive mediators (4-7). The VECs line the surface of the valve leaflet and are unique in their ability to undergo endothelial-mesenchymal transformation (EMT), a process that is crucial for valvulogenesis (8, 9). Recent clinical evidence of EMT has been observed in pathologies such as ischemic cardiomyopathy and concomitant mitral regurgitation and is correlated with increased leaflet mechanical strains (10, 11). These pathological strains can be oriented obliquely to cell and tissue orientation (12, 13), suggesting the possible interaction between mechanical forces and tissue architecture in regulating EMT. Prior work has focused on the regulation of EMT via soluble factors. Modulation of VEGF and increases in wnt/β-catenin and TGF-β1 expression, among other factors, direct EMT during valvulogenesis (8, 14) and in the mature valve (15, 16). Additionally, mechanical forces are known to modulate valve remodeling and disease progression (17, 18). However, the influence of mechanical forces and its synergy with tissue architecture in influencing cardiac valve EMT is unknown. During embryonic development, valve morphogenesis has been correlated with an increase in fluid shear stresses, mechanical strains, and altered geometry of the developing heart (19-22). These observations potentially suggests interaction between mechanical forces and the factors that regulate EMT. Additionally, it is also unknown if EMT results in a functional change of the VEC to a contractile myofibroblast-like VIC. We hypothesized that cyclic strain may potentiate valve EMT in a manner dependent on cell orientation and the direction of applied strain. We developed an in vitro model that combines cyclic stretching of engineered valve endothelium reconstituted from primary sheep VECs for biochemical and expression studies. In addition, we present a functional assay for EMT using valve thin films (vTFs), a biohybrid construct of the engineered valve endothelium on an elastomer thin film that is deformed during tissue contraction. We report strain-dependent dual-mode EMT, with TGF-β1 signaling triggering EMT under low strain (10%) and wnt/β-catenin signaling under high strain (20%). We also report strain-dependent increased contractility of transformed VEC tissues when treated with endothelin-1, suggesting transformation of the normally noncontractile VEC to a contractile VIC-like cell

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Funding The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)

Ensembles of engineered cardiac tissues for physiological and pharmacological study: Heart on a chip

Traditionally, muscle physiology experiments require multiple tissue samples to obtain morphometric, electrophysiological, and contractility data. Furthermore, these experiments are commonly completed one at a time on cover slips of single cells, isotropic monolayers, or in isolated muscle strips. In all of these cases, variability of the samples hinders quantitative comparisons among experimental groups. Here, we report the design of a “heart on a chip” that exploits muscular thin film technology – biohybrid constructs of an engineered, anisotropic ventricular myocardium on an elastomeric thin film – to measure contractility, combined with a quantification of action potential propagation, and cytoskeletal architecture in multiple tissues in the same experiment. We report techniques for real-time data collection and analysis during pharmacological intervention. The chip is an efficient means of measuring structure-function relationships in constructs that replicate the hierarchical tissue architectures of laminar cardiac muscle.Engineering and Applied Science

Vascular smooth muscle contractility depends on cell shape

The physiologic role of smooth muscle structure in defining arterial function is poorly understood. We aimed to elucidate the relationship between vascular smooth muscle architecture and functional contractile output. Using microcontact printing and muscular thin film technology, we engineered in vitro vascular tissues with strictly defined geometries and tested their contractile function. In all tissues, vascular smooth muscle cells (VSMCs) were highly aligned with in vivo-like spindle architecture, and contracted physiologically in response to stimulation with endothelin-1. However, tissues wherein the VSMCs were forced into exaggerated spindle elongation exerted significantly greater contraction force per unit cross-sectional area than those with smaller aspect ratios. Moreover, this increased contraction did not occur in conjunction with an increase in traditionally measured contractile phenotype markers. These results suggest that cellular architecture within vascular tissues plays a significant role in conferring tissue function and that, in some systems, traditional phenotype characterization is not sufficient to define a functionally contractile population of VSMCs.Engineering and Applied Science

Biohybrid thin films for measuring contractility in engineered cardiovascular muscle.

In vitro cardiovascular disease models need to recapitulate tissue-scale function in order to provide in vivo relevance. We have developed a new method for measuring the contractility of engineered cardiovascular smooth and striated muscle in vitro during electrical and pharmacological stimulation. We present a growth theory-based finite elasticity analysis for calculating the contractile stresses of a 2D anisotropic muscle tissue cultured on a flexible synthetic polymer thin film. Cardiac muscle engineered with neonatal rat ventricular myocytes and paced at 0.5 Hz generated stresses of 9.2 +/- 3.5 kPa at peak systole, similar to measurements of the contractility of papillary muscle from adult rats. Vascular tissue engineered with human umbilical arterial smooth muscle cells maintained a basal contractile tone of 13.1 +/- 2.1 kPa and generated another 5.1 +/- 0.8 kPa when stimulated with endothelin-1. These data suggest that this method may be useful in assessing the efficacy and safety of pharmacological agents on cardiovascular tissue.</p