bluuebunny/crossref_metadata_2025 huggingface dataset:
HOW TO CONSTRUCT THE PROPER GAUGE-INVARIANT DENSITY MATRIX IN STEADY-STATE NONEQUILIBRIUM: APPLICATIONS TO SPIN-TRANSFER AND SPIN-ORBIT TORQUES
Authors: MAHFOUZI FARZAD , NIKOLIĆ BRANISLAV K.
Published: July 2013

Experiments observing spin density and spin currents (responsible for, e.g., spin-transfer torque) in spintronic devices measure only the nonequilibrium contributions to these quantities, typically driven by injecting unpolarized charge current or by applying external time-dependent fields. On the other hand, theoretical approaches to calculate these quantities operate with both the nonequilibrium (carried by electrons around the Fermi surface) and the equilibrium (carried by the Fermi sea electrons) contributions to them. Thus, an unambiguous procedure should remove the equilibrium contributions, thereby rendering the nonequilibrium ones which are measurable and satisfy the gauge-invariant condition according to which expectation values of physical quantities should not change when electric potential everywhere is shifted by a constant amount. Using the framework of nonequilibrium Green functions, we delineate such procedure which yields the proper gauge-invariant nonequilibrium density matrix in the linear-response and elastic transport regime for current-carrying steady state of an open quantum system connected to two macroscopic reservoirs. Its usage is illustrated by computing: (i) conventional spin-transfer torque (STT) in asymmetric F/I/F magnetic tunnel junctions (MTJs); (ii) unconventional STT in asymmetric N/I/F semi-MTJs with the strong Rashba spin–orbit coupling (SOC) at the I/F interface and injected current perpendicular to that plane; and (iii) current-driven spin density within a clean ferromagnetic Rashba spin-split two-dimensional electron gas (2DEG) which generates SO torque in laterally patterned N/F/I heterostructures when such 2DEG is located at the N/F interface and injected charge current flows parallel to the plane. We also compare our results for these three examples with those that would be obtained using improper expressions for the density matrix, which are often found in the literature but which arbitrarily mix nonequilibrium and equilibrium expectation values due to a violation of the gauge invariance.
Volcanoes of the Diamante cross-chain: evidence for a mid-crustal felsic magma body beneath the Southern Izu–Bonin–Mariana arc
Authors: Stern Robert J. , Tamura Yoshi , Ishizuka Osamu , Shukano Hiroshi , Bloomer Sherman H. , Embley Robert W. , Leybourne Matthew , Kawabata Hiroshi , Nunokawa Akiko , Nichols Alexander R. L. , Kohut Edward , Pujana Ignacio
Published: June 2013

Three submarine Diamante cross-chain volcanoes in the southern Mariana arc mark a magma-healed zone of along-arc (north–south) extension that allows either mafic mantle-derived basalts or felsic magmas from the middle of thickened arc crust to erupt. The largest volcano is East Diamante, with a well-developed (5×10 km) caldera that formed via violent felsic submarine eruptions beginning nearly 0.5 Ma. One or more of these eruptions also formed a giant submarine dune field extending 30 km to the NW of the volcano. Felsic igneous activity continues at least as recently as
c.
20 000 years ago, with emplacement of resurgent dacite domes, some hot enough to power the only black smoker hydrothermal system known in the Mariana arc. In contrast, felsic eruptions do not occur on the two volcanoes to the west, implying that the mid-crustal felsic zone does not underlie the thinner crust of the Mariana Trough back-arc basin. Diamante cross-chain lavas define a medium K suite; mafic lava phenocryst assemblages show arc-like associations of anorthite-rich plagioclase with Fe-rich olivine. Magmatic temperatures for a basaltic andesite and three dacites are
c.
1100 °C and
c.
800 °C, respectively, typical for cool, wet, subduction-related felsic magmas. Felsic magmas formed under low-P crustal conditions. The Diamante cross-chain is the southernmost of at least seven and perhaps eight Mariana arc volcanoes in a
c.
115 km long arc segment characterized by felsic eruptions. This is the ‘Anatahan Felsic Province’, which may have formed above a mid-crustal tonalite body that formed by fractionation or was re-melted when heated by
c.
1200 °C mafic, mantle-derived magmas. Across- and along-arc variations suggest that felsic eruptions and dome emplacement occurred when midcrustal tonalite was remobilized by intrusions of mafic magma, while north–south extension facilitated the development of conduits to the surface.

Supplementary material:

Detailed Hyperdolphin ROV dive tracks, Cook 7 dredge locations,
40
Ar/
39
Ar analytical data, analytical methods, major and selected trace element analyses of whole rock samples, and compositional data for minerals are available at
http://www.geolsoc.org.uk/SUP18611
Generating targeted paraphrases for improved translation
Authors: Madnani Nitin , Dorr Bonnie J.
Published: July 2013

Today's Statistical Machine Translation (SMT) systems require high-quality human translations for parameter tuning, in addition to large bitexts for learning the translation units. This parameter tuning usually involves generating translations at different points in the parameter space and obtaining feedback against human-authored reference translations as to how good the translations. This feedback then dictates what point in the parameter space should be explored next. To measure this feedback, it is generally considered wise to have multiple (usually 4) reference translations to avoid unfair penalization of translation hypotheses which could easily happen given the large number of ways in which a sentence can be translated from one language to another. However, this reliance on multiple reference translations creates a problem since they are labor intensive and expensive to obtain. Therefore, most current MT datasets only contain a single reference. This leads to the problem of reference sparsity. In our previously published research, we had proposed the first paraphrase-based solution to this problem and evaluated its effect on Chinese-English translation. In this article, we first present extended results for that solution on additional source languages. More importantly, we present a novel way to generate “targeted” paraphrases that yields substantially larger gains (up to 2.7 BLEU points) in translation quality when compared to our previous solution (up to 1.6 BLEU points). In addition, we further validate these improvements by supplementing with human preference judgments obtained via Amazon Mechanical Turk.
Multitechnique paraphrase alignment
Authors: Bouamor Houda , Max Auréelien , Vilnat Anne
Published: July 2013

This work uses parallel monolingual corpora for a detailed study of the task of sub-sentential paraphrase acquisition. We argue that the scarcity of this type of resource is compensated by the fact that it is the most suited type for studies on paraphrasing. We propose a large exploration of this task with experiments on two languages with five different acquisition techniques, selected for their complementarity, their combinations, as well as four monolingual corpus types of varying comparability. We report, under all conditions, a significant improvement over all techniques by validating candidate paraphrases using a maximum entropy classifier. An important result of our study is the identification of
difficult-to-acquire
paraphrase pairs, which are classified and quantified in a bilingual typology.
Improving GPGPU concurrency with elastic kernels
Authors: Pai Sreepathi , Thazhuthaveetil Matthew J. , Govindarajan R.
Published: July 2013

Each new generation of GPUs vastly increases the resources available to GPGPU programs. GPU programming models (like CUDA) were designed to scale to use these resources. However, we find that CUDA programs actually do not scale to utilize all available resources, with over 30% of resources going unused on average for programs of the Parboil2 suite that we used in our work. Current GPUs therefore allow concurrent execution of kernels to improve utilization. In this work, we study concurrent execution of GPU kernels using multiprogram workloads on current NVIDIA Fermi GPUs. On two-program workloads from the Parboil2 benchmark suite we find concurrent execution is often no better than serialized execution. We identify that the lack of control over resource allocation to kernels is a major serialization bottleneck. We propose transformations that convert CUDA kernels into
elastic kernels
which permit fine-grained control over their resource usage. We then propose several elastic-kernel aware concurrency policies that offer significantly better performance and concurrency compared to the current CUDA policy. We evaluate our proposals on real hardware using multiprogrammed workloads constructed from benchmarks in the Parboil 2 suite. On average, our proposals increase system throughput (STP) by 1.21x and improve the average normalized turnaround time (ANTT) by 3.73x for two-program workloads when compared to the current CUDA concurrency implementation.
Optimizing database-backed applications with query synthesis
Authors: Cheung Alvin , Solar-Lezama Armando , Madden Samuel
Published: July 2013

Object-relational mapping libraries are a popular way for applications to interact with databases because they provide transparent access to the database using the same language as the application. Unfortunately, using such frameworks often leads to poor performance, as modularity concerns encourage developers to implement relational operations in application code. Such application code does not take advantage of the optimized relational implementations that database systems provide, such as efficient implementations of joins or push down of selection predicates. In this paper we present QBS, a system that automatically transforms fragments of application logic into SQL queries. QBS differs from traditional compiler optimizations as it relies on synthesis technology to generate invariants and postconditions for a code fragment. The postconditions and invariants are expressed using a new theory of ordered relations that allows us to reason precisely about both the contents and order of the records produced complex code fragments that compute joins and aggregates. The theory is close in expressiveness to SQL, so the synthesized postconditions can be readily translated to SQL queries. Using 75 code fragments automatically extracted from over 120k lines of open-source code written using the Java Hibernate ORM, we demonstrate that our approach can convert a variety of imperative constructs into relational specifications and significantly improve application performance asymptotically by orders of magnitude.
General data structure expansion for multi-threading
Authors: Yu Hongtao , Ko Hou-Jen , Li Zhiyuan
Published: July 2013

Among techniques for parallelizing sequential codes, privatization is a common and significant transformation performed by both compilers and runtime parallelizing systems. Without privatization, repetitive updates to the same data structures often introduce spurious data dependencies that hide the inherent parallelism. Unfortunately, it remains a significant challenge to compilers to automatically privatize dynamic and recursive data structures which appear frequently in real applications written in languages such as C/C++. This is because such languages lack a naming mechanism to define the address range of a pointer-based data structure, in contrast to arrays with explicitly declared bounds. In this paper we present a novel solution to this difficult problem by expanding general data structures such that memory accesses issued from different threads to contentious data structures are directed to different data fields. Based on compile-time type checking and a data dependence graph, this aggressive extension to the traditional scalar and array expansion isolates the address ranges among different threads, without struggling with privatization based on thread-private stacks, such that the targeted loop can be effectively parallelized. With this method fully implemented in GCC, experiments are conducted on a set of programs from well-known benchmark suites such as Mibench, MediaBench II and SPECint. Results show that the new approach can lead to a high speedup when executing the transformed code on multiple cores.
Almost-correct specifications
Authors: Blackshear Sam , Lahiri Shuvendu K.
Published: July 2013

Modular assertion checkers are plagued with false alarms due to the need for precise environment specifications (preconditions and callee postconditions). Even the fully precise checkers report assertion failures under the most demonic environments allowed by unconstrained or partial specifications. The inability to preclude overly adversarial environments makes such checkers less attractive to developers and severely limits the adoption of such tools in the development cycle.

In this work, we propose a parameterized framework for prioritizing the assertion failures reported by a modular verifier, with the goal of suppressing warnings from overly demonic environments. We formalize it almost-correct specifications as the minimal weakening of an angelic specification (over a set of predicates) that precludes any dead code intraprocedurally. Our work is inspired by and generalizes some aspects of semantic inconsistency detection. Our formulation allows us to lift this idea to a general class of warnings. We have developed a prototype acspec, which we use to explore a few instantiations of the framework and report preliminary findings on a diverse set of C benchmarks.
Solar Neutrinos: Status and Prospects
Authors: Haxton W.C. , Hamish Robertson R.G. , Serenelli Aldo M.
Published: June 2013

We describe the current status of solar neutrino measurements and of the theory—both neutrino physics and solar astrophysics—employed in interpreting measurements. Important recent developments include Super-Kamiokande's determination of the ν−e elastic scattering rate for 8B neutrinos to 3%; the latest Sudbury Neutrino Observatory (SNO) global analysis in which the inclusion of low-energy data from SNO I and II significantly narrowed the range of allowed values for the neutrino mixing angle θ12; Borexino results for both the 7Be and proton-electron-proton (pep) neutrino fluxes, the first direct measurements constraining the rate of proton-proton (pp) I and pp II burning in the Sun; global reanalyses of solar neutrino data that take into account new reactor results on θ13; a new decadal evaluation of the nuclear physics of the pp chain and CNO cycle defining best values and uncertainties in the nuclear microphysics input to solar models; recognition of an emerging discrepancy between two tests of solar metallicity, helioseismological mappings of the sound speed in the solar interior, and analyses of the metal photoabsorption lines based on our best current description of the Sun's photosphere; a new round of standard solar model calculations optimized to agree either with helioseismology or with the new photospheric analysis; and, motivated by the solar abundance problem, the development of nonstandard, accreting solar models, in order to investigate possible consequences of the metal segregation that occurred in the proto-solar disk. We review this progress and describe how new experiments such as SNO+ could help us further exploit neutrinos as a unique probe of stellar interiors.
Asteroseismology of Solar-Type and Red-Giant Stars
Authors: Chaplin William J. , Miglio Andrea
Published: June 2013

We are entering a golden era for stellar physics driven by satellite and telescope observations of unprecedented quality and scope. New insights on stellar evolution and stellar interiors physics are being made possible by asteroseismology, the study of stars by the observation of natural, resonant oscillations. Asteroseismology is proving to be particularly significant for the study of solar-type and red-giant stars. These stars show rich spectra of solar-like oscillations, which are excited and intrinsically damped by turbulence in the outermost layers of the convective envelopes. In this review we discuss the current state of the field, with a particular emphasis on recent advances provided by the Kepler and COROT (Convection, Rotation & Planetary Transits) space missions and the wider significance to astronomy of the results from asteroseismology, such as stellar populations studies and exoplanet studies.
Formation and Segmentation of the Vertebrate Body Axis
Authors: Bénazéraf Bertrand , Pourquié Olivier
Published: June 2013

Body axis elongation and segmentation are major morphogenetic events that take place concomitantly during vertebrate embryonic development. Establishment of the final body plan requires tight coordination between these two key processes. In this review, we detail the cellular and molecular as well as the physical processes underlying body axis formation and patterning. We discuss how formation of the anterior region of the body axis differs from that of the posterior region. We describe the developmental mechanism of segmentation and the regulation of body length and segment numbers. We focus mainly on the chicken embryo as a model system. Its accessibility and relatively flat structure allow high-quality time-lapse imaging experiments, which makes it one of the reference models used to study morphogenesis. Additionally, we illustrate conservation and divergence of specific developmental mechanisms by discussing findings in other major embryonic model systems, such as mice, frogs, and zebrafish.
How Microbiomes Influence Metazoan Development:Insights from History andDrosophilaModeling of Gut-Microbe Interactions
Authors: Lee Won-Jae , Brey Paul T.
Published: June 2013

Since Metchnikoff developed his views on the intestinal microflora, much effort has been devoted to understanding the role of gut microbiomes in metazoan physiology. Despite impressive data sets that have been generated by associating a phenotype-causing commensal community with its corresponding host phenotype, the field continues to suffer from descriptive and often contradictory reports. Hence, we cannot yet draw clear conclusions as to how the modifications of microbiomes cause physiological changes in metazoans. Unbiased, large-scale genetic screens to identify key genes, on both microbial and host sides, will be essential to gain mechanistic insights into gut-microbe interactions. The Drosophila genome–commensal microbiome genetic model has proven to be well suited to dissect the complex reciprocal cross talk between the host and its microbiota. In this review, we present a historical account, current views, and novel perspectives for future research directions based on the insights gleaned from the Drosophila gut-microbe interaction model.
Genetic Interaction Networks: Toward an Understanding of Heritability
Authors: Baryshnikova Anastasia , Costanzo Michael , Myers Chad L. , Andrews Brenda , Boone Charles
Published: June 2013

Understanding the relationship between the genotypes and phenotypes of individuals is key for identifying genetic variants responsible for disease and developing successful therapeutic strategies. Mapping the phenotypic effects of individual genetic variants and their combinations in human populations presents numerous practical and statistical challenges. However, model organisms, such as the budding yeast Saccharomyces cerevisiae, provide an incredible set of molecular tools and advanced technologies that should be able to efficiently perform this task. In particular, large-scale genetic interaction screens in yeast and other model systems have revealed common properties of genetic interaction networks, many of which appear to be maintained over extensive evolutionary distances. Indeed, despite relatively low conservation of individual genes and their pairwise interactions, the overall topology of genetic interaction networks and the connections between broad biological processes may be similar in most organisms. Taking advantage of these general principles should provide a fundamental basis for mapping and predicting genetic interaction networks in humans.
Genetic Analysis of Hypoxia Tolerance and Susceptibility in Drosophila and Humans
Authors: Zhou Dan , Haddad Gabriel G.
Published: June 2013

Oxygen is essential for metazoans' life on earth. Oxygen deprivation, or hypoxia, contributes significantly to the pathophysiology of many human diseases. A better understanding of the fundamental molecular and genetic basis for adaptation to low-oxygen environments will help us develop therapeutic strategies to prevent or treat diseases that have hypoxia as a major part of their pathogenesis. Different cells and organisms have evolved different ways to cope with this life-threatening challenge, and the molecular and genetic mechanisms remain largely unknown. The current revolution of genomic technology has advanced our understanding of the genetic basis of many diseases and conditions, including hypoxia tolerance and susceptibility. In this review, we highlight the progress made in understanding the molecular responses to hypoxia in an animal model organism (Drosophila melanogaster) and genetic adaptation to high-altitude hypoxia in humans.
Climate Change Influences on Marine Infectious Diseases: Implications for Management and Society
Authors: Burge Colleen A. , Mark Eakin C. , Friedman Carolyn S. , Froelich Brett , Hershberger Paul K. , Hofmann Eileen E. , Petes Laura E. , Prager Katherine C. , Weil Ernesto , Willis Bette L. , Ford Susan E. , Harvell C. Drew
Published: June 2013

Infectious diseases are common in marine environments, but the effects of a changing climate on marine pathogens are not well understood. Here we review current knowledge about how the climate drives host-pathogen interactions and infectious disease outbreaks. Climate-related impacts on marine diseases are being documented in corals, shellfish, finfish, and humans; these impacts are less clearly linked for other organisms. Oceans and people are inextricably linked, and marine diseases can both directly and indirectly affect human health, livelihoods, and well-being. We recommend an adaptive management approach to better increase the resilience of ocean systems vulnerable to marine diseases in a changing climate. Land-based management methods of quarantining, culling, and vaccinating are not successful in the ocean; therefore, forecasting conditions that lead to outbreaks and designing tools/approaches to influence these conditions may be the best way to manage marine disease.
Archaea in Biogeochemical Cycles
Authors: Offre Pierre , Spang Anja , Schleper Christa
Published: June 2013

Archaea constitute a considerable fraction of the microbial biomass on Earth. Like Bacteria they have evolved a variety of energy metabolisms using organic and/or inorganic electron donors and acceptors, and many of them are able to fix carbon from inorganic sources. Archaea thus play crucial roles in the Earth's global geochemical cycles and influence greenhouse gas emissions. Methanogenesis and anaerobic methane oxidation are important steps in the carbon cycle; both are performed exclusively by anaerobic archaea. Oxidation of ammonia to nitrite is performed by Thaumarchaeota. They represent the only archaeal group that resides in large numbers in the global aerobic terrestrial and marine environments on Earth. Sulfur-dependent archaea are confined mostly to hot environments, but metal leaching by acidophiles and reduction of sulfate by anaerobic, nonthermophilic methane oxidizers have a potential impact on the environment. The metabolisms of a large number of archaea, in particular those dominating the subsurface, remain to be explored.
Archaeal Biofilms: The Great Unexplored
Authors: Orell Alvaro , Fröls Sabrina , Albers Sonja-Verena
Published: June 2013

Biofilms are currently viewed as the most common form in which microorganisms exist in nature. Bacterial biofilms play important roles in disease and industrial applications, and they have been studied in great detail. Although it is well accepted that archaea are not only the extremists they were thought to be as they occupy nearly every habitat where also bacteria are found, it is surprising how little molecular details are known about archaeal biofilm formation. Therefore, we aim to highlight the available information and indicate open questions in this field.
Cnidarian-Microbe Interactions and the Origin of Innate Immunity in Metazoans
Authors: Bosch Thomas C.G.
Published: June 2013

Most epithelia in animals are colonized by microbial communities. These resident microbes influence fitness and thus ecologically important traits of their hosts, ultimately forming a metaorganism consisting of a multicellular host and a community of associated microorganisms. Recent discoveries in the cnidarian Hydra show that components of the innate immune system as well as transcriptional regulators of stem cells are involved in maintaining homeostasis between animals and their resident microbiota. Here I argue that components of the innate immune system with its host-specific antimicrobial peptides and a rich repertoire of pattern recognition receptors evolved in early-branching metazoans because of the need to control the resident beneficial microbes, not because of invasive pathogens. I also propose a mutual intertwinement between the stem cell regulatory machinery of the host and the resident microbiota composition, such that disturbances in one trigger a restructuring and resetting of the other.
Tip Growth in Filamentous Fungi: A Road Trip to the Apex
Authors: Riquelme Meritxell
Published: June 2013

Fungal hyphae extend by apical growth. This process involves the polarized traffic of secretory vesicles to the Spitzenkörper (SPK) and their subsequent distribution to specific domains of the plasma membrane, where they fuse to provide all the enzymes and material needed for cell wall expansion. Endocytic recycling and localized translation of specific mRNAs play an important role in hyphal apical growth. The traffic of vesicular carriers from synthesis sites to their destinations is coordinated by the combined action of coats, tethers, Rab GTPases, motors, and SNAREs in a mechanism that is just beginning to be understood. Only recently has it been confirmed that the different-sized vesicles present at the SPK contain distinct cell wall biosynthetic activities and are distributed in a stratified manner.
Structure and Operation of Bacterial Tripartite Pumps
Authors: Hinchliffe Philip , Symmons Martyn F. , Hughes Colin , Koronakis Vassilis
Published: June 2013

In bacteria such as Pseudomonas aeruginosa and Escherichia coli, tripartite membrane machineries, or pumps, determine the efflux of small noxious molecules, such as detergents, heavy metals, and antibiotics, and the export of large proteins including toxins. They are therefore influential in bacterial survival, particularly during infections caused by multidrug-resistant pathogens. In these tripartite pumps an inner membrane transporter, typically an ATPase or proton antiporter, binds and translocates export or efflux substrates. In cooperation with a periplasmic adaptor protein it recruits and opens a TolC family cell exit duct, which is anchored in the outer membrane and projects across the periplasmic space between inner and outer membranes. Assembled tripartite pumps thus span the entire bacterial cell envelope. We review the atomic structures of each of the three pump components and discuss how these have allowed high-resolution views of tripartite pump assembly, operation, and possible inhibition.
Plasmodium Nesting: Remaking the Erythrocyte from the Inside Out
Authors: Boddey Justin A. , Cowman Alan F.
Published: June 2013

One of the most fascinating and remarkable features of Plasmodium parasites, which cause malaria, is their choice of erythrocytes as the principal host cells in which to reside during infection of a vertebrate host. Parasites completely renovate the terminally differentiated cells, which lack most of the normal organelles and functions of other cells, such as a nucleus and the machinery to express and transport proteins to subcellular locations. Erythrocyte remodeling begins immediately after invasion by the Plasmodium parasite, by expression and export of many hundreds of proteins that assemble into molecular machinery in the host cell that permit protein trafficking, harvesting of nutrients, and mechanisms to evade host immune responses. In this review, we discuss recent studies on erythrocyte remodeling, including mechanisms of protein export as well as the identity, functions, and subcellular locations of key exported proteins.
Gender Similarities and Differences
Authors: Hyde Janet Shibley
Published: June 2013

Whether men and women are fundamentally different or similar has been debated for more than a century. This review summarizes major theories designed to explain gender differences: evolutionary theories, cognitive social learning theory, sociocultural theory, and expectancy-value theory. The gender similarities hypothesis raises the possibility of theorizing gender similarities. Statistical methods for the analysis of gender differences and similarities are reviewed, including effect sizes, meta-analysis, taxometric analysis, and equivalence testing. Then, relying mainly on evidence from meta-analyses, gender differences are reviewed in cognitive performance (e.g., math performance), personality and social behaviors (e.g., temperament, emotions, aggression, and leadership), and psychological well-being. The evidence on gender differences in variance is summarized. The final sections explore applications of intersectionality and directions for future research.
National Oil Companies and the Future of the Oil Industry
Authors: Victor David G.
Published: June 2013

Ever since the 1970s, a small number of national oil companies (NOCs) have dominated the world supply of oil and other hydrocarbons. Despite the huge influence that NOCs have on political economy, systematic scholarship remains surprisingly thin. I examine the factors that explain the wide variation in the strategy and performance of NOCs and survey the literature that has suggested the many ways in which NOCs play pivotal political and economic roles in resource-rich countries. As we look to the future, the fate of NOCs hinges on the price of oil, which may be eroded as new supplies (largely outside the control of most NOCs), such as deep water and shale oil, affect global markets.
Genome-wide transcriptome analysis identifies novel gene signatures implicated in human chronic liver disease
Authors: Smalling Rana V. , Delker Don A. , Zhang Yuxia , Nieto Natalia , Mcguiness Michael S. , Liu Shuanghu , Friedman Scott L. , Hagedorn Curt H. , Wang Li
Published: June 2013

The molecular mechanisms behind human liver disease progression to cirrhosis remain elusive. Nuclear receptor small heterodimer partner (SHP/ Nr0b2) is a hepatic tumor suppressor and a critical regulator of liver function. SHP expression is diminished in human cirrhotic livers, suggesting a regulatory role in human liver diseases. The goal of this study was to identify novel SHP-regulated genes that are involved in the development and progression of chronic liver disease. To achieve this, we conducted the first comprehensive RNA sequencing (RNA-seq) analysis of Shp−/− mice, compared the results with human hepatitis C cirrhosis RNA-seq and nonalcoholic steatohepatitis (NASH) microarray datasets, and verified novel results in human liver biospecimens. This approach revealed new gene signatures associated with chronic liver disease and regulated by SHP. Several genes were selected for validation of physiological relevance based on their marked upregulation, novelty with regard to liver function, and involvement in gene pathways related to liver disease. These genes include peptidoglycan recognition protein 2, dual specific phosphatase-4, tetraspanin 4, thrombospondin 1, and SPARC-related modular calcium binding protein-2, which were validated by qPCR analysis of 126 human liver specimens, including steatosis, fibrosis, and NASH, alcohol and hepatitis C cirrhosis, and in mouse models of liver inflammation and injury. This RNA-seq analysis identifies new genes that are regulated by the nuclear receptor SHP and implicated in the molecular pathogenesis of human chronic liver diseases. The results provide valuable transcriptome information for characterizing mechanisms of these diseases.
CXCL12 induces hepatic stellate cell contraction through a calcium-independent pathway
Authors: Saiman Yedidya , Agarwal Ritu , Hickman DaShawn A. , Fausther Michel , El-Shamy Ahmed , Dranoff Jonathan A. , Friedman Scott L. , Bansal Meena B.
Published: June 2013

Liver fibrosis, with subsequent development of cirrhosis and ultimately portal hypertension, results in the death of patients with end-stage liver disease if liver transplantation is not performed. Hepatic stellate cells (HSCs), central mediators of liver fibrosis, resemble tissue pericytes and regulate intrahepatic blood flow by modulating pericapillary resistance. Therefore, HSCs can contribute to portal hypertension in patients with chronic liver disease (CLD). We have previously demonstrated that activated HSCs express functional chemokine receptor, CXCR4, and that receptor engagement by its ligand, CXCL12, which is increased in patients with CLD, leads to further stellate cell activation in a CXCR4-specific manner. We therefore hypothesized that CXCL12 promotes HSC contraction in a CXCR4-dependent manner. Stimulation of HSCs on collagen gel lattices with CXCL12 led to gel contraction and myosin light chain (MLC) phosphorylation, which was blocked by addition of AMD3100, a CXCR4 small molecule inhibitor. These effects were further mediated by the Rho kinase pathway since both Rho kinase knockdown or Y-27632, a Rho kinase inhibitor, blocked CXCL12 induced phosphorylation of MLC and gel contraction. BAPTA-AM, a calcium chelator, had no effect, indicating that this pathway is calcium sensitive but not calcium dependent. In conclusion, CXCL12 promotes stellate cell contractility in a predominantly calcium-independent fashion. Our data demonstrates a novel role of CXCL12 in stellate cell contraction and the availability of small molecule inhibitors of the CXCL12/CXCR4 axis justifies further investigation into its potential as therapeutic target for portal hypertension.
Identifying cellular mechanisms of zinc-induced relaxation in isolated cardiomyocytes
Authors: Yi Ting , Vick Jonathan S. , Vecchio Marc J. H. , Begin Kelly J. , Bell Stephen P. , Delay Rona J. , Palmer Bradley M.
Published: June 2013

We tested several molecular and cellular mechanisms of cardiomyocyte contraction-relaxation function that could account for the reduced systolic and enhanced diastolic function observed with exposure to extracellular Zn2+. Contraction-relaxation function was monitored in isolated rat and mouse cardiomyocytes maintained at 37°C, stimulated at 2 or 6 Hz, and exposed to 32 μM Zn2+ or vehicle. Intracellular Zn2+ detected using FluoZin-3 rose to a concentration of ∼13 nM in 3–5 min. Peak sarcomere shortening was significantly reduced and diastolic sarcomere length was elongated after Zn2+ exposure. Peak intracellular Ca2+ detected by Fura-2FF was reduced after Zn2+ exposure. However, the rate of cytosolic Ca2+ decline reflecting sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) activity and the rate of Na+/Ca2+ exchanger activity evaluated by rapid Na+-induced Ca2+ efflux were unchanged by Zn2+ exposure. SR Ca2+ load evaluated by rapid caffeine exposure was reduced by ∼50%, and L-type calcium channel inward current measured by whole cell patch clamp was reduced by ∼70% in cardiomyocytes exposed to Zn2+. Furthermore, ryanodine receptor (RyR) S2808 and phospholamban (PLB) S16/T17 were markedly dephosphorylated after perfusing hearts with 50 μM Zn2+. Maximum tension development and thin-filament Ca2+ sensitivity in chemically skinned cardiac muscle strips were not affected by Zn2+ exposure. These findings suggest that Zn2+ suppresses cardiomyocyte systolic function and enhances relaxation function by lowering systolic and diastolic intracellular Ca2+ concentrations due to a combination of competitive inhibition of Ca2+ influx through the L-type calcium channel, reduction of SR Ca2+ load resulting from phospholamban dephosphorylation, and lowered SR Ca2+ leak via RyR dephosphorylation. The use of the low-Ca2+-affinity Fura-2FF likely prevented the detection of changes in diastolic Ca2+ and SERCA2a function. Other strategies to detect diastolic Ca2+ in the presence of Zn2+ are essential for future work.
A mathematical evaluation of hemodynamic parameters after carotid eversion and conventional patch angioplasty
Authors: Kamenskiy Alexey V. , Pipinos Iraklis I. , Dzenis Yuris A. , Gupta Prateek K. , Jaffar Kazmi Syed A. , MacTaggart Jason N.
Published: June 2013

Carotid endarterectomy has a long history in stroke prevention, yet controversy remains concerning optimal techniques. Two methods frequently used are endarterectomy with patch angioplasty (CEAP) and eversion endarterectomy (CEE). The objective of this study was to compare hemodynamics-related stress and strain distributions between arteries repaired using CEAP and CEE. Mathematical models were based on in vivo three-dimensional arterial geometry, pulsatile velocity profiles, and intraluminal pressure inputs obtained from 16 patients with carotid artery disease. These data were combined with experimentally derived nonlinear, anisotropic carotid artery mechanical properties to create fluid-structure interaction models of CEAP and CEE. These models were then used to calculate hemodynamic parameters thought to promote recurrent disease and restenosis. Combining calculations of stress and strain into a composite risk index, called the integral abnormality factor, allowed for an overall comparison between CEAP and CEE. CEE demonstrated lower mechanical stresses in the arterial wall, whereas CEAP straightened the artery and caused high stress and strain concentrations at the suture-artery interface. CEAP produced a larger continuous region of oscillatory, low-shear, vortical flow in the carotid bulb. There was a more than two-fold difference in the integral abnormality factor, favoring CEE. In conclusion, in a realistically simulated carotid artery, fluid-structure interaction modeling demonstrated CEE to produce less mechanical wall stress and improved flow patterns compared with CEAP. Clinical validation with larger numbers of individual patients will ultimately be required to support modeling approaches to help predict arterial disease progression and comparative effectiveness of reconstruction methods and devices.
Central endogenous angiotensin-(1–7) protects against aldosterone/NaCl-induced hypertension in female rats
Authors: Xue Baojian , Zhang Zhongming , Johnson Ralph F. , Guo Fang , Hay Meredith , Johnson Alan Kim
Published: June 2013

In comparison to male rodents, females are protected against angiotensin (ANG) II- and aldosterone (Aldo)-induced hypertension. However, the mechanisms underlying this protective effect are not well understood. ANG-(1–7) is formed from ANG II by angiotensin-converting enzyme 2 (ACE2) and has an antihypertensive effect in the central nervous system (CNS). The present study tested the hypothesis that central ANG-(1–7) plays an important protective role in attenuating the development of Aldo/NaCl-hypertension in female rats. Systemic infusion of Aldo into intact female rats with 1% NaCl as their sole drinking fluid resulted in a slight increase in blood pressure (BP). Intracerebroventricular (icv) infusion of A-779, an ANG-(1–7) receptor (Mas-R) antagonist, significantly augmented the pressor effects of Aldo/NaCl. In contrast, systemic Aldo/NaCl induced a significant increase in BP in ovariectomized (OVX) female rats, and central infusion of ANG-(1–7) significantly attenuated this Aldo/NaCl pressor effect. The inhibitory effect of ANG-(1–7) on the Aldo/NaCl pressor effect was abolished by concurrent infusion of A-779. RT-PCR analyses showed that there was a corresponding change in mRNA expression of several renin-angiotensin system components, estrogen receptors and an NADPH oxidase subunit in the lamina terminalis. Taken together these results suggest that female sex hormones regulate an antihypertensive axis of the brain renin-angiotensin system involving ACE2/ANG-(1–7)/Mas-R that plays an important counterregulatory role in protecting against the development of Aldo/NaCl-induced hypertension.
Primacy of angiotensin converting enzyme in angiotensin-(1–12) metabolism
Authors: Moniwa Norihito , Varagic Jasmina , Simington Stephen W. , Ahmad Sarfaraz , Nagata Sayaka , VonCannon Jessica L. , Ferrario Carlos M.
Published: June 2013

Angiotensin-(1–12) [ANG-(1–12)], a new member of the renin-angiotensin system, is recognized as a renin independent precursor for ANG II. However, the processing of ANG-(1–12) in the circulation in vivo is not fully established. We examined the effect of angiotensin converting enzyme (ACE) and chymase inhibition on angiotensin peptides formation during an intravenous infusion of ANG-(1–12) in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). WKY and SHR were assigned to a short ANG-(1–12) infusion lasting 5, 15, 30, or 60 min ( n = 4–10 each group). In another experiment WKY and SHR were assigned to a continuous 15-min ANG-(1–12) infusion with pretreatment of saline, lisinopril (10 mg/kg), or chymostatin (10 mg/kg) ( n = 7–13 each group). Saline or lisinopril were infused intravenously 15 min before the administration of ANG-(1–12) (2 nmol·kg−1·min−1), whereas chymostatin was given by bolus intraperitoneal injection 30 min before ANG-(1–12). Infusion of ANG-(1–12) increased arterial pressure and plasma ANG-(1–12), ANG I, ANG II, and ANG-(1–7) levels in WKY and SHR. Pretreatment with lisinopril caused increase in ANG-(1–12) and ANG I and large decreases in ANG II compared with the other two groups in both strains. Pretreatment of chymostatin had no effect on ANG-(1–12), ANG I, and ANG II levels in both strains, whereas it increased ANG-(1–7) levels in WKY. We conclude that ACE acts as the primary enzyme for the conversion of ANG-(1–12) to smaller angiotensin peptides in the circulation of WKY and SHR and that chymase may be an ANG-(1–7) degrading enzyme.
Termination of dobutamine infusion causes transient rebound left heart diastolic dysfunction in healthy elderly women but not in men: a cardiac magnetic resonance study
Authors: Ahtarovski Kiril A. , Iversen Kasper K. , Lønborg Jacob T. , Madsen Per L. , Engstrøm Thomas , Vejlstrup Niels G.
Published: June 2013

Men and women are known to react differently to stress. Thus, stress cardiomyopathy almost solely strikes women. Stress cardiomyopathy is suggested to relate to sex differences in catecholamine reaction. Left heart function during dobutamine stress is well described, but sex-specific inotropic and lusitropic response to abrupt termination of dobutamine stress is not. We aimed to investigate sex differences in left ventricular (LV) and atrial (LA) function during and after dobutamine stress. We enrolled 20 healthy elderly subjects (60–70 yr, 10 females) and measured their LV and LA volumes throughout the cardiac cycle by cardiac magnetic resonance imaging at rest, during dobutamine stress (15 μg·kg−1·min−1), 15 min after termination (T15), and 30 min after termination (T30) of dobutamine stress. We calculated LV ejection fractions, LV stroke volumes, LV peak filling rates, and LA passive, active, and conduit volumes. Sex differences were not observed at rest or during dobutamine stress. Compared with prestress values, at T15 a rebound decrease in LV peak filling rate was observed in women (−22 ± 3%, P < 0.001) but not in men. This was reflected in reduced LA passive emptying volume (−40 ± 3%, P < 0.001) and a corresponding increase in LA active emptying volume (36 ± 2%, P < 0.001). At T30 there were no differences between the sexes. We conclude that dobutamine causes greater stress to the female heart. This is revealed after termination of dobutamine stress where the left heart recovers in men, whereas women experience rebound LV stiffening with reduced diastolic relaxation. This is the first report of a sex-specific transient rebound phenomenon in cardiovascular response to catecholamines.
Eukaryotic elongation factor 2 kinase regulates the development of hypertension through oxidative stress-dependent vascular inflammation
Authors: Usui Tatsuya , Okada Muneyoshi , Hara Yukio , Yamawaki Hideyuki
Published: June 2013

Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca2+/calmodulin-dependent protein kinase. We recently demonstrated that eEF2K protein increases in mesenteric artery from spontaneously hypertensive rats (SHR). Pathogenesis of hypertension is regulated in part by vascular inflammation. We tested the hypothesis whether eEF2K mediates vascular inflammatory responses and development of hypertension. In vascular endothelial cells, small interfering RNA (siRNA) against eEF2K inhibited induction of VCAM-1 and endothelial-selectin as well as monocyte adhesion by TNF-α (10 ng/ml). eEF2K siRNA inhibited phosphorylation of JNK and NF-κB p65 as well as reactive oxygen species (ROS) production by TNF-α. In vascular smooth muscle cells, eEF2K siRNA also inhibited VCAM-1 induction and phosphorylation of JNK and NF-κB by TNF-α. In vivo, increased blood pressure in SHR and ROS production, induction of inflammatory molecules, and hypertrophy in SHR superior mesenteric artery were reduced by an eEF2K inhibitor NH125 (500 μg·kg−1·day−1). In SHR superior mesenteric artery, impairment of ACh-induced relaxation was normalized by NH125. The present results for the first time demonstrate that eEF2K mediates TNF-α-induced vascular inflammation via ROS-dependent mechanism, which is at least partly responsible for the development of hypertension in SHR.
Chronic atrial fibrillation causes left ventricular dysfunction in dogs but not goats: experience with dogs, goats, and pigs
Authors: Dosdall Derek J. , Ranjan Ravi , Higuchi Koji , Kholmovski Eugene , Angel Nathan , Li Li , MacLeod Rob , Norlund Layne , Olsen Aaron , Davies Christopher J. , Marrouche Nassir F.
Published: June 2013

Structural remodeling in chronic atrial fibrillation (AF) occurs over weeks to months. To study the electrophysiological, structural, and functional changes that occur in chronic AF, the selection of the best animal model is critical. AF was induced by rapid atrial pacing (50-Hz stimulation every other second) in pigs ( n = 4), dogs ( n = 8), and goats ( n = 9). Animals underwent MRIs at baseline and 6 mo to evaluate left ventricular (LV) ejection fraction (EF). Dogs were given metoprolol (50–100 mg po bid) and digoxin (0.0625–0.125 mg po bid) to limit the ventricular response rate to <180 beats/min and to mitigate the effects of heart failure. The pacing leads in pigs became entirely encapsulated and lost the ability to excite the heart, often before the onset of sustained AF. LV EF in dogs dropped from 54 ± 11% at baseline to 33 ± 7% at 6 mo ( P < 0.05), whereas LV EF in goats did not drop significantly (69 ± 8% at baseline vs. 60 ± 9% at 6 mo, P = not significant). After 6 mo of AF, fibrosis levels in dog atria and ventricles increased, whereas only atrial fibrosis levels increased in goats compared with control animals. In our experience, the pig model is not appropriate for chronic rapid atrial pacing-induced AF studies. Rate-controlled chronic AF in the dog model developed HF and LV fibrosis, whereas the goat model developed only atrial fibrosis without ventricular dysfunction and fibrosis. Both the dog and goat models are representative of segments of the patient population with chronic AF.