bluuebunny/crossref_metadata_2025 huggingface dataset:
Does regulation kill jobs?: The limits of quantification
Authors: Driesen David M.
Published: May 2015

This essay reviews a new edited volume entitled Does Regulation Kill Jobs? It concludes that this book brings much needed data and realism to the debate about jobs and the environment, showing that government regulation generally has minor impacts on employment. This essay focuses much of its attention on the suggestion, discussed by several of the contributors to this book, that cost–benefit analysis should include a dollar value representing an estimate of the value of employment changes a proposed regulation might cause. It discusses concerns about double counting, ex ante estimates of employment impacts, monetization of the value of employment impacts, and potentially misleading asymmetric analysis.
Understanding the Shift in Demand for Cash Value Life Insurance
Authors: Mulholland Barry , Finke Michael , Huston Sandra
Published: May 2015

Ownership of cash value life insurance in the United States has fallen in recent decades. Changes in age cohorts, family composition, and tax laws may have contributed to this decline. We identify factors that influence the demand for cash value life insurance and test whether they alone can explain the sharp decline in ownership. Demographic and tax code changes do not explain the decrease in permanent insurance. There is a consistent downward trend in demand from 1992 to 2010—particularly among middle‐age and younger households. The fewer households who own cash value policies are on average wealthier and more financially sophisticated, suggesting that permanent life insurance is increasingly being used as a tax shield rather than as a hedge against a loss in human capital.
Estimation of a Copula when a Covariate Affects only Marginal Distributions
Authors: Gijbels Irène , Omelka Marek , Veraverbeke Noël
Published: May 2015

This paper is concerned with studying the dependence structure between two random variables Y1 and Y2 in the presence of a covariate X, which affects both marginal distributions but not the dependence structure. This is reflected in the property that the conditional copula of Y1 and Y2 given X, does not depend on the value of X. This latter independence often appears as a simplifying assumption in pair‐copula constructions. We introduce a general estimator for the copula in this specific setting and establish its consistency. Moreover, we consider some special cases, such as parametric or nonparametric location‐scale models for the effect of the covariate X on the marginals of Y1 and Y2 and show that in these cases, weak convergence of the estimator, at
‐rate, holds. The theoretical results are illustrated by simulations and a real data example.
Adaptive Bayesian Procedures Using Random Series Priors
Authors: Shen Weining , Ghosal Subhashis
Published: May 2015

We consider a general class of prior distributions for nonparametric Bayesian estimation which uses finite random series with a random number of terms. A prior is constructed through distributions on the number of basis functions and the associated coefficients. We derive a general result on adaptive posterior contraction rates for all smoothness levels of the target function in the true model by constructing an appropriate ‘sieve’ and applying the general theory of posterior contraction rates. We apply this general result on several statistical problems such as density estimation, various nonparametric regressions, classification, spectral density estimation and functional regression. The prior can be viewed as an alternative to the commonly used Gaussian process prior, but properties of the posterior distribution can be analysed by relatively simpler techniques. An interesting approximation property of B‐spline basis expansion established in this paper allows a canonical choice of prior on coefficients in a random series and allows a simple computational approach without using Markov chain Monte Carlo methods. A simulation study is conducted to show that the accuracy of the Bayesian estimators based on the random series prior and the Gaussian process prior are comparable. We apply the method on Tecator data using functional regression models.
Globalization and the Ethnic Divide: Recent Longitudinal Evidence*
Authors: Wunnava Phanindra V. , Mitra Aniruddha , Prasch Robert E.
Published: May 2015

Objective

This article investigates the impact of increasing global integration on economic growth, emphasizing its interaction with the level of ethnic heterogeneity in a society.

Methods

We perform a feasible generalized least squares estimation of a random effects model on a longitudinal sample of 103 countries taken over the period 1992–2005.

Results

We find that economic globalization has generally had a beneficial impact on economic growth. We also find that societies marked by greater ethnic heterogeneity have gained more from global integration. Further, while ethnic heterogeneity has been a significant impediment to growth over the sample period, religious and linguistic heterogeneity have not. Finally, we find that democracies have significantly outperformed autocracies over this period.

Conclusion

Our results suggest that globalization may have a role in redressing the detrimental impact of ethnic cleavages in a society.
Chryseobacterium indologenes in four patients with leukemia
Authors: Deng L. , Li M.F. , Li Y.H. , Yang J.L. , Zhou X.
Published: May 2015

Chryseobacterium indologenes is a rare opportunistic pathogen causing hospital‐acquired infection. We present 4 patients with leukemia associated with C. indologenes infection. Two of the patients, undergoing peripheral blood allogeneic hematopoietic stem cell transplantation (alloHSCT) from human leukocyte antigen‐identical sibling donors, died of pneumonia caused by C. indologenes with or without Pseudomonas aeruginosa. Blood infection with C. indologenes was found in the other 2 patients during chemotherapy, 1 of which was a central venous catheter‐related bloodstream infection. Both patients were cured with or without the sensitive antibiotic. Three of these 4 isolates were susceptible to trimethoprim‐sulfamethoxazole only in vitro. Although C. indologenes has a weak toxicity, it can be lethal for the super‐immunocompromised patients, such as those treated with alloHSCT.
Regulators and effectors of bone morphogenetic protein signalling in the cardiovascular system
Authors: Luo Jiang‐Yun , Zhang Yang , Wang Li , Huang Yu
Published: May 2015

Bone morphogenetic proteins (BMPs) play key roles in the regulation of cell proliferation, differentiation and apoptosis in various tissues and organs, including the cardiovascular system. BMPs signal through both Smad‐dependent and ‐independent cascades to exert a wide spectrum of biological activities. Cardiovascular disorders such as abnormal angiogenesis, atherosclerosis, pulmonary hypertension and cardiac hypertrophy have been linked to aberrant BMP signalling. To correct the dysregulated BMP signalling in cardiovascular pathogenesis, it is essential to get a better understanding of how the regulators and effectors of BMP signalling control cardiovascular function and how the dysregulated BMP signalling contributes to cardiovascular dysfunction. We hence highlight several key regulators of BMP signalling such as extracellular regulators of ligands, mechanical forces, microRNAs and small molecule drugs as well as typical BMP effectors like direct downstream target genes, mitogen‐activated protein kinases, reactive oxygen species and microRNAs. The insights into these molecular processes will help target both the regulators and important effectors to reverse BMP‐associated cardiovascular pathogenesis.
Functional adaptation of the human β‐cells after frequent exposure to noradrenaline
Authors: Dela Flemming
Published: May 2015

Key points

Trained people produce less insulin than untrained; there is an adaptation of the insulin‐producing cells to the trained state.

The mechanism behind this adaptation is not known, but some sort of memory must be introduced into the insulin‐producing cells.

Here it is shown that this memory is introduced by 10 daily intravenous infusions of noradrenaline, mimicking the increases that occur during a 10 day training programme.

Thus, after the infusion period, the subjects produced less insulin in response to the same stimulus.

It is concluded that exercise‐induced increases in noradrenaline is most likely the stimulus that introduces a memory in the insulin‐producing cells.

Physical training decreases glucose‐ and arginine‐stimulated insulin secretion. The mechanism by which the pancreatic β‐cells adapt to the training status of the individual is not known. We hypothesized that the adaptation is mediated via the frequent exercise‐induced increases in sympathetic activity. Simulation of exercise‐induced increases in plasma noradrenaline (NA) concentrations was carried out in nine untrained men (age: 25 ± 1 years (mean ± SEM); BMI: 24 ± 1 kg m−2), who received infusions of NA (0.2 μg kg−1 min−1) for 45 min every day for 10 days. The insulin response to glucose was measured during hyperglycaemic (20 mmol l−1) clampsbefore and after the NA infusion period. During NA infusions mean arterial blood pressure increased (from 89 ± 2 to 110 ± 5 mmHg, P < 0.05) and heart rate decreased (from 78 ± 7 to 69 ± 12 beats min−1, P < 0.05). During NA infusions plasma insulin concentrations decreased to nadir by 68% (P < 0.05). Fasting plasma glucose and insulin were not different at the two clamps (5.3 ± 0.1 and 5.3 ± 0.3 mmol l−1; 47 ± 15 and 31 ± 4 pmol l−1, respectively). Plasma glucose concentrations during the hyperglycaemic clamps were similar (P > 0.05) and averaged 19.9 ± 0.1 mmol l−1 with a coefficient of variation of 3.8 ± 0.3%, while the insulin response decreased (P < 0.05) by 26 ± 2% after the 10 days of NA infusions. It is concluded that NA mediates the adaptation of the β‐cells seen in trained people.
Quantifying ligand–cell interactions and determination of the surface concentrations of ligands on hydrogel films: The measurement challenge
Authors: Beer Meike V. , Hahn Kathrin , Diederichs Sylvia , Fabry Marlies , Singh Smriti , Spencer Steve J. , Salber Jochen , Möller Martin , Shard Alexander G. , Groll Jürgen
Published: May 2015

Hydrogels are extensively studied for biomaterials application as they provide water swollen noninteracting matrices in which specific binding motifs and enzyme-sensitive degradation sites can be incorporated to tailor cell adhesion, proliferation, and migration. Hydrogels also serve as excellent basis for surface modification of biomaterials where interfacial characteristics are decisive for implant success or failure. However, the three-dimensional nature of hydrogels makes it hard to distinguish between the bioactive ligand density at the hydrogel-cell interface that is able to interact with cells and the ligands that are immobilized inside the hydrogel and not accessible for cells. Here, the authors compare x-ray photoelectron spectrometry (XPS), time-of-flight secondary ion mass spectroscopy (ToF-SIMS), enzyme linked immunosorbent assay (ELISA), and the correlation with quantitative cell adhesion using primary human dermal fibroblasts (HDF) to gain insight into ligand distribution. The authors show that although XPS provides the most useful quantitative analysis, it lacks the sensitivity to measure biologically meaningful concentrations of ligands. However, ToF-SIMS is able to access this range provided that there are clearly distinguishable secondary ions and a calibration method is found. Detection by ELISA appears to be sensitive to the ligand density on the surface that is necessary to mediate cell adhesion, but the upper limit of detection coincides closely with the minimal ligand spacing required to support cell proliferation. Radioactive measurements and ELISAs were performed on amine reactive well plates as true 2D surfaces to estimate the ligand density necessary to allow cell adhesion onto hydrogel films. Optimal ligand spacing for HDF adhesion and proliferation on ultrathin hydrogel films was determined as 6.5 ± 1.5 nm.
Development of cup shaped microneedle array for transdermal drug delivery
Authors: Vinayakumar Kadayar B. , Hegde Gopal M. , Ramachandra Subbaraya G. , Nayak Mangalore M. , Dinesh Narasimhian S. , Rajanna Konandur
Published: May 2015

Microneedle technology is one of the attractive methods in transdermal drug delivery. However, the clinical applications of this method are limited owing to: complexity in the preparation of multiple coating solutions, drug leakage while inserting the microneedles into the skin and the outer walls of the solid microneedle can hold limited quantity of drug. Here, the authors present the fabrication of an array of rectangular cup shaped silicon microneedles, which provide for reduced drug leakage resulting in improvement of efficiency of drug delivery and possibility of introducing multiple drugs. The fabricated solid microneedles with rectangular cup shaped tip have a total height of 200 μm. These cup shaped tips have dimensions: 60 × 60 μm (length × breadth) with a depth of 60 μm. The cups are filled with drug using a novel in-house built drop coating system. Successful drug dissolution was observed when the coated microneedle was used on mice. Also, using the above method, it is possible to fill the cups selectively with different drugs, which enables simultaneous multiple drug delivery.
A cysteine-clamp gene drives embryo polarity in the midge
Chironomus
Authors: Klomp Jeff , Athy Derek , Kwan Chun Wai , Bloch Natasha I. , Sandmann Thomas , Lemke Steffen , Schmidt-Ott Urs
Published: May 2015

How to generate head-to-tail polarity in a midge

Animal genomes do not remain static but gain and lose essential genes over time. One such case is the
bicoid
gene of flies.
Bicoid
plays an important role in early
Drosophila
development during the generation of head-to-tail polarity, but most flies lack
bicoid.
Which genes then serve the same function in other insects? Now, Klomp
et al.
report a structurally unrelated gene that serves essentially the same function as
bicoid
in a mosquito-related midge but does so through a different genetic mechanism.

Science
, this issue p.
1040
The rise of the social algorithm
Authors: Lazer David
Published: May 2015

Does content curation by Facebook introduce ideological bias?

[Also see Report by

Bakshy
et al.

]
Multiplex single-cell profiling of chromatin accessibility by combinatorial cellular indexing
Authors: Cusanovich Darren A. , Daza Riza , Adey Andrew , Pliner Hannah A. , Christiansen Lena , Gunderson Kevin L. , Steemers Frank J. , Trapnell Cole , Shendure Jay
Published: May 2015

Chromatin state and the single cell

Identifying the chromatin state of any single cell, which may or may not have a different function or represent different stages relative to others collected within any single culture, experiment, or tissue, has been challenging. Cusanovitchet al.skirted previously identified technological limitations to identify regions of accessible chromatin at single-cell resolution. Combinatorial cellular indexing, a strategy for multiplex barcoding of thousands of single cells per experiment, was successfully used to investigate the genome-wide chromatin accessibility landscape in each of over 15,000 single cells.

Science, this issue p.910
Polyradiculopathy secondary to severe hypertriglyceridemia
Authors: Nesbitt Cassie , Wong Daniel , Batchelor Peter
Published: May 2015

A 74-year-old man presented with a subacute severe thoracic polyradiculopathy affecting the T4–T8 dermatomes bilaterally. Extensive investigation demonstrated markedly raised triglyceride levels of 44 mmol/L (<1.7). The patient's unique presentation is discussed alongside a review of triglyceride-induced neurotoxicity and therapeutic management.
Coach development programmes to improve interpersonal coach behaviours: a systematic review using the re-aim framework
Authors: Evans M Blair , McGuckin Matthew , Gainforth Heather L , Bruner Mark W , Côté Jean
Published: May 2015

Objective

Although evidence supports the effectiveness of interpersonal Coach Development Programmes (CDPs), which are designed to foster coach–athlete relationships, an intervention's impact is shaped by numerous factors over and above effectiveness. The purpose of this systematic review was to examine the extent that published articles describing interpersonal CDP trials reported on indicators of internal and external validity, as conceptualised in the RE-AIM framework (ie, Reach, Effectiveness, Adoption, Implementation and Maintenance).

Methods

The search strategy was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, involving a database search and supplemental manual search of key articles and journals. After initial screening, the full-text search strategy involved identifying articles describing CDP trials and then selecting a specific subgroup of articles involving interpersonal CDP trials and excluding ineligible articles. Resulting trials were coded using a 47-item sport coaching adaptation of the RE-AIM coding sheet.

Results

17 published articles met eligibility criteria, representing 10 distinct CDP trials. After attaining coder agreement, global ratings of RE-AIM indicators within interpersonal CDP trials ranged from the low to moderate quality. Whereas indicators of effectiveness and implementation were reported to some extent across all studies, maintenance within sport organisations and a number of specific indicators from across dimensions were rarely reported.

Conclusions

These findings inform the future design and evaluation of CDPs that have the potential to be adopted in numerous settings and reach athletes and coaches who can most benefit.
Welfare generosity and population health among Canadian provinces: a time-series cross-sectional analysis, 1989–2009
Authors: Ng Edwin , Muntaner Carles
Published: May 2015

Background

Recent work in comparative social epidemiology uses an expenditures approach to examine the link between welfare states and population health. More work is needed that examines the impact of disaggregated expenditures within nations. This study takes advantage of provincial differences within Canada to examine the effects of subnational expenditures and a provincial welfare generosity index on population health.

Methods

Time-series cross-sectional data are retrieved from the Canadian Socio-Economic Information Management System II Tables for 1989–2009 (10 provinces and 21 years=210 cases). Expenditures are measured using 20 disaggregated indicators, total expenditures and a provincial welfare generosity index, a ombined measure of significant predictors. Health is measured as total, male and female age-standardised mortality rates per 1000 deaths. Estimation techniques include the Prais-Winsten regressions with panel-corrected SEs, a first-order autocorrelation correction model, and fixed-unit effects, adjusted for alternative factors.

Results

Analyses reveal that four expenditures effectively reduce mortality rates: medical care, preventive care, other social services and postsecondary education. The provincial welfare generosity index has even larger effects. For an SD increase in the provincial welfare generosity index, total mortality rates are expected to decline by 0.44 SDs. Standardised effects are larger for women (β=−0.57, z(19)=−5.70, p<0.01) than for men (β=−0.38, z(19)=−5.59, p<0.01).

Conclusions

Findings show that the expenditures approach can be effectively applied within the context of Canadian provinces, and that targeted spending on health, social services and education has salutary effects.
Effect of waste rock inclusions on the seismic stability of an upstream raised tailings impoundment: a numerical investigation
Authors: Ferdosi Behnam , James Michael , Aubertin Michel
Published: May 2015

Over the years, seismic activity has been a relatively common cause of tailings impoundment failure. The flow of liquefied tailings from such ruptures can result in very severe consequences, including loss of life and environmental damage. A co-disposal technique consisting of placing waste rock inclusions in tailings impoundments prior to and during tailings deposition was proposed by the authors. The waste rock is placed to create continuous inclusions within the impoundment, which provide a number of environmental and geotechnical benefits, particularly with respect to seismic stability. The results of numerical simulations previously performed have shown that the UBCSAND model can predict the seismic response of tailings. The UBCSAND constitutive model was used to conduct simulations to evaluate of the use of waste rock inclusions to improve the seismic stability of a tailings impoundment. The evaluation consists of numerical analyses of an actual tailings impoundment as constructed (without inclusions), and then assuming that it was constructed with inclusions, subjected to earthquake loads of various energy contents and with different predominant frequencies. The analyses were conducted in static, seismic, and post-shaking phases. The displacement of the surface of downstream slope of the tailings dyke was recorded during the analyses. The results indicate that the presence of waste rock inclusions can significantly improve the seismic behavior of the impoundment by reducing the displacements of the surface of the downstream slope and the extent of potential failure zones. Also, the results show that in most cases, the influence of a low-frequency earthquake on the displacement of the downstream slope of the tailings dyke is more important than that of a high-frequency earthquake. The performances of the tailings impoundment with different configurations of waste rock inclusions (varying width and center-to-center spacing) were classified based on the average normalized horizontal displacement of the downstream slope (ARx) for a range input ground motions. Charts were then developed to show how ARxis influenced by the total width of inclusions, their spacing, and the input ground motions.
Modeling St. John River (N.B., Canada) incomplete hydrometric data using bivariate distributions
Authors: Boisvert J. , Ashkar F. , El Adlouni S. , El-Jabi N. , Aucoin F.
Published: May 2015

This study deals with incomplete bivariate data in hydrology, where information contained in a hydrological series of relatively long length (X, the auxiliary variable) is utilized to enhance the quality of the quantile estimates for a series of shorter length (Y, the variable of main interest), when there is an association between X and Y. It is suggested that bivariate models for representing (X, Y) be constructed by means of copulas, which allows for flexibility in choosing both the marginals and the bivariate distributions. Parameter estimation is done by maximum likelihood (ML), where all the unknown parameters of the bivariate model are estimated simultaneously. A case study using flow records at three gauging stations on the St. John River (New Brunswick, Canada) is used to demonstrate the interest of using bivariate distributions for modeling incomplete data. By using (X, Y) bivariate data observed on the St. John River, the probability density function (pdf) obtained from a univariate frequency analysis of Y (Model A), is compared to the pdf constructed using a bivariate model relating X to Y (Model B). It is shown that Model B reduces the variability in the Y pdf as compared to the pdf obtained from Model A, and also corrects the quantile estimates for Y through a location shift.
A train track directed random walk on Out(Fr)
Authors: Kapovich Ilya , Pfaff Catherine
Published: May 2015

Several known results, by Rivin, Calegari-Maher and Sisto, show that an element φn ∈ Out (Fr), obtained after n steps of a simple random walk on Out (Fr), is fully irreducible with probability tending to 1 as n → ∞. In this paper, we construct a natural "train track directed" random walk 𝒲 on Out (Fr) (where r ≥ 3). We show that, for the element φn ∈ Out (Fr), obtained after n steps of this random walk, with asymptotically positive probability the element φn has the following properties: φn is an ageometric fully irreducible, which admits a train track representative with no periodic Nielsen paths and exactly one nondegenerate illegal turn, that φn has "rotationless index" [Formula: see text] (so that the geometric index of the attracting tree Tφn of φn is 2r - 3), has index list [Formula: see text] and the ideal Whitehead graph being the complete graph on 2r - 1 vertices, and that the axis bundle of φn in the Outer space CV r consists of a single axis.
BIO/MICRO-ROLLING FABRICATION OF BIOLOGICAL SHARKSKIN MORPHOLOGY ON SEMI-CURED COATING AND DRAG FORCE EXPERIMENTAL RESEARCH
Authors: LUO YUEHAO , ZHANG DEYUAN , LIU YUFEI , NG E. Y. K.
Published: May 2015

The artificial drag-reducing surface with biological sharkskin morphology was fabricated by the direct bio-replicated method, and the satisfactory drag reduction effect was validated in the water tunnel. However, the splicing step is necessary for the area larger than the entire surface of shark, the consequence of which is that the complexity of process will be increased seriously. At the meanwhile, two adverse effects may appear, namely, the stress contraction on the jointing seams and the drop-out phenomenon. Therefore, it is urgent to manufacture the continuous biomimetic sharkskin surface. In this paper, a novel and facile method to fabricate the drag-reducing surface on a semi-cured coating based on biological sharkskin is investigated and explored. Firstly, the sputtering and photo lithography processes are put into application to eliminate the wedge angle on scale’s back. Secondly, the relationship between forming precision and curing degree of epoxy resin is inspected and the appropriate time-zone fitting for bio/micro-rolling is attained. Thirdly, the continuous sharkskin surface is manufactured in a large area. Lastly, for evaluating the effect of drag reduction, an experiment is performed. The experimental results show the drag reduction efficiency of the surface fabricated by the bio/micro rolling method, which can expand more applications in the fluid engineering.
A COMPLEX NETWORKS PERSPECTIVE ON COLLABORATIVE SOFTWARE ENGINEERING
Authors: CATALDO MARCELO , SCHOLTES INGO , VALETTO GIUSEPPE
Published: May 2015

Large collaborative software engineering projects are interesting examples for evolving complex systems. The complexity of these systems unfolds both in evolving software structures, as well as in the social dynamics and organization of development teams. Due to the adoption of Open Source practices and the increasing use of online support infrastructures, large-scale data sets covering both the social and technical dimension of collaborative software engineering processes are increasingly becoming available. In the analysis of these data, a growing number of studies employ a network perspective, using methods and abstractions from network science to generate insights about software engineering processes. Featuring a collection of inspiring works in this area, with this topical issue, we intend to give an overview of state-of-the-art research. We hope that this collection of articles will stimulate downstream applications of network-based data mining techniques in empirical software engineering.
Application of Multiscale Process Zone Model to Simulate Fracture in Polycrystalline Solids
Authors: Fan Houfu , Shi Chunxiang , Li Shaofan
Published: May 2015

In this work, an early proposed atomistic-based multiscale process zone model is revised and employed to simulate crack propagation and spall fracture in polycrystalline solids. The multiscale process zone model is capable of describing heterogenous materials by incorporating the effect of inhomogeneities such as grain boundaries, slip lines and inclusions. A consistent depletion potential resulting from fundamental principles in colloidal physics is used to describe the cohesive laws for both the grain interfaces and process zones in bulk materials, which provides microstructure-based interface potentials in both normal and tangential directions with respect to finite element boundary separations in contrast to conventional cohesive methods. The polycrystalline microstructure are generated by using the Voronoi tessellations. Two different approaches of treating the process zone are proposed. The multiscale process zone model is implemented in a Lagrange framework based on the Galerkin weak form formulation. In addition, to eliminate the zero-energy modes and avoid shear locking in the interphase elements, a reduced integration technique is adopted in simulations. Numerical simulations on crack propagation in materials with various cohesive strengths have been carried out, and they can describe both inter-granular and trans-granular fractures. Finally, the spall-fracture of a specimen under high-impact load is captured using the proposed multiscale process zone model.
Modeling the Charge Transport in Graphene Nano Ribbon Interfaces for Nano Scale Electronic Devices
Authors: Kumar Ravinder , Engles Derick
Published: May 2015

In this research work we have modeled, simulated and compared the electronic charge transport for Metal-Semiconductor-Metal interfaces of Graphene Nano Ribbons (GNR) with different geometries using First-Principle calculations and Non-Equilibrium Green's Function (NEGF) method. We modeled junctions of Armchair GNR strip sandwiched between two Zigzag strips with (Z-A-Z) and Zigzag GNR strip sandwiched between two Armchair strips with (A-Z-A) using semi-empirical Extended Huckle Theory (EHT) within the framework of Non-Equilibrium Green Function (NEGF). I-V characteristics of the interfaces were visualized for various transport parameters. The distinct changes in conductance and I-V curves reported as the Width across layers, Channel length (Central part) was varied at different bias voltages from -1V to 1 V with steps of 0.25 V. From the simulated results we observed that the conductance through A-Z-A graphene junction is in the range of 10-13 Siemens whereas the conductance through Z-A-Z graphene junction is in the range of 10-5 Siemens. These suggested conductance controlled mechanisms for the charge transport in the graphene interfaces with different geometries is important for the design of graphene based nano scale electronic devices like Graphene FETs, Sensors.
Sustained release nitrite therapy results in myocardial protection in a porcine model of metabolic syndrome with peripheral vascular disease
Authors: Bradley Jessica M. , Islam Kazi N. , Polhemus David J. , Donnarumma Erminia , Brewster Luke P. , Tao Ya-Xiong , Goodchild Traci T. , Lefer David J.
Published: May 2015

Metabolic syndrome (MetS) reduces endothelial nitric oxide (NO) bioavailability and exacerbates vascular dysfunction in patients with preexisting vascular diseases. Nitrite, a storage form of NO, can mediate vascular function during pathological conditions when endogenous NO is reduced. The aims of the present study were to characterize the effects of severe MetS and obesity on dyslipidemia, myocardial oxidative stress, and endothelial NO synthase (eNOS) regulation in the obese Ossabaw swine (OS) model and to examine the effects of a novel, sustained-release formulation of sodium nitrite (SR-nitrite) on coronary vascular reactivity and myocardial redox status in obese OS subjected to critical limb ischemia (CLI). After 6 mo of an atherogenic diet, obese OS displayed a MetS phenotype. Obese OS had decreased eNOS functionality and NO bioavailability. In addition, obese OS exhibited increased oxidative stress and a significant reduction in antioxidant enzymes. The efficacy of SR-nitrite therapy was examined in obese OS subjected to CLI. After 3 wk of treatment, SR-nitrite (80 mg·kg−1·day−1 bid po) increased myocardial nitrite levels and eNOS function. Treatment with SR-nitrite reduced myocardial oxidative stress while increasing myocardial antioxidant capacity. Ex vivo assessment of vascular reactivity of left anterior descending coronary artery segments demonstrated marked improvement in vasoreactivity to sodium nitroprusside but not to substance P and bradykinin in SR-nitrite-treated animals compared with placebo-treated animals. In conclusion, in a clinically relevant, large-animal model of MetS and CLI, treatment with SR-nitrite enhanced myocardial NO bioavailability, attenuated oxidative stress, and improved ex vivo coronary artery vasorelaxation.
Combination of erythromycin and dexamethasone improves corticosteroid sensitivity induced by CSE through inhibiting PI3K-δ/Akt pathway and increasing GR expression
Authors: Sun Xue-Jiao , Li Zhan-Hua , Zhang Yang , Zhou Guang , Zhang Jian-Quan , Deng Jing-Min , Bai Jing , Liu Guang-Nan , Li Mei-Hua , MacNee William , Zhong Xiao-Ning , He Zhi-Yi
Published: May 2015

Corticosteroid insensitivity, which is induced by cigarette smoke extract (CSE), is a significant barrier when treating chronic obstructive pulmonary disease (COPD). Erythromycin (EM) has been shown to have an anti-inflammatory role in some chronic airway inflammatory diseases, particularly diffuse panbronchiolitis and cystic fibrosis. Here, we explored whether the combination therapy of EM and dexamethasone (Dex) reverses corticosteroid insensitivity and investigated the molecular mechanism by which this occurs. We demonstrated that the combination of EM and Dex restored corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) from COPD patients and U937 cells after CSE exposure. Moreover, pretreatment with 10, 50, or 100 μg/ml EM reversed the HDAC2 protein reduction induced by CSE exposure in a dose-dependent manner. U937 cells exposed to CSE show a reduction in histone deacetylase (HDAC) activity, which was potently reversed by EM or combination treatment. Although 10 and 17.5% CSE increased phosphorylated Akt (PAkt) expression in a concentration-dependent manner, preapplication of EM and the combination treatment in particular blocked this PAkt increase. Total Akt levels were unaffected by CSE or EM treatments. Furthermore, the combination treatment enhanced glucocorticoid receptor (GR)α expression. Our results demonstrate that the combination therapy of EM and Dex can restore corticosteroid sensitivity through inhibition of the PI3K-δ/Akt pathway and enhancing GRα expression.
Intranasal scopolamine affects the semicircular canals centrally and peripherally
Authors: Weerts Aurélie P. , Putcha Lakshmi , Hoag Stephen W. , Hallgren Emma , Van Ombergen Angelique , Van de Heyning Paul H. , Wuyts Floris L.
Published: May 2015

Space motion sickness (SMS), a condition caused by an intravestibular conflict, remains an important obstacle that astronauts encounter during the first days in space. Promethazine is currently the standard treatment of SMS, but scopolamine is used by some astronauts to prevent SMS. However, the oral and transdermal routes of administration of scopolamine are known to have substantial drawbacks. Intranasal administration of scopolamine ensures a fast absorption and rapid onset of therapeutic effect, which might prove to be suitable for use during spaceflights. The aim of this study was to evaluate the effects of intranasally administered scopolamine (0.4 mg) on the semicircular canals (SCCs) and the otoliths. This double-blind, placebo-controlled study was performed on 19 healthy male subjects. The function of the horizontal SCC and the vestibulo-ocular reflex, as well as the saccular function and utricular function, were evaluated. Scopolamine turned out to affect mainly the SCCs centrally and peripherally but also the utricles to a lesser extent. Centrally, the most probable site of action is the medial vestibular nucleus, where the highest density of muscarinic receptors has been demonstrated and afferent fibers from the SCCs and utricles synapse. Furthermore, our results suggest the presence of muscarinic receptors in the peripheral vestibular system on which scopolamine has a suppressive effect. Given the depressant actions on the SCCs, it is suggested that the pharmacodynamic effect of scopolamine may be attributed to the obliteration of intravestibular conflict that arises during (S)MS.
Heat shock protein 70 overexpression does not attenuate atrophy in botulinum neurotoxin type A-treated skeletal muscle
Authors: Houston Fraser E. , Hain Brian A. , Adams Thomas J. , Houston Kati L. , O'Keeffe Roderic , Dodd Stephen L.
Published: May 2015

Botulinum neurotoxin type A (BoNT/A) is used clinically to induce therapeutic chemical denervation of spastically contracted skeletal muscles. However, BoNT/A administration can also cause atrophy. We sought to determine whether a major proteolytic pathway contributing to atrophy in multiple models of muscle wasting, the ubiquitin proteasome system (UPS), is involved in BoNT/A-induced atrophy. Three and ten days following BoNT/A injection of rat hindlimb, soleus muscle fiber cross-sectional area was reduced 25 and 65%, respectively. The transcriptional activity of NF-κB and Foxo was significantly elevated at 3 days (2- to 4-fold) and 10 days (5- to 6-fold). Muscle RING-finger protein-1 (MuRF1) activity was elevated (2-fold) after 3 days but not 10 days, while atrogin-1 activity was not elevated at any time point. BoNT/A-induced polyubiquitination occurred after 3 days (3-fold increase) but was totally absent after 10 days. Proteasome activity was elevated (1.5- to 2-fold) after 3 and 10 days. We employed the use of heat shock protein 70 (Hsp70) to inhibit NF-κB and Foxo transcriptional activity. Electrotransfer of Hsp70 into rat soleus, before BoNT/A administration, was insufficient to attenuate atrophy. It was also insufficient to decrease BoNT/A-induced Foxo activity at 3 days, although NF-κB activity was abolished. By 10 days both NF-κB and Foxo activation were abolished by Hsp70. Hsp70-overexpression was unable to alter the levels of BoNT/A-induced effects on MuRF1/atrogin-1, polyubiquitination, or proteasome activity. In conclusion, Hsp70 overexpression is insufficient to attenuate BoNT/A-induced atrophy. It remains unclear what proteolytic mechanism/s are contributing to BoNT/A-induced atrophy, although a Foxo-MuRF1-ubiquitin-proteasome contribution may exist, at least in early BoNT/A-induced atrophy. Further clarification of UPS involvement in BoNT/A-induced atrophy is warranted.
Hepatocellular Shuttling and Recirculation of Sorafenib-Glucuronide Is Dependent on Abcc2, Abcc3, and Oatp1a/1b
Authors: Vasilyeva Aksana , Durmus Selvi , Li Lie , Wagenaar Els , Hu Shuiying , Gibson Alice A. , Panetta John C. , Mani Sridhar , Sparreboom Alex , Baker Sharyn D. , Schinkel Alfred H.
Published: May 2015

Recently, an efficient liver detoxification process dubbed “hepatocyte hopping” was proposed on the basis of findings with the endogenous compound, bilirubin glucuronide. According to this model, hepatocytic bilirubin glucuronide can follow a liver-to-blood shuttling loop via Abcc3 transporter-mediated efflux and subsequent Oatp1a/1b-mediated liver uptake. We hypothesized that glucuronide conjugates of xenobiotics, such as the anticancer drug sorafenib, can also undergo hepatocyte hopping. Using transporter-deficient mouse models, we show here that sorafenib-glucuronide can be extruded from hepatocytes into the bile by Abcc2 or back into the systemic circulation by Abcc3, and that it can be taken up efficiently again into neighboring hepatocytes by Oatp1a/1b. We further demonstrate that sorafenib-glucuronide excreted into the gut lumen can be cleaved by microbial enzymes to sorafenib, which is then reabsorbed, supporting its persistence in the systemic circulation. Our results suggest broad relevance of a hepatocyte shuttling process known as “hepatocyte hopping”—a novel concept in clinical pharmacology—for detoxification of targeted cancer drugs that undergo hepatic glucuronidation, such as sorafenib. Cancer Res; 75(13); 2729–36. ©2015 AACR.
Cholesterol Levels in Blood and the Risk of Prostate Cancer: A Meta-analysis of 14 Prospective Studies
Authors: YuPeng Liu , YuXue Zhang , PengFei Li , Cheng Cheng , YaShuang Zhao , DaPeng Li , Chen Du
Published: May 2015

Background: As a neutral lipid and prominent component of the Western diet, cholesterol levels might be a risk factor for prostate cancer. However, current evidence has been inconsistent. This meta-analysis aimed to evaluate the association between blood cholesterol levels and the risk of prostate cancer.

Methods: An extensive search was performed in MEDLINE and EMBASE for prospective studies that have reported the association between total cholesterol (TC), high-density lipoprotein cholesterol (HDL), and low-density lipoprotein cholesterol (LDL) levels in blood and risk of prostate cancer. Random-effects models were used to summarize the study-specific results.

Results: Fourteen studies were included in this meta-analysis. In the meta-analysis, the summarized risk ratios (RR) for the highest to lowest cholesterol levels were as follows: 1.05 [95% confidence interval (CI), 0.97–1.14; P = 0.21] for TC, 0.93 (95% CI, 0.80–1.10; P = 0.40) for HDL, and 1.17 (95% CI, 0.88–1.55; P = 0.51) for LDL. When restricting to high-grade prostate cancer, the pooled RR was 1.32 (95% CI, 0.93–1.87; P = 0.13) for TC. In dose–response analyses, a 1 mmol/L increment in blood TC, HDL, and LDL level conferred an RR of 1.01 (95% CI, 0.99–1.02; P = 0.38), 0.98 (95% CI, 0.91–1.07; P = 0.72), and 1.04 (95% CI, 0.98–1.10; P = 0.24), respectively.

Conclusion: In this meta-analysis of 14 large prospective studies, blood TC, HDL, and LDL levels were not associated with the risk of either overall prostate cancer or high-grade prostate cancer.

Impact: Our findings did not appear to support the hypothesis that hypercholesterolemia increases the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev; 24(7); 1086–93. ©2015 AACR.
Heritability of Biomarkers of Oxidized Lipoproteins
Authors: Rao Fangwen , Schork Andrew J. , Maihofer Adam X. , Nievergelt Caroline M. , Marcovina Santica M. , Miller Elizabeth R. , Witztum Joseph L. , O’Connor Daniel T. , Tsimikas Sotirios
Published: May 2015

Objective—

To determine whether biomarkers of oxidized lipoproteins are genetically determined. Lipoprotein(a) (Lp[a]) is a heritable risk factor and carrier of oxidized phospholipids (OxPL).

Approach and Results—

We measured oxidized phospholipids on apolipoprotein B–containing lipoproteins (OxPL-apoB), Lp(a), IgG, and IgM autoantibodies to malondialdehyde-modified low-density lipoprotein, copper oxidized low-density lipoprotein, and apoB-immune complexes in 386 monozygotic and dizygotic twins to estimate trait heritability (
h
2
) and determine specific genetic effects among traits. A genome-wide linkage study followed by genetic association was performed. The
h
2
(scale: 0–1) for Lp(a) was 0.91±0.01 and for OxPL-apoB 0.87±0.02, which were higher than physiological, inflammatory, or lipid traits.
h
2
of IgM malondialdehyde-modified low-density lipoprotein, copper oxidized low-density lipoprotein, and apoB-immune complexes were 0.69±0.04, 0.67±0.05, and 0.80±0.03, respectively, and for IgG malondialdehyde-modified low-density lipoprotein, copper oxidized low-density lipoprotein, and apoB-immune complexes 0.62±0.05, 0.52±0.06, and 0.53±0.06, respectively. There was an inverse correlation between the major apo(a) isoform and OxPL-apoB (
R
=−0.49;
P
<0.001) and Lp(a) (
R
=−0.48;
P
<0.001) and OxPL-apoB was modestly correlated with Lp(a) (ρ=0.57;
P
<0.0001). The correlation in major apo(a) isoform size was concordant (
R
=1.0;
P
<0.001) among monozygotic twins but not dizygotic twins (
R
=0.40;
P
=0.055). Lp(a) and OxPL-apoB shared genetic codetermination (genetic covariance, ρG=0.774±0.032;
P
=1.09×10
−38
), although not environmental determination (environmental covariance, ρE=0.081±0.15;
P
=0.15). In contrast, Lp(a) shared environmental but not genetic codetermination with autoantibodies to malondialdehyde-modified low-density lipoprotein and copper oxidized low-density lipoprotein, and apoB-immune complexes. Sib-pair genetic linkage of the Lp(a) trait revealed that single nucleotide polymorphism rs10455872 was significantly associated with OxPL-apoB after adjusting for Lp(a).

Conclusions—

OxPL-apoB and other biomarkers of oxidized lipoproteins are highly heritable cardiovascular risk factors that suggest novel genetic origins of atherothrombosis.
Significant Association Between
CAV1
Variant rs3807989 on 7p31 and Atrial Fibrillation in a Chinese Han Population
Authors: Chen Shanshan , Wang Chuchu , Wang Xiaojing , Xu Chengqi , Wu Manman , Wang Pengxia , Tu Xin , Wang Qing K.
Published: May 2015

Background

Recent genome‐wide association studies (
GWAS
) in European ancestry populations revealed several genomic loci for atrial fibrillation
(AF)
. We previously replicated the 4q25 locus (

PITX
2

) and 16q22 locus (

ZFHX
3

) in the Chinese population, but not the

KCNN
3

locus on 1q21. With single‐nucleotide polymorphism rs3807989 in

CAV
1

encoding caveolin‐1, however, controversial results were reported in 2 Chinese replication studies.

Methods and Results

Six remaining
AF
genetic loci from
GWAS
, including rs3807989/

CAV
1

, rs593479/

PRRX
1

, rs6479562/
C9orf3
, rs10824026/

SYNPO
2L

, rs1152591/

SYNE
2

, and rs7164883/

HCN
4

, were analyzed in a Chinese Han population with 941 cases and 562 controls. Only rs3807989 showed significant association with
AF
(
P
adj
=4.77×10
−5
), and the finding was replicated in 2 other independent populations with 709 cases and 2175 controls, 463 cases and 644 controls, and the combined population with a total of 2113 cases and 3381 controls (
P
adj
=2.20×10
−9
; odds ratio [
OR
]=1.34 for major allele G). Meta‐analysis, together with data from previous reports in Chinese and Japanese populations, also showed a significant association between rs3807989 and
AF
(
P
=3.40×10
−4
;
OR
=1.24 for allele G). We also found that rs3807989 showed a significant association with lone
AF
in 3 independent populations and in the combined population (
P
adj
=3.85×10
−8
;
OR
=1.43 for major allele G).

Conclusions

The data in this study revealed a significant association between rs3807989 and
AF
in the Chinese Han population. Together with the findings that caveolin‐1 interacts with potassium channels Kir2.1,
KCNH
2, and
HCN
4 and sodium channels Nav1.5 and Nav1.8,

CAV
1

becomes a strong candidate susceptibility gene for
AF
across different ethnic populations. This study is the first to show a significant association between rs3807989 and lone
AF
.