bluuebunny/crossref_metadata_2025 huggingface dataset:
Unilateral movement preparation causes task‐specific modulation of TMS responses in the passive, opposite limb
Authors: Chye Lilian , Riek Stephan , de Rugy Aymar , Carson Richard G. , Carroll Timothy J.
Published: May 2018

Key points

Activity in the primary motor cortices of both hemispheres increases during unilateral movement preparation, but the functional role of ipsilateral motor cortex activity is unknown.

Ipsilateral motor cortical activity could represent subliminal ‘motor planning’ for the passive limb. Alternatively, it could represent the state of the active limb, to support coordination between the limbs should a bimanual movement be required.

Here we assessed how preparation of forces toward different directions, with the left wrist, alters evoked responses to transcranial magnetic stimulation of left motor cortex.

Preparation of a unilateral movement caused excitability increases in ipsilateral motor cortex that reflected forces produced with the active limb in an intrinsic (body‐centred), rather than an extrinsic (world‐centred), coordinate system.

These results suggest that ipsilateral motor cortical activity prior to unilateral action reflects the state of the active limb, rather than subliminal motor planning for the passive limb.

Corticospinal excitability is modulated for muscles on both sides of the body during unilateral movement preparation. For the effector, there is a progressive increase in excitability, and a shift in direction of muscle twitches evoked by transcranial magnetic stimulation (TMS) toward the impending movement. By contrast, the directional characteristics of excitability changes in the opposite (passive) limb have not been fully characterized. Here we assessed how preparation of voluntary forces towards four spatially distinct visual targets with the left wrist alters muscle twitches and motor‐evoked potentials (MEPs) elicited by TMS of left motor cortex. MEPs were facilitated significantly more in muscles homologous to agonist rather than antagonist muscles in the active limb, from 120 ms prior to voluntary EMG onset. Thus, unilateral motor preparation has a directionally specific influence on pathways projecting to the opposite limb that corresponds to the active muscles rather than the direction of movement in space. The directions of TMS‐evoked twitches also deviated toward the impending force direction of the active limb, according to muscle‐based coordinates, following the onset of voluntary EMG. The data indicate that preparation of a unilateral movement increases task‐dependent excitability in ipsilateral motor cortex, or its downstream projections, that reflects the forces applied by the active limb in an intrinsic (body‐centred), rather than an extrinsic (world‐centred), coordinate system. The results suggest that ipsilateral motor cortical activity prior to unilateral action reflects the state of the active limb, rather than subliminal motor planning for the passive limb.
Monolithic integration of patterned BaTiO3 thin films on Ge wafers
Authors: Ponath Patrick , Posadas Agham , Schmidt Michael , Kelleher Anne-Marie , White Mary , O'Connell Dan , Hurley Paul K. , Duffy Ray , Demkov Alexander A.
Published: May 2018

Titanates exhibit electronic properties highly desirable for field effect transistors such as very high permittivity and ferroelectricity. However, the difficulty of chemically etching titanates hinders their commercial use in device manufacturing. Here, the authors report the selective area in finestra growth of highly crystalline BaTiO3 (BTO) within photolithographically defined openings of a sacrificial SiO2 layer on a Ge (001) wafer by molecular beam epitaxy. After the BaTiO3 deposition, the sacrificial SiO2 can be etched away, revealing isolated nanoscale gate stacks circumventing the need to etch the titanate thin film. Reflection high-energy electron diffraction in conjunction with scanning electron microscopy is carried out to confirm the crystallinity of the samples. X-ray diffraction is performed to determine the out-of-plane lattice constant and crystal quality of the BTO film. Electrical measurements are performed on electrically isolated Pt/BaTiO3/SrTiO3/Ge capacitor devices.
A Kinetic Study of the Replacement by Site Saturation Mutagenesis of Residue 119 in NDM-1 Metallo-β-Lactamase
Authors: Marcoccia Francesca , Mercuri Paola Sandra , Galleni Moreno , Celenza Giuseppe , Amicosante Gianfranco , Perilli Mariagrazia
Published: May 2018

New Delhi metallo-β-lactamase 1 (NDM-1) is a subclass B1 metallo-β-lactamase that exhibits a broad spectrum of activity against β-lactam antibiotics. Here we report the kinetic study of 6 Q119X variants obtained by site-directed mutagenesis of NDM-1. All Q119X variants were able to hydrolyze carbapenems, penicillins and first-, second-, third-, and fourth-generation cephalosporins very efficiently. In particular, Q119E, Q119Y, Q119V, and Q119K mutants showed improvements in
k

cat
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K
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values for penicillins, compared with NDM-1. The catalytic efficiencies of the Q119K variant for benzylpenicillin and carbenicillin were about 65- and 70-fold higher, respectively, than those of NDM-1. The Q119K and Q119Y enzymes had
k
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K
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values for ceftazidime about 25- and 89-fold higher, respectively, than that of NDM-1.
Ten-year incidence of primary angle closure in elderly Chinese: the Liwan Eye Study
Authors: Wang Lanhua , Huang Wenyong , Huang Shengsong , Zhang Jian , Guo Xinxing , Friedman David S , Foster Paul J , He Mingguang
Published: May 2018

Purpose

To determine the 10-year incidence of all forms of primary angle closure (PAC) in phakic eyes and its risk factors in an urban Chinese population aged 50 years and older.

Methods

Survivors of 1405 baseline participants were invited to attend the 10-year follow-up visit in the Liwan Eye Study. Participants with established baseline angle closure, including primary angle closure suspects (PACS), PAC and primary angle closure glaucoma (PACG), or those who underwent bilateral cataract surgery during the 10-year period, as well as those who did not tolerate gonioscopic examinations, were excluded from this analysis. Incident PAC was present when those with open angles at baseline developed angle closure in any form in either eye during the 10-year period.

Results

Among 791 participants who returned during the 10-year follow-up visit, 620 (78.4%) provided data on PAC incidence. The 10-year cumulative incidence of any forms of PAC was 20.5% (127/620, 95% CI 17.4% to 24.9%), including 16.9%, 2.4% and 1.1% with incident PACS, PAC and PACG in either eye, respectively. In multiple logistic regression, significant risk factors for incident angle closure were greater baseline lens thickness (OR=1.82 per mm, p=0.003), shallower anterior chamber depth (OR=3.18 per mm decreased, p=0.010) and narrower angle width (OR=1.63 per decreased angle width, p<0.0001).

Conclusions

Approximately one in five people aged 50 years and older developed some form of angle closure over a 10-year period. Small ocular dimensions and hyperopia at baseline were associated with the development of angle closure.
New advances in amblyopia therapy I: binocular therapies and pharmacologic augmentation
Authors: Kraus Courtney L , Culican Susan M
Published: May 2018

Amblyopia therapy options have traditionally been limited to penalisation of the non-amblyopic eye with either patching or pharmaceutical penalisation. Solid evidence, mostly from the Pediatric Eye Disease Investigator Group, has validated both number of hours a day of patching and days per week of atropine use. The use of glasses alone has also been established as a good first-line therapy for both anisometropic and strabismic amblyopia. Unfortunately, visual acuity equalisation or even improvement is not always attainable with these methods. Additionally, non-compliance with prescribed therapies contributes to treatment failures, with data supporting difficulty adhering to full treatment sessions. Interest in alternative therapies for amblyopia treatment has long been a topic of interest among researchers and clinicians alike. Incorporating new technology with an understanding of the biological basis of amblyopia has led to enthusiasm for binocular treatment of amblyopia. Early work on perceptual learning as well as more recent enthusiasm for iPad-based dichoptic training have each generated interesting and promising data for vision improvement in amblyopes. Use of pharmaceutical augmentation of traditional therapies has also been investigated. Several different drugs with unique mechanisms of action are thought to be able to neurosensitise the brain and enhance responsiveness to amblyopia therapy. No new treatment has emerged from currently available evidence as superior to the traditional therapies in common practice today. But ongoing investigation into the use of both new technology and the understanding of the neural basis of amblyopia promises alternate or perhaps better cures in the future.
Determining the pneumococcal conjugate vaccine coverage required for indirect protection against vaccine-type pneumococcal carriage in low and middle-income countries: a protocol for a prospective observational study
Authors: Chan Jocelyn , Nguyen Cattram D , Lai Jana Y R , Dunne Eileen M , Andrews Ross , Blyth Christopher C , Datta Siddhartha , Fox Kim , Ford Rebecca , Hinds Jason , La Vincente Sophie , Lehmann Deborah , Lim Ruth , Mungun Tuya , Newton Paul N , Phetsouvanh Rattanaphone , Pomat Willam S , Xeuatvongsa Anonh , von Mollendorf Claire , Dance David A B , Satzke Catherine , Muholland Kim , Russell Fiona M
Published: May 2018

Introduction

Pneumococcal conjugate vaccines (PCVs) prevent disease through both direct protection of vaccinated individuals and indirect protection of unvaccinated individuals by reducing nasopharyngeal (NP) carriage and transmission of vaccine-type (VT) pneumococci. While the indirect effects of PCV vaccination are well described, the PCV coverage required to achieve the indirect effects is unknown. We will investigate the relationship between PCV coverage and VT carriage among undervaccinated children using hospital-based NP pneumococcal carriage surveillance at three sites in Asia and the Pacific.

Methods and analysis

We are recruiting cases, defined as children aged 2–59 months admitted to participating hospitals with acute respiratory infection in Lao People’s Democratic Republic, Mongolia and Papua New Guinea. Thirteen-valent PCV status is obtained from written records. NP swabs are collected according to standard methods, screened usinglytAqPCR and serotyped by microarray. Village-level vaccination coverage, for the resident communities of the recruited cases, is determined using administrative data or community survey. Our analysis will investigate the relationship between VT carriage among undervaccinated cases (indirect effects) and vaccine coverage using generalised estimating equations.

Ethics and dissemination

Ethical approval has been obtained from the relevant ethics committees at participating sites. The results are intended for publication in open-access peer-reviewed journals and will demonstrate methods suitable for low- and middle-income countries to monitor vaccine impact and inform vaccine policy makers about the PCV coverage required to achieve indirect protection.
Arrhythmias in adult patients with congenital heart disease and pulmonary arterial hypertension
Authors: Drakopoulou Maria , Nashat Heba , Kempny Aleksander , Alonso-Gonzalez Rafael , Swan Lorna , Wort Stephen J , Price Laura C , McCabe Colm , Wong Tom , Gatzoulis Michael A , Ernst Sabine , Dimopoulos Konstantinos
Published: May 2018

Objectives

Approximately 5%–10% of adults with congenital heart disease (CHD) develop pulmonary arterial hypertension (PAH), which affects life expectancy and quality of life. Arrhythmias are common among these patients, but their incidence and impact on outcome remains uncertain.

Methods

All adult patients with PAH associated with CHD (PAH-CHD) seen in a tertiary centre between 2007 and 2015 were followed for new-onset atrial or ventricular arrhythmia. Clinical variables associated with arrhythmia and their relation to mortality were assessed using Cox analysis.

Results

A total of 310 patients (mean age 34.9±12.3 years, 36.8% male) were enrolled. The majority had Eisenmenger syndrome (58.4%), 15.2% had a prior defect repair and a third had Down syndrome. At baseline, 14.2% had a prior history of arrhythmia, mostly supraventricular arrhythmia (86.4%). During a median follow-up of 6.1 years, 64 patients developed at least one new arrhythmic episode (incidence 3.47% per year), mostly supraventricular tachycardia or atrial fibrillation (78.1% of patients). Arrhythmia was associated with symptoms in 75.0% of cases. The type of PAH-CHD, markers of disease severity and prior arrhythmia were associated with arrhythmia during follow-up. Arrhythmia was a strong predictor of death, even after adjusting for demographic and clinical variables (HR 3.41, 95% CI 2.10 to 5.53, p<0.0001).

Conclusions

Arrhythmia is common in PAH-CHD and is associated with an adverse long-term outcome, even when managed in a specialist centre.
Ethical arguments for access to abortion services in the Republic of Ireland: recent developments in the public discourse
Authors: McCarthy Joan , O’Donnell Katherine , Campbell Louise , Dooley Dolores
Published: May 2018

The Republic of Ireland has some of the most restrictive abortion legislation in the world which grants to the ‘unborn’ an equal right to life to that of the pregnant woman. This article outlines recent developments in the public discourse on abortion in Ireland and explains the particular cultural and religious context that informs the ethical case for access to abortion services. Our perspective rests on respect for two very familiar moral principles – autonomy and justice – which are at the centre of social and democratic societies around the world. This article explains the context for the deployment of these concepts in order to support the claim that the current legislation and its operationalisation in clinical practice poses serious risks to the health, lives and well-being of pregnant women, tramples on their autonomy rights and requires of them a self-sacrifice that is unreasonable and unjust.
Exercise and circulating BDNF: Mechanisms of release and implications for the design of exercise interventions
Authors: Walsh Jeremy J. , Tschakovsky Michael E.
Published: May 2018

Engagement in regular bouts of exercise confers numerous positive effects on brain health across the lifespan. Acute bouts of exercise transiently improve cognitive function, while long-term exercise training stimulates brain plasticity, improves brain function, and helps to stave off neurological disease. The action of brain-derived neurotrophic factor (BDNF) is a candidate mechanism underlying these exercise-induced benefits and is the subject of considerable attention in the exercise–brain health literature. It is well established that acute exercise increases circulating levels of BDNF and numerous studies have sought to characterize this response for the purpose of improving brain health. Despite the interest in BDNF responses to exercise, little focus has been given to understanding the sources and mechanisms that underlie this response for the purpose of deliberately increasing circulating levels of BDNF. Here we review evidence to support that exploiting these mechanisms of BDNF release can help to optimize brain plasticity outcomes via exercise interventions, which could be especially relevant in the context of multimodal training (i.e., exercise and cognitive stimulation). Therefore, the purpose of this paper is to review the candidate sources of BDNF during exercise and the mechanisms of release. As well, we discuss strategies for maximizing BDNF responses to exercise, and propose novel research directions for advancing our understanding of these mechanisms.
Comparison of the μ(I) and HBP models for simulating granular media
Authors: Kheirkhahan Mehran , Hosseini Khosrow
Published: May 2018

Application of Lagrangian meshless methods in modeling granular flow has been a major concern for researchers due to their particular nature. For modeling granular movement, it is assumed that the particles are continuous. The SPHysics code is developed for modeling the movement of Newtonian fluids in which the pressure is derived from the state equation. In this study, [Formula: see text] and Herschel–Bulkley–Papanastasiou (HBP) viscoplastic models are implemented in the SPHysics code to analyze the movement of grains induced by the applied stresses. In the first model, the movement of granular particles is based on the characteristics such as inertia and friction coefficient, and in the second model, the movement is related to the non-Newtonian viscoplastic behavior of fluids. The accuracy of the models is evaluated by simulating the experimental benchmarks for granular dam break. The effect of length-to-height ratio on the failure mode of dam break phenomenon is also investigated. The performance of the models is increased by introducing the gate removal speed and also the harmonic mean of the viscosity instead of the viscosity proper to each particle. This study shows that the models could capture the behavior of grains in the static and the dynamic parts of the mass body.
3D Reconstruction for Road Scene with Obstacle Detection Feedback
Authors: Gao Huanbing , Liu Lei , Tian Ya , Lu Shouyin
Published: May 2018

This paper presented 3D reconstruction method for road scene with the help of obstacle detection. 3D reconstruction for road scene can be used in autonomous driving, driver assistance system, car navigation systems. However, some errors often rose when 3D reconstructing due to the shade from the moving object in the road scene. The presented 3D reconstruction method with obstacle detection feedback can avoid this problem. Firstly, this paper offers a framework for the 3D reconstruction of road scene by laser scanning and vision. A calibration method based on the location of horizon is proposed, and a method of attitude angle measuring based on vanishing point is proposed to revise the 3D reconstruction result. Secondly, the reconstruction framework is extended by integrating with an object recognition that can automatically detect and discriminate obstacles in the input video streams by a RANSAC approach and threshold filter, and localizes them in the 3D model. 3D reconstruction and obstacle detection are tightly integrated and benefit from each other. The experiment result verified the feasibility and practicability of the proposed method.
Genetic Algorithm-based Reliability Optimization for High-Level Synthesis
Authors: Tosun Suleyman , Yaran Tohid Taghizad Gogjeh
Published: May 2018

Soft errors (SEs) are a type of transient errors in integrated circuits (ICs) caused by radiation effects in the chips. They have become the major concern in IC design process in each CMOS technology generation since the decrease in supply voltage levels for shrinking transistor sizes makes the circuits more vulnerable than before. Previous studies generally use hardware redundancy for combinational circuits and error correcting codes for memory elements to mitigate or eliminate the SEs. However, adding extra hardware in final design may not always be possible if the design has tight area constraints. Different implementations of the same function may have different soft error rates (SERs) due to their error masking capabilities. Therefore, we can obtain various versions of the same function with different area, latency, and reliability values. Allocating the best resources to the operations of the design under area and latency constraints to optimize the overall system reliability has NP-complete time complexity. Evolutionary computing-based methods suit very well for this optimization problem. Motivated by this fact, in this paper, we present a genetic algorithm (GA)-based design method to increase the reliability of application-specific integrated circuits (ASICs). In this method, we use different versions of the same resources, each having a different area, latency, and reliability values. The goal of the GA-based optimizer is to allocate the best available resources to the application nodes to maximize the reliability of the design under tight area and latency constraints. Our experimental results show that we achieve up to 20.86% reliability improvement against a heuristic method with no additional area overhead. In order to further increase the reliability of the final design, we also propose a heuristic-based post-processing method, which adds duplicate resources to the final design without violating the constraint.
Efficient Design of ADC BIST with an Analog Ramp Signal Generation and Digital Error Estimation
Authors: Senthil Sivakumar M. , Joy Vasantha Rani S. P.
Published: May 2018

This paper presents the design of linear ramp generator and digital BIST for an on-chip ADC testing. It replaces the costly and time-consuming traditional mixed signal test methods like DSP-based testing, ATE, etc. The proposed on-chip analog ramp generator uses only a few transistors to generate linear ramp signal. A TIQ comparator based 8-bit flash ADC is taken under test. The output response of the ADC is analyzed in the digital BIST to measure the primary nonidealities affecting the linearity and accuracy of the data conversion. In testing, ADC generates the digital data sequence as a test pattern in response to the ramp input while digital BIST estimates the conversion error. This method does not require DAC and any additional components which increase the area overhead of ADC test. The complete design of ramp generator is integrated with TIQ flash ADC and verified in 0.18[Formula: see text][Formula: see text]m CMOS technology with 1.8[Formula: see text]V of the power supply and 100[Formula: see text]kHz of the input frequency. Measurement of nonidealities shows that the design of an 8-bit flash ADC has good accuracy in data conversion with the differential nonlinearity of [Formula: see text]0.24/[Formula: see text]0.17[Formula: see text]LSB and integral nonlinearity of [Formula: see text]0.44/[Formula: see text]0.04[Formula: see text]LSB.
Mitigation of PQ Issues Using an Enhanced UPQC-Based ANN Approach
Authors: Sivakumar M. , Kannan P. , Chenthur Pandian S.
Published: May 2018

Nowadays, the power quality (PQ)-related issues have become more prominent in power electronic devices. For compensating PQ disturbances various types of power devices are used. The unified power quality conditioner (UPQC) is one of the power electronic devices that is used for compensating the PQ. To reduce the PQ disturbances, the performance of series and shunt active power filters (APFs) must be improved. In this paper, an enhanced controller is proposed for improving the performance of series and shunt APFs and compensating the PQ. The enhanced technique used is the combination of artificial neural network (ANN) and gravitational search algorithm (GSA) which is used for generating the control signals of the APF and reducing the PQ problem. The shunt APF is used for reducing the harmonic disturbances. The DC-link voltage is regulated by utilizing the proposed enhanced controller technique. Subsequently, the THD value of the proposed system is measured. The proposed method is implemented in MATLAB/Simulink platform and its performance is evaluated. The performance of the proposed method is evaluated and compared with the base controller and ANN controller.
Interaction of spermine derivative porphyrin with DNA
Authors: Gangemi Chiara M. A. , D’Agostino Bruno , Randazzo Rosalba , Gaeta Massimiliano , Fragalà Maria E. , Purrello Roberto , D’Urso Alessandro
Published: May 2018

Porphyrinoids are ideal compounds to be incorporated into DNA due to their peculiar spectroscopic characteristics, fascinating photochemistry and synthetic versatility. The ability to act as photosensitizers in the presence of oxygen promoted interest of the scientific community to study the non-covalent binding of porphyrins with DNA in order to use them in photodynamic therapy. Thus, the understanding of the mechanisms involved in the binding of porphyrins with DNA can help to find a porphyrin with specific base degradation activity. In this work we characterized the binding modes of spermine derivative porphyrin with three different polynucleotides: ct-DNA, poly(dG-dC)[Formula: see text] in both B- and Z-conformation using several spectroscopic techniques (UV-vis, Electronic Circular Dichroism and Resonance Light Scattering).
On the 8-rank of narrow class groups of ℚ(−4pq), ℚ(−8pq), and ℚ(8pq)
Authors: Milovic Djordjo Z.
Published: May 2018

Let [Formula: see text]. We study the [Formula: see text]-part of the narrow class group in thin families of quadratic number fields of the form [Formula: see text], where [Formula: see text] are prime numbers, and we prove new lower bounds for the proportion of narrow class groups in these families that have an element of order [Formula: see text]. In the course of our proof, we prove a general double-oscillation estimate for the quadratic residue symbol in quadratic number fields.
Almost universal mixed sums of squares and polygonal numbers
Authors: Wu Hai-Liang
Published: May 2018

For each integer [Formula: see text], let [Formula: see text] denote the generalized [Formula: see text]-gonal number [Formula: see text] with [Formula: see text]. Given positive integers [Formula: see text] and an odd prime number [Formula: see text] with [Formula: see text], we employ the theory of ternary quadratic forms to determine completely when the mixed sum [Formula: see text] represents all but finitely many positive integers.
Behavioral Isolation and Incipient Speciation in Birds
Authors: Uy J. Albert C. , Irwin Darren E. , Webster Michael S.
Published: May 2018

Behavioral changes, such as those involved in mating, foraging, and migration, can generate reproductive barriers between populations. Birds, in particular, are known for their great diversity in these behaviors, and so behavioral isolation is often proposed to be the major driver of speciation. Here, we review empirical evidence to evaluate the importance of behavioral isolation in the early stages of avian speciation. Experimentally measured mating preferences indicate that changes in mating behavior can result in premating barriers, with their strength depending on the extent of divergence in mating signals. Differences in migratory and foraging behavior also can play important roles in generating reproductive barriers in the early stages of speciation. However, because premating behavioral isolation is imperfect, extrinsic postzygotic barriers, in the form of selection against hybrids having intermediate phenotypes, also play an important role in avian diversification, especially in completing the speciation process.
Transnational Corporations and Global Governance
Authors: Bartley Tim
Published: May 2018

Scholars and critics often lament that corporations rule the world, but predominant accounts of global governance imply almost the opposite: With theories populated by national governments and intergovernmental and nongovernmental organizations, it might appear that nearly everyone except corporations writes the rules that govern across borders. This article compiles research on the varied ways in which multinational and transnational corporations have shaped global governance, drawing attention to the contours and limits of corporate power. Corporations can be seen variously as sponsors, inhibitors, and direct providers of global governance. They have, for example, been sponsors of neoliberal trade rules, inhibitors of some labor and environmental regimes, and providers of private standards for finance, safety, sustainability, and human rights. Scholars may be tempted to focus on just one of these roles or to presume unified corporate dominance, but it is important to grapple with all three and to investigate the conditions under which corporate actions are more or less unified and decisive.
Boundary-Spanning in Social Movements: Antecedents and Outcomes
Authors: Wang Dan , Piazza Alessandro , Soule Sarah A.
Published: May 2018

Social movement scholarship has increasingly sought to understand the relational dynamics of internal movement activity, from investigating the factors that enable movement coalitions to analyzing the trade-offs of organizational hybridity. We bring these and other related phenomena together under the label of boundary-spanning processes. Specifically, we organize research on boundary-spanning in social movements by identifying three types of boundaries that have symbolic significance as categorical demarcations: ( a) issue and identity boundaries, ( b) organizational boundaries, and ( c) tactical boundaries. We then elucidate the tension in work that has examined how each form of boundary-spanning either promotes or hinders the realization of three important movement outcomes: ( a) mobilization, ( b) internal movement solidarity and scope, and ( c) external social and political change. We relate our three types of boundary-spanning to these three types of outcomes in an organizing framework to locate future opportunities for research on boundary-spanning in social movements.
Inhibitor of lysyl oxidase improves cardiac function and the collagen/MMP profile in response to volume overload
Authors: El Hajj Elia C. , El Hajj Milad C. , Ninh Van K. , Gardner Jason D.
Published: May 2018

The cardiac extracellular matrix is a complex architectural network that serves many functions, including providing structural and biochemical support to surrounding cells and regulating intercellular signaling pathways. Cardiac function is directly affected by extracellular matrix (ECM) composition, and alterations of the ECM contribute to the progression of heart failure. Initially, collagen deposition is an adaptive response that aims to preserve tissue integrity and maintain normal ventricular function. However, the synergistic effects of proinflammatory and profibrotic responses induce a vicious cycle, which causes excess activation of myofibroblasts, significantly increasing collagen deposition and accumulation in the matrix. Furthermore, excess synthesis and activation of the enzyme lysyl oxidase (LOX) during disease increases collagen cross-linking, which significantly increases collagen resistance to degradation by matrix metalloproteinases (MMPs). In the present study, the aortocaval fistula model of volume overload (VO) was used to determine whether LOX inhibition could prevent adverse changes in the ECM and subsequent cardiac dysfunction. The major findings from this study were that LOX inhibition 1) prevented VO-induced increases in left ventricular wall stress; 2) partially attenuated VO-induced ventricular hypertrophy; 3) completely blocked the increases in fibrotic proteins, including collagens, MMPs, and their tissue inhibitors; and 4) prevented the VO-induced decline in cardiac function. It remains unclear whether a direct interaction between LOX and MMPs exists; however, our experiments suggest a potential link between the two because LOX inhibition completely attenuated VO-induced increases in MMPs. Overall, our study demonstrated key cardioprotective effects of LOX inhibition against adverse cardiac remodeling due to chronic VO.

NEW & NOTEWORTHY Although the primary role of lysyl oxidase (LOX) is to cross-link collagens, we found that elevated LOX during cardiac disease plays a key role in the progression of heart failure. Here, we show that inhibition of LOX in volume-overloaded rats prevented the development of cardiac dysfunction and improved ventricular collagen and matrix metalloproteinase/tissue inhibitor of metalloproteinase profiles.
Effect of healthy aging and sex on middle cerebral artery blood velocity dynamics during moderate-intensity exercise
Authors: Ward Jaimie L. , Craig Jesse C. , Liu Yumei , Vidoni Eric D. , Maletsky Rebecca , Poole David C. , Billinger Sandra A.
Published: May 2018

Blood velocity measured in the middle cerebral artery (MCAV) increases with finite kinetics during moderate-intensity exercise, and the amplitude and dynamics of the response provide invaluable insights into the controlling mechanisms. The MCAVresponse after exercise onset is well fit to an exponential model in young individuals but remains to be characterized in their older counterparts. The responsiveness of vasomotor control degrades with advancing age, especially in skeletal muscle. We tested the hypothesis that older subjects would evince a slower and reduced MCAVresponse to exercise. Twenty-nine healthy young (25 ± 1 yr old) and older (69 ± 1 yr old) adults each performed a rapid transition from rest to moderate-intensity exercise on a recumbent stepper. Resting MCAVwas lower in older than young subjects (47 ± 2 vs. 64 ± 3 cm/s, P < 0.001), and amplitude from rest to steady-state exercise was lower in older than young subjects (12 ± 2 vs. 18 ± 3 cm/s, P = 0.04), even after subjects were matched for work rate. As hypothesized, the time constant was significantly longer (slower) in the older than young subjects (51 ± 10 vs. 31 ± 4 s, P = 0.03), driven primarily by older women. Neither age-related differences in fitness, end-tidal CO2, nor blood pressure could account for this effect. Thus, MCAVkinetic analyses revealed a marked impairment in the cerebrovascular response to exercise in older individuals. Kinetic analysis offers a novel approach to evaluate the efficacy of therapeutic interventions for improving cerebrovascular function in elderly and patient populations.

NEW & NOTEWORTHY Understanding the dynamic cerebrovascular response to exercise has provided insights into sex-related cerebrovascular control mechanisms throughout the aging process. We report novel differences in the kinetics response of cerebrovascular blood velocity after the onset of moderate-intensity exercise. The exponential increase in brain blood flow from rest to exercise revealed that 1) the kinetics profile of the older group was blunted compared with their young counterparts and 2) the older women demonstrated a slowed response.
Humanin analog enhances the protective effect of dexrazoxane against doxorubicin-induced cardiotoxicity
Authors: Lue Yanhe , Gao Chen , Swerdloff Ronald , Hoang James , Avetisyan Rozeta , Jia Yue , Rao Meng , Ren Shuxun , Atienza Vince , Yu Junyi , Zhang Ye , Chen Mengping , Song Yang , Wang Yibin , Wang Christina
Published: May 2018

The chemotherapeutic effect of doxorubicin (Dox) is limited by cumulative dose-dependent cardiotoxicity in cancer survivors. Dexrazoxane (DRZ) is approved to prevent Dox-induced cardiotoxicity. Humanin and its synthetic analog HNG have a cytoprotective effect on the heart. To investigate the cardioprotective efficacy of HNG alone or in combination with DRZ against Dox-induced cardiotoxicity, 80 adult male mice were randomly divided into 8 groups to receive the following treatments via intraperitoneal injection: saline daily, HNG (5 mg/kg) daily, DRZ (60 mg/kg) weekly, Dox (3 mg/kg) weekly, DRZ + HNG, Dox + HNG, Dox + DRZ, and Dox + HNG + DRZ. Echocardiograms were performed before and at 4, 8, and 9.5 wk after the beginning of treatment. All mice were euthanized at 10 wk. In the absence of Dox, HNG, DRZ, or DRZ + HNG had no adverse effect on the heart. Dox treatment caused decreases in ejection fraction and cardiac mass and increases in cardiomyocyte apoptosis and intracardiac fibrosis. HNG or DRZ alone blunted the Dox-induced decrease in left ventricle posterior wall thickness and modestly ameliorated the Dox-induced decrease in ejection fraction. HNG + DRZ significantly ameliorated Dox-induced decreases in ejection function, cardiac fibrosis, and cardiac mass. Using a targeted analysis for the mitochondrial gene array and protein expression in heart tissues, we demonstrated that HNG + DRZ reversed DOX-induced altered transcripts that were biomarkers of cardiac damage and uncoupling protein-2. We conclude that HNG enhances the cardiac protective effect of DRZ against Dox-induced cardiotoxicity. HNG + DRZ protects mitochondria from Dox-induced cardiac damage and blunts the onset of cardiac dysfunction. Thus, HNG may be an adjuvant to DRZ in preventing Dox-induced cardiotoxicity.

NEW & NOTEWORTHY Doxorubicin (Dox) is commonly used for treating a wide range of human cancers. However, cumulative dosage-dependent carditoxicity often limits its clinical applications. We demonstrated in this study that treating young adult male mice with synthetic humanin analog enhanced the cardiac protective effect of dexrazoxane against chemotherapeutic agent Dox-induced cardiac dysfunction. Thus, humanin analog can potentially serve as an adjuvant to dexrazoxane in more effectively preventing Dox-induced cardiac dysfunction and cardiomyopathy.
Gene expression profile analysis of aortic vascular smooth muscle cells reveals upregulation of cadherin genes in myocardial infarction patients
Authors: Derda Anselm A. , Woo Chin Cheng , Wongsurawat Thidathip , Richards Mark , Lee Chuen Neng , Kofidis Theo , Kuznetsov Vladimir A. , Sorokin Vitaly A.
Published: May 2018

Myocardial infarction (MI) induced by acute coronary arterial occlusion is usually secondary to atherosclerotic plaque rupture. Dysregulated response of vascular smooth muscle cells (VSMCs) in atherosclerotic plaques may promote plaque rupture. Cadherins (CDHs) form adherens junctions and are known stabilizers of atherosclerotic plaques. To date, the expression patterns of cadherin have not been well investigated in MI aortic VSMCs. We aimed to investigate the expression of cadherin genes in the aortic wall of patients with and without MI. Laser capture microdissected VSMCs were obtained from aortic tissue samples of patients undergoing coronary artery bypass graft surgery. Integrative bioinformatic analysis of the microarray profiles of the VSMCs revealed that MI is discriminated at the whole transcriptome level by hundreds of differentially expressed genes, including genes involved in cell adhesion, of which the cadherin superfamily genes were among the top structural category. Eleven significantly deregulated candidates of the cadherin superfamily were chosen and formed a new classifier that collectively discriminated MI vs. non-MI with ~95% accuracy. Significance validation was performed with an independent cohort by quantitative RT-quantitative PCR, confirming overexpression of CDH2, CDH12, PCDH17, and PCDH18 in MI VSMCs. The dysregulation of these cadherin superfamily genes might be related to an MI-induced remote effect on aortic wall VSMCs and to imbalances in signaling pathways and myocardial repair mechanisms. Although pathophysiological significance of our findings requires functional studies, mRNA upregulation of the identified cadherin superfamily members in VSMCs might be associated with the progression of atherosclerosis and angiogenesis activation in MI.
Involvement of human monogenic cardiomyopathy genes in experimental polygenic cardiac hypertrophy
Authors: Prestes P. R. , Marques F. Z. , Lopez-Campos G. , Lewandowski P. , Delbridge L. M. D. , Charchar F. J. , Harrap S. B.
Published: May 2018

Hypertrophic cardiomyopathy thickens heart muscles, reducing functionality and increasing risk of cardiac disease and morbidity. Genetic factors are involved, but their contribution is poorly understood. We used the hypertrophic heart rat (HHR), a unique normotensive polygenic model of cardiac hypertrophy and heart failure, to investigate the role of genes associated with monogenic human cardiomyopathy. We selected 42 genes involved in monogenic human cardiomyopathies to study: 1) DNA variants, by sequencing the whole genome of 13-wk-old HHR and age-matched normal heart rat (NHR), its genetic control strain; 2) mRNA expression, by targeted RNA-sequencing in left ventricles of HHR and NHR at 5 ages (2 days old and 4, 13, 33, and 50 wk old) compared with human idiopathic dilated cardiomyopathy data; and 3) microRNA expression, with rat microRNA microarrays in left ventricles of 2-day-old HHR and age-matched NHR. We also investigated experimentally validated microRNA-mRNA interactions. Whole-genome sequencing revealed unique variants mostly located in noncoding regions of HHR and NHR. We found 29 genes differentially expressed in at least 1 age. Genes encoding desmoglein 2 ( Dsg2) and transthyretin ( Ttr) were significantly differentially expressed at all ages in the HHR, but only Ttr was also differentially expressed in human idiopathic cardiomyopathy. Lastly, only two microRNAs differentially expressed in the HHR were present in our comparison of validated microRNA-mRNA interactions. These two microRNAs interact with five of the genes studied. Our study shows that genes involved in monogenic forms of human cardiomyopathies may also influence polygenic forms of the disease.
SHP-1 Acts as a Tumor Suppressor in Hepatocarcinogenesis and HCC Progression
Authors: Wen Liang-Zhi , Ding Kai , Wang Ze-Rui , Ding Chen-Hong , Lei Shu-Juan , Liu Jin-Pei , Yin Chuan , Hu Ping-Fang , Ding Jin , Chen Wan-Sheng , Zhang Xin , Xie Wei-Fen
Published: May 2018

Src homology region 2 (SH2) domain–containing phosphatase 1 (SHP-1, also known as PTPN6) is a nonreceptor protein tyrosine phosphatase that acts as a negative regulator of inflammation. Emerging evidence indicates that SHP-1 plays a role in inhibiting the progression of hepatocellular carcinoma (HCC). However, the role of SHP-1 in hepatocarcinogenesis remains unknown. Here, we find that levels of SHP-1 are significantly downregulated in human HCC tissues compared with those in noncancerous tissues (P < 0.001) and inversely correlate with tumor diameters (r = −0.4130, P = 0.0002) and serum α-fetoprotein levels (P = 0.047). Reduced SHP-1 expression was associated with shorter overall survival of patients with HCC with HBV infection. Overexpression of SHP-1 suppressed proliferation, migration, invasion, and tumorigenicity of HCC cells, whereas knockdown of SHP-1 enhanced the malignant phenotype. Moreover, knockout of Ptpn6 in hepatocytes (Ptpn6HKO) enhanced hepatocarcinogenesis induced by diethylnitrosamine (DEN) as well as metastasis of primary liver cancer in mice. Furthermore, systemic delivery of SHP-1 by an adenovirus expression vector exerted a therapeutic effect in an orthotopic model of HCC in NOD/SCID mice and DEN-induced primary liver cancers in Ptpn6HKO mice. In addition, SHP-1 inhibited the activation of JAK/STAT, NF-κB, and AKT signaling pathways, but not the MAPK pathway in primary hepatocytes from DEN-treated mice and human HCC cells. Together, our data implicate SHP-1 as a tumor suppressor of hepatocarcinogenesis and HCC progression and propose it as a novel prognostic biomarker and therapeutic target of HCC.

Significance: The nonreceptor protein tyrosine phosphatase SHP-1 acts as a tumor suppressor in hepatocellular carcinoma. Cancer Res; 78(16); 4680–91. ©2018 AACR.
Kidney Disease in Women is Associated with Disadvantaged Childhood Socioeconomic Position
Authors: Canney Mark , Leahy Siobhan , Scarlett Siobhan , Kenny Rose Anne , Little Mark A. , O’Seaghdha Conall M. , McCrory Cathal
Published: May 2018

Background: Socioeconomic position (SEP) is an important determinant of health and it is dynamic across the entire lifespan. We sought to investigate the relationship between life-course SEP and chronic kidney disease (CKD) using 3 conceptual models: critical period, pathway and accumulation. Methods: Cross-sectional analysis of 4,996 participants from The Irish Longitudinal Study on Ageing, a nationally representative cohort of community-dwelling adults aged ≥50 years. We defined childhood and adulthood SEP according to father’s and respondent’s occupation respectively. SEP was categorised as high (reference), intermediate, low and never worked. CKD was defined as a glomerular filtration rate < 60 mL/min/1.73 m2 estimated from the combination of creatinine and cystatin C. We used logistic regression to estimate the age-adjusted association between SEP and CKD separately in men and women. Results: Low childhood SEP was strongly associated with CKD in women, after adjusting for adulthood SEP (OR 1.90 [95% CI 1.24–2.92]), supporting the critical period hypothesis. This association was not explained by traditional CKD risk factors. Women who experienced low childhood SEP and whose circumstances improved in adulthood also had increased odds of CKD, further supporting a critical period effect in childhood. There was comparatively less evidence in support of the pathway or accumulation models. We did not observe a statistically significant association between SEP and CKD in men. Conclusions: Our findings suggest that women exposed to disadvantaged SEP in childhood represent an at-risk group in whom there may be opportunities for identification of CKD and facilitation of health-promoting behaviours from an early age.
Welche Rolle spielen Entzündungsfaktoren bei der altersabhängigen Makuladegeneration?
Authors: Strauss Olaf
Published: May 2018

Purpose: To evaluate the dynamic changes of the aqueous humor levels of inflammatory factors between patients receiving intravitreal ranibizumab injection (IRI) and aflibercept injection (IAI) in patients with exudative age-related macular degenera- tion (AMD). Methods: The study was performed on 30 eyes with AMD that were scheduled to receive 3 doses of IRI (15 eyes) or IAI (15 eyes) at monthly intervals. Aqueous humor samples were collected when injection was done. The concentrations of VEGF, mono- cyte chemoattractant protein 1 (MCP-1), platelet-derived growth factor (PDGF)-AA, interleukin (IL)-6, and IL-8 were measured in aqueous humor samples from the 30 AMD patients and 10 cataract patients (as controls) by the suspension array method. Results: Aqueous levels of the inflammatory factors (MCP-1, PDGF-AA, IL-6, and IL-8) were significantly correlated with each other. In both the IRI-treated eyes and the IAI-treated eyes, visual acuity and central macular thickness improved significantly, and the aqueous level of VEGF showed a significant decrease. In IAI-treated eyes, the aqueous levels of MCP-1 and PDGF-AA were significantly decreased at 2 months. Conclusions: These findings suggest that the inflammatory factors are involved in the pathogenesis of AMD and also the possibility that the interaction between these inflammatory factors and IRI or IAI is different.
Juveniles Glaukom: Mitomycin C oder Ologen®?
Authors: Rohrschneider Klaus
Published: May 2018

Background: We assessed bleb morphology and the intraocular pressure(IOP)-lowering effect of trabeculectomy with ologen compared to mitomycin C (MMC) in juvenile open-angle glaucoma (JOAG). Methods: This is a prospective interventional comparative study conducted on 40 eyes (20 patients) with medically uncontrolled JOAG, randomly operating one eye for trabeculectomy with ologen (group A: 20 eyes) and the other with MMC (group B: 20 eyes). IOP measurement, SITA standard perimetry, and spectral domain optical coherence tomography (OCT) for retinal nerve fiber layer (RNFL) thickness were all done pre- and postoperatively. Postoperative blebs were assessed clinically using the Moorfields bleb grading system (MBGS) and anterior segment OCT (AS-OCT). All patients were examined for up to 1 year postoperatively. Results: The mean postoperative IOP was statistically significantly lower than the mean preoperative IOP at each follow-up in each group. At 1 year, the mean postoperative IOP was significantly lower in group A. According to the MBGS, blebs with an ologen implant showed significantly better scoring than those with MMC. AS-OCT showed that ologen-induced blebs had significantly more fluid-filled spaces, cleavage planes, and less fibrosis. Conclusion: Ologen resulted in a lower long-term postoperative IOP, a better bleb morphology, and fewer complications. Our results suggest that ologen may be a useful alternative to MMC in JOAG.