bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of prepubertal nutrition on cellular apoptosis and proliferation in at term placenta of Anglo‐Nubian goats
Authors: Turiello María P. , Cristofolini Andrea L. , Fiorimanti Mariana R. , Diaz Tomás , Cavaglieri Lilia R. , Merkis Cecilia I. 
Published: December 2018

ContentsThe aim of this study was to evaluate the effect of feed restriction with or without monensin supplementation, followed by a re‐feeding period on cellular apoptosis and proliferation in at term placenta of Anglo‐Nubian goats. To evaluate the induction of apoptosis through the intrinsic pathway, proteins Bax and Bcl‐2 were determinated. The apoptosis was related with the cell proliferation indices through Ki67 determination. The treatments were applied for 250 days and were (a) ad libitum feeding (control; n = 5); (b) restricted feeding at 70% of control (restricted; n = 7); and (c) restricted with monensin supplementation (monensin; n = 7). After treatments, all the animals were fed to support their requirements. After parturition, 27 placentas were gathered. The placental cellular structure was studied by high‐resolution light microscopy and transmission electron microscopy; the cellular proliferation was determined by Ki67 index, and Bax and Bcl‐2 proteins were localized by immunohistochemical analysis. Differences in cell proliferation through the Ki67 index were found in monensin group placentas. Monensin supplementation stimulated the placental cell proliferation reversing the effect of feed restriction during the peripuberal period. A significant increase of Bcl‐2 in placentas of restricted group was found, and it would provide a protective effect on the placental structure. A lack of the Bcl‐2 protective effect was observed in control and monensin group placentas, probably meaning that the observed apoptosis would be induced through the intrinsic signalling pathway. A balance between apoptosis and cell proliferation is necessary to maintain tissue homoeostasis during caprine placental development.
Does regulation matter? A cross‐national analysis of the impact of gun policies on homicide and suicide rates
Authors: Hurka Steffen , Knill Christoph 
Published: December 2018

AbstractIn this contribution, we evaluate the effectiveness of firearm regulations in curbing the number of homicides and suicides committed both with and without firearms. We develop a gun control index that enables us to compare the restrictiveness of firearm regulations across time and space. We model the effects of gun control on figures of (gun) homicide and (gun) suicide gained from public health records in 16 West European countries between 1980 and 2010. We thus shift the analytical focus away from the United States, which can be considered an extreme case in many ways and analyze the effects of gun control in a least likely setting: a world region in which gun control is comparably strict to begin with. Our analysis demonstrates that stricter gun control entails a strong and robust negative effect not only on homicides and suicides committed with firearms, but also on overall homicide and suicide rates.
Instruction-Level Abstraction (ILA)
Authors: Huang Bo-Yuan , Zhang Hongce , Subramanyan Pramod , Vizel Yakir , Gupta Aarti , Malik Sharad 
Published: December 2018

Modern Systems-on-Chip (SoC) designs are increasingly heterogeneous and contain specialized semi-programmable accelerators in addition to programmable processors. In contrast to the pre-accelerator era, when the ISA played an important role in verification by enabling a clean separation of concerns between software and hardware, verification of these “accelerator-rich” SoCs presents new challenges. From the perspective of hardware designers, there is a lack of a common framework for formal functional specification of accelerator behavior. From the perspective of software developers, there exists no unified framework for reasoning about software/hardware interactions of programs that interact with accelerators.
This article addresses these challenges by providing a formal specification and high-level abstraction for accelerator functional behavior. It formalizes the concept of an Instruction Level Abstraction (ILA), developed informally in our previous work, and shows its application in modeling and verification of accelerators. This formal ILA extends the familiar notion of instructions to accelerators and provides a uniform, modular, and hierarchical abstraction for modeling software-visible behavior of both accelerators and programmable processors. We demonstrate the applicability of the ILA through several case studies of accelerators (for image processing, machine learning, and cryptography), and a general-purpose processor (RISC-V). We show how the ILA model facilitates equivalence checking between two ILAs, and between an ILA and its hardware finite-state machine (FSM) implementation. Further, this equivalence checking supports accelerator upgrades using the notion of ILA compatibility, similar to processor upgrades using ISA compatibility.
Role of the cytoskeleton in the development of a hypofibrotic cardiac fibroblast phenotype in volume overload heart failure
Authors: Childers Rachel C. , Sunyecz Ian , West T. Aaron , Cismowski Mary J. , Lucchesi Pamela A. , Gooch Keith J. 
Published: December 2018

Hemodynamic load regulates cardiac remodeling. In contrast to pressure overload (increased afterload), hearts subjected to volume overload (VO; preload) undergo a distinct pattern of eccentric remodeling, chamber dilation, and decreased extracellular matrix content. Critical profibrotic roles of cardiac fibroblasts (CFs) in postinfarct remodeling and in response to pressure overload have been well established. Little is known about the CF phenotype in response to VO. The present study characterized the phenotype of primary cultures of CFs isolated from hearts subjected to 4 wk of VO induced by an aortocaval fistula. Compared with CFs isolated from sham hearts, VO CFs displayed a “hypofibrotic” phenotype, characterized by a ~50% decrease in the profibrotic phenotypic markers α-smooth muscle actin, connective tissue growth factor, and collagen type I, despite increased levels of profibrotic transforming growth factor-β1 and an intact canonical transforming growth factor-β signaling pathway. Actin filament dynamics were characterized, which regulate the CF phenotype in response to biomechanical signals. Actin polymerization was determined by the relative amounts of G-actin monomers versus F-actin. Compared with sham CFs, VO CFs displayed ~78% less F-actin and an increased G-actin-to-F-actin ratio (G/F ratio). In sham CFs, treatment with the Rho kinase inhibitor Y-27632 to increase the G/F ratio resulted in recapitulation of the hypofibrotic CF phenotype observed in VO CFs. Conversely, treatment of VO CFs with jasplakinolide to decrease the G/F ratio restored a more profibrotic response (>2.5-fold increase in α-smooth muscle actin, connective tissue growth factor, and collagen type I). NEW & NOTEWORTHY The present study is the first to describe a “hypofibrotic” phenotype of cardiac fibroblasts isolated from a volume overload model. Our results suggest that biomechanical regulation of actin microfilament stability and assembly is a critical mediator of cardiac fibroblast phenotypic modulation.
Transient outward K+ current can strongly modulate action potential duration and initiate alternans in the human atrium
Authors: Ni Haibo , Zhang Henggui , Grandi Eleonora , Narayan Sanjiv M. , Giles Wayne R. 
Published: December 2018

Efforts to identify the mechanisms for the initiation and maintenance of human atrial fibrillation (AF) often focus on changes in specific elements of the atrial “substrate,” i.e., its electrophysiological properties and/or structural components. We used experimentally validated mathematical models of the human atrial myocyte action potential (AP), both at baseline in sinus rhythm (SR) and in the setting of chronic AF, to identify significant contributions of the Ca2+-independent transient outward K+ current ( Ito) to electrophysiological instability and arrhythmia initiation. First, we explored whether changes in the recovery or restitution of the AP duration (APD) and/or its dynamic stability (alternans) can be modulated by Ito. Recent reports have identified disease-dependent spatial differences in expression levels of the specific K+ channel α-subunits that underlie Ito in the left atrium. Therefore, we studied the functional consequences of this by deletion of 50% of native Ito (Kv4.3) and its replacement with Kv1.4. Interestingly, significant changes in the short-term stability of the human atrial AP waveform were revealed. Specifically, this K+ channel isoform switch produced discontinuities in the initial slope of the APD restitution curve and appearance of APD alternans. This pattern of in silico results resembles some of the changes observed in high-resolution clinical electrophysiological recordings. Important insights into mechanisms for these changes emerged from known biophysical properties (reactivation kinetics) of Kv1.4 versus those of Kv4.3. These results suggest new approaches for pharmacological management of AF, based on molecular properties of specific K+ isoforms and their changed expression during progressive disease. NEW & NOTEWORTHY Clinical studies identify oscillations (alternans) in action potential (AP) duration as a predictor for atrial fibrillation (AF). The abbreviated AP in AF also involves changes in K+ currents and early repolarization of the AP. Our simulations illustrate how substitution of Kv1.4 for the native current, Kv4.3, alters the AP waveform and enhances alternans. Knowledge of this “isoform switch” and related dynamics in the AF substrate may guide new approaches for detection and management of AF. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/k-channel-isoforms-regulate-human-atrial-arrhythmogenesis/ .
Effect of melatonin on EGF- and VEGF-induced monolayer permeability of HUVECs
Authors: Yang Ling , Zhang Yujie , Ma Yadong , Du Jun , Gu Luo , Zheng Lu , Zhang Xiaoying 
Published: December 2018

Melatonin is a natural hormone involved in the regulation of circadian rhythm, immunity, and cardiovascular function. In the present study, we focused on the mechanism of melatonin in the regulation of vascular permeability. We found that melatonin could inhibit both VEGF- and EGF-induced monolayer permeability of human umbilical vein endothelial cells (HUVECs) and change the tyrosine phosphorylation of vascular-endothelial (VE-)cadherin, which was related to endothelial barrier function. In addition, phospho-AKT (Ser473) and phospho-ERK(1/2) played significant roles in the regulation of VE-cadherin phosphorylation. Both the phosphatidylinositol 3-kinase/AKT inhibitor LY49002 and MEK/ERK inhibitor U0126 could inhibit the permeability of HUVECs, but with different effects on tyrosine phosphorylation of VE-cadherin. Melatonin can influence the two growth factor-induced phosphorylation of AKT (Ser473) but not ERK(1/2). Our results show that melatonin can inhibit growth factor-induced monolayer permeability of HUVECs by influencing the phosphorylation of AKT and VE-cadherin. Melatonin can be a potential treatment for diseases associated with abnormal vascular permeability.NEW & NOTEWORTHY We found that melatonin could inhibit both EGF- and VEGF-induced monolayer permeability of human umbilical vein endothelial cells, which is related to phosphorylation of vascular-endothelial cadherin. Blockade of phosphatidylinositol 3-kinase/AKT and MEK/ERK pathways could inhibit the permeability of human umbilical vein endothelial cells, and phosphorylation of AKT (Ser473) might be a critical event in the changing of monolayer permeability and likely has cross-talk with the MEK/ERK pathway.
Novel role of the ER/SR Ca2+sensor STIM1 in the regulation of cardiac metabolism
Authors: Collins Helen E. , Pat Betty M. , Zou Luyun , Litovsky Silvio H. , Wende Adam R. , Young Martin E. , Chatham John C. 
Published: December 2018

The endoplasmic reticulum/sarcoplasmic reticulum Ca2+sensor stromal interaction molecule 1 (STIM1), a key mediator of store-operated Ca2+entry, is expressed in cardiomyocytes and has been implicated in regulating multiple cardiac processes, including hypertrophic signaling. Interestingly, cardiomyocyte-restricted deletion of STIM1 (crSTIM1-KO) results in age-dependent endoplasmic reticulum stress, altered mitochondrial morphology, and dilated cardiomyopathy in mice. Here, we tested the hypothesis that STIM1 deficiency may also impact cardiac metabolism. Hearts isolated from 20-wk-oldcrSTIM1-KO mice exhibited a significant reduction in both oxidative and nonoxidative glucose utilization. Consistent with the reduction in glucose utilization, expression of glucose transporter 4 and AMP-activated protein kinase phosphorylation were all reduced, whereas pyruvate dehydrogenase kinase 4 and pyruvate dehydrogenase phosphorylation were increased, incrSTIM1-KO hearts. Despite similar rates of fatty acid oxidation in control andcrSTIM1-KO hearts ex vivo,crSTIM1-KO hearts contained increased lipid/triglyceride content as well as increased fatty acid-binding protein 4, fatty acid synthase, acyl-CoA thioesterase 1, hormone-sensitive lipase, and adipose triglyceride lipase expression compared with control hearts, suggestive of a possible imbalance between fatty acid uptake and oxidation. Insulin-mediated alterations in AKT phosphorylation were observed incrSTIM1-KO hearts, consistent with cardiac insulin resistance. Interestingly, we observed abnormal mitochondria and increased lipid accumulation in 12-wkcrSTIM1-KO hearts, suggesting that these changes may initiate the subsequent metabolic dysfunction. These results demonstrate, for the first time, that cardiomyocyte STIM1 may play a key role in regulating cardiac metabolism.NEW & NOTEWORTHY Little is known of the physiological role of stromal interaction molecule 1 (STIM1) in the heart. Here, we demonstrate, for the first time, that hearts lacking cardiomyocyte STIM1 exhibit dysregulation of both cardiac glucose and lipid metabolism. Consequently, these results suggest a potentially novel role for STIM1 in regulating cardiac metabolism.
Right coronary artery ligation in mice: a novel method to investigate right ventricular dysfunction and biventricular interaction
Authors: Sicard Pierre , Jouitteau Timothée , Andrade-Martins Thales , Massad Abdallah , Rodrigues de Araujo Glaucy , David Hélène , Miquerol Lucile , Colson Pascal , Richard Sylvain 
Published: December 2018

Right ventricular (RV) dysfunction can lead to complications after acute inferior myocardial infarction (MI). However, it is unclear how RV failure after MI contributes to left-sided dysfunction. The aim of the present study was to investigate the consequences of right coronary artery (RCA) ligation in mice. RCA ligation was performed in C57BL/6JRj mice ( n = 38). The cardiac phenotypes were characterized using high-resolution echocardiography performed up to 4 wk post-RCA ligation. Infarct size was measured using 2,3,5-triphenyltetrazolium chloride staining 24 h post-RCA ligation, and the extent of the fibrotic area was determined 4 wk after MI. RV dysfunction was confirmed 24 h post-RCA ligation by a decrease in the tricuspid annular plane systolic excursion ( P < 0.001) and RV longitudinal strain analysis ( P < 0.001). Infarct size measured ex vivo represented 45.1 ± 9.1% of the RV free wall. RCA permanent ligation increased the RV-to-left ventricular (LV) area ratio ( P < 0.01). Septum hypertrophy ( P < 0.01) was associated with diastolic septal flattening. During the 4-wk post-RCA ligation, LV ejection fraction was preserved, yet it was associated with impaired LV diastolic parameters ( E/ E′, global strain rate during early diastole). Histological staining after 4 wk confirmed the remodeling process with a thin and fibrotic RV. This study validates that RCA ligation in mice is feasible and induces RV heart failure associated with the development of LV diastolic dysfunction. Our model offers a new opportunity to study mechanisms and treatments of RV/LV dysfunction after MI. NEW & NOTEWORTHY Right ventricular (RV) dysfunction frequently causes complications after acute inferior myocardial infarction. How RV failure contributes to left-sided dysfunction is elusive because of the lack of models to study molecular mechanisms. Here, we created a new model of myocardial infarction by permanently tying the right coronary artery in mice. This model offers a new opportunity to unravel mechanisms underlying RV/left ventricular dysfunction and evaluate drug therapy.
HIF-1 regulation of miR-29c impairs SERCA2 expression and cardiac contractility
Authors: Williams Allison Lesher , Walton Chad B. , MacCannell Keith A. , Avelar Abigail , Shohet Ralph V. 
Published: December 2018

The principal regulator of cellular response to low oxygen is hypoxia-inducible factor (HIF)-1, which is stabilized in several forms of heart failure. Our laboratory developed a mouse strain in which a stable form of HIF-1 can be inducibly expressed in cardiomyocytes. Strikingly, these mice show a rapid decrease in cardiac contractility and a rapid loss of SERCA2 protein, which is also seen in heart failure. Interestingly, while the SERCA2 transcript decreased, it did not fully account for the observed decrease in protein. We therefore investigated whether HIF-1-regulated microRNA could impair SERCA translation. Multiple screening analyses identified the microRNA miR-29c to be substantially upregulated upon HIF-1 induction and to have complementarity to SERCA, and therefore be a potential regulator of SERCA2 expression in hypoxia. Subsequent evaluation confirmed that miR-29c reduced SERCA2 expression and Ca2+ reuptake. Additionally, administration of an antagonist sequence (antimir) improved cardiac contractility and SERCA2 expression in HIF transgenic mice. To extend the significance of these findings, we examined miR-29c expression in physiological hypoxia. Surprisingly, miR-29c decreased in these settings. We also treated mice with antimir before infarction to see if further suppression of miR-29c could improve cardiac function. While no improvement in contractility or SERCA2 was observed, reduction of heart size after infarction indicated that the antimir could modulate cardiac physiology. These results demonstrate that while a HIF-1-regulated microRNA, miR-29c, can reduce SERCA2 expression and contractility, additional factors in the ischemic milieu may limit these effects. Efforts to develop miRNA-based therapies will need to explore and account for these additional countervailing effects. NEW & NOTEWORTHY Our study demonstrated hypoxia-inducible factor-1-dependent upregulation of miR-29c, which, in turn, inhibited SERCA2 expression and reduced cardiac contractility in a transgenic overexpression system. Interestingly, these results were not recapitulated in a murine myocardial infarction model. These results underscore the complexity of the pathological environment and highlight the need for therapeutic target validation in physiologically relevant models. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/hif1-regulates-mir-29c-and-serca2/ .
Acute heat stress reduces biomarkers of endothelial activation but not macro- or microvascular dysfunction in cervical spinal cord injury
Authors: Coombs Geoff B. , Barak Otto F. , Phillips Aaron A. , Mijacika Tanja , Sarafis Zoe K. , Lee Amanda H. X. , Squair Jordan W. , Bammert Tyler D. , DeSouza Noah M. , Gagnon Daniel , Krassioukov Andrei V. , Dujic Zeljko , DeSouza Christopher A. , Ainslie Philip N. 
Published: December 2018

Cardiovascular diseases (CVD) are highly prevalent in spinal cord injury (SCI), and peripheral vascular dysfunction might be a contributing factor. Recent evidence demonstrates that exposure to heat stress can improve vascular function and reduce the risk of CVD in uninjured populations. We therefore aimed to examine the extent of vascular dysfunction in SCI and the acute effects of passive heating. Fifteen participants with cervical SCI and 15 uninjured control (CON) participants underwent ultrasound assessments of vascular function and venous blood sampling for biomarkers of endothelial activation (i.e., CD62e+) and apoptosis (i.e., CD31+/42b−) before and after a 60-min exposure to lower limb hot water immersion (40°C). In SCI, macrovascular endothelial function was reduced in the brachial artery [SCI: 4.8 (3.2)% vs. CON: 7.6 (3.4)%, P = 0.04] but not the femoral artery [SCI: 3.7 (2.6)% vs. CON: 4.0 (2.1)%, P = 0.70]. Microvascular function, via reactive hyperemia, was ~40% lower in SCI versus CON in both the femoral and brachial arteries ( P < 0.01). Circulating concentrations of CD62e+ were elevated in SCI versus CON [SCI: 152 (106) microparticles/µl vs. CON: 58 (24) microparticles/µl, P < 0.05]. In response to heating, macrovascular and microvascular function remained unchanged, whereas increases (+83%) and decreases (−93%) in antegrade and retrograde shear rates, respectively, were associated with heat-induced reductions of CD62e+ concentrations in SCI to levels similar to CON ( P = 0.05). These data highlight the potential of acute heating to provide a safe and practical strategy to improve vascular function in SCI. The chronic effects of controlled heating warrant long-term testing. NEW & NOTEWORTHY Individuals with cervical level spinal cord injury exhibit selectively lower flow-mediated dilation in the brachial but not femoral artery, whereas peak reactive hyperemia was lower in both arteries compared with uninjured controls. After 60 min of lower limb hot water immersion, femoral artery blood flow and shear patterns were acutely improved in both groups. Elevated biomarkers of endothelial activation in the spinal cord injury group decreased with heating, but these biomarkers remained unchanged in controls.
The scalar property during isochronous tapping is disrupted by a D2-like agonist in the nonhuman primate
Authors: Yc Karyna , Prado Luis , Merchant Hugo 
Published: December 2018

Dopamine, and specifically the D2 system, has been implicated in timing tasks where the absolute duration of individual time intervals is encoded discretely, yet the role of D2 during beat perception and entrainment remains largely unknown. In this type of timing, a beat is perceived as the pulse that marks equally spaced points in time and, once extracted, produces the tendency in humans to entrain or synchronize their movements to it. Hence, beat-based timing is crucial for musical execution. In this study we investigated the effects of systemic injections of quinpirole (0.005–0.05 mg/kg), a D2-like agonist, on the isochronous rhythmic tapping of rhesus monkeys, a classical task for the study of beat entrainment. We compared the rhythmic timing accuracy, precision, and the asynchronies of the monkeys with or without the effects of quinpirole, as well as their reaction times in a control serial reaction time task (SRTT). The results showed a dose-dependent disruption in the scalar property of rhythmic timing due to quinpirole administration. Specifically, we found similar temporal variabilities as a function of the metronome tempo at the largest dose, instead of the increase in variability across durations that is characteristic of the timing Weber law. Notably, these effects were not due to alterations in the basic sensorimotor mechanism for tapping to a sequence of flashing stimuli, because quinpirole did not change the reaction time of the monkeys during SRTT. These findings support the notion of a key role of the D2 system in the rhythmic timing mechanism, especially in the control of temporal precision. NEW & NOTEWORTHY Perceiving and moving to the beat of music is a fundamental trait of musical cognition. We measured the effect of quinpirole, a D2-like agonist, on the precision and accuracy of rhythmic tapping to a metronome in two rhesus monkeys. Quinpirole produced a flattening of the temporal variability as a function of tempo duration, instead of the increase in variability across durations that is characteristic of the scalar property, a hallmark property of timing.