bluuebunny/crossref_metadata_2025 huggingface dataset:
Elevated trawling inside protected areas undermines conservation outcomes in a global fishing hot spot
Authors: Dureuil Manuel , Boerder Kristina , Burnett Kirsti A. , Froese Rainer , Worm Boris
Published: December 2018

Not as advertised

Marine protected areas (MPAs) have increasingly designated globally, with an associated advertised percentage of area protected. However, recent research has made it clear that many MPAs are not actually protecting marine biodiversity. Dureuil
et al.
focused on European MPAs and found that trawling, one of the most damaging types of fishing, occurs widely in these areas. Furthermore, using sharks and rays as indicator species, they found that many MPAs are failing to protect vulnerable species.

Science
, this issue p.
1403
Structural adaptations of photosynthetic complex I enable ferredoxin-dependent electron transfer
Authors: Schuller Jan M. , Birrell James A. , Tanaka Hideaki , Konuma Tsuyoshi , Wulfhorst Hannes , Cox Nicholas , Schuller Sandra K. , Thiemann Jacqueline , Lubitz Wolfgang , Sétif Pierre , Ikegami Takahisa , Engel Benjamin D. , Kurisu Genji , Nowaczyk Marc M.
Published: December 2018

Plugging into the pump

Photosynthetic organisms use light to fix carbon dioxide in a process that requires both chemical reducing equivalents and adenosine triphosphate (ATP). Balancing the ratio of these inputs is accomplished by a short circuit in electron flow through photosynthetic complex I, a proton pump that contributes to ATP production but does not increase net reducing equivalents in the cell. Schuller
et al.
solved a cryo–electron microscopy structure of photosynthetic complex I (see the Perspective by Brandt) and went on to reconstitute electron transfer using the electron carrier protein ferredoxin.

Science
, this issue p.
257
; see also p.
230
A hidden cradle of plant evolution in Permian tropical lowlands
Authors: Blomenkemper Patrick , Kerp Hans , Abu Hamad Abdalla , DiMichele William A. , Bomfleur Benjamin
Published: December 2018

Late Permian seed-plant evolution

The great evolutionary expansion of seed plants took place in the Mesozoic era, which began after the Permian mass extinction 252 million years ago. Blomenkemper
et al.
report the discovery of seed-plant fossils from Late Permian (252-million- to 260-million-year-old) deposits on the margins of the Dead Sea in Jordan. This area represents an equatorial habitat with pronounced dry seasons. These fossils, which include the earliest records of conifers, push back the ages of several important seed-plant lineages. Some of these lineages appear to span the mass extinction event at the end of the Permian, which suggests that the communities they supported may have been more stable than expected over this transition. Thus, early evolutionary innovations can occur in drought-prone tropical habitats—which rarely offer the conditions needed for fossil preservation.

Science
, this issue p.
1414
Tessellating tiny tetrahedrons
Authors: Wu Siyu , Sun Yugang
Published: December 2018

A tiling rule guides the formation of quasicrystalline superlattices of nanocrystals
Exploring organisms cell by cell
Authors: Berg Jeremy
Published: December 2018

In an imaginary universe, you have discovered a set of planets, each with its own complex civilization with many culturally distinct nations. You face the daunting task of exploring each planet, mapping national boundaries, and characterizing different cultural features. In discussing this challenge with your colleagues, you come up with an alternative plan. You can divide each planet into small sectors, tag each sector for identification, send out many small probes to land in random locations and send back data, and then use the tagging information to computationally assemble the information into detailed atlases and travel guides.
Science
's Breakthrough of the Year recognizes the application of this tag-analyze-assemble approach to one of the most fundamental and fascinating processes in biology—the seemingly miraculous transformation of single cells into complex organisms—providing rich information about cell-type inventories and laying the foundation for many future studies.
Campylobacter coli
Clade 3 Isolates Induce Rapid Cell Death
In Vitro
Authors: Johansson Cecilia , Nilsson Anna , Kaden René , Rautelin Hilpi
Published: December 2018

Campylobacter coli
is a common zoonotic cause of gastroenteritis in humans worldwide. The majority of infections are caused by
C. coli
clade 1 isolates, whereas infections due to clade 2 and 3 isolates are rare. Whether this depends on a low prevalence of clade 2 and 3 isolates in reservoirs important for human infections or their lower ability to cause human disease is unknown. Here, we studied the effects of
C. coli
clade 2 and 3 isolates on a human cell line. These isolates adhered to human cells to a higher degree than clinical clade 1 isolates. Furthermore, we could show that
C. coli
clade 3 isolates rapidly induced cell death, suggesting differences in the virulence of
C. coli
. The exact mechanism of cell death remains to be revealed, but selected genes showed interesting clade-specific expression patterns.
Impact of External Quality Assurance on the Quality of Xpert MTB/RIF Testing in Viet Nam
Authors: Gumma Vidyanidhi , DeGruy Kyle , Bennett Davara , Nguyen Thi Kim Thanh , Albert Heidi , Bond Kyle B. , Gutreuter Steve , Alexander Heather , Ngyuen Thi Phong Lan , Rush Thomas H. , Nguyen Viet Nhung , Nguyen Van Hung
Published: December 2018

Following the endorsement of the Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, USA) by the World Health Organization (WHO) in 2010, Viet Nam’s National Tuberculosis Control Program (NTP) began using GeneXpert instruments in NTP laboratories. In 2013, Viet Nam’s NTP implemented an Xpert MTB/RIF external quality assurance (EQA) program in collaboration with the U.S.
Klotho protein inhibits H2O2-induced oxidative injury in endothelial cells via regulation of PI3K/AKT/Nrf2/HO-1 pathways
Authors: Cui Wei , Leng Bin , Wang GaoPin
Published: December 2018

Klotho protein secreted in the blood could act as a hormone to regulate various target organs and have a protective effect on the cardiovascular system. Numerous studies had shown that Klotho protein had antioxidative stress, anti-inflammatory, and antiapoptotic effects on vascular endothelial cells. The purpose of this study was to investigate the protective mechanism of Klotho protein on oxidative damage of vascular endothelial cells induced by H2O2. Klotho protein significantly enhanced human umbilical vein endothelial cells viability and increased the activities of antioxidant enzymes (superoxide dismutase, catalase, and heme oxygenase-1 (HO-1)), scavenged reactive oxygen species, and inhibited tumor necrosis factor alpha and interleukin 6 secretion. Klotho protein also reduced the rate of apoptosis of cells and improved the function of vascular endothelial cells (increased nitric oxide secretion). Klotho protein activated nuclear translocation of Nrf2 and increased HO-1 expression. Klotho protein also activated phosphorylation of protein kinase B (AKT), whereas the addition of LY294002, a pharmacological inhibitor of phosphatidylinositol 3-kinase (PI3K), blocked Klotho-protein-induced Nrf2/HO-1 activation and cytoprotection. Klotho protein enhanced the antioxidant defense ability of the cells by activating the PI3K/AKT pathway, which upregulated the expression of Nrf2/HO-1, thereby inhibiting H2O2-induced oxidative damage.
Influence of body size and familiarity on mating and reproductive parameters in the zig-zag ladybird beetle, Menochilus sexmaculatus (Coleoptera: Coccinellidae)
Authors: Singh Priya , Mishra Geetanjali , Omkar
Published: December 2018

Body size often indicates an individual’s quality and so mate selection is typically for larger individuals, including in ladybirds (Coccinellidae). Many organisms including ladybirds are also are known to refuse mating attempts with familiar individuals, but whether at the expense of mating with larger individuals is not clear. We assessed the cumulative effect of body size and familiarity on mating and reproductive behaviour in the zig-zag ladybird beetle (Menochilus sexmaculatus (Fabricius, 1781) = Cheilomenes sexmaculata (Fabricius, 1781)). For this study, individuals were separated into small- and large-bodied individuals and allowed to mate in all possible combinations. Furthermore, following the first mating, an immediate second mating was provided to the males, with either a familiar (same as in the first mating) or an unfamiliar (new female with the same mating status) female. Mating and reproductive parameters were recorded. The mating duration was longer with familiar partners than unfamiliar individuals. Mating duration was shorter for the second mating, suggesting that mating and ejaculate transfer are costly, to assure higher reproductive success. In this ladybird beetle, familiarity modified mating duration, whereas fecundity and egg viability were influenced by body size.
Predicting seasonal occurrence of leatherback turtles (Dermochelys coriacea) in eastern Canadian waters from turtle and ocean sunfish (Mola mola) sighting data and habitat characteristics
Authors: Mosnier A. , Gosselin J.-F. , Lawson J. , Plourde S. , Lesage V.
Published: December 2018

Part of the western Atlantic population of leatherback turtles (Dermochelys coriacea (Vandelli, 1761)) forage in Canadian waters, where high-use areas have been identified using satellite telemetry and opportunistic sightings. Here, we use sightings of leatherback turtles and ocean sunfish (Mola mola (Linnaeus, 1758)) obtained during a systematic large-scale aerial survey, along with opportunistic turtle sightings, to examine the seasonal occurrence and distribution of leatherback turtles in eastern Canada. Using environmental correlates, we predict the spatial and seasonal development of potentially suitable habitats. All data sets confirmed the presence of leatherback turtles off Nova Scotia during summer. They also highlighted turtle occurrence off southern Newfoundland. Opportunistic sightings suggest a seasonal shift in main turtle concentrations from southwest to northeast, with use of southern Newfoundland waters extending into September. A generalized additive model linking environmental characteristics and turtle observations suggests adding the Grand Banks off Newfoundland and waters east of Anticosti Island in the Gulf of St. Lawrence to the potentially important habitat for leatherback turtles. Direct observations helped delineate habitat currently used by leatherback turtles. In the context of climate change, this modelling approach may improve our ability to forecast changes in turtle habitat suitability and the risks of entrapment or collision associated with potentially changing usage patterns.
Competitive Learning: A New Meta-Heuristic Optimization Algorithm
Authors: Afroughinia Afshin , Kardehi Moghaddam Reihaneh
Published: December 2018

This work proposes a new powerful meta-heuristic optimization algorithm in education process called Competitive Learning (CLA). The algorithm is benchmarked on 8 well-known test functions, and the results are verified by a comparative study with some meta-heuristic optimization methods including: Imperialist Competitive Algorithm (ICA), Teaching-Learning-Based Optimization (TLBO), Grey Wolf Algorithm (GWO), Particle Swarm Optimization (PSO) and Genetic Algorithm (GA). Analyzing the findings, it is shown that the CLA algorithm is able to provide more accurate results than other well-known meta-heuristic ones. Also, those results applied to famous unimodal and multimodal benchmarks show CLA is efficient in improving accuracy as well as computational speed.
Visual Analytics of Heterogeneous Data Using Hypergraph Learning
Authors: Xie Cong , Zhong Wen , Xu Wei , Mueller Klaus
Published: December 2018

For real-world learning tasks (e.g., classification), graph-based models are commonly used to fuse the information distributed in diverse data sources, which can be heterogeneous, redundant, and incomplete. These models represent the relations in different datasets as pairwise links. However, these links cannot deal with high-order relations which connect multiple objects (e.g., in public health datasets, more than two patient groups admitted by the same hospital in 2014). In this article, we propose a visual analytics approach for the classification on heterogeneous datasets using the hypergraph model. The hypergraph is an extension to traditional graphs in which a hyperedge connects multiple vertices instead of just two. We model various high-order relations in heterogeneous datasets as hyperedges and fuse different datasets with a unified hypergraph structure. We use the hypergraph learning algorithm for predicting missing labels in the datasets. To allow users to inject their domain knowledge into the model-learning process, we augment the traditional learning algorithm in a number of ways. In addition, we also propose a set of visualizations which enable the user to construct the hypergraph structure and the parameters of the learning model interactively during the analysis. We demonstrate the capability of our approach via two real-world cases.
Harvesting Row-Buffer Hits via Orchestrated Last-Level Cache and DRAM Scheduling for Heterogeneous Multicore Systems
Authors: Song Yang , Alavoine Olivier , Lin Bill
Published: December 2018

In heterogeneous multicore systems, the memory subsystem, including the last-level cache and DRAM, is widely shared among the CPU, the GPU, and the real-time cores. Due to their distinct memory traffic patterns, heterogeneous cores result in more frequent cache misses at the last-level cache. As cache misses travel through the memory subsystem, two schedulers are involved for the last-level cache and DRAM, respectively. Prior studies treated the scheduling of the last-level cache and DRAM as independent stages. However, with no orchestration and limited visibility of memory traffic, neither scheduling stage is able to ensure optimal scheduling decisions for memory efficiency. Unnecessary precharges and row activations happen in DRAM when the memory scheduler is ignorant of incoming cache misses, and DRAM row-buffer states are invisible to the last-level cache. In this article, we propose a unified memory controller for the the last-level cache and DRAM with orchestrated schedulers. The memory scheduler harvests row-buffer hit opportunities in cache request buffers during spare time without inducing significant implementation cost. We further introduce a dynamic orchestrated scheduling policy to improve memory efficiency while achieving target CPU IPC. Extensive evaluations show that the proposed controller improves the total memory bandwidth of DRAM by 16.8% on average and saves DRAM energy by up to 29.7% while achieving comparable CPU IPCs. With the dynamic scheduling policy, the unified controller achieves the same IPC as the conventional design and increases DRAM bandwidth by 9.2%. In addition, we explore the potential of the proposed memory controller to attain improvements on both memory bandwidth and CPU IPC.
Optimization of Fault-Tolerant Mixed-Criticality Multi-Core Systems with Enhanced WCRT Analysis
Authors: Choi Junchul , Yang Hoeseok , Ha Soonhoi
Published: December 2018

This article proposes a novel optimization technique of fault-tolerant mixed-criticality multi-core systems with worst-case response time (WCRT) guarantees. Typically, in fault-tolerant multi-core systems, tasks can be
replicated
or
re-executed
in order to enhance the reliability. In addition, based on the policy of mixed-criticality scheduling, low-criticality tasks can be dropped at runtime. Such uncertainties caused by hardening and mixed-criticality scheduling make WCRT analysis very difficult. We show that previous analysis techniques are pessimistic as they consider avoidably extreme cases that can be safely ignored within the given reliability constraint. We improve the analysis in order to tighten the pessimism of WCRT estimates by considering the maximum number of faults to be tolerated. Further, we improve the mixed-criticality scheduling by allowing partial dropping of low-criticality tasks. On top of those, we explore the design space of hardening, task-to-core mapping, and quality-of-service of the multi-core mixed-criticality systems. The effectiveness of the proposed technique is verified by extensive experiments with synthetic and real-life benchmarks.
Automatic Optimization of the VLAN Partitioning in Automotive Communication Networks
Authors: Smirnov Fedor , Reimann Felix , Teich Jürgen , Glaß Michael
Published: December 2018

Dividing the communication network into so-called
Virtual Local Area Networks
(VLANs), i.e., subnetworks that are isolated at the data link layer (OSI layer 2), is a promising approach to address the increasing security challenges in automotive networks. The automation of the VLAN partitioning is a well-researched problem in the domain of local or metropolitan area networks. However, the approaches used there are hardly applicable for the design of automotive networks as they mainly focus on reducing the amount of broadcast traffic and cannot capture the many design objectives of automotive networks like the message timing or the link load, which are affected by the VLAN partitioning. As a remedy, this article proposes an approach based on a set of Pseudo-Boolean constraints to generate a message routing which is feasible with respect to the VLAN-related routing restrictions in automotive networks. This approach can be used for a design space exploration to optimize not only the VLAN partitioning but also other routing-related objectives. We demonstrate both the efficiency of our message routing approach and the now accessible optimization potential for the complete Electric/Electronic architecture with a mixed-criticality system from the automotive domain. There we thoroughly investigate the impact of the VLAN partitioning on the message timing and the link loads by optimizing these design objectives concurrently. During the exploration of the huge design space, where each resource can be assigned to one of four VLANs, our approach requires less than 40ms for the creation of a valid solution and ensures that all messages satisfy their deadlines and link load bounds.
Social Media Ethics
Authors: Bay Morten
Published: December 2018

Targeted social media advertising based on psychometric user profiling has emerged as an effective way of reaching individuals who are predisposed to accept and be persuaded by the advertising message. This article argues that in the case of political advertising, this may present a democratic and ethical challenge. Hypertargeting methods such as psychometrics can “crowd out” political communication with opposing views due to individual attention and time limitations, creating inequities in the access to information essential for voting decisions. The use of psychometrics also appears to have been used to spread both information and misinformation through social media in recent elections in the U.S. and Europe. This article is an applied ethics study of these methods in the context of democratic processes and compared to purely commercial situations. The ethical approach is based on the theoretical, contractarian work of John Rawls, which serves as a lens through which the author examines whether the rights of individuals, as Rawls attributes them, are violated by this practice. The article concludes that within a Rawlsian framework, use of psychometrics in commercial advertising on social media platforms, though not immune to criticism, is not necessarily unethical. In a democracy, however, the individual cannot abandon the consumption of political information, and since using psychometrics in political campaigning makes access to such information unequal, it violates Rawlsian ethics and should be regulated.
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.
Genetic and pharmacological inactivation of apical Na+-K+-2Cl− cotransporter 1 in choroid plexus epithelial cells reveals the physiological function of the cotransporter
Authors: Gregoriades Jeannine M. C. , Madaris Aaron , Alvarez Francisco J. , Alvarez-Leefmans Francisco J.
Published: December 2018

Choroid plexus epithelial cells (CPECs) secrete cerebrospinal fluid (CSF). They express Na+-K+-ATPase and Na+-K+-2Cl− cotransporter 1 (NKCC1) on their apical membrane, deviating from typical basolateral membrane location in secretory epithelia. Given this peculiarity, the direction of basal net ion fluxes mediated by NKCC1 in CPECs is controversial, and cotransporter function is unclear. Determining the direction of basal NKCC1-mediated fluxes is critical to understanding the function of apical NKCC1. If NKCC1 works in the net efflux mode, it may be directly involved in CSF secretion. Conversely, if NKCC1 works in the net influx mode, it would have an absorptive function, contributing to intracellular Cl− concentration ([Cl−]i) and cell water volume (CWV) maintenance needed for CSF secretion. We resolve this long-standing debate by electron microscopy (EM), live-cell-imaging microscopy (LCIM), and intracellular Na+ and Cl− measurements in single CPECs of NKCC1+/+ and NKCC1−/− mouse. NKCC1-mediated ion and associated water fluxes are tightly linked, thus their direction is inferred by measuring CWV changes. Genetic or pharmacological NKCC1 inactivation produces CPEC shrinkage. EM of NKCC1−/− CPECs in situ shows they are shrunken, forming large dilations of their basolateral extracellular spaces, yet remaining attached by tight junctions. Normarski LCIM shows in vitro CPECs from NKCC1−/− are ~17% smaller than NKCC1+/+. CWV measurements in calcein-loaded CPECs show that bumetanide (10 μM) produces ~16% decrease in CWV in NKCC1+/+ but not in NKCC1−/− CPECs. Our findings suggest that under basal conditions apical NKCC1 is continuously active and works in the net inward flux mode maintaining [Cl−]i and CWV needed for CSF secretion.
Oxidative modifications of mitochondrial complex II are associated with insulin resistance of visceral fat in obesity
Authors: Ngo Doan T. M. , Sverdlov Aaron L. , Karki Shakun , Macartney-Coxson Donia , Stubbs Richard S. , Farb Melissa G. , Carmine Brian , Hess Donald T. , Colucci Wilson S. , Gokce Noyan
Published: December 2018

Obesity, particularly visceral adiposity, has been linked to mitochondrial dysfunction and increased oxidative stress, which have been suggested as mechanisms of insulin resistance. The mechanism(s) behind this remains incompletely understood. In this study, we hypothesized that mitochondrial complex II dysfunction plays a role in impaired insulin sensitivity in visceral adipose tissue of subjects with obesity. We obtained subcutaneous and visceral adipose tissue biopsies from 43 subjects with obesity (body mass index ≥ 30 kg/m2) during planned bariatric surgery. Compared with subcutaneous adipose tissue, visceral adipose tissue exhibited decreased complex II activity, which was restored with the reducing agent dithiothreitol (5 mM) ( P < 0.01). A biotin switch assay identified that cysteine oxidative posttranslational modifications (OPTM) in complex II subunit A (succinate dehydrogenase A) were increased in visceral vs. subcutaneous fat ( P < 0.05). Insulin treatment (100 nM) stimulated complex II activity in subcutaneous fat ( P < 0.05). In contrast, insulin treatment of visceral fat led to a decrease in complex II activity ( P < 0.01), which was restored with addition of the mitochondria-specific oxidant scavenger mito-TEMPO (10 µM). In a cohort of 10 subjects with severe obesity, surgical weight loss decreased OPTM and restored complex II activity, exclusively in the visceral depot. Mitochondrial complex II may be an unrecognized and novel mediator of insulin resistance associated with visceral adiposity. The activity of complex II is improved by weight loss, which may contribute to metabolic improvements associated with bariatric surgery.
Increased circulating miR-370-3p regulates steroidogenic factor 1 in endometriosis
Authors: Hu Zhuoying , Mamillapalli Ramanaiah , Taylor Hugh S.
Published: December 2018

Endometriosis is a gynecologic disease common among reproductive-aged women caused by the growth of endometrial tissue outside the uterus. Altered expression of numerous genes and microRNAs has been reported in endometriosis. Steroidogenic factor 1 (SF-1), an essential transcriptional regulator of multiple genes involved in estrogen biosynthesis, is aberrantly increased and plays an important role in the pathogenesis of endometriosis. Here, we show the expression of SF-1 in endometriosis is regulated by miR-370-3p. Sera and tissue were collected from 20 women surgically diagnosed with endometriosis and 26 women without endometriosis. We found that miR-370-3p levels were decreased in the serum of patients with endometriosis while SF-1 mRNA levels were inversely upregulated in endometriotic lesions compared with respective controls. Transfection of primary endometriotic cells with miR-370-3p mimic or inhibitor resulted in the altered expression of SF-1 and SF-1 downstream target genes steroidogenic acute regulatory protein (StAR) and CYP19A1. Overexpression of miR-370-3p inhibited cell proliferation and induced apoptosis in endometriotic cells. This study reveals that miR-370-3p functions as a negative regulator of SF-1 and cell proliferation in endometriotic cells. We suggest a novel therapeutic strategy for controlling SF-1 in endometriosis.
miRNA-451a regulates RPE function through promoting mitochondrial function in proliferative diabetic retinopathy
Authors: Shao Yan , Dong Li-jie , Takahashi Yusuke , Chen Jianglei , Liu Xun , Chen Qian , Ma Jian-xing , Li Xiao-rong
Published: December 2018

The purpose of this study was to explore the role of microRNA-451a (miR-451a) in diabetic retinopathy through activating transcription factor 2 (ATF2). The epiretinal membrane samples from patients with proliferative diabetic retinopathy (PDR) were immunolabeled with an antibody for Ki-67 to identify the proliferative cells. The expression of miR-451a was measured by qRT-PCR in the retina of Akita mice and in RPE cells under diabetic conditions. The potential downstream targets of miR-451a were predicted by bioinformatics and confirmed by dual luciferase assay, qRT-PCR, and Western blotting. Mitochondrial function, cell proliferation, and migration assays were used to detect the functional change after transfection of miR-451a mimic and inhibitor. Proliferative RPE cells were identified in the epiretinal membrane from PDR patients. The expression of miR-451a was downregulated both in the retina of Akita mice and 4-hydroxynonenal (4-HNE)-treated RPE cells. Bioinformatic analysis and luciferase assay identified ATF2 as a potential target of miR-451a. miR-451a inhibited proliferation and migration of RPE cells. The mitochondrial function was enhanced by miR-451a mimic, but suppressed by miR-451a inhibitor. In diabetic conditions, miR-451a showed a protective effect on mitochondrial function. The results of qRT-PCR and Western blotting revealed that overexpression of miR-451a downregulated the expression of ATF2 and its downstream target genes CyclinA1, CyclinD1, and MMP2. In conclusion, miR-451a/ATF2 plays a vital role in the regulation of proliferation and migration in RPE cells through regulation of mitochondrial function, which may provide new perspectives for developing effective therapies for PDR.
Myostatin/SMAD4 signaling-mediated regulation of miR-124-3p represses glucocorticoid receptor expression and inhibits adipocyte differentiation
Authors: Liu Kaiqing , Zhang Xinbao , Wei Wei , Liu Xin , Tian Ye , Han Haiyin , Zhang Lifan , Wu Wangjun , Chen Jie
Published: December 2018

The mechanism of adipocyte regulation specifically in muscle and the influence of muscle tissue on intramuscular fat deposition are unknown. Our previous studies have shown that myostatin, a myokine, is involved in inhibiting the differentiation of preadipocytes and may be a potential regulator that affects the deposition of intramuscular fat. Myostatin inhibited adipogenesis by downregulating the expression of glucocorticoid receptor (GR) in porcine preadipocytes. However, the mechanism of regulation is not yet clear. In this study, we demonstrate microRNA (miR-124-3p) mediates regulation of GR by myostatin. We found that miR-124-3p can target GR 3'-UTR and negatively regulate GR expression. We demonstrate that overexpression of miR-124-3p can reduce differentiation of 3T3-L1 cells by inhibiting GR, and vice versa. The expression of miR-124-3p was upregulated in 3T3-L1 cells treated with myostatin. Further study revealed that myostatin also promotes the expression of SMAD4 and its transfer and localization to the nucleus. The activated myostatin/SMAD4 signal promotes the expression of miR-124-3p by SMAD4 binding to the promoter region of miR-124-3p. When myostatin or SMAD4 activity is inhibited, the upregulation of miR-124-3p is also inhibited. All of these findings suggested that myostatin could inhibit adipogenic differentiation of 3T3-L1 cells by activating miR-124-3p to inhibit GR. These data may provide an explanation for how myostatin signaling affects intramuscular fat deposition in a tissue-specific manner.
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.