bluuebunny/crossref_metadata_2025 huggingface dataset:
DC4CD
Authors: Gaglio Salvatore , Re Giuseppe Lo , Martorella Gloria , Peri Daniele
Published: December 2017

In this article, we present Distributed Computing for Constrained Devices (DC4CD), a novel software architecture that supports symbolic distributed computing on wireless sensor networks. DC4CD integrates the functionalities of a high-level symbolic interpreter, a compiler, and an operating system, and includes networking abstractions to exchange high-level symbolic code among peer devices. Contrarily to other architectures proposed in the literature, DC4CD allows for changes at runtime, even on deployed nodes of both application and system code. Experimental results show that DC4CD is more efficient in terms of memory usage than existing architectures, with which it also compares well in terms of execution efficiency.
Exploiting Approximate MLC-PCM in Low-Power Embedded Systems
Authors: Nodeh Mohammad Taghi Teimoori , Bazzaz Mostafa , Ejlali Alireza
Published: December 2017

Multi-level cell phase change memory (MLC-PCM), because of its very low leakage power and high density, is promising for embedded systems. Furthermore, for applications with inherent low sensitivity to errors, approximate write operations can be exploited in MLC-PCM to improve endurance and performance. However, data that reside in the approximate MLC-PCM for a rather long time without refreshing are prone to soft errors due to resistance drift phenomenon, while even for an application with inherent low sensitivity to errors, a high soft error rate can degrade its Quality of Result (QoR). The architecture-level approaches to decrease the drift effect incur considerable power overhead (about 100%), which is a prominent issue in embedded systems, and are dependent on the number of logic levels stored in the PCM cell (e.g., most of them are designed for 4LC-PCM). This article, taking a different approach, proposes a drift-aware frequency and voltage management to alleviate the drift-based soft-error rate. To this end, first we characterize the application data based on the degree of being exposed to the drift to identify the drift-prone application data. Then we assign the execution frequency and voltage to different regions of the application considering the drift. This frequency assignment speeds up the application regions wherein the drift-prone data are accessed to shorten the lifetime of the drift-prone data, thereby decreasing the soft error rate. An integer linear programming model implements our proposed Dynamic Voltage Frequency Scaling (DVFS). Also, the proposed approach is independent of the number of levels of PCM cells and can be applied to any MLC-PCM system. To evaluate the approach, the approximate MLC-PCM is simulated using empirical models and is integrated into a full-system simulator as data memory. The experimental results show that, by exploiting the approach, QoR is in the acceptable range, while its power overhead is about 84% (on average) less than that of the architecture-level approach.
Underminer
Authors: Balkan Ayca , Tabuada Paulo , Deshmukh Jyotirmoy V. , Jin Xiaoqing , Kapinski James
Published: December 2017

Evaluation of industrial embedded control system designs is a time-consuming and imperfect process. While an ideal process would apply a formal verification technique such as model checking or theorem proving, these techniques do not scale to industrial design problems, and it is often difficult to use these techniques to verify performance aspects of control system designs, such as stability or convergence. For industrial designs, engineers rely on testing processes to identify critical or unexpected behaviors. We propose a novel framework called
Underminer
to improve the testing process; this is an automated technique to identify nonconverging behaviors in embedded control system designs. Underminer treats the system as a black box and lets the designer indicate the model parameters, inputs, and outputs that are of interest. It differentiates convergent from nonconvergent behaviors using Convergence Classifier Functions (CCFs).

The tool can be applied in the context of testing models created late in the controller development stage, where it assumes that the given model displays mostly convergent behavior and learns a CCF in an unsupervised fashion from such convergent model behaviors. This CCF is then used to guide a thorough exploration of the model with the help of optimization-guided techniques or adaptive sampling techniques, with the goal of identifying rare nonconvergent model behaviors. Underminer can also be used early in the development stage, where models may have some significant nonconvergent behaviors. Here, the framework permits designers to indicate their mental model for convergence by labeling behaviors as convergent/nonconvergent and then constructs a CCF using a supervised learning technique. In this use case, the goal is to use the CCF to test an improved design for the model. Underminer supports a number of convergence-like notions, such as those based on Lyapunov analysis and temporal logic, and also CCFs learned directly from labeled output behaviors using machine-learning techniques such as support vector machines and neural networks. We demonstrate the efficacy of Underminer by evaluating its performance on several academic as well as industrial examples.
Simulation-Driven Reachability Using Matrix Measures
Authors: Fan Chuchu , Kapinski James , Jin Xiaoqing , Mitra Sayan
Published: December 2017

Simulation-driven verification can provide formal safety guarantees for otherwise intractable nonlinear and hybrid system models. A key step in simulation-driven algorithms is to compute the reach set overapproximations from a set of initial states through numerical simulations and sensitivity analysis. This article addresses this problem by providing algorithms for computing
discrepancy functions
as the upper bound on the sensitivity, that is, the rate at which trajectories starting from neighboring states converge or diverge. The algorithms rely on computing local bounds on matrix measures as the exponential change rate of the discrepancy function. We present two techniques to compute the matrix measures under different norms: regular Euclidean norm or Euclidean norm under coordinate transformation, such that the exponential rate of the discrepancy function, and therefore, the conservativeness of the overapproximation, is locally minimized. The proposed algorithms enable automatic reach set computations of general nonlinear systems and have been successfully used on several challenging benchmark models. All proposed algorithms for computing discrepancy functions give soundness and relative completeness of the overall simulation-driven safety-bounded verification algorithm. We present a series of experiments to illustrate the accuracy and performance of the algorithms.
A Majority-Based Reliability-Aware Task Mapping in High-Performance Homogenous NoC Architectures
Authors: Namazi Alireza , Abdollahi Meisam , Safari Saeed , Mohammadi Siamak
Published: December 2017

This article presents a new reliability-aware task mapping approach in a many-core platform at design time for applications with DAG-based task graphs. The main goal is to devise a task mapping which meets a predefined reliability threshold considering a minimized performance degradation. The proposed approach uses a majority-voting replication technique to fulfill error-masking capability. A quantitative reliability model is also proposed for the platform. Our platform is a homogenous many-core architecture with mesh-based interconnection using traditional deterministic XY routing algorithm. Our iterative approach is applicable to an unlimited number of system fault types. All parts of the platform, including cores, links, and routers, are assumed to be prone to failures. We used the MNLP optimization technique to find the optimal mapping of the presented task graph. Experimental results show that our suggested task mappings not only comply with predefined reliability thresholds but also achieve notable time complexity reduction with respect to exhaustive space exploration.
Editor's Note/Chairs' Welcome
Authors: Karahalios Karrie , Fitzpatrick Geraldine , Monroy-Hernández Andrés
Published: December 2017

Welcome to this issue of the Proceedings of the ACM on Human-Computer Interaction, which will focus on contributions from the research community Computer-Supported Cooperative Work and Social Computing (CSCW). This diverse research community explores how different types of social groups affect, and are affected by, information and communication technology. The topics explored by this community can include social media use, crowdsourcing and micro-work, societal effects of computing, and much more. Like many other HCI communities, CSCW approaches these topics with a broad range of scientific techniques, theoretical perspectives and technology platforms.

The call for papers for this issue on CSCW attracted 385 submissions, from Asia, Canada, Australia, Europe, Africa, and the United States. After the first round of reviewing, 207 (54%) papers were invited to the Revise and Resubmit phase. The editorial committee worked hard over August 2017 to arrive at final decisions, with a Virtual Committee meeting held to discuss those papers that needed collective deliberation. In the end, 105 papers (27%) were accepted.

This issue exists because of the dedicated volunteer effort of 101 senior editors who served as Associate Chairs (ACs), and 885 expert reviewers to ensure high quality and insightful reviews for all papers in both rounds. Reviewers and committee members were kept constant for papers that submitted to both rounds. Senior members of the editorial group also helped shepherd some papers, reflecting the deep commitment of this research community.

We are excited by the compelling and thought-provoking work that resulted in this PACMHCI CSCW issue and look forward to equally high quality submissions for the next submission cycle from this research community in the Spring of 2018. For those interested in this area, this group holds their next annual conference November 3-7, 2018 in New York City's Hudson River (Jersey City). That conference will provide many opportunities to share ideas with other researchers and practitioners from institutions around the world.
On Making Data Actionable
Authors: Alvarado Garcia Adriana , Young Alyson L. , Dombrowski Lynn
Published: December 2017

In this paper, we examine how activist organizations, focused on human rights violations (HRVs) in Mexico, obtain and translate data to produce actionable insight for social change. Through interviews with 15 participants working in think tanks, human rights centers, non-governmental organizations, and nonprofit organizations, we identified two key data challenges that impact their work: absent and conflicting data. We then describe how these nonprofits try to understand these issues by building alliances to address specific, detrimental knowledge and data gaps. Next, we articulate how these activists use data to work towards social change by informing citizens, requesting action, and building capacity. Lastly, we propose recommendations on how to design for HRVs-focused data practices, focusing on issues related to addressing technology and infrastructure constraints, designing for safety, and supporting community data collection and dissemination.
By the Community & For the Community
Authors: Chen Chunyang , Xing Zhenchang , Liu Yang
Published: December 2017

Community edits to questions and answers (called post edits) plays an important role in improving content quality in Stack Overflow. Our study of post edits in Stack Overflow shows that a large number of edits are about formatting, grammar and spelling. These post edits usually involve small-scale sentence edits and our survey of trusted contributors suggests that most of them care much or very much about such small sentence edits. To assist users in making small sentence edits, we develop an edit-assistance tool for identifying minor textual issues in posts and recommending sentence edits for correction. We formulate the sentence editing task as a machine translation problem, in which an original sentence is "translated" into an edited sentence. Our tool implements a character-level Recurrent Neural Network (RNN) encoder-decoder model, trained with about 6.8 millions original-edited sentence pairs from Stack Overflow post edits. We evaluate our edit assistance tool using a large-scale archival post edits, a field study of assisting a novice post editor, and a survey of trusted contributors. Our evaluation demonstrates the feasibility of training a deep learning model with post edits by the community and then using the trained model to assist post editing for the community.
Privacy Leakage in Event-based Social Networks
Authors: Chung Taejoong , Han Jinyoung , Choi Daejin , Kwon Ted Taekyoung , Rha Jong-Youn , Kim Hyunchul
Published: December 2017

Event-based social networks (EBSNs) are increasingly popular since they provide platforms on which online and offline activities are combined. Despite the increasing interest in EBSNs, little research has paid attention to the privacy issues coming from the unique features of EBSNs; the on-site information of users is highly relevant to real lives. In this paper, we try to investigate privacy leakages in Meetup, one of the most popular EBSN service. More specifically, we answer what private information can be inferred from the site's publicly available data. To this end, we conduct a measurement study by crawling webpages from Meetup containing 240K groups, 8.9M users, 27M group affiliations and 78M topical interests. By analyzing the dataset, we find that LGBT status of users, which is one of the most sensitive privacy information, can be predicted with 93% accuracy. Finally we discuss the cause of the privacy leakage on EBSNs and its possible ensuing damages.
Community Engagement Triage
Authors: Dittus Martin , Aiello Luca Maria , Quercia Daniele
Published: December 2017

Among platform designers there is still little actionable knowledge about how to foster community engagement, and new community platforms are likely to fail. Much research has documented effects that could inform better designs, however there is a lack of practical methods to review particular concerns. We design a lightweight method for systematic reviews of community engagement scenarios, based on a catalogue of 59 techniques, presented in the form of method cards, and co-developed with community engagement experts. We validate it in problem-solving workshops with organisers, and find that a full review is feasible in under 15 minutes, that it provides effective prompts and important guidance, and can successfully support process innovation. Finally, we validate it for use in summative evaluations of online communities. In a large-scale observational study of 1 million Flickr users, application of the method reveals the surprising impact of a major site redesign: it successfully increased content engagement, but at the expense of social interactions.
Upvote My News
Authors: Leavitt Alex , Robinson John J.
Published: December 2017

Citizen participation in crisis communication increasingly occurs in social media contexts. As some platforms -- e.g., social news sites -- evolve around collaborative voting, filtering, and information sharing, the aggregation of breaking news information during crisis situations appears more often as an emergent practice in these online communities. Drawing from 53 interviews and descriptive quantitative analysis of reddit posts and comments, this paper presents a qualitative case study examining reddit.com members aggregate information during crisis events within the context of reddit's post/comment structure, crowd voting, and ranking algorithms. Using the lens of network gatekeeping, the paper shows how participants evaluate sources, organize information, and verify details to demonstrate how different affordances and limitations of information production allow or restrict particular types of network gatekeeping.
Most Teens Bounce Back
Authors: McHugh Bridget Christine , Wisniewski Pamela J. , Rosson Mary Beth , Xu Heng , Carroll John M.
Published: December 2017

Cross-sectional research suggests that online risk exposure (e.g., cyberbullying, sexual solicitations, and explicit content) may negatively impact teens, increasing concerns over the risks teens are exposed to online. Yet, there has been little research as to how these experiences impact teens' mood over time, or how long these effects may last. To examine the effects of online risk exposure on mood, we asked 68 teens to report their weekly online risk experiences, emotions, and sense of well-being for two months. We found that teens experienced more negative emotions the week that they reported cyberbullying and exposure to explicit content, but these effects were gone one week later. In addition, teens reported a slight in crease in positive emotions and mental well-being during weeks they were exposed to other risks. Our results suggest that most of the risks teens in our study experienced online only pose brief negative effects, if any, and initiates a discussion on how our society may overly problematize the negative effects of online risk exposure on teens.
Preserving the Margins
Authors: Mugar Gabriel
Published: December 2017

Online participatory platforms like Wikipedia and Zooniverse are designed to welcome contributions from anyone, however, to contend with a high volume of contributions, a range of constraints are deployed that align opportunities for participation toward ends defined by the experts and leaders of such platforms. In this paper I draw on extensive ethnographic work to describe how users encounter and negotiate opportunities for participation on two participatory platforms, demonstrating how platforms can exhibit distinct spaces and opportunities for participation, in some cases heavily enforcing standards of practice defined by experts and leaders while also leaving room for emergent and even divergent and deviant behavior. In describing this tension between conditions of normative and deviant participation, I highlight the importance of supporting opportunities for deviant and emergent participation to occur, emphasizing that design which uniquely supports narrow modes of participation can prevent opportunities for more inclusionary practice and evolving objectives.
Care as a Resource in Underserved Learning Environments
Authors: Karusala Naveena , Vishwanath Aditya , Kumar Arkadeep , Mangal Aman , Kumar Neha
Published: December 2017

We present results from an ethnographic inquiry of technology-based learning at an after-school learning center in Mumbai (India) that caters to students from neighboring slum communities.We conducted participant observation for 120 hours and 58 semi-structured interviews with different stakeholders (including teachers, staff, parents, and students) at the center over nine weeks from December 2015 to July 2016. Taking an assets-based approach in an underserved context, we uncover the role of care as a resource and present the rich and varied caring behaviors enacted in this sociotechnical system.We then discuss how care effects a greater sense of ownership, interdependency, and community. Examining the role of aligning values in motivating caring behavior, we conclude with recommendations for supporting, leveraging, and extending care via technology design in an underserved, technology-enhanced learning environment.
Everyday Resilience
Authors: Vyas Dhaval , Dillahunt Tawanna
Published: December 2017

People experiencing financial hardship often possess resilient and resourceful behaviors when handling their day-to-day activities. Understanding how these individuals manifest resilience during adversity could provide insights into how technologies can support their existing efforts. In a partnership with an Australian community care center, we identified resilient practices of people with low socioeconomic status. Following a strength-based approach, we collected data via home visits and semi-structured interviews involving 14 participants, and observed activities at the care center over 8 months. Our participants exhibited three key facets of resilience: (1) resilience as an integral part of their everyday lives, (2) a spirited phenomenon, and (3) a social and care-focused process. We contribute empirical insights into our participants' situated resilience and articulate ways through which design can support their existing social and collaborative practices. We compare and contrast our findings within and outside CSCW literature and advocate for a strength-based approach.
Why Users Do Not Want to Write Together When They Are Writing Together
Authors: Wang Dakuo , Tan Haodan , Lu Tun
Published: December 2017

This study builds upon the 30-years HCI research of collaborative writing and focuses on users' experience of writing together in today's context. By interviewing 30 participants from both academia and industry, the paper examines how people write together using today's commercially available systems. The analysis focuses on the new co-editing capabilities (e.g., track changes) that are integrated into commercial tools and thus adopted by users widely in the last decade. These capabilities enable new ways of working together (e.g., directly edit the content at the character level at the same time), but users reported reluctance to fully commit to these new working styles. We thus systematically analyze users' rationales of why they do not want to write together while they are writing together with other. We argue that the development of collaborative writing tools is far from finished and these findings provide insights for the design of technology, and suggest future directions for research.
Social Media for Earthquake Response
Authors: Wong-Villacres Marisol , Velasquez Cristina M. , Kumar Neha
Published: December 2017

When a 7.8 intensity earthquake caused widespread disaster in Ecuador on April 16, 2016, citizens across the country self-organized to gather, mobilize, and distribute supplies to affected populations, assuming the role of
ad hoc
humanitarian logisticians. Drawing on ethnographic findings, we present a situated perspective of how these citizens straddled the boundaries of online and offline activity for earthquake relief. In doing so, we offer an enriched understanding of how various social media channels might support informal, on-the-ground, crisis response, but also where they fall short in the process. Studying the emergence of care where social media fell short allows us to make recommendations for technology design to improve the effectiveness of logisticians in crisis response. By examining the bodily engagement of our participants at crisis sites, their efforts to deal with material convergence, and how they interacted with social media for technology-mediated care, we also contribute an understanding of the sociomateriality of care that emerges amidst efforts towards crisis relief.
CG-OoO
Authors: Mohammadi Milad , Aamodt Tor M. , Dally William J.
Published: December 2017

We introduce the Coarse-Grain Out-of-Order (CG-OoO) general-purpose processor designed to achieve close to In-Order (InO) processor energy while maintaining Out-of-Order (OoO) performance. CG-OoO is an energy-performance-proportional architecture. Block-level code processing is at the heart of this architecture; CG-OoO speculates, fetches, schedules, and commits code at block-level granularity. It eliminates unnecessary accesses to energy-consuming tables and turns large tables into smaller, distributed tables that are cheaper to access. CG-OoO leverages compiler-level code optimizations to deliver efficient static code and exploits dynamic block-level and instruction-level parallelism. CG-OoO introduces Skipahead, a complexity effective, limited out-of-order instruction scheduling model. Through the energy efficiency techniques applied to the compiler and processor pipeline stages, CG-OoO closes 62% of the average energy gap between the InO and OoO baseline processors at the same area and nearly the same performance as the OoO. This makes CG-OoO 1.8× more efficient than the OoO on the energy-delay product inverse metric. CG-OoO meets the OoO nominal performance while trading off the peak scheduling performance for superior energy efficiency.
Heterogeneity of signal transduction by Na-K-ATPase α-isoforms: role of Src interaction
Authors: Yu Hui , Cui Xiaoyu , Zhang Jue , Xie Joe X. , Banerjee Moumita , Pierre Sandrine V. , Xie Zijian
Published: December 2017

Of the four Na-K-ATPase α-isoforms, the ubiquitous α1 Na-K-ATPase possesses both ion transport and Src-dependent signaling functions. Mechanistically, we have identified two putative pairs of domain interactions between α1 Na-K-ATPase and Src that are critical for α1 signaling function. Our subsequent report that α2 Na-K-ATPase lacks these putative Src-binding sites and fails to carry on Src-dependent signaling further supported our proposed model of direct interaction between α1 Na-K-ATPase and Src but fell short of providing evidence for a causative role. This hypothesis was specifically tested here by introducing key residues of the two putative Src-interacting domains present on α1 but not α2 sequence into the α2 polypeptide, generating stable cell lines expressing this mutant, and comparing its signaling properties to those of α2-expressing cells. The mutant α2 was fully functional as a Na-K-ATPase. In contrast to wild-type α2, the mutant gained α1-like signaling function, capable of Src interaction and regulation. Consistently, the expression of mutant α2 redistributed Src into caveolin-1-enriched fractions and allowed ouabain to activate Src-mediated signaling cascades, unlike wild-type α2 cells. Finally, mutant α2 cells exhibited a growth phenotype similar to that of the α1 cells and proliferated much faster than wild-type α2 cells. These findings reveal the structural requirements for the Na-K-ATPase to function as a Src-dependent receptor and provide strong evidence of isoform-specific Src interaction involving the identified key amino acids. The sequences surrounding the putative Src-binding sites in α2 are highly conserved across species, suggesting that the lack of Src binding may play a physiologically important and isoform-specific role.
Protein arginine methyltransferase expression, localization, and activity during disuse-induced skeletal muscle plasticity
Authors: Stouth Derek W. , Manta Alexander , Ljubicic Vladimir
Published: December 2017

Protein arginine methyltransferase 1 (PRMT1), PRMT4, and PRMT5 catalyze the methylation of arginine residues on target proteins. Previous work suggests that these enzymes regulate skeletal muscle plasticity. However, the function of PRMTs during disuse-induced muscle remodeling is unknown. The purpose of our study was to determine whether denervation-induced muscle disuse alters PRMT expression and activity in skeletal muscle, as well as to contextualize PRMT biology within the early disuse-evoked events that precede atrophy, which remain largely undefined. Mice were subjected to 6, 12, 24, 72, or 168 h of unilateral hindlimb denervation. Muscle mass decreased by ~30% after 72 or 168 h of neurogenic disuse, depending on muscle fiber type composition. The expression, localization, and activities of PRMT1, PRMT4, and PRMT5 were modified, exhibiting changes in gene expression and activity that were PRMT-specific. Rapid alterations in canonical muscle atrophy signaling such as forkhead box protein O1, muscle RING-finger protein-1, as well as peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) content, AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase, were observed before measurable decrements in muscle mass. Denervation-induced modifications in AMPK-PRMT1 and PGC-1α-PRMT1 binding revealed a novel, putative PRMT1-AMPK-PGC-1α signaling axis in skeletal muscle. Here, PGC-1α-PRMT1 binding was elevated after 6 h of disuse, whereas AMPK-PRMT1 interactions were reduced following 168 h of denervation. Our data suggest that PRMT biology is integral to the mechanisms that precede and initiate skeletal muscle atrophy during conditions of neurogenic disuse. This study furthers our understanding of the role of PRMTs in governing skeletal muscle plasticity.
Functional and structural characterization of a novel malignant hyperthermia-susceptible variant of DHPR-β1a subunit (CACNB1)
Authors: Perez Claudio F. , Eltit Jose M. , Lopez Jose R. , Bodnár Dóra , Dulhunty Angela F. , Aditya Shouvik , Casarotto Marco G.
Published: December 2017

Malignant hyperthermia (MH) susceptibility has been recently linked to a novel variant of β1a subunit of the dihydropyridine receptor (DHPR), a channel essential for Ca2+ regulation in skeletal muscle. Here we evaluate the effect of the mutant variant V156A on the structure/function of DHPR β1a subunit and assess its role on Ca2+ metabolism of cultured myotubes. Using differential scanning fluorimetry, we show that mutation V156A causes a significant reduction in thermal stability of the Src homology 3/guanylate kinase core domain of β1a subunit. Expression of the variant subunit in β1-null mouse myotubes resulted in increased sensitivity to caffeine stimulation. Whole cell patch-clamp analysis of β1a-V156A-expressing myotubes revealed a −2 mV shift in voltage dependence of channel activation, but no changes in Ca2+ conductance, current kinetics, or sarcoplasmic reticulum Ca2+ load were observed. Measurement of resting free Ca2+ and Na+ concentrations shows that both cations were significantly elevated in β1a-V156A-expressing myotubes and that these changes were linked to increased rates of plasmalemmal Ca2+ entry through Na+/Ca2+ exchanger and/or transient receptor potential canonical channels. Overall, our data show that mutant variant V156A results in instability of protein subdomains of β1a subunit leading to a phenotype of Ca2+ dysregulation that partly resembles that of other MH-linked mutations of DHPR α1S subunit. These data prove that homozygous expression of variant β1a-V156A has the potential to be a pathological variant, although it may require other gene defects to cause a full MH phenotype.
Customization of biliopancreatic limb length to modulate and sustain antidiabetic effect of gastric bypass surgery
Authors: Pal A. , Rhoads D. B. , Tavakkoli A.
Published: December 2017

Although Roux-en-Y Gastric Bypass (RYGB) remains the most effective treatment for obesity and type 2 diabetes (T2D), many patients fail to achieve remission, or relapse. Increasing intestinal limb lengths of RYGB may improve outcomes, but the mechanistic basis for this remains unclear. We hypothesize biliopancreatic (BP) limb length modulates the antidiabetic effect of RYGB. Rats underwent RYGB with a 20-cm (RYGB-20cm) or 40-cm (RYGB-40cm) BP limb and were compared with control animals. After 2 and 4 wk, portal and systemic blood was sampled during intestinal glucose infusion. Portosystemic gradient was used to calculate intestinal glucose utilization (Gutil), absorption (Gabsorp), and hormone secretion. Intestinal morphology and gene expression were assessed. At 2 wk, Gabsorp progressively decreased with increasing BP limb length; this pattern persisted at 4 wk. Gutil increased ≈70% in both RYGB-20cm and -40cm groups at 2 wk. At 4 wk, Gutil progressively increased with limb length. Furthermore, Roux limb weight, and expression of hexokinase and preproglucagon, exhibited a similar progressive increase. At 4 wk, glucagon-like peptide-1 and -2 levels were higher after RYGB-40cm, with associated increased secretion. We conclude that BP limb length modulates multiple antidiabetic mechanisms, analogous to the dose-response relationship of a drug. Early postoperatively, a longer BP limb reduces Gabsorp. Later, Gutil, Roux limb hypertrophy, hormone secretion, and hormone levels are increased with longer BP limb. Sustained high incretin levels may prevent weight regain and T2D relapse. These data provide the basis for customizing BP limb length according to patient characteristics and desired metabolic effect.

NEW & NOTEWORTHY Biliopancreatic limb length in gastric bypass modulates multiple antidiabetic mechanisms, analogous to the dose-response relationship of a drug. With a longer biliopancreatic limb, Roux limb hypertrophy, increased glucose utilization, reduced glucose absorption, and sustained high incretin levels may prevent weight regain and diabetes relapse.
The prorenin receptor in the cardiovascular system and beyond
Authors: Hennrikus Matthew , Gonzalez Alexis A. , Prieto Minolfa C.
Published: December 2017

Since the prorenin receptor (PRR) was first reported, its physiological role in many cellular processes has been under intense scrutiny. The PRR is currently recognized as a multifunctional receptor with major roles as an accessory protein of the vacuolar-type H+-ATPase and as an intermediary in the Wnt signaling pathway. As a member of the renin-angiotensin system (RAS), the PRR has demonstrated to be of relevance in cardiovascular diseases (CVD) because it can activate prorenin and enhance the enzymatic activity of renin, thus promoting angiotensin II formation. Indeed, there is an association between PRR gene polymorphisms and CVD. Independent of angiotensin II, the activation of the PRR further stimulates intracellular signals linked to fibrosis. Studies using tissues and cells from a variety of organs and systems have supported its roles in multiple functions, although some remain controversial. In the brain, the PRR appears to be involved in the central regulation of blood pressure via activation of RAS- and non-RAS-dependent mechanisms. In the heart, the PRR promotes atrial structural and electrical remodeling. Nonetheless, animals overexpressing the PRR do not exhibit cardiac injury. In the kidney, the PRR is involved in the development of ureteric bud branching, urine concentration, and regulation of blood pressure. There is great interest in the PRR contributions to T cell homeostasis and to the development of visceral and brown fat. In this mini-review, we discuss the evidence for the pathophysiological roles of the PRR with emphasis in CVD.
VEGF nanoparticles repair the heart after myocardial infarction
Authors: Oduk Yasin , Zhu Wuqiang , Kannappan Ramaswamy , Zhao Meng , Borovjagin Anton V. , Oparil Suzanne , Zhang Jianyi (Jay)
Published: December 2017

Vascular endothelial growth factor (VEGF) is a well-characterized proangiogenic cytokine that has been shown to promote neovascularization in hearts of patients with ischemic heart disease but can also lead to adverse effects depending on the dose and mode of delivery. We investigated whether prolonged exposure to a low dose of VEGF could be achieved by encapsulating VEGF in polylactic coglycolic acid nanoparticles and whether treatment with VEGF-containing nanoparticles improved cardiac function and protected against left ventricular remodeling in the hearts of mice with experimentally induced myocardial infarction. Polylactic coglycolic acid nanoparticles with a mean diameter of ~113 nm were generated via double emulsion and loaded with VEGF; the encapsulation efficiency was 53.5 ± 1.7% (107.1 ± 3.3 ng VEGF/mg nanoparticles). In culture, VEGF nanoparticles released VEGF continuously for at least 31 days, and in a murine myocardial infarction model, VEGF nanoparticle administration was associated with significantly greater vascular density in the peri-infarct region, reductions in infarct size, and improvements in left ventricular contractile function 4 wk after treatment. Thus, our study provides proof of principle that nanoparticle-mediated delivery increases the angiogenic and therapeutic potency of VEGF for the treatment of ischemic heart disease.

NEW & NOTEWORTHY Vascular endothelial growth factor (VEGF) is a well-characterized proangiogenic cytokine but has a short half-life and a rapid clearance rate. When encapsulated in nanoparticles, VEGF was released for 31 days and improved left ventricular function in infarcted mouse hearts. These observations indicate that our new platform increases the therapeutic potency of VEGF.
Extracellular retention of PDGF-B directs vascular remodeling in mouse hypoxia-induced pulmonary hypertension
Authors: Tannenberg Philip , Chang Ya-Ting , Muhl Lars , Laviña Bàrbara , Gladh Hanna , Genové Guillem , Betsholtz Christer , Folestad Erika , Tran-Lundmark Karin
Published: December 2017

Pulmonary hypertension (PH) is a lethal condition, and current vasodilator therapy has limited effect. Antiproliferative strategies targeting platelet-derived growth factor (PDGF) receptors, such as imatinib, have generated promising results in animal studies. Imatinib is, however, a nonspecific tyrosine kinase inhibitor and has in clinical studies caused unacceptable adverse events. Further studies are needed on the role of PDGF signaling in PH. Here, mice expressing a variant of PDGF-B with no retention motif ( Pdgfbret/ret), resulting in defective binding to extracellular matrix, were studied. Following 4 wk of hypoxia, right ventricular systolic pressure, right ventricular hypertrophy, and vascular remodeling were examined. Pdgfbret/retmice did not develop PH, as assessed by hemodynamic parameters. Hypoxia did, however, induce vascular remodeling in Pdgfbret/retmice; but unlike the situation in controls where the remodeling led to an increased concentric muscularization of arteries, the vascular remodeling in Pdgfbret/retmice was characterized by a diffuse muscularization, in which cells expressing smooth muscle cell markers were found in the interalveolar septa detached from the normally muscularized intra-acinar vessels. Additionally, fewer NG2-positive perivascular cells were found in Pdgfbret/retlungs, and mRNA analyses showed significantly increased levels of Il6 following hypoxia, a known promigratory factor for pericytes. No differences in proliferation were detected at 4 wk. This study emphasizes the importance of extracellular matrix-growth factor interactions and adds to previous knowledge of PDGF-B in PH pathobiology. In summary, Pdgfbret/retmice have unaltered hemodynamic parameters following chronic hypoxia, possibly secondary to a disorganized vascular muscularization.
Transcriptional survey of alveolar macrophages in a murine model of chronic granulomatous inflammation reveals common themes with human sarcoidosis
Authors: Mohan Arjun , Malur Anagha , McPeek Matthew , Barna Barbara P. , Schnapp Lynn M. , Thomassen Mary Jane , Gharib Sina A.
Published: December 2017

To advance our understanding of the pathobiology of sarcoidosis, we developed a multiwall carbon nanotube (MWCNT)-based murine model that shows marked histological and inflammatory signal similarities to this disease. In this study, we compared the alveolar macrophage transcriptional signatures of our animal model with human sarcoidosis to identify overlapping molecular programs. Whole genome microarrays were used to assess gene expression of alveolar macrophages in six MWCNT-exposed and six control animals. The results were compared with the transcriptional profiles of alveolar immune cells in 15 sarcoidosis patients and 12 healthy humans. Rigorous statistical methods were used to identify differentially expressed genes. To better elucidate activated pathways, integrated network and gene set enrichment analysis (GSEA) was performed. We identified over 1,000 differentially expressed between control and MWCNT mice. Gene ontology functional analysis showed overrepresentation of processes primarily involved in immunity and inflammation in MCWNT mice. Applying GSEA to both mouse and human samples revealed upregulation of 92 gene sets in MWCNT mice and 142 gene sets in sarcoidosis patients. Commonly activated pathways in both MWCNT mice and sarcoidosis included adaptive immunity, T-cell signaling, IL-12/IL-17 signaling, and oxidative phosphorylation. Differences in gene set enrichment between MWCNT mice and sarcoidosis patients were also observed. We applied network analysis to differentially expressed genes common between the MWCNT model and sarcoidosis to identify key drivers of disease. In conclusion, an integrated network and transcriptomics approach revealed substantial functional similarities between a murine model and human sarcoidosis particularly with respect to activation of immune-specific pathways.
Elastase alters contractility and promotes an inflammatory synthetic phenotype in airway smooth muscle tissues
Authors: Lockett Angelia D. , Wu Yidi , Gunst Susan J.
Published: December 2017

Neutrophil elastase is secreted by inflammatory cells during airway inflammation and can elicit airway hyperreactivity in vivo. Elastase can degrade multiple components of the extracellular matrix. We hypothesized that elastase might disrupt the connections between airway smooth muscle (ASM) cells and the extracellular matrix and that this might have direct effects on ASM tissue responsiveness and inflammation. The effect of elastase treatment on ASM contractility was assessed in vitro in isolated strips of canine tracheal smooth muscle by stimulation of tissues with cumulatively increasing concentrations of acetylcholine (ACh) and measurement of contractile force. Elastase treatment potentiated contractile responses to ACh at low concentrations but suppressed the maximal contractile force generated by the tissues without affecting the phosphorylation of myosin regulatory light chain (RLC). Elastase also promoted the secretion of eotaxin and the activation of Akt in ASM tissues and decreased expression of smooth muscle myosin heavy chain, consistent with promotion of a synthetic inflammatory phenotype. As the degradation of matrix proteins can alter integrin engagement, we evaluated the effect of elastase on the assembly and activation of integrin-associated adhesion junction complexes in ASM tissues. Elastase led to talin cleavage, reduced talin binding to vinculin, and suppressed activation of the adhesome proteins paxillin, focal adhesion kinase, and vinculin, indicating that elastase causes the disassembly of adhesion junction complexes and the inactivation of adhesome signaling proteins. We conclude that elastase promotes an inflammatory phenotype and increased sensitivity to ACh in ASM tissues by disrupting signaling pathways mediated by integrin-associated adhesion complexes.
Heme oxygenase-1 is a potent inhibitor of placental ischemia-mediated endothelin-1 production in cultured human glomerular endothelial cells
Authors: Bakrania Bhavisha A. , Spradley Frank T. , Satchell Simon C. , Stec David E. , Rimoldi John M. , Gadepalli Rama S. V. , Granger Joey P.
Published: December 2017

Preeclampsia is a pregnancy-specific disorder of maternal hypertension and reduced renal hemodynamics linked to reduced endothelial function. Placental ischemia is thought to be the culprit of this disease, as it causes the release of factors like tumor necrosis factor (TNF)-α that induce vascular endothelin-1 (ET-1) production. Interestingly, placental ischemia-induced hypertension in rats [reduced uterine perfusion pressure (RUPP) model] is abolished by ETA receptor blockade, suggesting a critical role for ET-1. Although it has been found that systemic induction of heme oxygenase (HO)-1 is associated with reduced ET-1 production and attenuated hypertension, it is unclear whether HO-1 directly modulates the increased ET-1 response to placental factors. We tested the hypothesis that HO-1 or its metabolites inhibit ET-1 production in human glomerular endothelial cells induced by serum of RUPP rats or TNF-α. Serum (5%) from RUPP hypertensive (mean arterial blood pressure 119 ± 9 mmHg) vs. normotensive pregnant (NP, 101 ± 6 mmHg, P < 0.001) rats increased ET-1 production (RUPP 168.8 ± 18.1 pg/ml, NP 80.3 ± 22.7 pg/ml, P < 0.001, n = 12/group). HO-1 induction [25 µM cobalt photoporphyrin (CoPP)] abolished RUPP serum-induced ET-1 production (1.6 ± 0.8 pg/ml, P < 0.001), whereas bilirubin (10 µM) significantly attenuated ET-1 release (125.3 ± 5.2 pg/ml, P = 0.005). Furthermore, TNF-α-induced ET-1 production (TNF-α 31.0 ± 8.4 vs. untreated 7.5 ± 0.4 pg/ml, P < 0.001) was reduced by CoPP (1.5 ± 0.8 pg/ml, P < 0.001) and bilirubin (10.5 ± 4.3 pg/ml, P < 0.001). These results suggest that circulating factors released during placental ischemia target the maternal glomerular endothelium to increase ET-1, and that pharmacological induction of HO-1 or bilirubin could be a treatment strategy to block this prohypertensive pathway in preeclampsia.
Role of mitochondria-derived reactive oxygen species in microvascular dysfunction in chronic kidney disease
Authors: Kirkman Danielle L. , Muth Bryce J. , Ramick Meghan G. , Townsend Raymond R. , Edwards David G.
Published: December 2017

Cardiovascular disease is the leading cause of mortality in chronic kidney disease (CKD). Mitochondrial dysfunction secondary to CKD is a potential source of oxidative stress that may impair vascular function. This study sought to determine if mitochondria-derived reactive oxygen species contribute to microvascular dysfunction in stage 3–5 CKD. Cutaneous vasodilation in response to local heating was assessed in 20 CKD patients [60 ± 13 yr; estimated glomerular filtration rate (eGFR) 46 ± 13 ml·kg−1·1.73 m−2] and 11 matched healthy participants (58 ± 2 yr; eGFR >90 ml·kg−1·1.73 m−2). Participants were instrumented with two microdialysis fibers for the delivery of 1) Ringer solution, and 2) the mitochondria- specific superoxide scavenger MitoTempo. Skin blood flow was measured via laser Doppler flowmetry during standardized local heating (42°C). Cutaneous vascular conductance (CVC) was calculated as a percentage of the maximum conductance achieved with sodium nitroprusside infusion at 43°C. Urinary isofuran/F2-isoprostane ratios were assessed by gas-chromatography mass spectroscopy. Isofuran-to-F2-isoprostane ratios were increased in CKD patients (3.08 ± 0.32 vs. 1.69 ± 0.12 arbitrary units; P < 0.01) indicative of mitochondria-derived oxidative stress. Cutaneous vasodilation was impaired in CKD compared with healthy controls (87 ± 1 vs. 92 ± 1%CVCmax; P < 0.01). Infusion of MitoTempo significantly increased the plateau phase CVC in CKD patients (CKD Ringer vs. CKD MitoTempo: 87 ± 1 vs. 93 ± 1%CVCmax; P < 0.01) to similar levels observed in healthy controls ( P = 0.9). These data provide in vivo evidence that mitochondria-derived reactive oxygen species contribute to microvascular dysfunction in CKD and suggest that mitochondrial dysfunction may be a potential therapeutic target to improve CKD-related vascular dysfunction.