bluuebunny/crossref_metadata_2025_split huggingface dataset:
BoPF
Authors: Le Tan N. , Sun Xiao , Chowdhury Mosharaf , Liu Zhenhua 
Published: January 2019

Even though batch, interactive, and streaming applications all care about performance, their notions of performance are different. For instance, while the average completion time can suffciently capture the performance of a throughout-sensitive batch-job queue (TQ) [5], interactive sessions and streaming applications form latencysensitive queues (LQ): each LQ is a sequence of small jobs following an ON-OFF pattern. For these jobs [7], individual completion times or latencies are far more important than the average completion time or the throughput of the LQ.
Indeed, existing "fair" schedulers are inherently unfair to LQ jobs: when LQ jobs are present (ON state), they must share the resources equally with TQ jobs, but when they are absent (OFF state), batch jobs get all the resources. In the long run, TQs receive more resources than their fair shares because today's schedulers such as Dominant Resource Fairness [4] make instantaneous decisions
Clearly, it is impossible to achieve the best response time for LQ jobs under instantaneous fairness. In other words, there is a hard tradeoff between providing instantaneous fairness for TQs and minimizing the response time of LQs. However, instantaneous fairness is not necessary for TQs because average-completion time over a relatively long time horizon is their most important metric. This sheds light on the following question: how well can we simultaneously accommodate multiple classes of workloads with performance guarantees, in particular, isolation protection for TQs in terms of long-term fairness and low response times for LQs?
This work serves as our first step in answering the question by designing BoPF: the first multi-resource scheduler that achieves both isolation protection for TQs and response time guarantees for LQs in a strategyproof way. The key idea is "bounded" priority for LQs: as long as the burst is not too large to hurt the long-term fair share of TQs and other LQs, they are given higher priority so jobs can be completed as quickly as possible.
Maximizing Page-Level Cache Hit Ratios in LargeWeb Services
Authors: Wang Justin , Berg Benjamin , Berger Daniel S. , Sen Siddhartha 
Published: January 2019

Large web services typically serve pages consisting of many individual objects. To improve the response times of page-requests, these services store a small set of popular objects in a fast caching layer. A page-request is not considered complete until all of its objects have either been found in the cache or retrieved from a backend system. Hence, caching only speeds up a page request if all of its objects are found in the cache. We seek caching policies that maximize the page-level hit ratio-the fraction of requests that find all of their objects in the cache.
This work analyzes page requests served by a Microsoft production system.We find that in practice there is potential for improving the page-level hit ratio over existing caching strategies, but that analytically maximizing the page-level hit ratio is NP-hard.
Hepatic transcriptome signatures in patients with varying degrees of nonalcoholic fatty liver disease compared with healthy normal-weight individuals
Authors: Suppli Malte P. , Rigbolt Kristoffer T. G. , Veidal Sanne S. , Heebøll Sara , Eriksen Peter Lykke , Demant Mia , Bagger Jonatan I. , Nielsen Jens Christian , Oró Denise , Thrane Sebastian W. , Lund Asger , Strandberg Charlotte , Kønig Merete J. , Vilsbøll Tina , Vrang Niels , Thomsen Karen L. , Grønbæk Henning , Jelsing Jacob , Hansen Henrik H. , Knop Filip K. 
Published: January 2019

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of conditions ranging from simple steatosis (NAFL), over nonalcoholic steatohepatitis (NASH) with or without fibrosis, to cirrhosis with end-stage disease. The hepatic molecular events underlying the development of NAFLD and transition to NASH are poorly understood. The present study aimed to determine hepatic transcriptome dynamics in patients with NAFL or NASH compared with healthy normal-weight and obese individuals. RNA sequencing and quantitative histomorphometry of liver fat, inflammation and fibrosis were performed on liver biopsies obtained from healthy normal-weight ( n = 14) and obese ( n = 12) individuals, NAFL ( n = 15) and NASH ( n = 16) patients. Normal-weight and obese subjects showed normal liver histology and comparable gene expression profiles. Liver transcriptome signatures were largely overlapping in NAFL and NASH patients, however, clearly separated from healthy normal-weight and obese controls. Most marked pathway perturbations identified in both NAFL and NASH were associated with markers of lipid metabolism, immunomodulation, extracellular matrix remodeling, and cell cycle control. Interestingly, NASH patients with positive Sonic hedgehog hepatocyte staining showed distinct transcriptome and histomorphometric changes compared with NAFL. In conclusion, application of immunohistochemical markers of hepatocyte injury may serve as a more objective tool for distinguishing NASH from NAFL, facilitating improved resolution of hepatic molecular changes associated with progression of NAFLD. NEW & NOTEWORTHY Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries. NAFLD is associated with the metabolic syndrome and can progress to the more serious form, nonalcoholic steatohepatitis (NASH), and ultimately lead to irreversible liver damage. Using gold standard molecular and histological techniques, this study demonstrates that the currently used diagnostic tools are problematic for differentiating mild NAFLD from NASH and emphasizes the marked need for developing improved histological markers of NAFLD progression.
Desmoglein 1 Regulates Invadopodia by Suppressing EGFR/Erk Signaling in an Erbin-Dependent Manner
Authors: Valenzuela-Iglesias Alejandra , Burks Hope E. , Arnette Christopher R. , Yalamanchili Amulya , Nekrasova Oxana , Godsel Lisa M. , Green Kathleen J. 
Published: January 2019

Abstract

Loss of the desmosomal cell–cell adhesion molecule, Desmoglein 1 (Dsg1), has been reported as an indicator of poor prognosis in head and neck squamous cell carcinomas (HNSCC) overexpressing epidermal growth factor receptor (EGFR). It has been well established that EGFR signaling promotes the formation of invadopodia, actin-based protrusions formed by cancer cells to facilitate invasion and metastasis, by activating pathways leading to actin polymerization and ultimately matrix degradation. We previously showed that Dsg1 downregulates EGFR/Erk signaling by interacting with the ErbB2-binding protein Erbin (ErbB2 Interacting Protein) to promote keratinocyte differentiation. Here, we provide evidence that restoring Dsg1 expression in cells derived from HNSCC suppresses invasion by decreasing the number of invadopodia and matrix degradation. Moreover, Dsg1 requires Erbin to downregulate EGFR/Erk signaling and to fully suppress invadopodia formation. Our findings indicate a novel role for Dsg1 in the regulation of invadopodia signaling and provide potential new targets for development of therapies to prevent invadopodia formation and therefore cancer invasion and metastasis.

Implications:
Our work exposes a new pathway by which a desmosomal cadherin called Dsg1, which is lost early in head and neck cancer progression, suppresses cancer cell invadopodia formation by scaffolding ErbB2 Interacting Protein and consequent attenuation of EGF/Erk signaling.
FURIN Inhibition Reduces Vascular Remodeling and Atherosclerotic Lesion Progression in Mice
Authors: Yakala Gopala K. , Cabrera-Fuentes Hector A. , Crespo-Avilan Gustavo E. , Rattanasopa Chutima , Burlacu Alexandrina , George Benjamin L. , Anand Kaviya , Mayan David Castaño , Corlianò Maria , Hernández-Reséndiz Sauri , Wu Zihao , Schwerk Anne M.K. , Tan Amberlyn L.J. , Trigueros-Motos Laia , Chèvre Raphael , Chua Tricia , Kleemann Robert , Liehn Elisa A. , Hausenloy Derek J. , Ghosh Sujoy , Singaraja Roshni R. 
Published: January 2019

Objective—

Atherosclerotic coronary artery disease is the leading cause of death worldwide, and current treatment options are insufficient. Using systems-level network cluster analyses on a large coronary artery disease case-control cohort, we previously identified PCSK3 (proprotein convertase subtilisin/kexin family member 3;
FURIN
) as a member of several coronary artery disease–associated pathways. Thus, our objective is to determine the role of FURIN in atherosclerosis.

Approach and Results—

In vitro, FURIN inhibitor treatment resulted in reduced monocyte migration and reduced macrophage and vascular endothelial cell inflammatory and cytokine gene expression. In vivo, administration of an irreversible inhibitor of FURIN, α-1-PDX (α1-antitrypsin Portland), to hyperlipidemic
Ldlr
−/−
mice resulted in lower atherosclerotic lesion area and a specific reduction in severe lesions. Significantly lower lesional macrophage and collagen area, as well as systemic inflammatory markers, were observed. MMP2 (matrix metallopeptidase 2), an effector of endothelial function and atherosclerotic lesion progression, and a FURIN substrate was significantly reduced in the aorta of inhibitor-treated mice. To determine FURIN’s role in vascular endothelial function, we administered α-1-PDX to
Apoe
−/−
mice harboring a wire injury in the common carotid artery. We observed significantly decreased carotid intimal thickness and lower plaque cellularity, smooth muscle cell, macrophage, and inflammatory marker content, suggesting protection against vascular remodeling. Overexpression of FURIN in this model resulted in a significant 67% increase in intimal plaque thickness, confirming that FURIN levels directly correlate with atherosclerosis.

Conclusions—
We show that systemic inhibition of FURIN in mice decreases vascular remodeling and atherosclerosis. FURIN-mediated modulation of MMP2 activity may contribute to the atheroprotection observed in these mice.
Serum Dkk-1 (Dickkopf-1) Is a Potential Biomarker in the Prediction of Clinical Outcomes Among Patients With Acute Ischemic Stroke
Authors: Zhu Zhengbao , Guo Daoxia , Zhong Chongke , Wang Aili , Xie Xuewei , Xu Tan , Chen Chung-Shiuan , Peng Yanbo , Peng Hao , Li Qunwei , Ju Zhong , Geng Deqin , Chen Jing , Liu Liping , Wang Yilong , Zhang Yonghong , He Jiang 
Published: January 2019

Objective—
Serum Dkk-1 (dickkopf-1) level has been shown to be elevated in patients with ischemic stroke, but its impact on clinical outcomes of ischemic stroke remains unclear. The aim of this study is to investigate the association between serum Dkk-1 and prognosis of ischemic stroke.

Approach and Results—

We measured serum Dkk-1 levels in 3178 patients with ischemic stroke from CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). The primary outcome was a combination of all-cause mortality and major disability (modified Rankin scale score, ≥3) at 1 year after stroke. Secondary outcomes were stroke recurrence and vascular events. After multivariate adjustment, elevated Dkk-1 levels were associated with an increased risk of primary outcome (odds ratio, 1.40; 95% CI, 1.03–1.89;
P
trend
=0.015) when 2 extreme quartiles were compared. Each SD increase of log-transformed Dkk-1 was associated with 12% (95% CI, 1%–24%) increased risk of primary outcome. Multiple-adjusted spline regression model showed a linear association between serum Dkk-1 and risk of primary outcome (
P
for linearity, 0.039). Subgroup analyses further confirmed these associations. The addition of serum Dkk-1 to conventional risk factors improved the predictive power for primary outcome (net reclassification improvement: 10.11%,
P
=0.029; integrated discrimination improvement: 0.21%,
P
=0.028).

Conclusions—
High serum Dkk-1 levels at baseline were associated with poor prognosis at 1 year after ischemic stroke, suggesting that serum Dkk-1 may be a potential prognostic biomarker for ischemic stroke. Further studies from other samples of patients with ischemic stroke are needed to replicate our findings and to clarify the potential mechanisms.
Quantifying Importance of Major Risk Factors for Coronary Heart Disease
Authors: Pencina Michael J. , Navar Ann Marie , Wojdyla Daniel , Sanchez Robert J. , Khan Irfan , Elassal Joseph , D’Agostino Ralph B. , Peterson Eric D. , Sniderman Allan D. 
Published: January 2019

Background:
To optimize preventive strategies for coronary heart disease (CHD), it is essential to understand and appropriately quantify the contribution of its key risk factors. Our objective was to compare the associations of key modifiable CHD risk factors—specifically lipids, systolic blood pressure (SBP), diabetes mellitus, and smoking—with incident CHD events based on their prognostic performance, attributable risk fractions, and treatment benefits, overall and by age.

Methods:
Pooled participant-level data from 4 observational cohort studies sponsored by the National Heart, Lung, and Blood Institute were used to create a cohort of 22 626 individuals aged 45 to 84 years who were initially free of cardiovascular disease. Individuals were followed for 10 years from baseline evaluation for incident CHD. Proportional hazards regression was used to estimate metrics of prognostic model performance (likelihood ratio, C index, net reclassification, discrimination slope), hazard ratios, and population attributable fractions for SBP, non–high-density lipoprotein cholesterol (non–HDL-C), diabetes mellitus, and smoking. Expected absolute risk reductions for antihypertensive and lipid-lowering treatment were assessed.

Results:
Age, sex, and race capture 63% to 80% of the prognostic performance of cardiovascular risk models. In contrast, adding either SBP, non–HDL-C, diabetes mellitus, or smoking to a model with other risk factors increases the C index by only 0.004 to 0.013. However, primordial prevention could have a substantial effect as demonstrated by population attributable fractions of 28% for SBP≥130 mm Hg and 17% for non–HDL-C≥130 mg/dL. Similarly, lowering the SBP of all individuals to <130 mm Hg or lowering low-density lipoprotein cholesterol by 30% would be expected to lower a baseline 10-year CHD risk of 10.7% to 7.0 and 8.0, respectively (absolute risk reductions: 3.7% and 2.7%, respectively). Prognostic performance decreases with age (C indices for age groups 45–54, 55–64, 65–74, 75–84 are 0.75, 0.72, 0.66, and 0.62, respectively), whereas absolute risk reductions increase (SBP: 1.1%, 2.3%, 5.4%, 10.3%, respectively; non–HDL-C: 1.1%, 2.0%, 3.7%, 5.9%, respectively).

Conclusions:
Although individual modifiable CHD risk factors contribute only modestly to prognostic performance, our models indicate that eliminating or controlling these individual factors would lead to substantial reductions in total population CHD events. Metrics used to judge importance of risk factors should be tailored to the research objectives.
Endothelial C-Type Natriuretic Peptide Is a Critical Regulator of Angiogenesis and Vascular Remodeling
Authors: Bubb Kristen J. , Aubdool Aisah A. , Moyes Amie J. , Lewis Sarah , Drayton Jonathan P. , Tang Owen , Mehta Vedanta , Zachary Ian C. , Abraham David J. , Tsui Janice , Hobbs Adrian J. 
Published: January 2019

Background:
Angiogenesis and vascular remodeling are complementary, innate responses to ischemic cardiovascular events, including peripheral artery disease and myocardial infarction, which restore tissue blood supply and oxygenation; the endothelium plays a critical function in these intrinsic protective processes. C-type natriuretic peptide (CNP) is a fundamental endothelial signaling species that coordinates vascular homeostasis. Herein, we sought to delineate a central role for CNP in angiogenesis and vascular remodeling in response to ischemia.

Methods:

The in vitro angiogenic capacity of CNP was examined in pulmonary microvascular endothelial cells and aortic rings isolated from wild-type, endothelium-specific CNP
–/–
, global natriuretic peptide receptor (NPR)-B
–/–
and NPR-C
–/–
animals, and human umbilical vein endothelial cells. These studies were complemented by in vivo investigation of neovascularization and vascular remodeling after ischemia or vessel injury, and CNP/NPR-C expression and localization in tissue from patients with peripheral artery disease.

Results:

Clinical vascular ischemia is associated with reduced levels of CNP and its cognate NPR-C. Moreover, genetic or pharmacological inhibition of CNP and NPR-C, but not NPR-B, reduces the angiogenic potential of pulmonary microvascular endothelial cells, human umbilical vein endothelial cells, and isolated vessels ex vivo. Angiogenesis and remodeling are impaired in vivo in endothelium-specific CNP
–/–
and NPR-C
–/–
, but not NPR-B
–/–
, mice; the detrimental phenotype caused by genetic deletion of endothelial CNP, but not NPR-C, can be rescued by pharmacological administration of CNP. The proangiogenic effect of CNP/NPR-C is dependent on activation of G
i
, ERK1/2, and phosphoinositide 3-kinase γ/Akt at a molecular level.

Conclusions:
These data define a central (patho)physiological role for CNP in angiogenesis and vascular remodeling in response to ischemia and provide the rationale for pharmacological activation of NPR-C as an innovative approach to treating peripheral artery disease and ischemic cardiovascular disorders.
Influenza Vaccine in Heart Failure
Authors: Modin Daniel , Jørgensen Mads Emil , Gislason Gunnar , Jensen Jan Skov , Køber Lars , Claggett Brian , Hegde Sheila M. , Solomon Scott D. , Torp-Pedersen Christian , Biering-Sørensen Tor 
Published: January 2019

Background:
Influenza infection is a serious event for patients with heart failure (HF). Little knowledge exists about the association between influenza vaccination and outcome in patients with HF. This study sought to determine whether influenza vaccination is associated with improved long-term survival in patients with newly diagnosed HF.

Methods:
We performed a nationwide cohort study including all patients who were >18 years of age and diagnosed with HF in Denmark in the period of January 1, 2003, to June 1, 2015 (n=134 048). We collected linked data using nationwide registries. Vaccination status, number, and frequency during follow-up were treated as time-varying covariates in time-dependent Cox regression.

Results:

Follow-up was 99.8% with a median follow-up time of 3.7 years (interquartile range, 1.7–6.8 years). The vaccination coverage of the study cohort ranged from 16% to 54% during the study period. In unadjusted analysis, receiving ≥1 vaccinations during follow-up was associated with a higher risk of death. After adjustment for inclusion date, comorbidities, medications, household income, and education level, receiving ≥1 vaccinations was associated with an 18% reduced risk of death (all-cause: hazard ratio, 0.82; 95% CI, 0.81–0.84;
P
<0.001; cardiovascular causes: hazard ratio, 0.82; 95% CI, 0.81–0.84;
P
<0.001). Annual vaccination, vaccination early in the year (September to October), and greater cumulative number of vaccinations were associated with larger reductions in the risk of death compared with intermittent vaccination.

Conclusions:
In patients with HF, influenza vaccination was associated with a reduced risk of both all-cause and cardiovascular death after extensive adjustment for confounders. Frequent vaccination and vaccination earlier in the year were associated with larger reductions in the risk of death compared with intermittent and late vaccination.
Loss of Endothelium-Derived Wnt5a Is Associated With Reduced Pericyte Recruitment and Small Vessel Loss in Pulmonary Arterial Hypertension
Authors: Yuan Ke , Shamskhou Elya A. , Orcholski Mark E. , Nathan Abinaya , Reddy Sushma , Honda Hiroaki , Mani Vigneshwaran , Zeng Yitian , Ozen Mehmet O. , Wang Lingli , Demirci Utkan , Tian Wen , Nicolls Mark R. , de Jesus Perez Vinicio A. 
Published: January 2019

Background:
Pulmonary arterial hypertension (PAH) is a life-threatening disorder of the pulmonary circulation associated with loss and impaired regeneration of microvessels. Reduced pericyte coverage of pulmonary microvessels is a pathological feature of PAH and is caused partly by the inability of pericytes to respond to signaling cues from neighboring pulmonary microvascular endothelial cells (PMVECs). We have shown that activation of the Wnt/planar cell polarity pathway is required for pericyte recruitment, but whether production and release of specific Wnt ligands by PMVECs are responsible for Wnt/planar cell polarity activation in pericytes is unknown.

Methods:

Isolation of pericytes and PMVECs from healthy donor and PAH lungs was carried out with 3G5 or CD31 antibody–conjugated magnetic beads. Wnt expression profile of PMVECs was documented via quantitative polymerase chain reaction with a Wnt primer library. Exosome purification from PMVEC media was carried out with the ExoTIC device. Hemodynamic profile, right ventricular function, and pulmonary vascular morphometry were obtained in a conditional endothelium-specific Wnt5a knockout (
Wnt5a
ECKO
) mouse model under normoxia, chronic hypoxia, and hypoxia recovery.

Results:

Quantification of Wnt ligand expression in healthy PMVECs cocultured with pericytes demonstrated a 35-fold increase in Wnt5a, a known Wnt/planar cell polarity ligand. This Wnt5a spike was not seen in PAH PMVECs, which correlated with an inability to recruit pericytes in Matrigel coculture assays. Exosomes purified from media demonstrated an increase in Wnt5a content when healthy PMVECs were cocultured with pericytes, a finding that was not observed in exosomes of PAH PMVECs. Furthermore, the addition of either recombinant Wnt5a or purified healthy PMVEC exosomes increased pericyte recruitment to PAH PMVECs in coculture studies. Although no differences were noted in normoxia and chronic hypoxia,
Wnt5a
ECKO
mice demonstrated persistent pulmonary hypertension and right ventricular failure 4 weeks after recovery from chronic hypoxia, which correlated with significant reduction, muscularization, and decreased pericyte coverage of microvessels.

Conclusions:
We identify Wnt5a as a key mediator for the establishment of pulmonary endothelium-pericyte interactions, and its loss could contribute to PAH by reducing the viability of newly formed vessels. We speculate that therapies that mimic or restore Wnt5a production could help prevent loss of small vessels in PAH.
Expression of CUEDC2 in colorectal cancer with different invasion and migration abilities
Authors: Hu Shidong , Hu Zilong , Li Songyan , He Changzheng , Wu Youjun , Teng Da , Yan Yang , Li Hao , Xing Xiaowei , Zou Guijun , Li Yuxuan , Yang Yu , Wang Yufeng , Du Xiaohui 
Published: January 2019

Objective To investigate CUE domain containing 2 ( CUEDC2) expression in colorectal cancer with different invasion and migration abilities. Methods Fresh colon cancer tissues, obtained from patients with or without lymph node metastasis who were treated at the Department of General Surgery, Chinese People's Liberation Army General Hospital, and SW620 and HT29 colorectal cancer cell lines, were analysed for CUEDC2 expression. Results Real-time polymerase chain reaction showed significantly higher CUEDC2 mRNA levels in colon cancer tissue from patients with ( n = 8) versus without ( n = 8) lymph node metastasis, and in SW620 versus HT29 cells. Western blots revealed significantly higher CUEDC2 protein levels in colon cancer tissues from patients with versus without lymph node metastasis, and in SW620 versus HT29 cells. Colorectal cancer tissues from patients with lymph node metastasis showed more intense immunohistochemical staining and moderate staining of cell nuclei and cytoplasm versus less intense/weak staining in tissues from patients without lymph node metastasis. Conclusions CUEDC2 is highly expressed in colorectal cancer tissues and colorectal cancer cell lines with high invasion and migration ability. CUEDC2 may be involved in promoting invasion and metastasis in colorectal cancer.