bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatiotemporal Sequential Influence Modeling for Location Recommendations
Authors: Zhang Jia-Dong , Chow Chi-Yin
Published: October 2015

Recommending to users personalized locations is an important feature of Location-Based Social Networks (LBSNs), which benefits users who wish to explore new places and businesses to discover potential customers. In LBSNs,
social and geographical influences
have been intensively used in location recommendations. However, human movement also exhibits spatiotemporal sequential patterns, but only a few current studies consider the
spatiotemporal sequential influence
of locations on users’ check-in behaviors. In this article, we propose a new gravity model for location recommendations, called LORE, to exploit the spatiotemporal sequential influence on location recommendations. First, LORE extracts sequential patterns from historical check-in location sequences of all users as a
Location-Location Transition Graph
(L
2
TG), and utilizes the L
2
TG to predict the probability of a user visiting a new location through the developed additive Markov chain that considers the effect of all visited locations in the check-in history of the user on the new location. Furthermore, LORE applies our contrived gravity model to weigh the effect of each visited location on the new location derived from the personalized attractive force (i.e., the weight) between the visited location and the new location. The gravity model effectively integrates the spatiotemporal, social, and popularity influences by estimating a power-law distribution based on (i) the spatial distance and temporal difference between two consecutive check-in locations of the same user, (ii) the check-in frequency of social friends, and (iii) the popularity of locations from all users. Finally, we conduct a comprehensive performance evaluation for LORE using three large-scale real-world datasets collected from Foursquare, Gowalla, and Brightkite. Experimental results show that LORE achieves significantly superior location recommendations compared to other state-of-the-art location recommendation techniques.
Fault Monitoring with Sequential Matrix Factorization
Authors: Feng Dawei , Germain Cecile
Published: October 2015

For real-world distributed systems, the knowledge component at the core of the MAPE-K loop has to be inferred, as it cannot be realistically assumed to be defined a priori. Accordingly, this paper considers fault monitoring as a latent factors discovery problem. In the context of end-to-end probing, the goal is to devise an efficient sampling policy that makes the best use of a constrained sampling budget.

Previous work addresses fault monitoring in a collaborative prediction framework, where the information is a snapshot of the probes outcomes. Here, we take into account the fact that the system dynamically evolves at various time scales. We propose and evaluate Sequential Matrix Factorization (SMF) that exploits both the recent advances in matrix factorization for the instantaneous information and a new sampling heuristics based on historical information. The effectiveness of the SMF approach is exemplified on datasets of increasing difficulty and compared with state of the art history-based or snapshot-based methods. In all cases, strong adaptivity under the specific flavor of active learning is required to unleash the full potential of coupling the most confident and the most uncertain sampling heuristics, which is the cornerstone of SMF.
Welcome to AI Matter
Authors: Eaton Eric , Wagstaff Kiri L.
Published: October 2015

A welcome from the Editors of AI Matters and a summary of highlights in this issue.
Modeling social norms in real-world agent-based simulations
Authors: Beheshti Rahmatollah
Published: October 2015

This dissertation presents new methods for simulating social norms emergence in human populations and applies the resulting normative model to a smoking cessation scenario. Due to the complex nature of this problem, this work models numerous factors that affect smoking, employing several social and psychological theories in conjunction with various AI techniques.
ACM IUI 2015 conference highlights
Authors: Chau Duen Horng (Polo) , Brdiczka Oliver
Published: October 2015

The 2015 ACM International Conference on Intelligent User Interfaces (ACM IUI 2015) was a great success. A record number of submissions, an exciting program, a new cooperation with the ACM TiiS journal, and the southern hospitality of Atlanta all made it a memorable experience.
Early-life stress origins of gastrointestinal disease: animal models, intestinal pathophysiology, and translational implications
Authors: Pohl Calvin S. , Medland Julia E. , Moeser Adam J.
Published: October 2015

Early-life stress and adversity are major risk factors in the onset and severity of gastrointestinal (GI) disease in humans later in life. The mechanisms by which early-life stress leads to increased GI disease susceptibility in adult life remain poorly understood. Animal models of early-life stress have provided a foundation from which to gain a more fundamental understanding of this important GI disease paradigm. This review focuses on animal models of early-life stress-induced GI disease, with a specific emphasis on translational aspects of each model to specific human GI disease states. Early postnatal development of major GI systems and the consequences of stress on their development are discussed in detail. Relevant translational differences between species and models are highlighted.
An intact small animal model of myocardial ischemia-reperfusion: Characterization of metabolic changes by hyperpolarized 13C MR spectroscopy
Authors: Yoshihara Hikari A. I. , Bastiaansen Jessica A. M. , Berthonneche Corinne , Comment Arnaud , Schwitter Juerg
Published: October 2015

Hyperpolarized carbon-13 magnetic resonance spectroscopy (13C MRS) enables the sensitive and noninvasive assessment of the metabolic changes occurring during myocardial ischemia-reperfusion. Ischemia-reperfusion models using hyperpolarized 13C MRS are established in heart preparations ex vivo and in large animals in vivo, but an in vivo model in small animals would be advantageous to allow the study of reperfusion metabolism with neuroendocrine and inflammatory responses intact with the option to perform a greater number of experiments. A novel intact rat model of ischemia-reperfusion is presented that incorporates hyperpolarized 13C MRS to characterize reperfusion metabolism. Typically, in an in vivo model, a tissue input function (TIF) is required to account for apparent changes in the metabolism of injected hyperpolarized [1-13C]pyruvate resulting from changes in perfusion. Whereas the measurement of a TIF by metabolic imaging is particularly challenging in small animals, the ratios of downstream metabolites can be used as an alternative. The ratio of [13C]bicarbonate:[1-13C]lactate (RatioBic/Lac) measured within 1–2 min after coronary release decreased vs. baseline in ischemic rats ( n = 10, 15-min occlusion, controls: n = 10; P = 0.017 for interaction, 2-way ANOVA). The decrease in oxidative pyruvate metabolism [RatioBic/Lac(Ischemia)/RatioBic/Lac(Baseline)] modestly correlated with area at risk ( r = 0.66; P = 0.002). Hyperpolarized 13C MRS was also used to examine alanine production during ischemia, which is observed in ex vivo models, but no significant change was noted; metrics incorporating [1-13C]alanine did not substantially improve the discrimination of ischemic-reperfused myocardium from nonischemic myocardium. This intact rat model, which mimics the human situation of reperfused myocardial infarction, could be highly valuable for the testing of new drugs to treat reperfusion injury, thereby facilitating translational research.
Purinergic glio-endothelial coupling during neuronal activity: role of P2Y1 receptors and eNOS in functional hyperemia in the mouse somatosensory cortex
Authors: Toth Peter , Tarantini Stefano , Davila Antonio , Valcarcel-Ares M. Noa , Tucsek Zsuzsanna , Varamini Behzad , Ballabh Praveen , Sonntag William E. , Baur Joseph A. , Csiszar Anna , Ungvari Zoltan
Published: October 2015

Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of cognitive impairment associated with aging and pathological conditions associated with accelerated cerebromicrovascular aging (e.g., hypertension, obesity). Although previous studies demonstrate that endothelial dysfunction plays a critical role in neurovascular uncoupling in these conditions, the role of endothelial NO mediation in neurovascular coupling responses is not well understood. To establish the link between endothelial function and functional hyperemia, neurovascular coupling responses were studied in mutant mice overexpressing or deficient in endothelial NO synthase (eNOS), and the role of P2Y1 receptors in purinergic glioendothelial coupling was assessed. We found that genetic depletion of eNOS (eNOS−/−) and pharmacological inhibition of NO synthesis significantly decreased the CBF responses in the somatosensory cortex evoked by whisker stimulation and by administration of ATP. Overexpression of eNOS enhanced NO mediation of functional hyperemia. In control mice, the selective and potent P2Y1 receptor antagonist MRS2179 attenuated both whisker stimulation-induced and ATP-mediated CBF responses, whereas, in eNOS−/− mice, the inhibitory effects of MRS2179 were blunted. Collectively, our findings provide additional evidence for purinergic glio-endothelial coupling during neuronal activity, highlighting the role of ATP-mediated activation of eNOS via P2Y1 receptors in functional hyperemia.
The CUL4B/AKT/β-Catenin Axis Restricts the Accumulation of Myeloid-Derived Suppressor Cells to Prohibit the Establishment of a Tumor-Permissive Microenvironment
Authors: Qian Yanyan , Yuan Jupeng , Hu Huili , Yang Qifeng , Li Jisheng , Zhang Shuqian , Jiang Baichun , Shao Changshun , Gong Yaoqin
Published: October 2015

Cancer progression requires a permissive microenvironment that shields cancer from the host immunosurveillance. The presence of myeloid-derived suppressor cells (MDSC) is a key feature of a tumor-permissive microenvironment. Cullin 4B (CUL4B), a scaffold protein in the Cullin 4B-RING E3 ligase complex (CRL4B), represses tumor suppressors through diverse epigenetic mechanisms and is overexpressed in many malignancies. We report here that CUL4B unexpectedly functions as a negative regulator of MDSC functions in multiple tumor settings. Conditional ablation of CUL4B in the hematopoietic system, driven by Tek-Cre, resulted in significantly enhanced accumulation and activity of MDSCs. Mechanistically, we demonstrate that the aberrant abundance of MDSCs in the absence of CUL4B was mediated by the downregulation of the AKT/β-catenin pathway. Moreover, CUL4B repressed the phosphatases PP2A and PHLPP1/2 that dephosphorylate and inactivate AKT to sustain pathway activation. Importantly, the CUL4B/AKT/β-catenin axis was downregulated in MDSCs of healthy individuals and was further suppressed in tumor-bearing mice and cancer patients. Thus, our findings point to a pro- and antitumorigenic role for CUL4B in malignancy, in which its ability to impede the formation of a tumor-supportive microenvironment may be context-specific. Cancer Res; 75(23); 5070–83. ©2015 AACR.
Pigment Epithelium–Derived Factor Alleviates Tamoxifen-Induced Endometrial Hyperplasia
Authors: Goldberg Keren , Bar-Joseph Hadas , Grossman Hadas , Hasky Noa , Uri-Belapolsky Shiri , Stemmer Salomon M. , Chuderland Dana , Shalgi Ruth , Ben-Aharon Irit
Published: October 2015

Tamoxifen is a cornerstone component of adjuvant endocrine therapy for patients with hormone-receptor–positive breast cancer. Its significant adverse effects include uterine hyperplasia, polyps, and increased risk of endometrial cancer. However, the underlying molecular mechanism remains unclear. Excessive angiogenesis, a hallmark of tumorigenesis, is a result of disrupted balance between pro- and anti-angiogenic factors. VEGF is a pro-angiogenic factor shown to be elevated by tamoxifen in the uterus. Pigment epithelium–derived factor (PEDF) is a potent anti-angiogenic factor that suppresses strong pro-angiogenic factors, such as VEGF. Our aim was to investigate whether angiogenic balance plays a role in tamoxifen-induced uterine pathologies, elucidate the molecular impairment in that network, and explore potential intervention to offset the proposed imbalance elicited by tamoxifen. Using in vivo mouse models, we demonstrated that tamoxifen induced a dose-dependent shift in endogenous uterine angiogenic balance favoring VEGF over PEDF. Treatment with recombinant PEDF (rPEDF) abrogated tamoxifen-induced uterine hyperplasia and VEGF elevation, resulting in reduction of blood vessels density. Exploring the molecular mechanism revealed that tamoxifen promoted survival and malignant transformation pathways, whereas rPEDF treatment prevents these changes. Activation of survival pathways was decreased, demonstrated by reduction in AKT phosphorylation concomitant with elevation in JNK phosphorylation. Estrogen receptor-α and c-Myc oncoprotein levels were reduced. Our findings provide novel insight into the molecular mechanisms tamoxifen induces in the uterus, which may become the precursor events of subsequent endometrial hyperplasia and cancer. We demonstrate that rPEDF may serve as a useful intervention to alleviate the risk of tamoxifen-induced endometrial pathologies. Mol Cancer Ther; 14(12); 2840–9. ©2015 AACR.
The Efficacy of Mitomycin C in the Treatment of Laryngotracheal Stenosis: Results and Experiences with a Difficult Disease Entity
Authors: Reichert Lara K. , Zhao Alice S. , Galati Lisa T. , Shapshay Stanley M.
Published: October 2015

Background/Aims: Laryngotracheal stenosis (LTS) is a difficult entity to treat, with many patients requiring multiple procedures. Our study assessed the efficacy of mitomycin C (MMC) application as complimentary treatment of LTS. Methods: We reviewed clinical charts of patients with operative procedures for LTS between January 2005 and May 2013. Patients were grouped according to mitomycin use. Several outcome measures were assessed, including the number of procedures and time between procedures. Results: Seventy-one patients were included in the study (30 MMC, 41 non-MMC). They underwent similar numbers of procedures (2.3 MMC, 2.0 non-MMC, p > 0.05). The average time between procedures was 360 (MMC) and 178 (non-MMC) days (p = 0.015). Multiple treatments with mitomycin increased the duration between procedures (366 vs. 340 days, multiple vs. single application, p > 0.05). Fewer mitomycin patients underwent procedures for respiratory distress than non-MMC patients (6.6 vs. 19.5%, p > 0.05). Mitomycin use increased the duration between procedures in patients treated specifically for subglottic stenosis (375 vs. 186 days, p > 0.05). Conclusion: Our results and experiences with mitomycin demonstrate it is an effective agent for adjuvant treatment of LTS. Its use lengthens the symptom-free period, with further improvement demonstrated when patients expected to undergo multiple surgeries receive multiple mitomycin treatments.
Budesonide Inhibits Intracellular Infection with Non-Typeable Haemophilus influenzae despite Its Anti-Inflammatory Effects in Respiratory Cells and Human Lung Tissue: A Role for p38 MAP Kinase
Authors: Wagner Christopher , Goldmann Torsten , Rohmann Kristina , Rupp Jan , Marwitz Sebastian , Rotta detto Loria Johannes , Limmer Stefan , Zabel Peter , Dalhoff Klaus , Drömann Daniel
Published: October 2015

Background: Inhaled corticosteroids (ICS) are widely used in the treatment of obstructive lung diseases. Recent data suggest a higher pneumonia risk in chronic obstructive pulmonary disease (COPD) patients treated with ICS. Objective: Since non-typeable Haemophilus influenzae (NTHi) is the most common pathogen associated with acute exacerbations of COPD, we investigated the effects of budesonide (BUD) on NTHi-induced inflammation and invasive infection. Methods: The alveolar epithelial cell line A549 and specimens of human lung tissue (HLT) were used in our experiments. Intracellular infection was determined by a lysis/culture assay of infected cells. Activated p38 mitogen-associated protein kinase (MAPK) was assessed using Western blotting and immunohistochemistry, expression of toll-like receptor 2 (TLR2) was determined by PCR, and CXCL-8 levels were measured using ELISA. Immunohistochemistry was used for detection of CXCL-8, platelet-activating factor receptor (PAF-R) and NTHi. Results: BUD significantly reduced CXCL-8 secretion in A549 cells and lung tissue infected with NTHi. Furthermore, BUD decreased the expression of PAF-R in HLT and A549 cells. In A549 cells and HLT, BUD inhibited intracellular infection and - synergistically with NTHi - increased the expression of TLR2 (in A549 cells). TLR2 stimulation did not influence the intracellular infection of A549 cells, but p38 MAPK inhibition resulted in a significant reduction of infection. Conclusion: The present study adds new insights into the effects of glucocorticoids on pulmonary host defence after NTHi infection. Although the inflammatory response to infection is suppressed by BUD, interestingly, the intracellular infection is also inhibited. This effect seems to depend on the inhibition of p38 MAPK - a key enzyme in many pro-inflammatory pathways - as well as of PAF-R expression.
Study of Facial Sebum Levels and Follicular Red Fluorescence in Patients with Acne Vulgaris in Nigeria
Authors: Okoro Emeka O. , Bulus Naya Gadzama , Zouboulis Christos C.
Published: October 2015

Background: Increased sebum levels are triggering factors of acne vulgaris. No studies on sebum levels exist among acne patients in Africa. Aims/Methods: Cross-sectional study to determine facial sebum levels, acne lesions and red fluorescence among adolescents (n = 80) with acne vulgaris in Nigeria, who were interviewed and clinically examined. Results: Facial sebum levels were higher among adolescents with acne than among those without. There was a positive correlation between sebum levels and acne lesions in the U zone but not in the T zone. There was also a positive correlation between the size of red fluorescence and acne lesions and mean sebum levels. Both correlations were highly significant in the U zone but not in the T zone. Conclusion: Facial sebum levels are higher among black African acne patients. Sebum is responsible for facial red fluorescence. The U zone may serve as a more reliable site than the T zone for measurements of sebum levels in black African acne patients.
Neutrophil Gelatinase-Associated Lipocalin, but Not Kidney Injury Marker 1, Correlates with Duration of Delayed Graft Function
Authors: van den Akker Eline Kristina , Hesselink Dennis Alexander , Manintveld Olivier Christiaan , IJzermans Jan Nicolaas Maria , de Bruijn Ronald Wilhelm Frederik , Dor Frank Johan Marinus Frederik
Published: October 2015

Background: No specific early biomarker is available to measure kidney injury after kidney transplantation (KT). Both neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury marker 1 (KIM-1) increase after oxidative injury. Their potential as early biomarkers was evaluated in this one-arm pilot study. Materials and Methods: Twenty consecutive KT patients receiving a kidney from a donation after circulatory death donor were included. Graft perfusate was collected, as well as serum samples before transplantation, at the end of surgery, and 1, 4, and 7 days after transplantation. NGAL and KIM-1 were measured using ELISA. Kidney function and delayed graft function (DGF) were monitored. Results: In this cohort, 85% of the KT patients developed DGF. Perfusate NGAL correlated with donor age (r2 = 0.094, p = 0.01) and serum creatinine (r2 = 0.243, p = 0.05). A cardiac cause of death was associated with higher NGAL in the perfusate (p = 0.03). Serum NGAL at day 1 was significantly higher in patients with DGF (730 ng/ml, range 490-1,655, vs. 417 ng/ml, range 232-481; p = 0.01). Serum NGAL levels at day 1, 4, and 7 correlated with the duration of DGF. KIM-1 was not detectable in the perfusate or in the serum until postoperative day 4 in 80% of patients. Conclusions: NGAL in the perfusate correlates with known donor risk factors for DGF. For the first time, we describe that serum NGAL at day 1 can discriminate between DGF and immediate graft function. Also, serum NGAL levels at day 1, 4, and 7 correlate with the duration of DGF. No association with KIM-1 was found. These data suggest that NGAL may be used as an early biomarker to detect DGF and warrants further study.
Correlation between Manchester Grading Scale and American Orthopaedic Foot and Ankle Society Score in Patients with Hallux Valgus
Authors: Iliou Kalliopi , Paraskevas George , Kanavaros Panagiotis , Barbouti Alexandra , Vrettakos Aristidis , Gekas Christos , Kitsoulis Panagiotis
Published: October 2015

Objective: To evaluate the correlation between the Manchester Grading Scale and the American Orthopaedic Foot and Ankle Society (AOFAS) score in patients with a hallux valgus deformity. Subjects and Methods: The study sample included 181 feet of 122 patients with hallux valgus and 424 feet of 212 individuals without hallux valgus deformity as the control group. The severity of hallux valgus, utilizing a relative nonmetric scale, the Manchester Grading Scale, and the metric AOFAS score, was determined for all individuals in the hallux valgus and control groups. SPSS version 18 (Chicago, Ill., USA) was used for data analysis. Results: According to the Manchester Grading Scale, the 424 feet of the normal group were classified as ‘no deformity'. In the hallux valgus group, 85 feet were classified as ‘mild deformity', 67 as ‘moderate deformity' and 29 as ‘severe deformity'. The AOFAS total score in the control group was 99.14. In the hallux valgus group, patients with mild or moderate deformity had total scores of 86.20 and 68.19, respectively. For those with severe hallux valgus, the total score was 44.69 and the differences were statistically significant (p = 0.000). Using the Pearson correlation, strong negative correlations were found between the AOFAS score and the hallux valgus angle (HVA; r = -0.899, p = 0.000). Strong negative correlations were demonstrated between the AOFAS score and the first intermetatarsal angle (IMA) as well (r = -0.748, p = 0.000). Conclusions: The AOFAS score was negatively associated with the Manchester Grading Scale, HVA and first IMA. As the severity of hallux valgus increased, the AOFAS score seemed to decrease.
Mechanism of ER Stress and Inflammation for Hepatic Insulin Resistance in Obesity
Authors: Kim Ok-Kyung , Jun Woojin , Lee Jeongmin
Published: October 2015

Background: Obesity is a major risk factor in the development of hepatic insulin resistance, which is characterized by an impairment of insulin ability to inhibit glucose output. Although the underlying mechanism for the link between obesity and insulin resistance in the liver is unclear, it has been widely reported and suggested that hepatic endoplasmic reticulum (ER) stress and inflammation induced by obesity lead to the development of hepatic insulin resistance and gluconeogenesis. Summary: This review addresses the aspects of ER stress and inflammation currently understood to be involved in metabolic disease, including their role in obesity, hepatic insulin resistance, and hyperglycemia.
A arquitetura iconizante de “Luz do sol”
Authors: Saraiva José Américo Bezerra
Published: October 2015

O propósito deste artigo é analisar a canção Luz do sol, de Caetano Veloso, para verificar o seu suposto caráter icônico. O efeito iconizante desse texto parece já se evidenciar no tratamento melódico dedicado à letra, apreensível mesmo numa escuta despreocupada, mas não só. O lexema luz, por exemplo, aparenta
exercer papel de destaque em toda a composição, figurando como seu centro iconizante sob vários aspectos: sintático, semântico, estrófico, fônico e tonal. Promovemos aqui, então, uma análise minudente dessa canção, examinando-lhe a letra, sintática e semanticamente, a estruturação estrófica, a seleção lexical, a composição fônica e a ordenação tonal, para averiguar o grau de investimento em sua arquitetura iconizante.
A construção de humor e verdade na animação “Deu a louca na Chapeuzinho”
Authors: Farias Iara Rosa
Published: October 2015

A partir de Toy Story (1995), podemos dizer que as animações se tornaram cada vez mais presentes no cinema. O que seria uma produção para crianças atinge, cada vez mais, o público adulto. Em algumas delas o modo do encadeamento da narrativa, as disputas e associações abordam, mais explicitamente, questões do mundo adulto. É preciso pois olhar as animações além daquilo que aparentemente são: histórias para crianças. O objeto de análise deste artigo é a animação Deu a louca na Chapeuzinho (2005/2006). Esta animação resgata o conto imortalizado pelos irmãos Grimm e Perrault em uma versão, nada convencional se observado do ponto de vista dos clássicos infantis, pois as personagens principais (Chapeuzinho, Lobo, Lenhador e Vovó) recontam a história sob sua perspectiva. A história da menina que anda pela floresta de capuz e capa vermelhos ganha elementos que a torna uma comédia com aspecto de filmes policiais, de ação e de espionagem. O objetivo deste artigo é observar como processos de intertextualidade e de interdiscursividade constroem os efeitos de humor e de verdade, oferecendo à conhecida história mais do que uma versão para o cinema. Nos limites deste artigo, buscaremos analisar o trailer de Deu a louca na Chapeuzinho e o capítulo no qual a avó apresenta sua versão da história.
Deletion of Methionine Sulfoxide Reductase A Does Not Affect Atherothrombosis but Promotes Neointimal Hyperplasia and Extracellular Signal-Regulated Kinase 1/2 Signaling
Authors: Klutho Paula J. , Pennington Steven M. , Scott Jason A. , Wilson Katina M. , Gu Sean X. , Doddapattar Prakash , Xie Litao , Venema Ashlee N. , Zhu Linda J. , Chauhan Anil K. , Lentz Steven R. , Grumbach Isabella M.
Published: October 2015

Objective—

Emerging evidence suggests that methionine oxidation can directly affect protein function and may be linked to cardiovascular disease. The objective of this study was to define the role of the methionine sulfoxide reductase A (MsrA) in models of vascular disease and identify its signaling pathways.

Approach and Results—

MsrA was readily identified in all layers of the vascular wall in human and murine arteries. Deletion of the
MsrA
gene did not affect atherosclerotic lesion area in apolipoprotein E–deficient mice and had no significant effect on susceptibility to experimental thrombosis after photochemical injury. In contrast, the neointimal area after vascular injury caused by complete ligation of the common carotid artery was significantly greater in MsrA-deficient than in control mice. In aortic vascular smooth muscle cells lacking MsrA, cell proliferation was significantly increased because of accelerated G
1
/S transition. In parallel, cyclin D1 protein and cdk4/cyclin D1 complex formation and activity were increased in MsrA-deficient vascular smooth muscle cell, leading to enhanced retinoblastoma protein phosphorylation and transcription of E2F. Finally, MsrA-deficient vascular smooth muscle cell exhibited greater activation of extracellular signal-regulated kinase 1/2 that was caused by increased activity of the Ras/Raf/mitogen-activated protein kinase signaling pathway.

Conclusions—

Our findings implicate MsrA as a negative regulator of vascular smooth muscle cell proliferation and neointimal hyperplasia after vascular injury through control of the Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 signaling pathway.
Protein-Bound Plasma N
ε
-(Carboxymethyl)lysine Is Inversely Associated With Central Obesity and Inflammation and Significantly Explain a Part of the Central Obesity–Related Increase in Inflammation
Authors: Gaens Katrien H.J. , Ferreira Isabel , van de Waarenburg Marjo P.H. , van Greevenbroek Marleen M. , van der Kallen Carla J.H. , Dekker Jacqueline M. , Nijpels Giel , Rensen Sander S. , Stehouwer Coen D.A. , Schalkwijk Casper G.
Published: October 2015

Objective—

Adipose tissue inflammation contributes to the development of complications, such as insulin resistance and type 2 diabetes mellitus. We previously reported that plasma levels of N
ε
-(carboxymethyl)lysine (CML) were decreased in obese subjects resulting from CML accumulation in adipose tissue and that this CML accumulation plays an important role in adipose tissue inflammation. The objective of this study is to investigate associations between obesity (body mass index, waist circumference, and trunk fat mass), plasma CML (as an inversely correlated marker of CML accumulation in adipose tissue), and low-grade inflammation (LGI) in a large sample of individuals whose weight status ranged from normal to morbid obesity.

Approach and Results—

We studied 1270 individuals of the Cohort on Diabetes and Atherosclerosis Maastricht Study and Hoorn Study, in whom protein-bound CML levels were measured by UPLC-Tandem MS (ultra performance liquid chromatography-tandem mass spectrometry), and 6 inflammatory markers were measured with multiarrays. These inflammatory markers were compiled into an LGI score. Multiple linear regression, adjusted for covariates, showed that (1) waist circumference was inversely associated with protein-bound CML plasma levels (standardized regression coefficient [β]=−0.357 [95% confidence interval: −0.414; −0.301]); (2) protein-bound CML was inversely associated with LGI score (β=−0.073 [−0.130;-0.015]); and (3) the association between waist circumference and LGI (β=0.262 [0.203;0.321]) was attenuated after adjustment for protein-bound CML plasma levels and other potential mediators (to β=0.202 [0.138;0.266]), with CML explaining the greatest portion of the attenuation (≈12%). Further analysis with dual-energy X-ray absorptiometry measures of body composition confirmed a strong inverse association of fat mass preferentially accumulated in the trunk with protein-bound CML plasma levels, significantly explaining ≈21% of the trunk fat–LGI association.

Conclusions—

Obesity, in particular central obesity, is characterized by greater levels of LGI but by lower levels of circulating CML; the latter significantly explaining a portion of the positive association between central obesity and inflammation.
Three-Dimensional Vascular Network Assembly From Diabetic Patient-Derived Induced Pluripotent Stem Cells
Authors: Chan Xin Yi , Black Rebecca , Dickerman Kayla , Federico Joseph , Lévesque Mathieu , Mumm Jeff , Gerecht Sharon
Published: October 2015

Objective—

In diabetics, hyperglycemia results in deficient endothelial progenitors and cells, leading to cardiovascular complications. We aim to engineer 3-dimensional (3D) vascular networks in synthetic hydrogels from type 1 diabetes mellitus (T1D) patient–derived human-induced pluripotent stem cells (hiPSCs), to serve as a transformative autologous vascular therapy for diabetic patients.

Approach and Results—

We validated and optimized an adherent, feeder-free differentiation procedure to derive early vascular cells (EVCs) with high portions of vascular endothelial cadherin-positive cells from hiPSCs. We demonstrate similar differentiation efficiency from hiPSCs derived from healthy donor and patients with T1D. T1D-hiPSC–derived vascular endothelial cadherin-positive cells can mature to functional endothelial cells–expressing mature markers: von Willebrand factor and endothelial nitric oxide synthase are capable of lectin binding and acetylated low-density lipoprotein uptake, form cords in Matrigel and respond to tumor necrosis factor-α. When embedded in engineered hyaluronic acid hydrogels, T1D-EVCs undergo morphogenesis and assemble into 3D networks. When encapsulated in a novel hypoxia-inducible hydrogel, T1D-EVCs respond to low oxygen and form 3D networks. As xenografts, T1D-EVCs incorporate into developing zebrafish vasculature.

Conclusions—

Using our robust protocol, we can direct efficient differentiation of T1D-hiPSC to EVCs. Early endothelial cells derived from T1D-hiPSC are functional when mature. T1D-EVCs self-assembled into 3D networks when embedded in hyaluronic acid and hypoxia-inducible hydrogels. The capability of T1D-EVCs to assemble into 3D networks in engineered matrices and to respond to a hypoxic microenvironment is a significant advancement for autologous vascular therapy in diabetic patients and has broad importance for tissue engineering.
Severity of Psoriasis Associates With Aortic Vascular Inflammation Detected by FDG PET/CT and Neutrophil Activation in a Prospective Observational Study
Authors: Naik Haley B. , Natarajan Balaji , Stansky Elena , Ahlman Mark A. , Teague Heather , Salahuddin Taufiq , Ng Qimin , Joshi Aditya A. , Krishnamoorthy Parasuram , Dave Jenny , Rose Shawn M. , Doveikis Julia , Playford Martin P. , Prussick Ronald B. , Ehrlich Alison , Kaplan Mariana J. , Lockshin Benjamin N. , Gelfand Joel M. , Mehta Nehal N.
Published: October 2015

Objective—

To understand whether directly measured psoriasis severity is associated with vascular inflammation assessed by
18
F-fluorodeoxyglucose positron emission tomography computed tomography.

Approach—

In-depth cardiovascular and metabolic phenotyping was performed in adult psoriasis patients (n=60) and controls (n=20). Psoriasis severity was measured using psoriasis area severity index. Vascular inflammation was measured using average aortic target-to-background ratio using
18
F-fluorodeoxyglucose positron emission tomography computed tomography.

Results—

Both the psoriasis patients (28 men and 32 women, mean age 47 years) and controls (13 men and 7 women, mean age 41 years) were young with low cardiovascular risk. Psoriasis area severity index scores (median 5.4; interquartile range 2.8–8.3) were consistent with mild-to-moderate skin disease severity. Increasing psoriasis area severity index score was associated with an increase in aortic target-to-background ratio (β=0.41,
P
=0.001), an association that changed little after adjustment for age, sex, and Framingham risk score. We observed evidence of increased neutrophil frequency (mean psoriasis, 3.7±1.2 versus 2.9±1.2;
P
=0.02) and activation by lower neutrophil surface CD16 and CD62L in blood. Serum levels of S100A8/A9 (745.1±53.3 versus 195.4±157.8 ng/mL;
P
<0.01) and neutrophil elastase-1 (43.0±2.4 versus 30.8±6.7 ng/mL;
P
<0.001) were elevated in psoriasis. Finally, S100A8/A9 protein was related to both psoriasis skin disease severity (β=0.53;
P
=0.02) and vascular inflammation (β=0.48;
P
=0.02).

Conclusions—

Psoriasis severity is associated with vascular inflammation beyond cardiovascular risk factors. Psoriasis increased neutrophil activation and neutrophil markers, and S100A8/A9 was related to both skin disease severity and vascular inflammation.
Systematic Review of Guidelines for the Management of Asymptomatic and Symptomatic Carotid Stenosis
Authors: Abbott Anne L. , Paraskevas Kosmas I. , Kakkos Stavros K. , Golledge Jonathan , Eckstein Hans-Henning , Diaz-Sandoval Larry J. , Cao Longxing , Fu Qiang , Wijeratne Tissa , Leung Thomas W. , Montero-Baker Miguel , Lee Byung-Chul , Pircher Sabine , Bosch Marije , Dennekamp Martine , Ringleb Peter
Published: October 2015

Background and Purpose—

We systematically compared and appraised contemporary guidelines on management of asymptomatic and symptomatic carotid artery stenosis.

Methods—

We systematically searched for guideline recommendations on carotid endarterectomy (CEA) or carotid angioplasty/stenting (CAS) published in any language between January 1, 2008, and January 28, 2015. Only the latest guideline per writing group was selected. Each guideline was analyzed independently by 2 to 6 authors to determine clinical scenarios covered, recommendations given, and scientific evidence used.

Results—

Thirty-four eligible guidelines were identified from 23 different regions/countries in 6 languages. Of 28 guidelines with asymptomatic carotid artery stenosis procedural recommendations, 24 (86%) endorsed CEA (recommended it should or may be provided) for ≈50% to 99% average-surgical-risk asymptomatic carotid artery stenosis, 17 (61%) endorsed CAS, 8 (29%) opposed CAS, and 1 (4%) endorsed medical treatment alone. For asymptomatic carotid artery stenosis patients considered high-CEA-risk because of comorbidities, vascular anatomy, or undefined reasons, CAS was endorsed in 13 guidelines (46%). Thirty-one of 33 guidelines (94%) with symptomatic carotid artery stenosis procedural recommendations endorsed CEA for patients with ≈50% to 99% average-CEA-risk symptomatic carotid artery stenosis, 19 (58%) endorsed CAS and 9 (27%) opposed CAS. For high-CEA-risk symptomatic carotid artery stenosis because of comorbidities, vascular anatomy, or undefined reasons, CAS was endorsed in 27 guidelines (82%). Guideline procedural recommendations were based only on results of trials in which patients were randomized 12 to 34 years ago, rarely reflected medical treatment improvements and often understated potential CAS hazards. Qualifying terminology summarizing recommendations or evidence lacked standardization, impeding guideline interpretation, and comparison.

Conclusions—

This systematic review has identified many opportunities to modernize and otherwise improve carotid stenosis management guidelines.
Quantitative Intracerebral Hemorrhage Localization
Authors: Muschelli John , Ullman Natalie L. , Sweeney Elizabeth M. , Eloyan Ani , Martin Neil , Vespa Paul , Hanley Daniel F. , Crainiceanu Ciprian M.
Published: October 2015

Background and Purpose—

The location of intracerebral hemorrhage (ICH) is currently described in a qualitative way; we provide a quantitative framework for estimating ICH engagement and its relevance to stroke outcomes.

Methods—

We analyzed 111 patients with ICH from the Minimally Invasive Surgery Plus Recombinant-Tissue Plasminogen Activator for Intracerebral Evacuation (MISTIE) II clinical trial. We estimated ICH engagement at a population level using image registration of computed tomographic scans to a template and a previously labeled atlas. Predictive regions of National Institutes of Health Stroke Scale and Glasgow Coma Scale stroke severity scores, collected at enrollment, were estimated.

Results—

The percent coverage of the ICH by these regions strongly outperformed the reader-labeled locations. The adjusted
R
2
almost doubled from 0.129 (reader-labeled model) to 0.254 (quantitative location model) for National Institutes of Health Stroke Scale and more than tripled from 0.069 (reader-labeled model) to 0.214 (quantitative location model). A permutation test confirmed that the new predictive regions are more predictive than chance:
P<
0.001 for National Institutes of Health Stroke Scale and
P<
0.01 for Glasgow Coma Scale.

Conclusions—

Objective measures of ICH location and engagement using advanced computed tomographic imaging processing provide finer, objective, and more quantitative anatomic information than that provided by human readers.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00224770.
Intracerebral Hematoma Morphologic Appearance on Noncontrast Computed Tomography Predicts Significant Hematoma Expansion
Authors: Blacquiere Dylan , Demchuk Andrew M. , Al-Hazzaa Mohammed , Deshpande Anirudda , Petrcich William , Aviv Richard I. , Rodriguez-Luna David , Molina Carlos A. , Silva Blas Yolanda , Dzialowski Imanuel , Czlonkowska Anna , Boulanger Jean-Martin , Lum Cheemun , Gubitz Gord , Padma Vasantha , Roy Jayanta , Kase Carlos S. , Bhatia Rohit , Hill Michael D. , Dowlatshahi Dar
Published: October 2015

Background and Purpose—

Hematoma expansion in intracerebral hemorrhage is associated with higher morbidity and mortality. The computed tomography (CT) angiographic spot sign is highly predictive of expansion, but other morphological features of intracerebral hemorrhage such as fluid levels, density heterogeneity, and margin irregularity may also predict expansion, particularly in centres where CT angiography is not readily available.

Methods—

Baseline noncontrast CT scans from patients enrolled in the Predicting Hematoma Growth and Outcome in Intracerebral Hemorrhage Using Contrast Bolus CT (PREDICT) study were assessed for the presence of fluid levels and degree of density heterogeneity and margin irregularity using previously validated scales. Presence and grade of these metrics were correlated with the presence of hematoma expansion as defined by the PREDICT study on 24-hour follow-up scan.

Results—

Three hundred eleven patients were included in the analysis. The presence of fluid levels and increasing heterogeneity and irregularity were associated with 24-hour hematoma expansion (
P
=0.021, 0.003 and 0.049, respectively) as well as increases in absolute hematoma size. Fluid levels had the highest positive predictive value (50%; 28%–71%), whereas margin irregularity had the highest negative predictive value (78%; 71%–85). Noncontrast metrics had comparable predictive values as spot sign for expansion when controlled for vitamin K, antiplatelet use, and baseline National Institutes of Health Stroke Scale, although in a combined area under the receiver-operating characteristic curve model, spot sign remained the most predictive.

Conclusions—

Fluid levels, density heterogeneity, and margin irregularity on noncontrast CT are associated with hematoma expansion at 24 hours. These markers may assist in prediction of outcomes in scenarios where CT angiography is not readily available and may be of future help in refining the predictive value of the CT angiography spot sign.
Acute Loss of miR-221 and miR-222 in the Atherosclerotic Plaque Shoulder Accompanies Plaque Rupture
Authors: Bazan Hernan A. , Hatfield Samuel A. , O’Malley Chasity B. , Brooks Ashton J. , Lightell Daniel , Woods T. Cooper
Published: October 2015

Background and Purpose—

Atherosclerotic plaque vulnerability is accompanied by changes in the molecular and cellular function in the plaque shoulder, including a decrease in vascular smooth muscle cell proliferation. We aimed to determine whether the expression of 3 miRNAs that regulate vascular smooth muscle cell proliferation (miR-145, miR-221, and miR-222) is altered with plaque rupture, suggesting a role in regulating plaque stability.

Methods—

miRNAs were measured in the plaque shoulder of carotid plaques obtained from patients undergoing carotid endarterectomy (CEA) for 3 distinct clinical scenarios: (1) patients without previous neurological events but high-grade carotid stenosis (asymptomatic), (2) patients with an acute neurological event within 5 days of the CEA (urgent), and (3) patients undergoing CEA>5 days after a neurological event (symptomatic).

Results—

Mean time from plaque rupture event to CEA was 2.4 days in the urgent group. The urgent group exhibited a significant decrease in miR-221 and miR-222 expression in the plaque shoulder, whereas no significant differences were seen in miR-145 across the 3 groups. Regression analysis demonstrated a significant correlation between time from the neurological event to CEA and increasing miR-221 and miR-222, but not miR-145. mRNA encoding p27
Kip1
, a target of miR-221 and miR-222 that inhibits vascular smooth muscle cell proliferation, was increased in the urgent group.

Conclusions—

Atherosclerotic plaque rupture is accompanied by a loss of miR-221 and miR-222 and an increase in p27
Kip1
mRNA expression in the plaque shoulder, suggesting an association between these miRNAs and atherosclerotic plaque stability.
Nocturnal mating behaviour and dynamic male investment of copulation time in the southern blue-ringed octopus, Hapalochlaena maculosa (Cephalopoda: Octopodidae)
Authors: Morse Peter , Zenger Kyall R. , McCormick Mark I. , Meekan Mark G. , Huffard Christine L.
Published: October 2015

The southern blue-ringed octopus,Hapalochlaena maculosaHoyle (1883), is a nocturnal species that exhibits a mating system in which females hold sperm from multiple males over a one to two month breeding window before laying a single egg clutch. Contrary to most studied animal mating systems where anisogamy exists, gamete package production is limited for both males and females of this species (approx. 50 spermatophores/eggs). This presents an animal model for studying aspects of sperm competition and dynamic mate choice behaviours. The present study reports on the mating behaviour ofH. maculosaobserved under laboratory conditions using infrared closed-circuit television video footage. Rates of male copulation attempts increased with male size, while female receptivity to mating attempts increased with female size, resulting in larger animals of both sexes gaining more copulations and spending more time per day in copulation. There was some evidence of female preference of larger males, but no male preference of females based on measured morphological traits. Both sexes terminated copulations in equal frequencies but male-terminated copulations were significantly shorter in duration. Males were more likely to terminate copulation early with females they had previously mated with, however were less likely to do so if the female had recently mated with a different male. Among male-terminated copulations, males mated for longer with females that had previously mated with other males in the trial. Male–male mounts were as common as male–female mounts, suggesting that maleH. maculosaare not able to discriminate the sex of conspecifics. These findings suggest male strategic allocation of spermatophores based female mating history is an important factor influencing mating behaviours of this species.
Constraining a 3DVAR Radar Data Assimilation System with Large-Scale Analysis to Improve Short-Range Precipitation Forecasts
Authors: Vendrasco Eder Paulo , Sun Juanzhen , Herdies Dirceu Luis , Frederico de Angelis Carlos
Published: October 2015

It is known from previous studies that radar data assimilation can improve short-range forecasts of precipitation, mainly when radial wind and reflectivity are available. However, from the authors’ experience radar data assimilation, when using the three-dimensional variational data assimilation (3DVAR) technique, can produce spurious precipitation results and large errors in the position and amount of precipitation. One possible reason for the problem is attributed to the lack of proper balance in the dynamical and microphysical fields. This work attempts to minimize this problem by adding a large-scale analysis constraint in the cost function. The large-scale analysis constraint is defined by the departure of the high-resolution 3DVAR analysis from a coarser-resolution large-scale analysis. It is found that this constraint is able to guide the assimilation process in such a way that the final result still maintains the large-scale pattern, while adding the convective characteristics where radar data are available. As a result, the 3DVAR analysis with the constraint is more accurate when verified against an independent dataset. The performance of this new constraint on improving precipitation forecasts is tested using six convective cases and verified against radar-derived precipitation by employing four skill indices. All of the skill indices show improved forecasts when using the methodology presented in this paper.