bluuebunny/crossref_metadata_2025 huggingface dataset:
Emoticon Analysis for Chinese Social Media and E-commerce
Authors: Yu Shuo , Zhu Hongyi , Jiang Shan , Zhang Yong , Xing Chunxiao , Chen Hsinchun
Published: March 2019

This article presents a novel system, AZEmo, which extracts and classifies emoticons from the ever-growing critical Chinese social media and E-commerce. An emoticon is a meta-communicative pictorial representation of facial expressions, which helps to describe the sender’s emotional state. To complement non-verbal communication, emoticons are frequently used in social media websites. However, limited research has been done to effectively analyze the affects of emoticons in a Chinese context. In this study, we developed an emoticon analysis system to extract emoticons from Chinese text and classify them into one of seven affect categories. The system is based on a kinesics model that divides emoticons into semantic areas (eyes, mouths, etc.), with improvements for adaptation in the Chinese context. Machine-learning methods were developed based on feature vector extraction of emoticons. Empirical tests were conducted to evaluate the effectiveness of the proposed system in extracting and classifying emoticons, based on corpora from a video sharing website and an E-commerce website. Results showed the effectiveness of the system in detecting and extracting emoticons from text and in interpreting the affects conveyed by emoticons.
Stephen Elliott Fienberg 1942–2016, Founding Editor of the Annual Review of Statistics and Its Application
Authors: Carriquiry Alicia L. , Reid Nancy , Slavković Aleksandra B.
Published: March 2019

Stephen Elliott Fienberg was the founding editor of the Annual Review of Statistics and Its Application. Steve had an outsized personality and a passion for statistical science that was quite unique, and he combined these with his legendary energy to provide a remarkable level of leadership for the statistical science community, and a sweeping vision of the importance of statistical arguments for science, health and policy. The editorial team of the Annual Review of Statistics and Its Application is working hard to carry on his legacy for the journal. In this article we highlight some of his contributions through the voices of his students and collaborators. It is by no means a comprehensive assessment of his scholarship, but we hope it provides a window into his impact and influence on several generations of scholars. As Reid & Stigler (2017) wrote in Volume 4, “his lasting imprint on the science of statistics and its application defies simple categorization.”
Role of Parathyroid Hormone Assay and Bedside Ultrasound in the Emergency Department in Differentiating Acute Kidney Injury from Chronic Kidney Disease: A Systematic Review
Authors: Roy Deepali Junnarkar , Pande Shrikant Digambarrao , Liew Zhong Hong , Roy Debajyoti
Published: March 2019

Introduction. It is not uncommon for patients without preceding history of kidney disease to present to the Emergency department with renal failure. The absence of prior medical records or renal imaging presents a diagnostic challenge. Elevated parathyroid hormone levels or echogenic contracted kidneys on ultrasound are known to point to a diagnosis of chronic kidney disease. The literature in this regard is surprisingly limited. The objective of this study is to assess the role of intact parathyroid (iPTH) blood level and bedside ultrasound in differentiating acute kidney injury from chronic kidney disease. Methods. A systematic review which included a literature search of 3 databases, PubMed, Embase, and Cinahl (R) as also secondary sources, was done. The inclusion criteria evaluated studies which evaluated iPTH or bedside ultrasound in differentiating acute kidney injury from chronic kidney disease. We excluded studies which used other laboratory biomarkers like neutrophil gelatin associated lipocalin (NGAL) or carbamylated haemoglobin. A total of 2256 articles were identified. After screening, the relevant articles were reviewed, and an assessment of their methodological quality was made based on the CASP: Critical Appraisals Skill Programme. Results. Of the 2256 articles identified, after screening, only 5 were identified as relevant. Conclusions. An elevated parathyroid hormone level and echogenic contracted kidneys on bedside ultrasound in the Emergency department can help differentiate acute kidney injury from chronic kidney disease. This differentiation helps decide need for admission as well as further management. Although iPTH level may also rise in acute kidney injury, the value (2.5 times normal) can discriminate it from chronic kidney disease.
Oxidative Degradation of Amoxicillin in Aqueous Solution by Thermally Activated Persulfate
Authors: Zhao Juanjuan , Sun Yujiao , Wu Fachao , Shi Minjian , Liu Xurui
Published: March 2019

Antibiotic residues and antibiotic resistance genes (ARGs) pose a great threat to public health and food security via the horizontal transfer in the food production chain. Oxidative degradation of amoxicillin (AMO) in aqueous solution by thermally activated persulfate (TAP) was investigated. The AMO degradation followed a pseudo-first-order kinetic model at all tested conditions. The pseudo-first-order rate constants of AMO degradation well-fitted the Arrhenius equation when the reaction temperature ranged from 35°C to 60°C, with the apparent activate energy of 126.9 kJ·mol−1. High reaction temperature, high initial persulfate concentration, low pH, high Cl− concentration, and humic acid (HA) concentration increased the AMO degradation efficiency. The EPR test demonstrated that both ·OH and SO4·− were generated in the TAP system, and the radical scavenging test identified that the predominant reactive radical species were SO4·− in aqueous solution without adjusting the solution pH. In groundwater and drinking water, AMO degradation suggested that TAP could be a reliable technology for water remediation contaminated by AMO in practice.
Lysinibacillus sphaericusas a Nutrient Enhancer during Fire-Impacted Soil Replantation
Authors: Aguirre-Monroy A. M. , Santana-Martínez J. C. , Dussán J.
Published: March 2019

Over the past ten years, more than twenty fires have affected the El Noviciado estate located in Cerro Majuy, Colombia, leading to a loss of soil nutrients and infertility.Lysinibacillus sphaericus, a Gram-positive, mesophilic, and spore-forming bacterium, can be used in soil amendment in the replantation processes, given its ability to fix nitrogen, and nitrify, and solubilize phosphorus, increasing soil nutrients used for plant growth. In this study, we evaluated the soil-amendment potential ofL. sphaericusby monitoring the nutrient content of a selected fragment of soil in the El Noviciado estate. For this purpose, we added a mixture ofL. sphaericusOT4b.31, OT4b.49, CBAM5, III(3)7, and 2362 strains and determined the ammonium, nitrites, nitrates, phosphorus, and indole acetic acid concentrations in soil.Alnus acuminatasbsp.acuminata, a native model plant known for its restoration effect, was used for replantation. Results indicated that soils with addedL. sphaericuspresented significant differences in ammonium, nitrites, nitrates, phosphorus, and indole acetic acid concentrations when compared to control soils. Further, results showed no significant differences between soil that had been pre-inoculated in greenhouse and soil directly inoculated in field. We propose thatL. sphaericuscould be a good nutrient enhancer and plant growth promoter that can be used for the amendment of fire-impacted soils and replantation treatments.
Asymptotic Exponential Arbitrage in the Schwartz Commodity Futures Model
Authors: Welemical Tesfamariam Tadesse , Aduda Jane Akinyi , Bidima Martin Le Doux Mbele
Published: March 2019

In this paper, we consider the Schwartz’s one-factor model for a storable commodity and a futures contract on that commodity. We introduce the analysis of asymptotic arbitrage in storable commodity models by proving that the futures prices process allows asymptotic exponential arbitrage with geometric decaying failure probability. Next, we find by comparison that, under some similar conditions, our result is a corresponding commodity assets (stronger) version of Föllmer and Schachermayer’s result stated in the modeling setting of geometric Ornstein-Uhlenbeck process for financial security assets.
Effect of Lanthanum Doping on the Microstructure, Thermal Stability, and CO2 Adsorption Property of ZIF-8
Authors: Wang Sheng , Zhang Shengquan , Du Xueyan , Shen Yingying , Ma Zhiwei
Published: March 2019

The reaction materials La(NO3)3·6H2O, Zn(NO3)2·6H2O, and 2-methylimidazole were mixed in a certain proportion. A research process innovatively adopts the parallel flow-drop solvothermal method and a lanthanum-doping method to achieve the synthesis of metal organic frameworks. In this study, we successfully introduce lanthanum into the framework of ZIF-8 to stabilize the spatial structure and improve its performance. The structure and properties of La-ZIF-8 were characterized by the X-ray diffraction (XRD), scanning electron microscope (SEM), thermogravimetry analysis (TGA), and fourier transform infrared spectroscopy (FTIR). The relationship between microstructure stability and macroscopical properties is illustrated. The results show that the doping of lanthanum is beneficial for improving the thermal stability and CO2 adsorption property of ZIF-8 because of the improvement in the microstructure. The introduction of lanthanum to the ZIF-8 is also beneficial for forming porous frameworks and raising the thermal stability and CO2 adsorption properties. The crystallinity, structure, morphology, and thermal stability of La-ZIF-8 are optimal at the La content of 2 atom.%.
Vascular Depression and Cognition in Mexican Americans
Authors: Johnson Leigh Ann , Large Stephanie Ellen , Izurieta Munoz Haydee , Hall James Richard , O’Bryant Sid E.
Published: March 2019

Background: Mexican Americans are at increased risk of developing mild cognitive impairment (MCI) and Alzheimer’s disease compared to non-Hispanic whites. This study sought to examine the relationship between vascular risk, depression, and cognition in Mexican American elders. Methods: Data from 470 (390 normal controls, 80 MCI patients) Mexican Americans enrolled in the Health and Aging Brain among Latino Elders (HABLE) study were used. The cardiovascular risk was assessed by the Framingham Risk Score. Cognition was assessed with a neuropsychological battery, and depression was assessed based on scores from the Geriatric Depression Scale (GDS). ANOVAs were utilized to determine the differences in neuropsychological scores of normal controls with and without depression and CVD risk (low vs. high). Follow-up logistic regression was conducted to determine MCI risk. Results: The results of this study indicated that comorbid depression and a high CVD risk were associated with poorer cognitive performance in Mexican Americans. Depressed women with high CVD risk were more likely to have executive dysfunction, language deficits, and poorer global cognition than nondepressed women with a high CVD risk. In Mexican American men, those with a high vascular risk and depression were more likely to have executive dysfunction and poorer immediate memory than the nondepressed high-risk group. Higher GDS scores (OR = 1.10; 95% CI 1.02–1.10, p = 0.001) and higher vascular risk scores (OR = 1.05; 95% CI 1.02–1.10, p = 0.001) significantly predicted MCI status in Mexican Americans. Conclusion: The results of this study indicated that comorbid depression and a high CVD risk were associated with poorer cognitive performance and increased risk of MCI in Mexican Americans.
Cerebrospinal Fluid Biomarkers for the Diagnosis of Prodromal Alzheimer’s Disease in Amnestic Mild Cognitive Impairment
Authors: Park Jung Eun , Choi Kyu Yeong , Kim Byeong C. , Choi Seong-Min , Song Min-Kyung , Lee Jang Jae , Kim Jahae , Song Ho-Chun , Kim Hoo-Won , Ha Jung-Min , Seo Eun Hyun , Song Woo Keun , Park Sung-Gyoo , Lee Jung Sup , Lee Kun Ho
Published: March 2019

Background/Aims: Disease-modifying therapy for Alzheimer’s disease (AD) has led to a need for biomarkers to identify prodromal AD and very early stage of AD dementia. We aimed to identify the cutoff values of cerebrospinal fluid (CSF) biomarkers for detecting prodromal AD. Methods: We assessed 56 patients with amnestic mild cognitive impairment (aMCI) who underwent lumbar puncture. Additionally, 87 healthy elderly individuals and 34 patients with AD dementia served as controls. Positron emission tomography was performed using florbetaben as a probe. We analyzed the concentration of Aβ1–42, total tau protein (t-Tau), and tau protein phosphorylated at threonine 181 (p-Tau181) in CSF with INNOTEST enzyme-linked immunosorbent assay. Results: For the detection of prodromal AD in patients with aMCI, the cutoff values of CSF Aβ1–42, t-Tau, and p-Tau181 were 749.5 pg/mL, 225.6 pg/mL, and 43.5 pg/mL, respectively. To discriminate prodromal AD in patients with aMCI, the t-Tau/Aβ1–42 and ­p-Tau181/Aβ1–42 ratios defined cutoff values at 0.298 and 0.059, respectively. Conclusions: CSF biomarkers are very useful tools for the differential diagnosis of prodromal AD in aMCI patients. The concentration of CSF biomarkers is well correlated with the stages of the AD spectrum.
Representações de poder, mediações do Império: festas e cerimoniais na monarquia dos Habsburgo
Authors: Soutto Mayor Mariana
Published: March 2019

Resenha do livro: CREMADES, Fernando Checa & FERNÁNDEZ-GONZALEZ, Laura (ed.). Festival culture in the world of the Spanish Habsburgs . Nova York: Routledge, 2016 (Primeira publicação em 2015 por Ashgate Publishing).
A prisão em São Paulo no início do século XIX: demandas sociais, atores e contradições
Authors: Mantovani Rafael
Published: March 2019

Este artigo analisa os discursos sobre a demanda prisional ao longo do século XIX nos registros oficiais da Câmara Municipal de São Paulo, nos relatórios das comissões de inspeção e nos periódicos dos estudantes da Faculdade de Direito do Largo do São Francisco. A contradição entre a idealizada prisão moderna e a sua realidade na capital paulista – considerada uma instituição decadente por não cumprir com o seu papel manifesto – expressa o mesmo descompasso/paradoxo entre o pensamento político moderno e a realidade escravocrata brasileira. Mesmo em teoria, a prisão “regeneradora” só poderia ser sugerida em uma sociedade juridicamente livre; por outro lado, a prisão paulistana denunciada como atroz e desumana era a instituição socialmente legítima e necessária em uma sociedade escravocrata.
Using camera traps to study the elusive European Wildcat Felis silvestris silvestris Schreber, 1777 (Carnivora: Felidae) in central Germany: what makes a good camera trapping site?
Authors: Wening Harald , Werner Lynne , Waltert Matthias , Port Markus
Published: March 2019

Camera traping is a widely used method to study the abundance and population density of elusive terrestrial animals.  To make full use of this method, it is necessary to obtain high photographic capture rates of the target species.  We examine what characteristics of camera trapping sites are associated with high photographic capture rates of European Wildcat Felis silvestris silvestris.  We measured Wildcat capture rates across 25 camera trapping sites located in a 20km² study area within an unprotected low mountain range forest in central Germany.  We measured the distance of each trapping site to the forest boundary, to the next watercourse, and to the next human settlement, and broadly defined the type of forest structure the site was located in.  None of these site characteristics, however, predicted wildcat photographic capture success.  We also examined the degree of human disturbance at the site, measured as the photographic capture rate of humans (including vehicles).  Wildcats were detected at similar rates on dirt or gravel roads (heavily used by humans) as on soft-surfaced paths or logging trails (less frequently used by humans), and the degree of human disturbance across sites did not affect wildcat capture success.  We, therefore, suggest that trail features such as course, curvature and width, or vegetation density along the trail are more important determinants of Wildcat capture success than habitat characteristics.  We conclude that for European Wildcats, as for many larger felids, forest roads provide suitable camera trapping sites and that Wildcats are fairly tolerant towards human traffic on these roads.
Estimating Leopard Cat Prionailurus bengalensis Kerr, 1792 (Carnivora: Felidae) density in a degraded tropical forest fragment in northeastern Thailand
Authors: Petersen Wyatt Joseph , Savini Tommaso , Steinmetz Robert , Ngoprasert Dusit
Published: March 2019

The Leopard Cat Prionailurus bengalensis is thought to be Asia’s most abundant wild cat.  Yet, the species’ status is poorly known due to a lack of rigorous population estimates.  Based on the few studies available, Leopard Cats appear to be more abundant in degraded forests, potentially due to increased prey availability.  We conducted camera trap surveys, rodent live-trapping, and spatially-explicit capture-recapture analyses to estimate the density of Leopard Cats within a degraded tropical forest fragment (148km2) in northeastern Thailand.  A total effort of 12,615 camera trap nights across 65km2 of trapping area resulted in at least 25 uniquely identified individuals.  Average rodent biomass (the main prey of Leopard Cats) was highest in the dry evergreen forest (469.0g/ha), followed by dry dipterocarp forest (287.5g/ha) and reforested areas (174.2g/ha).  Accordingly, Leopard Cat densities were highest in the dry evergreen forest with 21.42 individuals/100km2, followed by the reforested areas with 7.9 individuals/100km2.  Only two detections came from the dry dipterocarp forest despite both an extensive survey effort (4,069 trap nights) and available prey.  Although the dipterocarp supported the second highest average rodent biomass, it lacked a key prey species, Maxomys surifer, possibly explaining low encounter rates in that habitat.  Our results provide important baseline information concerning the population status of Leopard Cat in southeastern Asia.  Further, our findings corroborate with other studies that found a tolerance among Leopard Cats for degraded forests, highlighting the potential for forest fragments to serve as long-term conservation areas for the species.
An update on the status of Fishing Cat Prionailurus viverrinus Bennett, 1833 (Carnivora: Felidae) in Thailand
Authors: Chutipong Wanlop , Kamjing Anucha , Klinsawat Worata , Ngoprasert Dusit , Phosri Kitipat , Sukumal Niti , Wongtung Pongnapa , Tantipisanuh Naruemon
Published: March 2019

Fishing Cat Prionailurus viverrinus is threatened throughout its range by habitat loss, persecution, and non-targeted hunting; it is listed as Vulnerable on the IUCN Red List of Threatened Species.  Even basic distribution data are still lacking in many parts of its range, particularly in southeastern Asia where most wildlife surveys focus on large charismatic carnivores in protected habitats, typically inland blocks of evergreen or semi-evergreen and deciduous forests.  This report aims to update on distribution and status of Fishing Cat in Thailand.  Historic (the 1980s) and current (2007–2017) records from Thailand were compiled based on personal communications, local news agencies, social media pages, and publications.  The current Thai Fishing Cat distribution seems to be highly fragmented and mostly in coastal wetlands of the Inner Gulf of Thailand and the Thai-Malay Peninsula with one confirmed record from a riverine habitat in central Thailand.  No confirmed records came from protected forested areas—perhaps these are marginal habitat for Fishing Cat.  Nevertheless, there were no targeted surveys in those areas.  Fishing Cat was so far not detected from on-going otters’ targeted camera trap surveys along Thailand’s Andaman coast.  Future surveys should focus on coastal and inland wetlands to expedite the discovery of remaining populations before these are extirpated.
Abstract 001: Skap2 Regulates Atherosclerosis through Macrophage Polarization and Efferocytosis
Authors: Schroeder Allison , Hyatt Danielle , Alenghat Francis J
Published: March 2019

Background:
Atherosclerosis causes more deaths than any other pathophysiologic process. It has a well-established inflammatory, macrophage-mediated component, but potentially protective intracellular macrophage processes in atherosclerosis remain enigmatic. Src Kinase-Associated Phosphoprotein 2 (Skap2) is a macrophage-predominant adaptor protein critical for cytoskeletal reorganization, and thereby, for macrophage migration and chemotaxis. The role of macrophage Skap2 in atherosclerosis is unknown and deserves exploration.

Results:
Human macrophages express Skap2, and in human arterial gene expression analysis,
Skap2
expression is enriched in macrophage-containing areas of human atheroma; the transcript level varies with plaque characteristics, with higher levels in more stable plaques. In
ApoE
-/-
mice on a standard diet, deletion of
Skap2
accelerates atherosclerosis by threefold at 18 and 24 weeks. We find that Skap2 expression is switched on only as monocytes differentiate into adherent macrophages, so
Skap2
-/-
monocytes do not have a defect in infiltrating the atheroma, as reflected by abundant macrophages in the Skap2
-/-
plaques. On the other hand, once they fully differentiate, Skap2-deficient macrophages cannot polarize efficiently into alternatively-activated, regulatory macrophages, and instead they preferentially polarize toward the classical pro-inflammatory phenotype both
ex vivo
and within the developing atheroma. This defect extends to polarized effector functions, as
ex vivo
analysis of macrophage phagocytosis of dying foam cells indicates that Skap2 is required for the regulatory process of efferocytosis. There are no differences in macrophage proliferation or apoptosis attributable to Skap2. Finally, Skap2 binds to Sirpα, whose interaction with CD47 has been shown to be important for efferocytosis, and we observe colocalization of actin, Sirpα, and CD47 at leading edges of macrophages in a Skap2-dependent manner.

Conclusions:
Taken together, our findings support a model in which Skap2 drives a regulatory, efferocytic mode of behavior to quell atherosclerosis.
Abstract 009: Ribosomal Profiling of Vascular Smooth Muscle Cells
in Vivo
Identifies Cell-type Specific Transcripts and Enrichment of Blood Pressure Associated Genes
Authors: Cleuren Audrey C , van der Ent Martijn A , Hunker Kristina L , Yang Min-Lee , Jiang Hui , Ginsburg David , Ganesh Santhi K
Published: March 2019

Background:
Vascular smooth muscle cells (vSMCs) are essential for maintaining blood vessel tone and vascular remodeling. Although they play an important role in cardiovascular pathologies, studying peripheral artery vSMCs
in vivo
has been complicated given their interspersed anatomic distribution and technical difficulties with isolating vSMCs from arteries and arterioles while preserving transcriptome profiles.

Methods and Results:
Combining the murine

Rpl22
fl

Ribotag model with a vSMC-specific Transgelin-Cre (
Tagln-Cre
) Recombinase knock-in, we performed translating ribosome affinity purification and isolation of mRNA derived specifically from
Cre
-expressing
+
cells only. Subsequent high-throughput sequencing of both whole tissue mRNA and the vSMC-selected mRNA of the brain, kidney and liver was followed by differential expression analysis to identify genes enriched in the vSMC compartment. Genes significantly enriched in all three tissues (FDR <5%) included well known vSMC markers such as Smooth muscle actin (
Acta2
) and Calponin-1 (
Cnn1
) in addition to
Tagln.
Furthermore, transcripts involved in biological processes associated with extracellular matrix and structure organization were enriched and significant overrepresentation of these genes was also seen by gene ontology analysis. Genes with roles in blood pressure regulation, such as Regulator of G protein signaling 5 (
Rgs5
) and Sphingosine-1-phosphate receptor 3 (
S1pr3
) were also significantly enriched in the vSMC transcriptome, and the expression and vSMC-specific localization of these genes were confirmed by fluorescent single-molecule
in situ
hybridization assays. Further, we performed gene set enrichment analysis of genes associated with blood pressure and hypertension based on human genome-wide association studies, and a significant number of these genes (
P
=0.003) showed vSMC-specific expression patterns in our
in vivo
data.

Conclusion:
Our data demonstrate the feasibility of profiling vSMC gene expression
in vivo.
Furthermore, we identified enrichment of blood pressure-associated genes in the vSMC transcriptome. This model has the potential to provide new insights into the role of vSMCs in physiology and a variety of cardiovascular pathologies.
Abstract 012: Aorta-on-a-chip: a Tool to Gain Molecular and Translational Insight Into Vascular Diseases
Authors: Paloschi Valentina , Rolli Claudio , Buchmann Benedikt , Meucci Sandro , Rogowitz Felix , Bausch Andreas , Maegdefessel Lars
Published: March 2019

Vascular cell biology research is focused on understanding how endothelial cells and smooth muscle cells react to relevant biological, chemical and physical stimuli. Importantly,
in vivo
, dynamic conditions are present: vascular endothelial cells (ECs) are constantly subjected to shear stress and smooth muscle cells (SMCs) are stretched due to pulsation during the cardiac cycle. A three-dimensional network composed of extracellular matrix proteins maintains the homeostasis of the cells. The aim of this project is to realize an
in vitro
model of the human aorta (
aorta-on-a-chip
), an innovative tool that by resembling the
in vivo
structure of the aorta allows us to study how cells layers and matrix are sensing and responding to a pro-atherogenic environment (i.e. low shear stress) and to gain insight in the pathological remodeling occurring during progression of vascular diseases. The device consists of two re-sealable glass slides, assembled with a membrane suspended in between them, which creates two separate flow chambers. After coating both sides of the membrane with fibronectin, ECs and SMCs are seeded sequentially, in order to obtain a confluent ECs-SMCs co-culture, mimicking the intima-media interface of the aortic wall. The co-culture device is connected to a microfluidic pump system where ECs are exposed to physiologically relevant shear stress (8-12 dyne/cm
2
). The SMCs flow-chamber is exposed to a low shear stress (0.0042 dyne/cm
2
) to ensure physiological turnover of influx of nutrients and efflux of waste. Molecular and phenotypic evaluation of the cells is performed by measuring gene expression changes (RNA sequencing) and protein analyses (immunofluorescence for cell markers), respectively. For translational purposes, cells deriving from patients with aortic diseases (compared to un-diseased organ donor controls) can be implemented and tested with the chip.
Abstract 016: Glucose Metabolism is Required for Platelet Hyperactivation in a Murine Model of Type 1 Diabetes Mellitus
Authors: Fidler Trevor P , Marti Alex P , Gerth Katelyn , Rondina Matthew T , Weyrich Andrew S , Abel Evan D
Published: March 2019

Patients with type 1 diabetes mellitus (T1DM) have increased thrombosis and platelet activation. The mechanisms for platelet hyperactivation in diabetes are incompletely understood. T1DM is accompanied by hyperglycemia, hyperlipidemia, increased inflammation, and an alternated hormonal milieu. In vitro analysis of platelets demonstrates that low glucose reduces platelet activation while hyperglycemic conditions increase platelet activation. We therefore hypothesized that hyperglycemia increases platelet glucose utilization, which directly increases platelet activation to promote thrombosis. To test this hypothesis platelets were isolated from mice treated with streptozotocin (STZ), to induce T1DM and revealed increased glucose uptake and glycolysis along with induction of glucose transporter 3 (GLUT3). Functionally, platelets from STZ-treated mice exhibited increased activation following administration of PAR4 peptide and convulxin. In contrast, platelets isolated from platelet specific (glucose transporter 1 (GLUT1 and GLUT3) double knockout (DKO) mice, which lack the ability to utilize glucose, failed to increase activation in hyperglycemic mice. In addition, diabetic mice displayed decreased survival in a collagen/epinephrine induced pulmonary embolism model relative to non-diabetic controls. In contrast, survival following pulmonary embolism was increased in diabetic DKO mice, relative to non-diabetic controls. Together these data reveal that in a model of T1DM hyperglycemia increases platelet GLUT3 protein expression, glucose metabolism, platelet activation and thrombosis.
Abstract 021:
ARHGEF26
is a Novel Genetic Risk Factor for Vascular Inflammation and Coronary Artery Disease
Authors: Zhu Qiuyu M , Klarin Derek , Emdin Connor A , Chaffin Mark , Horner Steven , McMillan Brian , Leed Alison , Weale Michael E , Spencer Chris C , Aguet François , Segrè Ayellet V , Ardlie Kristin G , Khera Amit V , Kaushik Virendar K , Natarajan Pradeep ,   CARDIoGRAMplusC4D Consortium, Kathiresan Sekar
Published: March 2019

Vascular inflammation drives the initiation and progression of coronary artery disease (CAD). However, the underlying genetic factors are not well understood. We performed a genome-wide association study in UK Biobank testing 9 million DNA variants for association with CAD (4,831 cases, 115,455 controls), followed by a meta-analysis with previous results. We identified
ARHGEF26
(Rho guanine nucleotide exchange factor 26) as a novel locus significantly associated with CAD (combined OR=1.08, 95% CI 1.06-1.11, P=1.02 х 10
–9
). We hypothesized that ARHGEF26 regulates vascular inflammation by affecting the function of vascular cells. Focusing on the haplotype tagged by the lead variant rs12493885 (ARHGEF26 p.Val29Leu), we performed eQTL and allele-specific expression analyses. There is no significant
ARHGEF26
transcription alteration or allelic imbalance associated with the risk allele in human coronary artery samples. Promoter luciferase assay showed no significant difference between the reference and alternative haplotypes. In contrast, expression of exogenous Leu29 mutant after depletion of endogenous ARHGEF26 led to rescued phenotypes consistently exceeding those observed with overexpression of wild-type ARHGEF26, including increased leukocyte transendothelial migration, leukocyte adhesion on endothelial cells, and smooth muscle cell proliferation. These data suggest that the CAD-risk allele (Leu29) may lead to a gain of protein function in vascular cells. To identify the molecular mechanism, we compared the nucleotide-exchange activity between the wild-type and mutant proteins and found no significant difference. Evaluation of ARHGEF26 protein stability by cycloheximide chase showed the Leu29 mutant displayed longer half-life than wild-type ARHGEF26, suggesting the gain-of-function phenotypes of Leu29 in cells may be secondary to its resistance to degradation. Quantitative proteomics revealed differential protein interaction between the wild-type and Leu29 ARHGEF26 in endothelial cells, highlighting critical inflammatory pathways impacted by the CAD-risk allele. In summary, our work identified a novel genetic risk factor for CAD, and enabled discovery of novel CAD-causing pathways in vascular inflammation.
Abstract 024: Association of APOL1 Risk Alleles with Coronary Heart Disease in Million Veteran Program
Authors: Bick Alexander G , Assimes Themistocles L , Giri Ayush , Klarin Derek , Lynch Julie , Robisson-Cohen Cassieanne , Huffman Jennifer E , Sun Yan V , Chang Kyong-Mi , Miller Donald R , Cho Kelly , Edwards Todd , O'Donnell Chris , Tsao Philip S , Wilson Peter W , Kathiresan Sekar , Rader Daniel J , Hung Adriana M , Damrauer Scott M
Published: March 2019

Background:
Approximately 13% of African-Americans carry 2 copies of the
APOL1
risk alleles G1 or G2, which are associated with increased risk of CKD. There have been conflicting reports as to whether an association also exists between
APOL1
and cardiovascular disease.

Objective:
Determine the association between
APOL1
and CAD in African Americans genotyped in the Million Veteran Program (MVP)

Methods and Results:
APOL1
risk alleles were genotyped in 64,792 African American MVP participants. 7,987 (12%) of the participants carried the high-risk genotype comprised of 2 risk alleles. Of the high-risk carriers, 36% were G1 homozygotes, 49% were G1/G2 compound heterozygotes, and 15% were G2 homozygotes. We first confirmed the known association of the
APOL1
risk genotype with end stage renal disease (OR 2.75, P=1.8 x 10
-66
). We then considered the association between the high-risk
APOL1
genotype and prevalent CAD. Based on electronic health record data, 11,902 (19.4%) of the participants had CAD. Individuals with 2 risk alleles trended toward increased rates of CAD compared to those with no risk alleles (OR 1.075, p=0.03). The strength of the association varied by the nature of composition of the high-risk genotype: G1/G1 carriers had increased rates of CAD (OR 1.19, p=0.002), G1/G2 carriers had a trend towards increased CAD (OR 1.08, p=0.1), and G2/G2 carriers had no differences in CAD rates (OR 0.99, p=0.9) than controls. Adjusting for traditional CAD risk factors and kidney disease in multivariable regression models attenuated the significance of the association between
APOL1
and CAD.

Conclusions:
APOL1
variant contribution to CAD risk is genotype dependent and likely mediated by the known
APOL1
association with CKD. The modest effect of
APOL1
on CVD, the differential presence of CKD, and the relative proportion of G1 and G2 alleles may explain the conflicting findings in the published literature.
Abstract 029: Interleukin-35 Suppresses Endothelial Activation by Inhibiting Mitochondrial Reactive Oxygen Species Mediated Site-specific Acetylation of Histone 3 Lysine 14
Authors: Li Xinyuan , Shao Ying , Sha Xiaojin , Fang Pu , Kuo Yin-Ming , Andrews Andrew J , Li Ya-feng , Yang William Y , Maddaloni Massimo , Pascual David W , Luo Jin J , Jiang Xiaohua , Wang Hong , Yang Xiao-feng
Published: March 2019

Recently we reported that IL-35 is an inflammation-induced ant-inflammatory cytokine; thus, function as a HAMP (homeostasis associated molecular patterns). However, whether IL-35 affects endothelial cell activation and subsequent development of atherosclerosis is not known. Hence, we studied the expression of IL-35 during early atherosclerosis; and its roles and mechanisms in suppressing EC activation. Initially, we analyzed whether endogenous IL-35 levels and its receptor expression was increased in early atherosclerosis. Our data revealed that IL-35 level was significantly increased in the plasma of hyperlipidemic patients and apolipoprotein E (ApoE-/-) deficient mice. Further, the expression of IL-35 receptor components were increased in ApoE-/- mouse aortas. IL-35 inhibited monocyte recruitment on to human aortic endothelial cells (EC) activated by pro-atherogenic lysophosphatidylcholine (LPC). Furthermore, our RNA-Seq analysis showed that IL-35 selectively inhibited ICAM-1 expression that mediates EC activation. Further analysis by flowcytometry and electron spin resonance analysis revealed that IL-35 blocked LPC-mediated mitochondrial-reactive oxygen species (mtROS) production. The subsequent mass spectrometry, ChIP-Seq analysis and EMSA showed that LPC-mediated mtROS promotes acetylation of histone 3 lysine 14 (H3K14). Acetylation of histones facilitate the transcription of EC activation-related genes. We found that acetylated H3K14 increased the binding of pro-inflammatory transcription factor Ap-1 on to ICAM-1 promoter region and induction of ICAM-1 gene transcription. IL-35 mediated Inhibition of mtROS attenuated H3K14 acetylation, inhibited AP-1 binding to ICAM-1 promoter and suppressed ICAM-1 transcription. Finally, IL-35 cytokine treatment inhibited the progression and development of atherosclerosis in ApoE-/- mice. Our study concluded that IL-35 is induced during atherosclerosis and plays an anti-atherogenic role by suppressing EC activation through mtROS and H3K14 acetylation dependent mechanism.
Abstract 030: IL-17A Induces Vascular Dysfunction via Downregulation of eNOS Expression
Authors: Schueler Rebecca , Karbach Susanne , Schaefer Katrin , Kossmann Sabine , Oelze Matthias , Garlapati Venkata , Huppert Juak , Croxford Andrew , Daiber Andreas , Muenzel Thomas , Waisman Ari , Wenzel Philip
Published: March 2019

Introduction:
Interleukin-17A is important in the development of vascular dysfunction. However, the mechanism behind is still not completely understood. The aim of our study was to investigate if IL-17A overexpression in T cells induces vascular dysfunction mainly via inflammatory cell recruitment to the vessel wall or if there are other mechanisms behind.

Methods:
We used a mouse model of T cell specific IL-17A overexpression (CD4-IL-17A
ind/+
mice) and a model of ubiquitous IL-17 receptor A knockout (IL-17RA
del
mice). Vascular dysfunction was induced via Angiotensin-II (Ang-II, 1mg/kg/day, 1 week). Aortic relaxation was determined using isometric tension studies. Blood pressure measurements were performed with tail-cuff method and ROS/RNS detection in whole blood was accomplished using L-012 ECL. Flow cytometric and histological analysis of aorta and perivascular adipose tissue (PVAT) were performed. Aortic NO
•
formation was detected by electron paramagnetic resonance spectroscopy (EPR).

Results:
The continuous overexpression of IL-17A in T cells indeed led to the development of vascular dysfunction accompanied by increased ROS/RNS formation under Angiotensin-II treatment compared to wildtype mice. These results go in line with an elevated blood pressure and a reduction of the left-ventricular ejection fraction in CD4-IL-17A
ind/+
mice. Although IL-17A plays an important role in neutrophil recruitment, chronic T cell specific overexpression of IL-17A did not lead to strongly elevated myeloid cells in the aortic vessel wall. Interestingly, IL-17A overexpression reduced NO
•
formation in aortas and decreased eNOS expression in PVAT. In contrast, the attenuation of IL-17A signaling in IL-17RA
del
mice significantly reduced the development of Ang-II induced vascular dysfunction as well as Ang-II induced aortic inflammation and peripheral ROS/RNS formation.

Conclusions:
Blockade of IL-17A signaling in IL-17RA
del
mice partially protects from Ang-II induced vascular dysfunction and inflammation. IL-17A overexpression in T cells led to vascular dysfunction. This was independent from inflammatory cell infiltration to the aortic vessel wall and associated with a reduction of NO-release and a down-regulation of eNOS expression PVAT.
Abstract 036: Functionalized Nanoparticle Based “Two-pronged” Approach to Attenuate/regress Atherosclerosis by Simultaneous Knock Down OfSR-A and LXR-mediated Stimulation of Macrophage Cholesterol Efflux
Authors: He Hongliang , Wang Jing , Yannie Paul , Yang Hu , Ghosh Shobha
Published: March 2019

Imbalance between lipoprotein uptake and cholesterol efflux from macrophages underlies the formation of foam cells and development of fatty streaks, a process that starts early in life. While currently available lipid lowering interventions attenuate the progression of atherosclerotic plaques, no targeted therapy is presently available for reduction of existing plaques, a process dependent not only on limiting further accumulation of cholesterol but also on stimulation of cholesterol efflux. We earlier reported the development of a mannose functionalized dendrimeric nanoparticles (mDNP)-based platform for targeted delivery of therapeutics to arterial plaque associated macrophages. In this study, we used the optimized mDNP platform to simultaneously deliver SR-A siRNA (to knock down SR-A and limit modified LDL uptake) and LXR ligand (LXR-L, to stimulate macrophage cholesterol efflux by inducing expression of ABCA1/G1) - a “

Two Pronged

” approach. Compared to non-specific NS-siRNA, mDNP mediated delivery of SR-A siRNA led to significant reduction in expression of SR-A (A&B) with a corresponding decrease in uptake of DiI-labeled oxLDL (C). Delivery of LXR-L increased expression of ABCA1/G1 (D) as well as cholesterol efflux (E) and simultaneous delivery of SR-A siRNA did not alter these LXR-L effects. However, combined delivery of siRNA and LXR-L led to significantly higher decrease in macrophage cholesterol content compared to either treatment alone (F). Administration of this
in vitro
optimized formulation of mDNP complexed with SR-A siRNA and LXR-L to atherosclerotic LDLR-/- mice fed western diet (TD88137) led to a dramatic reduction in lesion area compared to single treatment alone (G). In conclusion, targeted delivery of multiple therapeutics using mDNP platform represents a novel strategy to not only reduce lesion size but it can also be used to simultaneously alter many lesion characteristics such as reducing inflammation or enhancing efferocytosis.
Abstract 051: A New Model of Murine Stasis Pulmonary Thromboembolism in vivo With Assessment by Noninvasive Multimodal Molecular-Structural Imaging
Authors: Kessinger Chase W , Jaffer Farouc A
Published: March 2019

Objective:
Pulmonary embolism (PE) is a life-threatening cardiovascular disease that urgently requires improved diagnostic, prognostic and therapeutic options. Here we established and investigated a novel murine PE model based on embolization of a stasis-induced venous thrombus (VT). We further utilized in vivo molecular-structural imaging of fibrin accessibility to assess the healing status of the PE.

Methods:
Stasis VT was induced in the femoral veins of donor C57BL6 mice. VT was resected 24 hours (h) after induction and then intravenously injected into recipient mice to create PE. Pulse-wave Doppler of pulmonary artery flow was utilized to evaluate the pulmonary arterial pressure (PAP) before and 24h after embolization. One day after embolization, the fibrin-specific probe FTP11-CyAm7 (750/767nm ex/em, 150 nmoles/kg i.v.) assessed the FTP binding and spatial localization of PE via integrated fluorescence-mediated tomography and computed tomography (FMT-CT) pulmonary angiography. Mice were sacrificed 1, 4, 8, or 21 days following stasis-VT embolization, and underwent histological analysis of the PE.

Results:
Femoral vein stasis-VT exhibited similar temporal inflammatory neutrophil and monocyte/macrophage infiltration and FTP11 binding (fibrin accessibility) kinetics compared to inferior vena cava stasis-VT models. The mean VT width and length were 2.4±0.2mm and 0.65±0.02mm, respectively (n=29 thrombi). Noninvasive ultrasound assessment of the mouse PAP, assessed via the pulmonary acceleration time (PAT), showed a 22% decrease (p=0.03) in pre-to-post-PE PAT times, consistent with increased PAP due to PE. FMT-CT imaging using FTP11 demonstrated accessible fibrin in day 1 PE and visualized PE confined to the lungs, primarily (91%) in the right lung. Ex vivo fluorescence reflectance imaging and histological analysis verified the location PE reported by FMT-CT.

Conclusions:
These data validate the first in vivo model of PE based on stasis VT formed in vivo. The model reproducibly generates a survival PE that harbors accessible fibrin in recent stasis VT lodged in the lung, and acute increases PAP. This new clinically relevant model of PE is anticipated to facilitate research of acute PE and chronic thromboembolic pulmonary hypertension.
Abstract 055: TRAIL Protects Against Endothelial Dysfunction in vivo and Inhibits Angiotensin-II Induced Oxidative Stress in Vascular Endothelial Cells
in vitro
Authors: Manuneedhi Cholan Pradeep , Cartland Sian , Rayner Benjamin , Genner Scott , Dang Lei , Thomas Shane , Kavurma Mary
Published: March 2019

The vascular endothelium is critical for maintenance of cardiovascular homeostasis and vascular oxidative stress is a primary cause of endothelial dysfunction. TNF-related apoptosis-inducing ligand (TRAIL) is increasingly recognised to play a protective role in atherosclerosis, however the molecular mechanisms by which it exerts its beneficial effects are unclear. Our aim was to identify whether TRAIL could protect against atherosclerosis by reducing vascular oxidative stress and improve endothelial cell (EC) function.
In vivo
, 12 w high fat diet (HFD)-fed

Trail
-/-
Apoe
-/-

mice had more severe atherosclerosis, with significant impairment in vasorelaxation in response to acetylcholine, but not sodium nitroprusside. HFD

Trail
-/-
Apoe
-/-

vessels also had increased vascular reactive oxygen species (ROS) as evident by dihydroethidium (DHE) staining compared to HFD

Apoe
-/-

mice. Following injection of Evan’s blue dye, blood vessels from highly vascularised organs of

Trail
-/-

mice demonstrated increased vascular permeability compared to

Trail
+/+

organs, and altered expression of adhesion molecule and tight junction proteins.
In vitro
, AngII (50 ng/ml) increased DHE and mitosox staining in ECs within 2 h, which was inhibited by apocynin, rotenone and L-Name, suggesting that NADPH oxidases (NOXs), the mitochondria and eNOS are major producers of ROS. siRNA targeting NOX-4, but not NOX-1, -2, or -5 reduced AngII-induced DHE, whereas siRNA targeting eNOS significantly augmented DHE staining. Importantly, pre-treatment of TRAIL at 1 ng/ml inhibited AngII-inducible DHE and mitosox staining. Functionally, TRAIL reduced eNOS monomer expression and monocyte recruitment in response to AngII. Furthermore, AngII reduced VCAM-1 and PECAM-1 mRNA was no rescued with TRAIL treatment. These findings demonstrate for the first time that TRAIL protects against endothelial dysfunction via its ability to modulate oxidative stress. Understanding the role TRAIL plays in normal physiology and disease, may lead to potential new therapies to improve endothelial function and atherosclerosis.
Abstract 096: Comparison of Different Metabolic Syndrome Definitions for the Risks of Arterial Stiffness and Diabetes
Authors: Tsai Sung-Sheng , Chu Pao Hsien
Published: March 2019

Context:
The reported clinical outcomes of the metabolic syndrome (MetS), including cardiovascular disease and diabetes, vary according to the definitions used.

Objective:
To compare the performance of the Adult Treatment Panel III/ American Heart Association/National Heart, Lung, and Blood Institute (ATP III/AHA/NHLBI) and International Diabetes Federation (IDF) criteria for the risks of arterial stiffness and diabetes.

Design, Setting, Participants, and Outcome Measures:
In this Chinese population-based cross-sectional study, we screened subjects from a Health Examination Program from 1999-2015. The MetS scores were determined according to the ATP III/AHA/NHLBI and IDF criteria. A brachial-ankle pulse wave velocity (baPWV) ≧1400 cm/s indicated more severe arterial stiffness, and a high fasting glucose level ≧6.99 mmol/L or postprandial glucose level ≧11.10 mmol/L indicated diabetic-level hyperglycemia. Comparisons of the areas under receiver operating characteristic curves (AUC-ROC) for both MetS scores to predict a higher baPWV and diabetic-level hyperglycemia were evaluated.

Results:
Among the 26735 enrolled subjects (mean age 55 ± 12 years), 6633 (24.8%) and 7388 (27.6%) were classified as having MetS according to the ATP III/AHA/NHLBI and IDF criteria, respectively. The AUC-ROC for the ATP III/AHA/NHLBI-MetS score were higher than those for the IDF-MetS score (0.685 vs. 0.595 to predict a higher baPWV, P < 0.001; 0.791 vs. 0.665 to predict diabetic-level hyperglycemia, P < 0.001).

Conclusions:
To the best of our knowledge, this is the first study to show that through a holistic approach, the predictive performance of the ATP III/AHA/NHLBI-MetS score for the risks of arterial stiffness and diabetes was superior to the IDF-MetS score.