bluuebunny/crossref_metadata_2025 huggingface dataset:
Short-Term Debt and Bank Risk
Authors: Du Brian , Palia Darius
Published: March 2018

The extant literature suggests that one of the main causes of the recent financial crisis was the excessive use of short-term debt by banks. Using a large sample of banks, we find that increases in repurchase agreements (repos) were recognized by external capital markets to increase bank risk in the pre-crisis period. In the crisis, we find a negative relationship between repos and risk. We attribute this result to evidence suggesting that “good” banks were able to continue funding their repos, whereas “bad” banks had to significantly decrease their repo funding.
Auditory hallucinations in adults with hearing impairment: a large prevalence study
Authors: Linszen M. M. J. , van Zanten G. A. , Teunisse R. J. , Brouwer R. M. , Scheltens P. , Sommer I. E.
Published: March 2018

Background

Similar to visual hallucinations in visually impaired patients, auditory hallucinations are often suggested to occur in adults with hearing impairment. However, research on this association is limited. This observational, cross-sectional study tested whether auditory hallucinations are associated with hearing impairment, by assessing their prevalence in an adult population with various degrees of objectified hearing impairment.

Methods

Hallucination presence was determined in 1007 subjects aged 18–92, who were referred for audiometric testing to the Department of ENT-Audiology, University Medical Center Utrecht, the Netherlands. The presence and severity of hearing impairment were calculated using mean air conduction thresholds from the most recent pure tone audiometry.

Results

Out of 829 participants with hearing impairment, 16.2% (n = 134) had experienced auditory hallucinations in the past 4 weeks; significantly more than the non-impaired group [5.8%; n = 10/173; p < 0.001, odds ratio 3.2 (95% confidence interval 1.6–6.2)]. Prevalence of auditory hallucinations significantly increased with categorized severity of impairment, with rates up to 24% in the most profoundly impaired group (p < 0.001). The corrected odds of hallucination presence increased 1.02 times for each dB of impairment in the best ear. Auditory hallucinations mostly consisted of voices (51%), music (36%), and doorbells or telephones (24%).

Conclusions

Our findings reveal that auditory hallucinations are common among patients with hearing impairment, and increase with impairment severity. Although more research on potential confounding factors is necessary, clinicians should be aware of this phenomenon, by inquiring after hallucinations in hearing-impaired patients and, conversely, assessing hearing impairment in patients with auditory hallucinations, since it may be a treatable factor.
‘SUBTLE SHIFTS’: HOWARD SKEMPTON'S TWENTY-FIRST-CENTURY MODERNISM
Authors: Whittall Arnold
Published: March 2018

Howard Skempton's distinctive presence on the British musical scene, and his prolific compositional output since the mid-1960s, have presented commentators with certain challenges as they contemplate which labels to apply, and, for music analysts, which techniques to deploy. Skempton's own comments, in various interviews and essays down the years, remain the ideal starting point, suggest a range of contexts, some of which underpin this study. With reference to a few of his smaller vocal and keyboard compositions, the quality of constantly shifting rather than strictly fixed elements is explored. When pitch materials conform more or less exactly to tonal or modal tradition, rhythm is particularly important as a determinant of subtle shifting. But it is often the case that pitches identities themselves shift between functions best defined as tonal scale degrees at one extreme and post-tonal pitch classes at the other. The result is a very personal and unaggressive kind of modernism.
<> rainy days 2017
Authors: Corcoran-Tadd Athena
Published: March 2018

Questioning whether new music is ‘losing touch’, Lydia Rilling, in her first edition as artistic director of Luxembourg's rainy days festival, curated a programme which sought, via an exploration of ‘the emotional landscapes of contemporary music’, to ‘reveal’ that this is not the case. The festival's scope extended beyond concerts to sound installations, pre- and post-concert talks, an (all female-presented) conference dedicated to the festival topic, a newly affiliated composition academy, and a closing ‘bal contemporain’ which paired Frank Zappa and Alexander Schubert with onion soup, while composers, musicologists and curators let loose after such extensive reflection upon the question that had been posed at every turn, emblazoned on the yellow telephone book-sized festival programmes (from which all quotations in this review are taken), echoed on individual concert programmes, interrogating the listener from the tickets’ fine print: how does it feel?
Between philosophy and social science: Harm and its object in International Relations
Authors: Hoseason Alex
Published: March 2018

As a discipline, IR returns repeatedly to the ‘problem of harm’; debating what harm is or should mean. Exploring the discipline through this lens allows us to understand it as contributing to a broader process of negotiation centred on harm as a principle of restraint. However, existing accounts of what harm means for IR are challenged by the scale and visibility of large-scale harm. This article attempts to push beyond recent accounts of harm by Linklater and Mitchell by examining their respective framings of the relationship between harm and its explanation in IR. Building on their limitations, I propose a framework centred on arguments for ontological realism and structure as a focus for explanation. The resulting ontology sustains the concerns of both while: (a) more fully characterising the relationship between explanation and values in IR; and (b) providing a more adequate account of the role of abstraction. In developing upon existing accounts, this article seeks to provide a stronger ground for the analysis of harm in IR. More broadly, it contributes to contemporary debates centred on the relationship between ontology and values with a view to clarifying the nature of explanation in IR as a social science.
Damage and protection cost curves for coastal floods within the 600 largest European cities
Authors: Prahl Boris F. , Boettle Markus , Costa Luís , Kropp Jürgen P. , Rybski Diego
Published: March 2018

The economic assessment of the impacts of storm surges and sea-level rise in coastal cities requires high-level information on the damage and protection costs associated with varying flood heights. We provide a systematically and consistently calculated dataset of macroscale damage and protection cost curves for the 600 largest European coastal cities opening the perspective for a wide range of applications. Offering the first comprehensive dataset to include the costs of dike protection, we provide the underpinning information to run comparative assessments of costs and benefits of coastal adaptation. Aggregate cost curves for coastal flooding at the city-level are commonly regarded as by-products of impact assessments and are generally not published as a standalone dataset. Hence, our work also aims at initiating a more critical discussion on the availability and derivation of cost curves.
Time dependence of NMR observables reveals salient differences in the accumulation of early aggregated species between human islet amyloid polypeptide and amyloid-β
Authors: Hoffmann Anaïs R. F. , Caillon Lucie , Salazar Vazquez Lilian Shadai , Spath Pierre-Alexandre , Carlier Ludovic , Khemtémourian Lucie , Lequin Olivier
Published: March 2018

Proton NMR shows that IAPP fibril formation does not involve the accumulation of early aggregated species, in contrast with Aβ.
Freestanding χ3-borophene nanoribbons: a density functional theory investigation
Authors: Izadi Vishkayi Sahar , Bagheri Tagani Meysam
Published: March 2018

Here, we study the electronic and magnetic properties of χ3-borophene nanoribbons using density functional theory.
Advances in liquid metals for biomedical applications
Authors: Yan Junjie , Lu Yue , Chen Guojun , Yang Min , Gu Zhen
Published: March 2018

This tutorial review summarizes the common performances, featured properties and various state-of-the-art biomedical applications of liquid metals.
Combined HPLC-ICP-AES technique as an informative tool for the study of heteropolyniobates
Authors: Abramov Pavel A. , Romanova Tamara E. , Volchek Victoria V. , Mukhacheva Anna A. , Kompankov Nikolay B. , Sokolov Maxim N.
Published: March 2018

This paper summarizes the application of the coupled HPLC-ICP-AES technique to study the substitution of niobium by tungsten in [Nb6O19]8− or [(OH)TeNb5O18]6− Lindqvist anions and the screening of mixed [PMo12−xNbxO40]n− Keggin anion formation.
SERS-based lateral flow assay for quantitative detection of C-reactive protein as an early bio-indicator of a radiation-induced inflammatory response in nonhuman primates
Authors: Rong Zhen , Xiao Rui , Xing Shuang , Xiong Guolin , Yu Zuyin , Wang Limei , Jia Xiaofei , Wang Keli , Cong Yuwen , Wang Shengqi
Published: March 2018

We demonstrate a SERS-based lateral flow assay for rapid and quantitative detection of CRP and its potential for in-field evaluation of acute radiation syndrome.
A chiral organic base catalyst with halogen-bonding-donor functionality: asymmetric Mannich reactions of malononitrile with N-Boc aldimines and ketimines
Authors: Kuwano Satoru , Suzuki Takumi , Hosaka Yusei , Arai Takayoshi
Published: March 2018

Asymmetric Mannich reactions of malononitrile with various N-Boc imines were developed using a chiral organic base catalyst with halogen-bonding-donor functionality.
ESR evidence of the dynamic crossover in the supercooled liquid states of a series of solid n-alkanes
Authors: Bartoš Josef , Corsaro C. , Mallamace D. , Švajdlenková H. , Lukešová M.
Published: March 2018

A study of the rotation dynamics of the spin probe TEMPO by ESR in a series of six short- and medium-sized n-alkanes is presented.
Microsolvation of F−
Authors: Florez Elizabeth , Acelas Nancy , Ramírez Frank , Hadad Cacier , Restrepo Albeiro
Published: March 2018

The effective charge in F−is strong enough to induce water dissociation even for small molecularities in the gas phase.
Single pot selective hydrogenation of furfural to 2-methylfuran over carbon supported iridium catalysts
Authors: Date Nandan S. , Hengne Amol M. , Huang K.-W. , Chikate Rajeev C. , Rode Chandrashekhar V.
Published: March 2018

Various iridium supported carbon catalysts were prepared and screened for the direct hydrogenation of furfural (FFR) to 2-methyl furan (2-MF).
Hexammine cobalt(iii) coordination complex grafted reduced graphene oxide composite for sensitive and selective electrochemical determination of morin in fruit samples
Authors: Kokulnathan Thangavelu , Sakthinathan Subramanian , Chen Shen-Ming , Karthik Raj , Chiu Te-Wei
Published: March 2018

The RGO/[Co(NH3)6]3+/GCE modified GCE was potentially applied for the electrochemical detection of MR.
Efficient oxygen evolution electrocatalyzed by a Cu nanoparticle-embedded N-doped carbon nanowire array
Authors: Zhu Xiaojuan , Shi Xifeng , Asiri Abdullah M. , Luo Yonglan , Sun Xuping
Published: March 2018

A Cu nanoparticle-embedded N-doped carbon nanowire array on copper foam (Cu–N–C NA/CF) shows high catalytic activity, needing an overpotential of 314 mV to drive a geometrical current density of 20 mA cm−2 in 1.0 M KOH.
Domino cyclization/trifluoromethylation of 2-alkynylanilines using fluoroform-derived CuCF3: synthesis of 3-(trifluoromethyl)indoles
Authors: Ye Yibin , Cheung Kelvin Pak Shing , He Lisi , Tsui Gavin Chit
Published: March 2018

A domino cyclization/trifluoromethylation strategy for the construction of indole cores with concomitant installation of a CF3 group is described.
Visible light photoredox catalysis: conversion of a mixture of thiophenols and nitriles into 2-substituted benzothiazoles via consecutive C–S and C–N bond formation reactions
Authors: Natarajan Palani , Manjeet Manjeet , Muskan Muskan , Brar Navpreet Kaur , Jot Kaur Jaskamal
Published: March 2018

A novel, visible-light-mediated method for the synthesis of 2-substituted benzothiazoles from thiophenols and alkyl/aryl nitriles in the presence of eosin Y under air atmosphere is disclosed.
Nanopore-confined g-C3N4nanodots in N, S co-doped hollow porous carbon with boosted capacity for lithium–sulfur batteries
Authors: Zhang Han , Zhao Zongbin , Hou Ya-Nan , Tang Yongchao , Dong Yanfeng , Wang Shuang , Hu Xiaojing , Zhang Zhichao , Wang Xuzhen , Qiu Jieshan
Published: March 2018

Controllable synthesis of graphitic-C3N4nanodots embedded in N, S co-doped hollow porous carbonviaa double-solvent strategy for obtaining high performance of lithium–sulfur batteries.
Li2O–B2O3–GeO2 glass as a high performance anode material for rechargeable lithium-ion batteries
Authors: Choi Seung Ho , Lee Seung Jong , Kim Hye Jin , Park Seung Bin , Choi Jang Wook
Published: March 2018

Li2O–B2O3–GeO2 glass is demonstrated as a promising lithium-ion battery anode because the glass phase facilitates lithium ion conduction while buffering the volume expansion of the active material.
Electronic structure and photoluminescence properties of single component white emitting Sr3LuNa(PO4)3F:Eu2+,Mn2+ phosphor for WLEDs
Authors: Jiao Mengmeng , Xu Qinfeng , Yang Chuanlu , Liu Mingliang
Published: March 2018

A single-component white-emitting Sr3LuNa(PO4)3F:Eu2+,Mn2+ phosphor have been synthesized and the electronic structure and photoluminescence properties have been investigated firstly.
RNA glycosidase and other agents target Tat to inhibit HIV-1 transcription
Authors: Harrich David , Jin Hongping
Published: March 2018

The HIV-1 tat gene encodes a small 86–104 amino acid protein depending on the HIV-1 strain. Tat is essential for HIV-1 replication through interactions with numerous cellular transcription factors. The interaction between Tat and P-TEFb, which is a cellular protein complex composed of cyclin T1 and CDK9, delivers P-TEFb to the newly transcribed viral mRNAs where phosphorylation of RNA polymerase II by CDK9 leads to highly efficient mRNA transcription. It has long been recognized that Tat is a potential anti-HIV-1 target and possibly a viral Achilles' heel. However, specifically targeting Tat without affecting normal host cell functions has been challenging. Means to inactivate Tat have been reported that includes small compounds, transdominant negative Tat proteins, and by plant-derived antivirals. Investigations of these agents have reported encouraging outcomes that inform and may hopefully affect strategies for a functional HIV-1 cure.
The MALAT1 gene polymorphism and its relationship with the onset of congenital heart disease in Chinese
Authors: Li Qian , Zhu Wenying , Zhang Bei , Wu Yiping , Yan Sen , Yuan Yufeng , Zhang Haiyan , Li Jie , Sun Kai , Wang Hua , Yu Tingting
Published: March 2018

Many long non-coding RNAs (lncRNAs), including lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), are involved in various cardiac diseases. We evaluated the effects of tag single nucleotide polymorphisms (tag-SNPs) on MALAT1 gene in a Chinese population of children with congenital heart disease (CHD). In the present study, 713 CHD patients and 730 gender- and age-matched children without CHD were genotyped for MALAT1 tag-SNPs rs11227209, rs619586, and rs3200401. Further investigation of SNP’s function was performed by luciferase assay. Statistical analyses, including uni- and multivariate logistic regression were performed to quantitate the association between these tag SNPs and CHD. We discovered that MALAT1 rs619586 GG allele was significantly associated with lower risk of CHD (odds ratio (OR) = 0.77, 95% confidence interval (CI) = 0.59–0.92, P=0.014) in additive model. Functional investigation indicated that G allele of rs619586 could trigger higher expression of MALAT1. We demonstrated that the functional MALAT1 polymorphism rs619586 A>G was significantly associated with CHD susceptibility in Chinese population, potentially via regulating MALAT1 expression.
Cross-talk between renal lithogenesis and atherosclerosis: an unveiled link between kidney stone formation and cardiovascular diseases
Authors: Devarajan Asokan
Published: March 2018

The prevalence of kidney stones and cardiovascular diseases (CVDs) are increasing throughout the world. Both diseases are chronic and characterized by accumulation of oxidized proteins and lipids in the renal tissue and arterial wall, respectively. Emerging studies have revealed a positive association between nephrolithiasis and CVDs. Based on preclinical and clinical evidences, this review discusses: (i) stone forming risk factors, crystal nucleation, aggregation, injury-induced crystal retention, and stone formation, (ii) CVD risk factors such as dyslipidemia, perturbation of gut microbiome, obesity, free radical-induced lipoprotein oxidation, and retention in the arterial wall, subsequent foam cell formation, and atherosclerosis, (iii) mechanism by which stone forming risk factors such as oxalate, calcium, uric acid, and infection contribute toward CVDs, and (iv) how CVD risk factors, such as cholesterol, phospholipids, and uric acid, contribute to kidney stone formation are described.
Thumb positioning analysis of new elliptical‐shaped microwave sensors for non‐invasive glucose monitoring
Authors: Sethi W.T. , Ashraf M.A. , Alshebeili S.A. , Issa K.
Published: March 2018

Diabetes is a chronic disease where millions of sufferers invasively prick their skin over the course of a day to take blood samples. Non‐invasive glucose monitoring would bring relief to diabetics because it offers reduced skin damage. Microwave sensors are becoming a good choice for non‐invasive glucose monitoring. This Letter presents two designs based on microwave sensors. The sensors have elliptical shapes and consist of a patch reflector and dielectric resonator (DR) that resemble a human thumb. A four‐layer thumb model is presented, with a focus on the permittivity of the blood layer. The thumb was moved to various positions on the two microwave sensors to observe the effect it had on the frequency shift with various blood permittivity values. Observations showed that the elliptical DR sensor was less sensitive to errors and thumb positioning when taking glucose measurements than the elliptical patch sensor. The elliptical DR had an error of 55 MHz from the centre frequency, whereas that of the elliptical patch was 140 MHz. The effects of thumbs with various blood permittivity values were explored and explained.
Modular soft‐switching converter in DC micro‐grid system applications
Authors: Lin B.R.
Published: March 2018

Owing to environmental issue and global temperature rise, the growth of renewable energy sources such as photovoltaic arrays, fuel cells and wind turbine power has been developed. Therefore, the direct current (DC) micro‐grid distributed systems are more and more important to integrate renewable energy sources, energy storage devices, local DC loads or alternative current (AC) loads and AC micro‐grid through AC–DC converters to achieve high reliability and efficiency in power systems. For industry and transportation applications such as metro and light transit, the preferred voltage level on DC micro‐grid system is recommended as 600–900 V. The proposed DC–DC converter contains three half‐bridge circuits with a series–parallel connection at primary–secondary sides so as to decrease voltage rating of active devices and current rating of rectifier diodes. Asymmetric pulse‐width modulation scheme is used to realise the soft‐switching turn‐on for active devices and the switching losses of power devices can be further reduced. To overcome input split voltage balance issue, flying capacitors are employed between two cascaded half‐bridge circuits and the voltage rating of each active device is limited at Vin/3. Finally, experiments with a laboratory prototype are provided to verify the theoretical analysis and circuit performance.
Estimation of technology progression and cost analysis for a floating solar chimney power plant: a special case – Isfahan city in Iran
Authors: Masoudi Nejad Reza , Imanparast Mohammad
Published: March 2018

Regarding the growing need for cheap and unlimited energy sources, renewable energies have been considered. Solar energy is one of the main sources of energy. This article studies the performance of floating solar chimney technology for the manufacturing purpose in Isfahan city. In this purpose, Isfahan city is considered to determine the performance of floating solar chimney power plant (SCPP) to build this type of SCPP. The results have shown that the floating solar chimney power plant can produce 5–200 MW of electrical energy in Isfahan city. Then a study is performed according to return of finance rate, net price value, and finance return period criteria. The results have shown that these power plants are able to be built in large scales of 100 and 200 MW of electricity with an annual capacity of 381 and 712 GW with 44 and 60%, respectively. However, a comparison between the cost analyses of two tested models shows that the 200 MW power plant with a cost of 13,941.52 milliard Rials is more beneficial in Isfahan city.‏
J-PLUS: A wide-field multi-band study of the M 15 globular cluster
Authors: Bonatto Charles , Chies-Santos Ana L. , Coelho Paula R. T. , Varela Jesús , Larsen Søren S. , Javier Cenarro A. , San Roman Izaskun , Marín-Franch Antonio , Mendes de Oliveira Claudia , Molino Alberto , Ederoclite Alessandro , Cortesi Arianna , López-Sanjuan Carlos , Cristóbal-Hornillos David , Vázquez Ramió Héctor , Sodré Laerte , Sampedro Laura , Costa-Duarte Marcus V. , Novais Patrícia M. , Dupke Renato , Overzier Roderik A. , Ribeiro Tiago , Santos Walter A. , Schoennell William
Published: March 2018

Context. As a consequence of internal and external dynamical processes, Galactic globular clusters (GCs) have properties that vary radially. Wide-field observations covering the entire projected area of GCs out to their tidal radii (rtidal) can therefore give crucial information on these important relics of the Milky Way formation era.

Aims. The Javalambre Photometric Local Universe Survey (J-PLUS) provides wide field-of-view (2 deg2) images in 12 narrow, intermediate and broad-band filters optimized for stellar photometry. Here we have applied J-PLUS data for the first time for the study of Galactic GCs using science verification data obtained for the very metal-poor ([Fe/H] ≈−2.3) GC M 15 located at ~10 kpc from the Sun. Previous studies based on spectroscopy found evidence of multiple stellar populations (MPs) through their different abundances of C, N, O, and Na. Our J-PLUS data provide low-resolution spectral energy distributions covering the near-UV to the near-IR, allowing us to instead search for MPs based on pseudo-spectral fitting diagnostics.

Methods. We have built and discussed the stellar radial density profile (RDP) and surface brightness profiles (SBPs) reaching up to rtidal. Since J-PLUS FoV is larger than M 15’s rtidal, the field contamination can be properly taken into account. We also demonstrated the power of J-PLUS unique filter system by showing colour-magnitude diagrams (CMDs) using different filter combinations and for different cluster regions.

Results. J-PLUS photometric quality and depth are good enough to reach the upper end of M 15’s main-sequence. CMDs based on the colours (u − z) and (J0378 − J0861) are found to be particularly useful to search for splits in the sequences formed by the upper red giant branch (RGB) and asymptotic giant branch (AGB) stars. We interpret these split sequences as evidence for the presence of MPs. Furthermore, we show that the (u − z) × (J0378 − g) colour–colour diagram allows us to distinguish clearly between field and M 15 stars, which is important to minimize the sample contamination.

Conclusions. The J-PLUS filter combinations (u − z) and (J0378 − J0861), which are sensitive to metal abundances, are able to distinguish different sequences in the upper RGB and AGB regions of the CMD of M 15, showing the feasibility of identifying MPs without the need of spectroscopy. This demonstrates that the J-PLUS survey will have sufficient spatial coverage and spectral resolution to perform a large statistical study of GCs through multi-band photometry in the coming years.
Seroprevalence and risk factors of Neospora caninum infection among domestic sheep in Henan province, central China
Authors: Wang Shuai , Li Lingjuan , Lu Yi , Zhang Haizhu , Xie Qing , Zhang Zhenchao
Published: March 2018

This study aimed to determine the frequency of antibodies to Neospora caninum in domestic sheep raised in Henan province, central China. Serum samples from 779 domestic sheep were collected from March 2015 to May 2016, and antibodies to N. caninum were evaluated using an enzyme-linked immunosorbent assay (ELISA). The results showed an overall IgG positive rate of 7.32% (57/779). The risk factors significantly related to seropositivity to N. caninum in sheep were the age, the presence of dogs, and the rearing system. This is the first report of N. caninum infection and associated risk factors in domestic sheep in central China.
Cu-Catalyzed Borylative and Silylative Transformations of Allenes: Use of β-Functionalized Allyl Copper Intermediates in Organic Synthesis
Authors: Fujihara Tetsuaki , Tsuji Yasushi
Published: March 2018

Herein, copper-catalyzed borylative and silylative transformations of allenes using borylcopper or silylcopper as the active catalytic species are described. First, the synthesis and characterization of borylcopper and silylcopper complexes are briefly introduced. Next, the borylative transformations of allenes are summarized including hydro­boration, carboboration, and borylative allylation of carbonyl compounds. We next deal with the silylative transformations of allenes such as hydrosilylation, carbosilylation, and silylative allylation of carbonyl compounds.

1 Introduction

2 Synthesis of Borylcopper and Silylcopper Complexes

3 Borylative Transformations

4 Silylative Transformations

5 Conclusions and Future Outlook
Expanding the Chemical Diversity of DNA
Authors: Hili Ryan , Guo Chun , Kong Dehui , Lei Yi
Published: March 2018

Nucleic acid polymers can be evolved to exhibit desired properties, including molecular recognition of a molecular target and catalysis of a specific reaction. These properties can be readily evolved despite the dearth of chemical diversity available to nucleic acid polymers, especially when compared to the rich chemical complexity of proteins. Expansion of nucleic acid chemical diversity has therefore been an important thrust for improving their properties for analytical and biomedical applications. Herein, we briefly describe the current state-of-the-art for the sequence-defined incorporation of modifications throughout an evolvable nucleic acid polymer. This includes contributions from our own lab, which have expanded the chemical diversity of nucleic acid polymers closer to the level observed in proteinogenic polymers.

1 Introduction

2 Polymerase-Catalyzed Synthesis of Modified Nucleic Acid ­Polymers

3 Ligase-Catalyzed Oligonucleotide Polymerization (LOOPER)

4 LOOPER with Small Modifications

5 LOOPER with Large Modifications

6 Evolution of Aptamers Derived from LOOPER Libraries

7 Outlook
Similar Effects of Atorvastatin, Simvastatin and Pravastatin on Thrombogenic and Inflammatory Parameters in Patients with Hypercholesterolemia
Authors: Joukhadar Christian , Klein Nikolas , Prinz Mojgan , Schrolnberger Claudia , Vukovich Thomas , Wolzt Michael , Dorner Guido , Schmetterer Leopold
Published: March 2018

Background: Previous studies have suggested that statins exert beneficial effects beyond their favorable lipid lowering effect. Particularly, the modification of thrombus formation and degradation, alteration in inflammatory response, plaque stabilization and improved endothelial function are thought to be responsible for additional reduction of morbidity and mortality due to cardiovascular events. To date, however, it is still unclear whether these effects are elicited by all statins. Methods and Results: We set out to compare in a controlled, randomized, double-blind study design the effects of almost equieffective cholesterol lowering doses of three chemically and pharmacokinetically different statins (atorvastatin, simvastatin, pravastatin) on hemostatic and inflammatory markers in 99 hypercholesterolemic patients. At entry and 3 months after onset of statin therapy plasma cholesterol and von Willebrand factor antigen (vWf-Ag), fibrinogen, d-dimer, prothrombin fragment 1+2 (F1.2) and C-reactive protein (CRP) were measured. The effect on plasma values of F1.2, vWf-Ag, d-dimer and CRP was not significantly different between the three treatment groups. The effect of simvastatin on fibrinogen (p = 0.005) was more pronounced than the effects of atorvastatin (p = 0.48 n.s.) and pravastatin (p = 0.15 n.s.). Plasma levels of F1.2 and vWf-Ag (when data of all statins were pooled) were significantly reduced by 7% and 10% versus baseline, respectively. No significant reduction was observed for d-dimer (p = 0.26) and CRP (p = 0.5). Total plasma cholesterol levels decreased significantly (p <0.0001 in all groups) between 22% and 29% compared to baseline. Conclusion: The present study shows similar shortterm (3 months) effects of atorvastatin, simvastatin and pravastatin on selected hemostatic and inflammatory parameters in plasma in patients with hypercholesterolemia. Thus, chemical and pharmacological differences between statins appear to exert no major influence on these parameters.
Antithrombotic Efficacy in a Rat Model of the Low Molecular Weight Heparin, Reviparin Sodium, Administered by the Oral Route
Authors: Wice Sandra , Ping Tilly , Herr Dieter , Laux Volker , Hiebert Linda
Published: March 2018

Previous studies in rats show that unfractionated heparin and the low molecular weight heparin logiparin have a dose-dependent antithrombotic effect and are found in endothelium and plasma when administered orally. Objectives of the present study were to determine if similar evidence of absorption could be observed with oral reviparin sodium. Thrombosis incidence was determined 4 h after application of 10% formalin in methanol to the exposed jugular vein. A dose-dependent antithrombotic effect was observed when 0.01 to 7.5 mg/kg (20 rats/group) was administered by stomach tube immediately following thrombus initiation. Thrombotic incidence was also significantly reduced when 0.025 mg/kg was given 4 and 2 h prior to, immediately after, and 2 and 3 h following thrombus initiation. Reviparin was recovered from endothelium and plasma in trace amounts at all doses. At 0.025 mg/kg, peak aortic endothelial reviparin concentrations were found at 1 and 2 h and peak plasma anti-Xa activity was detected at 2 h. Trace amounts of plasma TFPI were found only at 8 h after administration. Dose-dependent antithrombotic activity and recovery from endothelium and plasma support the hypothesis that orally administered reviparin sodium is absorbed.
CD63 Associates with the αIIbβ3 Integrin-CD9 Complex on the Surface of Activated Platelets
Authors: McMillan-Ward Eileen , Easton Jeffrey , Robertson Catherine , McNicol Archibald , Israels Sara
Published: March 2018

The tetraspanins are integral membrane proteins expressed on cell surface and granular membranes of hematopoietic cells and have been identified in multi-molecular complexes with specific integrins. In resting platelets, CD63, a member of the tetraspanin superfamily, is present in dense granule and lysosomal membranes and, following platelet activation, translocates to the plasma membrane. In the present study, platelet activation by thrombin leads to incorporation of CD63 into the Triton-insoluble actin cytoskeletal fraction. This incorporation was inhibited by preincubation of platelets with RGDS or EGTA and did not occur in platelets from a patient with Glanzmann’s thrombasthenia, suggesting that it was dependent upon αIIbβ3. In activated platelets, the anti-CD63 MoAb, D545, co-immunoprecipitated CD63 with other surface-labeled proteins, including αIIbβ3 and another tetraspanin, CD9. The association of CD63 with CD9 and αIIbβ3 was not inhibited by preincubation of platelets with RGDS or EGtA. D545 did not inhibit the adhesion of activated platelets to purified extracellular matrix proteins, but significantly decreased adhesion of thrombin-activated platelets to neutrophils in a rosetting assay. D545 also caused disaggregation of platelets stimulated by ADP, but had no effect on aggregation induced by other agonists. These results are consistent with the proposal that CD63 becomes part of an αIIbβ3-CD9-CD63 integrintetraspanin complex in activated platelets – an association that may modulate the function of αIIbβ3-dependent interaction with other cells such as neutrophils.
Expression of Vascular Endothelial Growth Factor in Human Monocyte/Macrophages Stimulated with Lipopolysaccharide
Authors: Itaya Hiroyuki , Yoshida Hidemi , Koyama Masayuki , Suzuki Sohei , Satoh Kei , Imaizumi Tadaatsu
Published: March 2018

Vascular endothelial growth factor (VEGF) is a mitogen for endothelial cells. We have studied the production of VEGF by human macrophages in response to lipopolysaccharide (LPS). Macrophages stimulated with LPS expressed VEGF mRNA and protein in concentration- and time-dependent manners. The LPS-induced expression of VEGF was inhibited by cycloheximide pretreatment, which suggested that synthesis of certain factor(s) is required for the LPS activity. The induction of VEGF was also suppressed by SB203580, an inhibitor of p38 mitogen-activated protein (MAP) kinase. These results suggest that the LPS-induced VEGF expression depends on the p38-mediated expression of c-Jun, which constitutes the AP-1 complex and binds to the AP-1 site in the VEGF promoter. Pretreatment of the cells with dexamethasone did not affect the LPS-induced upregulation of VEGF mRNA but strongly inhibited VEGF protein production, and the involvement of posttranscriptional regulation on VEGF expression by dexamethasone was suggested. The conditioned medium of LPS-stimulated macrophages enhanced the growth of cultured endothelial cells and it was inhibited by an antibody against VEGF. We conclude that macrophages produce VEGF in response to the stimulation with LPS, which may be partly mediated by the p38 MAP kinase pathway.
Factor XIII – Circulating Levels and the Val34Leu Polymorphism in the Healthy Male Relatives of Patients with Severe Coronary Artery Disease
Authors: Mansfield Michael , Grant Peter , Mills Joseph
Published: March 2018

We aimed to investigate whether increased levels of FXIII and/or a low prevalence of the protective Leu allele (of the Val34Leu FXIII polymorphism) occur in relatives of patients with severe CAD. 185 healthy male relatives aged 65 or less were recruited from 125 patients with multi-vessel CAD and compared to 185 healthy, agematched controls. The relatives and controls were similar in terms of clinical parameters. FXIII B-subunit levels were elevated in relatives, 1.11 µg/mL (1.08-1.14), compared with controls, 1.00 µg/mL (0.97-1.04), P<0.0001 but FXIII A2B2 levels did not differ between the groups. There was a strong correlation between FXIII B-subunit and the insulin resistance syndrome, however, adjusted B-subunit levels remained significantly higher in relatives. There was no difference in genotype frequency at the FXIII Val34Leu polymorphism between relatives and controls. FXIII B-subunit levels are elevated in the relatives of CAD patients and this is independent of other cardiovascular risk factors.
Fibrinogen, Viscosity and White Blood Cell Count Predict Myocardial, but not Cerebral Infarction: Evidence from the Caerphilly and Speedwell Cohort
Authors: Pickering Janet , Elwood Peter , Bayer Antony , Ebrahim Shah , Baker Ian
Published: March 2018

Fibrinogen, plasma viscocity, and the white blood cell count predict ischaemic heart disease, but there is less certainty for their predictive power for ischaemic stroke. Studying stroke and ischaemic heart disease in the same cohort prospectively allows comparison of predictive strengths. The Caerphilly and Speedwell cohorts consist of a population sample of 4,860 men aged 45-59 years at recruitment who had baseline measurements of fibrinogen, plasma viscosity, and white blood cell counts. After 15-19 years of follow-up, men in the two cohorts experienced 312 ischaemic strokes and 557 ischaemic heart disease events. Mean fibrinogen, plasma viscosity and white blood cell counts differed significantly after adjustment for confounding factors between men with and without ischaemic heart disease, 0.25 g/l (95% CIs 0.18-0.32); 0.036 cp (95% CIs 0.027-0.044); 0.67 X 109/l (95% CIs 0.50-0.84) respectively. The same measurements showed no significant differences after adjustment for the same confounding factors for men with and without ischaemic stroke, 0.05 g/l (95% CIs -0.04-0.14); 0.008 cp (95% CIs -0.003-0.019); 0.16 X 109/l (95% CIs -0.06-0.38) respectively.
Identification of a New Type 2M von Willebrand Disease Mutation also at Position 1324 of von Willebrand Factor
Authors: Fressinaud E. , Ribba A. S. , Meyer D. , Mazurier C. , Hilbert L. ,   and the INSERM network on molecular abnormalities in von Willebrand disease
Published: March 2018

Type 2M von Willebrand disease (VWD) refers to variants with decreased platelet-dependent function that is not associated with the loss of high molecular weight (HMW) von Willebrand factor (VWF) multimers. This category includes the so-called “phenotype B” responsible for inexistent ristocetin-induced but normal botrocetin-induced binding of VWF to platelet glycoprotein Ib. The missense mutation G1324S was identified in the first patient reported to display “phenotype B”.

We report here on the identification in four members of a French family of a missense mutation also affecting this glycine residue but changing it into an alanine residue. These individuals are heterozygous for this mutation and two of them display an additional quantitative VWF deficiency resulting from a stop codon at position 2470. After transient transfection in Cos-7 cells, the mutated recombinant protein harbouring the G1324A substitution was shown to exhibit normal multimers and inexistent ristocetin-induced but normal botrocetininduced binding to GPIb, confirming the classification of this new mutation as a type 2M VWD mutation.
A 28-kDa Glycoprotein Functions as a Platelet Ligand for P-selectin (CD62P)
Authors: Li Ling , Qian Kai-Xian , Geng Jian-Guo
Published: March 2018

P-selectin (CD62P) is expressed on activated platelets and on stimulated endothelial cells. It interacts with P-selectin glycoprotein ligand-1 (PSGL-1; CD162) for adhesion of activated platelets on leukocytes and for rolling of leukocytes on stimulated endothelial cells. Recently, resting and activated platelets have been shown to roll on endothelial P-selectin, indicating that platelets express (a) ligand(s) for P-selectin. Here we show that P-selectin specifically precipitated one 28-kDa glycoprotein from the whole cell lysates and the membrane lysates of human platelets in a Ca2+-dependent manner. Further, the purified 28-kDa molecule could inhibit the binding of P-selectin to human resting and activated platelets. In contrast, KPL1 (a leukocyte adhesion blocking MoAb to PSGL-1) did not neutralize the binding of P-selectin to human platelets, even though it abolished the binding of P-selectin to human promyeloid HL-60 cells. Our results thus indicate that the 28-kDa glycoprotein may function as an important platelet ligand for P-selectin.
Evidence for Anticoagulant Activity and β2-GPI Accumulation in Late Endosomes of Endothelial Cells Induced by Anti-LBPA Antibodies
Authors: Sorice M. , Ferro D. , Misasi R. , Pittoni V. , Longo A. , Circella A. , Garofalo T. , Gradini R. , Violi F. , Gruenberg J. , Valesini G.
Published: March 2018

This investigation was undertaken to test whether anti-LBPA antibodies and IgG from patients with APS interfere with intracellular β2GPI distribution in EAhy926 endothelial cells and with the coagulation system. Cell incubation with anti-LBPA MoAb or with patients’ IgG resulted in antibody binding to late endosomes and caused β2GPI redistribution and accumulation within perinuclear vesicular structures reminiscent of late endosomes. This finding suggests that aPl may contribute to the pathogenic mechanisms of APS by modifying the intracellular traffic of proteins, by interactions between aPl and LBPA, β2GPI and/or LBPA- β2GPI complexes. The anticoagulant activity of anti-LBPA MoAb was analyzed in a sensitized activated partial thromboplastin time (aPTT) system and in a dilute Russell’s viper venom time (dRVVT). A significant, concentration-dependent effect of the antibody on both aPTT and dRVVT prolongation was found. These observations suggest that LBPA is an important lipid target for aPl with potential functional implications for the immunopathogenesis of APS.
Evaluation of Potential Antigenicity of Active-Site-Inhibited Recombinant Human FVIIa (FFR-rFVIIa) in an Immune-Tolerant Rat Model
Authors: Kristensen Hanne , Kristensen Annemarie , Hedner Ulla , Nicolaisen Else
Published: March 2018

Recombinant human FVIIa (rFVIIa) was inactivated by coupling Phe-Phe-Arg-CO- (FFR) covalently to the active site of the enzyme. To test the chemically-modified human protein for potential antigenicity prior to clinical trial an immune-tolerant rat model was established. Intraperitoneal injection of the parent compound, human rFVIIa, within 30 h after birth, followed by repeated subcutaneous challenge with rFVIIa in Freunds incomplete adjuvant resulted in 79% non-responding rats at day 32. Monthly subcutaneous challenge showed that the induced tolerance was stable over the 3 months study period in 80% of the rats. The clinically relevant route, intravenous administration, was used for evaluating the potential antigenicity of FFR-rFVIIa. Repeated intravenous administration of different dosages of FFR-rFVIIa did not break tolerance, indicating that FFR-rFVIIa might not be antigenic, for a limited number of intravenous administrations in a clinical setting.
A Novel Polymorphism, 70Leu/Phe, Disrupts a Consensus Leu Residue within the Leucine-rich Repeat Sequence of Platelet Glycoprotein Ibα
Authors: Matsubara Yumiko , Moriki Takanori , Yokoyama Kenji , Watanabe Naohide , Nakajima Hideaki , Handa Makoto , Kawano Koichi , Aoki Nobuo , Yoshino Hideaki , Ikeda Yasuo , Murata Mitsuru
Published: March 2018

Platelet glycoprotein (GP) Ib/IX/V complex mediates high-shear dependent platelet activation through an interaction with the von Willebrand factor (vWF). All four subunits of the complex have a structural motif, the leucine-rich repeat (LRR) sequence, with leucines in conserved positions. Here we report a new polymorphism, Leu/Phe at residue 70 of GPIbα, which disrupts the consensus sequence of the LRR in the vWF binding domain. Genotype frequencies among 142 healthy Japanese subjects were 92.3%, 7.7%, and 0.0%, for the 70Leu/Leu, 70Leu/Phe, and 70Phe/Phe genotypes, respectively.

Ristocetin-induced or shear-induced platelet aggregation was not significantly different between the 70Leu/Leu and 70Leu/Phe genotypes. In in vitro studies, a recombinant GPIbα fragment with 70Phe (L70F) as compared to that with 70Leu (WT) had low reactivity to anti-GPIbα monoclonal antibodies, GUR20-5 and Hip1, both of which recognize conformation-specific epitopes within the 45-kDa domain. Ristocetininduced 125I-vWF binding to L70F, however, did not differ from that to WT.
Function of Tissue-type Plasminogen Activator Releaser on Vascular Endothelial Cells and Thrombolysis In Vivo
Authors: Matsuno Hiroyuki , Hayashi Mikio , Horibuchi Koji , Okada Kiyotaka , Fukao Hideharu , Uematsu Toshihiko , Matsuo Osamu , Ueshima Shigeru
Published: March 2018

The effect of monosodium[2-(6-hydroxynaphthalen-2-yl)-6-methylpyrimidin-4-yloxy]acetate dihydrate (JTV-926) on fibrinolysis was investigated in vitro and in vivo. JTV-926 released tissue-type plasminogen activator (t-PA) from human vascular endothelial cells in a dose-dependent manner. The thrombolytic effect of JTV-926 was studied using three animal thrombosis models; a photo-irradiation-induced mouse carotid artery thrombosis model, a photo-irradiation-induced rat femoral artery thrombosis model and a thrombin-induced rat venous thrombosis model. In the mouse thrombosis model, t-PA deficient mice (t-PA−/−mice) and their wild-type (t-PA+/+) were used. JTV-926 was injected as a bolus 30 min after the interruption of blood flow by an occlusion thrombi. Blood flow was continuously monitored for 180 min after intravenous administration of JTV-926 (1 mg/kg). Although the recanalization rate of the occluded artery was 37.5% in t-PA +/+ mice with the vehicle control, it increased to 75% in t-PA+/+ mice after JTV-926 administration. However, when JTV-926 was administrated in t-PA−/−mice, vascular recanalization was not observed in any arteries. In the photo-irradiation-induced rat femoral artery thrombosis model, intra-duodenal administration of JTV-926 induced thrombolysis. Moreover, in the thrombin-induced rat venous thrombosis model, the dose-dependent thrombolysis was also observed by oral administration of JTV-926. It was suggested that JTV-926 revealed a sufficient thrombolytic effect through the absorption from the intestine. Thus, a newly synthesized compound, JTV-926 induced t-PA release from vascular endothelial cells and effective thrombolysis in vivo.
Focusing on transcription factor families in atherogenesis: the function of LKLF and TR3
Authors: Arkenbout E. Karin , Dekker Rob , de Vries Carlie , Horrevoets Anton , Pannekoek Hans
Published: March 2018

In this overview, two separate studies are discussed that emerged from a “discovery-driven” approach to identify genes that play an essential role in atherogenesis. First, by a combination of DNA micro-array and one-way linkage hierachical clustering, we selected genes that are induced in endothelial cells (EC) by prolonged steady- or pulsatile laminar flow, but of which expression is not affected by inflammatory and mitogenic agents (TGF-β, IL-1βTNF-α, VEGF, thrombin). The genes selected accordingly were: cytochrome P450 1B1, diaphorase and the transcription factor lung Krüppel-like factor (LKLF) of which only the latter is truly EC specific. LKLF meets the criteria of an anti-atherosclerotic gene, mainly since expression is restricted to areas subjected to laminar flow as shown by in situ hybridization with anatomically well-defined specimens. Second, neointimal (but not medial) smooth muscle cells (SMC) specifically synthesize the NGFI-B subfamily (TR3, MINOR, NOT) of the nuclear hormone superfamily of transcription factors. Again, evidence is presented, indicating that these proteins serve an anti-atherosclerotic function. Notably, transgenic mice, expressing either TR3 or a dominant-negative mutant TR3ΔTA in arterial SMC, were subjected to carotid artery ligation to induce SMC proliferation. Lesions in TR3-overexpressing transgenic mice were 5-fold smaller than isogenic wild-type mice, while mice overexpressing the TR3ΔTA mutant had a 3-fold larger lesion. It is proposed that (down-stream products of) TR3 inhibit the cell cycle, since adenovirus-mediated expression of TR3ΔTA and TR3, respectively, inhibit and promote the synthesis of the cyclin-dependent kinase inhibitor p27Kip1 in SMC.

Part of this work was presented at the 16th Congress of the International Society on Fibrinolysis and Proteolysis, Munich, Germany, September 2002.