bluuebunny/crossref_metadata_2025 huggingface dataset:
Is Financial Fragility a Matter of Illiquidity? An Appraisal for Italian Households
Authors: Brunetti Marianna , Giarda Elena , Torricelli Costanza
Published: March 2015

We investigate household financial fragility in Italy, providing three main contributions. First, we propose a novel characterization of financial fragility that is not necessarily linked to indebtedness, distinguishes between expected and unexpected expenses, takes portfolio composition into account, and is free of subjectivity bias. Second, we use it to assess the importance of household portfolio composition for determining the difficulties related to coping with unexpected expenditures, besides socio‐economic and demographic factors. Third, we test its ability to forecast future conditions of financial distress. The empirical analysis is based on the Bank of Italy Survey on Household Income and Wealth. The results highlight the relevance of portfolio choices as determinants of financial distress, that is, they provide evidence that homeownership increases the likelihood of financial fragility while the presence of a mortgage decreases it. Moreover our measure is shown to act as an early warning indicator of distress.
Looking for the Balkan (Br)other: The National Gaze in Dzhanik Faiziev's The Turkish Gambit
Authors: HASHAMOVA YANA
Published: March 2015

Dzhanik Faiziev's 2005 The Turkish Gambit, based on Boris Akunin's novel of the same name, presents a spy story unfolding against the backdrop of the Russo‐Turkish War (1877–78) in the Balkans (today's Bulgaria). Bulgarians occupy a particular place in the Russian imagination. During the Russo‐Turkish War, Bulgarians entered the Russian cultural space as southern Orthodox Slavs in need of help. This image changed during the Soviet period, when Bulgaria was considered one of the most faithful Soviet satellites and also a favorite vacation spot which comforted with its familiar culture but offered enough differences with exotic southern touches. The post‐Communist era, the turn of the twentieth century when the novel and film were created, brought more unexpected alterations to the Russian perception of Bulgarians. Analyzing the representation of Bulgaria and Bulgarians in Faiziev's film, I contend that the seemingly reassuring sameness is marked by awkward otherness. I utilize scholarship on Russia's imperial experience in relation to the Caucasus and its patterns of artistic othering in my analysis in order to shed more light on these patterns and reveal their persistent nature. To complicate matters further, I argue that Alexander Etkind's concept of “internal colonization” sheds some light on these alterations but falls short of fully illuminating Russia's post‐Communist national anxieties.
Go East, Young Man! Body Politics and the Asian Turn in Putin‐Era Cinema
Authors: BAER BRIAN JAMES
Published: March 2015

The deployment of the East as a discursive means to distinguish Russia from the West has been popular among Russians and foreigners alike for centuries, and it remains highly relevant in today's Russia. While many Western observers and a good number of Russian writers and thinkers have seen this association with the East in negative terms, invoking images of autocracy, violence and under‐development, other Russians have viewed Russia's connection to the East in a positive light, focusing on its traditions of spirituality and communalism and opposing them to “Western” values of individualism and materialism. This article analyzes the Asian martial artist as a corporeal metaphor in Putin‐era Russia, focusing on the role it plays not only in the self‐fashioning of the Russian male but also in the recent reevaluation of Russia's imperial past, and future. The article draws a connection between this cultural reevaluation of the East and Eurasianist revisionist interpretations of Russia's Mongol past and, specifically, the legacy of Genghis Khan. The conclusions demonstrate that Eurasianist theories, largely discarded by Western scholars, are not confined to the upper echelons of the Putin administration but in fact permeate Putin‐era culture.
Dmitrii Mileev and the Restoration of Wooden Architectural Monuments in Early Twentieth‐Century Russia
Authors: KHODAKOVSKY EVGENY V. , MELIUKH EKATERINA A.
Published: March 2015

This article brings to light the professional life of Dmitrii Vasil'evich Mileev (1878–1914), one of the leading Russian architects and architectural restorationists of the twentieth century. For various reasons, Mileev's work has not received much attention in Russian scholarly literature, and this article seeks to fill this gap by delving into the archives and publications of the Imperial Architectural Commission, as well as using other documents from the early 1900s. The focus is on the restoration of wooden architectural monuments of the Russian North, since Mileev was the first Russian architect to work out a systematic method of preservation that he followed while working on over fifty such buildings. The article continues its exploration into the Soviet period, taking note in particular of the theoretical and practical work of A. V. Opolovnikov, who continued Mileev's work. Together, their contribution to Russian culture was priceless, and their legacy helped to set the course for future Soviet restorationist efforts.
The Stalinist Subject and Mikhail Bulgakov's The Master and Margarita
Authors: MERRILL JESSICA E.
Published: March 2015

The article argues that Bulgakov's The Master and Margarita critiques the dominant Soviet ideology of the 1930s from a position that is at the same time informed by a Stalinist subjectivity. Recent work on Soviet subjectivity suggests that the Stalinist subject was produced from a hybrid of messianic spirituality and liberal self‐fashioning. Bulgakov's novel provisionally separates these two worldviews into the two worlds of his novel–Moscow and Jerusalem. The article demonstrates that the narrative structures of the novel's two plots create two different subject positions. In Moscow, the narrative presupposes the existence of an omnitemporal omniscience, and characters are treated as corporal beings, to be “unmasked” and punished for their sins as in the End of Days. In Jerusalem, the narrative adheres to the conventions of historical realism, and the hero, Pontius Pilate, is developed as a modern, liberal subject. The article concludes that Bulgakov presents these worlds ambivalently–finding fault and hope in both. Rather than read Bulgakov's novel as a liberal critique of Soviet culture, the article hopes to facilitate a recognition of how a fragmented Stalinist subject position can provide the material for a great work of art.
A new HLA‐A*26 family allele – HLA‐A*26:103
Authors: Street J. , Climer T. , Johnson J. , Pepperall J. , Darke C.
Published: March 2015

HLA‐A*26:103 differs from A*26:01:01 by one base (559C>G) in exon 3 resulting in an amino acid substitution of R163G.
Did the Gamemakers Fix the Lottery in the Hunger Games?
Authors: Caudle Kyle , Daniels Erica
Published: March 2015

The Hunger Games is an annual event in the fictional country of Panem. Each year, 24 children (tributes) are chosen by lottery from 12 districts to fight to the death in the arena for the entertainment of the Capitol citizens. Using statistical analysis and computer simulations, we will explore the possibility that the Gamemakers, those in charge of planning the Hunger Games, fixed the lottery. Using the fictitious data from Suzanne Collins' book the Hunger Games, we show how students can learn how to perform a permutation goodness of fit test.
Genome‐guided investigation of plant natural product biosynthesis
Authors: Kellner Franziska , Kim Jeongwoon , Clavijo Bernardo J. , Hamilton John P. , Childs Kevin L. , Vaillancourt Brieanne , Cepela Jason , Habermann Marc , Steuernagel Burkhard , Clissold Leah , McLay Kirsten , Buell Carol Robin , O'Connor Sarah E.
Published: March 2015

The medicinal plant Madagascar periwinkle, Catharanthus roseus (L.) G. Don, produces hundreds of biologically active monoterpene‐derived indole alkaloid (MIA) metabolites and is the sole source of the potent, expensive anti‐cancer compounds vinblastine and vincristine. Access to a genome sequence would enable insights into the biochemistry, control, and evolution of genes responsible for MIA biosynthesis. However, generation of a near‐complete, scaffolded genome is prohibitive to small research communities due to the expense, time, and expertise required. In this study, we generated a genome assembly for C. roseus that provides a near‐comprehensive representation of the genic space that revealed the genomic context of key points within the MIA biosynthetic pathway including physically clustered genes, tandem gene duplication, expression sub‐functionalization, and putative neo‐functionalization. The genome sequence also facilitated high resolution co‐expression analyses that revealed three distinct clusters of co‐expression within the components of the MIA pathway. Coordinated biosynthesis of precursors and intermediates throughout the pathway appear to be a feature of vinblastine/vincristine biosynthesis. The C. roseus genome also revealed localization of enzyme‐rich genic regions and transporters near known biosynthetic enzymes, highlighting how even a draft genome sequence can empower the study of high‐value specialized metabolites.
Efficacy and safety of deferasirox estimated by serum ferritin and labile plasma iron levels in patients with aplastic anemia, myelodysplastic syndrome, or acute myeloid leukemia with transfusional iron overload
Authors: Kim Il‐Hwan , Moon Joon‐Ho , Lim Sung‐Nam , Sohn Sang‐Kyun , Kim Hoon‐Gu , Lee Gyeong‐Won , Kim Yang‐Soo , Lee Ho‐Sup , Kwon Ki‐Young , Kim Sung‐Hyun , Park Kyung‐Tae , Chung Joo‐Seop , Lee Won‐Sik , Lee Sang‐Min , Hyun Myung‐Soo , Kim Hawk , Ryoo Hun‐Mo , Bae Sung‐Hwa , Joo Young‐Don
Published: March 2015

BACKGROUND

Patients receiving red blood cell (RBC) transfusions are at risk of iron overload, which can cause significant organ damage and is an important cause of morbidity and mortality.

STUDY DESIGN AND METHODS

This study was an open‐label, single‐arm, prospective clinical study to evaluate the efficacy and safety of deferasirox (DFX) in patients with aplastic anemia (AA), myelodysplastic syndrome (MDS), or acute myeloid leukemia (AML). Patients with serum ferritin levels of at least 1000 ng/mL and ongoing transfusion requirements were enrolled. DFX was administered for up to 1 year. A total of 100 patients were enrolled.

RESULTS

Serum ferritin levels decreased significantly following treatment (from 2000 to 1650 ng/mL, p = 0.004). The median absolute reduction in serum ferritin levels was −65 ng/mL in AA (p = 0.037), −647 ng/mL in lower‐risk MDS (MDS‐LR; p = 0.007), and −552 ng/mL in higher‐risk MDS (MDS‐HR)/AML (p = 0.482). Mean labile plasma iron (LPI) levels decreased from 0.24 μmol/L at baseline to 0.03 μmol/L at 1 year in all patients (p = 0.036). The mean LPI reduction in each group was −0.17 μmol/L in AA, −0.21 μmol/L in MDS‐LR, and −0.30 μmol/L in MDS‐HR/AML. Gastrointestinal disorders were commonly observed among groups (16.0%). DFX was temporarily skipped for adverse events in seven patients (7.0%) and was permanently discontinued in 11 patients (11.0%).

CONCLUSION

DFX reduced serum ferritin and LPI levels in patients with transfusional iron overload. Despite the relatively high percentage of gastrointestinal side effects, DFX was tolerable in all subgroups.
Dual roles of autologous CD8+ T cells in hematopoietic progenitor cell mobilization and engraftment
Authors: Russell Athena , Malik Sunita , Litzow Mark , Gastineau Dennis , Roy Vivek , Zubair Abba C.
Published: March 2015

BACKGROUND

Poor marrow cellularity alone cannot explain poor hematopoietic progenitor cell (HPC) mobilization. This study assessed the role of CD8+ T cells in HPC cell mobilization and engraftment.

STUDY DESIGN AND METHODS

Mobilization and engraftment were assessed in 192 autologous HPC donors. CD34+, CD4+, and CD8+ T‐cell contents in apheresis products were evaluated. Using a chemotaxis assay, we assessed the effect of purified autologous CD8+ T cells from low and high mobilizers on HPC migration from high to low stromal cell–derived factor (SDF‐1α) concentration gradients. We also assessed CD8+ T‐cell content association with days to neutrophil engraftment.

RESULTS

The median number of CD34+ cells/kg was 4.7 × 106. Patients were categorized according to their total CD34+ cell collection quartile distribution into low, moderate, and high mobilizers. We found that HPC products from low mobilizers contained more CD8+ T cells than HPC products from moderate and high mobilizers. Chemotaxis assays showed depletion of CD8+ T cells enhances HPC mobilization independent of SDF‐1α concentration. Neutrophil engraftment analysis showed that the higher the CD8+ T‐cell content per unit CD34+ cell, the faster the rate of engraftment.

CONCLUSION

Our findings suggest CD8+ T cells inhibit HPC mobilization and facilitate homing and engraftment.
Easier said than done: ABO compatibility and D matching in apheresis platelet transfusions
Authors: Dunbar Nancy M. , Katus Matthew C. , Freeman Christine M. , Szczepiorkowski Zbigniew M.
Published: March 2015

BACKGROUND

Many hospital transfusion services prioritize ABO plasma compatibility in platelet (PLT) transfusion to minimize risk for acute hemolytic transfusion reactions. In spite of the low risk of D alloimmunization associated with apheresis PLT transfusion, attempts may also be made to provide D– PLTs to D– patients. This study was undertaken to assess how often ABO compatibility and/or D matching occurs at our institution and how the ABO and D mix of our PLT supply impacts PLT selection.

STUDY DESIGN AND METHODS

We retrospectively reviewed the ABO and D type of all PLTs transfused plus the age, sex, and ABO and D type of all PLT recipients between January 2010 and March 2014 (51 months).

RESULTS

We provided ABO‐identical PLTs for 5281 (54.6%), ABO plasma–compatible and cellular‐incompatible for 3136 (32.4%), ABO low‐titer plasma‐incompatible and cellular‐compatible for 1150 (11.9%), ABO plasma–incompatible and cellular‐compatible for 30 (0.3%), and ABO plasma–incompatible and cellular‐incompatible for 72 (0.7%). PLT supply did not match PLT demand based on patient ABO type, primarily due to a lower than expected supply of group O PLTs and higher than expected supply of group A and AB. D– patients were less likely to receive ABO‐identical PLT transfusions (p = 0.0008), but were more likely to receive D– PLT transfusions (p < 0.0001).

CONCLUSION

At our hospital, available inventory and PLT selection practices resulted in the majority of group O patients receiving cellular‐incompatible PLT transfusions. Efforts to provide D– PLTs to D– patients also resulted in fewer D– patients receiving ABO‐identical PLT transfusions.
Skeletal muscle oxidative capacity in patients with cystic fibrosis
Authors: Erickson Melissa L. , Seigler Nichole , McKie Kathleen T. , McCully Kevin K. , Harris Ryan A.
Published: March 2015

New Findings

What is the central question of this study?

Do patients with cystic fibrosis have reduced skeletal muscle oxidative capacity, measured with near‐infrared spectroscopy, compared with demographically matched control subjects?

What is the main finding and is its importance?

Patients with cystic fibrosis have impairments in skeletal muscle oxidative capacity. This reduced skeletal muscle oxidative capacity not only appears to be accelerated by age, but it may also contribute to exercise intolerance in patients with cystic fibrosis.

Exercise intolerance predicts mortality in patients with cystic fibrosis (CF); however, the mechanisms have yet to be elucidated fully. Using near‐infrared spectroscopy, in this study we compared skeletal muscle oxidative capacity in patients with CF versus healthy control subjects. Thirteen patients and 16 demographically matched control subjects participated in this study. Near‐infrared spectroscopy was used to measure the recovery rate of oxygen consumption () of the vastus lateralis muscle after 15 s of electrical stimulation (4 Hz) and subsequent repeated transient arterial occlusions. The was reduced in patients with CF (1.82 ± 0.4 min−1) compared with control subjects (2.13 ± 0.5 min−1, P = 0.04). A significant inverse relationship between age and was observed in patients with CF (r = −0.676, P = 0.011) but not in control subjects (r = −0.291, P = 0.274). Patients with CF exhibit a reduction in skeletal muscle oxidative capacity compared with control subjects. It appears that the reduced skeletal muscle oxidative capacity is accelerated by age and could probably contribute to exercise intolerance in patients with CF.
Screw-System-Variation Enabled Reconfiguration of the Bennett Plano-Spherical Hybrid Linkage and Its Evolved Parallel Mechanism
Authors: Zhang Ketao , Dai Jian S.
Published: March 2015

This paper presents the Bennett plano-spherical hybrid linkage and proposes a novel metamorphic parallel mechanism consisting of this plano-spherical linkage as part of limbs. In light of geometrical modeling of the Bennett plano-spherical linkage, and with the investigation of the motion-screw system, the paper reveals for the first time the reconfigurability property of this plano-spherical linkage and identifies the design parameters that lead to change of constraint equations, and subsequently to variation of the order of the motion-screw system. Arranging this linkage as part of limbs, the paper further investigates the reconfiguration property of the plano-spherical linkage evolved parallel mechanism. The analysis reveals that the platform constraint-screw system varies following both bifurcation and trifurcation with motion branch variation in the 6R linkage integrated limb structure. Consequently, this variation of the platform constraint-screw system leads to reconfiguration of the proposed metamorphic parallel mechanism. The paper presents a way of analyzing reconfigurability of kinematic structures based on the screw-system approach.
Effect of Temperature on Electrical Resistivity of Carbon Nanotubes and Graphene Nanoplatelets Nanocomposites
Authors: Oskouyi Amirhossein Biabangard , Sundararaj Uttandaraman , Mertiny Pierre
Published: March 2015

The effect of the temperature on the electrical resistivity of polymer nanocomposites with carbon nanotube (CNT) and graphene nanoplatelets (GNP) fillers was investigated. A three-dimensional (3D) continuum Monte Carlo (MC) model was developed to first form percolation networks. A 3D resistor network was subsequently created to evaluate the nanocomposite electrical properties. The effect of temperature on the electrical resistivity of nanocomposites was thus investigated. Other aspects such as polymer tunneling and filler resistivities were considered as well. The presented comprehensive modeling approach is aimed at providing a better understanding of the electrical resistivity behavior of polymer nanocomposites in conjunction with experimental works.
Cancer in global health: How do prevention and early detection strategies relate?
Authors: Ilbawi André M. , Anderson Benjamin O.
Published: March 2015

Cancer prevention and early-detection strategies are distinct but complementary approaches that are adapted to population- and resource-specific factors and integrated into national cancer control plans can optimize cancer outcomes while strengthening health care delivery systems.
Therapeutic exercise attenuates neutrophilic lung injury and skeletal muscle wasting
Authors: Files D. Clark , Liu Chun , Pereyra Andrea , Wang Zhong-Min , Aggarwal Neil R. , D’Alessio Franco R. , Garibaldi Brian T. , Mock Jason R. , Singer Benjamin D. , Feng Xin , Yammani Raghunatha R. , Zhang Tan , Lee Amy L. , Philpott Sydney , Lussier Stephanie , Purcell Lina , Chou Jeff , Seeds Michael , King Landon S. , Morris Peter E. , Delbono Osvaldo
Published: March 2015

Exercise-induced modification of neutrophil chemokine signaling attenuates skeletal muscle wasting and limits lung injury in mice and patients with acute respiratory failure.
Stem cell hype: Media portrayal of therapy translation
Authors: Kamenova Kalina , Caulfield Timothy
Published: March 2015

Researchers have an ethical responsibility to portray the state of stem cell therapies accurately in the press.
Tumor cells, but not endothelial cells, mediate eradication of primary sarcomas by stereotactic body radiation therapy
Authors: Moding Everett J. , Castle Katherine D. , Perez Bradford A. , Oh Patrick , Min Hooney D. , Norris Hannah , Ma Yan , Cardona Diana M. , Lee Chang-Lung , Kirsch David G.
Published: March 2015

Tumor cells, rather than endothelial cells, are critical targets that regulate primary sarcoma eradication by radiation therapy.
Mycobacterium tuberculosis Gyrase Inhibitors as a New Class of Antitubercular Drugs
Authors: Blanco Delia , Perez-Herran Esther , Cacho Mónica , Ballell Lluís , Castro Julia , González del Río Rubén , Lavandera José Luis , Remuiñán Modesto J. , Richards Cindy , Rullas Joaquin , Vázquez-Muñiz María Jesús , Woldu Ermias , Zapatero-González María Cleofé , Angulo-Barturen Iñigo , Mendoza Alfonso , Barros David
Published: March 2015

One way to speed up the TB drug discovery process is to search for antitubercular activity among compound series that already possess some of the key properties needed in anti-infective drug discovery, such as whole-cell activity and oral absorption. Here, we present MGIs, a new series of
Mycobacterium tuberculosis
gyrase inhibitors, which stem from the long-term efforts GSK has dedicated to the discovery and development of novel bacterial topoisomerase inhibitors (NBTIs). The compounds identified were found to be devoid of fluoroquinolone (FQ) cross-resistance and seem to operate through a mechanism similar to that of the previously described NBTI GSK antibacterial drug candidate. The remarkable
in vitro
and
in vivo
antitubercular profiles showed by the hits has prompted us to further advance the MGI project to full lead optimization.
In Vitro
Antibacterial Activity of the Ceftazidime-Avibactam Combination against Enterobacteriaceae, Including Strains with Well-Characterized β-Lactamases
Authors: Levasseur Premavathy , Girard Anne-Marie , Miossec Christine , Pace John , Coleman Ken
Published: March 2015

The novel β-lactamase inhibitor avibactam is a potent inhibitor of class A, class C, and some class D enzymes. The
in vitro
antibacterial activity of the ceftazidime-avibactam combination was determined for a collection of
Enterobacteriaceae
clinical isolates; this collection was enriched for resistant strains, including strains with characterized serine β-lactamases. The inhibitor was added either at fixed weight ratios to ceftazidime or at fixed concentrations, with the latter type of combination consistently resulting in greater potentiation of antibacterial activity. In the presence of 4 μg/ml of avibactam, the ceftazidime MIC
50
and MIC
90
(0.25 and 2 μg/ml, respectively) were both below the CLSI breakpoint for ceftazidime. Further comparisons with reference antimicrobial agents were performed using this fixed inhibitor concentration. Against most ceftazidime-susceptible and -nonsusceptible isolates, the addition of avibactam resulted in a significant increase in ceftazidime activity, with MICs generally reduced 256-fold for extended-spectrum β-lactamase (ESBL) producers, 8- to 32-fold for CTX-M producers, and >128-fold for KPC producers. Overall, MICs of a ceftazidime-avibactam combination were significantly lower than those of the comparators piperacillin-tazobactam, cefotaxime, ceftriaxone, and cefepime and similar or superior to those of imipenem.
Lung Concentrations of Ceftazidime Administered by Continuous versus Intermittent Infusion in Patients with Ventilator-Associated Pneumonia
Authors: Cousson Joël , Floch Thierry , Guillard Thomas , Vernet Véronique , Raclot Pascal , Wolak-Thierry Aurore , Jolly Damien
Published: March 2015

Ceftazidime is a beta-lactam compound that exerts a time-dependent bactericidal effect. Numerous arguments are in favor of continuous administration of ceftazidime, both for reasons of clinical efficacy and to preserve bacteriological mutation. We report a prospective, single-center, parallel-group, randomized, controlled trial comparing two modes of administration of ceftazidime, namely, continuous administration (loading dose of 20 mg/kg of body weight followed by 60 mg/kg/day) versus intermittent administration (20 mg/kg over 30 min every 8 h) in 34 patients with ventilator-associated pneumonia due to Gram-negative bacilli. The study was performed over 48 h with 13 and 18 assessments of serum ceftazidime in the continuous-infusion group (group A) and the intermittent-fusion group (group B), respectively. Bronchoalveolar lavage (BAL) was performed at steady state in both groups at 44 h to determine ceftazidime levels in the epithelial lining fluid. We chose a predefined threshold of 20 mg/liter for serum concentrations of ceftazidime because of ecological conditions in our center. The median time above 20 mg/liter (
T
>20 mg) was 100% in group A versus 46% in group B. In group A, 14/17 patients had 100%
T
>20 mg, versus only 1/17 patients in group B. In the epithelial lining fluid, the median concentration of ceftazidime was 12 mg/liter in group A versus 6 mg/liter in group B. A threshold of 8 mg/liter in the epithelial lining fluid was achieved twice as often in group A as in group B. This study of ceftazidime concentrations in the epithelial lining fluid indicates that continuous infusion presents advantages in terms of pharmacodynamics and predictable efficacy in patients presenting ventilator-associated pneumonia.
Insights into the Mechanism of Inhibition of CXCR4: Identification of Piperidinylethanamine Analogs as Anti-HIV-1 Inhibitors
Authors: Das Debananda , Maeda Kenji , Hayashi Yasuhiro , Gavande Navnath , Desai Darshan V. , Chang Simon B. , Ghosh Arun K. , Mitsuya Hiroaki
Published: March 2015

The cellular entry of HIV-1 into CD4
+
T cells requires ordered interactions of HIV-1 envelope glycoprotein with C-X-C chemokine receptor type 4 (CXCR4) receptors. However, such interactions, which should be critical for rational structure-based discovery of new CXCR4 inhibitors, remain poorly understood. Here we first determined the effects of amino acid substitutions in CXCR4 on HIV-1
NL
4
-
3
glycoprotein-elicited fusion events using site-directed mutagenesis-based fusion assays and identified 11 potentially key amino acid substitutions, including D97A and E288A, which caused >30% reductions in fusion. We subsequently carried out a computational search of a screening library containing ∼604,000 compounds, in order to identify potential CXCR4 inhibitors. The computational search used the shape of IT1t, a known CXCR4 inhibitor, as a reference and employed various algorithms, including shape similarity, isomer generation, and docking against a CXCR4 crystal structure. Sixteen small molecules were identified for biological assays based on their high shape similarity to IT1t, and their putative binding modes formed hydrogen bond interactions with the amino acids identified above. Three compounds with piperidinylethanamine cores showed activity and were resynthesized. One molecule, designated CX6, was shown to significantly inhibit fusion elicited by X4 HIV-1
NL
4
-
3
glycoprotein (50% inhibitory concentration [IC
50
], 1.9 μM), to inhibit Ca
2+
flux elicited by stromal cell-derived factor 1α (SDF-1α) (IC
50
, 92 nM), and to exert anti-HIV-1 activity (IC
50
, 1.5 μM). Structural modeling demonstrated that CX6 bound to CXCR4 through hydrogen bond interactions with Asp97 and Glu288. Our study suggests that targeting CXCR4 residues important for fusion elicited by HIV-1 envelope glycoprotein should be a useful and feasible approach to identifying novel CXCR4 inhibitors, and it provides important insights into the mechanism by which small-molecule CXCR4 inhibitors exert their anti-HIV-1 activities.
Origin, Evolution, and Virulence of Porcine Deltacoronaviruses in the United States
Authors: Ma Yuanmei , Zhang Yu , Liang Xueya , Lou Fangfei , Oglesbee Michael , Krakowka Steven , Li Jianrong
Published: March 2015

A novel porcine deltacoronavirus (PdCV) was first discovered in Ohio and Indiana in February 2014, rapidly spread to other states in the United States and Canada, and caused significant economic loss in the swine industry. The origin and virulence of this novel porcine coronavirus are not known. Here, we characterized U.S. PdCV isolates and determined their virulence in gnotobiotic and conventional piglets. Genome analyses revealed that U.S. PdCV isolates possess unique genetic characteristics and share a close relationship with Hong Kong and South Korean PdCV strains and coronaviruses (CoVs) of Asian leopard cats and Chinese ferret-badgers. The PdCV-positive intestinal content (Ohio CVM1) and the cell culture-adapted PdCV Michigan (MI) strain were orally inoculated into gnotobiotic and/or conventional piglets. Within 1 to 3 days postinfection, profuse watery diarrhea, vomiting, and dehydration were observed. Clinical signs were associated with epithelial necrosis in the gastric pits and small intestine, the latter resulting in severe villous atrophy. Mild interstitial pneumonia was identified in the lungs of PdCV-infected piglets. High levels of viral RNA (8 to 11 log RNA copies/g) were detected in intestinal tissues/luminal contents and feces of infected piglets, whereas moderate RNA levels (2 to 5 log RNA copies/g) were detected in blood, lung, liver, and kidney, indicating multisystemic dissemination of the virus. Polyclonal immune serum against PdCV but not immune serum against porcine epidemic diarrhea virus (PEDV) reacted with PdCV-infected small-intestinal epithelial cells, indicating that PdCV is antigenically distinct from PEDV. Collectively, we demonstrate for the first time that PdCV caused severe gastrointestinal diseases in swine.

IMPORTANCE
Porcine coronaviruses (CoVs) are major viral infectious diseases of swine. Examples of porcine CoVs include porcine transmissible gastroenteritis coronavirus (TGEV), porcine epidemic diarrhea virus (PEDV), and porcine respiratory coronavirus (PRCV). In February 2014, another porcine CoV, porcine deltacoronavirus (PdCV), emerged in Ohio and Indiana and subsequently spread rapidly across the United States and Canada
,
causing significant economic losses. Here, we report the detailed genetic characterization, phylogeny, and virulence of emergent PdCV strains in the United States. We found that PdCV caused severe diarrhea, vomiting, and dehydration in gnotobiotic and conventional piglets, signs that were clinically indistinguishable from those caused by PEDV and TGEV. In addition to extensive intestinal lesions, PdCV caused significant lesions in the stomach and mild pulmonary lesions that have not been reported for TGEV and PEDV. The finding that PdCV is a significant enteric disease of swine highlights the need to develop effective measures to control this disease.
Identification of a Gamma Interferon-Activated Inhibitor of Translation-Like RNA Motif at the 3′ End of the Transmissible Gastroenteritis Coronavirus Genome Modulating Innate Immune Response
Authors: Marquez-Jurado Silvia , Nogales Aitor , Zuñiga Sonia , Enjuanes Luis , Almazán Fernando
Published: March 2015

A 32-nucleotide (nt) RNA motif located at the 3′ end of the transmissible gastroenteritis coronavirus (TGEV) genome was found to specifically interact with the host proteins glutamyl-prolyl-tRNA synthetase (EPRS) and arginyl-tRNA synthetase (RRS). This RNA motif has high homology in sequence and secondary structure with the gamma interferon-activated inhibitor of translation (GAIT) element, which is located at the 3′ end of several mRNAs encoding proinflammatory proteins. The GAIT element is involved in the translation silencing of these mRNAs through its interaction with the GAIT complex (EPRS, heterogeneous nuclear ribonucleoprotein Q, ribosomal protein L13a, and glyceraldehyde 3-phosphate dehydrogenase) to favor the resolution of inflammation. Interestingly, we showed that the viral RNA motif bound the GAIT complex and inhibited the
in vitro
translation of a chimeric mRNA containing this RNA motif. To our knowledge, this is the first GAIT-like motif described in a positive RNA virus. To test the functional role of the GAIT-like RNA motif during TGEV infection, a recombinant coronavirus harboring mutations in this motif was engineered and characterized. Mutations of the GAIT-like RNA motif did not affect virus growth in cell cultures. However, an exacerbated innate immune response, mediated by the melanoma differentiation-associated gene 5 (MDA5) pathway, was observed in cells infected with the mutant virus compared with the response observed in cells infected with the parental virus. Furthermore, the mutant virus was more sensitive to beta interferon than the parental virus. All together, these data strongly suggested that the viral GAIT-like RNA motif modulates the host innate immune response.

IMPORTANCE
The innate immune response is the first line of antiviral defense that culminates with the synthesis of interferon and proinflammatory cytokines to limit virus replication. Coronaviruses encode several proteins that interfere with the innate immune response at different levels, but to date, no viral RNA counteracting antiviral response has been described. In this work, we have characterized a 32-nt RNA motif located at the 3′ end of the TGEV genome that specifically interacted with EPRS and RRS. This RNA motif presented high homology with the GAIT element, involved in the modulation of the inflammatory response. Moreover, the disruption of the viral GAIT-like RNA motif led to an exacerbated innate immune response triggered by MDA5, indicating that the GAIT-like RNA motif counteracts the host innate immune response. These novel findings may be of relevance for other coronaviruses and could serve as the basis for the development of novel antiviral strategies.
A Group A Streptococcus ADP-Ribosyltransferase Toxin Stimulates a Protective Interleukin 1β-Dependent Macrophage Immune Response
Authors: Lin Ann E. , Beasley Federico C. , Keller Nadia , Hollands Andrew , Urbano Rodolfo , Troemel Emily R. , Hoffman Hal M. , Nizet Victor
Published: March 2015

The M1T1 clone of group A Streptococcus (GAS) is associated with severe invasive infections, including necrotizing fasciitis and septicemia. During invasive M1T1 GAS disease, mutations in the
covRS
regulatory system led to upregulation of an ADP-ribosyltransferase, SpyA. Surprisingly, a GAS Δ
spyA
mutant was resistant to killing by macrophages and caused higher mortality with impaired bacterial clearance in a mouse intravenous challenge model. GAS expression of SpyA triggered macrophage cell death in association with caspase-1-dependent interleukin 1β (IL-1β) production, and differences between wild-type (WT) and Δ
spyA
GAS macrophage survival levels were lost in cells lacking caspase-1, NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), or pro-IL-1β. Similar
in vitro
findings were identified in macrophage studies performed with pseudomonal exotoxin A, another ADP-ribosylating toxin. Thus, SpyA triggers caspase-1-dependent inflammatory cell death in macrophages, revealing a toxin-triggered IL-1β-dependent innate immune response pathway critical in defense against invasive bacterial infection.

IMPORTANCE
Group A Streptococcus (GAS) is a leading human pathogen capable of producing invasive infections even in healthy individuals. GAS bacteria produce a toxin called SpyA that modifies host proteins through a process called ADP ribosylation. We describe how macrophages, frontline defenders of the host innate immune system, respond to SpyA by undergoing a specialized form of cell death in which they are activated to release the proinflammatory cytokine molecule interleukin 1β (IL-1β). Release of IL-1β activates host immune cell clearance of GAS, as we demonstrated in tissue culture models of macrophage bacterial killing and
in vivo
mouse infectious-challenge experiments. Similar macrophage responses to a related toxin of
Pseudomonas
bacteria were also shown. Thus, macrophages recognize certain bacterial toxins to activate a protective immune response in the host.
Heparan Sulfate-Dependent Enhancement of Henipavirus Infection
Authors: Mathieu Cyrille , Dhondt Kévin P. , Châlons Marie , Mély Stéphane , Raoul Hervé , Negre Didier , Cosset François-Loïc , Gerlier Denis , Vivès Romain R. , Horvat Branka
Published: March 2015

Nipah virus and Hendra virus are emerging, highly pathogenic, zoonotic paramyxoviruses that belong to the genus
Henipavirus
. They infect humans as well as numerous mammalian species. Both viruses use ephrin-B2 and -B3 as cell entry receptors, and following initial entry into an organism, they are capable of rapid spread throughout the host. We have previously reported that Nipah virus can use another attachment receptor, different from its entry receptors, to bind to nonpermissive circulating leukocytes, thereby promoting viral dissemination within the host. Here, this attachment molecule was identified as heparan sulfate for both Nipah virus and Hendra virus. Cells devoid of heparan sulfate were not able to mediate henipavirus
trans
-infection and showed reduced permissivity to infection. Virus pseudotyped with Nipah virus glycoproteins bound heparan sulfate and heparin but no other glycosaminoglycans in a surface plasmon resonance assay. Furthermore, heparin was able to inhibit the interaction of the viruses with the heparan sulfate and to block cell-mediated
trans
-infection of henipaviruses. Moreover, heparin was shown to bind to ephrin-B3 and to restrain infection of permissive cells
in vitro
. Consequently, treatment with heparin devoid of anticoagulant activity improved the survival of Nipah virus-infected hamsters. Altogether, these results reveal heparan sulfate as a new attachment receptor for henipaviruses and as a potential therapeutic target for the development of novel approaches against these highly lethal infections.

IMPORTANCE
The
Henipavirus
genus includes two closely related, highly pathogenic paramyxoviruses, Nipah virus and Hendra virus, which cause elevated morbidity and mortality in animals and humans. Pathogenesis of both Nipah virus and Hendra virus infection is poorly understood, and efficient antiviral treatment is still missing. Here, we identified heparan sulfate as a novel attachment receptor used by both viruses to bind host cells. We demonstrate that heparin was able to inhibit the interaction of the viruses with heparan sulfate and to block cell-mediated
trans
-infection of henipaviruses. Moreover, heparin also bound to the viral entry receptor and thereby restricted infection of permissive cells
in vitro
. Consequently, heparin treatment improved survival of Nipah virus-infected hamsters. These results uncover an important role of heparan sulfate in henipavirus infection and open novel perspectives for the development of heparan sulfate-targeting therapeutic approaches for these emerging infections.
Impact of increased visceral adiposity with normal weight on the progression of arterial stiffness in Japanese patients with type 2 diabetes
Authors: Bouchi Ryotaro , Minami Isao , Ohara Norihiko , Nakano Yujiro , Nishitani Rie , Murakami Masanori , Takeuchi Takato , Akihisa Momoko , Fukuda Tatsuya , Fujita Masamichi , Yoshimoto Takanobu , Ogawa Yoshihiro
Published: March 2015

Objective

Normal-weight abdominal obesity has been reported to be associated with poor mortality. We aimed to investigate the impact of increased visceral adiposity with normal weight (OB(−)VA(+)) on the progression of arterial stiffness in patients with type 2 diabetes.

Methods

This was a cross-sectional study of 414 patients with type 2 diabetes (mean age 64±12 years; 40.3% female). Visceral fat area (VFA, cm2) was measured by a dual bioelectrical impedance analyzer. Arterial stiffness was assessed by brachial-ankle pulse wave velocity (baPWV, cm/s). Patients were divided into four groups by VFA and body mass index (BMI, kg/m2) as the following: BMI<25 kg/m2and VFA<100 cm2(obesity (OB)(−)visceral adiposity (VA)(−)), BMI≥25 kg/m2and VFA<100 cm2(OB(+)VA(−)), BMI<25 kg/m2and VFA≥100 cm2(OB(−)VA(+)), and BMI≥25 kg/m2and VFA≥100 cm2(OB(+)VA(+)). Multivariate linear regression analysis was done to determine the impact of OB(−)VA(+) on arterial stiffness.

Results

Among the patients, 7.2% were OB(−)VA(+) with higher baPWV levels (1956±444 cm/s) than those with OB(+)VA(−) (1671±416 cm/s, p=0.014), those with OB(+)VA(+) (1744±317 cm/s, p=0.048), and those with OB(−)VA(−) (1620±397 cm/s, p=0.024). In multivariate linear regression analysis, OB(−)VA(+) remained independently associated with baPWV (standardized β 0.184, p=0.001).

Conclusions

This study provides evidence for the burden of arterial stiffness in OB(−)VA(+) patients with type 2 diabetes; therefore, evaluation of visceral adiposity is of clinical relevance for the better management of non-obese individuals as well as obese populations.
Effectiveness of school-based smoking prevention curricula: systematic review and meta-analysis
Authors: Thomas Roger E , McLellan Julie , Perera Rafael
Published: March 2015

Objective

To assess effectiveness of school-based smoking prevention curricula keeping children never-smokers.

Design

Systematic review, meta-analysis. Data: MEDLINE (1966+), EMBASE (1974+), Cinahl, PsycINFO (1967+), ERIC (1982+), Cochrane CENTRAL, Health Star, Dissertation Abstracts, conference proceedings. Data synthesis: pooled analyses, fixed-effects models, adjusted ORs. Risk of bias assessed with Cochrane Risk of Bias tool.

Setting

50 randomised controlled trials (RCTs) of school-based smoking curricula.

Participants

Never-smokers age 5–18 (n=143 495); follow-up ≥6 months; all countries; no date/language limitations.

Interventions

Information, social influences, social competence, combined social influences/competence and multimodal curricula.

Outcome measure

Remaining a never-smoker at follow-up.

Results

Pooling all curricula, trials with follow-up ≤1 year showed no statistically significant differences compared with controls (OR 0.91 (0.82 to 1.01)), though trials of combined social competence/social influences curricula had a significant effect on smoking prevention (7 trials, OR 0.59 (95% CI 0.41 to 0.85)). Pooling all trials with longest follow-up showed an overall significant effect in favour of the interventions (OR 0.88 (0.82 to 0.95)), as did the social competence (OR 0.65 (0.43 to 0.96)) and combined social competence/social influences curricula (OR 0.60 (0.43 to 0.83)). No effect for information, social influences or multimodal curricula. Principal findings were not sensitive to inclusion of booster sessions in curricula or to whether they were peer-led or adult-led. Differentiation into tobacco-only or multifocal curricula had a similar effect on the primary findings. Few trials assessed outcomes by gender: there were significant effects for females at both follow-up periods, but not for males.

Conclusions

RCTs of baseline never-smokers at longest follow-up found an overall significant effect with average 12% reduction in starting smoking compared with controls, but no effect for all trials pooled at ≤1 year. However, combined social competence/social influences curricula showed a significant effect at both follow-up periods.

Systematic review registration

Cochrane Tobacco Review Group CD001293.
Cost-effectiveness of interventions to control cardiovascular diseases and type 2 diabetes mellitus in South Asia: protocol for a systematic review
Authors: Singh Kavita , Chandra Sekaran Ambalam M , Bhaumik Soumyadeep , Aisola Malini , Chattopadhyay Kaushik , Gamage Anuji U , de Silva Padmal , Selvaraj Sakthivel , Roy Ambuj , Prabhakaran Dorairaj , Tandon Nikhil
Published: March 2015

Introduction

While a number of strategies are being implemented to control cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM), the cost-effectiveness of these in the South Asian context has not been systematically evaluated. We aim to systematically review the economic (cost-effectiveness) evidence available on the individual-, group- and population-level interventions for control of CVD and T2DM in South Asia.

Methods and analysis

This review will consider all relevant economic evaluations, either conducted alongside randomised controlled trials or based on decision modelling estimates. These studies must include participants at risk of developing CVD/T2DM or with established disease in one or more of the South Asian countries (India, Bangladesh, Pakistan, Sri Lanka, Nepal, Maldives, Bhutan and Afghanistan). We will identify relevant papers by systematically searching all major databases and registries. Selected articles will be screened by two independent researchers. Methodological quality of the studies will be assessed using a modified Drummond and a Phillips checklist. Cochrane guidelines will be followed for bias assessment in the effectiveness studies.

Results

Results will be presented in line with the PRISMA (Preferred Reporting Items for Systematic review and Meta-analysis) checklist, and overall quality of evidence will be presented as per the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach.

Ethics and dissemination

The study has received ethics approval from the All India Institute of Medical Sciences, New Delhi, India. The results of this review will provide policy-relevant recommendations for the uptake of cost-effectiveness evidence in prioritising decisions on essential chronic disease care packages for South Asia.

Study registration number

PROSPERO CRD42013006479.
A cross-sectional study of shift work, sleep quality and cardiometabolic risk in female hospital employees
Authors: Lajoie P , Aronson K J , Day A , Tranmer J
Published: March 2015

Objectives

Investigating the potential pathways linking shift work and cardiovascular diseases (CVD), this study aimed to identify whether sleep disturbances mediate the relationship between shift work and the metabolic syndrome, a cluster of CVD risk factors.

Design

Cross-sectional study.

Setting

A tertiary-level, acute care teaching hospital in Southeastern Ontario, Canada.

Participants

Female hospital employees working a shift schedule of two 12 h days, two 12 h nights, followed by 5 days off (n=121) were compared with female day-only workers (n=150).

Primary and secondary outcome measures

Each of the seven components of the Pittsburgh Sleep Quality Index (PSQI) was measured. Of these, PSQI global score, sleep latency and sleep efficiency were examined as potential mediators in the relationship between shift work and the metabolic syndrome.

Results

Shift work status was associated with poor (>5) PSQI global score (OR=2.10, 95% CI 1.20 to 3.65), poor (≥2) sleep latency (OR=2.18, 95% CI 1.23 to 3.87) and poor (≥2) sleep efficiency (OR=2.11, 95% CI 1.16 to 3.84). Although shift work was associated with the metabolic syndrome (OR=2.29, 95% CI 1.12 to 4.70), the measured components of sleep quality did not mediate the relationship between shift work and the metabolic syndrome.

Conclusions

Women working in a rapid forward rotating shift pattern have poorer sleep quality according to self-reported indicators of the validated PSQI and they have a higher prevalence of the metabolic syndrome compared with women who work during the day only. However, sleep quality did not mediate the relationship between shift work and the metabolic syndrome, suggesting that there are other psychophysiological pathways linking shift work to increased risk for CVD.