bluuebunny/crossref_metadata_2025 huggingface dataset:
A store‐operated calcium channel inhibitor attenuates collagen‐induced arthritis
Authors: Gao X H , Gao R , Tian Y Z , McGonigle P , Barrett J E , Dai Y , Hu H
Published: February 2015

Background and Purpose

Store‐operated calcium (SOC) channels are thought to play a critical role in immune responses, inflammatory diseases and chronic pain. The aim of this study was to explore the potential role and mechanisms of SOC channels in collagen‐induced arthritis (CIA).

Experimental Approach

The CIA mouse model was used to examine the effects of the SOC channel inhibitor YM‐58483 on CIA and arthritic pain. Hargreaves' and von Frey hair tests were conducted to measure thermal and mechanical sensitivities of hind paws. elisa was performed to measure cytokine production, and haematoxylin and eosin staining was used to assess knee histological changes. Western blot analysis was performed to examine protein levels.

Key Results

Pretreatment with 5 or 10 mg·kg−1 of YM‐58483 reduced the incidence of CIA, prevented the development of inflammation and pain hypersensitivity and other signs and features of arthritis disease. Similarly, treatment with YM‐58483 after the onset of CIA: (i) reversed the clinical scores; (ii) reduced paw oedema; (iii) attenuated mechanical and thermal hypersensitivity; (iv) improved spontaneous motor activity; (v) decreased periphery production of IL‐1β, IL‐6 and TNF‐α; and (vi) reduced spinal activation of ERK and calmodulin‐dependent PKII (CaMKIIα).

Conclusions and Implications

This study provides the first evidence that inhibition of SOC entry prevents and relieves rheumatoid arthritis (RA) and arthritic pain. These effects are probably mediated by a reduction in cytokine levels in the periphery and activation of ERK and CaMKIIα in the spinal cord. These results suggest that SOC channels are potential drug targets for the treatment of RA.
Class A1 scavenger receptors in cardiovascular diseases
Authors: Ben Jingjing , Zhu Xudong , Zhang Hanwen , Chen Qi
Published: February 2015

Class A1 scavenger receptors (SR‐A1) are membrane glycoproteins that can form homotrimers. This receptor was originally defined by its ability to mediate the accumulation of lipids in macrophages. Subsequent studies reveal that SR‐A1 plays critical roles in innate immunity, cell apoptosis and proliferation. This review highlights recent advances in understanding the structure, receptor pathway and regulation of SR‐A1. Although its role in atherosclerosis is disputable, recent discoveries suggest that SR‐A1 function in anti‐inflammatory responses by promoting an M2 macrophage phenotype in cardiovascular diseases. Therefore, SR‐A1 may be a potential target for therapeutic intervention of cardiovascular diseases.

Linked Articles

This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23
The GPR55 agonist lysophosphatidylinositol relaxes rat mesenteric resistance artery and induces Ca2+ release in rat mesenteric artery endothelial cells
Authors: AlSuleimani Y M , Hiley C R
Published: February 2015

Background and Purpose

Lysophosphatidylinositol (LPI), a lipid signalling molecule, activates GPR55 and elevates intracellular Ca2+. Here, we examine the actions of LPI in the rat resistance mesenteric artery and Ca2+ responses in endothelial cells isolated from the artery.

Experimental Approach

Vascular responses were studied using wire myographs. Single‐cell fluorescence imaging was performed using a MetaFluor system. Hypotensive effects of LPI were assessed using a Biopac system.

Key Results

In isolated arteries, LPI‐induced vasorelaxation was concentration‐ and endothelium‐dependent and inhibited by CID 16020046, a GPR55 antagonist. The CB1 receptor antagonist AM 251 had no effect, whereas rimonabant and O‐1918 significantly potentiated LPI responses. Vasorelaxation was reduced by charybdotoxin and iberiotoxin, alone or combined. LPI decreased systemic arterial pressure. GPR55 is expressed in rat mesenteric artery. LPI caused biphasic elevations of endothelial cell intracellular Ca2+. Pretreatment with thapsigargin or 2‐aminoethoxydiphenyl borate abolished both phases. The PLC inhibitor U73122 attenuated the initial phase and enhanced the second phase, whereas the Rho‐associated kinase inhibitor Y‐27632 abolished the late phase but not the early phase .

Conclusions and Implications

LPI is an endothelium‐dependent vasodilator in the rat small mesenteric artery and a hypotensive agent. The vascular response involves activation of Ca2+‐sensitive K+ channels and is not mediated by CB1 receptors, but unexpectedly enhanced by antagonists of the ‘endothelial anandamide’ receptor. In endothelial cells, LPI utilizes PLC‐IP3 and perhaps ROCK‐RhoA pathways to elevate intracellular Ca2+. Overall, these findings support an endothelial site of action for LPI and suggest a possible role for GPR55 in vasculature.
Kaempferol enhances endothelium‐dependent relaxation in the porcine coronary artery through activation of large‐conductance Ca2+‐activated K+ channels
Authors: Xu Y C , Leung S W S , Leung G P H , Man R Y K
Published: February 2015

Background and Purpose

Kaempferol, a plant flavonoid present in normal human diet, can modulate vasomotor tone. The present study aimed to elucidate the signalling pathway through which this flavonoid enhanced relaxation of vascular smooth muscle.

Experimental Approach

The effect of kaempferol on the relaxation of porcine coronary arteries to endothelium‐dependent (bradykinin) and ‐independent (sodium nitroprusside) relaxing agents was studied in an in vitro organ chamber setup. The whole‐cell patch‐clamp technique was used to determine the effect of kaempferol on potassium channels in porcine coronary artery smooth muscle cells (PCASMCs).

Key Results

At a concentration without direct effect on vascular tone, kaempferol (3 × 10−6 M) enhanced relaxations produced by bradykinin and sodium nitroprusside. The potentiation by kaempferol of the bradykinin‐induced relaxation was not affected by Nω‐nitro‐L‐arginine methyl ester, an inhibitor of NO synthase (10−4 M) or TRAM‐34 plus UCL 1684, inhibitors of intermediate‐ and small‐conductance calcium‐activated potassium channels, respectively (10−6 M each), but was abolished by tetraethylammonium chloride, a non‐selective inhibitor of calcium‐activated potassium channels (10−3 M), and iberiotoxin, a selective inhibitor of large‐conductance calcium‐activated potassium channel (KCa1.1; 10−7 M). Iberiotoxin also inhibited the potentiation by kaempferol of sodium nitroprusside‐induced relaxations. Kaempferol stimulated an outward‐rectifying current in PCASMCs, which was abolished by iberiotoxin.

Conclusions and Implications

The present results suggest that, in smooth muscle cells of the porcine coronary artery, kaempferol enhanced relaxations caused by endothelium‐derived and exogenous NO as well as those due to endothelium‐dependent hyperpolarization. This vascular effect of kaempferol involved the activation of KCa1.1 channels.
Increased sialidase activity in serum of cancer patients: Identification of sialidase and inhibitor activities in human serum
Authors: Hata Keiko , Tochigi Tatsuo , Sato Ikuro , Kawamura Sadafumi , Shiozaki Kazuhiro , Wada Tadashi , Takahashi Kohta , Moriya Setsuko , Yamaguchi Kazunori , Hosono Masahiro , Miyagi Taeko
Published: February 2015

Aberrant sialylation in glycoproteins and glycolipids is a characteristic feature of malignancy. Human sialidases, which catalyze the removal of sialic acid residues from glycoconjugates, have been implicated in cancer progression. They have been detected in a wide variety of human cells and tissues, but few studies have focused on their existence in human serum. Among the four types identified to date, we previously demonstrated that plasma membrane‐associated ganglioside sialidase (NEU3) is markedly upregulated in various human cancers, including examples in the colon and prostate. Here, using a sensitive assay method, we found a significant increase of sialidase activity in the serum of patients with prostate cancer compared with that in healthy subjects having low activity, if any. Activity was apparent with gangliosides as substrates, but only to a very limited extent with 4‐methylumbelliferyl sialic acid, a good synthetic substrate for sialidases other than human NEU3. The serum sialidase was also almost entirely immunoprecipitated with anti‐NEU3 antibody, but not with antibodies for other sialidases. Interestingly, sera additionally contained inhibitory activity against the sialidase and also against recombinant human NEU3. The sialidase and inhibitor activities could be separated by exosome isolation and by hydrophobic column chromatography. The serum sialidase was assessed by a sandwich ELISA method using two anti‐NEU3 antibodies. The results provide strong evidence that the serum sialidase is, in fact, NEU3, and this subtype may, therefore, be a potential utility for novel diagnosis of human cancers.
NeuroD1 promotes neuroblastoma cell growth by inducing the expression of ALK
Authors: Lu Fangjin , Kishida Satoshi , Mu Ping , Huang Peng , Cao Dongliang , Tsubota Shoma , Kadomatsu Kenji
Published: February 2015

Neuroblastoma is derived from the sympathetic neuronal lineage of neural crest cells, and is the most frequently observed of the extracranial pediatric solid tumors. The neuronal differentiation factor, NeuroD1, has previously been shown to promote cell motility in neuroblastoma by suppressing the expression of Slit2. Here we report that NeuroD1 is also involved in the proliferation of neuroblastoma cells, including human cell lines and primary tumorspheres cultured from the tumor tissues of model mice. Interestingly, the growth inhibition of neuroblastoma cells induced by knockdown of NeuroD1 was accompanied by a reduction of ALK expression. ALK is known to be one of the important predisposition genes for neuroblastoma. The phenotype resulting from knockdown of NeuroD1 was suppressed by forced expression of ALK and, therefore, NeuroD1 appears to act mainly through ALK to promote the proliferation of neuroblastoma cells. Furthermore, we showed that NeuroD1 directly bound to the promoter region of ALK gene. In addition, the particular E‐box in the promoter was responsible for NeuroD1‐mediated ALK expression. These results indicate that ALK should be a direct target gene of NeuroD1. Finally, the expressions of NeuroD1 and ALK in the early tumor lesions of neuroblastoma model mice coincided in vivo. We conclude that the novel mechanism would regulate the expression of ALK in neuroblastoma and that NeuroD1 should be significantly involved in neuroblastoma tumorigenesis.
The emergent geography of biophysical dispersal barriers across the Indo‐West Pacific
Authors: Treml Eric A. , Roberts Jason , Halpin Patrick N. , Possingham Hugh P. , Riginos Cynthia
Published: February 2015

Aim

To discover and evaluate potential dispersal barriers across the Indo‐West Pacific Ocean and to develop spatially explicit hypotheses regarding the location of barriers and their capacity to filter taxa. Additionally, to compare model predictions with previously described barriers and build a more thorough understanding of the region's biogeographic patterns.

Location

The reefs of the Indo‐West Pacific Ocean, from 100 to 170°E and from 30°N to 30°S.

Methods

A biophysical larval dispersal model was used to quantify over 800,000 dispersal kernels by simulating 99 model taxa. Spatial analysis was used to map emergent patterns of potential multispecies population connectivity and predict geographic locations and strength of concordant dispersal barriers across the seascape.

Results

Although individual taxa varied in their predicted fine‐scale population connectivity, there was consistency in the location of dispersal barriers. Across all trait combinations, reproductive output (fecundity and density of reproductive adults), reproductive strategy (spawning phenology) and the length of the larval dispersal phase determined the strength of barriers across the seascape. More than 80% of the previously described marine boundaries in the region were predicted to restrict the dispersal of at least 10% of the simulated taxa. The location and strength of many additional multitaxa barriers were described at scales <200 km.

Main conclusions

The geographic structure of many previously described multispecies barriers across the Indo‐West Pacific were predicted with the biophysical dispersal model and spatial analysis. The permeability of individual dispersal barriers was primarily determined by reproductive output, spawning phenology and the length of the pelagic larval stage. Across all dispersal barriers analysed, Euclidean distance explained up to 49% of the variation in barrier strength.
Impact of treatment with saxagliptin on glycaemic stability and β‐cell function in the SAVOR‐TIMI 53 study
Authors: Leibowitz G. , Cahn A. , Bhatt D. L. , Hirshberg B. , Mosenzon O. , Wei C. , Jermendy G. , Sheu W. H.‐H. , Sendon J. L. , Im K. , Braunwald E. , Scirica B. M. , Raz I.
Published: February 2015

Aims

To study the effects of saxagliptin, a dipeptidyl peptidase‐4 inhibitor, on glycaemic stability and β‐cell function in the SAVOR‐TIMI 53 trial.

Methods

We randomized 16 492 patients with type 2 diabetes (T2D) to saxagliptin or placebo, added to current antidiabetic medications, and followed them for a median of 2.1 years. Glycaemic instability was defined by: (i) a glycated haemoglobin (HbA1c) increase of ≥0.5% post‐randomization; (ii) the initiation of new antidiabetic medications for ≥3 months; or (iii) an increase in dose of oral antidiabetic medication or ≥25% increase in insulin dose for ≥3 months. β‐cell function was assessed according to fasting homeostatic model 2 assessment of β‐cell function (HOMA‐2β) values at baseline and at year 2 in patients not treated with insulin.

Results

Compared with placebo, participants treated with saxagliptin had a reduction in the development of glycaemic instability (hazard ratio 0.71; 95% confidence interval 0.68–0.74; p < 0.0001). In participants treated with saxagliptin compared with placebo, the occurrence of an HbA1c increase of ≥0.5% was reduced by 35.2%; initiation of insulin was decreased by 31.7% and the increases in doses of an oral antidiabetic drug or insulin were reduced by 19.5 and 23.5%, respectively (all p < 0.0001). At 2 years, HOMA‐2β values decreased by 4.9% in participants treated with placebo, compared with an increase of 1.1% in those treated with saxagliptin (p < 0.0001).

Conclusions

Saxagliptin improved glycaemia and prevented the reduction in HOMA‐2β values. Saxagliptin may reduce the usual decline in β‐cell function in T2D, thereby slowing diabetes progression.
Hypothetical gene C18orf42 encodes a novel protein kinase A‐binding protein
Authors: Fukuda Makiha , Aizawa Yasunori
Published: February 2015

The substrate specificity of cAMP‐dependent protein kinase A (PKA) is controlled by its interaction with the A‐kinase anchoring protein (AKAP) family. Individual AKAP members are localized to particular intracellular sites and tether PKA specifically to the subcellular compartments where target substrates exist. Here, we report that the human hypothetical gene C18orf42 encodes a novel PKA‐binding protein that potentially regulates PKA–AKAP interactions. C18orf42 is expressed preferentially in neural tissues. Functional motif searching predicted that C18orf42 may encode a short protein that contains a putative PKA‐binding motif. To confirm this possibility, we applied the CRISPR/Cas9 genome‐editing system to incorporate the FLAG tag into the C‐terminus of the endogenous C18orf42 protein in the mouse neural cell line Neuro2a. Immunoprecipitation and immunoblotting using anti‐FLAG antibody showed translation of the endogenous C18orf42 protein and the physical interaction of the C18orf42 protein with PKA subunits. Immunoprecipitation and pull‐down assays showed that C18orf42 binds specifically to the type II regulatory subunits of PKA. Unlike the expression of many AKAPs, that of C18orf42 could block the AKAP‐mediated subcellular localization of PKA. These findings suggest that C18orf42 may be a novel PKA signaling gene that serves as an endogenous disruptor peptide for PKA–AKAP interactions.
Chemical genomics approach to identify genes associated with sensitivity to rapamycin in the fission yeast Schizosaccharomyces pombe
Authors: Doi Akira , Fujimoto Ayumi , Sato Shun , Uno Takaya , Kanda Yuki , Asami Keita , Tanaka Yuriko , Kita Ayako , Satoh Ryosuke , Sugiura Reiko
Published: February 2015

Rapamycin and its derivatives have now emerged as an attractive therapeutic strategy with both immunosuppressant and antitumor properties. In addition, rapamycin has been proposed as a calorie restriction mimetic to extend the life span of various organisms. The fission yeast Schizosaccharomyces pombe (S. pombe) serves as a valuable genetic model system to study the mechanism(s) of drug action as well as to determine genetic contexts associated with drug sensitivity or resistance. Here, we identified genes that when deleted modulate the rapamycin‐sensitive strains in S. pombe. We carried out a chemical genomics screen for rapamycin‐sensitive mutants using the genome‐deletion library which covers 95.3% of all nonessential fission yeast genes and confirmed 59 genes to be rapamycin sensitive. Gene Ontology (GO) enrichment analysis showed that strains sensitive to rapamycin are highly enriched in processes regulating tRNA modification and mitochondria as well as other ontologies, including cellular metabolic process, chromatin organization, cell cycle, signaling, translation, transport and other cellular processes. Analysis also showed that components of the Elongator complex are overrepresented in the sensitive strains. Here, the data obtained will provide valuable information for speculation on the actions of rapamycin as well as on TORC signaling, thereby presenting a strategy to enhance sensitivity to rapamycin.
Molecular characterization of ten F8 splicing mutations in RNA isolated from patient's leucocytes: assessment of in silico prediction tools accuracy
Authors: Martorell L. , Corrales I. , Ramirez L. , Parra R. , Raya A. , Barquinero J. , Vidal F.
Published: February 2015

Although 8% of reported FVIII gene (F8) mutations responsible for haemophilia A (HA) affect mRNA processing, very few have been fully characterized at the mRNA level and/or systematically predicted their biological consequences by in silico analysis. This study is aimed to elucidate the effect of potential splice site mutations (PSSM) on the F8 mRNA processing, investigate its correlation with disease severity, and assess their concordance with in silico predictions. We studied the F8 mRNA from 10 HA patient's leucocytes with PSSM by RT‐PCR and compared the experimental results with those predicted in silico. The mRNA analysis could explain all the phenotypes observed and demonstrated exon skipping in six cases (c.222G>A, c.601+1delG, c.602‐11T>G, c.671‐3C>G, c.6115+9C>G and c.6116‐1G>A) and activation of cryptic splicing sites, both donor (c.1009+1G>A and c.1009+3A>C) and acceptor sites (c.266‐3delC and c.5587‐1G>A). In contrast, the in silico analysis was able to predict the score variation of most of the affected splice site, but the precise mechanism could only be correctly determined in two of the 10 mutations analysed. In addition, we have detected aberrant F8 transcripts, even in healthy controls, so this must be taken into account as they could mask the actual contribution of some PSSM. We conclude that F8 mRNA analysis using leucocytes still constitutes an excellent approach to investigate the transcriptional effects of the PSSM in HA, whereas prediction in silico is not always reliable for diagnostic decision‐making.
Hepatitis B and elders: An underestimated issue
Authors: Loustaud‐Ratti Véronique , Jacques Jérémie , Debette‐Gratien Marilyne , Carrier Paul
Published: February 2015

As the world's population becomes older, the burden of hepatitis B virus in elderly has to be considered. The liver changes with aging and its function is eventually altered. The prevalence of hepatitis B virus is paradoxically more important in elderly in areas having vaccination programs, because of a loosening of the prevention in older patients. Some differences in hepatitis B presentation must be enhanced in elderly: lower spontaneous hepatitis B surface antigen clearance after a recent contamination, major risk of cirrhosis and hepatocarcinoma. Acute hepatitis B seems to be more often symptomatic, with a great risk of chronicity. Hepatocarcinoma linked to hepatitis B virus has a higher prevalence and a different presentation in elderly. Its treatment is the same as in younger people but is less often possible. Liver transplantation is contraindicated after 70 years old. Hepatitis B treatment panel is the same as in younger people (pegylated interferon, nucleoside or nucleotide agents). It gives identical results with no particular adverse events if the precautions for use are followed. Vaccination is less efficient, as in immunocompromised patients, and needs specific protocols.
miR‐486 regulates metastasis and chemosensitivity in hepatocellular carcinoma by targeting CLDN10 and CITRON
Authors: Sun Huiyan , Cui Chunping , Xiao Fengjun , Wang Hua , Xu Jun , Shi Xuefeng , Yang Yuefeng , Zhang Qunwei , Zheng Xiaofei , Yang Xiaoming , Wu Chutse , Wang Lisheng
Published: February 2015

Aim

miRNA‐486 (miR‐486) was first identified from the human fetal liver cDNA library and considered to be associated with hepatocellular carcinoma (HCC) development. Its roles in regulation of HCC metastasis and chemosensitivity have not been explored yet.

Methods

miR‐486 expression in HCC tissues, cell lines and serum was evaluated by real‐time polymerase chain reaction. miR‐486 overexpression or downregulation in the cell lines SMMC‐7721/LM3 was conducted by lentivirus transfection. Cell proliferation, migration and apoptosis were quantitated using commercial assays. Matrix metalloproteinase activity was quantitated by gelatin zymography. The target genes of miR‐486 were screened by 3′‐untranslated region luciferase report assays and their function was validated by small RNA interference.

Results

We show here that miR‐486 is frequently down‐expressed in HCC tissues and cell lines. Lentivirus‐mediated restoration of miR‐486 in HCC cell lines resulted in significant reduction in the ability of cell growth, colony formation and migration. However, miR‐486 inhibition enhances proliferation and invasion of HCC cells. Two genes, CITRON and CLDN10 which regulate cell proliferation and invasion, respectively, were identified as the direct targets of miR‐486 in HCC cells. CITRON and CLDN10 knockdown by siRNA results in similar phenotypes of miR‐486 restoration in HCC cell lines. In addition, miR‐486 enhances the chemosensitivity of HCC cells to sorafenib.

Conclusion

Our data indicated that miR‐486 may function as a novel tumor suppressor in HCC.
Serum miRNA‐122 in acute liver injury induced by kidney injury and sepsis in CD‐1 mouse models
Authors: Leelahavanichkul Asada , Somparn Poorichaya , Panich Thanaporn , Chancharoenthana Wiwat , Wongphom Jutamas , Pisitkun Trairak , Hirankarn Nattiya , Eiam‐Ong Somchai
Published: February 2015

Aim

miRNA‐122 (miR‐122) is a new, interesting liver injury biomarker but little is known about its effects when there is an indirect acute liver injury.

Methods

We investigated this by using indirect liver injury mice models with bilateral ureter obstruction (BUO), bilateral nephrectomy (BiNx) and cecal ligation and puncture (CLP). A direct liver injury model, liver ischemia/reperfusion injury (liver I/R), was performed in parallel. Liver injury (i.e. liver histology, alanine transaminase [ALT]), kidney damage (i.e. serum creatinine) and cytokines (i.e. tumor necrosis factor‐α, interleukin [IL]‐6, IL‐1β, IL‐10) were assessed.

Results

Six hours after BUO/BiNx/CLP, the ALT and serum cytokines were approximately 1.5‐fold higher than the baseline whereas miR‐122 did not change. After 6 h of BiNx, there were prominent hepatocyte vacuolization but no elevations of miR‐122. However, after 24 h of BUO/BiNx/CLP, ALT, hepatocyte vacuolization and miR‐122 increased. The cytokines at 6 h might have induced the production of miR‐122 at 24 h. The results from the in vitro study with HepG2 cells and each of the cytokines resulted in increased miR‐122. On the other hand, when the direct liver injury model was used, there was a fivefold and 22‐fold increase in the ALT at 0.5 and 1 h after surgery, respectively, and high serum miR‐122 which corroborated the results from the liver histopathology.

Conclusion

We demonstrated that prior serum cytokine accumulation increased serum miR‐122 in indirect liver injury induced by BUO/BiNx and less severe sepsis mouse models. Cytokine accumulation may be responsible for miR‐122 expression in these models. The clinical importance of liver injury demonstrated by the discordance between serum miR‐122 and ALT was an interesting issue.
Phase II, randomized, open, controlled study of AS03‐adjuvanted H5N1 pre‐pandemic influenza vaccine in children aged 3 to 9 years: follow‐up of safety and immunogenicity persistence at 24 months post‐vaccination
Authors: Díez‐Domingo Javier , Baldó José‐María , Planelles‐Catarino Maria Victoria , Garcés‐Sánchez María , Ubeda Isabel , Jubert–Rosich Angels , Marès Josep , Garcia‐Corbeira Pilar , Moris Philippe , Teko Maurice , Vanden Abeele Carline , Gillard Paul
Published: February 2015

Background

An AS03‐adjuvanted H5N1 influenza vaccine elicited broad and persistent immune responses with an acceptable safety profile up to 6 months following the first vaccination in children aged 3–9 years.

Methods

In this follow‐up of the Phase II study, we report immunogenicity persistence and safety at 24 months post‐vaccination in children aged 3–9 years. The randomized, open‐label study assessed two doses of H5N1 A/Vietnam/1194/2004 influenza vaccine (1·9 μg or 3·75 μg hemagglutinin antigen) formulated with AS03A or AS03B (11·89 mg or 5·93 mg tocopherol, respectively). Control groups received seasonal trivalent influenza vaccine. Safety was assessed prospectively and included potential immune‐mediated diseases (pIMDs). Immunogenicity was assessed by hemagglutination‐inhibition assay 12 and 24 months after vaccination; cross‐reactivity and cell‐mediated responses were also assessed. (NCT00502593).

Results

The safety population included 405 children. Over 24 months, five events fulfilled the criteria for pIMDs, of which four occurred in H5N1 vaccine recipients, including uveitis (n = 1) and autoimmune hepatitis (n = 1), which were considered to be vaccine‐related. Overall, safety profiles of the vaccines were clinically acceptable. Humoral immune responses at 12 and 24 months were reduced versus those observed after the second dose of vaccine, although still within the range of those observed after the first dose. Persistence of cell‐mediated immunity was strong, and CD4+ T cells with a TH1 profile were observed.

Conclusions

Two doses of an AS03‐adjuvanted H5N1 influenza vaccine in children showed low but persistent humoral immune responses and a strong persistence of cell‐mediated immunity, with clinically acceptable safety profiles up to 24 months following first vaccination.
Evidence of regenerative ability inMyxicola infundibulum(Annelida, Sabellida): evolutionary and systematic implications
Authors: Licciano Margherita , Watson Gordon James , Murray Joanna Michelle , Giangrande Adriana
Published: February 2015

Members of only a few species of annelids are reported as being incapable of regeneration; of these,Myxicola infundibulumis the only example in the family Sabellidae. Interestingly, its congenerMyxicola aestheticaexhibits noteworthy regenerative ability. Unambiguously identifying non‐regenerating species is critical to reconstructing how regenerative abilities evolved within the phylum. However, studies designed specifically to assess the regenerative potential ofM. infundibulumhave never been performed. In this study, we aimed to confirm the lack of regeneration ability ofM. infundibulum, reported previously for Atlantic specimens, or to determine the extent to which regeneration occurs. Our results showed that individuals from the Mediterranean Sea (Adriatic Sea) do undergo regeneration of lost body parts, although to a lesser extent than do other sabellids. Therefore,M. infundibulumshould no longer be considered a non‐regenerating species. At present, uncertainties regarding phylogenetic relationships of Sabellidae prevent inferences about the polarity of change inM. infundibulum. Since our findings are counter to those of previous studies which describe Atlantic specimens as non‐regenerating, more extensive analysis is required to ascertain if they could actually belong to a different species than MediterraneanM. infundibulum, accounting for these differences in reported regenerative capacity.
Wireless Smartphone ECG Enables Large‐Scale Screening in Diverse Populations
Authors: HABERMAN ZACHARY C. , JAHN RYAN T. , BOSE RUPAN , TUN HAN , SHINBANE JEROLD S. , DOSHI RAHUL N. , CHANG PHILIP M. , SAXON LESLIE A.
Published: February 2015

Twelve‐Lead ECG as a Cardiovascular Screening Tool

Background

The ubiquitous presence of internet‐connected phones and tablets presents a new opportunity for cost‐effective and efficient electrocardiogram (ECG) screening and on‐demand diagnosis. Wireless, single‐lead real‐time ECG monitoring supported by iOS and android devices can be obtained quickly and on‐demand. ECGs can be immediately downloaded and reviewed using any internet browser.

Objective

We compared the standard 12‐lead ECG to the smartphone ECG in healthy young adults, elite athletes, and cardiology clinic patients. Accuracy for determining baseline ECG intervals and rate and rhythm was assessed.

Methods

In 381 participants, 30‐second lead I ECG waveforms were obtained using an iPhone case or iPad. Standard 12‐lead ECGs were acquired immediately after the smartphone tracing was obtained. De‐identified ECGs were interpreted by automated algorithms and adjudicated by two board‐certified electrophysiologists.

Results

Both smartphone and standard ECGs detected atrial rate and rhythm, AV block, and QRS delay with equal accuracy. Sensitivities ranged from 72% (QRS delay) to 94% (atrial fibrillation). Specificities were all above 94% for both modalities.

Conclusion

Smartphone ECG accurately detects baseline intervals, atrial rate, and rhythm and enables screening in diverse populations. Efficient ECG analysis using automated discrimination and an enhanced smartphone application with notification capabilities are features that can be easily incorporated into the acquisition process.
Early childhood behavioral inhibition, adult psychopathology and the buffering effects of adolescent social networks: a twenty‐year prospective study
Authors: Frenkel Tahl I. , Fox Nathan A. , Pine Daniel S. , Walker Olga L. , Degnan Kathryn A. , Chronis‐Tuscano Andrea
Published: February 2015

Background

We examined whether the temperament of behavioral inhibition is a significant marker for psychopathology in early adulthood and whether such risk is buffered by peer social networks.

Methods

Participants (N = 165) were from a prospective study spanning the first two decades of life. Temperament was characterized during infancy and early childhood. Extent of involvement in peer social networks was measured during adolescence, and psychopathology was assessed in early adulthood. Latent Class Analyses generated comprehensive variables at each of three study time‐points. Regressions assessed (a) the direct effect of early behavioral inhibition on adult psychopathology (b) the moderating effect of adolescent involvement in social peer networks on the link between temperamental risk and adult psychopathology.

Results

Stable behavioral inhibition in early childhood was negatively associated with adult mental health (R2 = .07, p = .005, β = −.26), specifically increasing risk for adult anxiety disorders (R2 = .04, p = .037, β = .19). These temperament‐pathology relations were significantly moderated by adolescent peer group social involvement and network size (Total R2 = .13, p = .027, β = −.22). Temperament predicted heightened risk for adult anxiety when adolescent social involvement was low (p = .002, β = .43), but not when adolescent social involvement was high.

Conclusions

Stable behavioral inhibition throughout early childhood is a risk factor for adult anxiety disorders and interacts with adolescent social involvement to moderate risk. This is the first study to demonstrate the critical role of adolescent involvement in socially active networks in moderating long‐lasting temperamental risk over the course of two decades, thus informing prevention/intervention approaches.
Maternal thermal effect on diapause inTrichogrammaspecies (Hymenoptera: Trichogrammatidae)
Authors: Voinovich N. D. , Reznik S. Y. , Vaghina N. P.
Published: February 2015

Both direct thermal and maternal photoperiodic effects on diapause induction have been thoroughly investigated in many insect species, while maternal thermal effects have been infrequently studied. We studied the effect of temperature during development of maternal generation on the proportion of diapausing progeny in four species of the genusTrichogrammaWestw., minute egg parasitoids, widely used for biological control of lepidopteran pests. The maternal generations were reared at day lengths of 12 and 18 h and temperatures of 17, 20, 25 and 30°C, and their progeny developed under day length of 12 h and temperatures of 13 and 14°C. InT. evanescensandT. piceum, the proportion of diapausing progeny decreased with increasing temperature under all tested photoperiods and thermal regimes of progeny development; the high temperature of 30°C totally averted diapause of progeny. InT. buesiandT. principium,low temperatures of 17 and 20°C resulted in relatively high proportion of diapausing progeny only when the maternal generation developed under short‐day conditions. The threshold of the maternal thermal response varied from 17–18 to 22–23°C. Under field conditions,Trichogrammafemales are exposed to such high temperatures only during summer, when diapause in their progeny is in any case prevented by the maternal photoperiodic response and by the thermal response of the larvae. We conclude that the maternal thermal effect on diapause induction, although to a different extent, is inherent toTrichogrammaspecies but, at least as suggested by laboratory experiments, it does not play any role in the regulation of seasonal development under natural conditions. However, during mass rearing ofTrichogrammawasps, it should be taken into account that high temperature, even when combined with short photoperiod, can avert diapause in the next generation.
CEOs' Leadership Styles and Managers' Innovative Behaviour: Investigation of Intervening Effects in an Entrepreneurial Context
Authors: Kang Jae Hyeung , Solomon George T. , Choi David Y.
Published: February 2015

We examine the relationships and intervening mechanisms between founding CEOs' transformational/transactional leadership and the innovative behaviour of managers. We develop and test our hypotheses on a sample of 39 participating CEOs and 105 managers with the use of a multilevel structural equation model. The results show that both transformational and transactional leadership on the part of the CEO relate positively to managers' innovative behaviour. We also discover that firm's innovative climate mediates the relationship between transformational leadership and innovative behaviour. However, we fail to find the mediating effect of innovative climate between transactional leadership and innovative behaviour. Our findings contribute to an improved understanding of how founding CEOs' different leadership styles affect employees' innovative behaviour in start‐ups and to what extent the innovative climate influences the relationship.
“Liking” and “Take Away” Preferences for Mexican Consumers: Cross‐Cultural Comparison with Thais for Psychological Style
Authors: Calderón Eduardo , Angulo Ofelia , O'Mahony Michael , Wichchukit Sukanya
Published: February 2015

There are reports in the literature that for paired preference tests with a “No Preference” option, Mexican consumers have a lower frequency of “No Preference” responses than Thais. For a more exact comparison of these differences in psychophysical style, Mexican consumers performed preference tests using, as closely as possible, the experimental method used in the Thai experiments. Comparison between this study and the Thai studies confirmed the differences in “No Preference” frequencies, suggesting a systematic cross‐cultural effect of psychophysical style. Mexican consumers also performed “take away” preferences for the first time and their results corresponded more with the regular paired preference tests than was the case with Thais.

Practical Applications

Paired preference tests are a subset of measures available for consumer acceptance. Considering the importance of efforts to predict consumer acceptance, it is essential to understand the variables and biases associated with such tests. Because cross‐cultural measurement is becoming more critical in a globalized world, any systematic cross‐cultural differences should not be ignored. The present study investigated a possible stable cross‐cultural difference with the use of paired preference tests between two potential markets. For companies that sell their products in a variety of countries, such differences will need to be taken into account when interpreting paired preference data and accordingly are worthy of investigation.
Are ‘informative presuppositions’ presuppositions?
Authors: Tonhauser Judith
Published: February 2015

Presuppositions are contents of utterances that must be mutually known by the interlocutors, i.e. the speaker and the addressees, in order for an utterance of a sentence with the presupposition trigger to be judged to be acceptable. However, a substantial subset of contents traditionally taken to be presuppositions does not exhibit this property and can instead be used to inform the addressee about the supposedly presuppositional content. Classical analyses of these so‐called ‘informative presuppositions’ nevertheless assume that they are associated with a common ground requirement but one that can be accommodated. According to an alternative characterization, ‘informative presuppositions’ are not associated with a common ground requirement but are informative like Potts' conventional implicatures; such a characterization does not need to make reference to accommodation. The debate about the characterization of ‘informative presuppositions’ has been based almost exclusively on judgments about English provided by native speaker researchers. This paper explores how results from research with theoretically untrained speakers (including one‐on‐one elicitation and experiments) as well as corpus studies can bear on this debate. I argue that such results, though tenuous, support the alternative characterization at least for some ‘informative presuppositions’ and emphasize the merit of bringing data collected through a wide range of methodologies to bear on theoretical research on meaning.
R&D Expenditures and Geographical Sales Diversification
Authors: Baum Christopher F. , Caglayan Mustafa , Talavera Oleksandr
Published: February 2015

This paper empirically examines the role of diversification in export markets on firm‐level R&D activities taking account of the potential endogeneity in this relationship. We show that geographical sales diversification across different regions of the world induces UK firms to increase their R&D expenditures, as firms must innovate and develop new products to maintain a competitive edge over their rivals. This finding is robust to a battery of sensitivity checks. Furthermore, we find that R&D expenditures cause higher export sales but do not cause export sales diversification. Hence, the result that diversification causes higher R&D activity is not driven by reverse causality.
Bipolar disorders in the Arab world: a critical review
Authors: Kronfol Ziad , Zakaria Khalil Mostafa , Kumar Pankaj , Suhre Karsten , Karam Elie , McInnis Melvin
Published: February 2015

Bipolar disorders are common psychiatric disorders that affect 1–5% of the population worldwide. Major advances in the epidemiology, pathophysiology, and treatment of the disorders have recently occurred. The majority of published reports, however, originate from the Western hemisphere, mostly Europe and the United States. There is a shortage of data from the Arab world on bipolar disorders. In an era of globalization and rapid communication, it is not clear to what extent research findings pertaining to one part of the world are by necessity applicable to other parts. Psychiatric disorders are known to be affected by the culture in which they occur, and knowledge of variations in illness presentation in different ethnic groups is also increasing. However, knowledge of variations affecting Arab populations remains quite limited. This paper provides a critical review of the literature on bipolar affective disorders in the Arab world, pointing to major gaps in knowledge and future opportunities to fill these gaps.
Demonstrating mood repair with a situation‐based measure of self‐compassion and self‐criticism
Authors: Falconer Caroline J. , King John A. , Brewin Chris R.
Published: February 2015

Objectives

The clinical significance of self‐criticism and self‐compassion has prompted the development of questionnaires assessing these constructs. However, there is a lack of measures assessing their interaction within specific contexts and potential involvement in mood repair processes.

Design

To rectify this, we developed the Self‐Compassion and Self‐Criticism Scales (SCCS), based on responses to specific scenarios, and examined its psychometric properties in an online survey and an experimental situation.

Method

In study 1, standard psychometric procedures were used to investigate the reliability and validity of the SCCS. In study 2, an experimental challenge involving a difficult language task was used to test its sensitivity to change.

Results

In study 1, exploratory factor analysis (n = 413) showed a clear two‐factor structure of the SCCS denoting two orthogonal scales, with high internal validity (α ≥ .87). Correlations between the SCCS and existing measures also demonstrated appropriate convergent validity. Study 2 (n = 90) provided preliminary evidence that the SCCS can detect changes in self‐appraisals. Participants receiving no performance feedback from the challenge task showed reduced state self‐criticism and increased state self‐compassion, demonstrating mood repair.

Conclusions

The SCCS has promise as a situational measure of self‐compassion and self‐criticism.

Practitioner points

In the context of specific problem situations, clients' levels of self‐criticism and self‐compassion may well be orthogonal and can be assessed with the SCCS.

In setting treatment goals and assessing treatment outcome, it may be helpful to target both self‐compassion and self‐criticism separately.
Uniform Ergodicity of the Particle Gibbs Sampler
Authors: Lindsten Fredrik , Douc Randal , Moulines Eric
Published: February 2015

The particle Gibbs sampler is a systematic way of using a particle filter within Markov chain Monte Carlo. This results in an off‐the‐shelf Markov kernel on the space of state trajectories, which can be used to simulate from the full joint smoothing distribution for a state space model in a Markov chain Monte Carlo scheme. We show that the particle Gibbs Markov kernel is uniformly ergodic under rather general assumptions, which we will carefully review and discuss. In particular, we provide an explicit rate of convergence, which reveals that (i) for fixed number of data points, the convergence rate can be made arbitrarily good by increasing the number of particles and (ii) under general mixing assumptions, the convergence rate can be kept constant by increasing the number of particles superlinearly with the number of observations. We illustrate the applicability of our result by studying in detail a common stochastic volatility model with a non‐compact state space.
Effects of loaded voluntary wheel exercise on performance and muscle hypertrophy in young and old male C57Bl/6J mice
Authors: Soffe Z. , Radley‐Crabb H. G. , McMahon C. , Grounds M. D. , Shavlakadze T.
Published: February 2015

This study compared the capacity of young and old male C57Bl/6J mice to exercise with increasing resistance over 10 weeks, and its impact on muscle mass. Young mice (aged 15–25 weeks) were subjected to low (LR) and high (HR) resistance exercise, whereas only LR was used for old mice (107–117 weeks). Weekly patterns of voluntary wheel activity, food consumption and body weights were measured. Running patterns changed over time and with age, with two peaks of activity detected for young, but only one for old mice: speed and distance run was also less for old mice. The mass for six limb muscles was measured at the end of the experiment. The most pronounced increase in mass in response to exercise was for the soleus in young and old mice, and also quadriceps and gastrocnemius in young mice. Soleus and quadriceps muscles were analyzed histologically for myofiber number and size. A striking feature was the many small myofibers in response to exercise in young (but not old) soleus, whereas these were not present after exercise in young or old quadriceps. Overall, there was a striking difference in response to exercise between muscles and this was influenced by age.
Emotion Socialization in the Context of Risk and Psychopathology: Maternal Emotion Coaching Predicts Better Treatment Outcomes for Emotionally Labile Children with Oppositional Defiant Disorder
Authors: Dunsmore Julie C. , Booker Jordan A. , Ollendick Thomas H. , Greene Ross W.
Published: February 2015

We examined whether maternal emotion coaching at pretreatment predicted children's treatment response following a 12‐week program addressing children's oppositional defiant disorder (ODD) symptoms. A total of 89 mother–child dyads participated. At pretreatment, mothers and children engaged in an emotion talk task. Mothers also reported their beliefs about emotions at pretreatment and their child's disruptive behavior symptoms, emotion regulation, and emotion lability/negativity at pre‐, mid‐, and post‐treatment. Clinicians reported children's symptom severity at pre‐ and post‐treatment. Children's emotion lability/negativity moderated effects of maternal emotion coaching on children's post‐treatment ODD symptoms, with stronger benefits of emotion coaching for children high in emotion lability/negativity. Results suggest that emotion coaching may promote treatment response for children with ODD who are especially at risk due to their emotionality.