bluuebunny/crossref_metadata_2025 huggingface dataset:
p120-catenin binding masks an endocytic signal conserved in classical cadherins
Authors: Nanes Benjamin A. , Chiasson-MacKenzie Christine , Lowery Anthony M. , Ishiyama Noboru , Faundez Victor , Ikura Mitsuhiko , Vincent Peter A. , Kowalczyk Andrew P.
Published: October 2012

p120-catenin (p120) binds to the cytoplasmic tails of classical cadherins and inhibits cadherin endocytosis. Although p120 regulation of cadherin internalization is thought to be important for adhesive junction dynamics, the mechanism by which p120 modulates cadherin endocytosis is unknown. In this paper, we identify a dual-function motif in classical cadherins consisting of three highly conserved acidic residues that alternately serve as a p120-binding interface and an endocytic signal. Mutation of this motif resulted in a cadherin variant that was both p120 uncoupled and resistant to endocytosis. In endothelial cells, in which dynamic changes in adhesion are important components of angiogenesis and inflammation, a vascular endothelial cadherin (VE-cadherin) mutant defective in endocytosis assembled normally into cell–cell junctions but potently suppressed cell migration in response to vascular endothelial growth factor. These results reveal the mechanistic basis by which p120 stabilizes cadherins and demonstrate that VE-cadherin endocytosis is crucial for endothelial cell migration in response to an angiogenic growth factor.
Hedgehog pathway inhibition and the race against tumor evolution
Authors: Atwood Scott X. , Chang Anne Lynn S. , Oro Anthony E.
Published: October 2012

Dependence of basal cell carcinomas and medulloblastomas on the Hedgehog pathway provides an opportunity for targeted or “personalized” therapy. The recent effectiveness and FDA approval of the first Smoothened inhibitors validates this class of agents, but has revealed drug-resistant tumor variants that bypass Smoothened inhibition. Here, we summarize the effectiveness of Hedgehog pathway inhibitors and highlight promising areas for the development of next generation drug antagonists for Hedgehog-dependent cancers.
Guilt by association: What p120-catenin has to hide
Authors: Perez-Moreno Mirna , Fuchs Elaine
Published: October 2012

Members of the p120-catenin family associate with cadherins and regulate their stability at the plasma membrane. How p120-catenin limits cadherin endocytosis has long remained a mystery. In this issue, Nanes et al. (2012. J. Cell Biol. doi:10.1083/jcb.201205029) identify a conserved acidic motif within cadherins that acts as a physical platform for p120-catenin binding. However, in the absence of p120-catenin, the motif acts as an endocytic signal. These results provide new insight into p120-catenin’s role as guardian of intercellular junction dynamics.
Quasi-isometric co-Hopficity of non-uniform lattices in rank-one semi-simple Lie groups
Authors: Kapovich Ilya , Lukyanenko Anton
Published: October 2012

We prove that if

G
G

is a non-uniform lattice in a rank-one semi-simple Lie group

≠
Isom
(

H

R

2

)

\ne \text {Isom}( \mathbb {H}^2_{\mathbb {R}})

, then

G
G

is quasi-isometrically co-Hopf. This means that every quasi-isometric embedding

G
→
G

G\to G

is coarsely surjective and thus is a quasi-isometry.
Multinomial modeling and an evaluation of common data-mining algorithms for identifying signals of disproportionate reporting in pharmacovigilance databases
Authors: Johnson Kjell , Guo Cen , Gosink Mark , Wang Vicky , Hauben Manfred
Published: October 2012

Motivation: A principal objective of pharmacovigilance is to detect adverse drug reactions that are unknown or novel in terms of their clinical severity or frequency. One method is through inspection of spontaneous reporting system databases, which consist of millions of reports of patients experiencing adverse effects while taking one or more drugs. For such large databases, there is an increasing need for quantitative and automated screening tools to assist drug safety professionals in identifying drug–event combinations (DECs) worthy of further investigation. Existing algorithms can effectively identify problematic DECs when the frequencies are high. However these algorithms perform differently for low-frequency DECs.

Results: In this work, we provide a method based on the multinomial distribution that identifies signals of disproportionate reporting, especially for low-frequency combinations. In addition, we comprehensively compare the performance of commonly used algorithms with the new approach. Simulation results demonstrate the advantages of the proposed method, and analysis of the Adverse Event Reporting System data shows that the proposed method can help detect interesting signals. Furthermore, we suggest that these methods be used to identify DECs that occur significantly less frequently than expected, thus identifying potential alternative indications for these drugs. We provide an empirical example that demonstrates the importance of exploring underexpected DECs.

Availability: Code to implement the proposed method is available in R on request from the corresponding authors.

Contact:  kjell@arboranalytics.com or Mark.M.Gosink@Pfizer.com

Supplementary information:  Supplementary data are available at Bioinformatics online.
A counting renaissance: combining stochastic mapping and empirical Bayes to quickly detect amino acid sites under positive selection
Authors: Lemey Philippe , Minin Vladimir N. , Bielejec Filip , Kosakovsky Pond Sergei L. , Suchard Marc A.
Published: October 2012

Motivation: Statistical methods for comparing relative rates of synonymous and non-synonymous substitutions maintain a central role in detecting positive selection. To identify selection, researchers often estimate the ratio of these relative rates () at individual alignment sites. Fitting a codon substitution model that captures heterogeneity in across sites provides a reliable way to perform such estimation, but it remains computationally prohibitive for massive datasets. By using crude estimates of the numbers of synonymous and non-synonymous substitutions at each site, counting approaches scale well to large datasets, but they fail to account for ancestral state reconstruction uncertainty and to provide site-specific estimates.

Results: We propose a hybrid solution that borrows the computational strength of counting methods, but augments these methods with empirical Bayes modeling to produce a relatively fast and reliable method capable of estimating site-specific values in large datasets. Importantly, our hybrid approach, set in a Bayesian framework, integrates over the posterior distribution of phylogenies and ancestral reconstructions to quantify uncertainty about site-specific estimates. Simulations demonstrate that this method competes well with more-principled statistical procedures and, in some cases, even outperforms them. We illustrate the utility of our method using human immunodeficiency virus, feline panleukopenia and canine parvovirus evolution examples.

Availability: Renaissance counting is implemented in the development branch of BEAST, freely available at http://code.google.com/p/beast-mcmc/. The method will be made available in the next public release of the package, including support to set up analyses in BEAUti.

Contact:  philippe.lemey@rega.kuleuven.be or msuchard@ucla.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Halanaerobium sehlinense sp. nov., an extremely halophilic, fermentative, strictly anaerobic bacterium from sediments of the hypersaline lake Sehline Sebkha
Authors: Abdeljabbar Hedi , Cayol Jean-Luc , Ben Hania Wajdi , Boudabous Abdellatif , Sadfi Najla , Fardeau Marie-Laure
Published: October 2012

A strictly anaerobic, extremely halophilic, Gram-positive, rod-shaped bacterium was isolated from the hypersaline (>20 % NaCl) surface sediments of Sehline Sebkha in Tunisia. The strain, designated 1SehelT, was strictly halophilic and proliferated at NaCl concentrations of between 5 % and 30 % (saturation), with optimal growth at 20 % NaCl. Strain 1SehelT was non-spore-forming, non-motile, appearing singly or in pairs, or occasionally as long chains and measured 0.5–0.8 µm by 3–10 µm. Strain 1SehelT grew optimally at pH values of 7.4 but had a very broad pH range for growth (pH 5.2–9.4). It grew at temperatures between 20 and 50 °C with an optimum at 43 °C. Strain 1SehelT required yeast extract for growth. The isolate fermented glucose, galactose, fructose, glycerol, mannose, maltose, ribose, pyruvate and sucrose. The fermentation products from glucose utilization were lactate, acetate, formate, ethanol, CO2 and H2. The G+C ratio of the DNA was 32.7 mol%. The major fatty acids were C15 : 1ω6c/7c, C16 : 1ω7c, C16 : 0 and C15 : 0. On the basis of phylogenetic and physiological properties, strain 1SehelT ( = DSM 25582T = JCM 18213T) is proposed as the type strain of Halanaerobium sehlinense sp. nov., within the family

Halanaerobiaceae

.
Flavobacterium anatoliense sp. nov., isolated from fresh water, and emended description of

Flavobacterium ceti
Authors: Kacagan Murat , Inan Kadriye , Belduz Ali Osman , Canakci Sabriye
Published: October 2012

A Gram-staining-negative, catalase- and oxidase-positive, strictly aerobic, rod-shaped bacterial strain isolated from fresh water in Trabzon, Turkey and designated MK3T was characterized by phenotypic and molecular methods in order to determine its phylogenetic position. On the basis of 16S rRNA gene sequence similarity, strain MK3T was shown to belong to the genus

Flavobacterium

, being most closely related to

Flavobacterium ceti

CECT 7184T (93.6 %). Sequence similarity with other species of the genus

Flavobacterium

with validly published names was less than 91.6 %. Phenotypic and chemotaxonomic data supported the affiliation of strain MK3T to the genus

Flavobacterium

. The only menaquinone was MK-6; the major fatty acids were iso-C15 : 0 (45.2 %), summed feature 9 (C16 : 0 10-methyl and/or iso-C17 : 1ω9c; 20.4 %) and summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c; 13.3 %) and the major polar lipids were phosphatidylethanolamine, one unidentified aminophospholipid and two unidentified phospholipids. The G+C content of the genomic DNA was 38.6 mol%. The results of physiological and biochemical tests allowed strain MK3T to be distinguished phenotypically from

Flavobacterium ceti

CECT 7184T. Strain MK3T, therefore, represents a novel species of the genus

Flavobacterium

, for which the name Flavobacterium anatoliense sp. nov. is proposed. The type strain is MK3T ( = LMG 26441T = NCCB 100384T). An emended description of

Flavobacterium ceti

is also proposed.
Desulfotomaculum peckii sp. nov., a moderately thermophilic member of the genus

Desulfotomaculum

, isolated from an upflow anaerobic filter treating abattoir wastewaters
Authors: Jabari Linda , Gannoun Hana , Cayol Jean-Luc , Hamdi Moktar , Ollivier Bernard , Fauque Guy , Fardeau Marie-Laure
Published: October 2012

A novel anaerobic thermophilic sulfate-reducing bacterium designated strain LINDBHT1T was isolated from an anaerobic digester treating abattoir wastewaters in Tunisia. Strain LINDBHT1T grew at temperatures between 50 and 65 °C (optimum 55–60 °C), and at pH between 5.9 and 9.2 (optimum pH 6.0–6.8). Strain LINDBHT1T required salt for growth (1–40 g NaCl l−1), with an optimum of 20–30 g l−1. In the presence of sulfate as terminal electron acceptor, strain LINDBHT1T used H2/CO2, propanol, butanol and ethanol as carbon and energy sources but fumarate, formate, lactate and pyruvate were not utilized. Butanol was converted to butyrate, while propanol and ethanol were oxidized to propionate and acetate, respectively. Sulfate, sulfite and thiosulfate were utilized as terminal electron acceptors but elemental sulfur, iron (III), fumarate, nitrate and nitrite were not used. The G+C content of the genomic DNA was 44.4 mol%. Phylogenetic analysis of the small-subunit rRNA gene sequence indicated that strain LINDBHT1T was affiliated to the genus

Desulfotomaculum

with the type strains of

Desulfotomaculum halophilum

and

Desulfotomaculum alkaliphilum

as its closest phylogenetic relatives (about 89 % similarity). This strain represents a novel species of the genus

Desulfotomaculum

, Desulfotomaculum peckii sp. nov.; the type strain is LINDBHT1T ( = DSM 23769T = JCM 17209T).
Domibacillus robiginosus gen. nov., sp. nov., isolated from a pharmaceutical clean room
Authors: Seiler Herbert , Wenning Mareike , Scherer Siegfried
Published: October 2012

A novel red-pigmented bacterial strain, designated WS 4628T, was isolated from a pharmaceutical clean room of a vaccine-producing company and was investigated in a taxonomic study using a polyphasic approach. The strain was Gram-stain-positive, strictly aerobic, motile, catalase-positive and produced spherical to slightly ellipsoidal endospores in rods. The genomic DNA G+C content was 44.1 mol%. The major fatty acids were anteiso-C15 : 0, iso-C15 : 0 and anteiso-C17 : 0 and the predominant quinone was MK-6. The polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, an unidentified phosphoglycolipid and an unidentified phospholipid. meso-diaminopimelic acid (type A1γ) was present in the cell-wall peptidoglycan and the major whole-cell sugars were glucose and ribose. The closest phylogenetic neighbours were identified as

Bacillus badius

ATCC 14574T (95.8 % 16S rRNA gene sequence similarity),

Bacillus indicus

Sd/3T (94.8 %),

Jeotgalibacillus alimentarius

YKJ-13T (94.8 %) and

Bacillus cibi

JG-30T (94.8 %). Phylogenetic, physiological, biochemical and morphological differences between strain WS 4628T and its closest relatives in the families

Bacillaceae

and

Planococcaceae

suggest that this strain represents a novel species in a new genus in the family

Bacillaceae

for which the name Domibacillus robiginosus gen. nov., sp. nov. is proposed; the type strain of the type species is WS 4628T ( = DSM 25058T = LMG 26645T).
Regulated proteolysis of Trop2 drives epithelial hyperplasia and stem cell self-renewal via β-catenin signaling
Authors: Stoyanova Tanya , Goldstein Andrew S. , Cai Houjian , Drake Justin M. , Huang Jiaoti , Witte Owen N.
Published: October 2012

The cell surface protein Trop2 is expressed on immature stem/progenitor-like cells and is overexpressed in many epithelial cancers. However the biological function of Trop2 in tissue maintenance and tumorigenesis remains unclear. In this study, we demonstrate that Trop2 is a regulator of self-renewal, proliferation, and transformation. Trop2 controls these processes through a mechanism of regulated intramembrane proteolysis that leads to cleavage of Trop2, creating two products: the extracellular domain and the intracellular domain. The intracellular domain of Trop2 is released from the membrane and accumulates in the nucleus. Heightened expression of the Trop2 intracellular domain promotes stem/progenitor self-renewal through signaling via β-catenin and is sufficient to initiate precursor lesions to prostate cancer in vivo. Importantly, we demonstrate that loss of β-catenin or Trop2 loss-of-function cleavage mutants abrogates Trop2-driven self-renewal and hyperplasia in the prostate. These findings suggest that heightened expression of Trop2 is selected for in epithelial cancers to enhance the stem-like properties of self-renewal and proliferation. Defining the mechanism of Trop2 function in self-renewal and transformation is essential to identify new therapeutic strategies to block Trop2 activation in cancer.
Autocrine prolactin: an emerging market for homegrown (prolactin) despite the imports
Authors: Muthuswamy Senthil K.
Published: October 2012

Prolactin (PRL) is a peptide hormone that is produced by the pituitary gland and is known to regulate lactogenic differentiation. There is a significant body of evidence that points to autocrine production of prolactin and activation of an autocrine/paracrine signaling pathway to regulate cell proliferation and migration and inhibition of cell death. This perspective highlights the recent study in the October 1, 2012, issue of Genes & Development by Chen and colleagues (pp. 2154–2168) that describes a mechanism for autocrine prolactin production and places the finding in the context of a role for prolactin in breast development and cancer.
Linking the signaling cascades and dynamic regulatory networks controlling stress responses
Authors: Gitter Anthony , Carmi Miri , Barkai Naama , Bar-Joseph Ziv
Published: October 2012

Accurate models of the cross-talk between signaling pathways and transcriptional regulatory networks within cells are essential to understand complex response programs. We present a new computational method that combines condition-specific time-series expression data with general protein interaction data to reconstruct dynamic and causal stress response networks. These networks characterize the pathways involved in the response, their time of activation, and the affected genes. The signaling and regulatory components of our networks are linked via a set of common transcription factors that serve as targets in the signaling network and as regulators of the transcriptional response network. Detailed case studies of stress responses in budding yeast demonstrate the predictive power of our method. Our method correctly identifies the core signaling proteins and transcription factors of the response programs. It further predicts the involvement of additional transcription factors and other proteins not previously implicated in the response pathways. We experimentally verify several of these predictions for the osmotic stress response network. Our approach requires little condition-specific data: only a partial set of upstream initiators and time-series gene expression data, which are readily available for many conditions and species. Consequently, our method is widely applicable and can be used to derive accurate, dynamic response models in several species.
Evolutionary dynamism of the primate LRRC37 gene family
Authors: Giannuzzi Giuliana , Siswara Priscillia , Malig Maika , Marques-Bonet Tomas ,   NISC Comparative Sequencing Program, Mullikin James C. , Ventura Mario , Eichler Evan E.
Published: October 2012

Core duplicons in the human genome represent ancestral duplication modules shared by the majority of intrachromosomal duplication blocks within a given chromosome. These cores are associated with the emergence of novel gene families in the hominoid lineage, but their genomic organization and gene characterization among other primates are largely unknown. Here, we investigate the genomic organization and expression of the core duplicon on chromosome 17 that led to the expansion of LRRC37 during primate evolution. A comparison of the LRRC37 gene family organization in human, orangutan, macaque, marmoset, and lemur genomes shows the presence of both orthologous and species-specific gene copies in all primate lineages. Expression profiling in mouse, macaque, and human tissues reveals that the ancestral expression of LRRC37 was restricted to the testis. In the hominid lineage, the pattern of LRRC37 became increasingly ubiquitous, with significantly higher levels of expression in the cerebellum and thymus, and showed a remarkable diversity of alternative splice forms. Transfection studies in HeLa cells indicate that the human FLAG-tagged recombinant LRRC37 protein is secreted after cleavage of a transmembrane precursor and its overexpression can induce filipodia formation.
Nurture trumps nature in a longitudinal survey of salivary bacterial communities in twins from early adolescence to early adulthood
Authors: Stahringer Simone S. , Clemente Jose C. , Corley Robin P. , Hewitt John , Knights Dan , Walters William A. , Knight Rob , Krauter Kenneth S.
Published: October 2012

Variation in the composition of the human oral microbiome in health and disease has been observed. We have characterized inter- and intra-individual variation of microbial communities of 107 individuals in one of the largest cohorts to date (264 saliva samples), using culture-independent 16S rRNA pyrosequencing. We examined the salivary microbiome in up to three time-points during 10 yr spanning adolescence, and determined the influence of human genotype, gender, age, and weight class. Participants, including 27 monozygotic and 18 dizygotic twin pairs, were sampled mainly at ages 12–13, 17–18, and 22–24, with a few sampled as early as 8 yr of age. In contrast to gut or skin microbiomes, there is a core genus-level salivary microbiome. Individuals are more similar to themselves and their co-twins in the 12–17 and in the 17–22 cohorts than to the whole sample population, but not over the 10 yr from 12 to 22; and monozygotic twin pairs are statistically not more similar than dizygotic twin pairs. The data are most consistent with shared environment serving as the main determinant of microbial populations. Twins resemble each other more closely than the whole population at all time-points, but become less similar to each other when they age and no longer cohabit. Several organisms have age-specific abundance profiles, including members of the genera Veillonella, Actinomyces, and Streptococcus. There is no clear effect of weight class and gender. The results of this work will provide a basis to further study oral microbes and human health.
Sequencing the unsequenceable: Expanded CGG-repeat alleles of the fragile X gene
Authors: Loomis Erick W. , Eid John S. , Peluso Paul , Yin Jun , Hickey Luke , Rank David , McCalmon Sarah , Hagerman Randi J. , Tassone Flora , Hagerman Paul J.
Published: October 2012

The human fragile X mental retardation 1 (FMR1) gene contains a (CGG)n trinucleotide repeat in its 5′ untranslated region (5′UTR). Expansions of this repeat result in a number of clinical disorders with distinct molecular pathologies, including fragile X syndrome (FXS; full mutation range, greater than 200 CGG repeats) and fragile X–associated tremor/ataxia syndrome (FXTAS; premutation range, 55–200 repeats). Study of these diseases has been limited by an inability to sequence expanded CGG repeats, particularly in the full mutation range, with existing DNA sequencing technologies. Single-molecule, real-time (SMRT) sequencing provides an approach to sequencing that is fundamentally different from other “next-generation” sequencing platforms, and is well suited for long, repetitive DNA sequences. We report the first sequence data for expanded CGG-repeat FMR1 alleles in the full mutation range that reveal the confounding effects of CGG-repeat tracts on both cloning and PCR. A unique feature of SMRT sequencing is its ability to yield real-time information on the rates of nucleoside addition by the tethered DNA polymerase; for the CGG-repeat alleles, we find a strand-specific effect of CGG-repeat DNA on the interpulse distance. This kinetic signature reveals a novel aspect of the repeat element; namely, that the particular G bias within the CGG/CCG-repeat element influences polymerase activity in a manner that extends beyond simple nearest-neighbor effects. These observations provide a baseline for future kinetic studies of repeat elements, as well as for studies of epigenetic and other chemical modifications thereof.
Genotype calling and haplotyping in parent-offspring trios
Authors: Chen Wei , Li Bingshan , Zeng Zhen , Sanna Serena , Sidore Carlo , Busonero Fabio , Kang Hyun Min , Li Yun , Abecasis Gonçalo R.
Published: October 2012

Emerging sequencing technologies allow common and rare variants to be systematically assayed across the human genome in many individuals. In order to improve variant detection and genotype calling, raw sequence data are typically examined across many individuals. Here, we describe a method for genotype calling in settings where sequence data are available for unrelated individuals and parent-offspring trios and show that modeling trio information can greatly increase the accuracy of inferred genotypes and haplotypes, especially on low to modest depth sequencing data. Our method considers both linkage disequilibrium (LD) patterns and the constraints imposed by family structure when assigning individual genotypes and haplotypes. Using simulations, we show that trios provide higher genotype calling accuracy across the frequency spectrum, both overall and at hard-to-call heterozygous sites. In addition, trios provide greatly improved phasing accuracy—improving the accuracy of downstream analyses (such as genotype imputation) that rely on phased haplotypes. To further evaluate our approach, we analyzed data on the first 508 individuals sequenced by the SardiNIA sequencing project. Our results show that our method reduces the genotyping error rate by 50% compared with analysis using existing methods that ignore family structure. We anticipate our method will facilitate genotype calling and haplotype inference for many ongoing sequencing projects.
Strategic logistics management
Authors: Fojt Martin
Published: October 2012

The key to any successful organization must be its communication network. Bold statement, but is it true? It is, of course, a sweeping generalization and one with which anyone would have difficulty in picking an argument. One way to determine what is, and what is not, vital to your organization is by eliminating it from the equation and asking yourself where you would be without it. Do away with your communication system, apart from the most basic, and see what you are left with? If the answer is not a great deal, then you can, it is hoped, appreciate the importance of what you have, and realize the attention it deserves. Taking things for granted is an all too common phenomenon.
Novel acid resistance genes from the metagenome of the Tinto River, an extremely acidic environment
Authors: Guazzaroni María‐Eugenia , Morgante Verónica , Mirete Salvador , González‐Pastor José E.
Published: October 2012

Microorganisms that thrive in acidic environments are endowed with specialized molecular mechanisms to survive under this extremely harsh condition. In this work, we performed functional screening of six metagenomic libraries from planktonic and rhizosphere microbial communities of the Tinto River, an extremely acidic environment, to identify genes involved in acid resistance. This approach has revealed 15 different genes conferring acid resistance to Escherichia coli, most of which encoding putative proteins of unknown function or previously described proteins not known to be related to acid resistance. Moreover, we were able to assign function to one unknown and three hypothetical proteins. Among the recovered genes were the ClpXP protease, the transcriptional repressor LexA and nucleic acid‐binding proteins such as an RNA‐binding protein, HU and Dps. Furthermore, nine of the retrieved genes were cloned and expressed in Pseudomonas putida and Bacillus subtilis and, remarkably, most of them were able to expand the capability of these bacteria to survive under severe acid stress. From this set of genes, four presented a broad‐host range as they enhance the acid resistance of the three different organisms tested. These results expand our knowledge about the different strategies used by microorganisms to survive under extremely acid conditions.
Too hot to handle? Trust and human resource practitioners' implementation of anti‐bullying policy
Authors: Harrington Susan , Rayner Charlotte , Warren Samantha
Published: October 2012

In this article, we examine the dynamics of trust in the triadic relationship between HR, employees and managers when dealing with allegations of workplace bullying. Previous research has shown employees to be dissatisfied with HR practitioners' responses to complaints of workplace bullying, and we explore the novel angle of the HR practitioners' perspective through semistructured interviews. Paralleling extant employee accounts, the findings suggest that HR practitioners rarely judge situations as bullying where a manager is accused. Trust between employee, manager and HR practitioner is essential for the successful resolution of bullying claims, yet this study suggests multiple directions of distrust. By virtue of their role alignment and previous experiences of handling bullying, HR practitioners were found to prioritise their relationships with managers, automatically distrusting employees' bullying claims. Despite also distrusting managers to effectively deliver HRM practices, it appears that bullying complaints are ‘too hot to handle’ for HR practitioners given the risks to their relationships with managers.
Role of nitric oxide and endothelin in endothelial maintenance of vasoconstrictor responses in aortas of diabetic female rats (一氧化氮与内皮素对糖尿病雌性大鼠主动脉血管内皮维持血管收缩反应的影响)
Authors: Sartoretto Simone M. , Santos‐Eichler Rosângela , de Cássia A. Tostes Rita , Carvalho Maria Helena C. , Akamine Eliana H. , Fortes Zuleica B.
Published: October 2012

Background

Diabetes differentially affects the vascular system in males and females. Although various results have been reported, very few studies have focused on responses in females. In the present study, we investigated contractile responses to norepinephrine in aortas of alloxan‐diabetic female rats and evaluated endothelial modulation of these responses.

Methods

Concentration–response curves were constructed to norepinephrine in the absence or presence of NG‐nitro‐l‐arginine methyl ester (l‐NAME), indomethacin, losartan, tezosentan, and calphostin C; pre‐pro‐endothelin mRNA expression was evaluated; and norepinephrine‐stimulated expression of phosphorylated (p‐) Akt Ser473, p‐endothelial nitric oxide synthase (eNOS) Ser1177, and p‐eNOS Ser633 was determined in endothelial cells incubated in the presence of low (5 mmol/L) or high (25 mmol/L) glucose concentrations.

Results

Similar maximal responses (Rmax) to norepinephrine were seen in control and diabetic endothelium‐intact aortas; however, Rmax was reduced in diabetic endothelium‐denuded aortas. Incubation of endothelium‐intact aortas with 100 μmol/L l‐NAME increased Rmax in the control group only. Inhibition of cyclo‐oxygenase (10 μmol/L indomethacin) and blockade of angiotensin II receptors (10 μmol/L losartan) reduced Rmax in endothelium‐intact aortas in both the control and diabetic groups. Blockade of endothelin receptors (0.1 μmol/L tezosentan) and inhibition of protein kinase C (PKC; 0.1 μmol/L calphostin C) reduced Rmax only in endothelium‐intact aortas from diabetic rats. Pre‐pro‐endothelin mRNA expression was increased in aortas from diabetic female rats. Finally, p‐Akt Ser473, p‐eNOS Ser1177, and p‐eNOS Ser633 levels were enhanced after norepinephrine stimulation only in low glucose‐treated endothelial cells.

Conclusions

In aortas of diabetic female rats, reductions in smooth muscle contractile responses to norepinephrine are counterbalanced by the endothelium via reduced eNOS activation and increased endothelin release and PKC activation.
Telephone Support to Rural and Remote Patients with Heart Failure: The Chronic Heart Failure Assessment by Telephone (CHAT) study
Authors: Krum Henry , Forbes Andrew , Yallop Julie , Driscoll Andrea , Croucher Jo , Chan Bianca , Clark Robyn , Davidson Patricia , Huynh Luan , Kasper Edward K. , Hunt David , Egan Helen , Stewart Simon , Piterman Leon , Tonkin Andrew
Published: October 2012

Background

Heart failure (HF) remains a condition with high morbidity and mortality. We tested a telephone support strategy to reduce major events in rural and remote Australians with HF, who have limited healthcare access. Telephone support comprised an interactive telecommunication software tool (TeleWatch) with follow‐up by trained cardiac nurses.

Methods

Patients with a general practice (GP) diagnosis of HF were randomized to usual care (UC) or UC and telephone support intervention (UC+I) using a cluster design involving 143 GPs throughout Australia. Patients were followed up for 12 months. The primary endpoint was the Packer clinical composite score. Secondary endpoints included hospitalization for any cause, death or hospitalization, as well as HF hospitalization.

Results

Four hundred and five patients were randomized to CHAT. Patients were well matched at baseline for key demographic variables. The primary endpoint of the Packer score was not different between the two groups (P = 0.98), although more patients improved with UC+I. There were fewer patients hospitalized for any cause (74 vs. 114, adjusted HR 0.67 [95% CI 0.50–0.89], P = 0.006) and who died or were hospitalized (89 vs. 124, adjusted HR 0.70 [95% CI 0.53–0.92], P = 0.011), in the UC+I vs. UC group. HF hospitalizations were reduced with UC+I (23 vs. 35, adjusted HR 0.81 [95% CI 0.44–1.38]), although this was not significant (P = 0.43). There were 16 deaths in the UC group and 17 in the UC+I group (P = 0.43).

Conclusions

Although no difference was observed in the primary endpoint of CHAT (Packer composite score), UC+I significantly reduced the number of HF patients hospitalized among a rural and remote cohort. These data suggest that telephone support may be an efficacious approach to improve clinical outcomes in rural and remote HF patients.
The Effect of Prethrombolytic Cyclosporine‐A Injection on Clinical Outcome of Acute Anterior ST‐Elevation Myocardial Infarction
Authors: Ghaffari Samad , Kazemi Babak , Toluey Mehdi , Sepehrvand Nariman
Published: October 2012

Introduction

Reperfusion injury reduces the benefits of early reperfusion therapies after acute ST‐elevation myocardial infarction (STEMI). Cyclosporine‐A (CsA) is a potent inhibitor of opening of the mitochondrial permeability transition pore, which has been shown to play a key role in myocardial reperfusion injury. The impact of this treatment on clinical outcomes of acute STEMI remains unknown. Our aim was to investigate the clinical outcomes of using this drug in patients with acute anterior STEMI receiving thrombolytic treatment (TLT).

Methods

In this double‐blinded randomized clinical trial, 101 patients with acute anterior STEMI who were candidate for TLT, were enrolled and randomly assigned into treatment or control groups. Patients in the treatment group received an intravenous bolus injection of 2.5 mg/kg of CsA immediately before TLT. The patients in the control group received an equivalent volume of normal saline. Infarct size, occurrence of major arrhythmias, heart failure, left ventricular ejection fraction (LVEF), TLT‐related complications, in‐hospital and 6‐month mortality rates were investigated.

Results

There were no significant differences among the demographics, myocardial enzyme release, occurrence of major arrhythmias [9 (18%) vs. 12 (23.5%), P = 0.80], heart failure [18 (36%) vs. 19 (38.3%), P = 0.83], LVEF at first day [34.7 ± 9.9% vs. 33.5 ± 8.1%, P = 0.50] or at discharge [37.7 ± 10% vs. 36.1 ± 8.2%, P = 0.43], and in‐hospital [4 (8%) vs. 6 (11.8%), P = 0.74] or 6‐month mortality rates [9 (18%) vs. 10 (19.6%), P = 0.99] between the CsA vs. the control group.

Conclusion

In this study, the prethrombolytic administration of CsA was not associated with a reduction in the infarct size or any improvement in clinical outcomes.
Gene expression analysis of mTOR pathway: association with human longevity
Authors: Passtoors Willemijn M. , Beekman Marian , Deelen Joris , van der Breggen Ruud , Maier Andrea B. , Guigas Bruno , Derhovanessian Evelyna , van Heemst Diana , de Craen Anton J. M. , Gunn David A. , Pawelec Graham , Slagboom Pieternella E.
Published: October 2012

mTOR signalling is implicated in the development of disease and in lifespan extension in model organisms. This pathway has been associated with human diseases such as diabetes and cancer, but has not been investigated for its impact on longevity per se. Here, we investigated whether transcriptional variation within the mTOR pathway is associated with human longevity using whole‐blood samples from the Leiden Longevity Study. This is a unique cohort of Dutch families with extended survival across generations, decreased morbidity and beneficial metabolic profiles in middle‐age. By comparing mRNA levels of nonagenarians and middle‐aged controls, the mTOR signalling gene set was found to associate with old age (P = 4.6 × 10−7). Single gene analysis showed that seven of 40 mTOR pathway genes had a significant differential expression of at least 5%. Of these, the RPTOR (Raptor) gene was found to be differentially expressed also when the offspring of nonagenarians was compared with their spouses, indicating association with familial longevity in middle‐age. This association was not explained by variation between the groups in the prevalence of type 2 diabetes and cancer or glucose levels. Thus, the mTOR pathway not only plays a role in the regulation of disease and aging in animal models, but also in human health and longevity.
Deficiency of ovarian ornithine decarboxylase contributes to aging‐related egg aneuploidy in mice
Authors: Tao Yong , Liu X. Johné
Published: October 2012

It has been known for more than four decades that during mammalian estrous cycles, luteinizing hormone stimulates a transitory rise in the ovaries of ornithine decarboxylase (ODC) activity and its enzymatic product putrescine, concurrent with oocyte maturation in vivo. Inhibition of this transitory ODC/putrescine rise, however, does not appear to affect oocyte maturation or ovulation. Using several mouse models and combining in vitro and in vivo approaches, we demonstrated that deficiency of ODC during oocyte maturation is correlated with increased levels of egg aneuploidies. These results suggest that the transitory ovarian ODC rise in late proestrus is important for ensuring proper chromosome segregation during oocyte maturation. Older mice (8 months of age) exhibited about 1/3 that of young mice in LH‐stimulated ovarian ODC activity and a corresponding increase in egg aneuploidies. Moreover, a combination of putrescine supplementation in mouse drinking water leading up to oocyte retrieval and in oocyte maturation medium reduced egg aneuploidies of the older mice from 12.7% to 5.3%. Therefore, ovarian ODC deficiency might be an important etiology of maternal aging‐related aneuploidies, and peri‐ovulatory putrescine supplementation might reduce the risk of aneuploid conceptions in older women.
Adherence of Streptococcus mutans to orthodontic band cements
Authors: Gonzalez‐Perez JC , Scougall‐Vilchis RJ , Contreras‐Bulnes R , De La Rosa‐Gómez I , Uematsu S , Yamaguchi R
Published: October 2012

Background:  The aim of this study was to quantitatively determine the adherence of Streptococcus mutans to orthodontic band cements.

Methods:  Two hundred and ten blocks of seven different band cements for orthodontic prescription were made using a Teflon mould (4 × 4 × 1 mm). The obtained blocks were slightly polished and cleansed ultrasonically. Certified S. mutans ATCC 25175 were cultured with conventional methods for growth in Petri dishes and trypticase soy broth. Quantitative analysis was carried out with radioactive markers to codify the bacteria (3H). Subsequently, a combustion system was used to capture the residues, the radioactivity of the samples was measured, and the values recorded in disintegrations per minute (dpm). One‐way analysis of variance (ANOVA) with a Scheffé test for multiple comparisons was realized with a significance level of ≤0.05.

Results:  Significant differences were found among different band cement materials (p < 0.001). Two band cement materials showed statistically lower values than the others (Transbond Plus Band Cem and Ketac Cem). In contrast, GC Fuji Ortho Band presented the highest adherence of S. mutans.

Conclusions:  Among the cements evaluated, Transbond Plus Band Cem and Ketac Cem showed lower adherence of S. mutans.
Female Genital Cutting and HIV Transmission: Is There an Association?
Authors: Diouf Khady , Nour Nawal
Published: October 2012

Female Genital Cutting (FGC) refers to the practice of surgically removing all or part of the female external genitalia for non‐medical purposes. It is a common practice in many countries in Africa, the Middle East, and to a lesser extent, Asia. Over 130 million women worldwide have undergone this procedure, and over 2 million women and girls are subject to it every year. Various complications have been described, including infection, hemorrhage, genitourinary and obstetric complications, as well as psychological sequelae. Since the beginning of the HIV epidemic, a few reports have also described a potentially elevated risk of HIV transmission among women with FGC. In this report, we aim to review the evidence and identify unanswered questions and research gaps regarding a potential association between FGC and HIV transmission.
The rASRM score and the Enzian classification for endometriosis: their strengths and weaknesses
Authors: HAAS DIETMAR , SHEBL OMAR , SHAMIYEH ANDREAS , OPPELT PETER
Published: October 2012

The revised American Society for Reproductive Medicine (rASRM) score is currently the best‐known classification of endometriosis and is the one most widely used throughout the world. It is relatively easy to use, but it does not take into account the involvement of retroperitoneal structures with deeply infiltrating endometriosis. For this reason, the Enzian classification was developed as a supplement to the rASRM score, in order to provide a morphologically descriptive classification of deeply infiltrating endometriosis. The Enzian classification currently has a poor level of international acceptance and is mainly used in the German‐speaking countries. It was revised in 2011 and is now also easier to use. This article describes the strengths and weaknesses of the rASRM score and the Enzian classification and their common potential for classifying endometriosis.
Effect of play‐based summer break exercise on cardiovascular function in adolescents
Authors: Meucci Marco , Curry Chelsea D , Baldari Carlo , Guidetti Laura , Cook Carol , Collier Scott R
Published: October 2012

Aim

To compare the effects of 4 and 8 weeks of play‐based, supervised exercise during summer break versus an unsupervised break on cardiovascular function in adolescent children.

Methods

Twenty‐two subjects were divided into a 4‐week exercise group (age 10.1 ± 1.3 years), an 8‐week exercise group (age 9.4 ± 1.7 years) or a control group (age 10.0 ± 1.3 years). The activity groups participated in a supervised summer camp for 6 h/day, 5 days/week including a discontinuous play‐based physical activity program and a healthy lifestyle, while the control group were told to keep their regular summer break routines. Anthropometrics, pulse wave velocity, augmentation index, blood pressure and peak oxygen consumption were evaluated before and after the intervention.

Results

Normalized augmentation index (75 beats/min) significantly decreased after 4 and 8 weeks in the active groups (p = 0.04) while pulse wave velocity showed no significant changes in all groups. Mean arterial pressure decreased (p = 0.003) and peak oxygen consumption increased (p = 0.001) significantly in the 8 week group.

Conclusion

These data suggest that 8 weeks of supervised play‐based activity yield several cardio‐beneficial results in adolescents, which may act as a clinical prophylaxis throughout their lifetime.
Myelosuppression monitoring after immunomodulator initiation in veterans with inflammatory bowel disease: a national practice audit
Authors: Hou J. K. , Kramer J. R. , Richardson P. , Sansgiry S. , El‐Serag H. B.
Published: October 2012

Background

Immunomodulator medications (IMM) play a vital role in the care of patients with inflammatory bowel disease (IBD). IBD practice guidelines recommend myelosuppression monitoring after initiation of IMM.

Aim

To identify adherence rates and predictors of myelosuppression monitoring after IMM initiation in a large practice setting.

Methods

We identified a national cohort of VA users with IBD for the fiscal years 2003–2009 using the Veterans Affairs administrative datasets. Subjects with filled prescriptions for IMM were included. The primary endpoint was the proportion of subjects who had a white blood cell (WBC) test completed within 90 days of the IMM index date. Determinants of myelosuppression monitoring were identified by univariate and multivariate analyses.

Results

A total of 6045 unique IBD patients were identified with filled IMM prescriptions. Overall, only 57% of subjects completed a WBC test within 90 days of IMM index date. Monitoring rates increased over time, from 48% in 2003 to 75% in 2009. There was variability of monitoring rates by facility, ranging from 0 to 83%. In multivariate analyses, older age at IMM index date was associated with a lower rate of monitoring. Frequency of VA encounters and IMM index date were associated with increased rates of myelosuppression monitoring.

Conclusions

Monitoring for myelosuppression among veterans with inflammatory bowel disease after immunomodulator medications initiation is low with wide variability based on facility. This may reflect a low quality of care among veterans with IBD. Provider‐ and system‐wide interventions are needed to improve adherence and reduce variability of immunomodulator medications monitoring across facilities.
Does co‐treatment with immunosuppressors improve outcome in patients with Crohn's disease treated with adalimumab?
Authors: Reenaers C. , Louis E. , Belaiche J. , Seidel L. , Keshav S. , Travis S.
Published: October 2012

Background

There is clear benefit from combination therapy with infliximab and immunosuppressive drugs (IS), but few data are available for adalimumab (ADA).

Aim

To assess the efficacy of ADA monotherapy and ADA+IS for induction and maintenance therapy in Crohn's disease.

Methods

Retrospective study of patients with Crohn's disease treated with ADA in Oxford, UK or Liège, Belgium. Treatment periods were divided into 6‐month semesters. A combination therapy semester was defined as ADA+IS for at least 3 months; successful induction meant clinical response; a semester with flare as ADA dose escalation, starting steroids, perianal complication, or surgery; and ADA failure as ADA withdrawal for secondary loss of response or intolerance. Semesters with and without flares were compared through univariate and multivariate analysis.

Results

Successful induction was achieved in 171/207 (83%) patients, with no significant difference between ADA+IS and ADA monotherapy (85% vs. 82%, P = 0.50). Five hundred and sixty‐two semesters in 181 patients were included for maintenance analysis. ADA+IS was not associated with fewer semesters with flare (34% vs. 35%, P = 0.96), or with ADA failure (6% vs. 8%, P = 0.43). Nevertheless, combination therapy in the first semester was associated with a lower risk of ADA failure (5% vs. 10%, P = 0.04, OR = 0.48) and combination therapy beyond 6 months was associated with fewer semesters with flares (14% vs. 36%, P = 0.02, OR = 0.31).

Conclusions

There may be a benefit from adalimumab+immunosuppressive drugs combination therapy during the first semester of initiating adalimumab, with a slight decrease in adalimumab failure and lower need for adalimumab dosage escalation.
Predicting post‐traumatic stress disorder following first onset acute coronary syndrome: Testing a theoretical model
Authors: Marke Victoria , Bennett Paul
Published: October 2012

Objectives

This research identified which theoretically predicted factors (Joseph, Williams, & Yule, 1997) were associated with the severity of post‐traumatic stress disorder (PTSD) symptoms 1 and 6 months following onset of acute coronary syndrome (ACS). Predictor variables included event factors, peri‐traumatic distress; and maintaining factors including coping strategies, social support, re‐appraisal of event threat, and beliefs about the nature of ACS. Associations with alexithymia were also explored.

Method

One hundred and fifty participants completed questionnaires in hospital and at 1‐ and 6‐month follow‐up.

Results

Hierarchical multiple regression including both baseline and contemporaneous variables explained 52 and 42% of the variance in PTSD symptoms at each follow‐up. At 1‐month follow‐up, predictors of PTSD symptoms were as follows: peri‐traumatic distress, concern over symptoms, illness comprehension, and lack of social support. At 6‐month follow‐up, predictors were: peri‐traumatic distress, lack of social support, use of problem‐focused coping, and continued symptoms.

Conclusions

The Joseph et al. model was generally supported. The data allow some degree of prediction of high risk individuals and suggest some possible interventions.