bluuebunny/crossref_metadata_2025 huggingface dataset:
A predictive thermal dynamic model for parameter generation in the laser assisted direct write process
Authors: Shang Shuo , Fearon Eamonn , Wellburn Dan , Sato Taku , Edwardson Stuart , Dearden G , Watkins K G
Published: October 2011

The laser assisted direct write (LADW) method can be used to generate electrical circuitry on a substrate by depositing metallic ink and curing the ink thermally by a laser. Laser curing has emerged over recent years as a novel yet efficient alternative to oven curing. This method can be used in situ, over complicated 3D contours of large parts (e.g. aircraft wings) and selectively cure over heat sensitive substrates, with little or no thermal damage.

In previous studies, empirical methods have been used to generate processing windows for this technique, relating to the several interdependent processing parameters on which the curing quality and efficiency strongly depend. Incorrect parameters can result in a track that is cured in some areas and uncured in others, or in damaged substrates. This paper addresses the strong need for a quantitative model which can systematically output the processing conditions for a given combination of ink, substrate and laser source; transforming the LADW technique from a purely empirical approach, to a simple, repeatable, mathematically sound, efficient and predictable process.

The method comprises a novel and generic finite element model (FEM) that for the first time predicts the evolution of the thermal profile of the ink track during laser curing and thus generates a parametric map which indicates the most suitable combination of parameters for process optimization. Experimental data are compared with simulation results to verify the accuracy of the model.
The Pcdp1 complex coordinates the activity of dynein isoforms to produce wild-type ciliary motility
Authors: DiPetrillo Christen G. , Smith Elizabeth F.
Published: October 2011

Generating the complex waveforms characteristic of beating cilia requires the coordinated activity of multiple dynein isoforms anchored to the axoneme. We previously identified a complex associated with the C1d projection of the central apparatus that includes primary ciliary dyskinesia protein 1 (Pcdp1). Reduced expression of complex members results in severe motility defects, indicating that C1d is essential for wild-type ciliary beating. To define a mechanism for Pcdp1/C1d regulation of motility, we took a functional and structural approach combined with mutants lacking C1d and distinct subsets of dynein arms. Unlike mutants completely lacking the central apparatus, dynein-driven microtubule sliding velocities are wild type in C1d- defective mutants. However, coordination of dynein activity among microtubule doublets is severely disrupted. Remarkably, mutations in either outer or inner dynein arm restore motility to mutants lacking C1d, although waveforms and beat frequency differ depending on which isoform is mutated. These results define a unique role for C1d in coordinating the activity of specific dynein isoforms to control ciliary motility.
Microtubules support a disk-like septin arrangement at the plasma membrane of mammalian cells
Authors: Sellin Mikael E. , Holmfeldt Per , Stenmark Sonja , Gullberg Martin
Published: October 2011

Septin family proteins oligomerize through guanosine 5′-triphosphate–binding domains into core heteromers, which in turn polymerize at the cleavage furrow of dividing fungal and animal cells. Septin assemblies during the interphase of animal cells remain poorly defined and are the topic of this report. In this study, we developed protocols for visualization of authentic higher-order assemblies using tagged septins to effectively replace the endogenous gene product within septin core heteromers in human cells. Our analysis revealed that septins assemble into microtubule-supported, disk-like structures at the plasma membrane. In the absence of cell substrate adhesion, this is the predominant higher-order arrangement in interphase cells and each of the seven to eight septin family members expressed by the two analyzed cell types appears equally represented. However, studies of myeloid and lymphoid cell model systems revealed cell type–specific alterations of higher-order septin arrangements in response to substrate adhesion. Live-cell observations suggested that all higher-order septin assemblies are mutually exclusive with plasma membrane regions undergoing remodeling. The combined data point to a mechanism by which densely arranged cortical microtubules, which are typical for nonadhered spherical cells, support plasma membrane–bound, disk-like septin assemblies.
The strength of intron donor splice sites in human genes displays a bell-shaped pattern
Authors: Wang Kai , Wernersson Rasmus , Brunak Søren
Published: October 2011

Motivation: The gene concept has recently changed from the classical one protein notion into a much more diverse picture, where overlapping or fused transcripts, alternative transcription initiation, and genes within genes, add to the complexity generated by alternative splicing. Increased understanding of the mechanisms controlling pre-mRNA splicing is thus important for a wide range of aspects relating to gene expression.

Results: We have discovered a convex gene delineating pattern in the strength of 5′ intron splice sites. When comparing the strengths of >18 000 intron containing Human genes, we found that when analysing them separately according to the number of introns they contain, initial splice sites were always stronger on average than subsequent ones, and that a similar reversed trend exist towards the terminal gene part. The convex pattern is strongest for genes with up to 10 introns. Interestingly, when analysing the intron containing gene pool from mouse consisting of >15 000 genes, we found the convex pattern to be conserved despite >75 million years of evolutionary divergence between the two organisms. We also analysed an interesting, novel class of chimeric genes which during spliceosome assembly are fused and in tandem are transcribed and spliced into a single mature mRNA sequence. In their splice site patterns, these genes individually seem to deviate from the convex pattern, offering a possible rationale behind their fusion into a single transcript.

Contact:  brunak@cbs.dtu.dk

Supplementary Information:  Supplementary data are available at Bioinformatics online.
Neural fate decisions mediated by trans-activation and cis-inhibition in Notch signaling
Authors: Wang Ruiqi , Liu Kaihui , Chen Luonan , Aihara Kazuyuki
Published: October 2011

Motivation: In the developing nervous system, the expression of proneural genes, i.e. Hes1, Neurogenin-2 (Ngn2) and Deltalike-1 (Dll1), oscillates in neural progenitors with a period of 2–3 h, but is persistent in post-mitotic neurons. Unlike the synchronization of segmentation clocks, oscillations in neural progenitors are asynchronous between cells. It is known that Notch signaling, in which Notch in a cell can be activated by Dll1 in neighboring cells (trans-activation) and can also be inhibited by Dll1 within the same cell (cis-inhibition), is important for neural fate decisions. There have been extensive studies of trans-activation, but the operating mechanisms and potential implications of cis-inhibition are less clear and need to be further investigated.

Results: In this article, we present a computational model for neural fate decisions based on intertwined dynamics with trans-activation and cis-inhibition involving the Hes1, Notch and Dll1 proteins. In agreement with experimental observations, the model predicts that both trans-activation and cis-inhibition play critical roles in regulating the choice between remaining as a progenitor and embarking on neural differentiation. In particular, trans-activation is essential for generation of oscillations in neural progenitors, and cis-inhibition is important for the asynchrony between adjacent cells, indicating that the asynchronous oscillations in neural progenitors depend on cooperation between trans-activation and cis-inhibition. In contrast, cis-inhibition plays more critical roles in embarking on neural differentiation by inactivating intercellular Notch signaling. The model presented here might be a good candidate for providing the first qualitative mechanism of neural fate decisions mediated by both trans-activation and cis-inhibition.

Contact:  rqwang@shu.edu.cn

Supplementary Information:  Supplementary data are available at Bioinformatics online.
Visualization and quality assessment of de novo genome assemblies
Authors: Riba-Grognuz Oksana , Keller Laurent , Falquet Laurent , Xenarios Ioannis , Wurm Yannick
Published: October 2011

Summary: Recent technological progress has greatly facilitated de novo genome sequencing. However, de novo assemblies consist in many pieces of contiguous sequence (contigs) arranged in thousands of scaffolds instead of small numbers of chromosomes. Confirming and improving the quality of such assemblies is critical for subsequent analysis. We present a method to evaluate genome scaffolding by aligning independently obtained transcriptome sequences to the genome and visually summarizing the alignments using the Cytoscape software. Applying this method to the genome of the red fire ant Solenopsis invicta allowed us to identify inconsistencies in 7%, confirm contig order in 20% and extend 16% of scaffolds.

Contact:  oksana.ribagrognuz@unil.ch; yannick.wurm@unil.ch

Availability: Scripts that generate tables for visualization in Cytoscape from FASTA sequence and scaffolding information files are publicly available at https://github.com/ksanao/TGNet.

Supplementary Information:  Supplementary data are available at Bioinformatics online.
An automatic method for CASP9 free modeling structure prediction assessment
Authors: Cong Qian , Kinch Lisa N. , Pei Jimin , Shi Shuoyong , Grishin Vyacheslav N. , Li Wenlin , Grishin Nick V.
Published: October 2011

Motivation: Manual inspection has been applied to and is well accepted for assessing critical assessment of protein structure prediction (CASP) free modeling (FM) category predictions over the years. Such manual assessment requires expertise and significant time investment, yet has the problems of being subjective and unable to differentiate models of similar quality. It is beneficial to incorporate the ideas behind manual inspection to an automatic score system, which could provide objective and reproducible assessment of structure models.

Results: Inspired by our experience in CASP9 FM category assessment, we developed an automatic superimposition independent method named Quality Control Score (QCS) for structure prediction assessment. QCS captures both global and local structural features, with emphasis on global topology. We applied this method to all FM targets from CASP9, and overall the results showed the best agreement with Manual Inspection Scores among automatic prediction assessment methods previously applied in CASPs, such as Global Distance Test Total Score (GDT_TS) and Contact Score (CS). As one of the important components to guide our assessment of CASP9 FM category predictions, this method correlates well with other scoring methods and yet is able to reveal good-quality models that are missed by GDT_TS.

Availability: The script for QCS calculation is available at http://prodata.swmed.edu/QCS/.

Contact:  grishin@chop.swmed.edu

Supplementary Information:  Supplementary data are available at Bioinformatics online.
Modulation of Host Immunity by Beneficial Microbes
Authors: Zamioudis Christos , Pieterse Corné M. J.
Published: October 2011

In nature, plants abundantly form beneficial associations with soilborne microbes that are important for plant survival and, as such, affect plant biodiversity and ecosystem functioning. Classical examples of symbiotic microbes are mycorrhizal fungi that aid in the uptake of water and minerals, and Rhizobium bacteria that fix atmospheric nitrogen for the plant. Several other types of beneficial soilborne microbes, such as plant-growth-promoting rhizobacteria and fungi with biological control activity, can stimulate plant growth by directly suppressing deleterious soilborne pathogens or by priming aboveground plant parts for enhanced defense against foliar pathogens or insect herbivores. The establishment of beneficial associations requires mutual recognition and substantial coordination of plant and microbial responses. A growing body of evidence suggests that beneficial microbes are initially recognized as potential invaders, after which an immune response is triggered, whereas, at later stages of the interaction, mutualists are able to short-circuit plant defense responses to enable successful colonization of host roots. Here, we review our current understanding of how symbiotic and nonsymbiotic beneficial soil microbes modulate the plant immune system and discuss the role of local and systemic defense responses in establishing the delicate balance between the two partners.
Hepatitis C virus activates interleukin-1β via caspase-1-inflammasome complex
Authors: Burdette Dylan , Haskett Adam , Presser Lance , McRae Steven , Iqbal Jawed , Waris Gulam
Published: October 2011

Interleukin-1β (IL-1β) is a potent pro-inflammatory cytokine involved in the pathogenesis of HCV, but the sensors and underlying mechanisms that facilitate HCV-induced IL-1β proteolytic activation and secretion remains unclear. In this study, we have identified a signalling pathway leading to IL-1β activation and secretion in response to HCV infection. Previous studies have shown the induction and secretion of IL-1β through the inflammasome complex in macrophages/monocytes. Here, we report for the first time the induction and assembly of the NALP3-inflammasome complex in human hepatoma cells infected with HCV (JFH-1). We demonstrate that activation of IL-1β in HCV-infected cells involves the proteolytic processing of pro-caspase-1 into mature caspase-1 in a multiprotein inflammasome complex. Next, we demonstrate that HCV is sensed by NALP3 protein, which recruits the adaptor protein ASC for the assembly of the inflammasome complex. Using a small interfering RNA approach, we further show that components of the inflammasome complex are involved in the activation of IL-1β in HCV-infected cells. Our study also demonstrates the role of reactive oxygen species in HCV-induced IL-1β secretion. Collectively, these observations provide an insight into the mechanism of IL-1β processing and secretion, which is likely to provide novel strategies for targeting the viral or cellular determinants to arrest the progression of liver disease associated with chronic HCV infection.
Locating protein-coding sequences under selection for additional, overlapping functions in 29 mammalian genomes
Authors: Lin Michael F. , Kheradpour Pouya , Washietl Stefan , Parker Brian J. , Pedersen Jakob S. , Kellis Manolis
Published: October 2011

The degeneracy of the genetic code allows protein-coding DNA and RNA sequences to simultaneously encode additional, overlapping functional elements. A sequence in which both protein-coding and additional overlapping functions have evolved under purifying selection should show increased evolutionary conservation compared to typical protein-coding genes—especially at synonymous sites. In this study, we use genome alignments of 29 placental mammals to systematically locate short regions within human ORFs that show conspicuously low estimated rates of synonymous substitution across these species. The 29-species alignment provides statistical power to locate more than 10,000 such regions with resolution down to nine-codon windows, which are found within more than a quarter of all human protein-coding genes and contain ∼2% of their synonymous sites. We collect numerous lines of evidence that the observed synonymous constraint in these regions reflects selection on overlapping functional elements including splicing regulatory elements, dual-coding genes, RNA secondary structures, microRNA target sites, and developmental enhancers. Our results show that overlapping functional elements are common in mammalian genes, despite the vast genomic landscape.
The making of a new pathogen: Insights from comparative population genomics of the domesticated wheat pathogenMycosphaerella graminicolaand its wild sister species
Authors: Stukenbrock Eva H. , Bataillon Thomas , Dutheil Julien Y. , Hansen Troels T. , Li Ruiqiang , Zala Marcello , McDonald Bruce A. , Wang Jun , Schierup Mikkel H.
Published: October 2011

The fungusMycosphaerellagraminicolaemerged as a new pathogen of cultivated wheat during its domestication ∼11,000 yr ago. We assembled 12 high-quality full genome sequences to investigate the genetic footprints of selection in this wheat pathogen and closely related sister species that infect wild grasses. We demonstrate a strong effect of natural selection in shaping the pathogen genomes with only ∼3% of nonsynonymous mutations being effectively neutral. Forty percent of all fixed nonsynonymous substitutions, on the other hand, are driven by positive selection. Adaptive evolution has affectedM. graminicolato the highest extent, consistent with recent host specialization. Positive selection has prominently altered genes encoding secreted proteins and putative pathogen effectors supporting the premise that molecular host–pathogen interaction is a strong driver of pathogen evolution. Recent divergence between pathogen sister species is attested by the high degree of incomplete lineage sorting (ILS) in their genomes. We exploit ILS to generate a genetic map of the species without any crossing data, document recent times of species divergence relative to genome divergence, and show that gene-rich regions or regions with low recombination experience stronger effects of natural selection on neutral diversity. Emergence of a new agricultural host selected a highly specialized and fast-evolving pathogen with unique evolutionary patterns compared with its wild relatives. The strong impact of natural selection, we document, is at odds with the small effective population sizes estimated and suggest that population sizes were historically large but likely unstable.
The Binding Protein BiP Attenuates Stress-Induced Cell Death in Soybean via Modulation of the N-Rich Protein-Mediated Signaling Pathway
Authors: Reis Pedro A.A. , Rosado Gustavo L. , Silva Lucas A.C. , Oliveira Luciana C. , Oliveira Lucas B. , Costa Maximiller D.L. , Alvim Fátima C. , Fontes Elizabeth P.B.
Published: October 2011

The molecular chaperone binding protein (BiP) participates in the constitutive function of the endoplasmic reticulum (ER) and protects the cell against stresses. In this study, we investigated the underlying mechanism by which BiP protects plant cells from stress-induced cell death. We found that enhanced expression of BiP in soybean (Glycine max) attenuated ER stress- and osmotic stress-mediated cell death. Ectopic expression of BiP in transgenic lines attenuated the leaf necrotic lesions that are caused by the ER stress inducer tunicamycin and also maintained shoot turgidity upon polyethylene glycol-induced dehydration. BiP-mediated attenuation of stress-induced cell death was confirmed by the decreased percentage of dead cell, the reduced induction of the senescence-associated marker gene GmCystP, and reduced DNA fragmentation in BiP-overexpressing lines. These phenotypes were accompanied by a delay in the induction of the cell death marker genes N-RICH PROTEIN-A (NRP-A), NRP-B, and GmNAC6, which are involved in transducing a cell death signal generated by ER stress and osmotic stress through the NRP-mediated signaling pathway. The prosurvival effect of BiP was associated with modulation of the ER stress- and osmotic stress-induced NRP-mediated cell death signaling, as determined in transgenic tobacco (Nicotiana tabacum) lines with enhanced (sense) and suppressed (antisense) BiP levels. Enhanced expression of BiP prevented NRP- and NAC6-mediated chlorosis and the appearance of senescence-associated markers, whereas silencing of endogenous BiP accelerated the onset of leaf senescence mediated by NRPs and GmNAC6. Collectively, these results implicate BiP as a negative regulator of the stress-induced NRP-mediated cell death response.
Evolution of Diterpene Metabolism: Sitka Spruce CYP720B4 Catalyzes Multiple Oxidations in Resin Acid Biosynthesis of Conifer Defense against Insects
Authors: Hamberger Björn , Ohnishi Toshiyuki , Hamberger Britta , Séguin Armand , Bohlmann Jörg
Published: October 2011

Diterpene resin acids (DRAs) are specialized (secondary) metabolites of the oleoresin defense of conifers produced by diterpene synthases and cytochrome P450s of the CYP720B family. The evolution of DRA metabolism shares common origins with the biosynthesis of ent-kaurenoic acid, which is highly conserved in general (primary) metabolism of gibberellin biosynthesis. Transcriptome mining in species of spruce (Picea) and pine (Pinus) revealed CYP720Bs of four distinct clades. We cloned a comprehensive set of 12 different Sitka spruce (Picea sitchensis) CYP720Bs as full-length cDNAs. Spatial expression profiles, methyl jasmonate induction, and transcript enrichment in terpenoid-producing resin ducts suggested a role of CYP720B4 in DRA biosynthesis. CYP720B4 was characterized as a multisubstrate, multifunctional enzyme by the formation of oxygenated diterpenoids in metabolically engineered yeast, yeast in vivo transformation of diterpene substrates, in vitro assays with CYP720B4 protein produced in Escherichia coli, and alteration of DRA profiles in RNA interference-suppressed spruce seedlings. CYP720B4 was active with 24 different diterpenoid substrates, catalyzing consecutive C-18 oxidations in the biosynthesis of an array of diterpene alcohols, aldehydes, and acids. CYP720B4 was most active in the formation of dehydroabietic acid, a compound associated with insect resistance of Sitka spruce. We identified patterns of convergent evolution of CYP720B4 in DRA metabolism and ent-kaurene oxidase CYP701 in gibberellin metabolism and revealed differences in the evolution of specialized and general diterpene metabolism in a gymnosperm. The genomic and functional characterization of the gymnosperm CYP720B family highlights that the evolution of specialized metabolism involves substantial diversification relative to conserved, general metabolism.
Two-dimensional approach to fluorescence yield XANES measurement using a silicon drift detector. Erratum
Authors: Tamenori Y. , Morita M. , Nakamura T.
Published: October 2011

An error in the paper by Tamenoriet al.[(2011),J. Synchrotron Rad.18, 747–752] is corrected.
Individual psychomotor impairment in relation to zopiclone and ethanol concentrations in blood – a randomized controlled double‐blinded trial
Authors: Gustavsen Ingebjørg , Hjelmeland Knut , Bernard Jean‐Paul , Mørland Jørg
Published: October 2011

Aims  To investigate individual traffic‐relevant impairment related to measured blood zopiclone and ethanol concentrations. Also, we aimed to study possible development of acute tolerance.

Design  A randomized controlled four‐way cross‐over double‐blind trial. Study drugs were zopiclone 5 or 10 mg, 50 g ethanol or placebo.

Setting  Laboratory study with computerized tests: Connor's Continuous Performance test, Choice Reaction Time and Stockings of Cambridge. Altogether, the tests consisted of 15 test components, representing three levels of behaviour (automotive, control, executive planning), relevant to traffic safety.

Participants  Sixteen healthy male volunteers.

Measurements  Each study day, 10 blood samples were collected from each volunteer. Fifteen psychomotor test components were registered at baseline and a further three times after intake. Impairment was defined as any individual deterioration in performance compared to individual baseline performance.

Findings  Blood drug concentrations up to 74 µg/l zopiclone and 0.100% ethanol were measured. We found a clear positive concentration–effect relationship for zopiclone and ethanol for both automotive and control behaviours, and a modest relationship for executive planning behaviour. Significant impairment started to be observed at concentrations above 16 µg/l zopiclone (automotive and control behaviour) and above 0.026% ethanol (automotive behaviour). Acute tolerance was found for both drugs.

Conclusions  The hypnotic, zopiclone, can impair psychomotor performance at blood concentrations as low as 16 µg/l.
The effect of sterilisation on the light intensity of the reusable Trachlight™*
Authors: Milne A. D. , Cave A. L. , Brousseau P. A. , Hung O. R.
Published: October 2011

We examined the light intensity delivered by the Trachlight™ reusable lightwand and the effect of repeated sterilisation on this light intensity. Using a light meter and test chamber, the light intensity of 12 new Trachlights and 31 Trachlights available in operating theatres was measured. In addition, five new devices underwent 30 repeated sterilisations with light intensity measurement after each cleaning. There was no difference between the light intensity of new Trachlights (median (IQR [range]) 2282 (2202–2780 [1970–4400])) lux and the devices currently in service (2295 (2018–2796 [1649–3280]) lux (p = 0.27)). The median (range) number of uses for devices currently in service was only 3 (0–9). There was, however, significant light intensity loss after 10, 20 and 30 cleanings (p = 0.001). After 10 cleanings, the mean light intensity was 75% of initial output, and after 30 cycles, light intensity was 59% of initial output.
Genetic diversity and admixture of indigenous cattle from North Ethiopia: implications of historical introgressions in the gateway region to Africa
Authors: Zerabruk M. , Li M.‐H. , Kantanen J. , Olsaker I. , Ibeagha‐Awemu E. M. , Erhardt G. , Vangen O.
Published: October 2011

Microsatellite variation was surveyed to determine the genetic diversity, population structure and admixture of seven North Ethiopian cattle breeds by combining multiple microsatellite data sets of Indian and West African zebu, and European, African and Near‐Eastern taurine in genetic analyses. Based on allelic distribution, we identified four diagnostic alleles (HEL1‐123 bp, CSSM66‐201 bp, BM2113‐150 bp and ILSTS6‐285 bp) specific to the Near‐Eastern taurine. Results of genetic relationship and population structure analyses confirmed the previously established marked genetic distinction between taurine and zebu, and indicated further divergence among the bio‐geographical groupings of breeds such as North Ethiopian, Indian and West African zebu, and African, European and Near‐Eastern taurine. Using the diagnostic alleles for bio‐geographical groupings and a Bayesian method for population structure inference, we estimated the genetic influences of major historical introgressions in North Ethiopian cattle. The breeds have been heavily (>90%) influenced by zebu, followed by African, European and the Near‐Eastern taurine. Overall, North Ethiopian cattle show a high level of within‐population genetic variation (e.g. observed heterozygosity = 0.659–0.687), which is in the upper range of that reported for domestic cattle and indicates their potential for future breeding applications, even in a global context. Rather low but significant population differentiation (FST = 1.1%, P < 0.05) was recorded as a result of multiple introgression events and strong genetic exchanges among the North Ethiopian breeds.
Implementing a transition pathway in diabetes: a qualitative study of the experiences and suggestions of young people with diabetes
Authors: Price C. S. , Corbett S. , Lewis‐Barned N. , Morgan J. , Oliver L. E. , Dovey‐Pearce G.
Published: October 2011

Background  The prevalence of Type 1 diabetes is increasing with more children and adolescents being diagnosed with this chronic condition. There has been an increasing focus in recent years on the transition through adolescence and supporting young people who have chronic health conditions, with the recognition that young people are at risk of dropping out of healthcare services following transfer from paediatric to adult services. To date, there have been limited evaluations of transition models. The purpose of this study is to evaluate one such model in diabetes, the ‘Transition Pathway’ via interviews with young people who have experienced it first‐hand. The results are discussed in terms of understanding the unique needs of adolescents with regard to psychosocial developmental theory, and what this means for healthcare providers of transition/adolescent services.

Methods  Semi‐structured interviews were carried out with 11 young people, two of whom returned a year later for a second interview. Qualitative analysis of these interviews using a ‘Framework’ approach enabled the data to be sorted according to initial themes. Following this, further analysis enabled the identification of ‘super‐ordinate’ or overall themes.

Results  Six initial themes emerged from the data. These concerned the transition pathway process, the experience and organization of transfer, organization of services, information and education, the healthcare consultation and the need for services to be inclusive of all young people's needs. From these initial themes, two overall/super‐ordinate themes were identified: the need for transition services to be developmentally appropriate and to be based around individual needs. The consultation experience was central to keeping young people engaged with adolescent healthcare services.

Conclusion  Several key elements of adolescent/transition healthcare services have been proposed, one of which is training for professionals delivering the service. This study suggests that communication skills form a vital component of such training.
‘Down the rabbit hole’: enhancing the transition process for youth with cystic fibrosis and congenital heart disease by re‐imagining the future and time
Authors: Moola F. J. , Norman M. E.
Published: October 2011

Background  Although the transition from paediatric to adult clinical care is an important one, the process is far from seamless. Little is known about the transition experiences of youth with cystic fibrosis (CF) and congenital heart disease (CHD).

Method  Informed by the new social studies of childhood, this qualitative study adopted a thematic analytical approach in order to explore how 50 youth and 28 parents affected by CF and CHD at a large children's hospital in Canada negotiate constructions of ‘normal developmental time’– in both anticipating and dealing with the transition from adolescence to adulthood.

Results  Illness appeared to render the future as an uncertain terrain for youth living with CF and CHD. Concerns related to deteriorating health and occupational restrictions in the future were paramount for these youth. For young women with CF and CHD, the loss of ‘normal’ gendered roles – such as motherhood – was also a distressing future concern. For youth living with CF and their parents in particular, time was thought to be stolen and the future was abbreviated. Despite these seemingly anxiety‐inducing experiences, youth and their parents demonstrated considerable creativity as they devised strategies to deal with the future and stolen time.

Recommendations and conclusion  In addition to challenging ideological assumptions about developmental time which may alienate youth with chronic illnesses, the results from this study suggest that attending to youth's temporal anxieties and future concerns may ultimately enhance the transition process for youth with CF and CHD.
Interleukin‐4 and interleukin‐13 prime migrational responses of haemopoietic progenitor cells to stromal cell‐derived factor‐1α
Authors: Punia N. , Smith S. , Thomson J. V. , Irshad A. , Nair P. , Sehmi R.
Published: October 2011

Background

Lung‐homing of progenitor cells is associated with inflammatory and remodelling changes in asthma. Factors that modulate the increased traffic of progenitor cells to the site of inflammation in asthma remain to be defined. Interleukin (IL)‐4 and IL‐13 are Th2 cytokines that are key regulators of asthma pathology.

Objective

We investigated the role of IL‐4 and IL‐13 in modulating the trans‐migrational responses of haemopoietic progenitor cells (HPC).

Methods

HPC were enriched from cord blood (CB) and peripheral blood (PB) samples. Migration of HPC was assessed using transwell migration assays, and responding cells were enumerated by flow cytometry.

Results

IL‐4 and IL‐13 primed migration of CB‐ and PB‐derived HPC (CD34+45+ cells) to stromal cell‐derived factor‐1α (SDF‐1α), in vitro. However, these cytokines had no effect on migrational responses of eosinophil‐lineage committed progenitors (CD34+45+IL‐5Rα+ cells) or mature eosinophils to SDF‐1α. For HPC, priming effects of IL‐4 (0.1 ng/mL) and IL‐13 (0.1 ng/mL) were detectable within 1 h and optimal at 18‐h post‐incubation, and IL‐4 was the more effective priming agent. Pre‐incubation with IL‐4 or IL‐13 had no effect on the intensity of cell surface expression of SDF‐1α receptor, CXCR4. Disruption of cell membrane cholesterol content by pre‐incubation with polyene antibiotics inhibited IL‐4 priming of SDF‐1α stimulated migration of HPC indicating that increased incorporation of CXCR4 into membrane lipid rafts mediated the cytokine primed migrational response of HPC. This was confirmed by confocal fluorescent microscopy.

Conclusions and Clinical Relevance

IL‐4 and IL‐13 prime the migrational response of HPC to SDF‐1α by enhancing the incorporation of CXCR4 into lipid rafts. The priming effect of these cytokines is specific to primitive HPC. These data suggest that increased local production of IL‐4 and IL‐13 within the lungs may promote increased SDF‐1α mediated homing of HPC to the airways in asthma.
Utility of peripheral blood B cell subsets analysis in common variable immunodeficiency
Authors: Al Kindi M , Mundy J , Sullivan T , Smith W , Kette F , Smith A , Heddle R , Hissaria P
Published: October 2011

Abnormalities in peripheral blood B cell subsets have been identified in common variable immunodeficiency (CVID) patients and classification systems based upon their numbers have been proposed to predict the clinical features. We analysed B lymphocyte subsets by multi-colour flow cytometry (MFC) in a cohort of well-characterized CVID patients to look at their clinical relevance and validate the published association of different classification criteria (Freiburg, Paris and Euroclass) with clinical manifestations. CVID patients had a reduced proportion of total and switched memory B cells (MBC, swMBC) compared to normal controls (P < 0·0006). Patients classified in Freiburg Ia had a higher prevalence of granulomatous diseases (P = 0·0034). The previously published associations with autoimmune diseases could not be confirmed. The Euroclass classification was not predictive of clinical phenotypes. The absolute numbers of all B cell subsets were reduced in CVID patients compared to controls. There was a significant linear correlation between low absolute total B cells and MBC with granulomatous disease (P < 0·05) and a trend towards lower B cells in patients with autoimmune diseases (P = 0·07). Absolute number of different B cell subsets may be more meaningful than their relative percentages in assessing the risk of granulomatous diseases and possibly autoimmunity.
Serum total adiponectin level and risk of cardiovascular disease in Han Chinese populations: a meta‐analysis of 17 case–control studies
Authors: Zhang Bu‐Chun , Liu Wei‐Jing , Che Wen‐Liang , Xu Ya‐Wei
Published: October 2011

Objective  To systematically evaluate low serum adiponectin level as a risk factor for cardiovascular disease (CVD). A meta‐analysis was performed to quantitatively analyse the association of serum total adiponectin level with CVD using previous case–control studies in Han Chinese populations.

Methods  Several electronic databases were searched for relevant articles up to July 2011. A total of nine (n = 933), eight (n = 939) articles were included in each meta‐analysis regarding the association of serum adiponectin level with coronary heart disease (CHD) and ischaemic stroke, respectively. Publication bias was examined by the Egger’s linear regression test. Sensitivity analysis was performed by omitting one study at a time, and the pooled standardized mean difference (SMD) was estimated using fixed‐effects model and random‐effects model, respectively.

Results  Serum total adiponectin concentrations were lower in patients with CHD and ischaemic stroke, with pooled SMD of −1·41 (95% CI −1·69, −1·12, P < 0·00001) and −1·69 (95% CI −2·04, −1·33, P < 0·00001), respectively. By performing a meta‐regression analysis, homeostasis model assessment of insulin resistance, study size, adiponectin measurement assays, gender and mean body mass index of cases failed to account for heterogeneity for comparisons between lower adiponectin level and ischaemic stroke. However, study size had significant effect on the association of lower adiponectin level with CHD and accounted for 96·72% of the between‐study variance. No publication bias was detected. No single study was found to affect the overall result of each analysis by sensitivity testing.

Conclusions  The accumulated evidence suggested that low serum adiponectin level increased the risk of a first cardiovascular event in the Han Chinese population. Further study is recommended with larger sample size to explore the role of hypoadiponectinemia in the causation of CVD.
The consequences of growth hormone‐releasing hormone receptor haploinsufficiency for bone quality and insulin resistance
Authors: Gois Miburge B. , Salvatori Roberto , Aguiar‐Oliveira Manuel H. , Pereira Francisco A. , Oliveira Carla R. P. , Oliveira‐Neto Luiz A. , C. Pereira Rossana M. , Souza Anita H. O. , Melo Enaldo V. , de Paula Francisco J. A.
Published: October 2011

Objective Growth hormone (GH)/insulin‐like growth factor (IGF) axis and insulin are key determinants of bone remodelling. Homozygous mutations in the GH‐releasing hormone receptor (GHRHR) gene (GHRHR) are a frequent cause of genetic isolated GH deficiency (IGHD). Heterozygosity forGHRHRmutation causes changes in body composition and possibly an increase in insulin sensitivity, but its effects on bone quality are still unknown. The objective of this study was to assess the bone quality and metabolism and its correlation with insulin sensitivity in subjects heterozygous for anullmutation in theGHRHR.

Patients and methods A cross‐sectional study was performed on 76 normal subjects (68·4% females) (N/N) and 64 individuals (64·1% females) heterozygous for a mutation in theGHRHR(MUT/N). Anthropometric features, quantitative ultrasound (QUS) of the heel, bone markers [osteocalcin (OC) and CrossLaps], IGF‐I, glucose and insulin were measured, and homeostasis model assessment of insulin resistance (HOMAIR) was calculated.

Results There were no differences in age or height between the two groups, but weight (P = 0·007) and BMI (P = 0·001) were lower in MUT/N. There were no differences in serum levels of IGF‐I, glucose,T‐score or absolute values of stiffness and OC, but insulin (P = 0·01), HOMAIR(P = 0·01) and CrossLaps (P = 0·01) were lower in MUT/N. There was no correlation between OC and glucose, OC and HOMAIRin the 140 individuals as a whole or in the separate MUT/N or N/N groups.

Conclusions This study suggests that one allele mutation in theGHRHRgene has a greater impact on energy metabolism than on bone quality.
Recommendations for assessment, monitoring and follow‐up of patients with haemophilia
Authors: DE MOERLOOSE P. , FISCHER K. , LAMBERT T. , WINDYGA J. , BATOROVA A. , LAVIGNE‐LISSALDE G. , ROCINO A. , ASTERMARK J. , HERMANS C.
Published: October 2011

Summary.  Over the last few decades, clinical follow‐up of patients with haemophilia has become more complex as a result of the introduction of new treatment strategies, the presence of comorbidities related to haemophilia or ageing, as well as the emergence of new tools to evaluate the medical and social consequences of haemophilia. This publication describes the parameters and information that should be documented and the tests, examinations and interventions required for optimal follow‐up of a patient with haemophilia. In the absence of formal studies, the present recommendations have been established as result of a series of consensus meetings in the frame of the European Haemophilia Therapy Standardization Board (EHTSB). The following 11 domains were identified: Baseline information, Current status, Treatment, Inhibitor status, Bleeding, Joint status and pain, Comorbidities, Dental care, Physical activities, Social participation and Quality of life. For each domain, details are proposed for the relevant parameters to be captured and monitored as well as the relevant tools that facilitate data collection. Adopting these recommendations should help the individual care of patients and, even though this is not the primary objective of this article, it should also help at national and international level to shape a new approach to haemophilia by working towards a more standardized outcome assessment. Greater standardization should have implications for data collection, improvements in treatment evaluation and optimizing resources.
Addressing non‐adherence to antipsychotic medication: a harm‐reduction approach
Authors: ALDRIDGE M. A.
Published: October 2011

Accessible summary

Many people decide not to take prescribed antipsychotics once they are discharged from the hospital.

Stopping antipsychotics suddenly without support may result in harmful reactions and possible re‐admission to the hospital.

The ‘Non‐Adherence Harm Reduction’ approach aims to reduce the harm of stopping antipsychotics, by informing and supporting those who make this personal decision.

This approach values personal autonomy and may reduce the likelihood of harm and re‐admission in those who choose not to adhere to prescribed antipsychotics.

This paper discusses the evidence base for interventions addressing non‐adherence to prescribed antipsychotics. A case study approach is used, and the extent to which adherence improvement interventions might be used in collaboration with a specific patient is considered. The principles and application of harm‐reduction philosophy in mental health are presented in a planned non‐adherence harm‐reduction intervention. This intervention aims to acknowledge the patient's ability to choose and learn from experience and to reduce the potential harm of antipsychotic withdrawal. The intervention evaluation method is outlined.
Survival of the fittest: a role for phage‐encoded eukaryotic‐like kinases
Authors: Robertson Erle S.
Published: October 2011

Phages are often thought of as mortal enemies of bacteria. This dynamic relationship has led to the evolution of a number of processes in bacteria designed to defeat these attacks. Examples of these include blocking phage attachment, CRISPR, and restriction modification systems. Temperate phages provide another source of protection by excluding infection of heterologous phage, thwarting phage production and further infection. This strategy protects the rest of the bacterial population from attack. The lambdoid phage 933W, a source of the genes encoding Shiga toxin in the highly pathogenic O157:H7 enterohemorrhagic E. coli strain, also carries a gene encoding a eukaryotic‐like tyrosine kinase, Stk. In this issue of Molecular Microbiology, Friedman et al. (2011) show that Stk, through its kinase activity, excludes infection by another lambdoid phage HK97. This exclusion is very specific as it does not affect a number of other lambdoid phages. HK97 contributes to its own demise by expressing the product of an open reading frame, orf41, which is required for Stk activation. The authors further show that autophosphorylation increases the stability of Stk and suggest that autophosphorylation contributes to Stk activity. Whether or not this exclusion activity provides a selective advantage through maintenance of Stk activity is yet to be explored.
Effects of orexin and glucose microinjected into the hypothalamic paraventricular nucleus on gastric acid secretion in conscious rats
Authors: Chaleek N. , Kermani M. , Eliassi A. , Haghparast A.
Published: October 2011

Background  Orexin‐A is a novel peptide that appears to play a role in regulation of gastric acid secretion. However, little is known about sites of its action. In addition, evidences suggest that some of orexin‐A neurons respond to glucose. In this study, we address the hypothesis which demonstrates that orexin‐A and glucose act in the hypothalamic paraventricular nucleus (PVN) to increase gastric acid secretion and juice volume in pyloric‐ligated conscious rats.

Methods  Male Wistar rats were implanted with guide canula directed to the PVN. Orexin‐A (3–10 μg), glucose (350–750 ng) SB334867 (6–20 μg) were microinjected. The effect of pretreatment with an orexin‐1 receptor antagonist, SB334867, on orexin‐A and D‐glucose induced acid secretion was assessed. Gastric acid secretion was measured using the pylorus‐ligation method, and the amount of gastric acid was determined by titration with 0.01 N NaOH to a pH of 7.0.

Key Results  Intraparaventricular injection of orexin‐A or D‐glucose stimulated gastric acid secretion in a dose‐dependent manner. The PVN injections of orexin‐A receptor antagonist, SB334867, were associated with gastric acid secretion decrease and inhibited effects of PVN‐injected orexin‐A. Orexin‐stimulated gastric acid secretion was decreased (∼40%) after PVN lesions. Glucose‐stimulated gastric acid secretion was also suppressed by intraperitoneal (IP) injection of SB334867. In addition, it was observed that co‐injection of orexin‐A and glucose at ineffective doses increased gastric secretion significantly.

Conclusions & Inferences  We suggest that orexin‐A and glucose effects on the PVN stimulate gastric acid secretion. This stimulatory effect is probably mediated by orexin‐1 receptors.
Mephedrone (4‐methylmethcathinone, ‘meow’): acute behavioural effects and distribution of Fos expression in adolescent rats
Authors: Motbey Craig P. , Hunt Glenn E. , Bowen Michael T. , Artiss Suzanne , McGregor Iain S.
Published: October 2011

Mephedrone (4‐methylmethcathinone) is a novel recreational drug that has rapidly increased in popularity in recent years. Users report mephedrone as having the stimulant‐like qualities of methamphetamine and cocaine, combined with the prosocial, entactogenic effects of 3,4‐methylenedioxymethamphetamine (MDMA). Anecdotal and case study reports indicate that mephedrone may have the potential to engender compulsive patterns of use as well as toxicity in overdose. However, there have been almost no neuropharmacological investigations of the drug up to this point. Here we examined the effects of two different mephedrone doses [15 and 30 mg/kg, intraperitoneal (IP)] relative to the well‐known stimulant methamphetamine (2 mg/kg IP) in adolescent rats. Rats were injected, assessed for locomotor activity for 60 minutes and then tested in a 10‐minute social preference test (measuring time spent in close proximity to a real rat versus a dummy rat). Their brains were then processed using Fos immunohistochemistry to determine patterns of brain activation. Results showed that mephedrone caused profound locomotor hyperactivity at both dose levels while tending to reduce social preference. Patterns of Fos expression with mephedrone resembled a combination of those observed with methamphetamine and MDMA, with particularly strong Fos expression in the cortex, dorsal and ventral striatum, ventral tegmental area (typical of both MDMA and methamphetamine) and supraoptic nucleus (typical of MDMA). These results demonstrate for the first time the powerful stimulant effects of mephedrone in animal models and its capacity to activate mesolimbic regions. These results also provide some empirical basis to user reports that mephedrone subjectively resembles a MDMA/methamphetamine hybrid.