bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel spliced gene in alcelaphine herpesvirus 1 encodes a glycoprotein which is secreted in vitro
Authors: Russell George C. , Todd Helen , Deane David , Percival Ann , Dagleish Mark P. , Haig David M. , Stewart James P.
Published: August 2013

Herpesviruses often contain cryptic, spliced genes that are not obvious from the initial in silico annotation. Alcelaphine herpesvirus 1 (AlHV-1) contains 72 annotated ORFs but there are also a number of gaps between these that may have protein-coding potential. Comparative analysis of coding potential between AlHV-1 and the related ovine herpesvirus 2 (OvHV-2) revealed a putative novel spliced gene that we have termed A9.5. Analysis of cDNA clones from AlHV-1-infected cells revealed three overlapping clones corresponding to A9.5 and the coding sequence was confirmed by reverse transcription PCR of RNA from AlHV-1-infected cattle tissues. The A9.5 gene was predicted to encode a secreted glycoprotein with molecular mass 19 kDa. Empirical analysis showed that a recombinant haemagglutinin-tagged A9.5 fusion protein was secreted from transfected cells and had a molecular mass of 45 kDa, which was reduced to 20 kDa by endoglycosidase F treatment, confirming that A9.5 was a secreted glycoprotein. In situ RNA hybridization showed that A9.5 was expressed in cells associated with malignant catarrhal fever (MCF) lesions in infected cattle. Detailed analysis of the available OvHV-2 sequences revealed an homologous gene (Ov9.5) with conserved splicing signals and predicted amino acid sequence features in both sequenced isolates of this related virus. We have therefore identified a novel spliced gene in two related macaviruses that is expressed in MCF lesions. Future work will determine its importance for the pathogenesis of disease.
Do different tests of episodic memory produce consistent results in human adults?
Authors: Cheke Lucy G. , Clayton Nicola S.
Published: August 2013

A number of different philosophical, theoretical, and empirical perspectives on episodic memory have led to the development of very different tests with which to assess it. Although these tests putatively assess the same psychological capacity, they have rarely been directly compared. Here, a sample of undergraduates was tested on three different putative tests of episodic memory (What-Where-When, Unexpected Question/Source Memory, and Free Recall). It was predicted that to the extent to which these different tests are assessing the same psychological process, performance across the various tests should be positively correlated. It was found that not all tests were related and those relationships that did exist were not always linear. Instead, two tests showed a quadratic relationship, suggesting the contribution of multiple psychological processes. It is concluded that not all putative tests of episodic cognition are necessarily testing the same thing.
Neuronal nitric-oxide synthase deficiency impairs the long-term memory of olfactory fear learning and increases odor generalization
Authors: Pavesi Eloisa , Heldt Scott A. , Fletcher Max L.
Published: August 2013

Experience-induced changes associated with odor learning are mediated by a number of signaling molecules, including nitric oxide (NO), which is predominantly synthesized by neuronal nitric oxide synthase (nNOS) in the brain. In the current study, we investigated the role of nNOS in the acquisition and retention of conditioned olfactory fear. Mice lacking nNOS received six training trials, each consisting of an odor-CS co-terminating with a foot shock-US. Mice showed reduced freezing responses to the trained odor 24 h and 7 d after training, compared to wild-type mice. Pretraining systemic injections of the NO donor, molsidomine, rescued fear retention in nNOS knockout mice. In wild-type mice, pretraining systemic injections of L-NAME, a nonspecific nNOS blocker, disrupted odor-CS fear retention in a dose-dependent manner. To evaluate whether NO signaling is involved in generalization of fear memories, nNOS knockout mice and wild-type mice receiving L-NAME were trained to one odor and tested with a series of similar odors. In both cases, we found increased generalization, as measured by increased freezing to similar, unpaired odors. Despite the impairment in fear memory retention and generalization, neither mice receiving injections of L-NAME nor nNOS knockout mice showed any deficits in either novel odor investigation time or odor habituation, suggesting intact olfactory perception and short-term memory olfactory learning. These results support a necessary role for neuronal NO signaling in the normal expression and generalization of olfactory conditioned fear.
Requirement of the combination of mushroom body γ lobe and α/β lobes for the retrieval of both aversive and appetitive early memories in Drosophila
Authors: Xie Zhiyong , Huang Cheng , Ci Bo , Wang Lianzhang , Zhong Yi
Published: August 2013

Extensive studies of Drosophila mushroom body in formation and retrieval of olfactory memories allow us to delineate the functional logic for memory storage and retrieval. Currently, there is a questionable disassociation of circuits for memory storage and retrieval during Drosophila olfactory memory processing. Formation of the initial aversive olfactory memory involves mushroom body γ lobe, whereas α/β lobes are reported to be necessary for the retrieval of such memory. In contrast, formation and retrieval of the short-term appetitive olfactory memory appears to involve γ lobe. With the help of newly identified Gal4 lines and of focusing on 3-h memory for both aversive and appetitive conditionings, our reexamination of the retrieval of aversive and appetitive olfactory memories suggests a new view. Blocking γ lobe output led to severe deficiency of aversive early memory retrieval and partial impairment of appetitive early memory retrieval. Interrupting α/β lobe output impaired the retrieval of both aversive and appetitive early memories. The contribution of the γ lobe and α/β lobes appeared to be additive for the retrieval of appetitive early memory. Thus, these results suggest that the retrieval of aversive and appetitive olfactory early memories requires the synaptic outputs from both γ lobe and α/β lobe neurons. This discovery may help us to rethink how aversive and appetitive memories are processed from memory formation to memory retrieval.
Regulating the Redox Gatekeeper: Vacuolar Sequestration Puts Glutathione Disulfide in Its Place
Authors: Noctor Graham , Mhamdi Amna , Queval Guillaume , Foyer Christine H.
Published: August 2013

The case is made for the potential importance of compartmentalization in redox signaling with new data on the transporters that may be involved.
A Genomic-Scale Artificial MicroRNA Library as a Tool to Investigate the Functionally Redundant Gene Space inArabidopsis
Authors: Hauser Felix , Chen Wenxiao , Deinlein Ulrich , Chang Kenneth , Ossowski Stephan , Fitz Joffrey , Hannon Gregory J. , Schroeder Julian I.
Published: August 2013

Traditional forward genetic screens are limited in the identification of homologous genes with overlapping functions. Here, we report the analyses and assembly of genome-wide protein family definitions that comprise the largest estimate for the potentially redundant gene space in Arabidopsis thaliana. On this basis, a computational design of genome-wide family-specific artificial microRNAs (amiRNAs) was performed using high-performance computing resources. The amiRNA designs are searchable online (http://phantomdb.ucsd.edu). A computationally derived library of 22,000 amiRNAs was synthesized in 10 sublibraries of 1505 to 4082 amiRNAs, each targeting defined functional protein classes. For example, 2964 amiRNAs target annotated DNA and RNA binding protein families and 1777 target transporter proteins, and another sublibrary targets proteins of unknown function. To evaluate the potential of an amiRNA-based screen, we tested 122 amiRNAs targeting transcription factor, protein kinase, and protein phosphatase families. Several amiRNA lines showed morphological phenotypes, either comparable to known phenotypes of single and double/triple mutants or caused by overexpression of microRNAs. Moreover, novel morphological and abscisic acid–insensitive seed germination mutants were identified for amiRNAs targeting zinc finger homeodomain transcription factors and mitogen-activated protein kinase kinase kinases, respectively. These resources provide an approach for genome-wide genetic screens of the functionally redundant gene space in Arabidopsis.
Measuring the success of library 2.0 technologies in the African context
Authors: Tandi Lwoga Edda
Published: August 2013

Purpose

This study aims to examine the suitability of information systems (IS) success model in the adoption of library 2.0 technologies among undergraduate students in the African context, and focused at the Muhimbili University of Health and Allied Sciences (MUHAS) of Tanzania.

Design/methodology/approach

Based on the IS success model, the study re‐specified and validated the IS model to examine adoption of library 2.0 technologies via a structural equation modeling (SEM) approach. The study examined the role of quality (service quality, information quality and system quality) in influencing user perceived net benefits, satisfaction and intention to reuse library 2.0 application. A case study research design was used in this study. Self‐administered questionnaire were distributed to all first year undergraduate students (n=408) at MUHAS, with a rate of return of 71.8%.

Findings

The study findings confirm the validity of using the proposed IS model for library 2.0 adoption assessment. The users’ intention to reuse is quite important, and accurately predicts the usage behaviour of library 2.0 services. The perceived net benefits had the strongest effect on users’ intention to reuse library 2.0 systems than any other determinants within the model. Among the three quality‐related constructs, service quality had the strongest total effect on perceived net benefits and intention to reuse. Compared to system quality, information quality had the largest effect on user satisfaction. It is thus important for librarians to consider all these factors for effective adoption of library 2.0 projects in research and academic institutions.

Originality

This is the first comprehensive study focusing on the health sciences library patron's usage behaviour of library 2.0 applications in Tanzania, and reveals findings that are useful for planning and implementing library 2.0 initiatives in other institutions with similar conditions.
Student‐driven health promotion activities
Authors: Kostenius Catrine
Published: August 2013

Purpose

The aim was to examine how students in the arctic region of Sweden experienced creating, leading, and participating in student‐driven health promoting activities in cooperation with their teacher.

Design/methodology/approach

Inspired by the participatory appreciative action research (PAAR) method 19 Swedish students, ages 10‐11 participated in health promotion work in the classroom through creating, leading, participating in and evaluating their own and their peers’ health promoting activities.

Findings

Students developed three themes and related activities which they felt helped them reduce stress and have friendly fun: “the friendly touch” (music and student massage), “the outdoor run for fun” (student physical activity in outdoors), and the sounds of well‐being (music).

Practical implications

This paper provides a comprehensive understanding of how students experienced creating, leading, and participating in student‐driven health promoting activities in cooperation with their teacher, and reveals that when students were asked to choose health promoting activities, they were not only in line with existing research but were able to reflect on how to develop good practice. Students are competent to lead health promoting activities with the support of their teacher and participating in health promoting activities lead by their peers.

Originality/value

The empowerment‐based group assignment in this study offers an example of implementing health promoting activities in school to increase health literacy useful for health educators and teachers.
Moderating teen drinking: combining social marketing and education
Authors: Rundle‐Thiele Sharyn , Russell‐Bennett Rebekah , Leo Cheryl , Dietrich Timo
Published: August 2013

Purpose

This paper outlines a pilot study that was undertaken in Australia in 2011 that combined social marketing with education. An intervention targeting 14‐16 year olds to influence attitudes and behavioural intentions towards moderate drinking was developed and tested. Game On:Know alcohol (GO:KA) is a six‐module intervention that is delivered to a year level cohort in an auditorium. GO:KA combines a series of online and offline experiential activities to engage (with) students.

Design/methodology

Following social marketing benchmark criteria, formative research and competitive analysis were undertaken to create, implement and evaluate an intervention. The intervention was delivered in one all boys’ and one all girls’ school in April and June 2011, respectively. A total of 223 Year 10 students participated in GO:KA with the majority completing both pre‐ and post‐surveys. Paired samples t‐tests and descriptive analysis were used to assess attitudinal and behavioural intention change.

Findings

Attitudinal change was observed in both schools while behavioural intentions changed for girls and not boys according to paired samples t‐testing. Post hoc testing indicated gender differences.

Research limitations

The lack of a control group is a key limitation of the current research that can be overcome in the 20 school main study to be conducted in 2013‐2015.

Originality/value

The current study provides evidence to suggest that a combined social marketing and education intervention can change teenage attitudes towards moderate drinking whilst only changing behavioural intentions for female teenagers. Analysis of the intervention provides insight into gender differences and highlights the need for a segmented approach.
Workplace work‐family interventions
Authors: Riva Egidio
Published: August 2013

Purpose

The purpose of this article is to investigate work‐family interventions in Italian organizations within the context of a national welfare regime and in the face of recession.

Design/methodology/approach

The results of case studies carried out on eight leading companies in the field of workplace work‐family policies are presented. The case study research is supported by a literature review as well as an analysis of national legislation and political agenda concerning work‐family issues.

Findings

Findings indicate that, against the backdrop of the institutional framework, one impact of the recession may be the setting aside of workplace work‐family intervention, especially in small and medium‐sized organizations with limited resources. Evidence collected using case study research suggests that this has not happened in larger companies where employers have adopted a strategic approach to work‐family issues. In these larger firms, work‐family policies have been assessed and reorganized as a result of an increasing concern for workplace performance and efficiency. In this regard, resilience to the crisis in workplace arrangements is related to the fact that the adoption of an evidence‐based approach makes economic sense and contributes to obtaining the long‐term support needed from important stakeholders.

Research limitations/implications

The case study companies are not necessarily representative of current workplace intervention in the field; a generalization of the findings may not therefore be appropriate. They do however provide valuable insights for both future research on workplace support and public policy design.

Originality/value

The article investigates the links between the wider social, economic and political context and workplace work‐family arrangements in specific organizations.
Revisiting quality management and performance
Authors: Laosirihongthong Tritos , Teh Pei‐Lee , Adebanjo Dotun
Published: August 2013

Purpose

The purpose of this study is to examine the relationship between quality management practices as well as their impact on organisational performance in the ASEAN regional context.

Design/methodology/approach

A sample of 115 data collected from automotive parts/components manufacturing companies in five ASEAN countries (Indonesia, Malaysia, Philippines, Thailand, and Vietnam) was used to test the proposed research hypotheses. A two‐step modelling approach was employed to model the data by using structural equation modelling (SEM).

Findings

Leadership of the organisations tend to focus on their external (customers and suppliers) rather than internal (employees) partners. The result of this study also suggests that tier 1 suppliers of the automotive industry in ASEAN considered quality information and supplier relationship instead of people management, as the drivers of process management.

Research limitations/implications

The study was limited to a single industry. The study did not consider some aspects culture in its investigation.

Practical implications

The results of this study clarify differences in how quality is managed in an emerging region when compared to previous studies in developed countries.

Originality/value

This study is the first attempt to explore quality management implementation in a specific sector in the ASEAN region.
Prisoners with neurodevelopmental disorders
Authors: Underwood Lisa , Forrester Andrew , Chaplin Eddie , McCarthy Jane
Published: August 2013

Purpose

The purpose of this paper is to review the evidence on providing services to people with neurodevelopmental disorders in prisons, with a focus on those prisoners with autism spectrum disorder (ASD).

Design/methodology/approach

Electronic databases were used to search for literature specifically on ASD in prisons. The literature was supplemented with the authors’ experiences of carrying out research on ASD in prison.

Findings

The searches only identified four articles and therefore the broader literature on people with ASD and other developmental disorders was reviewed in relation to the prison context.

Originality/value

The paper highlights the current limited evidence base on prisoners with autism spectrum disorders.
An image analysis method to detect CSD on rocks with adjusted color images
Authors: Karsli Fevzi , Dihkan Mustafa
Published: August 2013

Purpose

– The purpose of this paper is to provide crystal size distribution (CSD) using photogrammetric and image analysis techniques. A new algorithm is proposed to detect CSDs and a comparison is carried out with conventional watershed segmentation algorithm.

Design/methodology/approach

– Polished granite plates were prepared to designate the metrics of CSD measurements. There are many important metrics for measurements on CSD. Some of them are orientation, size, position, area, aspect ratio, convexity, circularity, perimeter, convex hull, bounding box, eccentricity, shape, max-min length of CSD's fitted and corrected ellipse, and population density in a per unit area. Prior to image processing stage, camera calibration was performed to remove the image distortion errors. Image processing techniques were applied to corrected images for detecting the CSD parameters.

Findings

– The proposed algorithm showed the improved preservation of size and shape characteristics of the crystal material when compared to the watershed segmentation. According to the experimental results, proposed algorithm revealed promising results in identifying CSDs more easily and efficiently.

Originality/value

– This paper describes CSD of granitic rocks by using automated grain boundary detection methods in polished plate images. Some metrics of CSDs were detected by employing a new procedure. A computer-based image analysis technique was developed to measure the CSDs on the granitic rock plates. A validation is done by superimposing digitally detected CSD metrics to original samples.
Bti sprays do not adversely affect non‐target aquatic invertebrates in French Atlantic coastal wetlands
Authors: Lagadic Laurent , Roucaute Marc , Caquet Thierry
Published: August 2013

Both the increase in human mobility and climate change contribute to the globalization of vector‐borne diseases. Some mosquito species are efficient disease vectors in Europe, thus increasing the risk of epidemic (re)emergence.

Bacillus thuringiensis var. israelensis (Bti) is considered as the most efficient larvicide to control mosquito populations with negligible environmental impacts. However, repeated field applications of Bti over many years raise the question of possible long‐term effects on non‐target invertebrates with putative subsequent alterations of food webs.

Environmental effects of Bti have mainly been studied in continental freshwater wetlands. Much less is known for brackish water coastal wetlands. We investigated whether repeated treatments with Bti, applied as VectoBac® WG over seven consecutive years, may affect non‐target invertebrate communities in wetlands of the French Atlantic coast. Particular attention was devoted to invertebrates potentially used as food sources by shorebirds and wading birds.

Invertebrates were sampled in the water and sediment of control and VectoBac®‐treated saltmarsh pools between 2006 and 2012. Taxa abundance data were used to calculate community descriptors and to analyse the potential structural changes due to VectoBac® using the principal response curve method and similarity analysis. Physicochemical parameters were measured in the same pools so that homogeneity of the environmental conditions between the control and treated areas could be tested.

We demonstrated that long‐term use of VectoBac® WG in French Atlantic coastal wetlands had no influence on the temporal evolution of the taxonomic structure and taxa abundance of non‐target aquatic invertebrate communities, which is highly driven by abiotic factors. In addition, over the long term, the amount of invertebrates that could be used as food resources by birds is maintained in VectoBac®‐treated areas.

Synthesis and applications. Reduced application rate and targeted spraying of VectoBac® WG in mosquito breeding sites minimize potential environmental impacts of Bacillus thuringiensis var. israelensis (Bti). Even so, surveillance of its possible primary side effects is needed, which requires comparable control and treated areas. Indeed, systematic temporal trends and subtle differences in the range of variation of abiotic factors result in discrepancies between control and treated area in terms of invertebrate abundance, which could be wrongly attributed to VectoBac®. Management decisions and mitigation measures may therefore benefit from (i) extending surveillance to a time frame that allows for coverage of the immense temporal variation in taxa abundance and diversity and (ii) the inclusion of environmental variables in the monitoring of non‐target animal communities potentially exposed to Bti.
Restriction site‐associated DNA sequencing generates high‐quality single nucleotide polymorphisms for assessing hybridization between bighead and silver carp in the United States and China
Authors: Lamer James T. , Sass Greg G. , Boone Jason Q. , Arbieva Zarema H. , Green Stefan J. , Epifanio John M.
Published: August 2013

Bighead carp (Hypophthalmichthys nobilis) and silver carp (H. molitrix) are invasive species and listed as US federally injurious species under the Lacy Act. They have established populations in much of the Mississippi River Basin (MRB; Mississippi, Illinois, and Missouri rivers) and are capable of producing fertile hybrids and complex introgression. Characterizing the composition of this admixture requires a large set of high‐quality, evolutionarily conserved, diagnostic genetic markers to aid in the identification and management of these species in the midst of morphological ambiguity. Restriction site‐associated DNA (RAD) sequencing of 45 barcoded bighead and silver carp from the United States and China produced reads that were aligned to the silver carp transcriptome yielded 261 candidate single nucleotide polymorphisms (SNPs) with fixed allelic differences between the two species. We selected the highest quality 112 SNP loci for validation using 194 putative pure‐species and F1 hybrids from the MRB and putative bighead carp and silver carp pure species from China (Amur, Pearl and Yangtze rivers). Fifty SNPs were omitted due to design/amplification failure or lack of diagnostic utility. A total of 57 species‐diagnostic SNPs conserved between carp species in US and Chinese rivers were identified; 32 were annotated to functional gene loci. Twenty‐seven of the 181 (15%) putative pure species were identified as hybrid backcrosses after validation, including three backcrosses from the Amur River, where hybridization has not been documented previously. The 57 SNPs identified through RAD sequencing provide a diagnostic tool to detect population admixture and to identify hybrid and pure‐species Asian carps in the United States and China.
Sevoflurane is less sensitive than halothane for in vitro detection of malignant hyperthermia susceptibility
Authors: JOHANNSEN S. , KLINGLER W. , SCHNEIDERBANGER D. , HEIDERICH S. , ROEWER N. , SCHUSTER F.
Published: August 2013

Background

Sevoflurane is a known triggering agent of malignant hyperthermia (MH). The present study analyzed different effects of sevoflurane on skeletal muscle of MH susceptible and nonsusceptible individuals in vitro and compared the results to the standardized test protocol with halothane and caffeine. A potential influence of a present ryanodine receptor type 1 (RyR1) mutation was investigated.

Methods

Muscle bundles of 24 MH‐susceptible patients with or without an RyR1 mutation, 35 MH‐nonsusceptible and 10 MH‐equivocal patients were exposed either to sevoflurane 8 vol% bolus or increasing doses of 2, 4, 6, and 8 vol%. In MH‐positive patients, a screening for mutations in the RyR1 gene was performed.

Results

The in vitro parameters initial length, weight, predrug resting tension, and predrug twitch height did not differ between the groups. Sevoflurane caused significant contractures in MH‐susceptible but not in MH‐nonsusceptible muscle after increasing doses [1.4 (0.3–6.0) vs. 0 (0‐0) mN] and after bolus application [6.9 (2.4–21.4) vs. 0 (0‐0) mN]. However, only 50% of the susceptible patients developed contractures ≥ 2 mN after increasing concentrations while 83% did so after rapid bolus administration. Presence of an RyR1 mutation was detected in 36% of the examined MH‐positive patients but had no influence on developing contractures.

Conclusion

Sevoflurane‐induced contractures do not reliably detect MH susceptibility on an individual level. Therefore, sevoflurane is no suitable alternative for diagnostic use. Mutation‐specific effects regarding contracture sizes after incubation with sevoflurane, halothane, or caffeine were not found.
The conserved Mediator subunit MDT‐15 is required for oxidative stress responses in Caenorhabditis elegans
Authors: Goh Grace Y. S. , Martelli Katherine L. , Parhar Kulveer S. , Kwong Ada W. L. , Wong Marcus A. , Mah Allan , Hou Nicole S. , Taubert Stefan
Published: August 2013

Reactive oxygen species (ROS) play important signaling roles in metazoans, but also cause significant molecular damage. Animals tightly control ROS levels using sophisticated defense mechanisms, yet the transcriptional pathways that induce ROS defense remain incompletely understood. In the nematode Caenorhabditis elegans, the transcription factor SKN‐1 is considered a master regulator for detoxification and oxidative stress responses. Here, we show that MDT‐15, a subunit of the conserved Mediator complex, is also required for oxidative stress responses in nematodes. Specifically, mdt‐15 is required to express SKN‐1 targets upon chemical and genetic increase in SKN‐1 activity. mdt‐15 is also required to express genes in SKN‐1‐dependent and SKN‐1‐independent fashions downstream of insulin/IGF‐1 signaling and for the longevity of daf‐2/insulin receptor mutants. At the molecular level, MDT‐15 binds SKN‐1 through a region distinct from the classical transcription‐factor‐binding KIX‐domain. Moreover, mdt‐15 is essential for the transcriptional response to and survival on the organic peroxide tert‐butyl‐hydroperoxide (tBOOH), a largely SKN‐1‐independent response. The MDT‐15 interacting nuclear hormone receptor, NHR‐64, is specifically required for tBOOH but not arsenite resistance, but NHR‐64 is dispensable for the transcriptional response to tBOOH. Hence, NHR‐64 and MDT‐15's mode of action remain elusive. Lastly, the role of MDT‐15 in oxidative stress defense is functionally separable from its function in fatty acid metabolism, as exogenous polyunsaturated fatty acid complementation rescues developmental, but not stress sensitivity phenotypes of mdt‐15 worms. Our findings reveal novel conserved players in the oxidative stress response and suggest a broad cytoprotective role for MDT‐15.
Biological phenotypes underpin the physio‐somatic symptoms of somatization, depression, and chronic fatigue syndrome
Authors: Anderson G. , Berk M. , Maes M.
Published: August 2013

Objective

Somatization is a symptom cluster characterized by ‘psychosomatic’ symptoms, that is, medically unexplained symptoms, and is a common component of other conditions, including depression and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This article reviews the data regarding the pathophysiological foundations of ‘psychosomatic’ symptoms and the implications that this has for conceptualization of what may more appropriately be termed physio‐somatic symptoms.

Method

This narrative review used papers published in PubMed, Scopus, and Google Scholar electronic databases using the keywords: depression and chronic fatigue, depression and somatization, somatization and chronic fatigue syndrome, each combined with inflammation, inflammatory, tryptophan, and cell‐mediated immune (CMI).

Results

The physio‐somatic symptoms of depression, ME/CFS, and somatization are associated with specific biomarkers of inflammation and CMI activation, which are correlated with, and causally linked to, changes in the tryptophan catabolite (TRYCAT) pathway. Oxidative and nitrosative stress induces damage that increases neoepitopes and autoimmunity that contribute to the immuno‐inflammatory processes. These pathways are all known to cause physio‐somatic symptoms, including fatigue, malaise, autonomic symptoms, hyperalgesia, intestinal hypermotility, peripheral neuropathy, etc.

Conclusion

Biological underpinnings, such as immune‐inflammatory pathways, may explain, at least in part, the occurrence of physio‐somatic symptoms in depression, somatization, or myalgic encephalomyelitis/chronic fatigue syndrome and thus the clinical overlap among these disorders.
Predictive validation of single‐episode uncomplicated depression as a benign subtype of unipolar major depression
Authors: Wakefield J. C. , Schmitz M. F.
Published: August 2013

Objective

To evaluate the predictive validity of a proposed benign major depressive disorder (MDD) subtype, single‐episode ‘uncomplicatedMDD’, defined asMDDthat remits within 6 months and lacks severe impairment, psychotic ideation, suicidal ideation, psychomotor retardation, and feeling worthless.

Method

Using two‐wave National Epidemiologic Survey on Alcohol and Related Conditions data, four groups differing in wave 1 lifetimeMDDhistory (no history [n = 27 609]; single‐episode uncomplicated [n = 418]; other single‐episode [n = 1943]; multiple episode [n = 2473]) were evaluated for 3‐year follow‐up rates of major depressive episode (MDE), generalized anxiety disorder (GAD), and suicide attempt.

Results

Follow‐up rates for no‐MDD‐history, single‐episode uncomplicatedMDD, other single‐episodeMDD, and multiple‐episodeMDD, respectively, were depressive episode 6.1%, 6.9%, 19.5%, 27.1%;GAD2.7%, 4.3%, 7.8%, 11.2%; and suicide attempt 0.3%, 0.1%, 0.8%, 1.7%. For all validators, 3‐year rates for single‐episode uncomplicated cases were not significantly different from no‐MDD‐history rates, but significantly lower than both single‐ and multiple‐episode other‐MDDrates. MildMDD, defined by having only five or six symptoms, did not yield similarly benign results; logistic regression showed ‘uncomplicated’ provides incremental validity over ‘mild’ in explaining validator rates. Validator differences were not explainable by treatment‐rate differences.

Conclusion

Single‐episode uncomplicatedMDDis a benign subtype lacking typicalMDDnegative sequelae. The plannedDSM‐5.1 revision should reinstitute an extended bereavement exclusion applied to all stressors.
When less is more – microRNAs and psychiatric disorders
Authors: Kolshus E. , Dalton V. S. , Ryan K. M. , McLoughlin D. M.
Published: August 2013

Objective

MicroRNAs are small non‐coding RNA molecules that regulate gene expression, including genes involved in neuronal function and plasticity that have relevance for brain function and mental health. We therefore performed a systematic review of miRNAs in general adult psychiatric disorders.

Method

Systematic searches in PubMed/MEDLINE and Web of Science were conducted to identify published clinical articles on microRNAs in general adult psychiatric disorders. We also reviewed references from included articles.

Results

There is mounting evidence of microRNAs’ regulatory roles in a number of central nervous system processes, including neurogenesis and synaptic plasticity. The majority of clinical studies of microRNAs in psychiatric disorders are in schizophrenia, where a number of specific microRNAs have been identified in separate studies. There is some evidence of marked downregulation of some microRNAs in affective disorders. Treatment with antidepressants appears to upregulate microRNA levels. There is currently little evidence from human studies in anxiety, addiction or other psychiatric disorders.

Conclusion

MicroRNA research in psychiatry is currently in a nascent period, but represents an emerging and exciting area, with the potential to clarify molecular mechanisms of disease and identify novel biomarkers and therapeutic agents.
At the bench: the key role of PK–PD modelling in enabling the early discovery of biologic therapies
Authors: Penney Mark , Agoram Balaji
Published: August 2013

Pharmacokinetic–pharmacodynamic (PK–PD) modelling is already used extensively in pre‐clinical and clinical drug development to characterize drug candidates quantitatively, aid go/no‐go decisions and to inform future trial design and optimal dosing regimens. Less well known, although arguably as powerful, is its application at the earliest stages of drug development, at target selection and lead selection, where these same techniques can be used to predict and so bring forward drug candidates with the necessary characteristics or, for unachievable requirements, allow the abandonment of the programme for the minimum spend of time and cost. We consider three examples that illustrate the power of the application of modelling at this early stage. We start with the simple case of determining the optimal characteristics for a monoclonal antibody against a soluble ligand with its application to the investment decision for the development of best‐in‐class compounds. This is extended to the more complex situation of the target protein having an endogenous, inhibitory binding protein. We then illustrate how using physiologically‐based pharmacokinetic modelling enables the appropriate engineering and testing of biological therapeutics for optimal PK–PD characteristics. These examples illustrate how a minimal investment in modelling achieves orders of magnitude better returns in choosing the correct targets, mechanism of action and candidate characteristics to progress to clinical trials, streamlining drug development and delivering better medicines to patients.
Identification and Characterization of New Mechanisms in Vascular Oestrogen Signalling
Authors: Holm Anders , Nilsson Bengt‐Olof
Published: August 2013

Oestrogen exerts vasculoprotective effects in different experimental settings through inhibition of vascular smooth muscle cell proliferation, stimulation of nitric oxide production and attenuation of inflammation. Although these oestrogen‐evoked beneficial effects have been attributed to oestrogen receptor alpha (ERα), also ER beta (ERβ) and the novel ER G protein‐coupled receptor 30 (GPR30)/G protein‐coupled ER1 probably play significant roles in vascular oestrogen signalling. Oestrogen‐evoked vasculoprotective effects are well documented in various experimental models, but the underlying mechanisms are still incompletely understood. The age hypothesis represents an interesting and promising model to explain the discrepancy between experimental data showing beneficial vascular effects of oestrogen treatment and the clinical findings on hormone replacement therapy obtained in big epidemiology surveys, where no protective effect from supplementation with oestrogen is observed. Identification of novel ERs expressed also in the vascular system offers exciting opportunities for the future to find and characterize the mechanisms behind oestrogen‐evoked beneficial effects in vascular health and disease. Importantly, some vascular effects of pharmacological concentrations of oestrogen are ER‐independent, suggesting that oestrogen besides its specific effects through ERα, ERβ and GPR30 also affects vascular function via ER‐independent mechanisms probably reflecting interaction of the hydrophobic oestrogen molecule with cell membrane properties. In this MiniReview, we focus on the importance of these different vascular ER subtypes in health and disease.
The insulin sensitizing effect of topiramate involves KATP channel activation in the central nervous system
Authors: Coomans C P , Geerling J J , van den Berg S A A , van Diepen H C , Garcia‐Tardón N , Thomas A , Schröder‐van der Elst J P , Ouwens D M , Pijl H , Rensen P C N , Havekes L M , Guigas B , Romijn J A
Published: August 2013

Background and Purpose

Topiramate improves insulin sensitivity, in addition to its antiepileptic action. However, the underlying mechanism is unknown. Therefore, the present study was aimed at investigating the mechanism of the insulin‐sensitizing effect of topiramate both in vivo and in vitro.

Experimental Approach

Male C57Bl/6J mice were fed a run‐in high‐fat diet for 6 weeks, before receiving topiramate or vehicle mixed in high‐fat diet for an additional 6 weeks. Insulin sensitivity was assessed by hyperinsulinaemic‐euglycaemic clamp. The extent to which the insulin sensitizing effects of topiramate were mediated through the CNS were determined by concomitant i.c.v. infusion of vehicle or tolbutamide, an inhibitor of ATP‐sensitive potassium channels in neurons. The direct effects of topiramate on insulin signalling and glucose uptake were assessed in vivo and in cultured muscle cells.

Key results

In hyperinsulinaemic‐euglycaemic clamp conditions, therapeutic plasma concentrations of topiramate (∼4 μg·mL−1) improved insulin sensitivity (glucose infusion rate + 58%). Using 2‐deoxy‐D‐[3H]glucose, we established that topiramate improved the insulin‐mediated glucose uptake by heart (+92%), muscle (+116%) and adipose tissue (+586%). Upon i.c.v. tolbutamide, the insulin‐sensitizing effect of topiramate was completely abrogated. Topiramate did not directly affect glucose uptake or insulin signalling neither in vivo nor in cultured muscle cells.

Conclusion and Implications

In conclusion, topiramate stimulates insulin‐mediated glucose uptake in vivo through the CNS. These observations illustrate the possibility of pharmacological modulation of peripheral insulin resistance through a target in the CNS.
Structure–Activity Relationships of New 1‐substitutedmethyl‐4‐[5‐(N‐methyl‐N‐propylamino)pentyloxy]piperidines and Selected 1‐[(N‐substituted‐N‐methyl)‐3‐propyloxy]‐5‐(N‐methy‐l‐N‐propyl)‐pentanediamines as H3‐Antagonists
Authors: Masłowska‐Lipowicz Iwona , Walczyński Krzysztof
Published: August 2013

Novel, potent non‐imidazole histamine H3 receptor antagonists have been prepared and in vitro tested as H3‐receptor antagonists (the electrically evoked contraction of the guinea‐pig jejunum). The present compounds contain a 4‐hydroxypiperidine core, which behaves as a conformationally restricted version of the 3‐amino‐1‐propanol moiety common to the many previously described non‐imidazole H3 ligands. Detailed structure‐activity studies revealed that 1‐(2‐benzofuranylmethyl)‐ 5c (pA2 = 8.47 ± 0.05) and 1‐(3‐benzofuranylmethyl)‐4‐[5‐(N‐methyl‐N‐propyl)pentyloxy]piperidine 5d (pA2 = 8.15 ± 0.07) exhibit high potency for the H3 histamine receptor. In addition, the potency of selected 1‐[(N‐substituted‐N‐methyl)‐3‐propyloxy]‐5‐(N‐methyl‐N‐propyl)pentanediamines as antagonist of the H3 histamine receptor was also evaluated. Replacement of the 4‐hydroxypiperidine of the leads 7 and 5c by a highly flexible 3‐(methylamino)propyloxy chain yields compounds 6a (pA2 = 8.02) and 6b (pA2 = 6.23) with higher and lower potency than their piperidine analogues (7, pA2 = 7.79; 5c, pA2 = 8.47), respectively. The histaminergic H1 antagonism of selected compounds 5c, 5d and 6a has been established on the isolated guinea‐pig ileum by conventional methods; the pA2 values have compared with the potency of pyrilamine. None of them showed any H1‐antagonistic activity (pA2 < 4; for pyrilamine pA2 = 8.5).
Dentist‐specific variation in diagnosis of caries – a multilevel analysis
Authors: Dobloug Andreas , Grytten Jostein , Holst Dorthe
Published: August 2013

Background

There are few studies on practice variation within dentistry. This contrasts with medicine where numerous studies exist. A major finding from the field of medicine is that the size of the physician‐specific effects depends on the degree of uncertainty in diagnosis. The physician‐specific effects are small for diseases where the diagnostic criteria are unambiguous. Conversely, the effects are large for diseases where the diagnostic criteria are less unambiguous.

Objectives

To assess the size of provider‐specific variation in the diagnosis of caries among children and adolescents in Norway and to determine whether this variation depends on uncertainty in diagnosis.

Methods

Data on caries diagnosis for 709 611 children and adolescents aged 6–18 years were analysed using multilevel regression. Level‐1 was patients and level‐2 was public dental officers and dental hygienists. Caries was measured according to the following localization of the lesion: in the outer half of the enamel, in the inner half of the enamel, in the outer third of the dentine, in the middle and inner third of the dentine, to the pulp. The degree of uncertainty in diagnosis is expected to be least the deeper into the dentine the lesion goes. Our sample included 87.5% of all individuals aged 6–18 years.

Results

The provider‐specific variation, measured as the intraclass correlation coefficient, ranged from 15% for caries lesions localized in the outer half of the enamel to 2% for caries to the pulp.

Conclusions

The size of provider‐specific variation in the diagnosis of caries is fairly low. The size of the variability is dependent on the level of diagnostic uncertainty, which is coherent with the practice style hypothesis.
New insights into cell cycle and DNA damage response machineries through high‐resolution AMICO quantitative imaging cytometry
Authors: Tarnok A. , Darzynkiewicz Z.
Published: August 2013

Objective

Progress in biology and medicine research is being driven by development of new instrumentation and associated methodologies which open analytical capabilities that expand understanding of complexity of biological systems. Application of cytometry, which is now widely used in so many disciplines of biology, is the best example of such a progress.

Methodology

Recent publications push the envelope in expanding capabilities of cytometry by introducing a high resolution imaging cytometry defined as Automated Microscopy for Image CytOmetry (AMICO). This instrumentation is utilized to further elucidate mechanisms of the cell cycle progression and also the DNA damage response. This approach is going beyond the presently possible analytical technologies regarding throughput and depth of information.

Conclusions

The possibility of multiparametric analysis combined with the high resolution mapping of individual constituents of cell cycle and DNA damage response machineries provides new tools to probe molecular mechanism of these processes. The capability of analysis of proximity of these constituents to each other offered by AMICO is a novel and potentially important approach that can be used to elucidate mechanisms of other biological processes.
An inductive signalling network regulates mammalian tooth morphogenesis with implications for tooth regeneration
Authors: Li Z. , Yu M. , Tian W.
Published: August 2013

Sequential and reciprocal epithelial–mesenchymal interactions, essential throughout such aspects of tooth morphogenesis as patterning, size and number of teeth, involves a well‐ordered series of inductive and permissive signals that exert global control over cell proliferation, differentiation and organogenesis. In particular, growth factors, transcription factors and their corresponding receptors, as well as other soluble morphogens, make up a regulatory network at the molecular level that synergistically or antagonistically controls intra‐/inter‐cellular signal transduction during odontogenesis. This review summarizes recent advances in the study of crucial signalling pathways, for example of BMPs, Wnt, Notch, Shh and FGF, with emphasis on the potential integrated signalling network responsible for tooth formation. Our work probes into the complexity of these inductive signalling pathways to promote the understanding of tooth regeneration. Additionally, our study provides further insights into therapeutic strategies for various dental abnormalities in patterning and number, such as tooth agenesis and supernumerary teeth.
Test performance characteristics of quantitative nucleic acid testing for polyomaviruses in kidney and kidney‐pancreas transplant recipients
Authors: Myint T.M.M. , Turner R.M. , Craig J.C. , Cross N.B. , Kable K. , Nankivell B.J. , Chapman J.R. , Webster A.C. , O'Connell P. , Dwyer D.E. , Jeoffreys N. , Roger S.D. , Wong G.
Published: August 2013

Screening for polyoma BK virus (BK) using nucleic testing (NAT) is recommended for kidney and kidney‐pancreas transplant recipients, but the performance characteristics of quantitative BK NAT at different thresholds of plasma BK viral loads are unclear. We aim to evaluate the diagnostic accuracy of quantitative BK NAT as an add‐on test to qualitative polyoma NAT for the diagnosis of BK virus‐associated nephropathy (BKVAN) in kidney and kidney transplant recipients. We calculated the test sensitivity, specificity, and predictive values at the different thresholds of plasma BK viral load for BKVAN. At the recommended threshold of >1 × 103 serum BK copies/mL serum for test positivity, the sensitivity for BKVAN was 92.9% (95% confidence intervals [CI]: 66.1–99.8) and specificity 79.1% (95%: CI 67.4–88.1), with corresponding positive and negative predictive values of 42.0% (95% CI: 24.8–57.7%) and 98.6% (95% CI: 98.3–99.9%), respectively. The overall area under curve for the quantitative BK NAT was 0.92 (95% CI: 0.85–0.97). Quantitative BK NAT displays properties of high sensitivity and specificity that are fit for purpose as an add‐on test to qualitative polyomavirus NAT for kidney and kidney‐pancreas transplant recipients at risk of BKVAN.