bluuebunny/crossref_metadata_2025 huggingface dataset:
BRD4 inhibitors block telomere elongation
Authors: Wang Steven , Pike Alexandra M. , Lee Stella S. , Connelly Carla J. , Greider Carol W.
Published: February 2017

Cancer cells maintain telomere length equilibrium to avoid senescence and apoptosis induced by short telomeres, which are triggered by the DNA damage response. Limiting the potential for telomere maintenance in cancer cells has been long been proposed as a therapeutic target. Using an unbiased shRNA screen targeting known kinases, we identified bromodomain 4 (BRD4) as a telomere length regulator. Four independent BRD4 inhibitors blocked telomere elongation, in a dose dependent manner, in mouse cells overexpressing telomerase. Long-term treatment with BRD4 inhibitors caused telomere shortening in both mouse and human cells, suggesting BRD4 plays a role in telomere maintenancein vivo. Telomerase enzymatic activity was not directly affected by BRD4 inhibition. BRD4 is in clinical trials for a number of cancers, but its effects on telomere maintenance have not been previously reported investigated.
Comparative genomics approaches accurately predict deleterious variants in plants
Authors: Kono Thomas J. Y. , Lei Li , Shih Ching-Hua , Hoffman Paul J. , Morrell Peter L. , Fay Justin C.
Published: February 2017

Recent advances in genome resequencing have led to increased interest in prediction of the functional consequences of genetic variants. Variants at phylogenetically conserved sites are of particular interest, because they are more likely than variants at phylogenetically variable sites to have deleterious effects on fitness and contribute to phenotypic variation. Numerous comparative genomic approaches have been developed to predict deleterious variants, but the approaches are nearly always assessed based on their ability to identify known disease-causing mutations in humans. Determining the accuracy of deleterious variant predictions in nonhuman species is important to understanding evolution, domestication, and potentially to improving crop quality and yield. To examine our ability to predict deleterious variants in plants we generated a curated database of 2,910Arabidopsis thalianamutants with known phenotypes. We evaluated seven approaches and found that while all performed well, their relative ranking differed from prior benchmarks in humans. We conclude that deleterious mutations can be reliably predicted inA. thalianaand likely other plant species, but that the relative performance of various approaches does not necessarily translate from one species to another.
Twilightreloaded: the peptide experience
Authors: Weichenberger Christian X. , Pozharski Edwin , Rupp Bernhard
Published: February 2017

Thede factocommoditization of biomolecular crystallography as a result of almost disruptive instrumentation automation and continuing improvement of software allows any sensibly trained structural biologist to conduct crystallographic studies of biomolecules with reasonably valid outcomes: that is, models based on properly interpreted electron density. Robust validation has led to major mistakes in the protein part of structure models becoming rare, but some depositions of protein–peptide complex structure models, which generally carry significant interest to the scientific community, still contain erroneous models of the bound peptide ligand. Here, the protein small-molecule ligand validation toolTwilightis updated to include peptide ligands. (i) The primary technical reasons and potential human factors leading to problems in ligand structure models are presented; (ii) a new method used to score peptide-ligand models is presented; (iii) a few instructive and specific examples, including an electron-density-based analysis of peptide-ligand structures that do not contain any ligands, are discussed in detail; (iv) means to avoid such mistakes and the implications for database integrity are discussed and (v) some suggestions as to how journal editors could help to expunge errors from the Protein Data Bank are provided.
Technological innovation among internationality active SMEs in the Czech economy
Authors: Wadhwa Preeti , McCormick Marleen , Musteen Martina
Published: February 2017

Purpose

This paper aims to examine the impact of human and social capital of CEOs of internationally active small- and medium-sized enterprises (SMEs) in the Czech Republic on their firms’ approach to technological innovation.

Design/methodology/approach

The study sample was drawn from data collected from the population of Czech manufacturing firms. The final sample included 153 SMEs that met the criteria for inclusion in the study. The authors employed robust regression analysis to test their specific hypotheses.

Findings

This study found that human capital (in the form of CEOs’ professional background and foreign customer knowledge) and social capital (conceptualized as embeddedness in the international markets) of CEOs in the Czech Republic impacted their firms’ approach to technological innovation. Specifically, firms headed by CEOs with professional background in output functions (R&D and marketing) are more likely to invest in technological innovation. The same was found true for firms led by CEOs who possessed a strong knowledge of international customers and were socially embedded in international markets.

Originality/value

This study makes a twofold contribution to the extant literature. First, it develops and tests the theoretical link between human and social capital and technological innovation among internationally active firms. Second, it highlights factors that positively influence technological innovation in the context of a small Central European economy, a setting that has been generally viewed as unfavorable to such innovation.
Editing JAT and enabling publication: an afterword
Authors: Abbott Chris
Published: February 2017

Purpose

An afterword from the previous editor of this journal, looking back at what has been notable and ahead to what seem to be likely changes in the future. The paper aims to discuss this issue.

Design/methodology/approach

Overview of key issues in the first ten years of the Journal of Assistive Technologies.

Findings

Some key issues are identified and likely future foci are tentatively suggested.

Originality/value

An editorial perspective.
Corporate hedging, firm focus and firm size: the case of REITs
Authors: Wei Peihwang , Xu Li , Zeng Bei
Published: February 2017

Purpose

The purpose of this paper is to investigate the substitutability of corporate hedging and diversification in the real estate investment trusts (REITs) industry. The authors hypothesize that, relative to diversified firms, focused firms are more likely to be associated with hedging. The role of firm size is also analyzed.

Design/methodology/approach

The logistic regression approach is utilized to analyze the probability of hedging and the panel regression approach is used to examine the amount of hedging.

Findings

The authors find that, relative to diversified firms, firms focused on a single property type are more likely to engage in hedging. However, this finding is significant only for smaller firms, which implies a non-linear relation between hedging and firm size. The evidence is not as strong when firm focus is measured by geographic concentration. In terms of hedging amount, smaller firms’ average hedge ratio is greater than that of larger firms. For either small or large firms group, hedging amounts increase with firm focus measured by either property or geographic concentration and increase with firm sizes.

Research limitations/implications

The results imply that, relative to diversified REITs, REITs focused on a single property type are more likely to engage in hedging. However, this finding is significant only for smaller firms, which implies a non-linear relation between hedging and firm size. The evidence is not as strong when firm focus is measured by geographic concentration, suggesting that geographic concentration is perceived to be less risky than property type concentration. For either small or large firms group, hedging amounts increase with firm focus measured by either property or geographic concentration and increase with firm sizes, which implies that hedging amount does not depend on firm size. The sample period is limited to the years 2010 to 2013 because some data needs to be manually collected.

Practical implications

The results imply that REITs consider both property diversification and hedging in managing their risk.

Originality/value

The research represents an early attempt to investigate the relation between corporate hedging and diversification. The investigation into the REIT industry has several advantages such as a lower likelihood of using derivatives for speculation.
Towards reconnecting: creative formulation and understanding dissociation
Authors: Parry Sarah L. , Lloyd Mike
Published: February 2017

Purpose

The term dissociation can describe a coping strategy to protect oneself against something unwanted in the moment, a disconnection from sensations and experiences in the here and now. Although the more severe experiences of dissociation have been the subject of intense study over the last two decades, much less has been written about clients commonly seen in mental health services with mild to moderate dissociative conditions. Specifically, the purpose of this paper is to attend to therapeutic work with a client who experienced moderate dissociation, which caused disruptions to her autobiographical narrative and sense-of-self.

Design/methodology/approach

This single case design details the therapeutic journey of a Caucasian woman in her early 40s, who experienced moderate dissociation. The report illustrates how the process of creative artwork formulation helped address unwanted dissociative experiences whilst enhancing other coping strategies.

Findings

The client’s personal resources combined with a creative and responsive approach to formulation and reformulation facilitated the process of reconnecting with herself and others through developing awareness of her strengths and past means of coping, finally developing a consistent self-narrative.

Practical implications

The experiences of a creative approach to formulation are discussed in relation to the client’s past traumas and case relevant theory. These preliminary findings suggest creative artwork formulation is an effective tool in terms of developing trust and shared understanding within the therapeutic relationship and meaning making processes throughout therapy.

Originality/value

This case study presents an account of creative artwork formulation used as a method of formulation and reformulation specifically with a client experiencing moderate dissociative experiences following interpersonal traumas. Further, the report discusses the ways in which creative artwork formulation facilitated memory exploration and integration, as well as containing meaning making and healing.
A community hub approach to older people’s housing
Authors: Evans Simon , Atkinson Teresa , Darton Robin , Cameron Ailsa , Netten Ann , Smith Randall , Porteus Jeremy
Published: February 2017

Purpose

The purpose of this paper is to explore the potential of housing with care schemes to act as community hubs. The analysis highlights a range of benefits, barriers and facilitators.

Design/methodology/approach

Data are presented from the Adult Social Services Environments and Settings project which used a mixed methods approach including a review of the literature, surveys and in-depth case study interviews.

Findings

Most housing with care schemes have a restaurant or café, communal lounge, garden, hairdresser, activity room and laundrette, while many also have a library, gym, computer access and a shop. Many of these facilities are open not just to residents but also to the wider community, reflecting a more integrated approach to community health and adult social care, by sharing access to primary health care and social services between people living in the scheme and those living nearby. Potential benefits of this approach include the integration of older people’s housing, reduced isolation and increased cost effectiveness of local services through economies of scale and by maximising preventative approaches to health and wellbeing. Successful implementation of the model depends on a range of criteria including being located within or close to a residential area and having on-site facilities that are accessible to the public.

Originality/value

This paper is part of a very new literature on community hub models of housing with care in the UK. In the light of new requirements under the Care Act to better coordinate community services, it provides insights into how this approach can work and offers an analysis of the benefits and challenges that will be of interest to commissioners and providers as well as planners. This was a small scale research project based on four case studies. Caution should be taken when considering the findings in different settings.
Corporate citizenship and social responsibility policies in the United States of America
Authors: Camilleri Mark Anthony
Published: February 2017

Purpose

The aim of this case study is to outline relevant regulatory guidelines on environmental, social and governance issues in the USA. This contribution includes a thorough analysis of several institutional frameworks and guiding principles that have been purposely developed to foster corporate citizenship behaviours.

Design/methodology/approach

A case study methodology involved a broad analysis of US regulatory policies, voluntary instruments and soft laws that have stimulated organisations to implement and report their responsible behaviours.

Findings

This contribution ties the corporate citizenship behaviours with the institutional and stakeholder theories. The case study evaluated the US’s federal government, bureaus and its agencies’ policies on human rights, health and social welfare, responsible supply chain and procurement of resources, anticorruption, bribery and fraudulent behaviours, energy and water conservation practices as well as environmental protection, among other issues.

Research limitations/implications

Past research may have not sufficiently linked corporate citizenship with the corporate social responsibility (CSR) paradigm. This research reports how different US regulatory institutions and non-governmental organisations are pushing forward the social responsibility, environmental sustainability as well as the responsible corporate governance agenda.

Originality/value

This research critically analyses US policy and regulatory instruments including relevant legislation and executive orders that are primarily intended to unlock corporate citizenship practices from business and industry. It has also provided a conceptual framework for the corporate citizenship notion. In conclusion, it implies that there are business and political cases for corporate citizenship.
Controlling volatility but not growth: firms’ strategic orientations
Authors: Batra Safal
Published: February 2017

Purpose

While a lot is known about organizational growth, little is understood about how to manage volatility that comes along with growth. This paper, using existing research in this area and the empirical findings of a study by Moreno et al. (2014), offers crucial insights about managing volatility for firms trying to grow at the pace of technological changes. An attempt is made to highlight the differences of growth and volatility in a language that is easily comprehensible to practitioners.

Design/methodology/approach

The paper is based on existing literature in the area of growth and on author’s personal interactions with the founders of small firms.

Findings

In this paper, it is argued that firm’s strategic orientations can be used as a contingency of growth–volatility relationship. In other words, firms with a strong entrepreneurial and market orientation are positioned to benefit from the pursuit of growth while still keeping the issues of volatility in control.

Practical implications

By clearly elucidating the concept of volatility and growth, the paper helps practitioners in finding ways of benefiting from growth and controlling unnecessary volatility.

Originality/value

This paper is among the limited research attempts addressing the concept of volatility. The finding that growth and volatility are inter-linked but different can be used effectively by practitioners.
Why a buyer is much more than a cost-killer
Authors: Poissonnier Hugues
Published: February 2017

Purpose

This paper aims to show the evolutions of the missions given to buyers.

Design/methodology/approach

This study uses a historical approach.

Findings

Cost-killing is less and less the more important part of the buyer’s job.

Originality/value

This paper is aimed at showing the importance of alternative missions given to buyers, in addition to the traditional mission consisting in reducing costs. More and more supply security and value creation are considered as more strategic missions for purchasing.
Maximising evolutionary potential in functional proxies for extinct species: a conservation genetic perspective on de‐extinction
Authors: Steeves Tammy E. , Johnson Jeff A. , Hale Marie L.
Published: February 2017

De‐extinction sensu stricto is the resurrection of phenotypic traits once possessed by extinct species to create extant functional proxies. To realise the ecological benefit of de‐extinction, self‐sustaining (genetically viable) populations of functional proxies are required.

It is often implied, yet rarely stated, that the genetic challenges associated with the survival and recovery of extant threatened species in an effort to conserve biodiversity are also relevant to the use of functional proxies of extinct species as a conversation tool.

Here, we highlight the importance of prioritising evolutionary potential − the capacity to evolve (adapt) in response to environmental change − in populations of functional proxies.

We use conservation genetic principles to describe impediments to the creation and maintenance of evolutionary potential as a series of potentially unavoidable genetic bottlenecks (pre‐extinction, resurrection, captive, translocation).

To give any successfully translocated populations of functional proxies the best chance to survive beyond the first few generations in the wild, we advocate the use of a holistic framework that includes the creation of sufficiently large, genetically diverse populations that harbour the ability to adapt to a changing environment.

A lay summary is available for this article.
Student peer teaching in paediatric simulation training is a feasible low‐cost alternative for education
Authors: Wagner Michael , Mileder Lukas P. , Goeral Katharina , Klebermass‐Schrehof Katrin , Cardona Francesco S. , Berger Angelika , Schmölzer Georg M. , Olischar Monika
Published: February 2017

Aim

The World Health Organization recommends regular simulation training to prevent adverse healthcare events. We used specially trained medical students to provide paediatric simulation training to their peers and assessed feasibility, cost and confidence of students who attended the courses.

Methods

Students at the Medical University of Vienna, Austria were eligible to participate. Students attended two high‐fidelity simulation training sessions, delivered by peers, which were videorecorded for evaluation. The attendees then completed questionnaires before and after the training. Associated costs and potential benefits were analysed.

Results

From May 2013 to June 2015, 152 students attended the sessions and 57 (37.5%) completed both questionnaires. Satisfaction was high, with 95% stating their peer tutor was competent and 90% saying that peer tutors were well prepared. The attendees’ confidence in treating critically ill children significantly improved after training (p < 0.001). The average costs for a peer tutor were six Euros per working hour, compared to 35 Euros for a physician.

Conclusion

Using peer tutors for paediatric simulation training was a feasible and low‐cost option that increased the number of medical students who could be trained and increased the self‐confidence of the attendees. Satisfaction with the peer tutors was high.
WNT signalling events near the cell membrane and their pharmacological targeting for the treatment of cancer
Authors: Driehuis Else , Clevers Hans
Published: February 2017

WNT signalling is an essential signalling pathway for all multicellular animals. Although first described more than 30 years ago, new components and regulators of the pathway are still being discovered. Considering its importance in both embryonic development and adult homeostasis, it is not surprising that this pathway is often deregulated in human diseases such as cancer. Recently, it became clear that in addition to cytoplasmic components such as β‐catenin, other, membrane‐bound or extracellular, components of the WNT pathway are also altered in cancer. This review gives an overview of the recent discoveries on WNT signalling events near the cell membrane. Furthermore, membrane‐associated components of the WNT pathway, which are more accessible for therapeutic intervention, as well therapeutic approaches that already target those components will be discussed. In this way, we hope to stimulate the development of effective anti‐cancer therapies that target this fascinating pathway.

Linked Articles

This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc
The NmrA‐like family domain containing 1 pseudogene Loc344887 is amplified in gallbladder cancer and promotes epithelial–mesenchymal transition
Authors: Wu Xiao‐Cai , Wang Shou‐hua , Ou Hong‐hui , Zhu Bing , Zhu Yong , Zhang Qi , Yang Yang , Li Hua
Published: February 2017

The expression pattern and biological role of long non‐coding RNA (lncRNA) in cancer has been reported to be involved in many cancers. Here, we report the expression and biological role of a newly discovered lncRNA NmrA‐like family domain containing 1 pseudogene (Loc344887) in gallbladder cancer (GBC). In this study, we found that the expression of Loc344887 was significantly elevated in GBC tissues and cell lines when compared with matched normal tissues and normal epithelial bile duct cell line, respectively. High Loc344887 was associated with larger tumor size. Loc344887 was upregulated significantly after ectopic expression of nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) in GBC cells. Downregulation of Loc344887 in GBC cells suppressed cell proliferation, blocked cells in G0/S phase, and decreased the migration and invasion cell numbers. In addition, downregulation of Loc344887 decreased the expression of transcription factor Twist, mesenchymal marker Vimentin, and N‐cadherin and increased the expression of epithelial maker E‐cadherin, which could prompt a mesenchymal‐to‐epithelial transition phenotype. These results demonstrated that Loc344887 might contribute to cell proliferation and epithelial‐to‐mesenchymal transition process in GBC, which might be a potential therapeutic target.
Regulatory effects of bone morphogenetic protein‐4 on tumour necrosis factor‐α‐suppressed Runx2 and osteoprotegerin expression in cementoblasts
Authors: Wang Yunlong , He Hong , Cao Zhengguo , Fang Yi , Du Mingyuan , Liu Zhijian
Published: February 2017

Objectives

Root resorption is a common phenomenon presented in periodontitis and orthodontic treatment, both of which are accompanied by an elevated TNF‐α expression level in the periodontal tissues. Previously, we proved that TNF‐α showed an inhibitory effect on cementoblast differentiation, mineralization and proliferation. However, the effect of TNF‐α on Runx2 and osteoprotegerin (OPG) expression remains undetermined. This study aimed to identify the influence of TNF‐α on Runx2 and OPG expression in cementoblasts and to test whether BMP‐2,‐4,‐6,‐7 would affect TNF‐α‐regulated Runx2 and OPG.

Materials and methods

An immortalized murine cementoblast cell line OCCM‐30 was used in this study. The expression of Runx2 and OPG were examined by qRT‐PCR after stimulating cells with TNF‐α. The role of signalling pathways, including MAPK, PI3K‐Akt and NF‐κB, were studied with the use of specific inhibitors. Cells were treated with TNF‐α in combination with BMP‐2,‐4,‐6 or ‐7, then the expression of Runx2 and OPG, the activity of MAPK and NF‐κB pathways, and the proliferation ability were evaluated by qRT‐PCR, Western blot and MTS assay respectively.

Results

TNF‐α inhibited Runx2 and OPG mRNAs in OCCM‐30 cells, and the inhibitory effects were further aggravated by blocking p38 MAPK or NF‐κB pathway. TNF‐α‐inhibited Runx2 and OPG were up‐regulated by BMP‐4. The p38 MAPK and Erk1/2 pathways were further activated by the combined treatment of BMP‐4 and TNF‐α compared with TNF‐α alone. Finally, the TNF‐α‐suppressed proliferation was not obviously affected by BMP‐2,‐4,‐6 or ‐7.

Conclusions

TNF‐α inhibited Runx2 and OPG in cementoblasts, and the p38 MAPK and NF‐κB pathways acted in a negative‐feedback way to attenuate the inhibitory effects. TNF‐α‐inhibited Runx2 and OPG could be effectively up‐regulated by BMP‐4; however, further investigations are needed to fully elaborate the underlying mechanisms.
Safety issues with glucagon‐like peptide‐1 receptor agonists (pancreatitis, pancreatic cancer and cholelithiasis): Data from randomized controlled trials
Authors: Monami Matteo , Nreu Besmir , Scatena Alessia , Cresci Barbara , Andreozzi Francesco , Sesti Giorgio , Mannucci Edoardo
Published: February 2017

Aim

Glucagon‐like peptide 1 receptor agonists (GLP1‐RA) have been associated with an increased risk of pancreatitis and pancreatic cancer. Prior meta‐analyses of randomized controlled trials failed to show any significant increase of risk; however, those meta‐analyses did not include the recently published cardiovascular outcome trials (CVOT) with GLP1‐RA, which provide a substantial additional body of data. The aim of the present meta‐analysis is to assess the effect of GLP1‐RA on pancreatitis, pancreatic cancers and cholelithiasis.

Materials and methods

A Medline search for GLP‐1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide or semaglutide) was performed, collecting all randomized clinical trials with a duration >11 weeks, enrolling patients with type 2 diabetes and comparing a GLP‐1 receptor agonist with placebo or any other non‐GLP‐1 receptor agonist drug.

Results

Of the 113 trials fulfilling inclusion criteria, 13 did not report information on pancreatitis, whereas 72 reported no events in all treatment groups. The incidence of pancreatitis and pancreatic cancer with GLP1‐RA was not significantly different from that observed in comparator arms (MH‐OR [95% CI] 0.93 [0.65‐1.34], P = .71, and 0.94 [0.52‐1.70], P = .84, respectively), whereas, a significantly increased risk of cholelithiasis (MH‐OR [95% CI] 1.30 [1.01‐1.68], P = .041) was detected.

Conclusions

Presently available data confirm the safety of GLP‐1 receptor agonists for pancreatitis. Conversely, therapy with those drugs is associated with an increased risk of cholelithiasis, which deserves further investigation.
Glycogen synthase kinase 3 regulates photic signaling in the suprachiasmatic nucleus
Authors: Paul Jodi R. , McKeown Alex S. , Davis Jennifer A. , Totsch Stacie K. , Mintz Eric M. , Kraft Timothy W. , Cowell Rita M. , Gamble Karen L.
Published: February 2017

Glycogen synthase kinase 3 (GSK3) is a serine‐threonine kinase that regulates mammalian circadian rhythms at the behavioral, molecular and neurophysiological levels. In the central circadian pacemaker, the suprachiasmatic nucleus (SCN), inhibitory phosphorylation of GSK3 exhibits a rhythm across the 24 h day. We have recently shown that GSK3 is capable of influencing both the molecular clock and SCN neuronal activity rhythms. However, it is not known whether GSK3 regulates the response to environmental cues such as light. The goal of this study was to test the hypothesis that GSK3 activation mediates light‐induced SCN excitability and photic entrainment. Immunofluorescence staining in the SCN of mice showed that late‐night light exposure significantly increased GSK3 activity (decreased pGSK3β levels) 30–60 min after the light‐pulse. In addition, pharmacological inhibition of GSK3 blocked the expected light‐induced excitability in SCN neurons; however, this effect was not associated with changes in resting membrane potential or input resistance. Behaviorally, mice with constitutively active GSK3 (GSK3‐KI) re‐entrained to a 6‐h phase advance in the light‐dark cycle in significantly fewer days than WT control animals. Furthermore, the behavioral and SCN neuronal activity of GSK3‐KI mice was phase‐advanced compared to WT, in both normal and light‐exposed conditions. Finally, GSK3‐KI mice exhibited normal negative‐masking behavior and electroretinographic responses to light, suggesting that the enhanced photic entrainment is not due to an overall increased sensitivity to light in these animals. Taken together, these results provide strong evidence that GSK3 activation contributes to light‐induced phase‐resetting at both the neurophysiological and behavioral levels.
Chemogenetic enhancement of functional recovery after a sciatic nerve injury
Authors: Jaiswal Poonam B. , English Arthur W.
Published: February 2017

Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools used to modulate neuronal excitability. We hypothesized that activation of excitatory (Gq) DREADD by its designer ligand, clozapine‐N‐oxide (CNO), would increase the excitability of neurons whose axons have been transected following peripheral nerve injury, and that this increase will lead to an enhanced functional recovery. The lateral gastrocnemius (LG) muscle of adult female Lewis rats was injected unilaterally with AAV9‐ hsyn‐ hM3Dq‐mCherry (7.6 × 109 viral genomes/μL) to transduce Gq‐DREADD expression in LG neurons. The contralateral LG muscle served as an uninjected control. No significant changes in either spontaneous EMG activity or electrically evoked direct muscle (M) responses were found in either muscle after injection of CNO (1 mg/kg, i.p.). The amplitude of monosynaptic H‐reflexes in LG was increased after CNO treatment exclusively in muscles previously injected with virus, suggesting that Gq‐DREADD activation increased neuronal excitability. After bilateral sciatic nerve transection and repair, additional rats were treated similarly with CNO for up to three days after injury. Electrophysiological data were collected at 2, 4 and 6 weeks after injury. Evoked EMG responses were observed as early as 2 weeks after injury only in Gq‐DREADD expressing virus injected LG muscle. By 4 weeks after injury, both M‐response and H‐reflex amplitudes were significantly greater in muscles previously injected with viral vector than contralateral, uninjected muscles. Increases in the excitability of injured neurons produced by this novel use of Gq‐DREADD were sufficient to promote an enhancement in functional recovery after a sciatic nerve injury.
NF‐κB signalling is involved in immune‐modulation, but not basal functioning, of the mouse suprachiasmatic circadian clock
Authors: O'Keeffe S. M. , Beynon A. L. , Davies J. S. , Moynagh P. N. , Coogan A. N.
Published: February 2017

Circadian rhythms are recurring near‐24 hour patterns driven by an endogenous circadian timekeeping system. The master pacemaker in this system is the hypothalamic suprachiasmatic nucleus (SCN). Recently interest has been drawn to how the SCN clock responds to immune system stimulation. A major signalling component in the immune system is nuclear factor (NF)‐κB. In the present study we examined the role of NF‐κB in SCN function. Whilst serum shocked fibroblasts showed rhythmic nuclear localisation of p65 and p65‐dependent transcription, there were no circadian changes in the SCN in expression of the NF‐κB components p65, c‐Rel, p‐IκB or p‐IKK. Chronic treatment with the NF‐κB inhibitor PDTC did not impact on circadian or diurnal rhythms. Phase‐shifting light pulses did not impact on SCN expression of p65, and PDTC treatment did not attenuate the behavioural or molecular response to light pulses. Peripheral treatment with lipopolysaccharide resulted in increased NF‐κB component expression in the SCN. In vitro experiments with SCN slice cultures showed that treatment with NF‐κB inhibitors did not markedly alter rhythmic changes in PER2::LUC expression. Further, SCN slices from nf‐κb::luc mice did not show any evidence for circadian rhythms in NF‐κB‐mediated transcription. Experiments utilising older mice (~16 months old) showed that SCN treatment in vitro with PDTC resulted in increased amplitude of rhythmic PER2::LUC expression, and LPS treatment resulted in altered PER2::LUC rhythm acrophase. Overall, we interpret our results as providing evidence for the involvement of NF‐κB in the suprachiasmatic circadian clock following immune stimulation, but not under basal conditions.
Effect on cardiovascular disease risk factors of interventions to alter consultations between practitioners and patients with type 2 diabetes: A systematic review and meta‐analysis of trials in primary care
Authors: Dambha‐Miller Hajira , Cooper Andrew J. M. , Kinmonth Ann Louise , Griffin Simon J.
Published: February 2017

Objective

To examine the effect on cardiovascular (CVD) risk factors of interventions to alter consultations between practitioners and patients with type 2 diabetes.

Search Strategy

Electronic and manual citation searching to identify relevant randomized controlled trials (RCTs).

Inclusion Criteria

RCTs that compared usual care to interventions to alter consultations between practitioners and patients. The population was adults aged over 18 years with type 2 diabetes. Trials were set in primary care.

Data extraction and synthesis

We recorded if explicit theory‐based interventions were used, how consultations were measured to determine whether interventions had an effect on these and calculated weighted mean differences for CVD risk factors including glycated haemoglobin (HbA1c), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), LDL cholesterol (LDL‐C) and HDL cholesterol (HDL‐C).

Results

We included seven RCTs with a total of 2277 patients with type 2 diabetes. A range of measures of the consultation was reported, and underlying theory to explain intervention processes was generally undeveloped and poorly applied. There were no overall effects on CVD risk factors; however, trials were heterogeneous. Subgroup analysis suggested some benefit among studies in which interventions demonstrated impact on consultations; statistically significant reductions in HbA1c levels (weighted mean difference, −0.53%; 95% CI: [−0.77, −0.28]; P<.0001; I2=46%).

Conclusions

Evidence of effect on CVD risk factors from interventions to alter consultations between practitioners and patients with type 2 diabetes was heterogeneous and inconclusive. This could be explained by variable impact of interventions on consultations. More research is required that includes robust measures of the consultations and better development of theory to elucidate mechanisms.
Acute Cardiac MRI Assessment of Radiofrequency Ablation Lesions for Pediatric Ventricular Arrhythmia: Feasibility and Clinical Correlation
Authors: GRANT ELENA K. , BERUL CHARLES I. , CROSS RUSSELL R. , MOAK JEFFREY P. , HAMANN KARIN S. , SUMIHARA KOHEI , CRONIN ILEEN , O'BRIEN KENDALL J. , RATNAYAKA KANISHKA , HANSEN MICHAEL S. , KELLMAN PETER , OLIVIERI LAURA J.
Published: February 2017

Acute Pediatric VT Ablation Cardiac MRI Assessment

Background

Arrhythmia ablation with current techniques is not universally successful. Inadequate ablation lesion formation may be responsible for some arrhythmia recurrences. Periprocedural visualization of ablation lesions may identify inadequate lesions and gaps to guide further ablation and reduce risk of arrhythmia recurrence.

Methods

This feasibility study assessed acute postprocedure ablation lesions by MRI, and correlated these findings with clinical outcomes. Ten pediatric patients who underwent ventricular tachycardia ablation were transferred immediately postablation to a 1.5T MRI scanner and late gadolinium enhancement (LGE) imaging was performed to characterize ablation lesions. Immediate and mid‐term arrhythmia recurrences were assessed.

Results

Patient characteristics include median age 14 years (1–18 years), median weight 52 kg (11–81 kg), normal cardiac anatomy (n = 6), d‐transposition of great arteries post arterial switch repair (n = 2), anomalous coronary artery origin post repair (n = 1), and cardiac rhabdomyoma (n = 1). All patients underwent radiofrequency catheter ablation of ventricular arrhythmia with acute procedural success. LGE was identified at the reported ablation site in 9/10 patients, all arrhythmia‐free at median 7 months follow‐up. LGE was not visible in 1 patient who had recurrence of frequent premature ventricular contractions within 2 hours, confirmed on Holter at 1 and 21 months post procedure.

Conclusions

Ventricular ablation lesion visibility by MRI in the acute post procedure setting is feasible. Lesions identifiable with MRI may correlate with clinical outcomes. Acute MRI identification of gaps or inadequate lesions may provide the unique temporal opportunity for additional ablation therapy to decrease arrhythmia recurrence.
Predictive value of plasma copeptin level for the risk and mortality of heart failure: a meta‐analysis
Authors: Yan Jian‐Jun , Lu Ying , Kuai Zheng‐Ping , Yong Yong‐Hong
Published: February 2017

Epidemiologic studies are inconsistent regarding the association between plasma copeptin level and heart failure (HF). The aim of this study was to perform a meta‐analysis to determine whether high level of copeptin is correlated with incidence of HF and mortality in patients with HF. We searched PUBMED and EMBASE databases for studies conducted from 1966 through May 2016 to identify studies reporting hazard ratio (HR) estimates with 95% confidence intervals (CIs) for the association between plasma copeptin level and HF. A random‐effects model was used to combine study‐specific risk estimates. A total of 13 studies were included in the meta‐analysis, with five studies on the incidence of HF and eight studies on the mortality of patients with HF. For incidence of HF, the summary HR indicated a borderline positive association of high plasma copeptin level with HF risk (HR, 1.60; 95% CI, 0.90–2.85). Furthermore, an increase of 1 standard deviation in log copeptin level was associated with a 17% increase in the risk of incident HF (HR, 1.17; 95% CI, 1.02–1.33). For all‐cause mortality of patients with HF, we also found a significant association between elevated plasma copeptin level and increased mortality of HF (HR, 1.76; 95% CI, 1.33–2.33). Our dose–response analysis indicated that an increment in copeptin level of 1 pmol/l was associated with a 3% increase in all‐cause mortality (HR, 1.03; 95% CI, 1.01–1.05). In conclusion, our results suggest that elevated plasma copeptin level is associated with an increased risk of HF and all‐cause mortality in patients with HF.
Salvianolic acid B regulates gene expression and promotes cell viability in chondrocytes
Authors: Yang Xiaohong , Liu Shaojie , Li Siming , Wang Pengzhen , Zhu Weicong , Liang Peihong , Tan Jianrong , Cui Shuliang
Published: February 2017

Articular chondrocytes reside in lacunae distributed in cartilage responsible for the remodelling of the tissue with limited ability of damage repairing. The in vitro expanded chondrocytes enhanced by factors/agents to obtain large numbers of cells with strengthened phenotype are essential for successful repair of cartilage lesions by clinical cell implantation therapies. Because the salvianolic acid B (Sal B), a major hydrophilic therapeutic agent isolated from Salvia miltiorrhiza, has been widely used to treat diseases and able to stimulate activity of cells, this study examines the effects of Sal B on passaged chondrocytes. Chondrocytes were treated with various concentrations of Sal B in monolayer culture, their morphological properties and changes, and mitochondrial membrane potential were analysed using microscopic analyses, including cellular biochemical staining and confocal laser scanning microscopy. The proteins were quantified by BCA and Western blotting, and the transcription of genes was detected by qRT‐PCR. The passaged chondrocytes treated with Sal B showed strengthened cellular synthesis and stabilized mitochondrial membrane potential with upregulated expression of the marker genes for chondrocyte phenotype, Col2‐α1, Acan and Sox9, the key Wnt signalling molecule β‐catenin and paracrine cytokine Cytl‐1. The treatments using CYTL‐1 protein significantly increased expression of Col2‐α1 and Acan with no effect on Sox9, indicating the paracrine cytokine acts on chondrocytes independent of SOX9. Sal B has ultimately promoted cell growth and enhanced chondrocyte phenotype. The chondrocytes treated with pharmaceutical agent and cytokine in the formulated medium for generating large number of differentiated chondrocytes would facilitate the cell‐based therapies for cartilage repair.
Peripheral viral challenge elevates extracellular glutamate in the hippocampus leading to seizure hypersusceptibility
Authors: Hunsberger Holly C. , Konat Gregory W. , Reed Miranda N.
Published: February 2017

Peripheral viral infections increase seizure propensity and intensity in susceptible individuals. We have modeled this comorbidity by demonstrating that the acute phase response instigated by an intraperitoneal (i.p.) injection of a viral mimetic, polyinosinic‐polycytidylic acid (PIC), induces protracted hypersusceptibility to kainic acid‐induced seizures. We have further demonstrated that PIC challenge robustly increases the level of tonic extracellular glutamate and neuronal excitability in the hippocampus. This study was undertaken to determine a relationship between tonic glutamate and seizure susceptibility following PIC challenge. Briefly, glutamate‐sensing microelectrodes were permanently implanted into the CA1 of 8‐week‐old female C57BL/6 mice. Following a 3‐day recovery, acute phase response was induced by i.p. injection of 12 mg/kg of PIC, while saline‐injected mice served as controls. Tonic glutamate was measured at 1, 2, 3 and 4 days after PIC challenge. PIC challenge induced an approximately fourfold increase in tonic glutamate levels measured after 24 h. The levels gradually declined to the baseline values within 4 days. Twenty‐four hours after PIC challenge, the mice featured an approximately threefold increase in cumulative seizure scores and twofold increase in the duration of status epilepticus induced by subcutaneous injection of 12 mg/kg of kainic acid. Seizure scores positively correlated with pre‐seizure tonic glutamate. Moreover, seizures resulted in a profound (76%) elevation of extracellular glutamate in the CA1 of PIC‐challenged but not saline‐injected mice. Our results implicate the increase in extracellular glutamate as a mediator of seizure hypersusceptibility induced by peripheral viral challenge.

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Are They Not Worthy? How Partisan Political Blogs Legitimize the Tea Party Movement and Occupy Wall Street
Authors: Laschever Eulalie
Published: February 2017

Social movements struggle to gain acceptance as legitimate actors so that they can raise money, recruit members, and convince politicians to meet their demands. We know little, however, about how this legitimacy is granted by various political authorities, in part because legitimacy is often poorly operationalized. To operationalize legitimacy, I revise Charles Tilly's () classic concept of WUNC displays (i.e., public presentations of worthiness, unity, numbers, commitment) to assess how political authorities legitimize social movements. I analyze original data on the coverage the Tea Party and Occupy Wall Street received from 20 elite political blogs during a critical event early in each movement's development. I find that liberal and conservative blogs both use the same aspects of worthiness (and not unity, numbers, or commitment) to endorse their preferred movement but different aspects of unworthiness to denounce the movement they opposed. Conservative outlets were more partisan on both accounts. This suggests that these blogs' shared status as distinctly partisan political outsiders produces a similar, but not identical, relationship with social movements. While both sets of blogs legitimize and delegitimize a movement based on its specific strengths and weaknesses, conservative blogs act more as a partisan bullhorn and liberal blogs act more as a forum for debate.
Do foreign workers reduce trade barriers? Microeconomic evidence
Authors: Andrews Martyn , Schank Thorsten , Upward Richard
Published: February 2017

This paper provides evidence that foreign workers reduce firms’ trade costs and thus increase the probability that firms export. This informs both the literature on trade costs and the microeconomic literature on firms’ export behaviour. We identify the nationality of each worker in a large sample of German establishments and relate this to the exporting behaviour of these establishments. We allow for the possible endogeneity of an establishment's workforce by instrumenting the share of foreign workers with the regional distribution of foreign workers in the wider labour market. We find a significant effect of worker nationality on exporting which is not driven by the industrial, occupational or locational concentration of migrants. The effect is much stronger for senior occupations, who are more likely to have a role in exporting decisions by the establishment. The relationship is also stronger when we consider exports to particular regions and workers from these regions, consistent with a gravity model in which trade flows from country i to j are a function of migrants from j in i.
Feasibility of using respiration‐averaged MR images for attenuation correction of cardiac PET/MR imaging
Authors: Ai Hua , Pan Tinsu
Published: February 2017

Cardiac imaging is a promising application for combined PET/MR imaging. However, current MR imaging protocols for whole‐body attenuation correction can produce spatial mismatch between PET and MR‐derived attenuation data owing to a disparity between the two modalities' imaging speeds. We assessed the feasibility of using a respiration‐averaged MR (AMR) method for attenuation correction of cardiac PET data in PET/MR images. First, to demonstrate the feasibility of motion imaging with MR, we used a 3T MR system and a two‐dimensional fast spoiled gradient‐recalled echo (SPGR) sequence to obtain AMR images of a moving phantom. Then, we used the same sequence to obtain AMR images of a patient's thorax under free‐breathing conditions. MR images were converted into PET attenuation maps using a three‐class tissue segmentation method with two sets of predetermined CT numbers, one calculated from the patient‐specific (PS) CT images and the other from a reference group (RG) containing 54 patient CT datasets. The MR‐derived attenuation images were then used for attenuation correction of the cardiac PET data, which were compared to the PET data corrected with average CT (ACT) images. In the myocardium, the voxel‐by‐voxel differences and the differences in mean slice activity between the AMR‐corrected PET data and the ACT‐corrected PET data were found to be small (less than 7%). The use of AMR‐derived attenuation images in place of ACT images for attenuation correction did not affect the summed stress score. These results demonstrate the feasibility of using the proposed SPGR‐based MR imaging protocol to obtain patient AMR images and using those images for cardiac PET attenuation correction. Additional studies with more clinical data are warranted to further evaluate the method.

PACS number: 87.57.uk