bluuebunny/crossref_metadata_2025 huggingface dataset:
New insights into PGC‐1 coactivators: redefining their role in the regulation of mitochondrial function and beyond
Authors: Villena Josep A.
Published: December 2014

Members of the PGC‐1 family of coactivators have been revealed as key players in the regulation of energy metabolism. Early gain‐ and loss‐of‐function studies led to the conclusion that all members of the PGC‐1 family (PGC‐1α, PGC‐1β and PRC) play redundant roles in the control of mitochondrial biogenesis by regulating overlapping gene expression programs. Regardless of this, all PGC‐1 coactivators also appeared to differ in the stimuli to which they respond to promote mitochondrial gene expression. Although PGC‐1α was found to be induced by different physiological or pharmacological cues, PGC‐1β appeared to be unresponsive to such stimuli. Consequently, it has long been widely accepted that PGC‐1α acts as a mediator of mitochondrial biogenesis induced by cues that signal high‐energy needs, whereas the role of PGC‐1β is restricted to the maintenance of basal mitochondrial function. By contrast, the function of PRC appears to be restricted to the regulation of gene expression in proliferating cells. However, recent studies using tissue‐specific mouse models that lack or overexpress different PGC‐1 coactivators have provided emerging evidence not only supporting new roles for PGC‐1s, but also redefining some of the paradigms related to the precise function and mode of action of PGC‐1 coactivators in mitochondrial biogenesis. The present review discusses some of the new findings regarding the control of mitochondrial gene expression by PGC‐1 coactivators in a tissue‐specific context, as well as newly‐uncovered functions of PGC‐1s beyond mitochondrial biogenesis, and their link to pathologies, such as diabetes, muscular dystrophies, neurodegenerative diseases or cancer.
Frequent co‐inactivation of the SWI/SNF subunits SMARCB1, SMARCA2 and PBRM1 in malignant rhabdoid tumours
Authors: Rao Qiu , Xia Qiu‐yuan , Wang Zi‐yu , Li Li , Shen Qin , Shi Shan‐shan , Wang Xuan , Liu Biao , Wang Yan‐fen , Shi Qun‐li , Ma Heng‐hui , Lu Zhen‐feng , He Yan , Zhang Ru‐song , Yu Bo , Zhou Xiao‐jun
Published: December 2014

Aims

Malignant rhabdoid tumours (MRTs) are highly aggressive malignancies of early infancy characterized by inactivation of SMARCB1, a core member of the SWI/SNF chromatin‐remodelling complex. The aim of this study was to explore the status of multiple key subunits of the SWI/SNF complex in MRTs.

Methods and results

We screened the key subunits of the SWI/SNF complex, including SMARCB1, SMARCA2, PBRM1, SMARCA4, and ARID1A, in four MRTs by immunohistochemistry, sequencing, and fluorescence in‐situ hybridization (FISH). Complete loss of SMARCB1, SMARCA2 and PBRM1 expression and corresponding mutations in the same genes were observed in all cases. The mutations included seven missense, three same‐sense, four frameshift and two truncating mutations. FISH revealed heterozygous deletion of SMARCB1 in one case, and monoploidy of chromosome 22, which harbours SMARCB1, in another case. Furthermore, trisomy of chromosome 9, which harbours SMARCA2, was observed in two cases. Abnormality of PBRM1 was not found in any case.

Conclusions

We report, for the first time, co‐inactivation and frequent mutations of SMARCB1, SMARCA2 and PBRM1 in MRTs. Multiple subunit abnormalities of the SWI/SNF complex potentially act together to contribute to the tumorigenesis of MRTs, which provides unique insights into this disease.
Stability of coagulation proteins in lyophilized plasma
Authors: Jennings I. , Kitchen D. P. , Woods T. A. L. , Kitchen S. , Preston F. E. , Walker I. D.
Published: December 2014

Introduction

External quality assessment (EQA) is an important component of quality assurance for laboratory tests of haemostasis. Lyophilization of plasma confers stability of labile clotting factors, allowing valid comparison of results between participating centres. However, elevated ambient temperatures in some geographical areas could affect the stability of lyophilized samples in transit.

Methods

The effect on lyophilized plasma samples of consistent elevated temperature with respect to haemostasis tests was determined in a single centre. The temperature to which packages were exposed during transit was also monitored.

Results

Survey packages were exposed to average temperatures up to 31.9 °C and maximum temperatures up to 39.7 °C over delivery periods between 1 and 8 weeks. In‐house studies revealed samples to be stable over a 6‐week period at a constant 30 °C, and only small changes were observed for samples exposed to 37 °C for 4 weeks. 6‐week storage at 37 °C was associated with average changes of up to 15% in factor assay activity.

Conclusion

Lyophilized EQA material employed in UK NEQAS surveys is stable under conditions encountered for the majority of participants, but in cases of delayed delivery of samples, the effect of temperature on sample integrity must be considered when assessing laboratory performance.
Star CEOs or Political Connections? Evidence from China's Publicly Traded Firms
Authors: Conyon Martin J. , He Lerong , Zhou Xin
Published: December 2014

This paper studies China's “star CEOs” defined as members of the National People's Congress (NPC) or the National Committee of the Chinese People's Political Consultative Conference (CPPCC) and “politically connected” CEOs who have previous government or military experience. We evaluate the effect of “star CEOs” and “politically connected” CEOs on firm performance and CEO compensation. We find that announcement date returns, CEO compensation and incentives are all higher in firms that appoint “star CEOs”. However, the mechanism explaining these various premiums is largely political connectedness of these star CEOs. Our study finds only modest evidence that star‐CEO status directly determines firm performance. Our analysis strongly suggests that compensation and performance premiums are mostly driven by CEO political connections, as opposed to CEO talent/star effects.
Bergmann meets Scholander: geographical variation in body size and insulation in the koala is related to climate
Authors: Briscoe Natalie J. , Krockenberger Andrew , Handasyde Kathrine A. , Kearney Michael R.
Published: December 2014

Aim

Body size often varies clinally, with dominant explanations centred on how body size influences heat exchange (e.g. Bergmann's rule). However, for endotherms, pelage properties can also dramatically alter heat exchange – a point emphasized by Scholander in the 1950s but which has received little attention in biogeographical analyses. Here, we investigate how geographical variation in both body size and fur properties of the koala (Phascolarctos cinereus) is related to climate.

Location

Eastern Australia.

Methods

We measured head length and fur depths of koala museum specimens from across its geographical range, and quantified the relationship between fur depth and insulation. We used linear regression and regression tree analyses to test for associations between morphological traits and climate variables relating to four hypotheses: heat conservation (Bergmann's rule), heat dissipation, fasting endurance/survival of extremes, and productivity.

Results

Both body size and fur depth of koalas decrease substantially towards the tropics. Consistent with Scholander's view, fur properties showed stronger associations with climate than body size. Males, the larger sex, had shorter fur than females in hot environments but not in more temperate regions, suggesting that shorter fur compensates for sexual size dimorphism. While fur depth and male body size were more strongly associated with variables relating to heat dissipation, female body size was most strongly associated with minimum temperatures.

Main conclusions

Body size interacts strongly with other traits, such as fur properties, to influence how animals experience climate. Our results emphasize how the consideration of geographical variation in suites of functionally related traits can provide important insight into how species persist across broad environmental gradients.
Carbon Monoxide and Nitric Oxide interactions in Magnocellular Neurosecretory Neurones during Water Deprivation
Authors: Reis W. L. , Biancardi V. C. , Son S. , Antunes‐Rodrigues J. , Stern J. E.
Published: December 2014

Nitric oxide (NO) and carbon monoxide (CO) are diffusible gas messengers in the brain. Previously, we have shown their independent involvement in central fluid/electrolyte homeostasis control. In the present study, we investigated a possible functional interaction between NO/CO in the regulation of vasopressin (VP) and oxytocin (OT) magnocellular neurosecretory cells (MNCs) activity in euhydrated (EU) and dehydrated [48‐h water‐deprived (48WD)] rats. Using brain slices from EU and 48WD rats, we measured, by immunohistochemistry, the expression of neuronal NO synthase (nNOS, which synthesises NO) and haeme‐oxygenase (HO‐1, which synthesises CO) in the hypothalamic supraoptic nucleus (SON). In addition, we used patch‐clamp electrophysiology to investigate whether regulation of SON MNC firing activity by endogenous CO was dependent on NO bioavailability and GABAergic inhibitory synaptic function. We found a proportion of OT and VP SON MNCs in EU rats to co‐express both of HO‐1 and nNOS (33.2 ± 2.9% and 15.3 ± 1.4%, respectively), which was increased in 48WD rats (55.5 ± 0.9% and 21.0 ± 1.7%, respectively, P < 0.05 for both). Inhibition of endogenous HO activity [chromium mesoporphyrin IX chloride (CrMP) 20 μm] induced MNC membrane hyperpolarisation and decreased firing activity, and these effects were blunted by previous blockade of endogenous NOS activity (l‐NAME, 2 mm) or blockade of inhibitory GABA function [Picrotoxin (Sigma‐Aldrich, St Louis, MO, USA), 50 μm]. No significant changes in SON NO bioavailability (4,5 diaminofluorescein diacetate fluorescence) were observed after CrMP treatment. Taken together, our results support a state‐dependent functional inter‐relationship between NO and CO in MNCs, in which CO acts as an excitatory gas molecule, whose effects are largely dependent on interactions with the inhibitory SON signals NO and GABA.
Retrospective Analysis of Interobserver Spatial Variability in the Localization of Broca's and Wernicke's Areas Using Three Different fMRI Language Paradigms
Authors: Black David F. , DeLone David R. , Kaufmann Timothy J. , Fitz‐Gibbon Patrick D. , Carter Rickey E. , Machulda Mary M. , Welker Kirk M.
Published: December 2014

PURPOSE

To determine interobserver spatial variability in language area localization using three commonly employed language tasks.

MATERIALS AND METHODS

With institutional review board approval, 125 fMRI time series from 50 different clinical language cases were retrospectively reviewed by three blinded readers who selected 3‐dimensional points representing the perceived center of Wernicke's and Broca's areas using three language tasks (semantic decision, SD; sentence comprehension, SC; and silent word generation, WG). Point dispersion values were then calculated using the perimeter of the 3‐dimensional triangle defined by the three readers’ selections.

RESULTS

After resolving interobserver laterality disagreements, there was no difference in spatial variability between the three tasks (P = .069). The SD task had the fewest interobserver laterality disagreements (P = .028) and the SC task had fewer failed localizations for Broca's area (P = .050) and Wernicke's area (P = .013).

CONCLUSION

While there were no differences between interobserver spatial variability in language area localization between the three tasks, language task choice impacts the accuracy of fMRI language area identification because tasks vary in their rates of interobserver laterality disagreements and failed localizations. A combination of tasks including one with low laterality disagreements (eg, SD) and one with few failed localizations (eg, SC) may offer the best combination.
1α,25‐dihydroxyvitamin D3 promotes osteogenic activity and downregulates proinflammatory cytokine expression in human periodontal ligament cells
Authors: Nebel D. , Svensson D. , Arosenius K. , Larsson E. , Jönsson D. , Nilsson B.‐O.
Published: December 2014

Background and Objective

The aim of this study was to assess the impact of 1α,25‐dihydroxyvitamin D3 (vitamin D3) on osteogenic and inflammatory properties of human periodontal ligament (PDL) cells and investigate underlying mechanisms.

Material and Methods

Human PDL cells, obtained from four subjects, were stimulated with vitamin D3 for 4–48 h. The bone markers osteopontin and osteocalcin and proinflammatory cytokine/chemokine expression was determined by quantitative real‐time polymerase chain reaction and enzyme‐linked immunosorbent assay. Cytokine and chemokine expression was determined after stimulation with the inflammation promoter lipopolysaccharide (LPS) in the presence or absence of vitamin D3. Alkaline phosphatase activity was assessed using p‐nitrophenylphosphate substrate.

Results

Treatment with 30 ng/mL of vitamin D3, corresponding to an optimal plasma concentration of vitamin D, for 24 h had no effect on PDL cell number and morphology but increased PDL cell osteopontin and osteocalcin mRNA expression by about 70 and 40%, respectively, and, moreover, treatment with vitamin D3 for 48 h enhanced PDL cell alkaline phosphatase activity by about two times showing that vitamin D3 exerts pro‐osteogenic effects in human PDL cells. Stimulation with LPS (1 μg/mL) for 4 h increased PDL cell interleukin (IL)‐6 cytokine and chemokine ligand 1 (CXCL1) chemokine mRNA expression several fold. The LPS‐induced increase in IL‐6 and CXCL1 transcripts was attenuated by vitamin D3 (30 ng/mL). Treatment with vitamin D3 (3–300 ng/mL) for 24 h reduced the LPS‐evoked increase in PDL cell IL‐6 protein by about 50%. Vitamin D3 (30 ng/mL) had no effect on LPS‐induced IL‐1β and MCP‐1 mRNA expression.

Conclusions

Vitamin D3 promotes osteogenic differentiation but also downregulates inflammation promoter‐induced IL‐6 cytokine and CXCL1 chemokine expression in human PDL cells, suggesting that vitamin D3 both stimulates bone regeneration and antagonizes inflammation in human periodontal tissue.
A novel non‐surgical, minimally invasive technique for parathyroid autotransplantation: A case report
Authors: Aysan Erhan , Kilic Ulkan , Gok Ozlem , Altug Burcugul , Ercan Cilem , Idiz Ufuk Oguz , Kesgin Cemile , Muslumanoglu Mahmut
Published: December 2014

We present a case report of intramuscular autotransplantation of the parathyroid cell suspension acquired after total parathyroidectomy. A 15‐yr‐old female patient who had been undergoing hemodialysis due to chronic renal failure for eight yr was diagnosed with secondary hyperthyroidism and subsequently underwent total parathyroidectomy. The parathyroid cells were acquired from the resected tissues, processed through isolation and cultivation phases, and counted using a cell counter. A total of two million cells were injected into the left deltoid muscle using a 22‐gauge needle. After surgery, five and 10 million cells were injected in the fifth and 12 week, respectively. The desired serum levels of parathyroid hormones and calcium were not achieved after the first two transplantations. In addition, there was no regression in the patient's symptoms. However, at four wk after the third transplantation, serum parathyroid hormone level did not decrease to <3 pg/mL, the patient was asymptomatic, and the oral treatment was stopped. Our findings indicate that this new technique is applicable because it is minimally invasive, and it can be easily repeated.
Effects of FGF10 on Bovine Oocyte Meiosis Progression, Apoptosis, Embryo Development and Relative Abundance of Developmentally Important Genes In Vitro
Authors: Pomini Pinto RF , Fontes PK , Loureiro B , Sousa Castilho AC , Sousa Ticianelli J , Montanari Razza E , Satrapa RA , Buratini J , Moraes Barros C
Published: December 2014

Contents

Fibroblast growth factor (FGF10) acts at the cumulus oocyte complex, increasing the expression of cumulus cell expansion‐related genes and oocyte competency genes. We tested the hypothesis that addition of FGF10 to the maturation medium improves oocyte maturation, decreases the percentage of apoptotic oocytes and increases development to the blastocyst stage while increasing the relative abundance of developmentally important genes (COX2, CDX2 and PLAC8). In all experiments, oocytes were matured for 22 h in TCM‐199 supplemented with 0, 2.5, 10 or 50 ng/ml FGF10. In Experiment 1, after maturation, oocytes were stained with Hoechst to evaluate meiosis progression (metaphase I, intermediary phases and extrusion of the first polar body) and submitted to the TUNEL assay to evaluate apoptosis. In Experiment 2, oocytes were fertilized and cultured to the blastocyst stage. Blastocysts were frozen for analysis of COX2, CDX2 and PLAC8 relative abundance. In Experiment 1, 2.5 ng/ml FGF10 increased (p < 0.05) the percentage of oocytes with extrusion of the first polar body (35%) compared to 0, 10 and 50 ng/ml FGF10 (21, 14 and 12%, respectively) and FGF10 decreased the percentage of oocytes that were TUNEL positive in all doses studied. In Experiment 2, there was no difference in the percentage of oocytes becoming blastocysts between treatments and control. Real‐time RT‐PCR showed a tendency of 50 ng/ml FGF10 to increase the relative abundance of COX2 and PLAC8 and of 10 ng/ml FGF10 to increase CDX2. In conclusion, the addition of FGF10 to the oocyte maturation medium improves oocyte maturation in vitro, decreases the percentage of apoptotic oocytes and tends to increase the relative abundance of developmentally important genes.
Determinantal Point Process Models and Statistical Inference
Authors: Lavancier Frédéric , Møller Jesper , Rubak Ege
Published: December 2014

Statistical models and methods for determinantal point processes (DPPs) seem largely unexplored. We demonstrate that DPPs provide useful models for the description of spatial point pattern data sets where nearby points repel each other. Such data are usually modelled by Gibbs point processes, where the likelihood and moment expressions are intractable and simulations are time consuming. We exploit the appealing probabilistic properties of DPPs to develop parametric models, where the likelihood and moment expressions can be easily evaluated and realizations can be quickly simulated. We discuss how statistical inference is conducted by using the likelihood or moment properties of DPP models, and we provide freely available software for simulation and statistical inference.
Bayesian Non-Parametric Models for Spatially Indexed Data of Mixed Type
Authors: Papageorgiou Georgios , Richardson Sylvia , Best Nicky
Published: December 2014

We develop Bayesian non-parametric models for spatially indexed data of mixed type. Our work is motivated by challenges that occur in environmental epidemiology, where the usual presence of several confounding variables that exhibit complex interactions and high correlations makes it difficult to estimate and understand the effects of risk factors on health outcomes of interest. The modelling approach that we adopt assumes that responses and confounding variables are manifestations of continuous latent variables and uses multivariate Gaussian distributions to model these jointly. Responses and confounding variables are not treated equally as relevant parameters of the distributions of the responses only are modelled in terms of explanatory variables or risk factors. Spatial dependence is introduced by allowing the weights of the non-parametric process priors to be location specific, obtained as probit transformations of Gaussian Markov random fields. Confounding variables and spatial configuration have a similar role in the model, in that they influence, along with the responses, only the allocation probabilities of the areas into the mixture components, thereby allowing for flexible adjustment of the effects of observed confounders, while allowing for the possibility of residual spatial structure, possibly occurring because of unmeasured or undiscovered spatially varying factors. Aspects of the model are illustrated in simulation studies and an application to a real data set.
DEBATE: Should Dialysis at Home be Mandatory for All Suitable ESRD Patients?
Authors: Lewicki Michelle C. , Polkinghorne Kevan R. , Kerr Peter G.
Published: December 2014

Since their inception in the 1960s, home‐based dialysis therapies have been viable alternatives to conventional thrice weekly in center hemodialysis. In spite of this, uptake of these therapies has been steadily declining over past decades with utilization varying globally; dependent on training support, funding models, and prevailing Nephrologist beliefs. In the Australian context, home dialysis (predominantly peritoneal dialysis and extended hours nocturnal hemodialysis) is now again increasing in popularity—with enthusiasm driven not only by evidence of an array of physiological and psychological patient benefit but also significant economic advantage: critical in the current climate where dialysis therapies in Australia take approximately $1 billion dollars per year from the healthcare budget. When assessing the significant advantages of home‐based therapies, it is important to consider not only the increasing body of evidence around improved survival but also that for dramatically better health‐related quality of life, decreased economic burden and the overall benefits of undertaking treatment in the home. With patient‐centered care an increasingly important aspect of our decision making paradigm, home‐based dialysis should be considered as the default option in all patients transitioning to renal replacement therapy.
Recipient clinical risk factors predominate in possible transfusion‐related acute lung injury
Authors: Toy Pearl , Bacchetti Peter , Grimes Barbara , Gajic Ognjen , Murphy Edward L. , Winters Jeffrey L. , Gropper Michael A. , Hubmayr Rolf D. , Matthay Michael A. , Wilson Gregory , Koenigsberg Monique , Lee Deanna C. , Hirschler Nora V. , Lowell Clifford A. , Schuller Randy M. , Gandhi Manish J. , Norris Philip J. , Mair David C. , Sanchez Rosen Rosa , Looney Mark R.
Published: December 2014

Background

Possible transfusion‐related acute lung injury (pTRALI) cases by definition have a clear temporal relationship to an alternative recipient risk factor for acute respiratory distress syndrome (ARDS). We questioned whether transfusion factors are important for the development of pTRALI.

Study Design and Methods

In this nested case‐control study, we prospectively identified 145 consecutive patients with pTRALI and randomly selected 163 transfused controls over a 4‐year period at the University of California at San Francisco and the Mayo Clinic (Rochester, Minnesota).

Results

For pTRALI, we found evidence against transfusion being important: receipt of plasma from female donors (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.29‐2.3; p = 0.70), total number of units transfused (OR, 0.99; 95% CI, 0.89‐1.10; p = 0.86), and number of red blood cell and whole blood units transfused (OR, 0.78; 95% CI, 0.59‐1.03; p = 0.079). In contrast, we found that risk for pTRALI was associated with additional recipient factors: chronic alcohol abuse (OR, 12.5; 95% CI, 2.8‐55; p < 0.001), current smoker (OR, 4.2; 95% CI, 1.67‐10.8; p = 0.0024), shock before transfusion (OR, 4.6; 95% CI, 2.0‐10.7; p < 0.001), and positive fluid balance before transfusion (OR, 1.32/L; 95% CI, 1.20‐1.44; p < 0.001).

Conclusion

Recipient risk factors for ARDS rather than transfusion risk factors predominate in pTRALI.
Expression patterns of superficial epidermal adhesion molecules in an experimental dog model of acute atopic dermatitis skin lesions
Authors: Olivry Thierry , Dunston Stanley M.
Published: December 2014

Background

The stratum corneum is critical for providing a functional skin barrier, especially in humans and dogs with atopic dermatitis. An effective barrier also depends upon intact corneodesmosomes and superficial epidermal tight junctions.

Hypothesis/Objectives

To study the expression of selected corneodesmosome, desmosome, tight and adherens junction proteins in an experimental model of acute atopic dermatitis skin lesions in dogs.

Methods

Control and house dust mite (HDM) allergen‐containing patches (two types of patches) were applied to the skin of six Maltese–beagle atopic dogs hypersensitive to HDM. Patches were left on for 48 h, and biopsies were collected 24 h after removal. Frozen skin sections were stained by indirect immunofluorescence for corneodesmosin, desmoglein‐1, desmocollin‐1, claudin‐1 and E‐cadherin. Immunostains were assessed for their extent, intensity and patterns; they were compared between HDM and control patches on the same dogs.

Results

The immunostaining for E‐cadherin, desmocollin‐1 and desmoglein‐1 was homogeneous, intercellular and continuous in all control and HDM patches. The immunoreactivity of corneodesmosin and claudin‐1 was heterogeneous and reduced in intensity in 12 of 12 and eight of 12 HDM patches, respectively, in contrast to a normal expression seen in all control samples (Fisher's test, P < 0.001).

Conclusions and clinical importance

These observations suggest that HDM allergens, via proteolytic digestion and/or because of induced allergic inflammation, affect the expression and possible function of corneodesmosomal and tight junction proteins. Ensuing intercellular junction alterations might promote an abnormally increased penetration of allergens through the epidermis.
Antibody titres against canine papillomavirus 1 peak around clinical regression in naturally occurring oral papillomatosis
Authors: Sancak Arda , Favrot Claude , Geisseler Marco D. , Müller Martin , Lange Christian E.
Published: December 2014

Background

Most forms of canine papillomatosis are believed to be associated with papillomavirus infections. Canine papillomavirus type 1 (CPV1) is considered to be responsible for most oral cases and several forms of cutaneous papillomatosis.

Hypothesis/Objectives

The aim of this study was to evaluate cases of naturally occurring oral papillomatosis with regard to the type of virus involved, antibody induction and remission time.

Methods

Forty dogs showing different degrees of classical oral papillomatosis were included as a single study group. Tissue and serum samples were acquired upon initial presentation; serum samples were collected again upon remission (n = 13) and after 3 months of convalescence (n = 4). None of the dogs underwent antiviral therapy. Tissue samples were tested byPCRto detectCPV DNA, while serum samples were tested using a specific enzyme‐linked immunosorbent assay for antibodies against the L1 capsid protein ofCPV1.

Results

All tissue samples were positive forCPV1DNA, and 87.5% of all serum samples contained measurable levels of antibody against the virus (cut‐off value 0.3). The average optical density measured in the enzyme‐linked immunosorbent assay was 0.51 at initial presentation, 1.65 upon remission and 0.83 at 3 months postrecovery. Time to clinical regression varied between 1 month and 1 year.

Conclusions and clinical importance

These data support existing evidence for a high prevalence ofCPV1 in canine oral papillomatosis. The healing process seems to correlate with a strong antibody response, and antibody titres peaked around the time of clinical recovery. In contrast to previous data from laboratory settings, the variation in remission time was very high.
Cervical Cancer Screening in Adolescents: An Evidence‐Based Internet Education Program for Practice Improvement Among Advanced Practice Nurses
Authors: Choma Kim , McKeever Amy E.
Published: December 2014

Background

The literature reports great variation in the knowledge levels and application of the recent changes of cervical cancer screening guidelines into clinical practice. Evidence‐based screening guidelines for the prevention and early detection of cervical cancer offers healthcare providers the opportunity to improve practice patterns among female adolescents by decreasing psychological distress as well as reducing healthcare costs and morbidities associated with over‐screening.

Purpose

The purpose of this pilot intervention study was to determine the effects of a Web‐based continuing education unit (CEU) program on advanced practice nurses’ (APNs) knowledge of current cervical cancer screening evidence‐based recommendations and their application in practice. This paper presents a process improvement project as an example of a way to disseminate updated evidence‐based practice guidelines among busy healthcare providers.

Methods

This Web‐based CEU program was developed, piloted, and evaluated specifically for APNs. The program addressed their knowledge level of cervical cancer and its relationship with high‐risk human papillomavirus. It also addressed the new cervical cancer screening guidelines and the application of those guidelines into clinical practice.

Findings

Results of the study indicated that knowledge gaps exist among APNs about cervical cancer screening in adolescents. However, when provided with a CEU educational intervention, APNs’ knowledge levels increased and their self‐reported clinical practice behaviors changed in accordance with the new cervical cancer screening guidelines.

Linking Evidence to Practice

Providing convenient and readily accessible up‐to‐date electronic content that provides CEU enhances the adoption of clinical practice guidelines, thereby decreasing the potential of the morbidities associated with over‐screening for cervical cancer in adolescents and young women.
Prevalence of Type VI Secretion System in Spanish Campylobacter jejuni Isolates
Authors: Ugarte‐Ruiz M. , Stabler R. A. , Domínguez L. , Porrero M. C. , Wren B. W. , Dorrell N. , Gundogdu O.
Published: December 2014

Infections from Campylobacter jejuni pose a serious public health problem and are now considered the leading cause of foodborne bacterial gastroenteritis throughout the world. Sequencing of C. jejuni genomes has previously allowed a number of loci to be identified, which encode virulence factors that aid survival and pathogenicity. Recently, a Type VI secretion system (T6SS) consisting of 13 conserved genes was described in C. jejuni strains and recognised to promote pathogenicity and adaptation to the environment. In this study, we determined the presence of this T6SS in 63 Spanish C. jejuni isolates from the food chain and urban effluents using whole‐genome sequencing. Our findings demonstrated that nine (14%) strains harboured the 13 ORFs found in prototype strain C. jejuni 108. Further studies will be necessary to determine the prevalence and importance of T6SS‐positive C. jejuni strains.
On the algebraic unknotting number
Authors: Borodzik Maciej , Friedl Stefan
Published: December 2014

The algebraic unknotting number of a knot was introduced by Hitoshi Murakami. It equals the minimal number of crossing changes needed to turn into an Alexander polynomial one knot. In a previous paper, the authors used the Blanchfield form of a knot to define an invariant and proved that . They also showed that subsumes all previous classical lower bounds on the (algebraic) unknotting number. In this paper, we prove that .
Paired associative transcranial alternating current stimulation increases the excitability of corticospinal projections in humans
Authors: McNickle Emmet , Carson Richard G.
Published: December 2014

Key points

Repeatedly pairing short trains of peripheral afferent stimulation with bursts (500–1000 ms) of high frequency (≥80 Hz) transcranial alternating current stimulation (tACS) over the contralateral primary motor cortex (M1) induces reliable elevations in corticospinal excitability.

The effect can be obtained using a range of tACS current intensities and frequencies, and with different forms of peripheral afferent stimulation.

The generation of a temporally discrete cortical event is not a critical determinant of the increases in corticospinal excitability induced by associative stimulation protocols.

Many types of non‐invasive brain stimulation alter corticospinal excitability (CSE). Paired associative stimulation (PAS) has attracted particular attention as its effects ostensibly adhere to Hebbian principles of neural plasticity. In prototypical form, a single electrical stimulus is directed to a peripheral nerve in close temporal contiguity with transcranial magnetic stimulation delivered to the contralateral primary motor cortex (M1). Repeated pairing of the two discrete stimulus events (i.e. association) over an extended period either increases or decreases the excitability of corticospinal projections from M1, contingent on the interstimulus interval. We studied a novel form of associative stimulation, consisting of brief trains of peripheral afferent stimulation paired with short bursts of high frequency (≥80 Hz) transcranial alternating current stimulation (tACS) over contralateral M1. Elevations in the excitability of corticospinal projections to the forearm were observed for a range of tACS frequency (80, 140 and 250 Hz), current (1, 2 and 3 mA) and duration (500 and 1000 ms) parameters. The effects were at least as reliable as those brought about by PAS or transcranial direct current stimulation. When paired with tACS, muscle tendon vibration also induced elevations of CSE. No such changes were brought about by the tACS or peripheral afferent stimulation alone. In demonstrating that associative effects are expressed when the timing of the peripheral and cortical events is not precisely circumscribed, these findings suggest that multiple cellular pathways may contribute to a long term potentiation‐type response. Their relative contributions will differ depending on the nature of the induction protocol that is used.
Multiple blocks of intermittent and continuous theta‐burst stimulation applied via transcranial magnetic stimulation differently affect sensory responses in rat barrel cortex
Authors: Thimm Andreas , Funke Klaus
Published: December 2014

Key points

Theta‐burst stimulation (TBS) applied via transcranial magnetic stimulation is able to modulate human cortical excitability.

Here we investigated in a rat model how two different forms of TBS, intermittent (iTBS) and continuous (cTBS), affect sensory responses in rat barrel cortex.

We found that iTBS but less cTBS promoted late (>18 ms) sensory response components while not affecting the earliest response (8–18 ms). The effect increased with each of the five iTBS blocks applied.

cTBS somewhat reduced the early response component after the first block but had a similar effect as iTBS after four to five blocks.

We conclude that iTBS primarly modulates the activity of (inhibitory) cortical interneurons while cTBS may first reduce general neuronal excitability with a single block but reverse to iTBS‐like effects with application of several blocks.

Cortical sensory processing varies with cortical state and the balance of inhibition to excitation. Repetitive transcranial magnetic stimulation (rTMS) has been shown to modulate human cortical excitability. In a rat model, we recently showed that intermittent theta‐burst stimulation (iTBS) applied to the corpus callosum, to activate primarily supragranular cortical pyramidal cells but fewer subcortical neurons, strongly reduced the cortical expression of parvalbumin (PV), indicating reduced activity of fast‐spiking interneurons. Here, we used the well‐studied rodent barrel cortex system to test how iTBS and continuous TBS (cTBS) modulate sensory responses evoked by either single or double stimuli applied to the principal (PW) and/or adjacent whisker (AW) in urethane‐anaesthetized rats. Compared to sham stimulation, iTBS but not cTBS particularly enhanced late (>18 ms) response components of multi‐unit spiking and local field potential responses in layer 4 but not the very early response (<18 ms). Similarly, only iTBS diminished the suppression of the second response evoked by paired PW or AW–PW stimulation at 20 ms intervals. The effects increased with each of the five iTBS blocks applied. With cTBS a mild effect similar to that of iTBS was first evident after 4–5 stimulation blocks. Enhanced cortical c‐Fos and zif268 expression but reduced PV and GAD67 expression was found only after iTBS, indicating increased cortical activity due to lowered inhibition. We conclude that iTBS but less cTBS may primarily weaken a late recurrent‐type cortical inhibition mediated via a subset of PV+ interneurons, enabling stronger late response components believed to contribute to the perception of sensory events.
Anchoring protein AKAP79‐mediated PKA phosphorylation of STIM1 determines selective activation of the ARC channel, a store‐independent Orai channel
Authors: Thompson Jill L. , Shuttleworth Trevor J.
Published: December 2014

Key points

Although both the calcium store‐dependent CRAC channels and the store‐independent ARC channels are regulated by the protein STIM1, CRAC channels are regulated by STIM1 in the endoplasmic reticulum, whilst ARC channels are regulated by the STIM1 constitutively resident in the plasma membrane.

We now demonstrate that activation of the ARC channels, but not CRAC channels, is uniquely dependent on phosphorylation of a single residue (T389) in the extensive cytosolic domain of STIM1 by protein kinase A.

We further demonstrate that the phosphorylation of the T389 residue by protein kinase A is mediated by the association of plasma membrane STIM1 with the scaffolding protein AKAP79.

Together, these findings indicate that the phosphorylation status of this single residue in STIM1 represents a key molecular determinant of the relative activities of these two co‐existing Ca2+ entry channels that are known to play critical, but distinct, roles in modulating a variety of physiologically relevant activities.

The low‐conductance, highly calcium‐selective channels encoded by the Orai family of proteins represent a major pathway for the agonist‐induced entry of calcium associated with the generation and modulation of the key intracellular calcium signals that initiate and control a wide variety of physiologically important processes in cells. There are two distinct members of this channel family that co‐exist endogenously in many cell types: the store‐operated Ca2+ release‐activated CRAC channels and the store‐independent arachidonic acid‐regulated ARC channels. Although the activities of both channels are regulated by the stromal‐interacting molecule‐1 (STIM1) protein, two distinct pools of this protein are responsible, with the major pool of STIM1 in the endoplasmic reticulum membrane regulating CRAC channel activity, whilst the minor pool of plasma membrane STIM1 regulates ARC channel activity. We now show that a critical feature in determining this selective activation of the two channels is the phosphorylation status of a single threonine residue (T389) within the extensive (∼450 residue) cytosolic domain of STIM1. Specifically, protein kinase A (PKA)‐mediated phosphorylation of T389 of STIM1 is necessary for effective activation of the ARC channels, whilst phosphorylation of the same residue actually inhibits the ability of STIM1 to activate the CRAC channels. We further demonstrate that the PKA‐mediated phosphorylation of T389 occurs at the plasma membrane via the involvement of the anchoring protein AKAP79, which is constitutively associated with the pool of STIM1 in the plasma membrane. The novel mechanism we have described provides a means for the cell to precisely regulate the relative activities of these two channels to independently modulate the resulting intracellular calcium signals in a physiologically relevant manner.
Noradrenaline upregulates T‐type calcium channels in rat pinealocytes
Authors: Yu Haijie , Seo Jong Bae , Jung Seung‐Ryoung , Koh Duk‐Su , Hille Bertil
Published: December 2014

Key points

The mammalian pineal gland is a neuroendocrine organ that responds to circadian and seasonal rhythms. Its major function is to secrete melatonin as a hormonal night signal in response to nocturnal delivery of noradrenaline from sympathetic neurons.

Culturing rat pinealocytes in noradrenaline for 24 h induced a low‐voltage activated transient Ca2+ current whose pharmacology and kinetics corresponded to a CaV3.1 T‐type channel.

The upregulation of the T‐type Ca2+ current is initiated by β‐adrenergic receptors, cyclic AMP and cyclic AMP‐dependent protein kinase.

Messenger RNA for CaV3.1 T‐type channels is significantly elevated by noradrenaline at 8 h and 24 h.

The noradrenaline‐induced T‐type channel mediated an increased Ca2+ entry and supported modest transient electrical responses to depolarizing stimuli, revealing the potential for circadian regulation of pinealocyte electrical excitability and Ca2+ signalling.

Our basic hypothesis is that mammalian pinealocytes have cycling electrical excitability and Ca2+ signalling that may contribute to the circadian rhythm of pineal melatonin secretion. This study asked whether the functional expression of voltage‐gated Ca2+ channels (CaV channels) in rat pinealocytes is changed by culturing them in noradrenaline (NA) as a surrogate for the night signal. Channel activity was assayed as ionic currents under patch clamp and as optical signals from a Ca2+‐sensitive dye. Channel mRNAs were assayed by quantitative polymerase chain reaction. Cultured without NA, pinealocytes showed only non‐inactivating L‐type dihydropyridine‐sensitive Ca2+ current. After 24 h in NA, additional low‐voltage activated transient Ca2+ current developed whose pharmacology and kinetics corresponded to a T‐type CaV3.1 channel. This change was initiated by β‐adrenergic receptors, cyclic AMP and protein kinase A as revealed by pharmacological experiments. mRNA for CaV3.1 T‐type channels became significantly elevated, but mRNA for another T‐type channel and for the major L‐type channel did not change. After only 8 h of NA treatment, the CaV3.1 mRNA was already elevated, but the transient Ca2+ current was not. Even a 16 h wait without NA following the 8 h NA treatment induced little additional transient current. However, these cells were somehow primed to make transient current as a second NA exposure for only 60 min sufficed to induce large T‐type currents. The NA‐induced T‐type channel mediated an increased Ca2+ entry during short depolarizations and supported modest transient electrical responses to depolarizing stimuli. Such experiments reveal the potential for circadian regulation of excitability.
Chronic activation of CB2 cannabinoid receptors in the hippocampus increases excitatory synaptic transmission
Authors: Kim Jimok , Li Yong
Published: December 2014

Key points

The effects of cannabinoids are primarily mediated by two types of cannabinoid receptors, CB1 receptors in the nervous system and CB2 receptors in the immune system.

Recent evidence indicates that CB2 receptors are also widely expressed in the brain and involved in neuropsychiatric functions, such as schizophrenia‐like behaviours, anxiety, memory, vomiting and pain.

The cellular mechanisms by which CB2 receptors regulate neuronal functions are unknown.

We show that chronic activation of CB2 receptors in the hippocampus for 7–10 days increases excitatory synaptic transmission, whereas short‐term activation of CB2 receptors has little effect on synaptic activity.

This study reveals a novel role of CB2 receptors in the brain, which is clearly distinct from that of CB1 receptors, and thus, will help us to understand better the diverse effects of cannabinoids in the nervous system.

The roles of CB1 cannabinoid receptors in regulating neuronal activity have been extensively characterized. Although early studies show that CB1 receptors are present in the nervous system and CB2 cannabinoid receptors are in the immune system, recent evidence indicates that CB2 receptors are also expressed in the brain. Activation or blockade of CB2 receptors in vivo induces neuropsychiatric effects, but the cellular mechanisms of CB2 receptor function are unclear. The aim of this study is to determine how activation of CB2 receptors present in the hippocampus regulates synaptic function. Here, we show that when organotypic cultures of rodent hippocampal slices were treated with a CB2 receptor agonist (JWH133 or GP1a) for 7–10 days, quantal glutamate release became more frequent and spine density was increased via extracellular signal‐regulated kinases. Chronic intraperitoneal injection of JWH133 into mice also increased excitatory synaptic transmission. These effects were blocked by a CB2 receptor antagonist (SR144528) or absent from hippocampal slices of CB2 receptor knock‐out mice. This study reveals a novel cellular function of CB2 cannabinoid receptors in the hippocampus and provides insights into how cannabinoid receptor subtypes diversify the roles of cannabinoids in the brain.
Ratiometric Imaging of Extracellular pH in Bacterial Biofilms with C-SNARF-4
Authors: Schlafer Sebastian , Garcia Javier E. , Greve Matilde , Raarup Merete K. , Nyvad Bente , Dige Irene
Published: December 2014

pH in the extracellular matrix of bacterial biofilms is of central importance for microbial metabolism. Biofilms possess a complex three-dimensional architecture characterized by chemically different microenvironments in close proximity. For decades, pH measurements in biofilms have been limited to monitoring bulk pH with electrodes. Although pH microelectrodes with a better spatial resolution have been developed, they do not permit the monitoring of horizontal pH gradients in biofilms in real time. Quantitative fluorescence microscopy can overcome these problems, but none of the hitherto employed methods differentiated accurately between extracellular and intracellular microbial pH and visualized extracellular pH in all areas of the biofilms. Here, we developed a method to reliably monitor extracellular biofilm pH microscopically with the ratiometric pH-sensitive dye C-SNARF-4, choosing dental biofilms as an example. Fluorescent emissions of C-SNARF-4 can be used to calculate extracellular pH irrespective of the dye concentration. We showed that at pH values of <6, C-SNARF-4 stained 15 bacterial species frequently isolated from dental biofilm and visualized the entire bacterial biomass in
in vivo
-grown dental biofilms with unknown species composition. We then employed digital image analysis to remove the bacterial biomass from the microscopic images and adequately calculate extracellular pH values. As a proof of concept, we monitored the extracellular pH drop in
in vivo
-grown dental biofilms fermenting glucose. The combination of pH ratiometry with C-SNARF-4 and digital image analysis allows the accurate monitoring of extracellular pH in bacterial biofilms in three dimensions in real time and represents a significant improvement to previously employed methods of biofilm pH measurement.