bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of methods for stable isotope ratio (δ13C, δ15N, δ2H, δ18O) measurements of feathers
Authors: Bontempo Luana , Ceppa Florencia , Ziller Luca , Pedrini Paolo , Hobson Keith A. , Wassenaar Leonard I. , Camin Federica
Published: January 2014

Natural variations in the stable isotope ratios of bioelements in bird feathers are being increasingly used by animal ecologists to investigate different aspects of bird life. However, to ensure reliability of the data, a critical and very delicate aspect is the preparatory phase (cleaning, drying and subsampling) and the proper analysis, mainly in relation to δ2H and δ18O, respectively, for the presence of exchangeable Hs and of nitrogen and sulphur in keratin.

With respect to determination of the isotope ratios of C, N, O and H, in this work, we compare the cleaning mixture most commonly used in the literature (chloroform : methanol 2 : 1) with diethylether : methanol 2 : 1, which avoids the use of the carcinogenic solvent chloroform. We also compared oven‐drying with air‐drying of samples, as well as subsampling of feathers by cutting with surgical scissors or cryogenic pulverization. Finally, we investigated whether stable isotope ratios varied along the vane and between the rachis and vane.

The different methods compared in the three preparatory stages showed no differences performance‐wise and can therefore be used interchangeably. Variability in stable isotope ratios can be considerable, both along the vane and between rachis and vane, which is because their compositions register changes in diet, area and climate. However, in this specific study, when the parts of the feather closest to the calamus were removed, the delta values were clearly more homogeneous. Finally, we demonstrate that a casein with a known δ2H value, although probably differing from keratin in the number of exchangeable Hs, can be used to normalize the δ2H values of feathers, although only in the range of values close to that of the reference material. In determining δ18O, the use of a longer gas chromatography‐GC column, its frequent change and the use of a linear equation built with matrix match equivalent reference materials seems to reduce the drift of GC column performance due to the presence of nitrogen and the accumulation of sulphur.
Using commonality analysis in multiple regressions: a tool to decompose regression effects in the face of multicollinearity
Authors: Ray‐Mukherjee Jayanti , Nimon Kim , Mukherjee Shomen , Morris Douglas W. , Slotow Rob , Hamer Michelle
Published: January 2014

1. In the face of natural complexities and multicollinearity, model selection and predictions using multiple regression may be ambiguous and risky. Confounding effects of predictors often cloud researchers’ assessment and interpretation of the single best ‘magic model’. The shortcomings of stepwise regression have been extensively described in statistical literature, yet it is still widely used in ecological literature. Similarly, hierarchical regression which is thought to be an improvement of the stepwise procedure, fails to address multicollinearity.

2. We propose that regression commonality analysis (CA), a technique more commonly used in psychology and education research will be helpful in interpreting the typical multiple regression analyses conducted on ecological data.

3. CA decomposes the variance of R2 into unique and common (or shared) variance (or effects) of predictors, and hence, it can significantly improve exploratory capabilities in studies where multiple regressions are widely used, particularly when predictors are correlated. CA can explicitly identify the magnitude and location of multicollinearity and suppression in a regression model.

In this paper, using a simulated (from a correlation matrix) and an empirical dataset (human habitat selection, migration of Canadians across cities), we demonstrate how CA can be used with correlated predictors in multiple regression to improve our understanding and interpretation of data. We strongly encourage the use of CA in ecological research as a follow‐on analysis from multiple regressions.
Genetic risk factors for insidious equine recurrent uveitis inAppaloosa horses
Authors: Fritz K. L. , Kaese H. J. , Valberg S. J. , Hendrickson J. A. , Rendahl A. K. , Bellone R. R. , Dynes K. M. , Wagner M. L. , Lucio M. A. , Cuomo F. M. , Brinkmeyer‐Langford C. L. , Skow L. C. , Mickelson J. R. , Rutherford M. S. , McCue M. E.
Published: January 2014

Appaloosa horses are predisposed to equine recurrent uveitis (ERU), an immune‐mediated disease characterized by recurring inflammation of the uveal tract in the eye, which is the leading cause of blindness in horses. Nine genetic markers from theECA1 region responsible for the spotted coat color of Appaloosa horses, and 13 microsatellites spanning the equine major histocompatibility complex (ELA) onECA20, were evaluated for association withERUin a group of 53 AppaloosaERUcases and 43 healthy Appaloosa controls. Three markers were significantly associated (correctedP‐value <0.05): aSNPwithin intron 11 of theTRPM1gene onECA1, anELAclass I microsatellite located near the boundary of theELAclassIIIand classIIregions and anELAclassIImicrosatellite located in intron 1 of theDRAgene. Association between these three genetic markers and theERUphenotype was confirmed in a second population of 24 insidiousERUAppaloosa cases and 16 Appaloosa controls. The relative odds of being anERUcase for each allele of these three markers were estimated by fitting a logistic mixed model with each of the associated markers independently and with all three markers simultaneously. The risk model using these markers classified ~80% ofERUcases and 75% of controls in the second population as moderate or high risk, and low risk respectively. Future studies to refine the associations atECA1 andELAloci and identify functional variants could uncover alleles conferring susceptibility toERUin Appaloosa horses.
Comprehensive screening for a complete set of Japanese‐population‐specific filaggrin gene mutations
Authors: Kono M. , Nomura T. , Ohguchi Y. , Mizuno O. , Suzuki S. , Tsujiuchi H. , Hamajima N. , McLean W. H. I. , Shimizu H. , Akiyama M.
Published: January 2014

Mutations in FLG coding profilaggrin cause ichthyosis vulgaris and are an important predisposing factor for atopic dermatitis. Until now, most case–control studies and population‐based screenings have been performed only for prevalent mutations. In this study, we established a high‐throughput FLG mutation detection system by real‐time PCR with a set of two double‐dye probes and conducted comprehensive screening for almost all of the Japanese‐population‐specific FLG mutations (ten FLG mutations). The present comprehensive screening for all ten FLG mutations provided a more precise prevalence rate for FLG mutations (11.1%, n = 820), which seemed high compared with data of previous reports based on screening for limited numbers of FLG mutations. Our comprehensive screening suggested that population‐specific FLG mutations may be a significant predisposing factor for hay fever (odds ratio = 2.01 [95% CI: 1.027–3.936, P < 0.05]), although the sample sizes of this study were too small for reliable subphenotype analysis on the association between FLG mutations and hay fever in the eczema patients and the noneczema individuals, and it is not clear whether the association between FLG mutations and hay fever is due to the close association between FLG mutations and hay fever patients with eczema.
Rituximab, alkylating agents or combination therapy for gastric mucosa‐associated lymphoid tissue lymphoma: a monocentric non‐randomised observational study
Authors: Amiot A. , Lévy M. , Copie‐Bergman C. , Dupuis J. , Szablewski V. , Le Baleur Y. , Baia M. , Belhadj K. , Sobhani I. , Leroy K. , Haioun C. , Delchier J‐C.
Published: January 2014

Background

There is no consensus on the standard treatment of gastric mucosa‐associated lymphoid tissue (MALT) lymphoma for Helicobacter pylori‐negative patients and for patients with persistent disease despite H. pylori eradication.

Aim

To evaluate the comparative efficacy and safety of alkylating agents and rituximab alone or in combination.

Methods

In this monocentric retrospective study, which included 106 patients who had not been previously treated with anti‐cancer agents, we evaluated the efficacy and safety of oral alkylating agents monotherapy (n = 48), rituximab monotherapy (n = 28) and the therapy combining both drugs (n = 30). Evaluations were performed at weeks 6 (W6), 25 (W25), and 52 (W52) and after 2 years (W104).

Results

After a median follow‐up period of 4.9 years (range 0.4–17.2 years), complete remission and overall response were significantly higher in patients in the combination therapy group at W104 (92% and 100% respectively) compared with patients treated with alkylating agents alone (66% and 68%) and rituximab alone (64% and 73%). The 5‐year progression‐free survival probabilities were 68%, 70% and 89% in patients treated with alkylating agents alone, rituximab alone and combination therapy respectively. Haematological adverse events were reported in 32 (30%) patients (mostly grade 1) and were more frequent in the two groups receiving alkylating agents (P = 0.05 and P < 0.001). No toxicity‐related death was reported.

Conclusions

The use of anti‐cancer systemic therapy is safe and efficient in gastric MALT lymphoma. In this retrospective study, the combination of rituximab plus chlorambucil seems more efficient than rituximab or alkylating agents alone. Rituximab has a better safety profile than regimens containing alkylating agents.
In Vitro Approaches for Detection of Chemical Sensitization
Authors: Roggen Erwin L.
Published: January 2014

Concerns, legislation and research needs have precipitated developments such as the mode of action concept, the Tox21 strategy, the concept of pathways of toxicity and the adverse outcome pathway framework. New technologies and paradigms are currently transforming these concepts into applicable animal‐free toxicity testing systems. The adverse outcome pathway framework provides a structure for collecting, organizing and evaluating the available data that describe the compound and the events resulting in an adverse outcome at a biological level of organization. The current chapter intends to provide a non‐exhaustive review of (i) our current understanding of the molecular mechanisms driven the key events of the mode of action for sensitization induction by chemicals, (ii) the tools that were developed on the basis of the available knowledge and (iii) the major gaps that need to be filled.
Chronic myelomonocytic leukaemia: a concise clinical and pathophysiological review
Authors: Patnaik Mrinal M. , Parikh Sameer A. , Hanson Curtis A. , Tefferi Ayalew
Published: January 2014

Chronic myelomonocytic leukaemia (CMML) is a clonal haematopoietic stem cell disorder with myelodysplastic and myeloproliferative overlap features, and an inherent tendency to transform to acute myeloid leukaemia. Approximately 30% of patients present with clonal cytogenetic abnormalities, while almost 90% have molecular aberrations involving epigenetic regulation, the spliceosome component machinery, tumour suppressor genes and transcription factors/regulators. Numerous prognostic models exist for CMML, with more recent models incorporating prognostic mutations, such as those involving ASXL1. Other variables that seem to consistently affect outcomes include the degree of leucocytosis/monocytosis, anaemia and thrombocytopenia. Allogeneic stem cell transplant remains the only curative option for CMML, while hypomethylating agents can be used for transplant‐ineligible patients or those without suitable stem cell sources. Targeting biological pathways activated in CMML offers potential hope for more effective and less toxic therapies.
The role of apoptosis in megakaryocytes and platelets
Authors: Kile Benjamin T.
Published: January 2014

The role of apoptotic pathways in the development and function of the megakaryocyte lineage has generated renewed interest in recent years. This has been driven by the advent of BH3 mimetic drugs that target BCL2 family proteins to induce apoptosis in tumour cells: agents such as ABT‐263 (navitoclax, which targets BCL2, BCL‐XL [BCL2L1] and BCL2L2) and ABT‐199 (a BCL2‐specific agent) are showing great promise in early stage clinical trials. However, the major dose‐limiting toxicity of navitoclax has proven to be thrombocytopenia, an on‐target effect of inhibiting BCL‐XL. It transpires that the anucleate platelet contains a classical intrinsic apoptosis pathway, which at steady state regulates its life span in the circulation. BCL‐XL is the critical pro‐survival protein that restrains apoptosis and maintains platelet viability. These findings have paved the way to a deeper understanding of apoptotic pathways and processes in platelets, and their precursor cell, the megakaryocyte.
Epac and the high affinity rolipram binding conformer of PDE4 modulate neurite outgrowth and myelination using an in vitro spinal cord injury model
Authors: Boomkamp S D , McGrath M A , Houslay M D , Barnett S C
Published: January 2014

Background and Purpose

cAMP and pharmacological inhibition of PDE4, which degrades it, are promising therapeutic targets for the treatment of spinal cord injury (SCI). Using our previously described in vitro SCI model, we studied the mechanisms by which cAMP modulators promote neurite outgrowth and myelination using enantiomers of the PDE4‐specific inhibitor rolipram and other modulators of downstream signalling effectors.

Experimental Approach

Rat mixed neural cell myelinating cultures were cut with a scalpel and treated with enantiomers of the PDE4‐specific inhibitor rolipram, Epac agonists and PKA antagonists. Neurite outgrowth, density and myelination were assessed by immunocytochemistry and cytokine levels analysed by qPCR.

Key Results

Inhibition of the high‐affinity rolipram‐binding state (HARBS), rather than the low‐affinity rolipram binding state (LARBS) PDE4 conformer promoted neurite outgrowth and myelination. These effects were mediated through the activation of Epac and not through PKA. Expression of the chemokine CXCL10, known to inhibit myelination, was markedly elevated in astrocytes after Rho inhibition and this was blocked by inhibition of Rho kinase or PDE4.

Conclusions and Implications

PDE4 inhibitors targeted at the HARBS conformer or Epac agonists may provide promising novel targets for the treatment of SCI. Our study demonstrates the differential mechanisms of action of these compounds, as well as the benefit of a combined pharmacological approach and highlighting potential promising targets for the treatment of SCI. These findings need to be confirmed in vivo.
δ‐Opioid receptor agonists inhibit migraine‐related hyperalgesia, aversive state and cortical spreading depression in mice
Authors: Pradhan Amynah A , Smith Monique L , Zyuzin Jekaterina , Charles Andrew
Published: January 2014

Background and Purpose

Migraine is an extraordinarily common brain disorder for which treatment options continue to be limited. Agonists that activate the δ‐opioid receptor may be promising for the treatment of migraine as they are highly effective for the treatment of chronic rather than acute pain, do not induce hyperalgesia, have low abuse potential and have anxiolytic and antidepressant properties. The aim of this study was to investigate the therapeutic potential of δ‐opioid receptor agonists for migraine by characterizing their effects in mouse migraine models.

Experimental Approach

Mechanical hypersensitivity was assessed in mice treated with acute and chronic doses of nitroglycerin (NTG), a known human migraine trigger. Conditioned place aversion to NTG was also measured as a model of migraine‐associated negative affect. In addition, we assessed evoked cortical spreading depression (CSD), an established model of migraine aura, in a thinned skull preparation.

Key Results

NTG evoked acute and chronic mechanical and thermal hyperalgesia in mice, as well as conditioned place aversion. Three different δ‐opioid receptor agonists, SNC80, ARM390 and JNJ20788560, significantly reduced NTG‐evoked hyperalgesia. SNC80 also abolished NTG‐induced conditioned place aversion, suggesting that δ‐opioid receptor activation may also alleviate the negative emotional state associated with migraine. We also found that SNC80 significantly attenuated CSD, a model that is considered predictive of migraine preventive therapies.

Conclusions and Implications

These data show that δ‐opioid receptor agonists modulate multiple basic mechanisms associated with migraine, indicating that δ‐opioid receptors are a promising therapeutic target for this disorder.
Elucidation of the molecular mechanism and the efficacy in vivo of a novel 1,4‐benzoquinone that inhibits 5‐lipoxygenase
Authors: Schaible A M , Filosa R , Temml V , Krauth V , Matteis M , Peduto A , Bruno F , Luderer S , Roviezzo F , Di Mola A , de Rosa M , D'Agostino B , Weinigel C , Barz D , Koeberle A , Pergola C , Schuster D , Werz O
Published: January 2014

Background and Purpose

1,4‐Benzoquinones are well‐known inhibitors of 5‐lipoxygenase (5‐LOX, the key enzyme in leukotriene biosynthesis), but the molecular mechanisms of 5‐LOX inhibition are not completely understood. Here we investigated the molecular mode of action and the pharmacological profile of the novel 1,4‐benzoquinone derivative 3‐((decahydronaphthalen‐6‐yl)methyl)‐2,5‐dihydroxycyclohexa‐2,5‐diene‐1,4‐dione (RF‐Id) in vitro and its effectiveness in vivo.

Experimental Approach

Mechanistic investigations in cell‐free assays using 5‐LOX and other enzymes associated with eicosanoid biosynthesis were conducted, along with cell‐based studies in human leukocytes and whole blood. Molecular docking of RF‐Id into the 5‐LOX structure was performed to illustrate molecular interference with 5‐LOX. The effectiveness of RF‐Id in vivo was also evaluated in two murine models of inflammation.

Key Results

RF‐Id consistently suppressed 5‐LOX product synthesis in human leukocytes and human whole blood. RF‐Id also blocked COX‐2 activity but did not significantly inhibit COX‐1, microsomal PGE2 synthase‐1, cytosolic PLA2 or 12‐ and 15‐LOX. Although RF‐Id lacked radical scavenging activity, reducing conditions facilitated its inhibitory effect on 5‐LOX whereas cell stress impaired its efficacy. The reduced hydroquinone form of RF‐Id (RED‐RF‐Id) was a more potent inhibitor of 5‐LOX as it had more bidirectional hydrogen bonds within the 5‐LOX substrate binding site. Finally, RF‐Id had marked anti‐inflammatory effects in mice in vivo.

Conclusions and Implications

RF‐Id represents a novel anti‐inflammatory 1,4‐benzoquinone that potently suppresses LT biosynthesis by direct inhibition of 5‐LOX with effectiveness in vivo. Mechanistically, RF‐Id inhibits 5‐LOX in a non‐redox manner by forming discrete molecular interactions within the active site of 5‐LOX.
Identification of Novel Compounds for Human Bitter Taste Receptors
Authors: Ji Mingfei , Su Xubo , Su Xiaohong , Chen Yingyi , Huang Wenkang , Zhang Jian , Gao Zhaobin , Li Chuangang , Lu Xuefeng
Published: January 2014

The finely tuned bitter taste sensing in humans is orchestrated by a group of 25 bitter taste receptors (TAS2Rs), which belong to the G‐protein‐coupled receptor superfamily. TAS2Rs are expressed in the specialized taste bud cells of the gustatory system and perceive a plethora of bitter substances with versatile structures. To date, more than one hundred bitter ligands have been matched with their cognate receptors, but the understanding of the molecular mechanisms of TAS2Rs remains limited. Additionally, the extraoral expression of TAS2R genes was found in the gastrointestinal tract and respiratory system, which suggests other important physiological functions for TAS2Rs. To gain insight into the physiological functions of TAS2Rs, we established a heterologous expression system and characterized the response of 24 TAS2Rs against a library of potential bitter compounds. Among these bitter compounds of interest, 18 bitter compounds activated 16 TAS2Rs, representing 42 tastant–receptor pairs. We then calculated 14 descriptor properties for the 18 positive compounds. By comparison with 102 previously annotated bitter compounds in the database, we discovered common descriptor properties that may contribute to the discovery of additional bitter ligands and further expand the known molecular receptive ranges of human TAS2Rs.
Education for Democratic Citizenship through A Literacy‐based Approach: A Case of South African Township Children
Authors: Joubert Ina , Phatudi Nkidi , Harris Teresa , Moen Melanie
Published: January 2014

The study contextualises the position of child citizens in the South African democracy and highlights how education for democratic citizenship is employed through a literacy‐based approach. The qualitative study was exploratory and based on a lesson presented to nine‐year‐old township children by giving them language‐related tasks. Through the children's voices we present the life experiences that expressed their need for basic services, education, extra facilities and security. We argue that children need to experience the benefits of democracy and education for democratic citizenship to build and sustain a resilient democratic society.
The thorax of Mantophasmatodea, the morphology of flightlessness, and the evolution of the neopteran insects
Authors: Wipfler Benjamin , Klug Rebecca , Ge Si‐Qin , Bai Ming , Göbbels Jürgen , Yang Xing‐Ke , Hörnschemeyer Thomas
Published: January 2014

Mantophasmatodea was described as a new insect order in 2002. Since then, this small group of wingless insects has developed into one of the best investigated insect taxa. Nevertheless, many aspects of mantophasmatodean morphology as well as their evolutionary relationships remain ambiguous. To determine the phylogenetic relationships of Mantophasmatodea based on an extended character set and to elucidate possible morphological adaptions towards flightlessness, we investigated the thoracic morphology of two species,Austrophasma caledonensisandMantophasmasp. The morphological similarity between these two species is striking and no differences in musculature were found. The mantophasmatodean thorax strongly resembles that of ice crawlers (Grylloblattodea), especially with respect to the presence of pleural processes in the meso‐ and metathorax, branched furcae in all segments, and similar muscle equipment. In a cladistic analysis containing all major lineages of Neoptera, the monophyly of Polyneoptera is supported by the presence of an anal fan and several modifications of the wing joint. Within Polyneoptera, a sister‐group relationship between stoneflies and the remaining Polyneoptera is supported. A clade comprising Mantophasmatodea and the Grylloblattodea gains strong support from thoracic morphology and can be considered assured. Potential thoracic apomorphies include prothoracic paracoxal invaginations, pterothoracic pleural arms that originate from the epimeron, and a unique metathoracic sterno‐coxal musculature. The monophyly of Orthoptera and Dictyoptera is further supported while the deeper polyneopteran nodes remain unresolved. Among the wingless taxa investigated we found few general morphological adaptations whereas, in other aspects, especially in the musculature, strong differences could be observed. However, much more research on the strongly neglected topic of flightlessness is required to make reliable statements.
A National Strategy to Develop Pragmatic Clinical Trials Infrastructure
Authors: Concannon Thomas W. , Guise Jeanne‐Marie , Dolor Rowena J. , Meissner Paul , Tunis Sean , Krishnan Jerry A. , Pace Wilson D. , Saltz Joel , Hersh William R. , Michener Lloyd , Carey Timothy S.
Published: January 2014

An important challenge in comparative effectiveness research is the lack of infrastructure to support pragmatic clinical trials, which compare interventions in usual practice settings and subjects. These trials present challenges that differ from those of classical efficacy trials, which are conducted under ideal circumstances, in patients selected for their suitability, and with highly controlled protocols. In 2012, we launched a 1‐year learning network to identify high‐priority pragmatic clinical trials and to deploy research infrastructure through the NIH Clinical and Translational Science Awards Consortium that could be used to launch and sustain them. The network and infrastructure were initiated as a learning ground and shared resource for investigators and communities interested in developing pragmatic clinical trials. We followed a three‐stage process of developing the network, prioritizing proposed trials, and implementing learning exercises that culminated in a 1‐day network meeting at the end of the year. The year‐long project resulted in five recommendations related to developing the network, enhancing community engagement, addressing regulatory challenges, advancing information technology, and developing research methods. The recommendations can be implemented within 24 months and are designed to lead toward a sustained national infrastructure for pragmatic trials.
Endometrial carcinoma in high‐risk populations: is it time to consider a screening policy?
Authors: Fambrini M. , Sorbi F. , Sisti G. , Cioni R. , Turrini I. , Taddei G. , Guaschino S.
Published: January 2014

Endometrial carcinoma (EC) is the leading female genital tract malignancy in industrialized countries. It will become an important public health problem in the coming years in the USA and Europe, where its incidence is increasing, and next‐generation interventions should include periodical screening in high‐risk women. In this review, we discuss the importance to gynaecologists of detecting women at high risk and offering an adequate screening programme. Screening for EC is particularly challenging and there is currently no proven programme for the surveillance of women estimated to be at an increased risk of developing this form of cancer. The data in the literature, including this and previous issues of Cytopathology, and personal experience suggest that endometrial liquid‐based cytology (LBC) might play an essential role in a screening policy for EC. LBC may enable practitioners to reduce age‐adjusted mortality for women at high risk for EC.
Interleukin 10 and clustering of metabolic syndrome components in pediatrics
Authors: Chang Jung‐Su , Bai Chyi‐Huey , Huang Zu‐Chieh , Owaga Eddy , Chao Kuo‐Ching , Chang Chun‐Chao , Chiou Hung‐Yi
Published: January 2014

Background

Interleukin 10 (IL‐10) has multifaceted anti‐inflammatory properties that are known to regulate insulin sensitivity and atherosclerotic development. However, studies in children are limited and have yielded conflicting results. The aim of this study was to evaluate whether changes in this circulating anti‐inflammatory cytokine is a marker for metabolic syndrome.

Materials and methods

This cross‐sectional study involved children and young adolescents from eight elementary schools and two junior high schools located in Taipei and New Taipei City. A total of 553 children ages 8, 11 and 13 years old were included in the analysis. Parameters for obesity, anti‐ and pro‐inflammatory cytokines, and metabolic risk profiles were evaluated.

Results

Overweight/obese children had lower serum IL‐10 concentrations compared with normal weight children in the same age group (all P < 0·001). IL‐10 quartiles were negatively associated with body mass index (BMI) and percentage (%) body fat (all P < 0·05). Multivariate regression analysis showed significant inverse relationship between IL‐10 concentrations and % body fat (β = −0·009, P < 0·0001), and total cholesterol (β = −0·726, P = 0·003), and a small positive correlation between IL‐10 and systolic blood pressure (β = 0·980, P = 0·027). In normal weight children, IL‐10 concentrations were independently associated with fasting plasma insulin (β = 0·2912, P = 0·001) and waist circumference (β = 0·0069, P = 0·022). By contrast, % body fat (β = −0·016, P = 0·0009) was independently associated with IL‐10 concentrations in overweight and obese children. Association between IL‐10 and fasting plasma insulin concentrations was weaker in overweight/obese children compared with normal weight (β = 0·283, P = 0·011 vs. β = 0·2912, P = 0·001).

Conclusion

Our data indicate that changes in circulating IL‐10 concentrations are marker of metabolic risk in children.
Where Are the Global Rankings Leading Us? An Analysis of Recent Methodological Changes and New Developments
Authors: Rauhvargers Andrejs
Published: January 2014

This article is based on the analysis of the changes in global university rankings and the new ‘products’ based on rankings data in the period since mid‐2011. It is a summary and continuation of the European University Association (EUA)‐commissioned report ‘Global University Rankings Their Impact, Report II’ which was launched in April 2013. It covers the changes in the ranking methodologies which have been the most visible in the CWTS Leiden Ranking and Webometrics and which have replaced some indicators with newly designed ones. Changes have been made in other rankings as well, but they are less visible. A new U21 ranking was launched in 2012. It is an attempt to rank national higher education systems rather than individual universities. New rankings by conventional ranking providers have demonstrated that in reputation rankings or reputation indicators the scores drop even more sharply than in the most élitist rankings and therefore can be used for even narrower groups of universities.

Several ranking providers have started their own data collections and combine ranking data with the data from the newly established data collections and use them for several multi‐indicator classifications or profiling tools. QS has been most productive and has added not only classification and profiling tools, but has also launched a ranking of student cities, and ‘stars’ that universities can obtain.

Generally, the rankings’ impact is growing. Let us see where it will bring us.

At the same time, some rankings providers have changed language and explain the biases, flaws and misunderstandings created through misuse of rankings or using ranking indicators without proper knowledge.
Differential role of N‐methyl‐D‐aspartate receptor‐mediated glutamate transmission in the nucleus accumbens shell and core in nicotine seeking in rats
Authors: D'Souza Manoranjan S. , Markou Athina
Published: January 2014

Nicotine, a major psychoactive component of tobacco smoke, increases glutamate transmission in the nucleus accumbens (NAcc). However, the role of the N‐methyl‐D‐aspartate (NMDA)‐mediated glutamatergic neurotransmission in the NAcc shell and core subdivisions in nicotine‐dependent behaviors has not been studied. The present study evaluated, in rats, the effects of bilateral administration of the competitive NMDA receptor antagonist LY235959 (0, 0.1, 1, and 10 ng/0.5 μL/side) into the NAcc shell or core on intravenous nicotine (fixed‐ and progressive‐ratio schedules) and food (fixed‐ratio schedule) self‐administration, and cue‐induced reinstatement of nicotine‐seeking behavior. In addition, the effects of LY235959 injections in the NAcc shell were evaluated on nicotine‐induced conditioned taste aversion, a procedure that assesses the aversive effects of nicotine. LY235959 injections into the NAcc shell significantly increased nicotine self‐administration under both fixed‐ and progressive‐ratio schedules, and decreased food self‐administration, but had no effect on nicotine‐induced conditioned taste aversion or cue‐induced nicotine seeking. Furthermore, injections of LY235959 in the lateral septal nucleus, originally intended as an anatomical control site for the NAcc shell, increased nicotine self‐administration and decreased food self‐administration under the fixed‐ratio schedule. In contrast, LY235959 injections into the NAcc core increased the cue‐induced reinstatement of nicotine seeking and decreased food self‐administration, but had no effect on nicotine self‐administration. The present data suggest that NMDA receptor‐mediated glutamatergic neurotransmission in the NAcc shell and core differentially regulates food‐ and nicotine‐maintained responding. Importantly, the data suggest an inhibitory role for NMDA‐mediated glutamatergic neurotransmission in the NAcc shell and core in nicotine self‐administration and the cue‐induced reinstatement of nicotine seeking, respectively.
Apolipoprotein E polymorphisms and ischaemic stroke: a two‐center Greek study
Authors: Chatzistefanidis D. , Giannopoulos S. , Spengos K. , Vassilopoulou S. , Vemmos K. , Dova L. , Vartholomatos G. , Kyritsis A. P. , Georgiou I. , Markoula S.
Published: January 2014

Background and purpose

Apolipropotein E(apoE) is a plasma protein exhibiting three common isoforms (E2, E3, E4). Its involvement in lipoprotein metabolism may have an impact on stroke occurrence. As results in the literature are inconclusive further studies are needed to elucidate its role. Our objective was to study the role of apoE isoforms and the interplay with environmental risk factors in patients with first ischaemic stroke occurrence in the Greek population.

Methods

Three hundred and twenty‐nine patients with first‐ever ischaemic stroke were included in our study. Strokes of cardioembolic origin and patients with autoimmune or prothrombotic syndromes were excluded. A control group of 361 subjects with no stroke history were also included in our study. Risk factors (hyperlipidemia, hypertension, diabetes mellitus and smoking) were assessed. ApoE alleles were determined in all subjects participating in the study.

Results

Genotype ε3/ε3 was found to have a protective role against stroke occurrence compared with other genotypes (odds ratio 0.674, 95% confidence interval 0.480–0.946) especially in the female patient subgroup. In multivariate analysis after adjustment for age, body mass index (BMI), hypertension, dyslipidemia, diabetes mellitus and smoking, the role of genotype was limited and outweighed by risk factors in both genders. No association between apoE alleles and BMI, cholesterol, triglycerides or high‐density lipoprotein plasma levels was noted.

Conclusions

Our study was indicative of a protective role of the ε3/ε3 genotype, especially in female patients. However, risk factors such as age, BMI, hypertension, dyslipidemia, diabetes mellitus and smoking have a strong impact on stroke occurrence and outweigh the protective role of the ε3/ε3 genotype.
Huntingtin gene CAG repeat numbers in Chinese patients with Huntington's disease and controls
Authors: Jiang H. , Sun Y. M. , Hao Y. , Yan Y. P. , Chen K. , Xin S. H. , Tang Y. P. , Li X. H. , Jun T. , Chen Y. Y. , Liu Z. J. , Wang C. R. , Li H. , Pei Z. , Shang H. F. , Zhang B. R. , Gu W. H. , Wu Z. Y. , Tang B. S. , Burgunder J.‐M. ,   The Chinese HD Network
Published: January 2014

Background and purpose

Huntington's disease is due to a CAG triplet repeat elongation in the huntingtin gene. Boundaries in CAG numbers have been found between healthy people with and without risk to pass the disorder to the next generation, and between people without, with a mild, or with a fully penetrant phenotype. These data have been generated in western populations and it is not clear whether they are also valid amongst Chinese.

Methods

In order to establish normative data in the huntingtin gene for Chinese people, 966 chromosomes from normal controls were tested. Further, the range of CAG repeats was examined in a cohort from six centres and a total of 368 patients with the disease were included.

Results

The CAG triplet repeat range in normal controls was between 9 and 35 (mean 18.9, SD 2.57). Triplets in the range between 26 and 35 were found in 2.5%. In the patient cohort, triplet repeats in the shorter allele were between 8 and 37 (mean 17.7, SD 1.6). In the longer allele, a range between 36 and 120 was found. There was a negative correlation (−0.65, r = 0.42) between age at onset and the number of triplet repeats in the larger allele. The mean age at onset was 38 years, with a range between 2 and 70 years. In 23 patients (6%) a childhood or juvenile onset was noted.

Conclusion

These data show comparable ranges of huntingtin gene CAG triplet repeats in normal people and in patients with Huntington's disease as in western populations.
An immunomodulatory role for the Mycobacterium tuberculosis region of difference 1 locus proteins PE35 (Rv3872) and PPE68 (Rv3873)
Authors: Tiwari Bhavana , Soory Amarendranath , Raghunand Tirumalai R.
Published: January 2014

The pathogenesis of Mycobacterium tuberculosis involves the coordinate action of multiple bacillary components that modulate host immune responses to ensure its survival. One such group of factors is the multigenic PE_PPE protein family, several members of which have been implicated in host immune evasion. Here we investigate the function of the PE–PPE gene pair PE35 (Rv3872)–PPE68 (Rv3873), located in the region of difference 1, encoding a specialized mycobacterial secretion system that is deleted in all vaccine strains of Mycobacterium bovis BCG. We report that this gene pair is co‐operonic in M. tuberculosis, and demonstrate that its gene products interact with each other. Stimulation of THP‐1 macrophages with recombinant PE35 and PPE68, singly or in combination, led to a dose‐dependent increase in levels of the anti‐inflammatory cytokine interleukin (IL)‐10 and the chemokine monocyte chemoattractant protein‐1, and caused a reciprocal decrease in levels of the proinflammatory cytokine IL‐12. PE35/PPE68‐stimulated production of IL‐10 and monocyte chemoattractant protein‐1 was observed to be dependent on toll‐like receptor 2, as receptor blockade caused a significant reduction in their levels. Pharmacological inhibition indicated that this induction involved activation of the mitogen‐activated protein kinase signalling axis. In a transwell migration assay, culture supernatants from PE35/PPE68‐treated THP‐1 cells were observed to stimulate the migration of monocytes. Our findings suggest that the PE35–PPE68 gene pair plays an important immunomodulatory role in regulating the pathophysiology of M. tuberculosis.

Structured digital abstract

TLR2 physically interacts with PPE68 by anti bait coimmunoprecipitation (View interaction)

PE35 binds to PPE68 by pull down (View interaction)

PE35 physically interacts with PPE68 by anti tag coimmunoprecipitation (View interaction)

TLR2 physically interacts with PE35 by anti bait coimmunoprecipitation (View interaction)

PPE68 and PE35 physically interact by dihydrofolate reductase reconstruction (View interaction)
Crystal structure of mouse mu‐crystallin complexed with NADPH and the T3 thyroid hormone
Authors: Borel Franck , Hachi Isma , Palencia Andres , Gaillard Marie‐Claude , Ferrer Jean‐Luc
Published: January 2014

Mu‐crystallin (CRYM), first described as a structural component of the eye lens in marsupials, has been characterized as an NADPH‐dependent cytosolic T3 thyroid hormone (triiodothyronine) binding protein. More recently, CRYM has also been associated with ketimine reductase activity. Here, we report three crystal structures: mouse CRYM (mCRYM) in its apo form, in a form complexed with NADPH, and in a form with both NADPH and triiodothyronine bound. Comparison of the apo and NADPH forms reveals a rearrangement of the protein upon NADPH binding that reduces the degrees of freedom of several residues and traps the conformation of the binding pocket in a more T3 competent state. These findings are in agreement with the cooperative mechanism identified using isothermal titration calorimetry. Our structure with T3 reveals for the first time the location of the hormone binding site and shows its detailed interactions. T3 binding involves mainly hydrophobic interactions. Only five residues, either directly or through bridging water molecules, are hydrogen bonded to the hormone. Using in silico docking analysis, a series of ring‐containing hydrophobic molecules were identified as potential mCRYM ligands, suggesting that the specificity for the recognition of the hydrophobic part of the hormone might be low. This is in agreement with the ketimine reductase activity that has been identified for ovine CRYM, as it demonstrates how a protein known as a thyroid hormone transporter can accommodate the ringed molecules required for its ketimine reductase activity. In the light of our results, a putative role of CRYM in thyroid hormone metabolism is also discussed.

Structured digital abstract

CRYM and CRYM bind by x-ray crystallography (View interaction)
Study Abroad in Central Spain: The Development of Regional Phonological Features
Authors: George Angela
Published: January 2014

This study investigated the development of two regional pronunciation features by 25 Spanish major or minors from a variety of universities in the United States who studied abroad for one semester in central Spain. Data were collected at the beginning, middle, and end of the semester using three tasks that ranged from reading a formal passage aloud to informal spontaneous speech. All tasks elicited the interdental and the uvular fricative, both salient phonological features of Castilian Spanish. Several linguistic and extralinguistic factors may account for the increase in use of the features throughout the semester by a small percentage of students.
Change in French Second Language Writing in Study Abroad and Domestic Contexts
Authors: Godfrey LeeAnne , Treacy Corbin , Tarone Elaine
Published: January 2014

This descriptive case study examines the writing of eight university learners of French—four during study abroad and four in on‐campus courses—over the course of a semester. The study abroad students all improved their ACTFL writing proficiency scores, while the domestic students' writing proficiency levels tended to stay the same or even decreased. But what specific features of students' writing changed over the semester? This study applied fine‐grained measures focused on the complexity, accuracy, fluency, and form‐function relationships of writing samples collected at the beginning and end of the semester. Results showed that students' writing developed in both study abroad and domestic contexts, although in different ways. Given the complexity of writing development, multiple measures should be used to assess second language writing across learning contexts.
Elementary School Foreign Language Teaching: Lessons Learned Over Three Decades (1980–2010)
Authors: Rhodes Nancy C.
Published: January 2014

The purpose of this research was to investigate the major successes and challenges of elementary school language teaching from 1980 to 2010 through the voices of some of the individuals who were instrumental in the development of the field. The author conducted interviews with 16 leaders in the field of early language education to elicit their views on such topics as program models, instructional approaches, proficiency assessment, and advocacy. Ten lessons learned are presented in the form of recommendations for the expansion of proficiency‐based language programs in elementary schools. These recommendations will help the field learn from past successes and failures, develop the highest possible levels of language proficiency, and build on the methodologies (e.g., immersion and content‐based instruction) that have been demonstrated to be best practices.
Focal adhesion protein expression in human diffuse large B‐cell lymphoma
Authors: Bosch Rosa , Dieguez‐Gonzalez Rebeca , Moreno María José , Gallardo Alberto , Novelli Silvana , Espinosa Iñigo , Céspedes María Virtudes , Pavón Miguel Ángel , Briones Javier , Grañena Albert , Sierra Jorge , Mangues Ramon , Casanova Isolda
Published: January 2014

Aims

Focal adhesions have been associated with poor prognosis in multiple cancer types, but their prognostic value in diffuse large B‐cell lymphoma (DLBCL) has not been evaluated. The aim of this study was to investigate the expression patterns and the prognostic value of the focal adhesion proteins FAK, Pyk2, p130Cas and HEF1 in DLBCL.

Methods and results

Focal adhesion protein expression was examined using immunohistochemistry in normal lymphoid tissues and in 60 DLBCL patient samples. Kaplan–Meier survival and Cox regression analysis were performed to evaluate the correlation of focal adhesion protein expression with patient prognosis. FAK, Pyk2, p130Cas and HEF1 expression was mostly found in the germinal centres of normal human lymphoid tissues. When assessed in DLBCL samples, FAK, Pyk2, p130Cas and HEF1 were highly expressed in 45%, 34%, 42% and 45% of the samples, respectively. Multivariate Cox analysis revealed that decreased FAK expression was a significant independent predictor of poorer disease outcome.

Conclusions

FAK expression is an independent prognostic factor in DLBCL. Our results suggest that the addition of FAK immunostaining to the current immunohistochemical algorithms may facilitate risk stratification of DLBCL patients.
Diagnostic criteria for ductal adenocarcinoma of the prostate: interobserver variability among 20 expert uropathologists
Authors: Seipel Amanda H , Delahunt Brett , Samaratunga Hemamali , Amin Mahul , Barton Joel , Berney Daniel M , Billis Athanase , Cheng Liang , Comperat Eva , Evans Andrew , Fine Samson W , Grignon David , Humphrey Peter A , Magi‐Galluzzi Cristina , Montironi Rodolfo , Sesterhenn Isabell , Srigley John R , Trpkov Kiril , van der Kwast Theo , Varma Murali , Zhou Ming , Ahmad Amar , Moss Sue , Egevad Lars
Published: January 2014

Aims

Ductal adenocarcinoma of the prostate (DAC) is clinically important, because its behaviour may differ from that of acinar adenocarcinoma. Our aims were to investigate the interobserver variability of this diagnosis among experts in uropathology and to define diagnostic criteria.

Methods and results

Photomicrographs of 21 carcinomas with ductal features were distributed among 20 genitourinary pathologists from eight countries. DAC was diagnosed by 18 observers (mean 13.2 cases, range 6–19). In 11 (52%) cases, a 2/3 consensus was reached for a diagnosis of DAC, and in five (24%) there was consensus against. In DAC, the respondents reported papillary architecture (86%), stratification of nuclei (82%), high‐grade nuclear features (54%), tall columnar epithelium (53%), elongated nuclei (52%), cribriform architecture (40%), and necrosis (7%). The most important diagnostic feature reported for DAC was papillary architecture (59%), whereas nuclear and cellular features were considered to be most important in only 2–11% of cases. The most common differential diagnoses were intraductal prostate cancer (52%), high‐grade PIN (37%), and acinar adenocarcinoma (17%). The most common reason for not diagnosing DAC was lack of typical architecture (33%).

Conclusions

Papillary architecture was the most useful diagnostic feature of DAC, and nuclear and cellular features were considered to be less important.
Topographies of Flesh: Women, Nonhuman Animals, and the Embodiment of Connection and Difference
Authors: McWeeny Jennifer
Published: January 2014

Because of risks of essentialism and homogenization, feminist theorists frequently avoid making precise ontological claims, especially in regard to specifying bodily connections and differences among women. However well‐intentioned, this trend may actually run counter to the spirit of intersectionality by shifting feminists' attention away from embodiment, fostering oppressor‐centric theories, and obscuring privilege within feminism. What feminism needs is not to turn from ontological specificity altogether, but to engage a new kind of ontological project that can account for the material complexity of social space in the twenty‐first century. Taking inspiration from the phenomenological concept of flesh as well as ecofeminism and María Lugones's theory of the colonial/modern gender system, this essay argues that our own flesh is related to that of others through lines of intercorporeal relations that collectively form topographies of flesh. When we attend to those material relationships present in a particular locality at a point in time, we are able to recognize topographical aggregates of beings that can serve as a basis for this new feminist ontology. An example from Toni Morrison's Beloved involving a human woman and a nonhuman one is used as a paradigm for thinking ontological connection and difference at the same time.