bluuebunny/crossref_metadata_2025 huggingface dataset:
Methotrexate Restores Regulatory T Cell Function Through Demethylation of the FoxP3 Upstream Enhancer in Patients With Rheumatoid Arthritis
Authors: Cribbs Adam P. , Kennedy Alan , Penn Henry , Amjadi Parisa , Green Patricia , Read Jordan E. , Brennan Fionula , Gregory Bernard , Williams Richard O.
Published: January 2015

Objective

We have previously shown, in a cohort of untreated rheumatoid arthritis (RA) patients, that the suppressive function of Treg cells is defective. However, other studies in cohorts of patients with established RA have shown that Treg cell function is normal. We hypothesized that treatment may restore Treg cell function and lead to reduced disease activity. The aim of this study was to investigate whether treatment with methotrexate (MTX) can result in epigenetic changes that lead to restoration of the Treg cell suppressive function in RA.

Methods

Peripheral blood samples from RA patients were assessed using 3H‐thymidine incorporation to measure Treg cell suppression of T cell proliferation, and by enzyme‐linked immunosorbent assay to determine Treg cell suppression of interferon‐γ production. CTLA‐4 and FoxP3 expression was measured by flow cytometry and quantitative polymerase chain reaction (qPCR) in Treg cells from healthy individuals and RA patients. CD4+ T cells isolated from healthy individuals were cultured with interleukin‐2 (IL‐2), IL‐6, and tumor necrosis factor α in the presence or absence of MTX, and FoxP3 expression was determined using qPCR and flow cytometry. Methylation of the FOXP3 upstream enhancer was analyzed by bisulfite sequencing PCR.

Results

Defective Treg cell function was observed only in RA patients who had not been treated with MTX, whereas Treg cells from MTX‐exposed RA patients had restored suppressive function. This restored suppression was associated with increased expression of FoxP3 and CTLA‐4 in Treg cells. Bisulfite sequencing PCR of Treg cells cultured in MTX revealed a significant reduction in methylation of the FOXP3 upstream enhancer.

Conclusion

This study identifies a novel mechanism of action of MTX, in which treatment of RA patients with MTX restores defective Treg cell function through demethylation of the FOXP3 locus, leading to a subsequent increase in FoxP3 and CTLA‐4 expression.
In vitro–in vivo extrapolations to evaluate the effect of concomitant drugs on tacrolimus (FK506) exposure
Authors: Oda Kazuo , Yamano Katsuhiro , Otsuka Yukio
Published: January 2015

The effect of concomitant drugs having a cytochrome P450 (CYP) 3A inhibitory potency on tacrolimus exposure was predicted from in vitro metabolism results. In this study, the IC50 values of concomitant drugs on the formation of M‐I, the major metabolite of tacrolimus, were determined, and the effect on oral exposure (AUCp.o.) of tacrolimus was assessed from static models. When an absorbed fraction (Fa) of 0.97, intestinal wall availability (Fg) of 0.27 and fraction metabolized by CYP3A (fm(CYP3A)) of 0.8 were used, the least bias was observed for the prediction of the AUCp.o. of tacrolimus. The relationship of the IC50 values of 11 inhibitors between tacrolimus and typical CYP3A substrates (midazolam and testosterone) was also analysed. A strong correlation was found between the IC50 values of tacrolimus and typical CYP3A substrates (r2 ≥ 0.85). The predictability of the effect of inhibitors on tacrolimus AUCp.o. was investigated based on the same static models with the use of published IC50 values for midazolam and testosterone. The bias for the prediction of tacrolimus AUCp.o. was minimal with the use of IC50 values determined using tacrolimus itself as a substrate. These results suggest that tacrolimus itself is still the best choice for predicting the AUCp.o. of tacrolimus, although our findings suggest that midazolam or testosterone may be used instead of tacrolimus to estimate roughly (predicted AUCp.o. within an approximately 2‐fold range of observed values) the effect of CYP3A inhibitors on the tacrolimus AUCp.o.. Copyright © 2015 John Wiley & Sons, Ltd.
Importance ofin situpreservation of parathyroid glands during total thyroidectomy
Authors: Lorente-Poch L , Sancho J J , Ruiz S , Sitges-Serra A
Published: January 2015

Background

Parathyroid failure is the most common complication after total thyroidectomy but factors involved are not completely understood. Accidental parathyroidectomy and parathyroid autotransplantation resulting in fewer than four parathyroid glands remaining in situ, and intensity of medical treatment of postoperative hypocalcaemia may have relevant roles. The aim of this study was to determine the relationship between the number of parathyroid glands remaining in situ and parathyroid failure after total thyroidectomy.

Methods

Consecutive patients undergoing first-time total thyroidectomy were studied prospectively, recording the number of Parathyroid Glands Remaining In Situ (PGRIS = 4 − (glands autografted + glands in the specimen)) and the occurrence of postoperative hypocalcaemia, and protracted and permanent hypoparathyroidism. Demographic, disease-related, laboratory and surgical variables were recorded. Patients were classified according to the PGRIS number into group 1–2 (one or two PGRIS), group 3 (three PGRIS) and group 4 (all four glands remaining in situ), and were followed for at least 1 year.

Results

A total of 657 patients were included, 43 in PGRIS group 1–2, 186 in group 3 and 428 in group 4. The prevalence of hypocalcaemia, and of protracted and permanent hypoparathyroidism was inversely related to the PGRIS score (group 1–2: 74, 44 and 16 per cent respectively; group 3: 51·1, 24·7 and 6·5 per cent; group 4: 35·3, 13·1 and 2·6 per cent; P < 0·001). Intact parathyroid hormone concentrations at 24 h and 1 month were inversely correlated with PGRIS score (P < 0·001). Logistic regression identified PGRIS score as the most powerful variable influencing acute and chronic parathyroid failure. In addition, a normal–high serum calcium concentration 1 month after thyroidectomy influenced positively the recovery rate from protracted hypoparathyroidism in all PGRIS categories.

Conclusion

In situ parathyroid preservation is critical in preventing permanent hypoparathyroidism after total thyroidectomy. Active medical treatment of postoperative hypocalcaemia has a positive synergistic effect.
Low expression of chloride channel accessory 1 predicts a poor prognosis in colorectal cancer
Authors: Yang Bo , Cao Lin , Liu Jiaen , Xu Yanjie , Milne Gillian , Chan Wanhei , Heys Steven D. , McCaig Colin D. , Pu Jin
Published: January 2015

BACKGROUND

Chloride channel accessory 1 (CLCA1) is a CLCA protein that plays a functional role in regulating the differentiation and proliferation of colorectal cancer (CRC) cells. Here we investigated the relationship between the level of CLCA1 and the prognosis of CRC.

METHODS

First, the level of CLCA1 was detected quantitatively in normal and cancerous colonic epithelial tissues with immunohistochemistry. Next, the correlations between CLCA1 expression, pathological tumor features, and the overall survival rate of patients was analyzed. Finally, 3 publicly available data sets from the Gene Expression Omnibus were examined: normal CRC versus early CRC (GSE4107), primary CRC versus metastatic lesions (GSE28702), and low chromosomal instability versus high chromosomal instability (GSE30540).

RESULTS

The expression of CLCA1 was decreased markedly in tumor specimens. CLCA1 expression was correlated significantly with the histological grade (P < .01) and lymph node metastasis (P < .01). A significantly poorer overall survival rate was found in patients with low levels of CLCA1 expression versus those with high expression levels (P < .05). The results confirmed that the low expression of CLCA1 in CRC was highly associated with tumorigenesis, metastasis, and high chromosomal instability. In addition, the loss of CLCA1 disrupted the differentiation of human colon adenocarcinoma cells (Caco‐2) in vitro.

CONCLUSIONS

These findings suggest that CLCA1 levels may be a potential predictor of prognosis in primary human CRC. Low expression of CLCA1 predicts disease recurrence and lower survival, and this has implications for the selection of patients most likely to need and benefit from adjuvant chemotherapy. Cancer 2015;121:1570–1580. © 2015 American Cancer Society.
Image‐based quantification and mathematical modeling of spatial heterogeneity in ESC colonies
Authors: Herberg Maria , Zerjatke Thomas , de Back Walter , Glauche Ingmar , Roeder Ingo
Published: January 2015

Pluripotent embryonic stem cells (ESCs) have the potential to differentiate into cells of all three germ layers. This unique property has been extensively studied on the intracellular, transcriptional level. However, ESCs typically form clusters of cells with distinct size and shape, and establish spatial structures that are vital for the maintenance of pluripotency. Even though it is recognized that the cells' arrangement and local interactions play a role in fate decision processes, the relations between transcriptional and spatial patterns have not yet been studied. We present a systems biology approach which combines live‐cell imaging, quantitative image analysis, and multiscale, mathematical modeling of ESC growth. In particular, we develop quantitative measures of the morphology and of the spatial clustering of ESCs with different expression levels and apply them to images of both in vitro and in silico cultures. Using the same measures, we are able to compare model scenarios with different assumptions on cell–cell adhesions and intercellular feedback mechanisms directly with experimental data. Applying our methodology to microscopy images of cultured ESCs, we demonstrate that the emerging colonies are highly variable regarding both morphological and spatial fluorescence patterns. Moreover, we can show that most ESC colonies contain only one cluster of cells with high self‐renewing capacity. These cells are preferentially located in the interior of a colony structure. The integrated approach combining image analysis with mathematical modeling allows us to reveal potential transcription factor related cellular and intercellular mechanisms behind the emergence of observed patterns that cannot be derived from images directly. © 2015 International Society for Advancement of Cytometry
Poor classroom behavior, conduct violations common for those with ASD, survey reveals
Authors: Gomez Cynthia
Published: January 2015

Students with autism‐spectrum disorder are often viewed as being somehow odd by those who don't know about their condition or don't understand it. Meanwhile, students on the spectrum frequently lack an understanding of nonverbal communication and what constitutes acceptable behavior. That can lead to misunderstandings between students with ASD and college faculty, staff and their peers.
Consider digital solutions to streamline your unit's functions
Authors: Gomez Cynthia
Published: January 2015

Tom Merrell is the assistant dean and director of student disability services at the University of San Francisco, where he has used technology to improve the efficiency and effectiveness of his office's myriad functions, deliver more personal service, and improve accountability through the use of a digital database.
Review how EpiPen laws can limit liability for college camps
Authors: Wilson Mark
Published: January 2015

While the national health care initiative is a divisive force among politicians, one area of health care — providing emergency medication to children who suffer from allergies — has received bipartisan support.
An Enantioselective Synthesis of (R)‐5,6‐Octadecadienoic Acid
Authors: Yu Qiong , Ma Shengming
Published: January 2015

A convenient, scalable, and highly enantioselective total synthesis of (R)‐5,6‐octadecadienoic acid was developed by using the recently established ATA (allenylation of terminal alkynes) reaction of TBS‐protected (TBS = tert‐butyldimethylsilyl) propargyl alcohol with n‐dodecanal in the presence of (R)‐α,α‐diphenylprolinol as the chiral source. The axial chirality of the allene unit withstood the many common organic transformations that were needed to achieve the total synthesis with a high ee (enantiomeric excess) value.
Generation and Trapping of Ketenes in Flow
Authors: Henry Cyril , Bolien David , Ibanescu Bogdan , Bloodworth Sally , Harrowven David C. , Zhang Xunli , Craven Andy , Sneddon Helen F. , Whitby Richard J.
Published: January 2015

Ketenes were generated by the thermolysis of alkoxyalkynes under flow conditions, and then trapped with amines and alcohols to cleanly give amides and esters. For a 10 min reaction time, temperatures of 180, 160, and 140 °C were required for >95 % conversion of EtO, iPrO, and tBuO alkoxyalkynes, respectively. Variation of the temperature and flow rate with inline monitoring of the output by IR spectroscopy allowed the kinetic parameters for the conversion of 1‐ethoxy‐1‐octyne to be easily estimated (Ea = 105.4 kJ/mol). Trapping of the in‐situ‐generated ketenes by alcohols to give esters required the addition of a tertiary amine catalyst to prevent competitive [2+2] addition of the ketene to the alkoxyalkyne precursor.
Online monitoring of Fenton‐mediated reactive red 6B oxidation kinetics
Authors: Xu Hang , Yu Tianlong , Wang Jianxu , Li Mei , Liu Yana
Published: January 2015

Online spectrophotometric technology was used to monitor the Fenton oxidation of the model dye Reactive Red 6B (RR6B) in an aqueous solution. The results showed that online monitoring technology was well equipped to record detailed information during the Fenton process. RR6B was successfully decomposed by Fenton oxidation and it was determined that optimal experimental conditions yielded nearly 100% dye removal to be 3.5 × 10−5 M ferrous ion, 2.5 × 10−3 M hydrogen peroxide and 3.85 pH. Both first‐order and Behnajady–Modirshahla–Ghanbery kinetics models described the Fenton process well with correlation coefficients above 0.99. The instant concentration of hydroxyl radicals and the reaction rate at different conditions were also calculated based on the above two models. © 2015 American Institute of Chemical Engineers Environ Prog, 34: 1019–1027, 2015
Mother–Daughter Coping and Disordered Eating
Authors: Lantzouni Eleni , Cox Molly Havnen , Salvator Ann , Crosby Ross D.
Published: January 2015

This study explores whether the coping style of teenage girls with and without an eating disorder is similar to that of their mothers' (biological and adoptive), and whether teens with disordered eating utilize more maladaptive coping compared with those without. Eating disorder was diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria, and the Coping Inventory for Stressful Situations was administered to distinguish the coping style of the participants. Our findings suggest that daughters coped very similarly to their mothers in either group. Contrary to previous studies, our sample of teenage girls with eating disorders as well as their mothers utilized less frequently the avoidance–distraction coping compared with the girls without eating disorders and their mothers. These findings reinforce the importance for family involvement and for simultaneous focus on intrapersonal and interpersonal maintenance factors during eating disorder treatment. Copyright © 2015 John Wiley & Sons, Ltd and Eating Disorders Association.
Eating Disorder Psychopathology, Brain Structure, Neuropsychological Correlates and Risk Mechanisms in Very Preterm Young Adults
Authors: Micali Nadia , Kothari Radha , Nam Kie Woo , Gioroukou Elena , Walshe Muriel , Allin Matthew , Rifkin Larry , Murray Robin M. , Nosarti Chiara
Published: January 2015

This study investigates the prevalence of eating disorder (ED) psychopathology, neuropsychological function, structural brain correlates and risk mechanisms in a prospective cohort of very preterm (VPT) young adults. We assessed ED psychopathology and neuropsychological correlates in 143 cohort individuals born at <33 weeks of gestation. Structural brain correlates and risk factors at birth, in childhood and adolescence, were investigated using prospectively collected data throughout childhood/adolescence. VPT‐born individuals had high levels of ED psychopathology at age 21 years. Executive function did not correlate with ED symptomatology. VPT adults presenting with ED psychopathology had smaller grey matter volume at age 14/15 years in the left posterior cerebellum and smaller white matter volume in the fusiform gyrus bilaterally, compared with VPT adults with no ED psychopathology. Caesarean delivery predicted engaging in compensatory behaviours, and severe eating difficulty at age 14 years predicted ED symptomatology in young adulthood. VPT individuals are at risk for ED symptomatology, with evidence of associated structural alterations in posterior brain regions. Further prospective studies are needed to clarify the pathways that lead from perinatal/obstetric complications to ED and relevant neurobiological mechanisms. Copyright © 2015 John Wiley & Sons, Ltd and Eating Disorders Association.
Heterogeneity of Property Rights Strategies in A Global Context: The Case of Genetically Modified Soybean Seeds
Authors: Monteiro Guilherme Fowler A. , Zylbersztajn Decio
Published: January 2015

The protection of property rights is a pressing strategic issue in the genetically modified soybean seed industry. Because the soybean plant is characterized by self‐reproducibility, it is essential for biotechnology firms to establish strategies of property rights appropriation. To obtain new insights into this issue, we investigate in two directions. First, we propose a model of value appropriation in which property rights strategies are influenced by the institutional conditions and the monitoring technology in a given country. Second, we analyze three cases of property rights protection with respect to soybean seeds. We then present a comparative discussion of the cases and develop some propositions based on the theoretical framework and the case studies. We conclude with a discussion of our model's managerial implications.
Is There Room for Not Knowing “Everything”?
Authors: Johnston Josephine
Published: January 2015

This fall, a recurrent theme at the meetings and conferences I attended was the benefit of learning as much as possible about one's genome and the genomes of one's children, including newborn babies. Genetic science is progressing fast, and scientists can now unravel and understand ever more about the tiny ways in which one person's genome differs from another's. This emerging data is useful, the argument goes, because (occasionally now but mainly in the promised near future) it can be used to tailor medical care, make more informed lifestyle choices, and chart a personalized education.

From here, a related argument can be developed: that one ought to learn as much as possible about one's genome and the genome of one's children. I keep wondering, however, how well I could actually process all this information and whether much of it would, in fact, help me become a better and healthier person, or a better parent.
Ongoing Controversy over SUPPORT
Authors: Kaebnick Gregory E.
Published: January 2015

It has been a couple of years now since debate erupted over the study known as the Surfactant, Positive Pressure, and Oxygenation Randomized Trial, which sought to gauge the risks and benefits of different blood oxygen levels currently targeted in the care of premature infants. Both articles in this issue of the Hastings Center Report try to take the debate to a new level, but as expressed in the title of one of three commentaries on the articles, the controversy shows no signs of abating.
Safeguarding the Public's Health: Ethical Nursing
Authors: Rushton Cynda Hylton , Broome Marion E.
Published: January 2015

With the landmark 2010 Future of Nursing report by the Institute of Medicine largely silent about the ethical foundation of nursing and with growing concerns about the prominence of ethical issues that arise for individuals across all roles within nursing, it is clearly time for the profession to pause and consider its ethical foundations anew. In August 2014, fifty nursing leaders participated in the national summit Nursing Ethics for the 21st Century, sponsored by The Johns Hopkins University School of Nursing and Berman Institute of Bioethics. Together, we and our colleagues identified priorities and created a blueprint for the future.
Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload
Authors: McLaren Christine E. , Emond Mary J. , Subramaniam V. Nathan , Phatak Pradyumna D. , Barton James C. , Adams Paul C. , Goh Justin B. , McDonald Cameron J. , Powell Lawrie W. , Gurrin Lyle C. , Allen Katrina J. , Nickerson Deborah A. , Louie Tin , Ramm Grant A. , Anderson Gregory J. , McLaren Gordon D.
Published: January 2015

To identify polymorphisms associated with variability of iron overload severity in HFE‐associated hemochromatosis, we performed exome sequencing of DNA from 35 male HFE C282Y homozygotes with either markedly increased iron stores (n = 22; cases) or with normal or mildly increased iron stores (n = 13; controls). The 35 participants, residents of the United States, Canada, and Australia, reported no or light alcohol consumption. Sequencing data included 82,068 single‐nucleotide variants, and 10,337 genes were tested for a difference between cases and controls. A variant in the GNPAT gene showed the most significant association with severe iron overload (P = 3 × 10−6; P = 0.033 by the likelihood ratio test after correction for multiple comparisons). Sixteen of twenty‐two participants with severe iron overload had glyceronephosphate O‐acyltransferase (GNPAT) polymorphism p.D519G (rs11558492; 15 heterozygotes, one homozygote). No control participant had this polymorphism. To examine functional consequences of GNPAT deficiency, we performed small interfering RNA–based knockdown of GNPAT in the human liver‐derived cell line, HepG2/C3A. This knockdown resulted in a >17‐fold decrease in expression of the messenger RNA encoding the iron‐regulatory hormone, hepcidin. Conclusion: GNPAT p.D519G is associated with a high‐iron phenotype in HFE C282Y homozygotes and may participate in hepcidin regulation. (Hepatology 2015;62:429–439
Stability of 13C‐Urea Breath Test Samples Over Time in the Diagnosis of Helicobacter pylori
Authors: Perets Tsachi Tsadok , Shporn Einav , Boltin Doron , Dickman Ram , Niv Yaron
Published: January 2015

Background

The accuracy and repeatability of breath test in the diagnosis of Helicobacter pylori infection have not been adequately investigated. Although it has been shown that storage for long periods does not affect the analysis results, no data are available on the effect of repetitive testing. In this study, our aim was to evaluate the repeatability of the analyses of breath samples at room temperature.

Methods

A total of 202 positive breath samples were collected in duplicates, before and after administration of 75 mg 13C‐ urea dissolved in 100 ml of orange juice. Breath test results were expressed as delta 13CO2. The cut‐off value was 3.5 parts per thousand. Each sample was analyzed in a mass spectrometer 7, 14, 21, and 28 days after collection. The accuracy calculation was based on the comparison of the delta 13CO2 obtained in the three consecutive weeks following the first test run to the delta 13CO2 obtained in the first test run.

Results

Two hundred (99%), 197 (97.52%), and 196 (97%) of the 202 samples tested positive in the second, third, and fourth test runs, respectively. The accuracy of the delta 13CO2 was 98.6%, 99.2%, and 96.7% in the three consecutive runs, respectively.

Conclusion

Short‐term storage of 1 month does not affect sample stability or the results of 13C‐urea breath tests in up to three consecutive repeats.
Light microscopy and scanning electron microscopy study on microstructure of gallbladder mucosa in pig
Authors: Prozorowska Ewelina , Jackowiak Hanna
Published: January 2015

The present light microscopy (LM) and scanning electron microscopy (SEM) studies on porcine gallbladder mucosa provide a description of the microstructures of great functional importance such as mucosal folds, the epithelium, glands, and lymphatic nodules. The results showed the regional structural differences of the porcine gallbladder wall. Depending on the part of the gallbladder, three types of mucosal structures were described: simple and branched folds and mucosal crypts. An important structural feature found in the mucosa is connected with the structural variety of type of mucosal folds, which change from simple located in the neck, to most composed, i.e., branched or joined, in the polygonal crypts toward the fundus of the gallbladder. The morphometric analysis showed statistically significantly differences in the form and size of the folds and between the fundus, body, and neck of the gallbladder. Differences in the size of mucosal epithelium are discussed in terms of processes of synthesis and secretion of glycoproteins. Regional, species‐specific differences in morphology of mucosal subepithelial glands, i.e., their secretory units and openings, and intensity of mucus secretion were described.

Our results on the pig gallbladder show adaptation and/or specialization in particular areas of the mucosa for (1) secretion of mucus in the neck or body of gallbladder and (2) for cyclic volume changes, especially in the fundus of gallbladder. The description of the microstructures of mucosa in the porcine gallbladder could be useful as reference data for numerous experiments on the bile tract in the pig. Microsc. Res. Tech. 78:220–229, 2015. © 2015 Wiley Periodicals, Inc.
Development of a surface plasmon resonance assay to measure the binding affinity of wild‐type influenza neuraminidase and its H274Y mutant to the antiviral drug zanamivir
Authors: Somasundaram Balaji , Fee Conan J. , Fredericks Rayleen , Watson Andrew J. A. , Fairbanks Antony J.
Published: January 2015

Influenza is one of the most common infections of the upper respiratory tract. Antiviral drugs that are currently used to treat influenza, such as oseltamivir and zanamivir, are neuraminidase (NA) inhibitors. However, the virus may develop resistance through single‐point mutations of NA. Antiviral resistance is currently monitored by a labelled enzymatic assay, which can be inconsistent because of the short half‐life of the labelled product and variations in the assay conditions. In this paper, we describe a label‐free surface plasmon resonance (SPR) assay for measuring the binding affinity of NA‐drug interactions. Wild‐type (WT) NA and a histidine 274 tyrosine (H274Y) mutant were expressed in High Five™ (Trichoplusia ni) insect cells. A spacer molecule (1,6‐hexanediamine) was site‐specifically conjugated to the 7‐hydroxyl group of zanamivir, which is not involved in binding to NA, and the construct was immobilized onto a SPR sensor Chip to obtain a final immobilization response of 431 response units. Binding responses obtained for WT and H274Y mutant NAs were fitted to a simple Langmuir 1:1 model with drift to obtain the association (ka) and dissociation (kd) rate constants. The ratio between the binding affinities for the two isoforms was comparable to literature values obtained using labelled enzyme assays. Significant potential exists for an extension of this approach to test for drug resistance of further NA mutants against zanamivir and other antiviral drugs, perhaps paving the way for a reliable SPR biosensor assay that may replace labelled enzymatic assays. Copyright © 2015 John Wiley & Sons, Ltd.
Effects of (R)‐(−)‐5‐methyl‐1‐nicotinoyl‐2‐pyrazoline on glutamate transporter 1 and cysteine/glutamate exchanger as well as ethanol drinking behavior in male, alcohol‐preferring rats
Authors: Aal‐Aaboda Munaf , Alhaddad Hasan , Osowik Francis , Nauli Surya M. , Sari Youssef
Published: January 2015

Alcohol consumption is largely associated with alterations in the extracellular glutamate concentrations in several brain reward regions. We recently showed that glutamate transporter 1 (GLT‐1) is downregulated following chronic exposure to ethanol for 5 weeks in alcohol‐preferring (P) rats and that upregulation of the GLT‐1 levels in nucleus accumbens and prefrontal cortex results, in part, in attenuating ethanol consumption. Cystine glutamate antiporter (xCT) is also downregulated after chronic ethanol exposure in P rats, and its upregulation could be valuable in attenuating ethanol drinking. This study examines the effect of a synthetic compound, (R)‐(−)‐5‐methyl‐1‐nicotinoyl‐2‐pyrazoline (MS‐153), on ethanol drinking and expressions of GLT‐1 and xCT in the amygdala and the hippocampus of P rats. P rats were exposed to continuous free‐choice access to water, 15% and 30% ethanol, and food for 5 weeks, after which they received treatments of MS‐153 or vehicle for 5 days. The results show that MS‐153 treatment significantly reduces ethanol consumption. It was revealed that GLT‐1 and xCT expressions were downregulated in both the amygdala and the hippocampus of ethanol–vehicle‐treated rats (ethanol–vehicle group) compared with water‐control animals. MS‐153 treatment upregulated GLT‐1 and xCT expressions in these brain regions. These findings demonstrate an important role for MS‐153 in these glutamate transporters for the attenuation of ethanol‐drinking behavior. © 2015 Wiley Periodicals, Inc.
Potential of neural stem cell‐based therapies for Alzheimer's disease
Authors: Li Xue‐Yuan , Bao Xin‐Jie , Wang Ren‐Zhi
Published: January 2015

Alzheimer's disease (AD), known to be a leading cause of dementia that causes heavy social and financial burdens worldwide, is characterized by progressive loss of neurons and synaptic connectivity after depositions of amyloid‐β (Aβ) protein. Current therapies for AD patients can only alleviate symptoms but cannot deter the neural degeneration, thus providing no long‐term recovery. Neural stem cells (NSCs), capable of self‐renewal and of differentiation into functional neurons and glia, have been shown to repair damaged networks and reverse memory and learning deficits in animal studies, providing new hope for curing AD patients by cell transplantation. Under AD pathology, the microenvironment also undergoes great alterations that affect the propagation of NSCs and subsequent therapeutic efficiency, calling for measures to improve the hostile environment for cell transplantation. This article reviews the therapeutic potential of both endogenous and exogenous NSCs in the treatment of AD and the challenges to application of stem cells in AD treatment, particularly those from the microenvironmental alterations, in the hope of providing more information for future research in exploiting stem cell‐based therapies for AD. © 2015 Wiley Periodicals, Inc.
Effects of autumn tillage and residue management on soil respiration in a long‐term field experiment in Sweden
Authors: Kainiemi Veera , Arvidsson Johan , Kätterer Thomas
Published: January 2015

Several previous field studies in temperate regions have shown decreased soil respiration after conventional tillage compared with reduced or no‐tillage treatments. Whether this decrease is due to differences in plant residue distribution or changes in soil structure following tillage remains an open question. This study investigated (1) the effects of residue management and incorporation depth on soil respiration and (2) biological activity in different post‐tillage aggregates representing the actual size and distribution of aggregates observed in the tilled layer. The study was conducted within a long‐term tillage experiment on a clay soil (Eutric Cambisol) in Uppsala, Sweden. After 38 y, four replicate plots in two long‐term treatments (moldboard plowing (MP) and shallow tillage (ST)) were split into three subplots. These were then used for a short‐term trial in which crop residues were either removed, left on the surface or incorporated to about 6 cm depth (ST) or at 20 cm depth (MP). Soil respiration, soil temperature, and water content were monitored during a 10‐d period after tillage treatment. Respiration from aggregates of different sizes produced by ST and MP was also measured at constant water potential and temperature in the laboratory. The results showed that MP decreased short‐term soil respiration compared with ST or no tillage. Small aggregates (< 16 mm) were biologically most active, irrespective of tillage method, but due to their low proportion of total soil mass they contributed < 1.5% to total respiration from the tilled layer. Differences in respiration between tillage treatments were found to be attributable to indirect effects on soil moisture and temperature profiles and the depth distribution of crop residues, rather than to physical disturbance of the soil.
Preparation of 4‐butylaniline‐bonded silica gel for the solid‐phase extraction of flavone glycosides
Authors: Chu Ganghui , Cai Wensheng , Shao Xueguang
Published: January 2015

To extract flavone glycosides efficiently, a new extraction material based on 4‐butylaniline‐bonded silica gel was prepared using a two‐step grafting method including a ring‐opening reaction and synchronous hydrolysis. Preparation of the silica‐based material was easily achieved under mild conditions, and the material was characterized by Fourier transform infrared spectroscopy, elemental analysis, and scanning electron microscopy. The material was used in solid‐phase extraction, and the extraction can be performed in neutral conditions without regard to ionic strength. Selectivity tests of 14 compounds on the extraction cartridge showed that the material has a high affinity to flavone glycosides in contrast to octadecyl silica, and the extraction yields for four flavone glycosides were found to be >93%. Selectivity tests further reveal that the adsorption on its surface is likely attributed to multiple interactions, including hydrophobic interactions, π–π interactions, and hydrogen bonding. To explore the applicability of 4‐butylaniline‐bonded silica gel, naringin and hesperidin from Simotang oral liquid were extracted, and the extraction yields were >90%, which is distinguished from <28% on octadecyl silica cartridge.
Ultra high performance liquid chromatography with synapt high‐definition mass spectrometry and a pattern recognition approach to characterize chemical constituents and rat metabolites after the oral administration of Phellinus igniarius
Authors: Dong Yu , Wang Huiyu , Zhang Yang , An Na , Zhang Yue , Shou Dan
Published: January 2015

Phellinus igniarius has antibacterial, antiviral, antioxidative, antitumor, and antimutagenic effects. In this study, an integrative pattern recognition approach using principal component analysis and orthogonal partial least squares discriminant analysis was successfully applied for the rapid analysis of natural compounds in traditional Chinese medicine. An ultra high performance liquid chromatography with synapt high‐definition mass spectrometry method and MassLynx software was used. This method employed gradient elution to rapidly analyze and characterize chemical constituents and metabolites after the oral administration of a P. igniarius ethanol extract. There were 24 peaks within 10 min of the analysis time and 20 of these were identified or tentatively characterized on the basis of their fragmentation behaviors. In the S‐plot of the orthogonal partial least squares discriminant analysis, 27 ions were extracted to make the serum. Among them, nine absorbed the prototype components and 18 metabolites were identified in vivo. Glucuronidation, oxidation, and methylation were the major metabolic reactions. This study is the first systematic analysis and characterization of the chemical constituents and metabolites in an ethanol extract of P. igniarius. This method can be applied to the rapid analysis and characterization of constituents in rat serum after the oral administration of other compounds used in traditional Chinese medicines.
Familial aggregation of Parkinson's disease in the Faroe Islands
Authors: Petersen Maria Skaalum , Bech Sara , Nosova Ekaterina , Aasly Jan , Farrer Matthew J.
Published: January 2015

The Faroe Islands are a geographic population isolated in the North Atlantic with a high prevalence of Parkinson's disease (PD). Although environmental risk factors are well described, the familial aggregation of PD on the Islands has yet to be explored. Complete ascertainment of all patients with PD was performed, including 217 cases and 251 control subjects. All patients were neurologically assessed and diagnosed using UK Brain Bank criteria and Hohn and Yahr staging. Comprehensive genealogical and detailed cartographic analyses were performed. Relative risk and risk ratios were calculated with respect to the general population. Patients with PD in the Faroes have a higher age at symptom onset and diagnosis than for neighboring countries. Clinically, patients are similar; however, they are more likely to have affected relatives than randomly selected control subjects, matched by sex and age. Disease is most prevalent within two geographic regions. Overall, the relative risk for PD was 2.3 (95% confidence interval [CI], 1.2‐4.3; P = 0.008) for siblings and 1.4 (95% CI, 1.01‐1.99, P = 0.04) for first cousins. The etiology and excess prevalence of PD on the Faroes is complicated. Regional and familial clustering, and subsequent segregation analysis, suggests the disease best fits a genetic etiology with limited support for an environmental contribution. Pedigree‐based analysis of PD on the Faroe Islands which has few founders and a relatively homogeneous background may elaborate on these possibilities and their joint contribution. © 2015 International Parkinson and Movement Disorder Society
Combination therapy to relieve storage symptoms
Authors: Chaplin Steve , Kirby Roger
Published: January 2015

Vesomni, a modified‐release formulation, can significantly relieve storage symptoms in men for whom monotherapy has proved insufficient.
Numerical simulation and compact modelling of AlGaN/GaN HEMTs with mitigation of self‐heating effects by substrate materials
Authors: Rodríguez Raúl , González Benito , García Javier , Yigletu Fetene M. , Tirado José M. , Iñiguez Benjamín , Nunez Antonio
Published: January 2015

In this paper, DC characteristics of an AlGaN/GaN on sapphire high‐electron mobility transistor (HEMT) are measured, numerically simulated, and modelled accounting for self‐heating effects (SHEs), with the main electrical parameters being extracted. Decomposing the transistor thermal resistance into the buffer and substrate components, our study can be easily extended to other substrate materials. Thus, sapphire is substituted with silicon, molybdenum, and SiC, which reduce current‐collapse due to SHEs thanks to their considerably higher thermal conductivity, which improves transistor performance. Furthermore, we implement a compact model available for AlGaN/GaN HEMTs, incorporating the temperature dependence of extrinsic source/drain ohmic resistances, which are numerically evaluated for the different substrates.
Detection of dislocation‐related midgap levels in pulsed laser deposited GaN by photo‐induced current transient spectroscopy
Authors: Kumar M. Senthil , Srivatsa K. M. K. , Kushvaha S. S.
Published: January 2015

Deep levels in unintentionally doped GaN epilayers grown on sapphire (0001) by ultra high vacuum pulsed laser deposition at 600 and 700 °C have been studied using photo‐induced current transient spectroscopy (PICTS). The GaN epitaxial layers were deposited by laser ablating a hydride vapor phase epitaxy grown bulk GaN polycrystalline target in the ambient of r.f. nitrogen radicals. The activation energy of dark conductivity for these layers lies in the range 0.17–0.25 eV. An acceptor‐like deep trap level is detected in the PICTS spectrum with activation energy of 1.32 eV. For the 700 °C grown GaN layer, an additional well‐pronounced acceptor‐like defect level near mid‐gap at 1.52 eV has been observed. From the analysis of trap capture kinetics, both defect levels are identified to be extended ‘bandlike’ electronic states associated with extended defects such as dislocations present in GaN layers.
Resistivity in Ba(FeCo)As: Comparison of thin films and single crystals
Authors: Ummarino G. A. , Galasso S. , Pecchio P. , Daghero D. , Gonnelli R. S. , Kurth F. , Iida K. , Holzapfel B.
Published: January 2015

The temperature dependence of the resistivity of epitaxial Ba(FeCo)As thin films (with nominal doping and ) has been analysed and compared with analogous measurements on single crystals taken from literature. The of thin films looks different from that of single crystals, even when the cobalt content is the same. All curves can be fitted by considering an effective two‐band model (with holes and electrons bands) in which the electrons are more strongly coupled with the bosons (spin fluctuations) than holes, while the effect of impurities is mainly concentrated in the hole band. Within this model the mediating boson has the same characteristic energy in single crystals and thin films, but the shape of the transport spectral function at low energy has to be very different, leading to a “hardening” of the electron–boson spectral function in thin films, associated with the strain induced by the substrate.
Brillouin zone and band structure of β‐Ga2O3
Authors: Peelaers Hartwin , Van de Walle Chris G.
Published: January 2015

Gallium oxide is increasingly used in a variety of applications, but confusion reigns over the Brillouin zone and the band structure of monoclinic β‐Ga2O3. We present a detailed study of the shape of the Brillouin zone and the location of high‐symmetry points. Combined with a study of electronic structure based on hybrid density functional theory, this allows us to derive an accurate band structure. We discuss the nature of the band gap and the location of the band extrema.
Optical studies of non‐polar m‐plane () InGaN/GaN multi‐quantum wells grown on freestanding bulk GaN
Authors: Sutherland Danny , Zhu Tongtong , Griffiths James T. , Tang Fengzai , Dawson Phil , Kundys Dmytro , Oehler Fabrice , Kappers Menno J. , Humphreys Colin J. , Oliver Rachel A.
Published: January 2015

We report on the optical properties of non‐polar m‐plane InGaN/GaN multi‐quantum wells (MQWs) grown on ammonothermal bulk GaN substrates. The low temperature continuous wave (CW) photoluminescence spectra are broad with a characteristic low energy tail. The majority of the emission bands decay with a time constant ~300 ps, but detailed photoluminescence time decay and time resolved spectroscopy measurements revealed the existence of a distinct slowly decaying emission band. This slowly decaying component is responsible for the low energy tails observed in the CW spectra. Scanning electron microscopy–cathodo­luminescence (SEM‐CL) studies show that the low energy emission band originates from regions across step‐bunches, which are associated to the GaN substrate miscut. Subsequent scanning transmission electron microscopy imaging demonstrates that semi‐polar QWs had formed continuous layers on the step bunches between the m‐plane QWs and were responsible for the slower decaying, low energy emission band. Thus we assign the asymmetric low energy emission tails observed in photoluminescence studies to the formation of semi‐polar facet QWs across the step bunches associated with the GaN miscut.
Transparent, conductive bulk GaN by high temperature ammonothermal growth
Authors: Jiang Wenkan , Ehrentraut Dirk , Cook Jonathan , Kamber Derrick S. , Pakalapati Rajeev T. , D'Evelyn Mark P.
Published: January 2015

A novel, highly scalable apparatus has been employed to perform high temperature ammonothermal growth of (0001) GaN bulk crystals up to 52 mm in diameter and to a thickness of greater than 2 mm. X‐ray characterization of the crystals shows excellent crystallinity with radii of curvature > 20 m and a 201 rocking curve FWHM of <30 arcsec. Hall effect and optical absorption measurements performed on the crystal show a free carrier concentration of 1.1 × 1018 cm−3 and an absorption coefficient of 1 cm−1 at 450 nm and 2 cm−1 at 410 nm, meeting the substrate requirements for use as a native substrate in blue or violet LED devices. To the best of our knowledge, this is the lowest optical absorption coefficient reported for ammonothermally‐grown GaN having a carrier concentration above 1018 cm−3.
Nanorippling of ion irradiated GaAs (001) surface near the sputter‐threshold energy
Authors: Chowdhury Debasree , Ghose Debabrata , Mollick Safiul Alam , Satpati Biswarup , Bhattacharyya Satya Ranjan
Published: January 2015

Ripple formation driven by Ehrlich–Schwoebel barrier is evidenced for normal incidence 30 eV Ar+ bombardment of GaAs (001) surface at elevated target temperature. The pattern follows the twofold symmetry of the bombarded crystal surface. The ridges of the ripples are found to align along the direction. The results are described by a non‐linear continuum equation based on biased diffusion of adspecies created by ion impact.

Ripple topography on ion bombarded GaAs (001) surface: AFM image (left panel) and XTEM image (right panel).
Representation of daytime moist convection over the semi‐arid Tropics by parametrizations used in climate and meteorological models
Authors: Couvreux F. , Roehrig R. , Rio C. , Lefebvre M.‐P. , Caian M. , Komori T. , Derbyshire S. , Guichard F. , Favot F. , D'Andrea F. , Bechtold P. , Gentine P.
Published: January 2015

A case of daytime development of deep convection over tropical semi‐arid land is used to evaluate the representation of convection in global and regional models. The case is based on observations collected during the African Monsoon Multidisciplinary Analysis (AMMA) field campaign and includes two distinct transition phases, from clear sky to shallow cumulus and from cumulus to deep convection. Different types of models, run with identical initial and boundary conditions, are intercompared: a reference large‐eddy simulation (LES), single‐column model (SCM) version of four different Earth system models that participated in the Coupled Model Intercomparison Project 5 exercise, the SCM version of the European Centre for Medium‐range Weather Forecasts operational forecast model, the SCM version of a mesoscale model and a bulk model. Surface fluxes and radiative heating are prescribed preventing any atmosphere–surface and cloud–radiation coupling in order to simplify the analyses so that it focuses only on convective processes. New physics packages are also evaluated within this framework.

As the LES correctly reproduces the observed growth of the boundary layer, the gradual development of shallow clouds, the initiation of deep convection and the development of cold pools, it provides a basis to evaluate in detail the representation of the diurnal cycle of convection by the other models and to test the hypotheses underlying convective parametrizations. Most SCMs have difficulty in representing the timing of convective initiation and rain intensity, although substantial modifications to boundary‐layer and deep‐convection parametrizations lead to improvements. The SCMs also fail to represent the mid‐level troposphere moistening during the shallow convection phase, which we analyse further. Nevertheless, beyond differences in timing of deep convection, the SCM models reproduce the sensitivity to initial and boundary conditions simulated in the LES regarding boundary‐layer characteristics, and often the timing of convection triggering.