bluuebunny/crossref_metadata_2025 huggingface dataset:
Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture
Authors: Malenczyk Katarzyna , Keimpema Erik , Piscitelli Fabiana , Calvigioni Daniela , Björklund Peyman , Mackie Kenneth , Di Marzo Vincenzo , Hökfelt Tomas G. M. , Dobrzyn Agnieszka , Harkany Tibor
Published: October 2015

Significance

Glucagon and insulin are produced in distinct cell populations within pancreatic Langerhans islets, where intercellular interactions control their production and release. Modifications to the microstructure of pancreatic islets are implicated in disease pathogenesis, but the developmental rules underlying cell commitment and segregation are incompletely understood. We show that endocannabinoids (ω-6) via CB
1
cannabinoid receptors and endovanilloid ligands via transient receptor potential cation channel subfamily V member 1, as well as dietary ω-3 polyunsaturated fatty acids, affect the cellular organization of pancreatic islets during organ development. Thus, lipid signaling emerges as a key determinant of tissue organization and can program hormone secretion for life.
Evaluating slogan translation from the readers’ perspective
Authors: Lim Lily , Loi Kwok Ying
Published: October 2015

Slogans play an important role in conveying information to targeted audiences, and the translation of slogans tends to be studied under the rubric of public-notice translation. Previous research mainly uses researchers’ expertise to evaluate the quality of this type of translation. Yet, little is known about what the targeted readers think about the translation, although their opinions present key information that helps to determine whether the translation has achieved the intended effect. This paper elicits and systematically analyzes readers’ responses. We investigate the case of Macao, a rapidly growing economy where the demand for English translation has markedly increased in recent decades. Public administration bodies in Macao have commissioned Chinese-to-English translation in varied areas such as tourism, social security and welfare, cultural and sports events. We sampled ten translated slogans that were used in the public sector, and administered survey questionnaires (n=130) to both source-text and target-text readers. The two groups of readers’ evaluations, based on the criteria of fluency, conciseness, persuasiveness and mnemonic effect, reveal that the translations are perceived significantly less favorably than the originals are. Readers most strongly disliked word-for-word translations, and pointed out numerous problems with the translations such as ungrammaticality, inappropriate word use, lack of appeal, and unintelligibility due to insufficient background knowledge. This research demonstrates the tangible value of using readers’ responses to evaluate translation quality. It also has implications for translator training, and recommends that public authorities should institute a rigorous quality assurance system.
Pulmonary Vascular Changes 22 Years after Single Lung Transplantation for Pulmonary Arterial Hypertension: A Case Report with Molecular and Pathological Analysis
Authors: Zhao Yidan D. , Peng Jenny , Granton Elise , Lin Kathleen , Lu Catherine , Wu Licun , Machuca Tiago , Waddell Thomas K. , Keshavjee Shaf , de Perrot Marc
Published: October 2015

This study was undertaken to characterize the molecular and pathological mechanisms of pulmonary vascular remodeling in a patient who developed chronic lung allograft dysfunction and recurrent pulmonary hypertension (PH) 22 years after undergoing a right single lung transplantation for pulmonary arterial hypertension (PAH). Histopathologic examination of the explanted lungs at the time of retransplantation showed characteristics of diffuse vascular remodeling combined with features of acute and chronic thromboemboli and evidence of bronchiolitis obliterans in the right lung allograft. In contrast, the native left lung demonstrated pulmonary arterial changes in keeping with PAH associated with disseminated pulmonary ossification. Real‐time polymerase chain reaction and Western blot—performed on the first lung allograft, the native lung, and the new donor lung—demonstrated increased expression of apoptotic‐related gene and protein levels in the lung allograft compared with the native PAH lung and the donor lung. Localization of cell apoptosis determined by triple immunostaining for caspase 3, CD31, and smooth muscle actin was positive in the pulmonary endothelial cells but not the smooth muscle cells of the lung allograft, while no positive staining was detected for cell death in the native PAH lung. The presence of PH in the lung allograft 22 years after transplantation was associated with upregulation of apoptotic markers and evidence of apoptotic endothelial cell death compared with the native lung and donor lung.
The bar involution for quantum symmetric pairs
Authors: Balagović Martina , Kolb Stefan
Published: October 2015

We construct a bar involution for quantum symmetric pair coideal subalgebras

B

c

,

s

B_{\mathbf {c},\mathbf {s}}

corresponding to involutive automorphisms of the second kind of symmetrizable Kac-Moody algebras. To this end we give unified presentations of these algebras in terms of generators and relations, extending previous results by G. Letzter and the second-named author. We specify precisely the set of parameters

c

\mathbf {c}

for which such an intrinsic bar involution exists.
Temporary Endobronchial Stent as a Bridge to Corrective Surgery For Severe Kyphoscoliosis-associated Central-Airway Extrinsic Compression
Authors: Sriratanaviriyakul Narin , Nguyen Lam-Phuong , Ismail Heba , Roberto Rolando F. , Yoneda Ken Y.
Published: October 2015

Kyphoscoliosis is known to compromise lung function, with the primary mechanism being reduced chest wall compliance with a resultant restrictive pulmonary physiology. Severe scoliosis can also cause extrinsic compression of the central airways, leading to recurrent respiratory infections, lobar atelectasis, and potentially acute respiratory failure. Definitive therapy is corrective surgery of the spine. However, patients with severe scoliosis are at a potentially high risk of perioperative pulmonary complications. To our knowledge, we report the first successful use of retrievable endobronchial stents as a bridge to corrective surgery for kyphoscoliosis-associated complete central-airway extrinsic compression in a patient who was considered as too high risk for surgical correction due to her respiratory status. After surgery, the stents were removed and our patient experienced sustained improvement in pulmonary function and the clinical respiratory status.
Mediastinitis
Authors: Voldby Nina , Folkersen Birgitte H. , Rasmussen Torben R.
Published: October 2015

Mediastinitis is a rare but a serious complication of endobronchial ultrasound–guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound–guided fine needle aspiration (EUS-FNA). We present 3 cases of mediastinitis following these diagnostic procedures. In 2 of the patients oropharyngeal bacteria were found in the cultures from the mediastinal abscess. All 3 cases were treated successfully with thoracotomy and drainage of the abscess together with intravenous antibiotics. On the basis of these cases and an updated review of the literature we discuss the most likely etiology for mediastinitis in association with EBUS-TBNA and EUS-FNA procedures and propose how to reduce the risk for this serious complication. The possibility of mediastinitis should always be kept in mind when a patient complains of fever over a long period of time as well as chest pain and malaise after an EBUS-TBNA or EUS-FNA procedure.
Relative Citation Ratio (RCR): A new metric that uses citation rates to measure influence at the article level
Authors: Ian Hutchins B. , Yuan Xin , Anderson James M. , Santangelo George M.
Published: October 2015

Despite their recognized limitations, bibliometric assessments of scientific productivity have been widely adopted. We describe here an improved method that makes novel use of the co-citation network of each article to field-normalize the number of citations it has received. The resulting Relative Citation Ratio is article-level and field-independent, and provides an alternative to the invalid practice of using Journal Impact Factors to identify influential papers. To illustrate one application of our method, we analyzed 88,835 articles published between 2003 and 2010, and found that the National Institutes of Health awardees who authored those papers occupy relatively stable positions of influence across all disciplines. We demonstrate that the values generated by this method strongly correlate with the opinions of subject matter experts in biomedical research, and suggest that the same approach should be generally applicable to articles published in all areas of science. A beta version of iCite, our web tool for calculating Relative Citation Ratios of articles listed in PubMed, is available athttps://icite.od.nih.gov.
SiteOut: an online tool to design binding site-free DNA sequences
Authors: Estrada Javier , Ruiz-Herrero Teresa , Scholes Clarissa , Wunderlich Zeba , DePace Angela H.
Published: October 2015

DNA-binding proteins control many fundamental biological processes such as transcription, recombination and replication. A major goal is to decipher the role that DNA sequence plays in orchestrating the binding and activity of such regulatory proteins. To address this goal, it is useful to rationally design DNA sequences with desired numbers, affinities and arrangements of protein binding sites. However, removing binding sites from DNA is computationally non-trivial since one risks creating new sites in the process of deleting or moving others. Here we present an online binding site removal tool, SiteOut, that enables users to design arbitrary DNA sequences that entirely lack binding sites for factors of interest. SiteOut can also be used to delete sites from a specific sequence, or to introduce site-free spacers between functional sequences without creating new sites at the junctions. In combination with commercial DNA synthesis services, SiteOut provides a powerful and flexible platform for synthetic projects that interrogate regulatory DNA. Here we describe the algorithm and illustrate the ways in which SiteOut can be used; it is publicly available athttps://depace.med.harvard.edu/siteout/.
RapMap: A Rapid, Sensitive and Accurate Tool for Mapping RNA-seq Reads to Transcriptomes
Authors: Srivastava Avi , Sarkar Hirak , Gupta Nitish , Patro Rob
Published: October 2015

Motivation:The alignment of sequencing reads to a transcriptome is a common and important step in many RNA-seq analysis tasks. When aligning RNA-seq reads directly to a transcriptome (as is common in thede novosetting or when a trusted reference annotation is available), care must be taken to report the potentially large number of multi-mapping locations per read. This can pose a substantial computational burden for existing aligners, and can considerably slow downstream analysis.

Results:We introduce a novel concept, quasi-mapping, and an efficient algorithm implementing this approach for mapping sequencing reads to a transcriptome. By attempting only to report the potential loci of origin of a sequencing read, and not the base-to-base alignment by which it derives from the reference,RapMap— our tool implementing quasi-mapping— is capable ofmappingsequencing reads to a target transcriptome substantially faster than existing alignment tools. The algorithm we employ to implement quasi-mapping uses several efficient data structures and takes advantage of the special structure of shared sequence prevalent in transcriptomes to rapidly provide highly-accurate mapping information. We demonstrate how quasi-mapping can be successfully applied to the problems of transcript-level quantification from RNA-seq reads and the clustering of contigs fromde novoassembled transcriptomes into biologically-meaningful groups.

Availability:RapMapis implemented inC++11and is available as open-source software, under GPL v3, athttps://github.com/COMBINE-lab/RapMap.

Contact:rob.patro@cs.stonybrook.edu
Flowr: Robust and efficient pipelines using a simple language-agnostic approach
Authors: Seth Sahil , Amin Samir , Song Xingzhi , Mao Xizeng , Sun Huandong , Futreal Andrew , Zhang Jianhua
Published: October 2015

Motivation: Bioinformatics analyses have become increasingly intensive computing processes, with lowering costs and increasing numbers of samples. Each laboratory spends time creating and maintaining a set of pipelines, which may not be robust, scalable, or efficient. Further, the existence of different computing environments across institutions hinders both collabo-ration and the portability of analysis pipelines. Results: Flowr is a robust and scalable framework for designing and deploying computing pipelines in an easy-to-use fashion. It implements a scatter-gather approach using computing clusters, simplifying the concept to the use of five simple terms (in submission and dependency types). Most importantly, it is flexible, such that customizing existing pipelines is easy, and since it works across several computing environments (LSF, SGE, Torque, and SLURM), it is portable. Availability: http://docs.flowr.space
Silencio/CG9754 connects the Piwi–piRNA complex to the cellular heterochromatin machinery
Authors: Sienski Grzegorz , Batki Julia , Senti Kirsten-André , Dönertas Derya , Tirian Laszlo , Meixner Katharina , Brennecke Julius
Published: October 2015

The repression of transposable elements in eukaryotes often involves their transcriptional silencing via targeted chromatin modifications. In animal gonads, nuclear Argonaute proteins of the PIWI clade complexed with small guide RNAs (piRNAs) serve as sequence specificity determinants in this process. How binding of nuclear PIWI–piRNA complexes to nascent transcripts orchestrates heterochromatin formation and transcriptional silencing is unknown. Here, we characterize CG9754/Silencio as an essential piRNA pathway factor that is required for Piwi-mediated transcriptional silencing in Drosophila. Ectopic targeting of Silencio to RNA or DNA is sufficient to elicit silencing independently of Piwi and known piRNA pathway factors. Instead, Silencio requires the H3K9 methyltransferase Eggless/SetDB1 for its silencing ability. In agreement with this, SetDB1, but not Su(var)3-9, is required for Piwi-mediated transcriptional silencing genome-wide. Due to its interaction with the target-engaged Piwi–piRNA complex, we suggest that Silencio acts as linker between the sequence specificity factor Piwi and the cellular heterochromatin machinery.
Firm characteristics and intellectual capital disclosure in IPO prospectuses
Authors: Alcaniz Leire , Gomez-Bezares Fernando , Ugarte Jose Vicente
Published: October 2015

Purpose

Initial Public Offerings (IPOs) have been studied from different perspectives. The purpose of this paper is to analyse the type of intellectual capital (IC) information provided in the Spanish IPO prospectuses and the characteristics of the firms that go public and supply more information. The paper also compares the results with similar previous studies carried out in different countries.

Design/methodology/approach

The database gathers Spanish IPOs from 1996 to 2007 (after which the number of IPOs in Spain plummeted due to the crisis). Content analysis is used to obtain information about IC from the IPO prospectuses and, afterwards, the authors apply different statistical methods to analyse any relation between IC disclosure and firms’ characteristics.

Findings

The paper concludes that the companies that provide more information about IC in IPO prospectuses are high-tech companies, larger firms and those whose previous shareholders do not retain the majority after the IPO.

Originality/value

The authors have created an original database with the Spanish data. Moreover, this is the first study with these characteristics carried out in Spain, and some original conclusions are obtained, such as the importance of retained share percentage by previous shareholders. The authors have developed a statistical methodology suitable for the data. Both, the conclusions and the methodology will be especially useful for markets such as the Latin American ones, which are not as developed as Anglo-Saxon markets.
The country-brand in the wine industry: how important is variety specialization?
Authors: Berríos Rodrigo , Saens Rodrigo
Published: October 2015

Purpose

The purpose of this paper is to analyze whether or not the reputation of a region/country in the international wine market depends on a region/country’s efforts to specialize in a specific grape variety.

Design/methodology/approach

Data on 19,959 bottles of wine corresponding to six vintages across ten wine producing regions worldwide are used to estimate a hedonic price model that measures consumer valuations of the different wine attributes.

Findings

The results of this study show that although variety specialization has successfully underpinned the reputation of some New World regions, such as the Napa Valley (with its Cabernet Sauvignon) or Oregon (with its Pinot Noir); in others, such as Australia (with its Shiraz), this has not been successful.

Practical implications

Over the last ten years, the exponential growth of Australian bulk wine exports has seriously harmed the reputation of Australian wine. With respect to the Napa Valley wines, price discount received by Australian wines increases between the 1997 and 2007 vintage from 33 to 61 percent. Thus, in order to successfully build a collective reputation of an entrant (New World) country, an institutional framework that mediates differences of interest between the large and small vineyards and, above all, that regulates the free-rider problem in the wine market is required.

Originality/value

This paper empirically illustrates how cooperative (and non-cooperative) behavior between firms can help to build (and to destroy) collective reputation of wines that come from the same region or country.
A decade of supply chain collaboration and directions for future research
Authors: Soosay Claudine Antoinette , Hyland Paul
Published: October 2015

Purpose

– This paper aims to conduct a systematic review of the literature on supply chain collaboration published over a 10-year period from 2005 to 2014. It explores the nature and extent of research undertaken to identify key themes emerging in the field and gaps that need to be addressed.

Design/methodology/approach

– The authors review a sample of 207 articles from 69 journals, after using an iterative cycle of defining appropriate search keywords, searching the literature and conducting the analysis.

Findings

– Key themes include the meaning of collaboration; considerations for supply chain collaboration theory; emerging areas in collaboration for sustainability, technology-enabled supply chains and humanitarian supply chains; and the need for a more holistic approach, multi-tier perspectives and research into B2C collaborations.

Research limitations/implications

– The paper provides discussion and scope for future research into the area which would contribute to the field tremendously.

Originality/value

– There have been very few reviews in the past on supply chain collaboration, and this is one of the first extensive reviews conducted to address how well the body of knowledge on supply chain collaboration corresponds with our contemporary society.
Improvising Prescription: Evidence from the Emergency Room
Authors: Batista Maria da Graça , Clegg Stewart , Pina e Cunha Miguel , Giustiniano Luca , Rego Arménio
Published: October 2015

Global medical practice is increasingly standardizing through evidence‐based approaches and quality certification procedures. Despite this increasing standardization, medical work in emergency units necessarily involves sensitivity to the individual, the particular and the unexpected. While much medical practice is routine, important improvisational elements remain significant. Standardization and improvisation can be seen as two conflicting logics. However, they are not incompatible, although the occurrence of improvisation in highly structured and institutionally complex environments remains underexplored. The study presents the process of improvisation in the tightly controlled work environment of the emergency room. The authors conducted an in situ ethnographic observation of an emergency unit. An inductive approach shows professionals combining ostensive compliance with protocols with necessary and occasional ‘underlife’ improvisations. The duality of improvisation as simultaneously present and absent is related to pressures in the institutional domain as well as to practical needs emerging from the operational realm. The intense presence of procedures and work processes enables flexible improvised performances that paradoxically end up reinforcing institutional pressures for standardization.
Foraging and growth responses of cotton armyworm Spodoptera litura to the biophysical characteristics of five cotton varieties
Authors: Amin Md Ruhul , Roy Miltan Chandra , Rahman Md Mahbubar , Miah Md Giashuddin , Kwon Yong Jung , Suh Sang Jae
Published: October 2015

This study investigated the morphological and biochemical characteristics of the CB1, CB3, CB5, CB8 and CB12 cotton varieties and evaluated their effects on third instar larval movement, and body weight of the cotton armyworm Spodoptera litura at different developmental stages. The cotton varieties differed in their plant architecture, branching, stem color and hairiness, leaf color and hairiness, leaf trichome density, flower color, numbers of leaves and bolls per plant, concentrations of protein and starch, and boll length, width and weight. The CB1 and CB3 varieties possessed significantly higher trichome densities, while CB8 produced larger and heavier bolls. Boll bearing was found to be highest in CB1 and lowest in CB8. Biochemical analyses indicated the highest percentage of protein in CB5, and of starch in CB8; concentrations of both were lowest in CB12. Cotton varieties did not affect larval foraging, but their abundance on leaflet, mature and square differed significantly. Analysis of the growth response parameters of S. litura as a result of feeding on the tested varieties revealed that larval instars, pupae and adult moths attained the highest body weight on CB8, followed by CB5, and the lowest weight on CB12. Collectively, the results of this study show that the CB5 and CB8 varieties are favorable host‐plants for cotton armyworms; therefore, these varieties are the least suitable for cultivation.
New insights into desert kites in Armenia: the fringes of the Ararat Depression
Authors: Nadel Dani , Bar‐Oz Guy , Malkinson Dan , Spivak Polina , Langgut Dafna , Porat Naomi , Khechoyan Anna , Nachmias Amnon , Crater‐Gershtein Eli , Katinaa Amir , Bermatov‐Paz Gal , Nahapetyan Samvel , Gasparyan Boris
Published: October 2015

The Armenian kites are the northernmost known kites in south‐west Asia. In contrast to those in the deserts further south, their research has only recently begun. The Armenian kites are situated at high elevations, mostly between 900 and 1500 m above mean sea level, in steppic conditions whereArtemisiais at present the dominant shrub on the landscape. In our ongoing project we excavated three V‐shaped kites and one enclosure kite. The two kinds are similar in construction details, but they differ in size and location: the former run down into gullies, while the latter were placed on the plateau. SixOSLages suggest terminal Late Bronze Age and Early Iron Age construction dates, while geomorphological considerations and surface artefacts suggest earlier dates. A preliminary palynological study suggests a gradual increase in grazing‐resistant vegetation since the mid‐Holocene, probably reflecting human impact on the natural vegetation through the herding of grazing animals.
Unity and diversity of the kite phenomenon: a comparative study between Jordan, Armenia and Kazakhstan
Authors: Barge Olivier , Brochier Jacques Élie , Régagnon Emmanuelle , Chambrade Marie‐Laure , Crassard Rémy
Published: October 2015

Desert kites are found across a vast region. This paper presents a detailed description of kites from the Harrat al‐Shaam region (Jordan) and proposes a comparative study, as well as an analysis of the morphology and organisation of kites known from Mount Aragats (Armenia) and the Ustyurt Plateau (Kazakhstan). A complete inventory of the structures in each region highlights their architectural characteristics and their spatial distribution in the landscape. Some preliminary results were obtained by comparing both regions: the core area in eastern Jordan, and peripheries—sometimes very distant—such as in the Caucasus and Central Asia. Chronological data were also compared, when available. All these different and complementary aspects were finally combined with satellite imagery analyses. The interactive process between satellite images and fieldwork observations has enriched both approaches, while yielding preliminary key elements of interpretation for a better understanding of the kite phenomenon on a global scale.
Postsecularity, Political Resistance, and Protest in the Occupy Movement
Authors: Cloke Paul , Sutherland Callum , Williams Andrew
Published: October 2015

This paper examines and critically interprets the interrelations between religion and the Occupy movements of 2011. It presents three main arguments. First, through an examination of the Occupy Movement in the UK and USA—and in particular of the two most prominent Occupy camps (Wall Street and London Stock Exchange)—the paper traces the emergence of postsecularity evidenced in the rapprochement of religious and secular actors, discourses, and practices in the event‐spaces of Occupy. Second, it examines the specific set of challenges that Occupy has posed to the Christian church in the UK and USA, arguing that religious participation in the camps served at least in part to identify wider areas of religious faith that are themselves in need of redemption. Third, the paper considers the challenges posed by religious groups to Occupy, not least in the emphasis on postmaterial values in pathways to resistance against contemporary capitalism.
The challenge of antibiotic resistance in haematology patients
Authors: Blennow Ola , Ljungman Per
Published: October 2015

Bacterial infections were once a major obstacle to the treatment of acute leukaemia. Improvement in management strategies, including the use of broad‐spectrum antibacterial drugs targeting Gram‐negative bacteria, has reduced the mortality in neutropenic patients developing blood stream infections and other severe infections. In many countries these achievements are threatened by development of multi‐resistant bacteria, such as Klebsiella pneumoniae, Pseudomonas aeruginosa and methicillin‐resistant Staphylococcus aureus. This review addresses the epidemiology, clinical importance and possible management of these multi‐resistant organisms.
Risk factor analysis of cerebral white matter hyperintensities in children with sickle cell disease
Authors: van der Land Veronica , Mutsaerts Henri J. M. M. , Engelen Marc , Heijboer Harriët , Roest Mark , Hollestelle Martine J. , Kuijpers Taco W. , Nederkoorn Paul. J. , Cnossen Marjon H. , Majoie Charles B. L. M. , Nederveen Aart J. , Fijnvandraat Karin
Published: October 2015

Sickle cell disease (SCD) is complicated by silent cerebral infarcts, visible as white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI). Both local vaso‐occlusion, elicited by endothelial dysfunction, and insufficiency of cerebral blood flow (CBF) have been proposed to be involved in the aetiology. We performed an explorative study to investigate the associations between WMHs and markers of endothelial dysfunction and CBF by quantifying WMH volume on 3·0 Tesla MRI. We included 40 children with HbSS or HbSβ0thalassaemia, with a mean age of 12·1 ± 2·6 years. Boys demonstrated an increased risk for WMHs (odds ratio 4·5, 95% confidence interval 1·2–17·4), unrelated to glucose‐6‐phosphate dehydrogenase deficiency. In patients with WMHs, lower fetal haemoglobin (HbF) was associated with a larger WMH volume (regression coefficient = −0·62, R2 = 0·25, P = 0·04). Lower ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) levels were associated with lower CBF in the white matter (regression coefficient = 0·07, R2 = 0·15, P = 0·03), suggesting that endothelial dysfunction could potentially hamper CBF. The findings of our explorative study suggest that a high level of HbF may be protective for WMHs and that endothelial dysfunction may contribute to the development of WMHs by reducing CBF.
Understanding Aspects of Aluminum Exposure in Alzheimer's Disease Development
Authors: Kandimalla Ramesh , Vallamkondu Jayalakshmi , Corgiat Edwin B , Gill Kiran Dip
Published: October 2015

Aluminum is a ubiquitously abundant nonessential element. Aluminum has been associated with neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis, and dialysis encephalopathy. Many continue to regard aluminum as controversial although increasing evidence supports the implications of aluminum in the pathogenesis of AD. Aluminum causes the accumulation of tau protein and Aβ protein in the brain of experimental animals. Aluminum induces neuronal apoptosis in vivo and in vitro, either by endoplasmic stress from the unfolded protein response, by mitochondrial dysfunction, or a combination of them. Some, people who are exposed chronically to aluminum, either from through water and/or food, have not shown any AD pathology, apparently because their gastrointestinal barrier is more effective. This article is written keeping in mind mechanisms of action of aluminum neurotoxicity with respect to AD.
Mirabegron relaxes urethral smooth muscle by a dual mechanism involving β3‐adrenoceptor activation and α1‐adrenoceptor blockade
Authors: Alexandre E C , Kiguti L R , Calmasini F B , Silva F H , da Silva K P , Ferreira R , Ribeiro C A , Mónica F Z , Pupo A S , Antunes E
Published: October 2015

Linked Article

This article is commented on by Michel, M. C., pp. 429‐430 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.13379.

Background and Purpose

Mirabegron is the first β3‐adrenoceptor agonist approved for treatment of overactive bladder syndrome. This study aimed to investigate the effects of β3‐adrenoceptor agonist mirabegron in mouse urethra. The possibility that mirabegron also exerts α1‐adrenoceptor antagonism was also tested in rat smooth muscle preparations presenting α1A‐ (vas deferens and prostate), α1D‐ (aorta) and α1B‐adrenoceptors (spleen).

Experimental Approach

Functional assays were carried out in mouse and rat isolated tissues. Competition assays for the specific binding of [3H]prazosin to membrane preparations of HEK‐293 cells expressing each of the human α1‐adrenoceptors, as well as β‐adrenoceptor mRNA expression and cyclic AMP measurements in mouse urethra, were performed.

Key Results

Mirabegron produced concentration‐dependent urethral relaxations that were shifted to the right by the selective β3‐adrenoceptor antagonist L‐748,337 but unaffected by β1‐ and β2‐adrenoceptor antagonists (atenolol and ICI‐118,551 respectively). Mirabegron‐induced relaxations were enhanced by the PDE4 inhibitor rolipram, and the agonist stimulated cAMP synthesis. Mirabegron also produced rightward shifts in urethral contractions induced by the α1‐adrenoceptor agonist phenylephrine. Schild regression analysis revealed that mirabegron behaves as a competitive antagonist of α1‐adrenoceptors in urethra, vas deferens and prostate (α1A‐adrenoceptor, pA2 ≅ 5.6) and aorta (α1D‐adrenoceptor, pA2 ≅ 5.4) but not in spleen (α1B‐adrenoceptor). The affinities estimated for mirabegron in functional assays were consistent with those estimated in radioligand binding with human recombinant α1A‐ and α1D‐adrenoceptors (pKi ≅ 6.0).

Conclusion and Implications

The effects of mirabegron in urethral smooth muscle are the result of β3‐adrenoceptor agonism together with α1A and α1D‐adrenoceptor antagonism.
Bcl‐2 phosphorylation confers resistance on chronic lymphocytic leukaemia cells to the BH3 mimetics ABT‐737, ABT‐263 and ABT‐199 by impeding direct binding
Authors: Song Ting , Chai Gaobo , Liu Yubo , Yu Xiaoyan , Wang Ziqian , Zhang Zhichao
Published: October 2015

Background and Purpose

Although the ongoing clinical trials of ABT‐263 and ABT‐199 in chronic lymphocytic leukaemia (CLL) have indicated that BH3 mimetics hold considerable promise, understanding the mechanism of CLL resistance to BH3 mimetics remains a challenge.

Experimental Approach

The LD50 values of ABT‐737, ABT‐263 and ABT‐199 in a number of primary CLL cells from 40 patients, were determined. The levels of Bcl‐2 family proteins, including phosphorylated Bcl‐2 (pBcl‐2) and their interactions were measured by immunoblotting and co‐immunoprecipitation. In vitro binding assays were performed by isothermal titration calorimetry and ELISA. BH3 profiling in isolated mitochondria was analysed.

Key Results

The ratio of (Mcl‐1 + pBcl‐2) to Bcl‐2 expression provided the most significant predictive marker for the cytotoxic potential of ABT‐737, ABT‐263 and ABT‐199 in the panel of CLL samples. Mechanistically, pBcl‐2 inhibited the effects of the ABT compounds on the displacement of Bax and Bim from Bcl‐2, thereby suppressing mitochondrial apoptosis. The ABT compounds exhibited 100–300‐fold lower binding affinity to the glutamic acid, phosphomimetic, mutant of Bcl‐2 (T69E, S70E and S87E; EEE‐Bcl‐2). BH3 peptides exhibited different rank orders of binding affinities to full‐length WT‐Bcl‐2 and full‐length EEE‐Bcl‐2.

Conclusions and Implications

Our study suggested that a structural alteration in the BH3‐binding groove was induced by phosphorylation of Bcl‐2. Our data also provided a framework to overcome resistance of CLL cells to the ABT compounds by combining pBcl‐2 kinase inhibitors with the ABT compounds.
Enhanced serelaxin signalling in co‐cultures of human primary endothelial and smooth muscle cells
Authors: Sarwar M , Samuel C S , Bathgate R A , Stewart D R , Summers R J
Published: October 2015

Background and Purpose

In the phase III clinical trial, RELAX‐AHF, serelaxin caused rapid and long‐lasting haemodynamic changes. However, the cellular mechanisms involved are unclear in humans.

Experimental Approach

This study examined the effects of serelaxin in co‐cultures of human primary endothelial cells (ECs) and smooth muscle cells (SMCs) on cAMP and cGMP signalling.

Key Results

Stimulation of HUVECs or human coronary artery endothelial cells (HCAECs) with serelaxin, concentration‐dependently increased cGMP accumulation in co‐cultured SMCs to a greater extent than in monocultures of either cell type. This was not observed in human umbilical artery endothelial cells (HUAECs) that do not express the relaxin receptor, RXFP1. Treatment of ECs with l‐NG‐nitro arginine (NOARG; 30 μM, 30 min) inhibited serelaxin‐mediated (30 nM) cGMP accumulation in HUVECs, HCAECs and co‐cultured SMCs. In HCAECs, but not HUVECs, pre‐incubation with indomethacin (30 μM, 30 min) also inhibited cGMP accumulation in SMCs. Pre‐incubation of SMCs with the guanylate cyclase inhibitor ODQ (1 μM, 30 min) had no effect on serelaxin‐mediated (30 nM) cGMP accumulation in HUVECs and HCAECs but inhibited cGMP accumulation in SMCs. Serelaxin stimulation of HCAECs, but not HUVECs, increased cAMP accumulation concentration‐dependently in SMCs. Pre‐incubation of HCAECs with indomethacin, but not l‐NOARG, abolished cAMP accumulation in co‐cultured SMCs, suggesting involvement of prostanoids.

Conclusions and Implications

In co‐cultures, treatment of ECs with serelaxin caused marked cGMP accumulation in SMCs and with HCAEC also cAMP accumulation. Responses involved EC‐derived NO and with HCAEC prostanoid production. Thus, serelaxin differentially modulates vascular tone in different vascular beds.
CREB, AP‐1, ternary complex factors and MAP kinases connect transient receptor potential melastatin‐3 (TRPM3) channel stimulation with increased c‐Fos expression
Authors: Rubil Sandra , Rössler Oliver G. , Thiel Gerald
Published: October 2015

Background and Purpose

The rise in intracellular Ca2+ stimulates the expression of the transcription factor c‐Fos. Depending on the mode of entry of Ca2+ into the cytosol, distinct signal transducers and transcription factors are required. Here, we have analysed the signalling pathway connecting a Ca2+ influx via activation of transient receptor potential melastatin‐3 (TRPM3) channels with enhanced c‐Fos expression.

Experimental Approach

Transcription of c‐Fos promoter/reporter genes that were integrated into the chromatin via lentiviral gene transfer was analysed in HEK293 cells overexpressing TRPM3. The transcriptional activation potential of c‐Fos was measured using a GAL4‐c‐Fos fusion protein.

Key Results

The signalling pathway connecting TRPM3 stimulation with enhanced c‐Fos expression requires the activation of MAP kinases. On the transcriptional level, three Ca2+‐responsive elements, the cAMP‐response element and the binding sites for the serum response factor (SRF) and AP‐1, are essential for the TRPM3‐mediated stimulation of the c‐Fos promoter. Ternary complex factors are additionally involved in connecting TRPM3 stimulation with the up‐regulation of c‐Fos expression. Stimulation of TRPM3 channels also increases the transcriptional activation potential of c‐Fos.

Conclusions and Implications

Signalling molecules involved in connecting TRPM3 with the c‐Fos gene are MAP kinases and the transcription factors CREB, SRF, AP‐1 and ternary complex factors. As c‐Fos constitutes, together with other basic region leucine zipper transcription factors, the AP‐1 transcription factor complex, the results of this study explain TRPM3‐induced activation of AP‐1 and connects TRPM3 with the biological functions regulated by AP‐1. © 2015 The British Pharmacological Society
Young Children's Preferences: Gender, Race, and Social Status
Authors: Shutts Kristin
Published: October 2015

In this article, I consider how two aspects of society—social categories (in particular, gender and race) and social status—guide young children's preferences. Research on children's social categories reveals that gender‐based social preferences emerge earlier than race‐based preferences. Recent studies also show that children are attuned to social status, and the association of race with status differences could explain why race influences children's social preferences. I conclude with questions and suggestions for research.
Helping Head Start Parents Promote Their Children's Kindergarten Adjustment: The Research‐Based Developmentally Informed Parent Program
Authors: Bierman Karen L. , Welsh Janet A. , Heinrichs Brenda S. , Nix Robert L. , Mathis Erin T.
Published: October 2015

Head Start enhances school readiness during preschool, but effects diminish after children transition into kindergarten. Designed to promote sustained gains, the Research‐based Developmentally Informed (REDI) Parent program (REDI‐P) provided home visits before and after the kindergarten transition, giving parents evidence‐based learning games, interactive stories, and guided pretend play to use with their children. To evaluate impact, two hundred 4‐year‐old children in Head Start REDI classrooms were randomly assigned to REDI‐P or a comparison condition (mail‐home math games). Beyond the effects of the classroom program, REDI‐P promoted significant improvements in child literacy skills, academic performance, self‐directed learning, and social competence, demonstrating the utility of the approach in promoting gains in cognitive and social‐emotional skills evident after the transition into kindergarten.
Pathogenic T helper type 17 cells contribute to type 1 diabetes independently of interleukin-22
Authors: Bellemore S M , Nikoopour E , Krougly O , Lee-Chan E , Fouser L A , Singh B
Published: October 2015

We have shown that pathogenic T helper type 17 (Th17) cells differentiated from naive CD4+ T cells of BDC2·5 T cell receptor transgenic non-obese diabetic (NOD) mice by interleukin (IL)-23 plus IL-6 produce IL-17, IL-22 and induce type 1 diabetes (T1D). Neutralizing interferon (IFN)-γ during the polarization process leads to a significant increase in IL-22 production by these Th17 cells. We also isolated IL-22-producing Th17 cells from the pancreas of wild-type diabetic NOD mice. IL-27 also blocked IL-22 production from diabetogenic Th17 cells. To determine the functional role of IL-22 produced by pathogenic Th17 cells in T1D we neutralized IL-22 in vivo by using anti-IL-22 monoclonal antibody. We found that blocking IL-22 did not alter significantly adoptive transfer of disease by pathogenic Th17 cells. Therefore, IL-22 is not required for T1D pathogenesis. The IL-22Rα receptor for IL-22 however, increased in the pancreas of NOD mice during disease progression and based upon our and other studies we suggest that IL-22 may have a regenerative and protective role in the pancreatic islets.
Quantification of normal cerebral oxygen extraction and oxygen metabolism by phase‐based MRI susceptometry: evaluation of repeatability using two different imaging protocols
Authors: Kämpe Robin , Lind Emelie , Ståhlberg Freddy , van Westen Danielle , Knutsson Linda , Wirestam Ronnie
Published: October 2015

Introduction

Global oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) were quantified in a test–retest study. Cerebral blood flow (CBF) data, required for CMRO2 estimation, were obtained using dynamic susceptibility contrast MRI (DSC‐MRI). OEF and CMRO2 were quantified using two separate data sets, that is, conventional high‐resolution (HR) gradient echo (GRE) phase maps as well as echo planar imaging (EPI) phase maps taken from the baseline (precontrast) part of the DSC‐MRI time series. The EPI phase data were included to elucidate whether an extra HR‐GRE scan is needed to obtain information about OEF and CMRO2, or if this information can be extracted from the DSC‐MRI experiment only.

Methods

Twenty healthy volunteers were scanned using 3 T MRI on two occasions. Oxygen saturation levels were obtained from phase data measured in the great cerebral vein of Galen, based on HR‐GRE as well as EPI phase maps. In combination with DSC‐MRI CBF, this allowed for calculation of OEF and CMRO2.

Results

High‐resolution‐gradient echo‐ and EPI‐based phase images resulted in similar OEF spread and repeatability, with coefficients of variation/intraclass correlation coefficients of 0·26/0·95 and 0·23/0·81, respectively. Absolute OEF values (HR‐GRE: 0·40 ± 0·11, EPI: 0·35 ± 0·08) were consistent with literature data. CMRO2 showed similar repeatability, somewhat increased spread and reasonable absolute values (HR‐GRE: 3·23 ± 1·26 ml O2/100 g min−1, EPI: 2·79 ± 0·89 ml O2/100 g min−1).

Discussion

In general, the results obtained by HR‐GRE and EPI showed comparable characteristics. The EPI methodology could potentially be improved using a slightly modified DSC‐MRI protocol (e.g. with regard to spatial resolution and slice gap).
Filgrastim versus TBO‐filgrastim to reduce the duration of neutropenia after autologous hematopoietic stem cell transplantation: TBO, or not TBO, that is the question
Authors: Trifilio Steven , Zhou Zheng , Galvin John , Fong Jessica L. , Monreal Joanne , Mehta Jayesh
Published: October 2015

After a hospital‐wide formulary change resulted in the replacement of filgrastim with TBO‐filgrastim for all on‐ and off‐label indications, we performed a retrospective comparison of patients with myeloma receiving 200 mg/m2 melphalan with autologous hematopoietic stem cell transplantation to see whether the type of growth factor used post‐transplant made a difference. One hundred and eighty‐two consecutive patients with myeloma were studied, 91 receiving filgrastim immediately prior to the change and 91 receiving TBO‐filgrastim afterward. The CD34+ cell dose was comparable, as were other characteristics. Although the overall time to neutrophil recovery was similar for both groups, early engraftment (≤12 d) occurred more often (p = 0.05), and late engraftment (≥14 d) less often (p = 0.09) in filgrastim‐treated patients. The number of documented infections was significantly less in the TBO‐filgrastim group. Day 100 mortality and hospital stay were similar for the two groups. These data indicate that there is no material difference between filgrastim and TBO‐filgrastim in this clinical setting.
Practicable methods for delimiting a plant invasion
Authors: Hauser Cindy E. , Giljohann Katherine M. , Rigby Michael , Herbert Karen , Curran Iris , Pascoe Charlie , Williams Nicholas S. G. , Cousens Roger D. , Moore Joslin L.
Published: October 2015

Aim

Invasive populations are often irregularly distributed due to sporadic dispersal events and patchy distribution of suitable habitat, making it difficult to recognize the population boundary and effectively target management. We designed a survey prioritization that addresses these irregularities and tested it on an invasive King Devil Hawkweed (Hieracium praealtum) population.

Location

Bogong High Plains, Victoria, Australia.

Methods

Our optimal design prioritized discovery of infestations beyond the known population boundary, while accounting for the diminishing likelihood of occurrence, plant detectability and the search resources available. Hawkweed management agencies implemented this design in the field. We evaluated its practicality and their progress towards delimitation.

Results

The survey design favoured locations outside the known population boundary with a relatively high likelihood of species occurrence and high capacity to detect individuals. Difficult‐to‐search sites were selected for intensive survey when the likelihood of occurrence was sufficiently high. The GPS tracks recorded by managing agencies during the survey corresponded well with the priority rankings, but did not include search effort information. In subsequent surveys, managing agencies have improved recording protocols and expanded their performance metrics. This will facilitate future evaluation of progress towards delimitation and eradication.

Main conclusions

Our optimization method effectively identified priorities for delimiting an invading population, accounting for the agencies' budget and the risk of detection failures. Probabilistic maps proved useful for communicating search priorities, and GPS track logs provided valuable spatial data for inferring where the species is likely to be absent. When comprehensive spatio‐temporal data are available, survey findings can be used to update species occurrence models and thus our quantitative understanding of the population's extent. A probabilistic map provides a more nuanced view of delimitation than drawing a strict boundary around known infestations. Burgman et al.'s extended delimitation score is a promising summary statistic for reporting.