bluuebunny/crossref_metadata_2025 huggingface dataset:
Brief Report: Clinical and Molecular Phenotypes of Low‐Penetrance Variants of NLRP3: Diagnostic and Therapeutic Challenges
Authors: Kuemmerle‐Deschner J. B. , Verma D. , Endres T. , Broderick L. , de Jesus A. A. , Hofer F. , Blank N. , Krause K. , Rietschel C. , Horneff G. , Aksentijevich I. , Lohse P. , Goldbach‐Mansky R. , Hoffman H. M. , Benseler S. M.
Published: July 2017

Objective

Cryopyrin‐associated periodic syndromes (CAPS) result from gain‐of‐function mutations in the NLRP3 gene, which causes excessive release of interleukin‐1β (IL‐1β) and systemic inflammation. While pathogenetic NLRP3 variant phenotypes are well‐characterized, low‐penetrance NLRP3 variants represent a significant clinical challenge. The aims of this study were to determine the clinical phenotype, the in vitro biologic phenotype, and the effect of anti–IL‐1 treatment in patients with low‐penetrance NLRP3 variants.

Methods

A multicenter study of consecutive symptomatic patients with low‐penetrance NLRP3 variants recruited from 7 centers between May 2012 and May 2013 was performed. The observed findings were transferred into a study database, from which they were extracted for analysis. Controls were patients with a known pathogenetic NLRP3 variant. Clinical presentation and CAPS markers of inflammation were captured. Functional assays of inflammasome activation, including caspase 1 activity, NF‐κB release, cell death, and IL‐1β release, were performed. Treatment effects of IL‐1 were determined. Comparisons between low‐penetrance and pathogenetic NLRP3 variants were performed.

Results

The study included 45 patients, 21 of which were female (47%); 26 of the patients (58%) were children. NLRP3 low‐penetrance variants identified in the patients were Q703K (n = 19), R488K (n = 6), and V198M (n = 20). In the controls, 28 had pathogenetic NLRP3 variants. Patients with low‐penetrance NLRP3 variants had significantly more fever (76%) and gastrointestinal symptoms (73%); eye disease, hearing loss, and renal involvement were less common. Functional inflammasome testing identified an intermediate phenotype in low‐penetrance NLRP3 variants as compared to wild‐type and pathogenetic NLRP3 variants. All treated patients responded to IL‐1 inhibition, with complete response documented in 50% of patients.

Conclusion

Patients with low‐penetrance NLRP3 variants display a distinct clinical phenotype and an intermediate biologic phenotype, including IL‐1β and non–IL‐1β–mediated inflammatory pathway activation.
Oxygen‐Deficient Three‐Dimensional Porous Co3O4 Nanowires as an Electrode Material for Water Oxidation and Energy Storage
Authors: Fan Xiaolei , Balogun Muhammad‐Sadeeq , Huang Yongchao , Tong Yexiang
Published: July 2017

Energy storage and conversion have become two of the most promising aspects of study, and both fields share a common approach in the search for new and advanced materials to store/convert energy and catalyze electrochemical reactions. Owing to their environmental friendliness, transition‐metal oxides have been widely applied as electrode materials for energy systems. However, the application of these metal oxides, in one way or another, tends to suffer from several disadvantages, which urge many researchers to concentrate on improving the performance of the metal oxides so as to meet the demand of different applications. Herein, oxygen vacancies were introduced into 3D Co3O4 nanowires and utilized as suitable electrodes for water oxidation and lithium‐ion batteries.
Particle Generation Using High‐Pressure Atomization
Authors: Stein Oliver , Bröckel Ulrich , Riebel Ulrich , Hansen Herbert
Published: July 2017

Feinstpartikel in der Größenordnung weniger Mikrometer finden Anwendung in den unterschiedlichsten Industriezweigen. Als Alternative zu bekannten Herstellungsverfahren wird ein lösungsmittelfreies Hochdrucksprühverfahren zur Feststoffmikronisierung vorgestellt. Die Basis bildet ein gepulst arbeitender Diesel‐Injektor eines handelsüblichen Common‐Rail‐Systems aus dem Automotive‐Bereich. Die Modellsubstanzen werden als Schmelze oder konzentrierte Lösungen vorgelegt. Die mikroskaligen Feststoffpartikel resultieren aus dem erstarrten bzw. getrockneten Produktspray und weisen eine enge Partikelgrößenverteilung auf.
Optimization and standardization of fluorescent cell barcoding for multiplexed flow cytometric phenotyping
Authors: Giudice Valentina , Feng Xingmin , Kajigaya Sachiko , Young Neal S. , Biancotto Angélique
Published: July 2017

Fluorescent cell barcoding (FCB) is a cell‐based multiplexing technique for high‐throughput flow cytometry. Barcoded samples can be stained and acquired collectively, minimizing staining variability and antibody consumption, and decreasing required sample volumes. Combined with functional measurements, FCB can be used for drug screening, signaling profiling, and cytokine detection, but technical issues are present. We optimized the FCB technique for routine utilization using DyLight 350, DyLight 800, Pacific Orange, and CBD500 for barcoding six, nine, or 36 human peripheral blood specimens. Working concentrations of FCB dyes ranging from 0 to 500 μg/ml were tested, and viability dye staining was optimized to increase robustness of data. A five‐color staining with surface markers for Vβ usage analysis in CD4+ and CD8+ T cells was achieved in combination with nine sample barcoding. We provide improvements of the FCB technique that should be useful for multiplex drug screening and for lymphocyte characterization and perturbations in the diagnosis and during the course of disease. Published 2017 by Wiley Periodicals, Inc., on behalf of International Society for Advancement of Cytometry. This article is a US government work and as such, is in the public domain in the United States of America.
Effects of different nitrogen additions on soil microbial communities in different seasons in a boreal forest
Authors: Yan Guoyong , Xing Yajuan , Xu Lijian , Wang Jianyu , Dong Xiongde , Shan Wenjun , Guo Liang , Wang Qinggui
Published: July 2017

In the global change scenario, nitrogen (N) deposition has the potential to affect the soil microbial communities that play critical roles in ecosystem functioning. Although the impacts of N deposition on soil microbial communities have been reasonably well studied, microorganism responses to the N addition combined with the seasonal change have rarely been reported. This study was conducted to evaluate the effects of different levels of N addition (0, 2.5, 5.0, and 7.5 g N·m−2·yr−1) on soil microbial communities in different seasons (spring, summer, and autumn) in a boreal forest. Our results showed that the soil physical–chemical properties were found to be changed by N addition and seasonal changes were correlated with microbial community structure. The N addition and seasonal changes significantly affect the diversity and abundance of the microbial community, while their interactions only affect the bacterial abundance and the fungal diversity. In addition, our results also provided clear evidence for specific responses of microorganisms to the different N additions and each season. Our findings suggest that the microbial community response to N deposition could be the seasonal change and will strongly correlate with environmental change.
Ending cervical cancer: A call to action
Authors: Aranda Sanchia , Berkley Seth , Cowal Sally , Dybul Mark , Evans Tim , Iversen Katja , Moeti Matshidiso , Osotimehin Babatunde , Peterson Stefan , Piot Peter , Purandare Chittaranjan N. , Sidibé Michel , Trimble Ted , Tsu Vivien Davis
Published: July 2017

The outlook for elimination of the scourge of cervical cancer is bright, because we now have the tools to achieve this goal. In recent years human papillomavirus (HPV) vaccination in high‐income countries has resulted in dramatic decreases in HPV infection and associated cervical disease. If all countries with a substantial burden of disease introduce the vaccine nationally, we can protect the vast majority of women and girls most at risk. For women who are beyond the vaccination target age, progress has been made in screening and treatment for cervical precancer, but we must accelerate this momentum to reduce incidence and mortality worldwide to the very low rates found in wealthier countries. Human and financial resources must be increased and directed to programs that follow best practices and reach all women, including the marginalized or disadvantaged. Seven key actions are recommended. Now is the time for action at national, regional, and global levels.
Community‐Engaged Pedagogy in the Virtual Classroom: Integrating eService‐Learning Into Online Leadership Education
Authors: Purcell Jennifer W.
Published: July 2017

Evidence suggests community‐engaged pedagogies are as effective in online courses as in traditional face‐to‐face delivery; however, guidance and examples for potential early adopters is limited, particularly in leadership education. As online delivery for leadership education expands, leadership educators may be hesitant to redesign community‐engaged learning experiences for the online environment as a result of pedagogical and logistical concerns. Nevertheless, virtual community‐engaged learning, or e‐service‐learning, has promise as an effective high‐impact educational practice within leadership education. The current paper describes theoretical and practical considerations for leadership educators who intend to development community‐engaged online courses.
Comparison of reduced field‐of‐view diffusion‐weighted imaging (DWI) and conventional DWI techniques in the assessment of rectal carcinoma at 3.0T: Image quality and histological T staging
Authors: Peng Yang , Li Zhen , Tang Hao , Wang Yanchun , Hu Xuemei , Shen Yaqi , Hu Daoyu
Published: July 2017

Purpose

To compare image quality (IQ) of reduced field‐of‐view (rFOV) and full FOV (fFOV) diffusion‐weighted imaging (DWI) sequences at 3T, with histological T staging of rectal cancer as a reference standard.

Materials and Methods

In all, 81 patients with rectal cancer received magnetic resonance (MR) scans (3.0T), including both rFOV and fFOV DWI sequences. The signal‐to‐noise ratio (SNR) and contrast‐to‐noise ratio (CNR) were quantitatively evaluated using the paired t‐test. Two radiologists independently assessed subjective IQ parameters, including image sharpness, distortion, artifacts, lesion conspicuity, and overall subjective IQ of both sequences. The Wilcoxon signed rank test was used to compare subjective IQ scores and tumor apparent diffusion coefficients (ADCs) between DWI sequences. Spearman correlation analysis was used to correlate ADC values and corresponding T staging of rectal cancer.

Results

CNR was significantly higher in rFOV DWI than in fFOV DWI (7.15 ± 2.77 vs. 5.39 ± 2.08, P < 0.001). SNR was significantly higher in rFOV DWI than in fFOV DWI (44.17 ± 11.01 vs. 34.76 ± 13.30, P < 0.001). The subjective IQ parameters of rFOV DWI sequence were rated superior to those of fFOV DWI sequence by both readers (P < 0.001). No significant differences between mean tumor ADC values of both sequences (0.991 ± 0.121 vs. 0.100 ± 0.126 × 10‐3 mm2/s, P = 0.617) were noted. Apart from T1 stage, T staging of rectal cancer was inversely correlated with ADC values of rFOV DWI (r = –0.688, P < 0.001) and fFOV DWI sequences (r = –0.641, P < 0.001).

Conclusion

The rFOV DWI sequence provided significantly better IQ and lesion conspicuity than the fFOV DWI sequence. In addition, rFOV and fFOV DWI sequences can be used in evaluation of histological T staging of rectal cancer.

Level of Evidence: 3

Technical Efficacy: Stage 2

J. Magn. Reson. Imaging 2018;47:967–975.
A new design methodology to predict wind farm energy production by means of a spiking neural network–based system
Authors: Brusca Sebastian , Capizzi Giacomo , Lo Sciuto Grazia , Susi Gianluca
Published: July 2017

In this paper, a spiking neural network–based architecture for the prediction of wind farm energy production is proposed. The model is also able to evaluate the wake effects due to interactions between the elements of a wind farm on the energy production of the whole farm. This method has been applied to a large wind power plant, composed of 28 turbines and 3 anemometric towers, located in the rural area of Vizzini's municipality in province of Catania, Italy, that is characterised by a complex orography and an extension of 30 km2. For the implementation of this architecture it was used the “NeuCube” simulator. The results show that the presented method can be successfully applied for predictions of wind energy generation in real wind farm also in presence of faults.
Structural Effects in the Iridium Complex Series: Photoredox Catalysis and Photoinitiation of Polymerization Reactions under Visible Lights
Authors: Tehfe Mohamad‐Ali , Lepeltier Marc , Dumur Frédéric , Gigmes Didier , Fouassier Jean‐Pierre , Lalevée Jacques
Published: July 2017

A series of 18 iridium complexes (Ir) have been prepared and studied. Their abilities to initiate both a ring‐opening cationic polymerization (CP) using an Ir/iodonium salt couple and a free radical polymerization (FRP) in the presence of an Ir/amine/alkyl halide system under very soft irradiation (i.e., halogen lamp) or upon exposure to laser diodes @457 nm and @532 nm are investigated. Interestingly, these photoinitiating systems operate through an oxidative or a reductive photoredox catalytic cycle, respectively. Excellent polymerization profiles are obtained (reactive function conversions >70% for the CP of an epoxide and >60% for the FRP of low viscosity triacrylate). The photochemical mechanisms are studied by fluorescence, steady state photolysis, cyclic voltammetry, and electron spin resonance spin trapping experiments.
Self‐Forming Interlocking Interfaces on the Immiscible Polymer Bilayers via Gelation‐Mediated Phase Separation
Authors: Zhou Xiaozhuang , Ma Guoqiang , Zhao Huaixia , Cui Jiaxi
Published: July 2017

Gelation‐mediated phase separation is applied to prepare immiscible polymer bilayer films with an interlocking interface structure. Polymer systems consisting of copolymer of urea and polydimethylsiloxane and epoxy are selected to demonstrate the feasibility. When the epoxy fraction exceeds 25 wt%, well‐defined bilayer structures self‐form by a one‐pot casting method in which the phase separation state is fixed by an evaporation‐induced gelation. Microscopy studies of the resulting bilayers clearly reveal that interlocking structures form during the bilayer films construct. The interlocking structures lead to an enhanced interfacial adhesion and higher fracture energy. The current strategy might offer a facile way to in situ create an interlocking interface between immiscible polymer systems.
A New Focus on Nonprofit ­Entrepreneurship Research
Authors: Andersson Fredrik O.
Published: July 2017

One distinctive contribution nonprofit entrepreneurship research brings to the broader domain of nonprofit studies is an explicit focus on the process of new nonprofit organizational emergence. This article asserts that in order for nonprofit entrepreneurship scholarship to continue to evolve, it is necessary to focus more on what happens before a new nonprofit is formally founded, during the so‐called nascent phase. Using conceptual as well as empirically derived arguments, this article illuminates why nascent nonprofit research is necessary and valuable to nonprofit entrepreneurship scholarship and highlights promising areas for future research.
Crystal structure of the UBR‐box from UBR6/FBXO11 reveals domain swapping mediated by zinc binding
Authors: Muñoz‐Escobar Juliana , Kozlov Guennadi , Gehring Kalle
Published: July 2017

The UBR‐box is a 70‐residue zinc finger domain present in the UBR family of E3 ubiquitin ligases that directly binds N‐terminal degradation signals in substrate proteins. UBR6, also called FBXO11, is an UBR‐box containing E3 ubiquitin ligase that does not bind N‐terminal signals. Here, we present the crystal structure of the UBR‐box domain from human UBR6. The dimeric crystal structure reveals a unique form of domain swapping mediated by zinc coordination, where three independent protein chains come together to regenerate the topology of the monomeric UBR‐box fold. Analysis of the structure suggests that the absence of N‐terminal residue binding arises from the lack of an amino acid binding pocket.
Structures of designed armadillo repeat proteins binding to peptides fused to globular domains
Authors: Hansen Simon , Kiefer Jonathan D. , Madhurantakam Chaithanya , Mittl Peer R. E. , Plückthun Andreas
Published: July 2017

Designed armadillo repeat proteins (dArmRP) are α‐helical solenoid repeat proteins with an extended peptide binding groove that were engineered to develop a generic modular technology for peptide recognition. In this context, the term “peptide” not only denotes a short unstructured chain of amino acids, but also an unstructured region of a protein, as they occur in termini, loops, or linkers between folded domains. Here we report two crystal structures of dArmRPs, in complex with peptides fused either to the N‐terminus of Green Fluorescent Protein or to the C‐terminus of a phage lambda protein D. These structures demonstrate that dArmRPs bind unfolded peptides in the intended conformation also when they constitute unstructured parts of folded proteins, which greatly expands possible applications of the dArmRP technology. Nonetheless, the structures do not fully reflect the binding behavior in solution, that is, some binding sites remain unoccupied in the crystal and even unexpected peptide residues appear to be bound. We show how these differences can be explained by restrictions of the crystal lattice or the composition of the crystallization solution. This illustrates that crystal structures have to be interpreted with caution when protein–peptide interactions are characterized, and should always be correlated with measurements in solution.
Effects of pyriproxyfen on wild populations of the housefly, Musca domestica, and compatibility with its principal parasitoids
Authors: Biale Haim , Geden Christopher J , Chiel Elad
Published: July 2017

BACKGROUND

The housefly, Musca domestica L., is an important pest of animal agriculture. Effective fly management requires integration of manure management, mass trapping, biological control, and selective insecticide use. Insecticidal control of houseflies is difficult due to the rapidity of resistance development, yet the insect growth regulator pyriproxyfen (PPF) is one of few insecticides that may still be effective. Here, we tested the susceptibility of wild housefly populations in the USA and in Israel to PPF, as well as the effect of PPF on housefly parasitoids of the genera Muscidifurax and Spalangia.

RESULTS

Most housefly populations from both countries were completely eliminated at PPF concentrations of 100 mg kg–1 (USA) and 600 mg kg–1 (Israel). One population from each country exhibited initial levels of PPF tolerance. PPF efficacy significantly decreased in cow manure. Emergence rates of parasitoids developing in PPF‐treated hosts at concentrations of ≥600 mg kg–1 were significantly affected, whereas other fitness parameters were moderately to non‐affected.

CONCLUSIONS

PPF is still an effective tool for housefly control, but resistance management practices should be employed to avoid resistance. PPF is compatible with principal housefly parasitoids at concentrations <600 mg kg–1, and is suitable for use in integrated pest management. © 2017 Society of Chemical Industry
Effects of imperfect testing on presence‐absence sampling plans
Authors: Santos‐Fernández Edgar , Govindaraju Kondaswamy , Jones Geoff
Published: July 2017

Sampling inspection plans are used in the food industry to determine whether a batch of food is contaminated or not. Testing for pathogens is mandatory in several foodstuffs because some bacteria pose a significant risk to human health, even when these are consumed in minute quantity. Test performance measures such as sensitivity and specificity are generally ignored in microbiological risk assessment and food quality assurance. In this research, we examine the impact of imperfect analytical tests on sampling inspection plans for presence‐absence characteristics. We discuss several plausible scenarios and assess the risk for the consumers. The method is illustrated using data collected over 2 years forCronobacterspp (formerlyEnterobactersakazakii) in skimmed milk powder. The probability of contamination and the test sensitivity and specificity are estimated using Bayesian methods. We examine the sampling plans proposed by the Codex Alimentarius and by the New Zealand's Ministry of Primary Industries for this pathogen. A cost analysis is performed to show the economic loss due to measurement errors. We describe the strengths and limitations of these plans under different conditions and propose a plan that could provide better protection to the consumers as well as to the producers.
Multistimuli Response Micro‐ and Nanolayers of a Coordination Polymer Based on Cu2I2 Chains Linked by 2‐Aminopyrazine
Authors: Conesa‐Egea J. , Gallardo‐Martínez J. , Delgado S. , Martínez J. I. , Gonzalez‐Platas J. , Fernández‐Moreira V. , Rodríguez‐Mendoza U. R. , Ocón P. , Zamora F. , Amo‐Ochoa P.
Published: July 2017

A nonporous laminar coordination polymer of formula [Cu2I2(2‐aminopyrazine)]n is prepared by direct reaction between CuI and 2‐aminopyrazine, two industrially available building blocks. The fine tuning of the reaction conditions allows obtaining [Cu2I2(2‐aminopyrazine)]n in micrometric and nanometric sizes with same structure and composition. Interestingly, both materials show similar reversible thermo‐ and pressure‐luminescent response as well as reversible electrical response to volatile organic solvents such as acetic acid. X‐ray diffraction studies under different conditions, temperatures and pressures, in combination with theoretical calculations allow rationalizing the physical properties of this compound and its changes under physical stimuli. Thus, the emission dramatically increases when lowering the temperature, while an enhancement of the pressure produces a decrease in the emission intensity. These observations emerge as a direct consequence of the high structural flexibility of the Cu2I2 chains which undergo a contraction in CuCu distances as far as temperature decreases or pressure increases. However, the strong structural changes observed under high pressure lead to an unexpected effect that produces a less effective CuCu orbital overlapping that justifies the decrease in the intensity emission. This work shows the high potential of materials based on Cu2I2 chains for new applications.
Pick‐and‐Place Assembly of Single Microtubules
Authors: Tarhan Mehmet Cagatay , Yokokawa Ryuji , Jalabert Laurent , Collard Dominique , Fujita Hiroyuki
Published: July 2017

Intracellular transport is affected by the filament network in the densely packed cytoplasm. Biophysical studies focusing on intracellular transport based on microtubule–kinesin system frequently use in vitro motility assays, which are performed either on individual microtubules or on random (or simple) microtubule networks. Assembling intricate networks with high flexibility requires the manipulation of 25 nm diameter microtubules individually, which can be achieved through the use of pick‐and‐place assembly. Although widely used to assemble tiny objects, pick‐and‐place is not a common practice for the manipulation of biological materials. Using the high‐level handling capabilities of microelectromechanical systems (MEMS) technology, tweezers are designed and fabricated to pick and place single microtubule filaments. Repeated picking and placing cycles provide a multilayered and multidirectional microtubule network even for different surface topographies. On‐demand assembly of microtubules forms crossings at desired angles for biophysical studies as well as complex networks that can be used as nanotransport systems.
Maintenance efficacy designs in psychiatry: Randomized discontinuation trials – enriched but not better
Authors: Ghaemi S. N. , Selker Harry P.
Published: July 2017

Introduction

Although classical randomized clinical trials (RCTs) are the gold standard for proof of drug efficacy, randomized discontinuation trials (RDTs), sometimes called “enriched” trials, are used increasingly, especially in psychiatric maintenance studies.

Methods

A narrative review of two decades of experience with RDTs.

Results

RDTs in psychiatric maintenance trials tend to use a dependent variable as a predictor: treatment response. Treatment responders are assessed for treatment response. This tautology in the logic of RDTs renders them invalid, since the predictor and the outcome are the same variable. Although RDTs can be designed to avoid this tautologous state of affairs, like using independent predictors of outcomes, such is not the case with psychiatric maintenance studies

Further, purported benefits of RDTs regarding feasibility were found to be questionable. Specifically, RDTs do not enhance statistical power in many settings, and, because of high dropout rates, produce results of questionable validity. Any claimed benefits come with notably reduced generalizability.

Conclusions

RDTs appear to be scientifically invalid as used in psychiatric maintenance designs. Their purported feasibility benefits are not seen in actual trials for psychotropic drugs. There is warrant for changes in federal policy regarding marketing indications for maintenance efficacy using the RDT design.
Analyzing Free-Free Beams by Green's Functions and Fredholm Alternative Theorem
Authors: Rezaiee-Pajand M. , Aftabi Sani A. , Hozhabrossadati S. M.
Published: July 2017

This article deals with the analysis of free-free beams by an analytical method. The well-known Green's function method is employed, and exact solution for the problem is obtained. As a second problem, the simply supported-free beam with rotational rigid body motion is analyzed. It is initially shown that ordinary Green's functions cannot be constructed due to a mathematical contradiction. To remedy this limitation, the Fredholm Alternative Theorem is utilized. This theorem eliminates the contradiction and enables analysts to obtain modified Green's functions. The fundamental existence conditions are derived and thoroughly investigated from the structural point of view. Finally, the deflection functions of these beams are found using modified Green's functions.
Learning English to fly: A study of Chinese cargo airline pilots’ learning engagement
Authors: Zhao Ke , Guo Xiaohang , Gao Xuesong
Published: July 2017

Due to a growing concern with the English language competence of international airline pilots, a growing body of research has been conducted on issues related to the International Aviation English Test, which pilots need to pass in order to fly on international routes (e.g. Jones, 2003; Ragan, 1997; Seiler, 2009). This paper contributes to this research by reporting on a mixed method inquiry into Chinese pilots’ engagement with learning English for aviation. The study involved a survey of 165 pilots working for a major Chinese cargo airline, and follow-up interviews with two of the surveyed participants (one senior and one junior) to explore their International Civil Aviation Organization (ICAO) test preparation and learning engagement. The findings of the study indicate that policy-makers and relevant English language education specialists need to develop tailor made courses that will better help these pilots to improve their command of English and thus ensure aviation safety.
Squaring the Circle: Comparing the Fortune and the Globe
Authors: Gurr Andrew
Published: July 2017

In the many discussions of the different shapes and capacities of the playhouses of Elizabethan and Jacobean London, insufficient attention has been paid to the impact of differing theatre forms upon the spectators. In this article, Andrew Gurr points out that the first Globe on Bankside, built from the timbers of the Theatre in Shoreditch, and the Fortune, erected for Henslowe's company on the other side of the river, just to the north of the City, were both the work of the same builder, Peter Street. He discusses the differences the shapes of the two playhouses – the Globe polygonal, the Fortune square – had on their construction and the spectators’ reception. Because the audience capacity had to be similar, this meant that spectators at the Fortune, especially latecomers, would need to squeeze into corners of the building, with their ability to see and hear what was happening on stage much restricted. In addition to his many books, among them the now classic study, The Shakespearean Stage, 1574–1642 (1992), Andrew Gurr was chief academic advisor in the ‘rebuilding’ of Shakespeare's Globe on the South Bank. He is Professor Emeritus at the University of Reading.
Crises and Brazilian Theatre
Authors: LABAKI AIMAR
Published: July 2017

Brazil is going through a political and economic crisis of major proportions – an unprecedented recession and the rise of an illegitimate government following the impeachment of the elected president. Theatre responds to this crisis with a timely production of reflection and, eventually, militancy. It also responds to another crisis: that of the pertinence of language and of modes of theatrical production in the context of a society in which relationships take place in a virtual environment, to the detriment of real social and political action. The objective of this text is to identify the general lines of this kind of production.
A multinational and multidisciplinary approach to treat CHD in paediatric age in Angola: initial experience of a medical-surgical centre for children with heart disease in Angola
Authors: Nunes Maria Ana S. , Magalhães Manuel P. , Uva Miguel S. , Heitor Patrícia , Henriques Ana , Manuel Valdano , Miguel Gade , Júnior António F.
Published: July 2017

Background

Epidemiological patterns of cardiac disease differ between developed countries and African nations. Despite the collaborative efforts of developed countries, several obstacles hinder the implementation of successful programmes for the management of children with heart disease in Africa.

Materials and methods

This study is a retrospective analysis of a bi-national two-institution partnership programme for the treatment of children with congenital and acquired heart disease. In April, 2011, a continuous medical-surgical programme was inaugurated at Clínica Girassol in Luanda. The main goals were to initiate permanent and local delivery of services while training local teams, allowing autonomous medical and surgical management of children with heart disease.

Results

Between April, 2011 and August, 2015, a total of 1766 procedures were performed on 1682 children. Of them, 1539 had CHD and 143 had acquired heart disease; 94 children underwent interventional treatment. A total of 1672 paediatric surgeries were performed on 1588 children: 1087 (65%) were performed with extracorporeal circulation and 585 (35%) were off-pump. The age distribution of the children was 4.5% (n=76) neonatal, 40.4% (n=675) between 30 days and 1 year, and 55.1% (n=921) over 1 year. There were 76 re-operations (4.5%) due to complications. The 30-day mortality rate was 4.2% (71 patients). Education-wise, several Angolan medical and surgical specialists were trained, allowing near-autonomous cardiac care delivery in children with heart disease.

Conclusion

An innovative cooperation model between a European and an African centre based on permanent delivery of care and education allowed for effective training of local teams and treatment of children with heart disease in their own environment.
Multiplex PCR effectively identifies tetraploid Triticum AABB – or AAGG-genome species
Authors: Tanno Ken-Ichi , Takeuchi Ayaka , Akahori Eri , Kobayashi Keiko , Kawahara Taihachi , Yamane Kyoko
Published: July 2017

We developed a multiplex PCR DNA marker for quick and easy identification of the AAGG-genome timopheevii lineage, including Triticum timopheevii, Triticum araraticum and hexaploid Triticum zhukovskyi (AAAmAmGG), and the AABB-genome emmer wheat lineage, including Triticum durum, Triticum dicoccum and Triticum dicoccoides. Distinguishing between tetraploid AAGG- and AABB-genome wheat species based on morphology is known to be difficult. This multiplex PCR system is based on the simultaneous PCR amplification of two chloroplast regions, matK and rbcL. The matK region molecularly distinguishes the two lineages, whereas the rbcL region is a positive control amplicon. We also examined whether the simple sequence repeat is a fixed mutation within species, using genetic resources in the collection of KOMUGI, Kyoto University, which comprises accessioned species collected across diverse geographical areas. The multiplex PCR marker distinguished AAGG from AABB species with complete accuracy.
Wafer-scale single-crystal perovskite patterned thin films based on geometrically-confined lateral crystal growth
Authors: Lee Lynn , Baek Jangmi , Park Kyung Sun , Lee Yong-EunKoo , Shrestha Nabeen K. , Sung Myung M.
Published: July 2017

We report a facile roll-printing method, geometrically confined lateral crystal growth, for the fabrication of large-scale, single-crystal CH3NH3PbI3perovskite thin films. Geometrically confined lateral crystal growth is based on transfer of a perovskite ink solution via a patterned rolling mould to a heated substrate, where the solution crystallizes instantly with the immediate evaporation of the solvent. The striking feature of this method is that the instant crystallization of the feeding solution under geometrical confinement leads to the unidirectional lateral growth of single-crystal perovskites. Here, we fabricated single-crystal perovskites in the form of a patterned thin film (3 × 3 inch) with a high carrier mobility of 45.64 cm2 V−1 s−1. We also used these single-crystal perovskite thin films to construct solar cells with a lateral configuration. Their active-area power conversion efficiency shows a highest value of 4.83%, which exceeds the literature efficiency values of lateral perovskite solar cells.
Generation and comparison of CRISPR-Cas9 and Cre-mediated genetically engineered mouse models of sarcoma
Authors: Huang Jianguo , Chen Mark , Whitley Melodi Javid , Kuo Hsuan-Cheng , Xu Eric S. , Walens Andrea , Mowery Yvonne M. , Van Mater David , Eward William C. , Cardona Diana M. , Luo Lixia , Ma Yan , Lopez Omar M. , Nelson Christopher E. , Robinson-Hamm Jacqueline N. , Reddy Anupama , Dave Sandeep S. , Gersbach Charles A. , Dodd Rebecca D. , Kirsch David G.
Published: July 2017

Genetically engineered mouse models that employ site-specific recombinase technology are important tools for cancer research but can be costly and time-consuming. The CRISPR-Cas9 system has been adapted to generate autochthonous tumours in mice, but how these tumours compare to tumours generated by conventional recombinase technology remains to be fully explored. Here we use CRISPR-Cas9 to generate multiple subtypes of primary sarcomas efficiently in wild type and genetically engineered mice. These data demonstrate that CRISPR-Cas9 can be used to generate multiple subtypes of soft tissue sarcomas in mice. Primary sarcomas generated with CRISPR-Cas9 and Cre recombinase technology had similar histology, growth kinetics, copy number variation and mutational load as assessed by whole exome sequencing. These results show that sarcomas generated with CRISPR-Cas9 technology are similar to sarcomas generated with conventional modelling techniques and suggest that CRISPR-Cas9 can be used to more rapidly generate genotypically and phenotypically similar cancers.
Comparative effectiveness of a portion-controlled meal replacement program for weight loss in adults with and without diabetes/high blood sugar
Authors: Coleman C D , Kiel J R , Mitola A H , Arterburn L M
Published: July 2017

Background:

Individuals with type 2 diabetes (DM2) may be less successful at achieving therapeutic weight loss than their counterparts without diabetes. This study compares weight loss in a cohort of adults with DM2 or high blood sugar (D/HBS) to a cohort of adults without D/HBS. All were overweight/obese and following a reduced or low-calorie commercial weight-loss program incorporating meal replacements (MRs) and one-on-one behavioral support.

Subjects/Methods:

Demographic, weight, body composition, anthropometric, pulse and blood pressure data were collected as part of systematic retrospective chart review studies. Differences between cohorts by D/HBS status were analyzed using Mann–Whitney U-tests and mixed model regression.

Results:

A total of 816 charts were included (125 with self-reported D/HBS). The cohort with D/HBS had more males (40.8 vs 25.6%), higher BMI (39.0 vs 36.3 kg m−2) and was older (56 vs 48 years). Among clients continuing on program, the cohorts with and without D/HBS lost, on average, 5.6 vs 5.8 kg (NS) (5.0 vs 5.6%; P=0.005) of baseline weight at 4 weeks, 11.0 vs 11.6 kg (NS) (9.9 vs 11.1%; P=0.027) at 12 weeks and 16.3 vs 17.1 kg (13.9 vs 15.7%; NS) at 24 weeks, respectively. In a mixed model regression controlling for baseline weight, gender and meal plan, and an intention-to-treat analysis, there was no significant difference in weight loss between the cohorts at any time point. Over 70% in both cohorts lost ⩾5% of their baseline weight by the final visit on their originally assigned meal plan. Both cohorts had significant reductions from baseline in body fat, blood pressure, pulse and abdominal circumference.

Conclusion:

Adults who were overweight/obese and with D/HBS following a commercial weight-loss program incorporating MRs and one-on-one behavioral support achieved therapeutic weight loss. The program was equally effective for weight loss and reductions in cardiometabolic risk factors among adults with and without D/HBS.
Spontaneous loss of B lineage transcription factors leads to pre-B leukemia in Ebf1+/–Bcl-xLTg mice
Authors: Ramírez-Komo J A , Delaney M A , Straign D , Lukin K , Tsang M , Iritani B M , Hagman J
Published: July 2017

Early B-cell factor 1 (EBF1) plays a central role in B-cell lineage specification and commitment. Loss of this critical transcription factor is strongly associated with high-risk, relapsed and therapy-resistant B–cell-acute lymphoblastic leukemia, especially in children. However, Ebf1 haploinsufficient mice exhibit a normal lifespan. To determine whether prolonged survival of B cells would enable tumorigenesis in Ebf1 haploinsufficient animals, we generated Ebf1+/–Bcl-xLTg mice, which express the anti-apoptotic factor Bcl-xL in B cells. Approximately half of Ebf1+/–Bcl-xLTg mice develop aggressive oligoclonal leukemia as they age, which engrafts in congenic wild-type recipients without prior conditioning. The neoplastic cells display a pre-B phenotype and express early developmental- and natural killer cell/myeloid-markers inappropriately. In addition, we found tumor cell-specific loss of several transcription factors critical for maintaining differentiation: EBF1, TCF3 and RUNX1. However, in the majority of tumors, loss of Ebf1 expression was not due to loss of heterozygosity. This is the first spontaneous mouse model of pre-B leukemia to demonstrate inappropriate expression of non-B-cell-specific genes associated with loss of Ebf1, Tcf3 and Runx1 expression.
Epigenetic silencing of microRNA-137 enhances ASCT2 expression and tumor glutamine metabolism
Authors: Dong J , Xiao D , Zhao Z , Ren P , Li C , Hu Y , Shi J , Su H , Wang L , Liu H , Li B , Gao P , Qing G
Published: July 2017

Tumor cells must activate specific transporters to meet their increased glutamine metabolic demands. Relative to other glutamine transporters, the ASC family transporter 2 (ASCT2, also called SLC1A5) is profoundly elevated in a wide spectrum of human cancers to coordinate metabolic reprogramming and malignant transformation. Understanding the molecular mechanisms whereby tumor cells frequently upregulate this transporter is therefore vital to develop potential strategies for transporter-targeted therapies. Combining in-silico algorithms with systemic experimental screening, we herein identify the tumor suppressor microRNA, miR-137, as an essential regulator that targets ASCT2 and cancer cell glutamine metabolism. Metabolic analysis shows that miR-137 derepression, similar to ASCT2 inactivation, significantly inhibits glutamine consumption and TCA cycle anaplerosis. Mechanistically, methyl-CpG-binding protein 2 (MeCP2) and DNA methyltransferases (DNMTs) cooperate to promote active methylation of the miR-137 promoter and inhibit its transcription, conversely reactivating ASCT2 expression and glutamine metabolism. Moreover, expression between miR-137 and ASCT2 is inversely correlated in tumor specimens from multiple cancer types, and ectopic ASCT2 expression markedly rescued miR-137 suppression of tumorigenesis. These findings thus elucidate a previously unreported mechanism responsible for ASCT2 deregulation in human cancers and identify ASCT2 as a critical downstream effector of miR-137, revealing a molecular link between DNA methylation, microRNA and tumor metabolism.
Reduced ultrafine particle levels in São Paulo’s atmosphere during shifts from gasoline to ethanol use
Authors: Salvo Alberto , Brito Joel , Artaxo Paulo , Geiger Franz M.
Published: July 2017

Despite ethanol’s penetration into urban transportation, observational evidence quantifying the consequence for the atmospheric particulate burden during actual, not hypothetical, fuel-fleet shifts, has been lacking. Here we analyze aerosol, meteorological, traffic, and consumer behavior data and find, empirically, that ambient number concentrations of 7–100-nm diameter particles rise by one-third during the morning commute when higher ethanol prices induce 2 million drivers in the real-world megacity of São Paulo to substitute to gasoline use (95% confidence intervals: +4,154 to +13,272 cm−3). Similarly, concentrations fall when consumers return to ethanol. Changes in larger particle concentrations, including US-regulated PM2.5, are statistically indistinguishable from zero. The prospect of increased biofuel use and mounting evidence on ultrafines’ health effects make our result acutely policy relevant, to be weighed against possible ozone increases. The finding motivates further studies in real-world environments. We innovate in using econometrics to quantify a key source of urban ultrafine particles.
Deletion of the B-B’ and C-C’ regions of inverted terminal repeats reduces rAAV productivity but increases transgene expression
Authors: Zhou Qingzhang , Tian Wenhong , Liu Chunguo , Lian Zhonghui , Dong Xiaoyan , Wu Xiaobing
Published: July 2017

Inverted terminal repeats (ITRs) of the adeno-associated virus (AAV) are essential for rescue, replication, packaging, and integration of the viral genome. While ITR mutations have been identified in previous reports, we designed a new truncated ITR lacking the B-B’ and C-C’ regions named as ITRΔBC and investigated its effects on viral genome replication, packaging, and expression of recombinant AAV (rAAV). The packaging ability was compared between ITRΔBC rAAV and wild-type (wt) ITR rAAV. Our results showed the productivity of ITRΔBC rAAV was reduced 4-fold, which is consistent with the 8-fold decrease in the replication of viral genomic DNA of ITRΔBC rAAV compared with wt ITR rAAV. Surprisingly, transgene expression was significantly higher for ITRΔBC rAAV. A preliminary exploration of the underlying mechanisms was carried out by inhibiting and degrading the ataxia telangiectasia mutated (ATM) protein and the Mre11 complex (MRN), respectively, since the rAAV expression was inhibited by the ATM and/or MRN through cis interaction or binding with wt ITRs. We demonstrated that the inhibitory effects were weakened on ITRΔBC rAAV expression. This study suggests deletion in ITR can affect the transgene expression of AAV, which provides a new way to improve the AAV expression through ITRs modification.
Spatiotemporal expression patterns of wheat amino acid transporters reveal their putative roles in nitrogen transport and responses to abiotic stress
Authors: Wan Yongfang , King Robert , Mitchell Rowan A. C. , Hassani-Pak Keywan , Hawkesford Malcolm J.
Published: July 2017

Amino acid transporters have roles in amino acid uptake from soil, long-distance transport, remobilization from vegetative tissues and accumulation in grain. Critically, the majority of wheat grain nitrogen is derived from amino acids remobilized from vegetative organs. However, no systematic analysis of wheat AAT genes has been reported to date. Here, 283 full length wheat AAT genes representing 100 distinct groups of homeologs were identified and curated by selectively consolidating IWGSC CSSv2 and TGACv1 Triticum aestivum genome assemblies and reassembling or mapping of IWGSC CSS chromosome sorted reads to fill any gaps. Gene expression profiling was performed using public RNA-seq data from root, leaf, stem, spike, grain and grain cells (transfer cell (TC), aleurone cell (AL), and starchy endosperm (SE)). AATs highly expressed in roots are good candidates for amino acid uptake from soil whilst AATs highly expressed in senescing leaves and stems may be involved in translocation to grain. AATs in TC (TaAAP2 and TaAAP19) and SE (TaAAP13) may play important roles in determining grain protein content and grain yield. The expression levels of AAT homeologs showed unequal contributions in response to abiotic stresses and development, which may aid wheat adaptation to a wide range of environments.
Phthalide Derivatives from Angelica Sinensis Decrease Hemoglobin Oxygen Affinity: A New Allosteric-Modulating Mechanism and Potential Use as 2,3-BPG Functional Substitutes
Authors: Chen Wei-Ren , Yu Youqing , Zulfajri Muhammad , Lin Ping-Cheng , Wang Chia C.
Published: July 2017

Angelica sinensis (AS), one of the most versatile herbal medicines remains widely used due to its multi-faceted pharmacologic activities. Besides its traditional use as the blood-nourishing tonic, its anti-hypertensive, anti-cardiovascular, neuroprotective and anti-cancer effects have been reported. Albeit the significant therapeutic effects, how AS exerts such diverse efficacies from the molecular level remains elusive. Here we investigate the influences of AS and four representative phthalide derivatives from AS on the structure and function of hemoglobin (Hb). From the spectroscopy and oxygen equilibrium experiments, we show that AS and the chosen phthalides inhibited the oxygenated Hb from transforming into the high-affinity “relaxed” (R) state, decreasing Hb’s oxygen affinity. It reveals that phthalides cooperate with the endogenous Hb modulator, 2,3-bisphosphoglycerate (2,3-BPG) to synergetically regulate Hb allostery. From the docking modeling, phthalides appear to interact with Hb mainly through its α1/α2 interface, likely strengthening four (out of six) Hb “tense” (T) state stabilizing salt-bridges. A new allosteric-modulating mechanism is proposed to rationalize the capacity of phthalides to facilitate Hb oxygen transport, which may be inherently correlated with the therapeutic activities of AS. The potential of phthalides to serve as 2,3-BPG substitutes/supplements and their implications in the systemic biology and preventive medicine are discussed.