bluuebunny/crossref_metadata_2025 huggingface dataset:
Uma visão interdisciplinar do ensino de ciências por meio do teatro científico
Authors: Bezerra Roseana Da Silva , Alves Leonardo Alcântara , Nunes Albino Oliveira
Published: November 2018

Discutir interdisciplinaridade, na escola, é sempre um desafio. É necessário compreender a sua importância real na formação do aluno como cidadão, e como se pode abordá-la para contribuir na referida formação. O presente trabalho tem como objetivo discutir esses pontos, mediante uma ferramenta de ensino usada por professores de ciências, chamada "Teatro Científico". Em uma pesquisa qualitativa, realizou-se uma entrevista semiestruturada com três professores de Química que usam esta ferramenta em diferentes escolas de ensino médio na cidade de Mossoró, no Rio Grande do Norte, questionando como a interdisciplinaridade é abordada nesses projetos, e como esta ferramenta pode contribuir para o ensino e para a formação cidadã dos alunos envolvidos nos projetos. Por meio da análise de conteúdo, foi possível perceber que o trabalho com o Teatro Cientifico possibilita a aplicação de uma abordagem interdisciplinar. Ressalta-se, também, a contribuição com a formação crítica do aluno, já que ele ou ela exercita diversas habilidades cognitivas, como trabalho em grupo, solidariedade, compromisso e responsabilidade. Apesar disso, várias dificuldades foram percebidas ao se trabalhar com esta ferramenta, nas escolas, devido à falta de cooperação de outros professores. Isso acontece, de acordo com os professores, com qualquer atividade interdisciplinar. Segundo eles, isso é resultado da falta de tempo e de motivação dos professores para o planejamentos de tais atividades, devido ao trabalho em outras instituições,  baixos salários, fadiga e outros fatores.
Proposta de um Modelo para Comparação e Escolha de Frameworks para o Desenvolvimento de Software Baseado em Requisitos não Funcionais
Authors: Sandy José Mauro da Silva , Schiavoni Flávio Luiz
Published: November 2018

A escolha dos frameworks utilizados ao longo do desenvolvimento de software causa um impacto direto na qualidade do produto desenvolvido, mas, muitas vezes, é realizada de forma subjetiva. Neste contexto, este artigo visa apresentar um modelo para realizar a escolha de frameworks de maneira racional por meio de um modelo iterativo, baseado nos requisitos não funcionais dos frameworks que serão avaliados. O modelo define três etapas que podem ser repetidas, caso exista alguma dúvida após o término de cada iteração. Na primeira etapa, a configuração do questionário é realizada com a definição das questões que serão utilizadas durante a avaliação e seus respectivos pesos. A próxima etapa consiste na aplicação do questionário configurado na primeira etapa, para posterior apuração dos resultados. Na terceira e última etapa, as respostas dadas são quantificadas para determinar qual o framework é mais indicado para o contexto avaliado. Ao terminar, caso ainda não seja possível definir qual o mais adequado, uma nova iteração pode ser realizada. O modelo proposto tem por objetivo decidir de forma racional qual framework deve ser adotado. Por fim, apresentamos um estudo de caso desse modelo na escolha do framework com bibliotecas gráficas para o projeto Mosaicode.
Germany’s New Right-wing Populist Party – the Alternative for Germany
Authors: Klikauer Thomas
Published: November 2018

In the year 2017, a new political party entered Germany’s parliament called ‘Alternative for Germany’ or AfD. Mainstream media labels the party far right, radical-right, right wing, national-conservative, populist, etc. Despite this, the AfD has tendencies towards Nazism. Nine books published between 2016 and 2018 examine the stratospheric rise of the AfD, founded in 2013. The review starts with a conservative view that examines ‘what the AfD wants.’ The next book discusses the ‘AfD-Pegida’ link. Pegida is the AfD’s East-German and mostly Dresden-based street-fighting movement. The third book presents arguments on the AfD from across Germany’s political spectrum. This leads to a book written as a ‘letter to AfD voters’. The book outlines many inconstancies found in the AfD’s party programme and its public announcements. Since the AfD claims to protect the occident, Europe and Germany in particular against hordes of Muslims and the Islamic religion, these issues are discussed in the next book. A quick look at the ideological background of the AfD points to an analysis of the party’s relationship with the media. The final two books show how the AfD seeks to conquer Germany’s political centre, based on a wealth of empirical data. Overall, the nine books provide one of the first comprehensive examinations of Germany’s new radical-right party drawn from recent German language books.
Amending the Slovak Parliamentary Rules of Procedure: Effective Changes or the Government’s Weapon against the Opposition?
Authors: Chovancová Katarína
Published: November 2018

Parliament is considered one of the most important institutions in representative democracies. However, Rules of Procedure as institutional regulation of its activity have been rarely analysed. This paper aims to fill this gap by conducting an analysis of amending the Rules of Procedure of the Slovak legislature in the period 1998–2016, almost its entire existence. The analysis not only covers passed amendments but also looks at proposed but unpassed ones. The main assumption is that through changing the parliamentary rules, the parliament adapts itself to specific trends. These are identified in the paper, as well as the main categories the proposed amendments concentrated on, distinguishing between redistributive and effective amendments. One of the key findings of the paper is that it is not the government that dominates the process of proposing amendments to the parliamentary rules. On the other hand, when we look at passed amendments only, the government is, then, the dominant actor. The assumption that the amendments of the Rules of Procedure are primarily of a redistributive character was not verified. Despite the fact that amending these rules may be used by the governmental majority to redistribute the power in the Slovak parliament, in practise, such behaviour is rather infrequent and cannot be described as the government’s weapon against the opposition.
Gender Equality in Law: Uncovering the Legacies of Czech State Socialism
Authors: Crema Juliana
Published: November 2018

Havelková, Barbara: Gender Equality in Law: Uncovering the Legacies of Czech State Socialism. Oxford: Hart Publishing, 2017, 358 pages.
Coffee's Dark Secrets: Linguistic Variation in Starbucks and Dunkin Donuts
Authors: Butler Lilah
Published: November 2018

This paper explores the linguistic implications of language in coffee shops, focusing on Starbucks and Dunkin Donuts stores located around Boston College. I interviewed baristas, recorded menus, tallied the greetings used by baristas, thereby focusing on coffee-related jargon as well as the language used towards entering customers. My research demonstrated a difference in practice in the two chains, with Starbucks utilizing a self-invented code of coffee-specific jargon, something Dunkin Donuts avoided. Dunkin Donuts baristas also showed a preference for simple, single-word greetings, whereas Starbucks tended towards questions regarding the customer’s specific order, shifting focus onto the drink itself. Baristas at Starbucks used elaborate, detailed phrases to describe their coffee; contrastingly, Dunkin Donuts employees politely but very briefly answered my questions. In conclusion, Starbucks-lexicon markets itself as differentiated from the majority of coffee shops, whereas Dunkin Donuts seeks a solidarity-based approach, implying a different audience. Future research could compare other chains of coffee shops, determining whether Starbucks is alone in its brand-specific lexicon or if other coffee shops have adopted its use as well.
Review of scribal education in ancient Israel: The Old Hebrew epigraphic evidence by Christopher Rollston
Authors: Hewett Matthew R
Published: November 2018

In this illustrative and thorough article, Christopher Rollston argues for the existence of, in R’s words, “a formal, standardized scribal education” in Ancient Israel (47). R bases his argument on a systematic analysis of the epigraphic evidence of Old Hebrew (i.e. Iron Age II Hebrew, ca. 1000-550 ce) and offers the following as his supporting arguments: (i) In terms of the ductus, the stance, and the relative spatial relationship of graphs, the Old Hebrew (OH) script: (a) displays synchronic consistency, (b) demonstrates discernable, diachronic development, and (c) differs markedly from those of nearby polities (Phoenicia, Arameans); (ii) In terms of orthography, the OH script exhibits synchronic (and arguably regional) consistency with distinctive features that were in opposition with the features of the Phoenician and Aramaic national scripts; and (iii) In terms of content, hieratic numerals (which derive from a complex number system originally borrowed from Egypt) were inscribed on many OH documents, suggesting that an administrative or governing body routinized their usage (and practical dissemination) throughout Iron Age Israel
INFANTILNA FORMA POMPEOVE BOLESTI
Authors: Marić Nina , Đukić Dario , Đurđević Banjac Biljana , Malčić-Zanić Dragana
Published: November 2018

Pompeova bolest je rijetko autozomno recesivno nasljedno metaboličko oboljenjeuzrokovano nedostatkom enzima kisele alfa glukozidaze usljed mutacije GAA gena.Karakteriše se nakupljanjem glikogena u lizozomima svih ćelija, posebno ćelija mišića,jetre, srca i mozga. Simptomi bolesti mogu se javiti u različitoj dobi i mogu biti različitetežine, što najviše zavisi od prirode mutacije i rezidualne enzimske aktivnosti. Najteži jeinfantilni oblik kod koga rano nastaju kardiomegalija, hepatomegalija, hipotonija i mišićnaslabosti, i kod koga do smrtnog ishoda dolazi u toku prve godine života. Od 2006.godine dostupno je i odobreno liječenje Pompeove bolesti enzimskom supstitucionomterapijom. Uspješnost ovog vida liječenja najviše zavisi od stadija bolesti u vrijeme započinjaliječenja, genotipa i CRIM statusa. Većinom pacijenti sa CRIM negativnim statusomimaju loš odgovor na liječenje, više komplikacija i samim tim lošiju prognozu.U ovom radu smo prikazali prvi slučaj infantilne forme Pompeove bolesti koju smoliječili enzimskom supstitucionom terapijom u našoj zdravstvenoj ustanovi. Pompeovabolest se kod ovog pacijenta prvo manifestovala hipertrofičnom kardiomiopatijom iimala je brzu progresiju sa razvojem hepatomegalije, teške hipotonije, mišićne slabostii konačno srčane i respiratorne slabosti. Enzimsku supstitucionu terapijou pacijent jepočeo da prima u dobi od 3 mjeseca. Odgovor na terapiju je bio loš i pacijent je umrou dobi od 6 mjeseci.Smatramo da bi prepoznavanje ove bolesti u ranijoj dobi i započinjanje liječenja prijerazvoja kliničkih simptoma vjerojatno dalo bolji rezultat liječenja i produžilo životnivijek oboljelih od Pompeove bolesti.
New tools for automated high-resolution cryo-EM structure determination in RELION-3
Authors: Zivanov Jasenko , Nakane Takanori , Forsberg Björn O , Kimanius Dari , Hagen Wim JH , Lindahl Erik , Scheres Sjors HW
Published: November 2018

Here, we describe the third major release of RELION. CPU-based vector acceleration has been added in addition to GPU support, which provides flexibility in use of resources and avoids memory limitations. Reference-free autopicking with Laplacian-of-Gaussian filtering and execution of jobs from python allows non-interactive processing during acquisition, including 2D-classification, de novo model generation and 3D-classification. Per-particle refinement of CTF parameters and correction of estimated beam tilt provides higher resolution reconstructions when particles are at different heights in the ice, and/or coma-free alignment has not been optimal. Ewald sphere curvature correction improves resolution for large particles. We illustrate these developments with publicly available data sets: together with a Bayesian approach to beam-induced motion correction it leads to resolution improvements of 0.2–0.7 Å compared to previous RELION versions.
A real-time PCR assay for quantification of parasite burden in murine models of leishmaniasis
Authors: Antonia Alejandro L. , Wang Liuyang , Ko Dennis C.
Published: November 2018

Eukaryotic parasites in the genusLeishmaniaplace approximately 350 million people per year at risk of disease. In addition to their global health significance,Leishmaniaspp. have served as an important model for delineating basic concepts in immunology such as T-helper cell polarization. There have been many qPCR-based assays reported for measuring parasite burden in humans and animals. However, these are largely optimized for use in clinical diagnosis and not specifically for animal models. This has led several of these assays to have suboptimal characteristics for use in animal models. For example, multi-copy number genes have been frequently used to increase sensitivity but are subject to greater plasticity within the genome and thus may confound effects of experimental manipulations in animal models. In this study, we developed a sybr-green based quantitative touchdown PCR assay for a highly conserved and single-copy putative RNA-binding protein, DRBD3. With primers that share greater than 90% sequence identity across all sequencedLeishmaniaspp., we demonstrate that this assay has a lower limit of detection of 100 fg of parasite DNA forLeishmania major,L. donovani,L. venezuelensis, andL. panamensis. Using C57BL6/J mice, we used this assay to monitor parasite burden over 1 month of infection with two strains ofL. major(Seidman and Friedlin), andL. venezeuelensis.These characteristics rival the sensitivity of previously reported qPCR based methods of parasite quantitation while amplifying a stable, single copy gene. Use of this protocol in the future will lead to improved accuracy in animal based models and help to tease apart differences in biology of host-parasite interactions.
Development and evaluation of a novel MR‐compatible pelvic end‐to‐end phantom
Authors: Cunningham Justine M. , Barberi Enzo A. , Miller John , Kim Joshua P. , Glide‐Hurst Carri K.
Published: November 2018

MR‐only treatment planning and MR‐IGRT leverage MRI's powerful soft tissue contrast for high‐precision radiation therapy. However, anthropomorphic MR‐compatible phantoms are currently limited. This work describes the development and evaluation of a custom‐designed, modular, pelvic end‐to‐end (PETE) MR‐compatible phantom to benchmark MR‐only and MR‐IGRT workflows. For construction considerations, subject data were assessed for phantom/skeletal geometry and internal organ kinematics to simulate average male pelvis anatomy. Various materials for the bone, bladder, and rectum were evaluated for utility within the phantom. Once constructed, PETE underwent CT‐SIM, MR‐Linac, and MR‐SIM imaging to qualitatively assess organ visibility. Scans were acquired with various bladder and rectal volumes to assess component interactions, filling capabilities, and filling reproducibility via volume and centroid differences. PETE simulates average male pelvis anatomy and comprises an acrylic body oval (height/width = 23.0/38.1 cm) and a cast‐mold urethane skeleton, with silicone balloons simulating bladder and rectum, a silicone sponge prostate, and hydrophilic poly(vinyl alcohol) foam to simulate fat/tissue separation between organs. Access ports enable retrofitting the phantom with other inserts including point/film‐based dosimetry options. Acceptable contrast was achievable in CT‐SIM and MR‐Linac images. However, the bladder was challenging to distinguish from background in CT‐SIM. The desired contrast for T1‐weighted and T2‐weighted MR‐SIM (dark and bright bladders, respectively) was achieved. Rectum and bone exhibited no MR signal. Inputted volumes differed by <5 and <10 mL from delineated rectum (CT‐SIM) and bladder (MR‐SIM) volumes. Increasing bladder and rectal volumes induced organ displacements and shape variations. Reproduced volumes differed by <4.5 mL, with centroid displacements <1.4 mm. A point dose measurement with an MR‐compatible ion chamber in an MR‐Linac was within 1.5% of expected. A novel, modular phantom was developed with suitable materials and properties that accurately and reproducibly simulate status changes with multiple dosimetry options. Future work includes integrating more realistic organ models to further expand phantom options.
Extending the verifiability approach framework: The effect of initial questioning
Authors: Harvey Adam Charles , Vrij Aldert , Sarikas George , Leal Sharon , Jupe Louise , Nahari Galit
Published: November 2018

The verifiability approach (VA) is a lie‐detection tool that examines reported checkable details. Across two studies, we attempt to exploit liar's preferred strategy of repeating information by examining the effect of questioning adult interviewees before the VA. In Study 1, truth tellers (n = 34) and liars (n = 33) were randomly assigned to either an initial open or closed questioning condition. After initial questioning, participants were interviewed using the VA. In Study 2, truth tellers (n = 48) and liars (n = 48) were interviewed twice, with half of each veracity group randomly assigned to either the Information Protocol (an instruction describing the importance of reporting verifiable details) or control condition. Only truth tellers revised their initial statement to include verifiable detail. This pattern was most pronounced when initial questioning was open (Study 1) and when the information protocol was employed (Study 2). Thus, liar's preferred strategy of maintaining consistency between statements appears exploitable using the VA.
Graphene‐Sensitized Perovskite Oxide Monolayer Nanosheets for Efficient Photocatalytic Reaction
Authors: Li Di , Zhao Huaping , Li Longhua , Mao Baodong , Chen Min , Shen Hao , Shi Weidong , Jiang Deli , Lei Yong
Published: November 2018

Efficient visible light harvesting and fast charge transfer are of high importance for solar‐energy conversion over semiconducting metal oxide photocatalysts. Here, a proof‐of‐concept strategy is developed to enable visible‐light photocatalytic activity of wide bandgap Ca2Nb3O10 monolayer nanosheet by incorporation of reduced graphene oxide (RGO) nanosheet as a photosensitizer. The Ca2Nb3O10 monolayer nanosheet/RGO 2D–2D nanohybrids exhibit largely elevated performance in photocatalytic H2 evolution with a H2 production rate of 820.76 µmol h−1 g−1 and tetracycline hydrochloride degradation reactions under the visible light irradiation. The combined experimental and theoretical results demonstrate that the electrons generated from the photoexcited RGO transfer to the Ca2Nb3O10 monolayer nanosheet and then participate in the photocatalytic reactions. The constructed RGO sensitized monolayer perovskite photocatalyst nanohybrids are demonstrated as an efficient photosensitizer for enhancing visible light harvesting of wide bandgap semiconductor in solar‐energy conversion, and elaborated in details of the charge transfer process of this type of nanohybrid photocatalyst.
Autonomous Ultrafast Self‐Healing Hydrogels by pH‐Responsive Functional Nanofiber Gelators as Cell Matrices
Authors: Gačanin Jasmina , Hedrich Jana , Sieste Stefanie , Glaßer Gunnar , Lieberwirth Ingo , Schilling Corinna , Fischer Stephan , Barth Holger , Knöll Bernd , Synatschke Christopher V. , Weil Tanja
Published: November 2018

The synthesis of hybrid hydrogels by pH‐controlled structural transition with exceptional rheological properties as cellular matrix is reported. “Depsi” peptide sequences are grafted onto a polypeptide backbone that undergo a pH‐induced intramolecular O–N–acyl migration at physiological conditions affording peptide nanofibers (PNFs) as supramolecular gelators. The polypeptide–PNF hydrogels are mechanically remarkably robust. They reveal exciting thixotropic behavior with immediate in situ recovery after exposure to various high strains over long periods and self‐repair of defects by instantaneous reassembly. High cytocompatibility, convenient functionalization by coassembly, and controlled enzymatic degradation but stability in 2D and 3D cell culture as demonstrated by the encapsulation of primary human umbilical vein endothelial cells and neuronal cells open many attractive opportunities for 3D tissue engineering and other biomedical applications.
General Resolution Enhancement Method in Atomic Force Microscopy Using Deep Learning
Authors: Liu Yue , Sun Qiaomei , Lu Wanheng , Wang Hongli , Sun Yao , Wang Zhongting , Lu Xin , Zeng Kaiyang
Published: November 2018

Here, a resolution enhancement method is developed for post‐processing images from atomic force microscopy (AFM). This method is based on deep learning neural networks in the AFM topography measurements. In this study, a very deep convolution neural network is developed to derive a high‐resolution topography image from a low‐resolution topography image. The AFM measured images from various materials are tested in this study. The derived high‐resolution AFM images are comparable with the experimental measured high‐resolution images measured at the same locations. The results suggest that this method can be developed as a general post‐processing method for AFM image analysis.
Biomarkers for major depressive and bipolar disorders using metabolomics: A systematic review
Authors: MacDonald Kellie , Krishnan Ankur , Cervenka Emily , Hu Grace , Guadagno Elena , Trakadis Yannis
Published: November 2018

Major depressive disorder (MDD) and bipolar disorder (BD) lack robust biomarkers useful for screening purposes in a clinical setting. A systematic review of the literature was conducted on metabolomic studies of patients with MDD or BD through the use of analytical platforms such as in vivo brain imaging, mass spectrometry, and nuclear magnetic resonance. Our search identified a total of 7,590 articles, of which 266 articles remained for full‐text revision. Overall, 249 metabolites were found to be dysregulated with 122 of these metabolites being reported in two or more of the studies included. A list of biomarkers for MDD and BD established from metabolites found to be abnormal, along with the number of studies supporting each metabolite and a comparison of which biological fluids they were reported in, is provided. Metabolic pathways that may be important in the pathophysiology of MDD and BD were identified and predominantly center on glutamatergic metabolism, energy metabolism, and neurotransmission. Using online drug registries, we also illustrate how metabolomics can facilitate the discovery of novel candidate drug targets.
Visible‐Light‐Mediated Metal‐Free Difunctionalization of Alkenes with CO2 and Silanes or C(sp3)−H Alkanes
Authors: Hou Jing , Ee Aloysius , Cao Hui , Ong Han‐Wee , Xu Jin‐Hui , Wu Jie
Published: November 2018

Catalytic alkene difunctionalization via Si−H and C−H activations represents an ideal atom‐ and step‐economic pathway for quick assembly of molecular complexity. We herein developed a visible‐light‐promoted metal‐free difunctionalization of alkenes using abundant CO2 and readily available Si−H and C(sp3)−H bonds as feedstocks. Through the merger of photoredox and hydrogen‐atom‐transfer catalysis, a variety of value‐added compounds, such as β‐silacarboxylic acids and acids bearing a γ‐heteroatom (e.g., N, O, S) could be directly accessed from simple alkenes in a redox‐neutral fashion.
Musical Moments in the Creative Practice of Family Therapy
Authors: Yeow James L. H.
Published: November 2018

This article uses music as a metaphor for family therapy process and practice. The overture begins looking at the family using the symphony as an analogy highlighting insight into musical improvisation as integral to the progression of acceptance to change. Several other key music therapy strategies discussed include therapeutic songwriting, song discussions, and lyric substitution, all within the framework of family therapy. The finale concludes with a caution on the fundamental importance of building rapport rather than being too technique‐focused, for music itself is ultimately the social glue that binds people together.
Maximum Bony Gape in Primates
Authors: Fricano Ellen E. I. , Perry Jonathan M. G.
Published: November 2018

Maximum jaw gape has important functional implications for behavior and feeding habits in primates. It has been suggested that gape is correlated to canine height and ingested food size. Extending these correlations to the fossil record would provide insights about the diets and/or social behavior of extinct primates. However, this can be problematic due to uncertainty about size and location of musculature, and it depends on reliability and repeatability of maximum gape estimation using only skeletal elements. In this study, maximum bony gape (MBG) was estimated using reliable landmarks and repeatable methods. The cranium was fixed in position and then the mandible was rotated and translated to the point immediately prior to loss of condyle‐glenoid contact. Then it was photographed in a steady position using an adjustable wooden frame. This protocol allowed for photographs and linear measurements to be obtained for many museum specimens in a short time. The sample included 203 individuals, representing 42 species of primates. When scaled for body size, linear MBG correlates with maximum anesthetized gape (Hylander: Am J Phys Anthropol 150 (2013) 247–259), ingested food size (Perry and Hartstone‐Rose: Am J Phys Anthropol 142 (2010) 625–635), and canine length but not condylar height. Anat Rec, 302:215–225, 2019. © 2018 Wiley Periodicals, Inc.
Disruption of RHOA‐ROCK Signaling Results in Atrioventricular Block and Disturbed Development of the Putative Atrioventricular Node
Authors: Kelder Tim P. , Vicente‐Steijn Rebecca , Poelmann Robert E. , Schalij Martin J. , Deruiter Marco C. , Jongbloed Monique R. M. , Gittenberger‐de Groot Adriana C.
Published: November 2018

The RHOA‐ROCK signaling pathway is involved in numerous developmental processes, including cell proliferation, differentiation and migration. RHOA is expressed in the atrioventricular node (AVN) and altered expression of RHOA results in atrioventricular (AV) conduction disorders in mice. The current study aims to detect functional AVN disorders after disturbing RHOA‐ROCK signaling in chicken embryos. RHOA‐ROCK signaling was inhibited chemically by using the Rho‐kinase inhibitor compound Y‐27632 in avian embryos (20 experimental and 29 control embryos). Morphological examination of control embryos show a myocardial sinus venosus to atrioventricular canal continuity, contributing to the transitional zone of the AVN. ROCK inhibited embryos revealed lateralization and diminished myocardial sinus venosus to atrioventricular canal continuity and at the severe end of the phenotype hypoplasia of the AVN region. Ex ovo micro‐electrode recordings showed an AV conduction delay in all treated embryos as well as cases with first, second (Wenkebach and Mobitz type) and third‐degree AV block which could be explained by the spectrum of severity of the morphological phenotype. Laser capture microdissection and subsequent qPCR of tissue collected from this region revealed disturbed expression of HCN1, ISL1, and SHOX2. We conclude that RHOA‐ROCK signaling is essential for normal morphological development of the myocardial continuity between the sinus venosus and AVN, contributing to the transitional zone, and possibly the compact AVN region. Disturbing the RHOA‐ROCK signaling pathway results in AV conduction disturbances including AV block. The RHOA‐ROCK inhibition model can be used to further study the pathophysiology and therapeutic strategies for AV block. Anat Rec, 302:83–92, 2019. © 2018 Wiley Periodicals, Inc.
Control Interventions Can Impact Alveolarization and the Transcriptome in Developing Mouse Lungs
Authors: Fehl Joshua , Pozarska Agnieszka , Nardiello Claudio , Rath Philipp , Surate Solaligue David E. , Vadász István , Mayer Konstantin , Herold Susanne , Seeger Werner , Morty Rory E.
Published: November 2018

There is currently much interest in understanding the mechanisms of normal and aberrant lung alveolarization, particularly in the context of bronchopulmonary dysplasia, a common complication of preterm birth where alveolarization is impeded. To this end, the parenteral administration of pharmacological agents that modulate biochemical pathways, or facilitate modulation of gene expression in transgenic animals, has facilitated the discovery and validation of mechanisms that direct lung development. Such studies include control interventions, where the solvent vehicle, perhaps containing an inactive form of the agent applied, is administered; thereby providing a well‐controlled point of reference for the analysis of the partner experiment. In the present study, the impact of several widely used control interventions in developing C57Bl/6J mouse pups was examined for effects on lung structure and the lung transcriptome. Parenteral administration of scrambled microRNA inhibitors (called antagomiRs) that are used to control in vivo microRNA neutralization studies, impacted lung volume, septal thickness, and the transcriptome of developing mouse lungs; with some effects dependent upon nucleotide sequence. Repeated intraperitoneal isotonic saline injections altered lung volume, with limited impact on the transcriptome. Parenteral administration of the tamoxifen solvent Miglyol accelerated mouse pup growth, and changed the abundance of 73 mRNA transcripts in the lung. Tamoxifen applied in Miglyol—in the absence of Cre recombinase—decreased pup growth, lung volume, and lung alveolarization and changed the abundance of 298 mRNA transcripts in the lung. These data demonstrate that widely used control interventions can directly impact lung alveolarization and the lung transcriptome in studies on lung development. Anat Rec, 302:346–363, 2019. © 2018 Wiley Periodicals, Inc.
Learning Acetabular Fracture Classification using a Three‐Dimensional Interactive Software: A Randomized Controlled Trial
Authors: Wang Huixiang , Lyu Fei , Sugand Kapil , Wong Sheungting , Lin Yanping , Wang Qiugen
Published: November 2018

Acetabular fractures are a real challenge for junior doctors as well as experienced orthopedic surgeons. Correct fracture classification is crucial for appreciating the fracture type, surgical planning, and predicting prognosis. Although three‐dimensional (3D) tutorial is believed to improve the understanding of the complex anatomy structure, there have been few applications and randomized controlled trials to confirm it in orthopedics. This study aims to develop a 3D interactive software system for teaching acetabular fracture classification and evaluate its efficacy. Participants were randomly but evenly allocated into either the experimental group (who learned the acetabular fracture classification using a 3D software) or the control group (who used a traditional two‐dimensional [2D] tutorial). Both groups were then tasked to classify 10 acetabular fractures and complete a five‐point Likert scale on their satisfaction of each learning modality. To calculate significance (P < 0.05), independent t‐test was used for normally distributed data whereas Mann‐Whitney U test for non‐normally distributed data. The experimental group significantly outperformed the control group (t (28) = 2.526, P = 0.017) with identifying correct acetabular fracture classification. Moreover, Likert scale score in the experimental group was also significantly higher than in the control group (Z = 2.477, P = 0.013). This 3D classification software has objectively and subjectively showed an advantage over the traditional 2D tutorial, resulting in an improved classification accuracy and higher Likert scale score. The 3D software has the potential to improve both clinical knowledge as well as identifying correct patient management in orthopedics.
Incurred sample reanalysis in drug discovery bioanalysis
Authors: Giri Poonam , Patel Nirmal , Joshi Vipul , Giri Shyamkumar , Srinivas Nuggehally R.
Published: November 2018

Bioanalysis plays a key role during the drug discovery process to generate the pharmacokinetic data to facilitate unbiased evaluation of leads, optimized leads and drug candidates. Such pharmacokinetic data are used to enable key decisions in the drug discovery process. The aim of the work is to put forward a new strategy of performing the incurred sample reanalysis for select small molecule novel chemical entities at different stages of drug discovery prior to candidate selection. Three discovery programs representing hits, leads and optimized lead candidates were selected for the incurred sample reanalysis (ISR) analysis. From each discovery program, two novel chemical entities were selected for the ISR analysis. The time points considered for ISR generally varied among the programs; however, samples coinciding with drug absorption, distribution and elimination were considered in the ISR assessment. With the exception of a single ISR value that gave a high deviation (about 63%), the observed ISR values supported the discovery bioanalytical assays. While the individual bioanalytical laboratory can draw an algorithm for selecting novel chemical entities and fixing the acceptance criteria for the ISR data, it is proposed that the percentage difference between ISR vs. original concentration for 67% of the repeat samples is contained within ±30% for discovery bioanalysis.
Pathological tumor infiltrative pattern and sites of initial recurrence in stage II/III gastric cancer: Propensity score matching analysis of a multi‐institutional dataset
Authors: Nakagawa Nobuhiko , Kanda Mitsuro , Ito Seiji , Mochizuki Yoshinari , Teramoto Hitoshi , Ishigure Kiyoshi , Murai Toshifumi , Asada Takahiro , Ishiyama Akiharu , Matsushita Hidenobu , Tanaka Chie , Kobayashi Daisuke , Fujiwara Michitaka , Murotani Kenta , Kodera Yasuhiro
Published: November 2018

Background

Advanced gastric cancer frequently recurs even after radical resection followed by adjuvant chemotherapy. The aim of this study was to evaluate the relationship between pathological infiltrative pattern (INF) and initial recurrence patterns in patients with stage II/III gastric cancer using a large multicenter database.

Methods

We retrospectively analyzed 1098 eligible patients who underwent curative gastrectomy for stage II/III gastric cancer at nine institutions between 2010 and 2014. Patients were categorized into the INF‐a/b and INF‐c groups and adjusted using propensity score matching.

Results

After propensity score matching, 686 patients (343 for each) were classified in the INF‐a/b and INF‐c groups. There were no significant differences in overall and disease‐free survival between the two groups. In the INF‐a/b group, frequencies of recurrence at the peritoneum, lymph node, and liver were equivalent. In contrast, the peritoneum was the most frequent site and accounted for 60% of the total recurrences in the INF‐c group. The cumulative peritoneal recurrence rate was significantly higher in the INF‐c group than in the INF‐a/b group (hazard ratio 2.47). INF‐c was a significant risk factor for peritoneal recurrences in most subgroups including age, sex, macroscopic type, tumor differentiation, and disease stage, and whether the postoperative treatment was given. Multivariate analysis identified INF‐c as an independent risk factor for peritoneal recurrences. The cumulative liver recurrence rate was significantly higher in the INF‐a/b group than in the INF‐c group (hazard ratio 3.44).

Conclusions

INF may represent an important predictor of recurrence patterns after curative resection of stage II/III gastric cancer.
LRRK2 impairs autophagy by mediating phosphorylation of leucyl‐tRNA synthetase
Authors: Ho Dong Hwan , Kim Hyejung , Nam Daleum , Sim Hyuna , Kim Janghwan , Kim Hyung Gun , Son Ilhong , Seol Wongi
Published: November 2018

Leucine‐rich repeat kinase 2 (LRRK2) is a causal gene of Parkinson disease. G2019S pathogenic mutation increases its kinase activity. LRRK2 regulates various phenotypes including autophagy, neurite outgrowth, and vesicle trafficking. Leucyl‐tRNA synthetase (LRS) attaches leucine to tRNALeuand activates mTORC1. Down‐regulation of LRS induces autophagy. We investigated the relationship between LRRK2 and LRS in regulating autophagy and observed interaction between endogenous LRRK2 and LRS proteins and LRS phosphorylation by LRRK2. Mutation studies implicated that T293 in the LRS editing domain was a putative phosphorylation site. Phospho‐Thr in LRS was increased in cells overexpressing G2019S and dopaminergic neurons differentiated from induced pluripotent stem (iPS) cells of a G2019S carrier. It was decreased by treatment with an LRRK2 kinase inhibitor (GSK2578215A). Phosphomimetic T293D displayed lower leucine bindings than wild type (WT), suggesting its defective editing function. Cellular expression of T293D increased expression of GRP78/BiP, LC3B‐II, and p62 proteins and number of LC3 puncta. Increase of GRP78 and phosphorylated LRS was diminished by treatment with GSK2578215A. Levels of LC3B, GRP78/BiP, p62, and α‐synuclein proteins were also increased in G2019S transgenic (TG) mice. These data suggest that LRRK2‐mediated LRS phosphorylation impairs autophagy by increasing protein misfolding and endoplasmic reticulum stress mediated by LRS editing defect.

Significance of the study

Leucine‐rich repeat kinase 2 (LRRK2) is the most common genetic cause of Parkinson disease (PD), and the most prevalent pathogenic mutation, G2019S, increases its kinase activity. In this study, we elucidated that leucyl‐tRNA synthetase (LRS) was an LRRK2 kinase substrate and identified T293 as an LRRK2 phosphorylation site. LRRK2‐meidated LRS phosphorylation or G2019S can lead to impairment of LRS editing, increased ER stress, and accumulation of autophagy markers. These results demonstrate that LRRK2 kinase activity can facilitate accumulation of misfolded protein, suggesting that LRRK2 kinase might be a potential PD therapeutic target along with previous studies.
Role of estradiol and testosterone in Ucp1 expression in brown/beige adipocytes
Authors: Suzuki Mika , Murakami Masaru , Shirai Mitsuyuki , Hashimoto Osamu , Kawada Teruo , Matsui Tohru , Funaba Masayuki
Published: November 2018

Activity of brown/beige adipocytes is higher in women than in men. The expression level of uncoupling protein 1 (UCP1) is largely consistent with the thermogenic activity in brown/beige adipocytes. The present study examined the direct effects of sex hormones on Ucp1 expression in brown adipocytes and beige adipocytes, which were differentiated from HB2 brown preadipocytes and 3T3‐L1 white preadipocytes, respectively; treatment with estradiol or testosterone was used during the early (days 0‐8) or late stage (days 8‐12) of brown adipogenesis and beige adipogenesis. On day 8 or day 12, cells were treated with or without isoproterenol (Iso), an agonist for the β‐adrenergic receptor, for 4 hours. Furthermore, the sex of cells was examined; the sex‐determining region y gene, which is located on the y chromosome, was present in HB2 cells, but not in 3T3‐L1 cells, suggesting that HB2 cells and 3T3‐L1 cells are male and female cells, respectively. Treatment with 17β‐estradiol during the early stage of brown adipogenesis enhanced the responsiveness to Iso on Ucp1 induction, whereas treatment during the late stage of brown adipogenesis decreased Ucp1 expression in unstimulated brown adipocytes. Estradiol decreased Iso‐induced Ucp1 expression during the early stage of beige adipogenesis. Treatment with testosterone during the early stage of brown adipogenesis did not affect Ucp1 expression but increased the responsiveness to Iso on Ucp1 induction by the treatment during the late stage of brown adipogenesis. The present results suggest that sex hormones modulate the expression level of Ucp1 in brown/beige adipocytes in a stage‐dependent manner. Direct effects of sex hormones in brown/beige adipogenesis were evaluated. Treatment with 17β‐estradiol during the early stage of brown adipogenesis enhanced the responsiveness to isoproterenol (Iso), an agonist for the β‐adrenergic receptor, on Ucp1 induction, whereas treatment during the late stage of brown adipogenesis decreased Ucp1 expression in unstimulated brown adipocytes. Estradiol decreased Iso‐induced Ucp1 expression during the early stage of beige adipogenesis. Testosterone during the late stage of brown adipogenesis increased the responsiveness to Iso on Ucp1 induction. Sex hormones modulate the expression level of Ucp1 in brown/beige adipocytes in a stage‐dependent manner.
Stoichiometric Regeneration of ATP by A NAD(P)/CoA‐free and Phosphate‐balanced In Vitro Synthetic Enzymatic Biosystem
Authors: Wei Xinlei , Xie Leipeng , Job Zhang Yi‐Heng P. , You Chun
Published: November 2018

The regeneration of adenosine triphosphate is crucial for establishing a cost‐effective biosystem in which energy‐dependent processes are involved. Here, an in vitro synthetic enzymatic biosystem was designed to utilize low‐cost starch‐based material as energy source for the stoichiometric regeneration of ATP. This system required neither NAD(P) nor coenzyme A, and theoretically produced 3 ATPs per glucose equivalent of starch. When integrated with the L‐theanine‐producing enzymatic reaction which consumes 1 ATP to generate 1 L‐theanine molecule, our system resulted in a near‐theoretical yield of 2.94 L‐theanine per glucose equivalent. Furthermore, inorganic phosphate concentration of the system was nearly constant throughout the reaction period, suggesting the homeostatic reaction environment for enzymatic processes. This work provides a useful strategy for cost‐effective ATP regeneration which facilitates the production of ATP‐dependent value‐added chemicals.
CaII, YbII and SmII Bis(Amido) Complexes Coordinated by NHC Ligands: Efficient Catalysts for Highly Regio‐ and Chemoselective Consecutive Hydrophosphinations with PH3
Authors: Lapshin Ivan V. , Basalov Ivan V. , Lyssenko Konstantin A. , Cherkasov Anton V. , Trifonov Alexander A.
Published: November 2018

The first example of intermolecular hydrophosphination of styrene, 2‐vinylpyridine and phenylacetylene with PH3 catalyzed by bis‐(amido) complexes [(Me3Si)2N]2M(NHC)2 (M=Ca, Yb, Sm) coordinated by NHC ligands is described. The reactions of styrene with PH3 proceed under mild conditions in quantitative yields to afford only anti‐Markovnikov product and allow for the chemoselective synthesis of primary, secondary and tertiary phosphines. Addition of phenylacetylene to PH3 regardless the initial molar substrates ratio results in the exclusive formation of a tertiary tris‐(Z‐styryl)‐phosphine. Crucial effect of the Lewis base coordinated to the metal ion in precatalyst on catalytic activity in styrene hydrophosphination with PH3 was demonstrated. Free NHCs were also found to be able to promote addition of PH3 to styrene, however they provide much lower reaction rates compared to the metal complexes.
Asymmetric Cyclizative Dimerization of (ortho‐Alkynyl Phenyl) (Methoxymethyl) Sulfides with Palladium(II) Bisoxazoline Catalyst
Authors: Peng Cheng , Kusakabe Taichi , Kikkawa Shoko , Mochida Tomoyuki , Azumaya Isao , Dhage Yogesh Daulat , Takahashi Keisuke , Sasai Hiroaki , Kato Keisuke
Published: November 2018

The first example of an asymmetric cyclization–dimerization of (ortho‐alkynyl phenyl) (methoxymethyl) sulfides with a palladium(II) bisoxazoline (box) catalyst has been developed. The box ligand enhances the alkynophilicity of benzothienyl palladium(II) intermediate A and thus promotes coordination of the second alkyne substrate, leading to the dimerization. The characteristic properties of the box ligand were supported by density functional theory (DFT) calculations of the intermediate. Axially chiral bibenzothiophenes were obtained in good yields with good enantioselectivities.
Rhodium Complexes of a New‐Generation Sapphyrin: Unique Structures, Axial Chirality, and Catalysis
Authors: Chen Qiu‐Cheng , Saltsman Irena , Kaushansky Alexander , Xiao Zi‐Ye , Fridman Natalia , Zhan Xuan , Gross Zeev
Published: November 2018

Invited for the cover of this issue is the group of Zeev Gross at the Technion‐Israel Institute of Technology. The image, designed by Qiu‐Cheng Chen and Zeev Gross, was inspired by space walking and depicts rhodium(I) floating between the five nitrogen atoms of sapphyrin and how this affects chirality of the corresponding complex. Here the first co‐author, Q.‐C. Chen, shares some insights. Read the full text of the article at 10.1002/chem.201804138.
Potential role of cancer stem cells as biomarkers and therapeutic targets in cervical cancer
Authors: Sudhalkar Niyati , Rathod Nidul P. , Mathews Ashwathi , Chopra Supriya , Sriram Harshini , Shrivastava Shyam K. , Goda Jayant S.
Published: November 2018

Background

Eradicating cancer stem cells (CSCs) that are termed as the “beating heart” of various malignant tumors, including cervical cancer, holds great importance in cancer therapeutics. CSCs not only confer chemo‐radio resistance but also play an important role in tumor metastasis and thereby pose a potential barrier for the cure of cervical cancer. Cervical cancer, a common malignancy among females, is associated with high morbidity and mortality rates, and the study on CSCs residing in the niche is promising.

Recent findings

Biomarker approach to screen the cervical CSCs has gained impetus since the past decade. Progress in identification and characterization of the stem cell biomarkers has led to many insights. For the diagnostic purpose, several biomarkers like viral (HPV16), stem cell markers, transcription factors (viz, SOX2, OCT 4, and c‐Myc), and CSC surface markers (viz, ALDH1 and CD44) have been identified. The research so far has been directed to study the CSC stemness and demonstrates various gene expression signatures in cervical CSCs. Such studies hold a potential to improve diagnostic accuracy and predict therapeutic response and clinical outcome in patients.

Conclusions

Stem cell biomarkers have been validated and their therapeutic targets are being developed as “strategies to improve therapeutic ratio in personalized medicine.” This review gives a brief overview of the cervical CSC biomarkers, their current and future diagnostic, prognostic, and therapeutic potential.
Energetic, Topological and Electric Field Analyses of Cation‐Cation Nucleic Acid Interactions in Watson‐Crick Disposition
Authors: Alkorta Ibon , Mata Ignasi , Molins Elies , Espinosa Enrique
Published: November 2018

A theoretical study of the effect of the diprotonation on the nucleic acid bases (A : U, A : T and G : C) in Watson‐Crick conformation has been carried out by means of DFT computational methods in vacuum. In addition, the corresponding neutral and monoprotonated binary complexes have been considered. Most of the diprotonated species studied are stable, even though the binding energy is positive due to the overall repulsive electrostatic term. Local electrostatic attractive forces in the regions of hydrogen bonds (HBs) are responsible for equilibrium geometries, as shown by the electric field lines connecting the electrophilic and nucleophilic sites involved in the HB interactions. Secondary electrostatic effects also affect the assembling of the nucleic acid complexes in either neutral or cationic form. In particular, the electric field lines flowing from electrophilic sites in one base to nucleophilic sites in the other reinforce the linking between them. Hence, when the nucleophilic site concerns the free lone pair of the heteroatom involved in the HB interaction as acceptor, the HB distance shortens. However, if the free lone pair of the HB acceptor interacts with an electrophilic site in the same molecule, the HB distance elongates, weakening the HB interaction. The topological analysis of the electron density distribution in HB regions indicates that neutral, monoprotonated and diprotonated complexes show no differences in the nature of their HB's.