bluuebunny/crossref_metadata_2025 huggingface dataset:
Stage Actors and Modern Acting Methods Move to Hollywood in the 1930s
Authors: Baron Cynthia
Published: May 2015

In this article, the author considers factors in commercial 1930s American theatre and film which led to the unusual circumstance of many stage-trained actors employing ostensibly theatrical acting methods to respond effectively to the challenges and opportunities of industrial sound film production. The author proposes that with American sound cinema fundamentally changing employment prospects on Broadway and Hollywood production practices, the 1930s represent a unique moment in the history of American performing arts, wherein stage-trained actors in New York and Hollywood developed performances according to principles of modern acting articulated by Stanislavsky, the American Academy of Dramatic Arts in New York and the acting manuals written by theatre-trained professionals and used by both stage and screen actors. To illustrate certain aspects of the era’s conception of modern acting, the author analyzes a scene fromCaptains Courageous(Victor Flemining, 1937) with Spencer Tracy and a scene fromThe Guardsman(Sidney Franklin, 1931) with Alfred Lunt and Lynn Fontanne.
Endoplasmic reticulum stress-independent activation of unfolded protein response kinases by a small molecule ATP-mimic
Authors: Mendez Aaron S , Alfaro Jennifer , Morales-Soto Marisol A , Dar Arvin C , McCullagh Emma , Gotthardt Katja , Li Han , Acosta-Alvear Diego , Sidrauski Carmela , Korennykh Alexei V , Bernales Sebastian , Shokat Kevan M , Walter Peter
Published: May 2015

Two ER membrane-resident transmembrane kinases, IRE1 and PERK, function as stress sensors in the unfolded protein response. IRE1 also has an endoribonuclease activity, which initiates a non-conventional mRNA splicing reaction, while PERK phosphorylates eIF2α. We engineered a potent small molecule, IPA, that binds to IRE1's ATP-binding pocket and predisposes the kinase domain to oligomerization, activating its RNase. IPA also inhibits PERK but, paradoxically, activates it at low concentrations, resulting in a bell-shaped activation profile. We reconstituted IPA-activation of PERK-mediated eIF2α phosphorylation from purified components. We estimate that under conditions of maximal activation less than 15% of PERK molecules in the reaction are occupied by IPA. We propose that IPA binding biases the PERK kinase towards its active conformation, which trans-activates apo-PERK molecules. The mechanism by which partial occupancy with an inhibitor can activate kinases may be wide-spread and carries major implications for design and therapeutic application of kinase inhibitors.
An excitatory amacrine cell detects object motion and provides feature-selective input to ganglion cells in the mouse retina
Authors: Kim Tahnbee , Soto Florentina , Kerschensteiner Daniel
Published: May 2015

Retinal circuits detect salient features of the visual world and report them to the brain through spike trains of retinal ganglion cells. The most abundant ganglion cell type in mice, the so-called W3 ganglion cell, selectively responds to movements of small objects. Where and how object motion sensitivity arises in the retina is incompletely understood. In this study, we use 2-photon-guided patch-clamp recordings to characterize responses of vesicular glutamate transporter 3 (VGluT3)-expressing amacrine cells (ACs) to a broad set of visual stimuli. We find that these ACs are object motion sensitive and analyze the synaptic mechanisms underlying this computation. Anatomical circuit reconstructions suggest that VGluT3-expressing ACs form glutamatergic synapses with W3 ganglion cells, and targeted recordings show that the tuning of W3 ganglion cells' excitatory input matches that of VGluT3-expressing ACs' responses. Synaptic excitation of W3 ganglion cells is diminished, and responses to object motion are suppressed in mice lacking VGluT3. Object motion, thus, is first detected by VGluT3-expressing ACs, which provide feature-selective excitatory input to W3 ganglion cells.
Azimuthal inhomogeneity in the MHD waveguide in the outer magnetosphere
Authors: Mazur V. A. , Chuiko D. A.
Published: May 2015

Geomagnetic field and plasma inhomogeneities in the outer equatorial part of the magnetosphere create a channel with low Alfvén speeds which spans from the nose to the far flanks of the magnetosphere, in both the morning and the evening sectors. This channel plays the role of a waveguide for fast magnetosonic waves. The waveguide eigenmodes and corresponding Alfvén resonance (field line resonance) regions are directly related to geomagnetic pulsations Pc3 and Pc5. U‐shaped model of the waveguide allows for full analytical investigation of waveguide eigenmodes. Quantities such as mode wave numbers, group velocities, and their energy density distribution are found as functions of coordinate along the waveguide. The linkage of the waveguide magnetosonic oscillation energy to the Alfvén waves in the vicinity of the field line resonance deeper inside the magnetosphere is investigated, and corresponding energy leakage coefficient is found. Thus, the influence of longitudinal (i.e., azimuthal) waveguide inhomogeneity on wave propagation is analytically investigated. Obtained results can be used for interpretation of the observed wave power distribution in the frequency bands of geomagnetic pulsations Pc3 and Pc5, as well as for explanation of their spectral properties in the outer magnetosphere.
Dynamic rupture models of earthquakes on the Bartlett Springs Fault, Northern California
Authors: Lozos Julian C. , Harris Ruth A. , Murray Jessica R. , Lienkaemper James J.
Published: May 2015

The Bartlett Springs Fault (BSF), the easternmost branch of the northern San Andreas Fault system, creeps along much of its length. Geodetic data for the BSF are sparse, and surface creep rates are generally poorly constrained. The two existing geodetic slip rate inversions resolve at least one locked patch within the creeping zones. We use the 3‐D finite element code FaultMod to conduct dynamic rupture models based on both geodetic inversions, in order to determine the ability of rupture to propagate into the creeping regions, as well as to assess possible magnitudes for BSF ruptures. For both sets of models, we find that the distribution of aseismic creep limits the extent of coseismic rupture, due to the contrast in frictional properties between the locked and creeping regions.
Effects of the Fe3+ spin transition on the equation of state of bridgmanite
Authors: Mao Zhu , Lin Jung‐Fu , Yang Jing , Inoue Toru , Prakapenka Vitali B.
Published: May 2015

We have investigated the equation of state of Fe‐bearing bridgmanite, (Mg0.9Fe0.1)SiO3, using synchrotron X‐ray diffraction in diamond anvil cells up to 125 GPa and 300 K. Combined with previous synchrotron Mössbauer spectroscopy results, we have found that the occurrence of the low‐spin Fe3+ in the octahedral sites (B site) of bridgmanite has produced a 0.5(±0.1)% reduction in the unit cell volume at 18–25 GPa and has increased the isothermal bulk modulus to 284(±4) GPa, consistent with recent theoretical calculations. Together with literature results, we note that the addition of Fe can cause an increase in the density, bulk modulus, and bulk sound velocity in both Al‐free and Al‐bearing bridgmanite at lower mantle pressures. The presence of Fe3+ in the B site of bridgmanite can further enhance this increase. The observed spin transition of B site Fe3+ in bridgmanite is thus important for understanding the density and velocity structures of the lower mantle.
Propagation characteristics of young hot flow anomalies near the bow shock: Cluster observations
Authors: Xiao T. , Zhang H. , Shi Q. Q. , Zong Q.‐G. , Fu S. Y. , Tian A. M. , Sun W. J. , Wang S. , Parks G. K. , Yao S. T. , Rème H. , Dandouras I.
Published: May 2015

Based on Cluster observations, the propagation velocities and normal directions of hot flow anomaly (HFA) boundaries upstream the Earth's bow shock are calculated. Twenty‐one young HFAs, which have clear leading and trailing boundaries, were selected, and multispacecraft timing method considering errors was employed for the investigation. According to the difference in the propagation velocity of the leading and trailing edges, we categorized these events into three groups, namely, contracting, expanding, and stable events. The contraction speed is a few tens of kilometers per second for the contracting HFAs, and the expansion speed is tens to more than hundred kilometers per second for expanding events. For the stable events, the leading and trailing edges propagate at almost the same speed within the error range. We have further investigated what causes them to contract, expand, or stay stable by carefully calculating the thermal pressure of the young HFAs which have two distinct ion populations (solar wind beam and reflected flow). It is found that the extreme value of the sum of the magnetic and thermal pressure inside the HFAs compared with that of the nearest point outside of the leading edges is higher for expanding events and lower for contracting events, and there is no significant difference for the stable events, and the total pressure (sum of thermal, magnetic, and dynamic pressure) variation has a significant effect on the evolution for most (70%) of the HFAs, which implies that the pressure plays an important role in the evolution of young HFAs.
The Holocaust Memorial in Berlin and Its Information Center: Concepts, Controversies, Reactions
Authors: Quack Sibylle
Published: May 2015

The Memorial to the Murdered Jews of Europe located in the center of Berlin next to the Brandenburg Gate underlines the significance of Holocaust commemoration for German society after the country's reunification. This chapter argues that the long process of debating and building the memorial was part of Germany's attempts to come to terms with the country's Nazi past, and explores the special relationship between the memorial in the design of the architect Peter Eisenman and its almost hidden underground information center. It describes the making of the center's exhibition on the Holocaust which was accompanied by divergent interests and demands regarding design and content. It is a fascinating story about how controversies and fights can be overcome and end in an astonishing result: a highly regarded and exceptional site of Holocaust remembrance in the heart of Berlin.
Recirculating Images of the “Terrorist” in Postcolonial Museums: The Case of the National Museum of Struggle in Nicosia, Cyprus
Authors: Koureas Gabriel
Published: May 2015

This chapter discusses the National Museum of Struggle in Nicosia, Cyprus, and its exhibitionary strategies, especially the insistence of its instigator and first director on portraying the consequences of the uprising and the torture regime adopted by the colonial authorities. Rather than promoting the visitor's empathetic response or voyeuristic experience, the images of the mutilated male body graphically repeat the trauma. They create a space where an embodied witnessing can take place and provide the opportunity for the renegotiation of the traumatized body and masculinity in the context of the specific historical circumstances of the violence inflicted by the British colonial regime. In doing so the museum also offers an opportunity to understand through the legacy of the colonial past the intertwined conflict between Greek and Turkish Cypriot communities
On Not Looking: Economies of Visuality in Digital Museums
Authors: Christen Kimberly
Published: May 2015

Museums take as their primary mandate the display of works of art, photographs, cultural materials, artifacts, and various other objects. In recent years there has been an exponential growth of online exhibits, digital repositories, and virtual databases by international institutions, small communities, national repositories, and individuals alike. A global movement by indigenous peoples and museum and library professionals to redress erasures of the past and open the museum to a range of stakeholders has resulted in a new climate for curation in general and digital displays more particularly. We need to take seriously divergent knowledge systems that place emphasis elsewhere – systems that ask us to lookdifferently. It is one thing to call attention to difference; it is another to alter our museum display practices, question modes of privacy, and/or redefine collecting priorities based on systems of accountability that define an ethical field of visuality based onnot looking.
Preserving the Physical Object in Changing Cultural Contexts
Authors: Clavir Miriam
Published: May 2015

Has the professional conservation of museum collections, centered on safeguarding tangible materials, changed any of its practices in keeping with the transformation of museums themselves in the postcolonial context? This chapter discusses conservation in the many contemporary museums which now focus more on the needs of people and less on the needs of collections. Core conservation values are illustrated, and developments in theory and practice are discussed in relation particularly to the Canadian context and to First Nations perspectives and challenges. Direct quotations from Indigenous people illustrate these viewpoints. Discussion in this chapter also focuses on developments and trends in the conservation profession in response to changes in both internal museum and external global contexts.
Against the Edifice Complex: Vivan Sundaram's
History Project
and the Colonial Museum in India
Authors: Mathur Saloni
Published: May 2015

This chapter offers a sustained investigation of the contemporary Delhi‐based artist Vivan Sundaram's site‐specific work of 1997, titled
History Project
, which was commissioned in part to mark the occasion of the fiftieth anniversary of Indian independence. The project, a multisensory installation inside the vast domed space of the Victoria Memorial Museum in Calcutta, a grand monument from the colonial era, presented a far‐reaching examination of several key categories inaugurated by the site: “memorial,” “history,” “museum,” and “memory.” The chapter considers Sundaram's intervention in relation to the aesthetic strategy known as “institutional critique,” and through the theoretical insights of discussions within Indian historiography, and subaltern studies in particular. It further asks: What is the role of contemporary art in relation to the legacy of museums in South Asia? And how can “history” or the “past” find regeneration through the strategies deployed by a visual arts practice?
Spectrum of Muscle Histopathologic Findings in Forty‐Two Scleroderma Patients With Weakness
Authors: Paik Julie J. , Wigley Fredrick M. , Lloyd Thomas E. , Corse Andrea M. , Casciola‐Rosen Livia , Shah Ami A. , Boin Francesco , Hummers Laura K. , Mammen Andrew L.
Published: May 2015

Objective

To determine if distinct muscle pathologic features exist in scleroderma subjects with weakness.

Methods

This retrospective study included weak scleroderma subjects with muscle biopsies available for review. Biopsies were systematically assessed for individual pathologic features, including inflammation, necrosis, fibrosis, and acute neurogenic atrophy. Based on the aggregate individual features, biopsies were assigned a histopathologic category of polymyositis, dermatomyositis, necrotizing myopathy, nonspecific myositis, “acute denervation,” “fibrosis only,” or “other.” Clinical data analyzed included autoantibody profiles, scleroderma subtype and disease duration, Medsger muscle severity scores, creatine kinase, electromyography, and muscle magnetic resonance imaging.

Results

A total of 42 subjects (79% female and 64% diffuse scleroderma) were included in this study. Necrosis (67%), inflammation (48%), acute neurogenic atrophy (48%), and fibrosis (33%) were the most prevalent pathologic features. The presence of fibrosis was strongly associated with anti–PM‐Scl antibodies. Histopathologic categories included nonspecific myositis (36%), necrotizing myopathy (21%), dermatomyositis (7%), “acute denervation” (7%), “fibrosis only” (7%), and polymyositis (5%). Disease duration of scleroderma at the time of muscle biopsy was shorter in polymyositis than other histopathologic categories. Patients with anti–PM‐Scl and Scl‐70 antibodies also had a shorter disease duration than those with other autoantibody profiles.

Conclusion

Nonspecific myositis and necrotizing myopathy were the most common histopathologic categories in weak scleroderma subjects. Surprisingly, nearly half of the subjects studied had histologic evidence of acute motor denervation (acute neurogenic atrophy); this has not been previously reported. Taken together, these observations suggest that a variety of pathologic mechanisms may underlie the development of myopathy in scleroderma.
Arene cis‐Diol Dehydrogenase‐Catalysed Regio‐ and Stereoselective Oxidation of Arene‐, Cycloalkane‐ and Cycloalkene‐cis‐diols to Yield Catechols and Chiral α‐Ketols
Authors: Boyd Derek R. , Sharma Narain D. , Berberian M. Victoria , Cleij Marcel , Hardacre Christopher , Ljubez Vera , McConville Gareth , Stevenson Paul J. , Kulakov Leonid A. , Allen Christopher C. R.
Published: May 2015

Benzene cis‐diol dehydrogenase and naphthalene cis‐diol dehydrogenase enzymes, expressed in Pseudomonas putida wild‐type and Escherichia coli recombinant strains, were used to investigate regioselectivity and stereoselectivity during dehydrogenations of arene, cyclic alkane and cyclic alkene vicinal cis‐diols. The dehydrogenase‐catalysed production of enantiopure cis‐diols, α‐ketols and catechols, using benzene cis‐diol dehydrogenase and naphthalene cis‐diol dehydrogenase, involved both kinetic resolution and asymmetric synthesis methods. The chemoenzymatic production and applications of catechol bioproducts in synthesis were investigated.

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A novel interstitial deletion of 2q22.3 q23.3 in a patient with dysmorphic features, epilepsy, aganglionosis, pure red cell aplasia, and skeletal malformations
Authors: Bravo‐Oro Antonio , Lurie Iosif W. , Elizondo‐Cárdenas Gabriela , Peña‐Zepeda Claudia , Salazar‐Martínez Abel , Correa‐González Cecilia , Castrillo José Luis , Avila Silvia , Esmer Carmen
Published: May 2015

Many chromosomal deletions encompassing the 2q23.1 region have been described ranging from small deletions of 38 kb up to >19 Mb. Most phenotypic features of the 2q23.1 deletion syndrome are due to a MBD5 gene loss independent of the size of the deletion. Here, we describe a male patient harboring a novel interstitial deletion encompassing the 2q22.3 q23.3 chromosomal region. Array‐CGH revealed a 7.1 Mb deletion causing haploinsufficiency of several genes including MBD5, ACVR2, KIF5C, and EPC2. This patient presents with additional findings to those already described in individuals who have deletions of MBD5 including toes absence of halluces, pure red cell aplasia, and intestinal aganglionosis. Interestingly, in the deleted region there are previously identified regulatory sequences which are located upstream to ZEB2, which is associated with Hirschsprung disease (HSCR). Several genes have been associated with pure red cell aplasia, but to our knowledge, this is the first time that 2q deletion is associated with this phenotype. These additional findings should be added to the list of manifestations associated with 2q deletion, and provide support for the hypothesis that this individual has a true contiguous gene deletion syndrome. © 2015 Wiley Periodicals, Inc.
Biochemical, molecular and outcome analysis of eight chinese asymptomatic individuals with methyl malonic acidemia detected through newborn screening
Authors: Han Lianshu , Wu Shengnan , Ye Jun , Qiu Wenjuan , Zhang Huiwen , Gao Xiaolan , Wang Yu , Gong Zhuwen , Jin Jing , Gu Xuefan
Published: May 2015

Methyl malonic academia (MMA) is characterized by abnormal accumulation of methyl malonic acid in body fluids. Patients usually have a variety of clinical symptoms including recurrent vomiting, metabolic acidosis, developmental delay, seizure, or death. However, a few cases where the patients have no symptom are also reported. Here, we conducted clinical, biochemical, and molecular analysis of eight Chinese patients identified through newborn screening between 2003 and 2013. All the patients had significantly higher blood propionylcarnitine (C3) concentrations, ratio of propionylcarnitine/acetylcarnitine (C3/C2); and their urine methyl malonic acid and methylcitric acid (MCA) excretions were remarkably higher than normal at diagnosis and during follow‐ups. In addition, five different known mutations were identified in seven of the eight patients in either MUT or MMACHC. All these mutations were expected to produce defective proteins that would result in decreased or even total loss of methyl malonyl‐CoA mutase activity. However, normal outcomes were found in all patients in physical growth, intellectual performance and cerebral MRI analysis at diagnosis (range, 14–53 days) and during follow‐ups (range, 1.8–10 years). Our study is the first report of Chinese MMA patients with increased secretion of methyl malonic acid and molecular defects in MUT or MMACHC yet remain asymptomatic. © 2015 Wiley Periodicals, Inc.
Children with Williams syndrome: Developmental trajectories for intellectual abilities, vocabulary abilities, and adaptive behavior
Authors: Mervis Carolyn B. , Pitts C. Holley
Published: May 2015

To examine longitudinal trajectories of intellectual abilities, single‐word vocabulary abilities, and adaptive behavior for 76 children with Williams syndrome (WS) aged 4–15 years, we compared their standard scores (SSs) at two time points approximately 3 years apart on the same standardized measures. At the group level, mean SS declined significantly for 8 of the 12 measures and showed a slight (nonsignificant) increase or decrease for 4 measures. However, for most measures significant changes in SS were found for only a small proportion of the children, with some children evidencing significant declines and a smaller proportion evidencing significant increases. Significant SS changes were most common for adaptive behavior. For all measures, the mean magnitude of SS change was smaller for older children (>7.5 years at Time 1) than for younger children (<7.5 years at Time 1). Furthermore, correlations between Time 1 and Time 2 SSs were larger for the older cohort than for the younger cohort, indicating that SS stability was greater for older children than for younger children. Although mean SSs declined for most measures, indicating that children with WS as a group were not making the expected amount of progress relative to their general population peers who earned the same SS at Time 1, there was little evidence either of regression (loss of skills) or stagnation (failure to increase raw scores). The relations of these results to those of previous smaller‐sample longitudinal studies of children with WS and the implications of the findings are considered. © 2015 Wiley Periodicals, Inc.
The Arteries of the Brain in Hare (Lepus europaeus Pallas, 1778)
Authors: Brudnicki Witold , Kirkiłło‐Stacewicz Krzysztof , Skoczylas Benedykt , Nowicki Włodzimierz , Jabłoński Ryszard , Brudnicki Adam , Wach Jan
Published: May 2015

Research into course and variability of brain arteries in hare were performed on 38 adult hares of both sexes (males 23 and females 15). The arteries were filled with a synthetic latex at a constant pressure introduced with a medical syringe to the left ventricle. The source of blood supply to the brain was internal carotid arteries, whose branches formed an arterial circle of the brain, vertebral arteries, and basilar artery as the result of its anastomosis. Variability focused on a method of departure of middle cerebral arteries, which were multiple vessels in 39.5% of cases and rostral cerebellar arteries. Caudal communicating arteries in hare comprised bilateral anastomosis of internal carotid arteries and final branches of the basilar artery. It stabilized the steady flow of blood to all parts of the brain. Caudal cerebral arteries comprised final branches of the basilar artery. The largest capacity of all the arteries of the brain was observed in the main trunk of the basilar artery. The capacity of these vessels was 4.53 mm3 on average. The factor of capacity of cerebral arteries in relation to weight of the brain reaches a high value in hare. Anat Rec, 298:1774–1779, 2015. © 2015 Wiley Periodicals, Inc.
Brief Report: Cryopyrin‐Associated Periodic Syndrome Caused by a Myeloid‐Restricted Somatic NLRP3 Mutation
Authors: Zhou Qing , Aksentijevich Ivona , Wood Geryl M. , Walts Avram D. , Hoffmann Patrycja , Remmers Elaine F. , Kastner Daniel L. , Ombrello Amanda K.
Published: May 2015

Objective

To identify the cause of disease in an adult patient presenting with recent‐onset fevers, chills, urticaria, fatigue, and profound myalgia, who was found to be negative for cryopyrin‐associated periodic syndrome (CAPS) NLRP3 mutations by conventional Sanger DNA sequencing.

Methods

We performed whole‐exome sequencing and targeted deep sequencing using DNA from the patient's whole blood to identify a possible NLRP3 somatic mutation. We then screened for this mutation in subcloned NLRP3 amplicons from fibroblasts, buccal cells, granulocytes, negatively selected monocytes, and T and B lymphocytes and further confirmed the somatic mutation by targeted sequencing of exon 3.

Results

We identified a previously reported CAPS‐associated mutation, p.Tyr570Cys, with a mutant allele frequency of 15% based on exome data. Targeted sequencing and subcloning of NLRP3 amplicons confirmed the presence of the somatic mutation in whole blood at a ratio similar to the exome data. The mutant allele frequency was in the range of 13.3–16.8% in monocytes and 15.2–18% in granulocytes. Notably, this mutation was either absent or present at a very low frequency in B and T lymphocytes, in buccal cells, and in the patient's cultured fibroblasts.

Conclusion

Our findings indicate the possibility of myeloid‐restricted somatic mosaicism in the pathogenesis of CAPS, underscoring the emerging role of massively parallel sequencing in clinical diagnosis.
Derivation and Internal Validation of an Expanded Cardiovascular Risk Prediction Score for Rheumatoid Arthritis: A Consortium of Rheumatology Researchers of North America Registry Study
Authors: Solomon D. H. , Greenberg J. , Curtis J. R. , Liu M. , Farkouh M. E. , Tsao P. , Kremer J. M. , Etzel C. J.
Published: May 2015

Objective

Cardiovascular disease (CVD) is the leading cause of mortality in rheumatoid arthritis (RA), but CV risk prediction scores derived from the general population do not accurately predict CV risk in RA patients. The goal of these analyses was to develop and internally validate an expanded CV risk prediction score for RA.

Methods

Study participants were patients with RA and no known CVD from the Consortium of Rheumatology Researchers of North America registry. Two‐thirds of the cohort were used to derive the CV risk prediction score, and one‐third for internal validation. Traditional CV risk factors were included in the base Cox regression model, and RA‐related variables were assessed in an expanded model predicting confirmed CV events. Fit and utility of the expanded model were evaluated.

Results

The study cohort included 23,605 RA patients with 437 CV events over a median followup of 2.2 years. The RA variables found to be significant in the regression models and included in the expanded risk model were disease activity (Clinical Disease Activity Index >10 versus ≤10), disability (modified Health Assessment Questionnaire disability index >0.5 versus ≤0.5), daily prednisone use (any versus none), and disease duration (≥10 years versus <10 years). The expanded model had good fit (Hosmer‐Lemeshow goodness of fit P = 0.94) and a lower Akaike's information criterion than the base model. In the internal validation cohort, the c‐statistic for model discrimination was significantly improved from the base model to the expanded model (from 0.7261 to 0.7609; P = 0.0104). The net reclassification index of CV risk in models using a 4‐category CV risk prediction tool was 40% (95% confidence interval 37–44%).

Conclusion

This newly developed, expanded risk score for CV outcomes in RA performs well and improves the classification of CV risk in comparison to a risk prediction score in which only traditional risk factors were included.
Leptin and Neutrophil‐Activating Peptide 2 Promote Mesenchymal Stem Cell Senescence Through Activation of the Phosphatidylinositol 3‐Kinase/Akt Pathway in Patients With Systemic Lupus Erythematosus
Authors: Chen Haifeng , Shi Bingyu , Feng Xuebing , Kong Wei , Chen Weiwei , Geng Linyu , Chen Jinyun , Liu Rui , Li Xia , Chen WanJun , Gao Xiang , Sun Lingyun
Published: May 2015

Objective

Mesenchymal stem cells (MSCs) derived from patients with systemic lupus erythematosus (SLE) exhibit enhanced senescence. Cellular senescence has been reported to be induced by several inflammatory cytokines, including interferon‐α (IFNα) and IFNγ, that are involved in the pathogenesis of SLE. We undertook this study to investigate whether the inflammatory environment in SLE could affect MSC senescence.

Methods

Cellular senescence was measured by staining of senescence‐associated β‐galactosidase and by expression of the cell cycle inhibitors p53 and p21. Eighty cytokines and chemokines in serum from healthy controls and patients with SLE were identified by cytokine antibody array.

Results

SLE serum promoted senescence of MSCs, which was reversed by the phosphatidylinositol 3‐kinase (PI3K)/Akt signaling inhibitor LY294002 but not by the JAK/STAT inhibitor AG490 and not by the MEK/ERK inhibitor PD98059. Cytokine antibody array analysis revealed that leptin and neutrophil‐activating peptide 2 (NAP‐2) were the 2 factors most significantly elevated in SLE serum compared with normal serum. Blockade of leptin or NAP‐2 in MSC cultures abolished SLE serum–induced senescence, while direct addition of these 2 factors could promote senescence in cultures of normal MSCs. Inhibition of PI3K/Akt signaling with LY294002 reduced leptin‐ and NAP‐2–induced senescence in MSCs.

Conclusion

Taken together, our data show that leptin and NAP‐2 act synergistically to promote MSC senescence through enhancement of the PI3K/Akt signaling pathway in SLE patients.
Analysis of Published Criteria for Clinically Inactive Disease in a Large Juvenile Dermatomyositis Cohort Shows That Skin Disease Is Underestimated
Authors: Almeida Beverley , Campanilho‐Marques Raquel , Arnold Katie , Pilkington Clarissa A. , Wedderburn Lucy R. , Nistala Kiran ,   on behalf of the Juvenile Dermatomyositis Research Group
Published: May 2015

Objective

The Pediatric Rheumatology International Trials Organisation (PRINTO) recently published criteria for classification of patients with juvenile dermatomyositis (DM) as having clinically inactive disease. The criteria require that at least 3 of 4 conditions be met, i.e., creatine kinase level ≤150 units/liter, Childhood Myositis Assessment Scale score ≥48, Manual Muscle Testing in 8 muscles score ≥78, and physician's global assessment of overall disease activity (PGA) ≤0.2. The present study was undertaken to test these criteria in a UK cohort of patients with juvenile DM.

Methods

We assessed 1,114 patient visits for the 4 items in the PRINTO criteria for clinically inactive disease. Each visit was analyzed to determine whether skin disease was present. The Disease Activity Score (DAS) for juvenile DM was determined in 59 patients.

Results

At 307 of the 1,114 visits, clinically inactive disease was achieved based on the 3 muscle criteria (but with a PGA of >0.2); rash was present at 65.8% of these visits and nailfold capillary abnormalities at 35.2%. When PGA ≤0.2 was one of the 3 criteria that were met, the frequency of skin signs was significantly lower (rash in 23.1% and nailfold capillary abnormalities in 8.7%). If PGA was considered an essential criterion for clinically inactive disease (P‐CID), patients with active skin disease were less likely to be categorized as having clinically inactive disease (a median DAS skin score of 0 [of a possible maximum of 9] in visits where the PGA was ≤0.2, versus a median DAS skin score of 4 in patients meeting the 3 muscle criteria [with a PGA of >0.2]; P < 0.001). Use of the P‐CID led to improvements in the positive predictive value and the positive likelihood ratio (85.4% and 11.0, respectively, compared to 72.9% and 5.1 with the current criteria).

Conclusion

There was a high frequency of skin disease among patients with juvenile DM who did not meet the PGA criterion for inactive disease but met the other 3 criteria. Incorporating PGA as an essential criterion for clinically inactive disease helps prevent the misclassification of patients with active skin disease.
Molecular Subsetting of Interferon Pathways in Sjögren's Syndrome
Authors: Hall John C. , Baer Alan N. , Shah Ami A. , Criswell Lindsey A. , Shiboski Caroline H. , Rosen Antony , Casciola‐Rosen Livia
Published: May 2015

Objective

Sjögren's syndrome (SS) is an autoimmune disease that targets the salivary and lacrimal glands. While all patients demonstrate inflammatory infiltration and abnormal secretory function in the target tissues, the disease features, pathology, and clinical course can vary. Activation of distinct inflammatory pathways may drive disease heterogeneity. The purpose of this study was to investigate whether activation of the interferon (IFN) pathway correlates with key phenotypic features.

Methods

Clinical data and 1 labial salivary gland (stored frozen) were obtained from each of 82 participants (53 patients with primary SS and 29 control subjects) in the Sjögren's International Collaborative Clinical Alliance (SICCA) registry. Salivary gland lysates were immunoblotted with markers of type I or type II IFN, and patterns of IFN activity were determined by hierarchical clustering. Correlations between SS phenotypic features and IFN activity in the salivary gland were performed.

Results

A total of 58% of the SS participants had high IFN activity and differed significantly from those with low IFN activity (higher prevalence of abnormal findings on sialometry, leukopenia, hyperglobulinemia, high‐titer antinuclear antibody, anti‐SSA, and high focus score on labial salivary gland [LSG] biopsy). Three distinct patterns of IFN were evident: type I–predominant, type II–predominant, and type I/II mixed IFN. These groups were clinically indistinguishable except for the LSG focus score, which was highest in those with type II–predominant IFN.

Conclusion

The SS phenotype includes distinct molecular subtypes, which are segregated by the magnitude and pattern of IFN responses. Associations between IFN pathways and disease activity suggest that IFNs are relevant therapeutic targets in SS. Patients with distinct patterns of high IFN activity are clinically similar, demonstrating that IFN‐targeting therapies must be selected according to the specific pathway(s) that is active in vivo in the individual patient.
Different weights of tests within a start‐up demonstration procedure
Authors: Gera Amos E.
Published: May 2015

The reliability of various types of equipment within electronics, communications systems and others is often demonstrated with aid of acceptance (rejection) tests. According to the new weighted total successes consecutive successes total failures consecutive failures model, the tested equipment is accepted if a certain total weight of successes or a certain total weight of a run of consecutive successes appears before a certain total weight of failures and before a certain total weight of a run of consecutive failures. A constrained optimization procedure is set up for the minimization of the duration time of the tests subject to some confidence level requirements. In some cases, it involves the determination of the weights of the tests. A significant reduction in the required time for testing is thus achieved. Examples are provided to show the utility of the new method. Copyright © 2015 John Wiley & Sons, Ltd.
Shaping mitotic chromosomes: From classical concepts to molecular mechanisms
Authors: Kschonsak Marc , Haering Christian H.
Published: May 2015

How eukaryotic genomes are packaged into compact cylindrical chromosomes in preparation for cell divisions has remained one of the major unsolved questions of cell biology. Novel approaches to study the topology of DNA helices inside the nuclei of intact cells, paired with computational modeling and precise biomechanical measurements of isolated chromosomes, have advanced our understanding of mitotic chromosome architecture. In this Review Essay, we discuss – in light of these recent insights – the role of chromatin architecture and the functions and possible mechanisms of SMC protein complexes and other molecular machines in the formation of mitotic chromosomes. Based on the information available, we propose a stepwise model of mitotic chromosome condensation that envisions the sequential generation of intra‐chromosomal linkages by condensin complexes in the context of cohesin‐mediated inter‐chromosomal linkages, assisted by topoisomerase II. The described scenario results in rod‐shaped metaphase chromosomes ready for their segregation to the cell poles.
Is STEP the future for patients requiring proctocolectomy? A new therapeutic proposal from pediatric experience
Authors: Mangray Hansraj , Ghimenton Fernando
Published: May 2015

Key Clinical Message

We present a pediatric case of medically unmanageable juvenile colonic polyposis, initially treated with subtotal colectomy and an ileostomy followed by a proctectomy, ileal‐J‐pouch and serial transverse enteroplasties (STEP) of the distal ileum. The STEP procedure in an adequate length was able to control stooling of our patient.
Affective commitment and future purchase intentions in the performing arts: An empirical approach
Authors: Quero María José , Ventura Rafael
Published: May 2015

We examine whether affective commitment can influence customers' future purchase intentions. Our empirical approach focuses on the performing arts sector in which we interviewed 927 theatregoers at the entrances or exits to 150 theatres throughout Spain. The theoretical relationship management model proposed herein provides an analysis of the role played by satisfaction, trust, and commitment in future purchase intentions. Our findings reveal that affective commitment mediates the relationship between future purchase intention and both satisfaction and trust. We discuss the theoretical and management implications of our findings and identify some possible future research directions. Copyright © 2015 ASAC. Published by John Wiley & Sons, Ltd.
A phase I trial of mushroom powder in patients with biochemically recurrent prostate cancer: Roles of cytokines and myeloid‐derived suppressor cells for Agaricus bisporus–induced prostate‐specific antigen responses
Authors: Twardowski Przemyslaw , Kanaya Noriko , Frankel Paul , Synold Timothy , Ruel Christopher , Pal Sumanta K. , Junqueira Maribel , Prajapati Manisha , Moore Tina , Tryon Pamela , Chen Shiuan
Published: May 2015

BACKGROUND

Each year in the United States, nearly 50,000 prostate cancer patients exhibit a rise in prostate‐specific antigen (PSA) levels, which can indicate disease recurrence. For patients with biochemically recurrent prostate cancer, we evaluated the effects of white button mushroom (WBM) powder on serum PSA levels and determined the tolerability and biological activity of WBM.

METHODS

Patients with continuously rising PSA levels were enrolled in the study. Dose escalation was conducted in cohorts of 6; this ensured that no more than 1 patient per cohort experienced dose‐limiting toxicity (DLT). The primary objective was to evaluate treatment feasibility and associated toxicity. The secondary objectives were to determine WBM's effect on serum PSA/androgen levels; myeloid‐derived suppressor cells (MDSCs); and cytokine levels.

RESULTS

Thirty‐six patients were treated; no DLTs were encountered. The overall PSA response rate was 11%. Two patients receiving 8 and 14 g/d demonstrated complete response (CR): their PSA declined to undetectable levels that continued for 49 and 30 months. Two patients who received 8 and 12 g/d experienced partial response (PR). After 3 months of therapy, 13 (36%) patients experienced some PSA decrease below baseline. Patients with CR and PR demonstrated higher levels of baseline interleukin‐15 than nonresponders; for this group, we observed therapy‐associated declines in MDSCs.

CONCLUSIONS

Therapy with WBM appears to both impact PSA levels and modulate the biology of biochemically recurrent prostate cancer by decreasing immunosuppressive factors. Cancer 2015;121:2942–2950. © 2015 American Cancer Society.
Differences in CART expression and cell cycle behavior discriminate sympathetic neuroblast from chromaffin cell lineages in mouse sympathoadrenal cells
Authors: Hei Chan Wing , Gonsalvez David G. , Young Heather M. , Michelle Southard‐Smith E. , Cane Kylie N. , Anderson Colin R.
Published: May 2015

Adrenal medullary chromaffin cells and peripheral sympathetic neurons originate from a common sympathoadrenal (SA) progenitor cell. The timing and phenotypic changes that mark this lineage diversification are not fully understood. The present study investigated the expression patterns of phenotypic markers, and cell cycle dynamics, in the adrenal medulla and the neighboring suprarenal ganglion of embryonic mice. The noradrenergic marker, tyrosine hydroxylase (TH), was detected in both presumptive adrenal medulla and sympathetic ganglion cells, but with significantly stronger immunostaining in the former. There was intense cocaine and amphetamine‐regulated transcript (CART) peptide immunostaining in most neuroblasts, whereas very few adrenal chromaffin cells showed detectable CART immunostaining. This phenotypic segregation appeared as early as E12.5, before anatomical segregation of the two cell types. Cell cycle dynamics were also examined. Initially, 88% of Sox10 positive (+) neural crest progenitors were proliferating at E10.5. Many SA progenitor cells withdrew from the cell cycle at E11.5 as they started to express TH. Whereas 70% of neuroblasts (TH+/CART+ cells) were back in the cell cycle at E12.5, only around 20% of chromaffin (CART negative) cells were in the cell cycle at E12.5 and subsequent days. Thus, chromaffin cell and neuroblast lineages showed differences in proliferative behavior from their earliest appearance. We conclude that the intensity of TH immunostaining and the expression of CART permit early discrimination of chromaffin cells and sympathetic neuroblasts, and that developing chromaffin cells exhibit significantly lower proliferative activity relative to sympathetic neuroblasts. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 137–149, 2016
Public concerns about violent video games are moral concerns—How moral threat can make pacifists susceptible to scientific and political claims against violent video games
Authors: Rothmund Tobias , Bender Jens , Nauroth Peter , Gollwitzer Mario
Published: May 2015

Public discussions about the harmfulness of violent media are often held in the aftermath of violent felony. At the same time, we know little about whether and how experiencing real‐life violence impacts the way laypersons perceive and evaluate debates about virtual violence. In Study 1, we provided data indicating that both real‐life violence and violent video games are perceived as morally threatening by people who regard nonviolence to be an important moral value (i.e., pacifists). In Study 2, we hypothesized and found that when pacifists perceive threat from the presence of real‐life violence, they are especially susceptible to scientific and political claims indicating that violent video games are harmful. Our findings are in line with the value protection model and research on the psychological consequences of threat. Implications of the present findings are discussed with regard to a better understanding of the violent video games debate in the general public.
An assessment of fiscal space for health in Bhutan
Authors: Sharma Jayendra
Published: May 2015

Several factors are expected to put a strain on health financing in Bhutan. In a predominantly public‐financed healthcare, ensuring that the health system gains sufficient fiscal space to ensure the sustainability of its financing is a critical policy concern. This fiscal space assessment bases its analysis on national surveys and statistics, international databases and review of official documents and reports. Assuming that the government health spending will continue to respond in the same way to growth as in the period 2002–2012, Bhutan can expect to see a robust increase in government investments in health. If elasticity of health expenditure with respect to GDP does not change significantly, projections indicate that per‐capita government spending for health could more than double in the period 2012 to 2019. This increase from Ngultrum 2632 in 2012 to Ngultrum 6724 in 2019 could correspond to government health spending from 2.65% of GDP to 3.98% of GDP in the respective years. The country, however, needs to closely monitor and ensure that government investment in healthcare keeps pace with the growth of the national economy. Along with this, supplementary resources for healthcare could be explored through earmarked taxes and by generating efficiency gains. Copyright © 2015 John Wiley & Sons, Ltd.
Differential Hematopoietic Activity in White Adipose Tissue Depending on its Localization
Authors: Luche Elodie , Sengenès Coralie , Arnaud Emmanuelle , Laharrague Patrick , Casteilla Louis , Cousin Beatrice
Published: May 2015

White adipose tissue (WAT) can be found in different locations in the body, and these different adipose deposits exhibit specific physiopathological importance according to the subcutaneous or abdominal locations. We have shown previously the presence of functional hematopoietic stem/progenitor cells (HSPC) in subcutaneous adipose tissue (SCAT). These cells exhibit a specific hematopoietic activity that contributes to the renewal of the immune cell compartment within this adipose deposit. In this study, we investigated whether HSPC can be found in visceral adipose tissue (VAT) and whether a putative difference in in situ hematopoiesis may be related to anatomical location and to site‐specific immune cell content in VAT compared to SCAT. Therein, we identified for the first time the presence of HSPC in VAT. Using both in vitro assays and in vivo competitive repopulation experiments with sorted HSPC from VAT or SCAT, we showed that the hematopoietic activity of HSPC was lower in VAT, compared to SCAT. In addition, this altered hematopoietic activity of HSPC in VAT was due to their microenvironment, and may be related to a specific combination of secreted factors and extracellular matrix molecules expressed by adipose derived stromal cells. Our results indicate that WAT specific hematopoietic activity may be generalized to all adipose deposits, although with specificity according to the fat pad location. Considering the abundance of WAT in the body, this emphasizes the potential importance of this hematopoietic activity in physiopathological situations. J. Cell. Physiol. 230: 3076–3083, 2015. © 2015 Wiley Periodicals, Inc.
Recent developments in atmospheric pressure photoionization‐mass spectrometry
Authors: Kauppila Tiina J. , Syage Jack A. , Benter Thorsten
Published: May 2015

Recent developments in atmospheric pressure photoionization (APPI), which is one of the three most important ionization techniques in liquid chromatography‐mass spectrometry, are reviewed. The emphasis is on the practical aspects of APPI analysis, its combination with different separation techniques, novel instrumental developments ‐ especially in gas chromatography and ambient mass spectrometry ‐ and the applications that have appeared in 2009–2014. © 2015 Wiley Periodicals, Inc. Mass Spec Rev 36:423–449, 2017