bluuebunny/crossref_metadata_2025 huggingface dataset:
Inflammatory Gene Expression Profile and Defective Interferon‐γ and Granzyme K in Natural Killer Cells From Systemic Juvenile Idiopathic Arthritis Patients
Authors: Put Karen , Vandenhaute Jessica , Avau Anneleen , van Nieuwenhuijze Annemarie , Brisse Ellen , Dierckx Tim , Rutgeerts Omer , Garcia‐Perez Josselyn E. , Toelen Jaan , Waer Mark , Leclercq Georges , Goris An , Van Weyenbergh Johan , Liston Adrian , De Somer Lien , Wouters Carine H. , Matthys Patrick
Published: October 2016

Objective

Systemic juvenile idiopathic arthritis (JIA) is an immunoinflammatory disease characterized by arthritis and systemic manifestations. The role of natural killer (NK) cells in the pathogenesis of systemic JIA remains unclear. The purpose of this study was to perform a comprehensive analysis of NK cell phenotype and functionality in patients with systemic JIA.

Methods

Transcriptional alterations specific to NK cells were investigated by RNA sequencing of highly purified NK cells from 6 patients with active systemic JIA and 6 age‐matched healthy controls. Cytokines (NK cell–stimulating and others) were quantified in plasma samples (n = 18). NK cell phenotype and cytotoxic activity against tumor cells were determined (n = 10), together with their interferon‐γ (IFNγ)–producing function (n = 8).

Results

NK cells from the systemic JIA patients showed an altered gene expression profile compared to cells from the healthy controls, with enrichment of immunoinflammatory pathways, increased expression of innate genes including TLR4 and S100A9, and decreased expression of immune‐regulating genes such as IL10RA and GZMK. In the patients’ plasma, interleukin‐18 (IL‐18) levels were increased, and a decreased ratio of IFNγ to IL‐18 was observed. NK cells from the patients exhibited specific alterations in the balance of inhibitory and activating receptors, with decreased killer cell lectin‐like receptor G1 and increased NKp44 expression. Although NK cells from the patients showed increased granzyme B expression, consistent with intact cytotoxicity and degranulation against a tumor cell line, decreased granzyme K expression in CD56bright NK cells and defective IL‐18–induced IFNγ production and signaling were demonstrated.

Conclusion

NK cells are active players in the inflammatory environment typical of systemic JIA. Although their cytotoxic function is globally intact, subtle defects in NK‐related pathways, such as granzyme K expression and IL‐18–driven IFNγ production, may contribute to the immunoinflammatory dysregulation in this disease.
CD8+ T Cells Contribute to the Development of Coronary Arteritis in the Lactobacillus casei Cell Wall Extract–Induced Murine Model of Kawasaki Disease
Authors: Noval Rivas Magali , Lee Youngho , Wakita Daiko , Chiba Norika , Dagvadorj Jargalsaikhan , Shimada Kenichi , Chen Shuang , Fishbein Michael C. , Lehman Thomas J. A. , Crother Timothy R. , Arditi Moshe
Published: October 2016

Objective

Kawasaki disease (KD) is the leading cause of acquired heart disease among children in developed countries. Coronary lesions in KD in humans are characterized by an increased presence of infiltrating CD3+ T cells; however, the specific contributions of the different T cell subpopulations in coronary arteritis development remain unknown. Therefore, we sought to investigate the function of CD4+ and CD8+ T cells, Treg cells, and natural killer (NK) T cells in the pathogenesis of KD.

Methods

We addressed the function of T cell subsets in KD development by using a well‐established murine model of Lactobacillus casei cell wall extract (LCWE)–induced KD vasculitis. We determined which T cell subsets were required for development of KD vasculitis by using several knockout murine strains and depleting monoclonal antibodies.

Results

LCWE‐injected mice developed coronary lesions characterized by the presence of inflammatory cell infiltrates. Frequently, this chronic inflammation resulted in complete occlusion of the coronary arteries due to luminal myofibroblast proliferation (LMP) as well as the development of coronary arteritis and aortitis. We found that CD8+ T cells, but not CD4+ T cells, NK T cells, or Treg cells, were required for development of KD vasculitis.

Conclusion

The LCWE‐induced murine model of KD vasculitis mimics many histologic features of the disease in humans, such as the presence of CD8+ T cells and LMP in coronary artery lesions as well as epicardial coronary arteritis. Moreover, CD8+ T cells functionally contribute to the development of KD vasculitis in this murine model. Therapeutic strategies targeting infiltrating CD8+ T cells might be useful in the management of KD in humans.
Reduced visual disengagement but intact phasic alerting in young children with autism
Authors: Kleberg Johan Lundin , Thorup Emilia , Falck‐Ytter Terje
Published: October 2016

Children with autism may have difficulties with visual disengagement—that is, inhibiting current fixations and orienting to new stimuli in the periphery. These difficulties may limit these children's ability to flexibly monitor the environment, regulate their internal states, and interact with others. In typical development, visual disengagement is influenced by a phasic alerting network that increases the processing speed of the visual system after salient events. The role of the phasic alerting effect in the putative atypical disengagement performance in autism spectrum disorder (ASD) is not known. Here, we compared visual disengagement in six‐year‐old children with autism (N = 18) and typically developing children (N = 17) matched for age and nonverbal IQ. We manipulated phasic alerting during a visual disengagement task by adding spatially nonpredictive sounds shortly before the onset of the visual peripheral targets. Children with ASD showed evidence of delayed disengagement compared to the control group. Sounds facilitated visual disengagement similarly in both groups, suggesting typical modulation by phasic alerting in ASD in the context of this task. These results support the view that atypical visual disengagement in ASD is related to other factors than atypicalities in the alerting network. Autism Res 2017, 10: 539–545. © 2016 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.
Exploring the relationship between cortical GABA concentrations, auditory gamma‐band responses and development in ASD: Evidence for an altered maturational trajectory in ASD
Authors: Port Russell G. , Gaetz William , Bloy Luke , Wang Dah‐Jyuu , Blaskey Lisa , Kuschner Emily S. , Levy Susan E. , Brodkin Edward S. , Roberts Timothy P.L.
Published: October 2016

Autism spectrum disorder (ASD) is hypothesized to arise from imbalances between excitatory and inhibitory neurotransmission (E/I imbalance). Studies have demonstrated E/I imbalance in individuals with ASD and also corresponding rodent models. One neural process thought to be reliant on E/I balance is gamma‐band activity (Gamma), with support arising from observed correlations between motor, as well as visual, Gamma and underlying GABA concentrations in healthy adults. Additionally, decreased Gamma has been observed in ASD individuals and relevant animal models, though the direct relationship between Gamma and GABA concentrations in ASD remains unexplored. This study combined magnetoencephalography (MEG) and edited magnetic resonance spectroscopy (MRS) in 27 typically developing individuals (TD) and 30 individuals with ASD. Auditory cortex localized phase‐locked Gamma was compared to resting Superior Temporal Gyrus relative cortical GABA concentrations for both children/adolescents and adults. Children/adolescents with ASD exhibited significantly decreased GABA+/Creatine (Cr) levels, though typical Gamma. Additionally, these children/adolescents lacked the typical maturation of GABA+/Cr concentrations and gamma‐band coherence. Furthermore, children/adolescents with ASD additionally failed to exhibit the typical GABA+/Cr to gamma‐band coherence association. This altered coupling during childhood/adolescence may result in Gamma decreases observed in the adults with ASD. Therefore, individuals with ASD exhibit improper local neuronal circuitry maturation during a childhood/adolescence critical period, when GABA is involved in configuring of such circuit functioning. Provocatively a novel line of treatment is suggested (with a critical time window); by increasing neural GABA levels in children/adolescents with ASD, proper local circuitry maturation may be restored resulting in typical Gamma in adulthood. Autism Res 2017, 10: 593–607. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.
Outdoor cultivation of Dunaliella salina KU 11 using brine and saline lake water with raceway ponds in northeastern Thailand
Authors: Wu Zhe , Dejtisakdi Wipawee , Kermanee Prasart , Ma Chunhong , Arirob Wallop , Sathasivam Ramaraj , Juntawong Niran
Published: October 2016

To evaluate the potential of algal biotechnology to replace traditional agriculture in northeastern Thailand, an open raceway cultivation system was developed to produce biomass and beta‐carotene. Dunaliella salina KU 11 isolated from local saline soil was cultured in open raceway tanks using brine and saline lake water. Grown in modified Johnson's medium (with 2–3.5 M NaCl), the algae reached a maximum cell density on the fourth day (1.8 × 106 cells mL−1). Increasing KNO3 and NaHCO3 from 0.5 and 0.043 g L−1 to 1 and 2.1 g L−1, respectively, significantly improved the yields of biomass (0.33 g L−1) and beta‐carotene (19 mg L−1). Expected profits for algal production were evaluated, and it was found that this strain was suitable for outdoor cultivation and the developing algal industry in northeastern Thailand could produce high economic benefits (at least $64,120 per year per 0.16 ha).
Investigation of an “alternate water supply system” in enzymatic hydrolysis in the processive endocellulase Cel7A from Rasamsonia emersonii by molecular dynamics simulation
Authors: Sun Xun , Qian Meng‐dan , Guan Shan‐shan , Shan Ya‐ming , Dong Ying , Zhang Hao , Wang Song , Han Wei‐wei
Published: October 2016

Cel7A from Rasamsonia emersonii is one of the processive endocellulases classified under family 7 glycoside hydrolase. Molecular dynamics simulations were carried out to obtain the optimized sliding and hydrolyzing conformations, in which the reducing ends of sugar chains are located on different sites. Hydrogen bonds are investigated to clarify the interactions between protein and substrate in either conformation. Nine hydrogen bonding interactions are identified in the sliding conformation, and six similar interactions are also found correspondingly in the hydrolyzing conformation. In addition, four strong hydrophobic interactions are also determined. The domain cross‐correlation map analysis shows movement correlation of protein including autocorrelation between residues. The root mean square fluctuations analysis represents the various flexibilities of different fragment in the two conformations. Comparing the two conformations reveals the water‐supply mechanism of selective hydrolysis of cellulose in Cel7A. The mechanism can be described as follow. When the reducing end of substrate slides from the unhydrolyzing site (sliding conformation) to the hydrolyzing site (hydrolyzing conformation), His225 is pushed down and rotated, the rotation leads to the movement of Glu209 with the interstrand hydrogen bonding in β‐sheet. It further makes Asp211 close to the hydrolysis center and provides a water molecule bounding on its carboxyl in the previous unhydrolyzing site. After the hydrolysis takes place and the product is excluded from the enzyme, the Asp211 comes back to its initial position. In summary, Asp211 acts as an elevator to transport outer water molecules into the hydrolysis site for every other glycosidic bond.
Investigating the effects of peptoid substitutions in self‐assembly of Fmoc‐diphenylalanine derivatives
Authors: Rajbhandary Annada , Nilsson Bradley L.
Published: October 2016

Low molecular weight agents that undergo self‐assembly into fibril networks with hydrogel properties are promising biomaterials. Most low molecular weight hydrogelators are discovered empirically or serendipitously due to imperfect understanding of the mechanisms of self‐assembly, the packing structure of self‐assembled materials, and how the self‐assembly process corresponds to emergent hydrogelation. Herein, the mechanisms of self‐assembly and hydrogelation of N‐fluorenylmethoxycarbonyl diphenylalanine (Fmoc‐PhePhe), a well‐studied low molecular weight hydrogelator, is probed by systematic comparison with derivatives in which Phe residues are replaced by corresponding N‐benzyl glycine peptoid (Nphe) analogs. Peptoids are peptidomimetics that shift display of side chain functionality from the α‐carbon to the terminal nitrogen. This alters the hydrogen bonding capacity, the side chain presentation geometry, amide cis/trans isomerization equilibrium, and β‐sheet potential of the peptoid relative to the corresponding amino acid in the context of peptidic polymers. It was found that amino acid/peptoid hybrids Fmoc‐Phe‐Nphe and Fmoc‐Nphe‐Phe have altered fibril self‐assembly propensity and reduced hydrogelation capacity relative to the parent dipeptide, and that fibril self‐assembly of the dipeptoid, Fmoc‐Nphe‐Nphe, is completely curtailed. These findings provide insight into the potential of low molecular weight peptoids and peptide/peptoid hybrids as hydrogelation agents and illuminate the importance of hydrogen bonding and π–π interaction geometry in facilitating self‐assembly of Fmoc‐Phe‐Phe.
Determination of ethyl glucuronide and fatty acid ethyl esters in hair samples
Authors: Oppolzer David , Barroso Mário , Passarinha Luís , Gallardo Eugenia
Published: October 2016

Hair testing for alcohol biomarkers is an important tool for monitoring alcohol consumption. We propose two methods for assessing alcohol exposure through combined analysis of ethyl glucuronide (EtG) and fatty acid ethyl esters (FAEEs) species (ethyl myristate, palmitate, stearate and oleate) in hair (30 mg). EtG was analysed by liquid chromatography–tandem mass spectrometry, while FAEEs were analysed by gas chromatography–tandem mass spectrometry using electron impact ionization. Both methods were validated according to internationally accepted guidelines. Linearity was proven between 3 and 500 pg/mg for EtG and 30–5000 pg/mg for FAEEs, and the limits of quantification were 3 pg/mg for EtG and 30 pg/mg for each of the four FAEEs. Precision and accuracy were considered adequate, processed EtG samples were found to be stable for up to 96 h left in the injector and processed FAEEs samples for up to 24 h. Matrix effects were not significant. Both methods were applied to the analysis of 15 authentic samples, using the cut‐off values proposed by the Society of Hair Testing for interpretation. The results agreed well with the self‐reported alcohol consumption in most cases, and demonstrated the suitability of the methods to be applied in routine analysis of alcohol biomarkers, allowing monitoring consumption using low sample amounts.
Hazards in chromatographic bioanalysis method development and applications
Authors: Hooshfar Shirin , Bartlett Michael G.
Published: October 2016

Bioanalytical methods are employed for the quantitative determination of drugs and their metabolites in biological matrices, in all stages of the drug development process. However, because of the highly complex nature of these matrices there is a wide range of potential biological, chemical and physical hazards that can influence the quality of the data produced by these methods. The present review focuses on the evaluation of the most important and frequent errors that may be encountered during bioanalytical method development/validation and analysis of clinical or preclinical samples mainly using chromatography. Additionally, the most practical ways for avoiding and managing these hazards during routine bioanalysis are presented.
Covariation between plasma phosphate and daytime cortisol in early Parkinson's disease
Authors: Håglin Lena , Bäckman Lennart
Published: October 2016

Background

Disturbed phosphate homeostasis in early Parkinson′s disease (PD) may originate from a stress‐related condition and nutritional status among other risk factors, age, and gender.

Methods

Risk of malnutrition using Mini‐nutritional assessment (MNA score) and plasma levels of protein markers and daytime cortisol at the time of diagnosis in PD (n = 75) were compared with a control group (n = 24). Cognition was assessed using the Mini‐Mental State Examination (MMSE score) and motor function using Unified Parkinson′s Disease Rating Scale (UPDRS‐part III scale).

Results

The patients with PD had significantly lower MNA score than controls which correlated with plasma phosphate levels. The logistic regression revealed that increasing MNA protected from low plasma phosphate, final score (OR = 0.399; 95% CI = 0.196–0.816; p = .012) and total score (OR = 0.656; 95% CI = 0.422–1.018; p = .060). Phosphate correlated with albumin (r = .315; p < .006), transferrin (r = .331; p < .004) and cortisol (r = −0.355; p < .002) confirmed by logistic regressions. Increasing albumin protects from low phosphate after adjusting in logistic regression (OR = 0.806; 95% CI = 0.682–0.952; p = .011) and after including variables from Table 1 in backwards elimination, final step (OR = 0.800; 95% CI = 0.660–0.969; p = .022). MNA total score and cortisol correlated inversely, confirmed in logistic regression for MNA total score (OR = 0.786; 95% CI = 0.627–0.985; p = .037) and for MNA initial score (OR = 0.650; 95% CI = 0.453–0.930; p = .020).

Conclusion

This study highlights the importance of phosphate for optimal nutritional status by association with MNA score and albumin in plasma. An inverse relationship between phosphate and cortisol indicate, in addition, that low phosphate levels may affect cognition and motor function in PD.
Measuring Retailers' Sustainable Development
Authors: Youn Chorong , Kim So‐young , Lee Yuri , Choo Ho Jung , Jang Seyoon , Jang Jae Im
Published: October 2016

This study aimed to develop a framework and measurement items for retailers to assess sustainability while avoiding potential subjectivity by combining top‐down and bottom‐up approaches, and verifying their validity based on consumer perceptions of sustainable retailing. The framework consisted of 54 measurement items categorized into a three‐order hierarchical model. At the top level of the model, there were three third‐order dimensions respectively related to consumers, retailers, and society. At the middle level, eight second‐order sub‐dimensions associated with retailing mix were classified into the aforementioned third‐order dimensions. At the bottom level, there were 21 first‐order sub‐dimensions related to the sustainable retailing activities. The development of sustainability assessment by combining top‐down and bottom‐up approaches and including consumer perceptions will allow retailers to assess their sustainability more strategically, as it will reduce the subjectivity and increase consumers' recognition of sustainable retailing. Copyright © 2016 John Wiley & Sons, Ltd and ERP Environment
Green Product Innovation in Manufacturing Firms: A Sustainability‐Oriented Dynamic Capability Perspective
Authors: Dangelico Rosa Maria , Pujari Devashish , Pontrandolfo Pierpaolo
Published: October 2016

Despite environmental sustainability being identified as one of the key drivers of innovation, extant literature lacks a theoretically sound and empirically testable framework that can provide specific insights into green product innovation from a capability perspective. This study develops a theoretical framework from a sustainability‐oriented dynamic capability (SODC) perspective. We conceive SODCs as consisting of three underlying processes (external resource integration, internal resource integration, and resource building and reconfiguration) that influence the change/renewal of sustainability‐oriented ordinary capabilities (SOOCs) (green innovation capability and eco‐design capability). This study answers two key questions: which SODCs are needed to develop green innovation and eco‐design capabilities? Which of these capabilities lead to better market performance of green products? We test a structural model linking SODCs to market performance in 189 Italian manufacturing firms. First, we find that the nature of the SODC–performance link (direct or indirect) depends on the SODC type. Specifically, resource building and reconfiguration is the only SODC with a direct effect on market performance. Second, all three types of SODC affect the eco‐design capability, which mediates the link between SODCs and market performance. Third, we find that external resource integration is the only SODC affecting the green innovation capability, which mediates the link between external resource integration and market performance. Resource building and reconfiguration is the SODC with the overall (direct and indirect) highest impact on market performance. This study, among the first to consider capabilities for green product innovation under a dynamic capability perspective, provides implications for scholars, managers and policy makers. Copyright © 2016 John Wiley & Sons, Ltd and ERP Environment
Robust factor selection in early cell culture process development for the production of a biosimilar monoclonal antibody
Authors: Sokolov Michael , Ritscher Jonathan , MacKinnon Nicola , Bielser Jean‐Marc , Brühlmann David , Rothenhäusler Dominik , Thanei Gian , Soos Miroslav , Stettler Matthieu , Souquet Jonathan , Broly Hervé , Morbidelli Massimo , Butté Alessandro
Published: October 2016

This work presents a multivariate methodology combining principal component analysis, the Mahalanobis distance and decision trees for the selection of process factors and their levels in early process development of generic molecules. It is applied to a high throughput study testing more than 200 conditions for the production of a biosimilar monoclonal antibody at microliter scale. The methodology provides the most important selection criteria for the process design in order to improve product quality towards the quality attributes of the originator molecule. Robustness of the selections is ensured by cross‐validation of each analysis step. The concluded selections are then successfully validated with an external data set. Finally, the results are compared to those obtained with a widely used software revealing similarities and clear advantages of the presented methodology. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:181–191, 2017
Metabolic profiling of recombinant Escherichia coli cultivations based on high‐throughput FT‐MIR spectroscopic analysis
Authors: Sales Kevin C. , Rosa Filipa , Cunha Bernardo R. , Sampaio Pedro N. , Lopes Marta B. , Calado Cecília R. C.
Published: October 2016

Escherichia coli is one of the most used host microorganism for the production of recombinant products, such as heterologous proteins and plasmids. However, genetic, physiological and environmental factors influence the plasmid replication and cloned gene expression in a highly complex way. To control and optimize the recombinant expression system performance, it is very important to understand this complexity. Therefore, the development of rapid, highly sensitive and economic analytical methodologies, which enable the simultaneous characterization of the heterologous product synthesis and physiologic cell behavior under a variety of culture conditions, is highly desirable. For that, the metabolic profile of recombinant E. coli cultures producing the pVAX‐lacZ plasmid model was analyzed by rapid, economic and high‐throughput Fourier Transform Mid‐Infrared (FT‐MIR) spectroscopy. The main goal of the present work is to show as the simultaneous multivariate data analysis by principal component analysis (PCA) and direct spectral analysis could represent a very interesting tool to monitor E. coli culture processes and acquire relevant information according to current quality regulatory guidelines. While PCA allowed capturing the energetic metabolic state of the cell, e.g. by identifying different C‐sources consumption phases, direct FT‐MIR spectral analysis allowed obtaining valuable biochemical and metabolic information along the cell culture, e.g. lipids, RNA, protein synthesis and turnover metabolism. The information achieved by spectral multivariate data and direct spectral analyses complement each other and may contribute to understand the complex interrelationships between the recombinant cell metabolism and the bioprocess environment towards more economic and robust processes design according to Quality by Design framework. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:285–298, 2017
Immobilization of recombinant pectate lyase from Clostridium thermocellum ATCC‐27405 on magnetic nanoparticles for bioscouring of cotton fabric
Authors: Chakraborty Soumyadeep , Jagan Mohan Rao Tingirikari , Goyal Arun
Published: October 2016

Recombinant pectate lyase from family 1 polysaccharide lyase (PL1B) was immobilized on synthesized magnetic nanoparticles (MNPs) after 1‐ethyl‐3‐(3‐dimethylaminopropyl) carbodiimide hydrochloride activation. At 70 mg/mL MNPs 100% binding of 1 mg/mL PL1B was achieved. The immobilized PL1B‐MNP displayed activity of 20.3 and 18.2 U/mg against polygalacturonic acid and citrus pectin, respectively, which was higher than the activity of free PL1B, on the same substrates of 17.8 and 16.2 U/mg. The immobilized PL1B‐MNP showed 32 fold and 14 fold enhanced thermal stability at 80°C and 90°C, respectively as compared with free PL1B at same temperatures. At high temperature the immobilized PL1B‐MNP retained its activity for a longer duration than free PL1B. The immobilized PL1B‐MNP could be reused till five cycles and after that it retained 70% of initial activity. It could be easily recovered from the reaction mixture with the help of a magnet. Bioscouring of cotton fabric was carried out with immobilized PL1B‐MNP which showed efficient removal of pectin from the fabric surface. The enhanced wettability of fabric resulted in the decrease of the water absorbing time period from 3 min taken by the free PL1B treated fabric to 15 s taken by the immobilized PL1B‐MNP treated fabric. As per our knowledge this is the first attempt of bioscouring of coarse cotton fabric by pectinase immobilized on magnetic nanoparticles. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:231–244, 2017
β‐caryophyllene and β‐caryophyllene oxide—natural compounds of anticancer and analgesic properties
Authors: Fidyt Klaudyna , Fiedorowicz Anna , Strządała Leon , Szumny Antoni
Published: October 2016

Natural bicyclic sesquiterpenes, β‐caryophyllene (BCP) and β‐caryophyllene oxide (BCPO), are present in a large number of plants worldwide. Both BCP and BCPO (BCP(O)) possess significant anticancer activities, affecting growth and proliferation of numerous cancer cells. Nevertheless, their antineoplastic effects have hardly been investigated in vivo. In addition, both compounds potentiate the classical drug efficacy by augmenting their concentrations inside the cells. The mechanisms underlying the anticancer activities of these sesquiterpenes are poorly described. BCP is a phytocannabinoid with strong affinity to cannabinoid receptor type 2 (CB2), but not cannabinoid receptor type 1 (CB1). In opposite, BCP oxidation derivative, BCPO, does not exhibit CB1/2 binding, thus the mechanism of its action is not related to endocannabinoid system (ECS) machinery. It is known that BCPO alters several key pathways for cancer development, such as mitogen‐activated protein kinase (MAPK), PI3K/AKT/mTOR/S6K1 and STAT3 pathways. In addition, treatment with this compound reduces the expression of procancer genes/proteins, while increases the levels of those with proapoptotic properties. The selective activation of CB2 may be considered a novel strategy in pain treatment, devoid of psychoactive side effects associated with CB1 stimulation. Thus, BCP as selective CB2 activator may be taken into account as potential natural analgesic drug. Moreover, due to the fact that chronic pain is often an element of cancer disease, the double activity of BCP, anticancer and analgesic, as well as its beneficial influence on the efficacy of classical chemotherapeutics, is particularly valuable in oncology. This review is focused on anticancer and analgesic activities of BCP and BCPO, the mechanisms of their actions, and potential therapeutic utility.
From Super Mario to Skyrim: A framework for the evolution of video game consumption
Authors: Kuo Andrew , Hiler Jacob L. , Lutz Richard J.
Published: October 2016

In contrast with traditional forms of entertainment media (e.g., movies, novels, and television), video games are unique in their ability to provide immersion, agency, and transformation (IAT) during the consumptive experience. As the video game medium has evolved over generations of consoles, the experience of IAT has become increasingly complex from the perspective of consumers. To better understand this phenomenon, this research presents a framework for understanding the consumption of video games by examining the intersection of player, narrative, and gameplay. Our findings suggest that advancements in video game technology and design have gradually increased the degree of integration among these domains. Although the subjective experience of IAT has generally improved as a function of greater integration, various conflicts arise from the tensions that exist between player, narrative, and gameplay. Consequently, this research explores the specific nature of such conflicts to provide a richer understanding of video game consumption and the impact of its evolution on consumers. Copyright © 2016 John Wiley & Sons, Ltd.
Integrated Exploitation of the Structural Diversity Space of Chemotherapy Drugs to Selectively Inhibit HER2 T798M Mutant in Lung Cancer
Authors: Wang Ya‐Wei , Zhang Hai‐Yan , Li Ji‐Sheng , Wang Xiu‐Wen
Published: October 2016

An acquired T798M gatekeeper mutation in human epidermal growth factor receptor 2 (HER2) kinase can cause drug resistance to anti‐HER2 chemotherapy drugs in lung cancer. Previously, the reversible pan‐kinase inhibitor staurosporine has been found to selectively inhibit the HER2 T798M mutant over wild‐type kinase, suggesting that the staurosporine scaffold is potentially to develop mutant‐selective inhibitors. Here, we systematically evaluated the chemical space of staurosporine scaffold‐based compounds in response to HER2 T798M mutation at structural, energetic and molecular levels by using an integrated analysis strategy. With this strategy, we were able to identify several novel wild‐type sparing inhibitors with high or moderate selectivity, which are comparable to or even better than that of the parent compound staurosporine. Molecular modeling and structural analysis revealed that noncovalent contacts can form between the side chain of mutated residue Met798 and selective inhibitor ligands, which may improve the favorable interaction energy between the kinase and inhibitor and reduce the unfavorable desolvation penalty upon the kinase–inhibitor binding.
Transcatheter aortic valve implantation with a Sapien 3 Commander 20 mm valves in patients with degenerated 19 mm bioprosthetic aortic valve
Authors: Loyalka Pranav , Nascimbene Angelo , Schechter Michael , Petrovic Marija , Sundara Raman Ajay , Gregoric Igor D. , Kar Biswajit
Published: October 2016

Introduction

Transcatheter aortic valve implantation (TAVI) in patients with degenerated bioprosthetic aortic valve has been successfully performed as an alternative to surgery. We describe our initial experience of valve‐in‐valve TAVI in five patients, using new generation Edwards Sapien 3 transcatheter heart valves implanted into degenerated 19 mm bioprosthetic valves. 20‐mm Edwards S3 valves were offered for compassionate use. All patients had significant aortic valve stenosis.

Methods and Results

The main vascular access was achieved and pre‐closed with two Proglide closure devices in one patient and Prostar closure devices in four patients. For each TAVI procedure an Edwards 14 French sheath was inserted without complication and sutured in place. The Sapien 3 Commander delivery system was inserted and the valve was aligned in the descending aorta. The 20‐mm Sapien 3 valve was deployed with slow continuous inflation during rapid right ventricular pacing. The cranial edge of the Edwards S3 valve was aligned with the cranial radiopaque markers of bioprosthesis to minimize paravalvular leak. Post‐deployment angiography, transesophageal echocardiography and aortogram confirmed absence of mild aortic insufficiency and no increase in trans‐aortic gradient when compared to a naïve 19 mm bioprosthetic valve.

Conclusion

Valve‐in‐valve TAVI with the Edwards S3 transcatheter heart valve for degenerative bioprosthetic aortic valves is technically feasible. The proper position of the stented valve minimizes the risk for post‐procedure paravalvular insufficiency and provides good transaortic pressure gradient. © 2016 Wiley Periodicals, Inc.
A Star‐shaped Oligo(phenylenevinylene) Liquid Crystal Host with an Anthracene Guest—A Double Nanosegregating Supermesogen
Authors: Maier Philipp , Grüne Matthias , Lehmann Matthias
Published: October 2016

Hexasubstituted C3‐symmetric benzenes with three elongated shape‐persistent oligo(phenylenevinylene) arms and three pyridyl hydrogen‐bond acceptors have been synthesized. These mesogens assemble in a double‐helical columnar liquid crystal (LC) structure, owing to the compensation of free spaces between conjugated arms by dimer formation. The void is filled also by up to three anthracene carboxylic acids as guests forming hydrogen bonded supermesogens assembling in columnar LC and soft‐crystal phases. Thin film fluorescence and solid‐state NMR spectroscopy imply a transition from a disordered columnar LC to an unexpected double nanosegregated morphology of a filled soft columnar crystal phase. An additional intracolumnar separation of anthracene and oligo(phenylenevinylene) chromophores occurs, separate to the general segregation of aliphatic and aromatic building blocks in LC structures. The new type of supermesogens will enable the rational design of host–guest double cables with a wide range of different conjugated building blocks.
Non‐Newtonian versus numerical rheology: Practical impact of shear‐thinning on the prediction of stable and unstable flows in intracranial aneurysms
Authors: Khan M. O. , Steinman D. A. , Valen‐Sendstad K.
Published: October 2016

Computational fluid dynamics (CFD) shows promise for informing treatment planning and rupture risk assessment for intracranial aneurysms. Much attention has been paid to the impact on predicted hemodynamics of various modelling assumptions and uncertainties, including the need for modelling the non‐Newtonian, shear‐thinning rheology of blood, with equivocal results. Our study clarifies this issue by contextualizing the impact of rheology model against the recently demonstrated impact of CFD solution strategy on the prediction of aneurysm flow instabilities. Three aneurysm cases were considered, spanning a range of stable to unstable flows. Simulations were performed using a high‐resolution/accuracy solution strategy with Newtonian and modified‐Cross rheology models and compared against results from a so‐called normal‐resolution strategy. Time‐averaged and instantaneous wall shear stress (WSS) distributions, as well as frequency content of flow instabilities and dome‐averaged WSS metrics, were minimally affected by the rheology model, whereas numerical solution strategy had a demonstrably more marked impact when the rheology model was fixed. We show that point‐wise normalization of non‐Newtonian by Newtonian WSS values tended to artificially amplify small differences in WSS of questionable physiological relevance in already‐low WSS regions, which might help to explain the disparity of opinions in the aneurysm CFD literature regarding the impact of non‐Newtonian rheology. Toward the goal of more patient‐specific aneurysm CFD, we conclude that attention seems better spent on solution strategy and other likely “first‐order” effects (eg, lumen segmentation and choice of flow rates), as opposed to “second‐order” effects such as rheology.
NMR Diffusion Measurements as a Simple Method to Examine Solvent–Solvent and Solvent–Solute Interactions in Mixtures of the Ionic Liquid [Bmim][N(SO2CF3)2] and Acetonitrile
Authors: Keaveney Sinead T. , Schaffarczyk McHale Karin S. , Stranger James W. , Ganbold Batchimeg , Price William S. , Harper Jason B.
Published: October 2016

The self‐diffusion coefficients of each component in mixtures of 1‐butyl‐3‐methylimidazolium bis(trifluoromethanesulfonyl)imide ([Bmim][N(SO2CF3)2]) and acetonitrile were determined. The results suggest that the hydrodynamic boundary conditions change from “stick” to “slip” as the solvent composition transitions from “ionic liquid dissolved in acetonitrile” (χIL<0.4) to “acetonitrile dissolved in ionic liquid” (χIL>0.4). At higher χIL, the acetonitrile species are affected by “cage” and “jump” events, as the acetonitrile molecules reside nearer to the charged centre on the ions than in the “non‐polar” regions. The self‐diffusion coefficients of hexan‐1‐amine, dipropylamine, 1‐hexanol and dipropylether in mixtures of [Bmim][N(SO2CF3)2] and acetonitrile were determined. In general, the nitrogen‐containing solutes were found to diffuse slower than the oxygen‐containing solutes; this indicates that there are greater ionic liquid–N interactions than ionic liquid–O interactions. This work demonstrates that the self‐diffusion coefficients of species can provide valuable information about solvent–solvent and solvent–solute interactions in mixtures containing an ionic liquid.
Instability and violence in Imperial Rome: A “laboratory” for studying social contagion?
Authors: Nimgade Ashok
Published: October 2016

Imperial Rome with its >50% assassination rate of emperors, many of whom are depicted in history as ‘deranged’, initially appears a chaotic period of history beyond the purview of science. But time series analysis indicates this violence occurred non‐randomly: reign length was autocorrelated and demonstrated ‘memory persistence,’ and short reigns occurred in clusters. Additionally, deviations from average reign‐length occurred in patterns matching the Empire's rise and decline. A model is proposed for how army‐backed usurpation and post‐coup instability likely generated the observed cycles. The five‐century span of Imperial Rome likely makes it the longest‐lived regime with fair documentation, and potentially provides a ‘laboratory’ with ongoing relevance for studying transmission of violence and instability. © 2016 Wiley Periodicals, Inc. Complexity 21: 613–622, 2016
Mutant analysis by rescue gene excision: New tools for mosaic studies in Drosophila
Authors: Zhou Qingxiang , Neal Scott J. , Pignoni Francesca
Published: October 2016

A host of classical and molecular genetic tools make Drosophila a tremendous model for the dissection of gene activity. In particular, the FLP‐FRT technique for mitotic recombination has greatly enhanced gene loss‐of‐function analysis. This technique efficiently induces formation of homozygous mutant clones in tissues of heterozygous organisms. However, the dependence of the FLP‐FRT method on cell division, and other constraints, also impose limits on its effectiveness. We describe here the generation and testing of tools for Mutant Analysis by Rescue Gene Excision (MARGE), an approach whereby mutant cells are formed by loss of a rescue transgene in a homozygous mutant organism. Rescue‐transgene loss can be induced in any tissue or cell‐type and at any time during development or in the adult using available heat‐shock‐induced or tissue‐specific flippases, or combinations of UAS‐FLP with Gal4 and Gal80ts reagents. The simultaneous loss of a constitutive fluorescence marker (GFP or RFP) identifies the mutant cells. We demonstrate the efficacy of the MARGE technique by flip‐out (clonal and disc‐wide) of a Ubi‐GFP‐carrying construct in imaginal discs, and by inducing a known yki mutant phenotype in the Drosophila ovary.
Adaptation and plasticity in aboveground allometry variation of four pine species along environmental gradients
Authors: Vizcaíno‐Palomar Natalia , Ibáñez Inés , González‐Martínez Santiago C. , Zavala Miguel A. , Alía Ricardo
Published: October 2016

Plant species aboveground allometry can be viewed as a functional trait that reflects the evolutionary trade‐off between above‐ and belowground resources. In forest trees, allometry is related to productivity and resilience in different environments, and it is tightly connected with a compromise between efficiency‐safety and competitive ability. A better understanding on how this trait varies within and across species is critical to determine the potential of a species/population to perform along environmental gradients. We followed a hierarchical framework to assess tree height‐diameter allometry variation within and across four common European Pinus species. Tree height‐diameter allometry variation was a function of solely genetic components –approximated by either population effects or clinal geographic responses of the population's site of origin– and differential genetic plastic responses –approximated by the interaction between populations and two climatic variables of the growing sites (temperature and precipitation)–. Our results suggest that, at the species level, climate of the growing sites set the tree height‐diameter allometry of xeric and mesic species (Pinus halepensis, P. pinaster and P. nigra) apart from the boreal species (P. sylvestris), suggesting a weak signal of their phylogenies in the tree height‐diameter allometry variation. Moreover, accounting for interpopulation variability within species for the four pine species aided to: (1) detect genetic differences among populations in allometry variation, which in P. nigra and P. pinaster were linked to gene pools –genetic diversity measurements–; (2) reveal the presence of differential genetic variation in plastic responses along two climatic gradients in tree allometry variation. In P. sylvestris and P. nigra, genetic variation was the result of adaptive patterns to climate, while in P. pinaster and P. halepensis, this signal was either weaker or absent, respectively; and (3) detect local adaptation in the exponent of the tree height‐diameter allometry relationship in two of the four species (P. sylvestris and P. nigra), as it was a function of populations' latitude and altitude variables. Our findings suggest that the four species have been subjected to different historical and climatic constraints that might have driven their aboveground allometry and promoted different life strategies.
Coast‐wide recruitment dynamics of Olympia oysters reveal limited synchrony and multiple predictors of failure
Authors: Wasson Kerstin , Hughes Brent B. , Berriman John S. , Chang Andrew L. , Deck Anna K. , Dinnel Paul A. , Endris Charlie , Espinoza Michael , Dudas Sarah , Ferner Matthew C. , Grosholz Edwin D. , Kimbro David , Ruesink Jennifer L. , Trimble Alan C. , Vander Schaaf Dick , Zabin Chela J. , Zacherl Danielle C.
Published: October 2016

Recruitment of new propagules into a population can be a critical determinant of adult density. We examined recruitment dynamics in the Olympia oyster (Ostrea lurida), a species occurring almost entirely in estuaries. We investigated spatial scales of interannual synchrony across 37 sites in eight estuaries along 2,500 km of Pacific North American coastline, predicting that high vs. low recruitment years would coincide among neighboring estuaries due to shared exposure to regional oceanographic factors. Such synchrony in recruitment has been found for many marine species and some migratory estuarine species, but has never been examined across estuaries in a species that can complete its entire life cycle within the same estuary. To inform ongoing restoration efforts for Olympia oysters, which have declined in abundance in many estuaries, we also investigated predictors of recruitment failure. We found striking contrasts in absolute recruitment rate and frequency of recruitment failure among sites, estuaries, and years. Although we found a positive relationship between upwelling and recruitment, there was little evidence of synchrony in recruitment among estuaries along the coast, and only limited synchrony of sites within estuaries, suggesting recruitment rates are affected more strongly by local dynamics within estuaries than by regional oceanographic factors operating at scales encompassing multiple estuaries. This highlights the importance of local wetland and watershed management for the demography of oysters, and perhaps other species that can complete their entire life cycle within estuaries. Estuaries with more homogeneous environmental conditions had greater synchrony among sites, and this led to the potential for estuary‐wide failure when all sites had no recruitment in the same year. Environmental heterogeneity within estuaries may thus buffer against estuary‐wide recruitment failure, analogous to the portfolio effect for diversity. Recruitment failure was correlated with lower summer water temperature, higher winter salinity, and shorter residence time: all indicators of stronger marine influence on estuaries. Recruitment failure was also more common in estuaries with limited networks of nearby adult oysters. Large existing oyster networks are thus of high conservation value, while estuaries that lack them would benefit from restoration efforts to increase the extent and connectivity of sites supporting oysters.
Inferring species interactions from co‐occurrence data with Markov networks
Authors: Harris David J.
Published: October 2016

Inferring species interactions from co‐occurrence data is one of the most controversial tasks in community ecology. One difficulty is that a single pairwise interaction can ripple through an ecological network and produce surprising indirect consequences. For example, the negative correlation between two competing species can be reversed in the presence of a third species that outcompetes both of them. Here, I apply models from statistical physics, called Markov networks or Markov random fields, that can predict the direct and indirect consequences of any possible species interaction matrix. Interactions in these models can be estimated from observed co‐occurrence rates via maximum likelihood, controlling for indirect effects. Using simulated landscapes with known interactions, I evaluated Markov networks and six existing approaches. Markov networks consistently outperformed the other methods, correctly isolating direct interactions between species pairs even when indirect interactions or abiotic factors largely overpowered them. Two computationally efficient approximations, which controlled for indirect effects with partial correlations or generalized linear models, also performed well. Null models showed no evidence of being able to control for indirect effects, and reliably yielded incorrect inferences when such effects were present.