bluuebunny/crossref_metadata_2025_split huggingface dataset:
The sensitivity to Hsp90 inhibitors of both normal and oncogenically transformed cells is determined by the equilibrium between cellular quiescence and activity
Authors: Echeverria Pablo C. , Bhattacharya Kaushik , Joshi Abhinav , Wang Tai , Picard Didier 
Published: November 2018

AbstractThe molecular chaperone Hsp90 is an essential and highly abundant central node in the interactome of eukaryotic cells. Many of its large number of client proteins are relevant to cancer. A hallmark of Hsp90-dependent proteins is that their accumulation is compromised by Hsp90 inhibitors. Combined with the anecdotal observation that cancer cells may be more sensitive to Hsp90 inhibitors, this has led to clinical trials aiming to develop Hsp90 inhibitors as anti-cancer agents. However, the sensitivity to Hsp90 inhibitors has not been studied in rigorously matched normal versus cancer cells, and despite the discovery of important regulators of Hsp90 activity and inhibitor sensitivity, it has remained unclear, why cancer cells might be more sensitive. To revisit this issue more systematically, we have generated an isogenic pair of normal and oncogenically transformed NIH-3T3 cell lines. Our proteomic analysis of the impact of three chemically different Hsp90 inhibitors shows that these affect a substantial portion of the oncogenic program and that indeed, transformed cells are hypersensitive. Targeting the oncogenic signaling pathway reverses the hypersensitivity, and so do inhibitors of DNA replication, cell growth, translation and energy metabolism. Conversely, stimulating normal cells with growth factors or challenging their proteostasis by overexpressing an aggregation-prone sensitizes them to Hsp90 inhibitors. Thus, the differential sensitivity to Hsp90 inhibitors may not stem from any particular intrinsic difference between normal and cancer cells, but rather from a shift in the balance between cellular quiescence and activity.
Detoxification of host plant phenolic aglycones by the spruce budworm
Authors: Donkor Dominic , Mirzahosseini Zahra , Bede Jacquie , Bauce Eric , Despland Emma 
Published: November 2018

AbstractThis study examines the post-ingestive fate of two host-plant derived small-molecule phenolics (the acetophenones piceol and pungenol) that have previously been shown to be toxic to the outbreaking forest pest, spruce budworm (Choristoneura fumiferana). We test first whether these compounds are transformed during passage through the midgut, and second whether the budworm upregulates activity of the detoxification enzyme glutathione-s-transferase (GST) in response to feeding on these compounds. Insects were reared on either foliage or artificial diet to the fourth instar, when they were transferred individually to one of two treatment diets, either control or phenolic-laced, for approximately 10 days, after which midguts were dissected out and used for Bradford soluble protein and GST enzyme activity analysis. Frass was collected and subjected to HPLC-DAD-MS. HPLC showed that the acetophenones do not autoxidize under midgut pH conditions, but that glucose- and glutathione-conjugates are present in the frass of insects fed the phenolic-laced diet. GST enzyme activity increases in insects fed the phenolic-laced diet, in both neutral pH and alkaline assays. These data show that the spruce budwom exhibits counter-adaptations to plant phenolics similar to those seen in angiosperm feeders, upregulating an important detoxifying enzyme (GST) and partially conjugating these acetophenones prior to elimination, but that these counter-measures are not totally effective at mitigating toxic effects of the ingested compounds in the context of our artifical-diet based laboratory experiment.
5’ UTR recruitment of eIF4GI or DAP5 drives cap-independent translation for a subset of human mRNAs
Authors: Haizel Solomon A. , Bhardwaj Usha , Gonzalez Ruben L. , Mitra Somdeb , Goss Dixie J. 
Published: November 2018

AbstractDuring unfavorable human cellular conditions (e.g., tumor hypoxia, viral infection, etc.), canonical, cap-dependent mRNA translation is suppressed. Nonetheless, a subset of physiologically important mRNAs (e.g., HIF-1α, FGF-9, and p53) is still translated by an unknown, cap-independent mechanism. Additionally, expression levels of eIF4G and its homolog, death associated protein 5 (DAP5), are elevated. Using fluorescence anisotropy binding studies, luciferase reporter-based in vitro translation assays, and mutational analyses, here we demonstrate that eIF4GI and DAP5 specifically bind to the 5’ UTRs of these cap-independently translated mRNAs. Surprisingly, we find that the eIF4E binding domain of eIF4GI increases not only the binding affinity, but also the selectivity among these mRNAs. We further demonstrate that the affinities of eIF4GI and DAP5 binding to these 5’ UTRs correlate with the efficiency with which these factors drive cap-independent translation of these mRNAs. Integrating the results of our binding and translation assays, we show that eIF4GI and/or DAP5 are critical for recruitment of a specific subset of mRNAs to the ribosome and provide mechanistic insight into their cap-independent translation.
Best practice example of CSR and S&E engagement in emerging economies: analysis of a case study based in China
Authors: Fornes Gaston , Lopez Belen , Bierens de Haan Melanie , Blanch Javier 
Published: November 2018

PurposeThe paper analyses social and environmental engagement, stakeholders’ relations and corporate social responsibility (CSR) strategies/options along with their underlying mechanisms of firms operating in China.Design/methodology/approachIt does this through the analysis of a unique case study using data collected from internal members and external stakeholders of the company framed within stakeholder theory.FindingsWithin the Aguinis and Glavas (2012) framework, the results show that the company’s resources and values can act as a mediator, their high visibility and scale can act as a moderator, and their self-regulation can act as a predictor in weak institutional contexts. Also, the findings show that employees’ perceptions of visionary leadership can act as a mediator, and that the alignment in the vision/values/beliefs of the chief executive officer with those of the shareholders can act as moderators.Originality/valueThe paper intends to contribute to the literature on CSR in China by analysing a specific type of investor, the socially responsible investor, neglected in the CSR literature, and by studying multilevel (individual/organisational/institutional) social and environmental engagement, stakeholders’ relations and CSR strategies/options in an evolving institutional environment.
A second KRT71 allele in curly coated dogs
Authors: Bauer A. , Hadji Rasouliha S. , Brunner M. T. , Jagannathan V. , Bucher I. , Bannoehr J. , Varjonen K. , Bond R. , Bergvall K. , Welle M. M. , Roosje P. , Leeb T. 
Published: November 2018

SummaryMajor characteristics of coat variation in dogs can be explained by variants in only a few genes. Until now, only one missense variant in the KRT71 gene, p.Arg151Trp, has been reported to cause curly hair in dogs. However, this variant does not explain the curly coat in all breeds as the mutant 151Trp allele, for example, is absent in Curly Coated Retrievers. We sequenced the genome of a Curly Coated Retriever at 22× coverage and searched for variants in the KRT71 gene. Only one protein‐changing variant was present in a homozygous state in the Curly Coated Retriever and absent or present in a heterozygous state in 221 control dogs from different dog breeds. This variant, NM_001197029.1:c.1266_1273delinsACA, was an indel variant in exon 7 that caused a frameshift and an altered and probably extended C‐terminus of the KRT71 protein NP_001183958.1:p.(Ser422ArgfsTer?). Using Sanger sequencing, we found that the variant was fixed in a cohort of 125 Curly Coated Retrievers and segregating in five of 14 additionally tested breeds with a curly or wavy coat. KRT71 variants cause curly hair in humans, mice, rats, cats and dogs. Specific KRT71 variants were further shown to cause alopecia. Based on this knowledge from other species and the predicted molecular consequence of the newly identified canine KRT71 variant, it is a compelling candidate causing a second curly hair allele in dogs. It might cause a slightly different coat phenotype than the previously published p.Arg151Trp variant and could potentially be associated with follicular dysplasia in dogs.
Ticagrelor does not impact patient‐reported pain in young adults with sickle cell disease: a multicentre, randomised phase IIb study
Authors: Kanter Julie , Abboud Miguel R. , Kaya Banu , Nduba Videlis , Amilon Carl , Gottfridsson Christer , Rensfeldt Martin , Leonsson‐Zachrisson Maria ,   the HESTIA2 study investigators
Published: November 2018

SummaryTicagrelor is an antiplatelet agent for adults with coronary artery disease. The inhibition of platelet activation may decrease the frequency of vaso‐occlusion crisis (VOC) in sickle cell disease (SCD). The HESTIA2 study (NCT02482298) randomised 87 adults with SCD (aged 18–30 years) 1:1:1 to twice‐daily ticagrelor 10, 45 mg or placebo for 12 weeks. Numerical decreases from baseline in mean proportion of days with patient‐reported pain (primary endpoint) were seen in all three groups, as well as in pain intensity and analgesic use, with no significant differences between placebo and ticagrelor treatment groups. Plasma ticagrelor concentrations and platelet inhibition increased with dose. Adverse events were distributed evenly across groups and two non‐major bleeding events occurred per group. Ticagrelor was well tolerated with a low bleeding risk, but no effect on diary‐reported pain was detected. Potential effects on frequency of VOCs will need to be evaluated in a larger and longer study.
Pharmacological modulation of mitochondrial ion channels
Authors: Leanza Luigi , Checchetto Vanessa , Biasutto Lucia , Rossa Andrea , Costa Roberto , Bachmann Magdalena , Zoratti Mario , Szabo Ildiko 
Published: November 2018

The field of mitochondrial ion channels has undergone a rapid development during the last three decades, due to the molecular identification of some of the channels residing in the outer and inner membranes. Relevant information about the function of these channels in physiological and pathological settings was gained thanks to genetic models for a few, mitochondria‐specific channels. However, many ion channels have multiple localizations within the cell, hampering a clear‐cut determination of their function by pharmacological means. The present review summarizes our current knowledge about the ins and outs of mitochondrial ion channels, with special focus on the channels that have received much attention in recent years, namely, the voltage‐dependent anion channels, the permeability transition pore (also called mitochondrial megachannel), the mitochondrial calcium uniporter and some of the inner membrane‐located potassium channels. In addition, possible strategies to overcome the difficulties of specifically targeting mitochondrial channels versus their counterparts active in other membranes are discussed, as well as the possibilities of modulating channel function by small peptides that compete for binding with protein interacting partners. Altogether, these promising tools along with large‐scale chemical screenings set up to identify new, specific channel modulators will hopefully allow us to pinpoint the actual function of most mitochondrial ion channels in the near future and to pharmacologically affect important pathologies in which they are involved, such as neurodegeneration, ischaemic damage and cancer.Linked ArticlesThis article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc
Character: A Developmental System
Authors: Nucci Larry 
Published: November 2018

AbstractIn this article, I discuss character as a system that includes four components: moral cognition, other‐related social–emotional capacities and skills, self‐regarding capacities for executive control and self‐regulation, and discourse skills for responsive engagement and an orientation for principled moral change. The character system is active, adjusting itself in response to social and emotional experiences and in an effort to keep the components of the system working harmoniously. It is dynamically related to the context, generating decisions and actions that are coherent within but not entirely consistent across contexts. Decisions and actions alter the self‐system, thereby affecting subsequent decisions and actions. The character system is located within a larger self‐system, and it interacts with that self‐system in a relationship that is also self‐maintaining. This two‐way interaction alters both the character system and the self‐system, leading to growth in character and related changes in personal identity and the sense of self. This system view contrasts with traditional definitions of character in terms of virtues.
High prevalence of toothache among Great East Japan Earthquake survivors living in temporary housing
Authors: Tsuchiya Masahiro , Aida Jun , Watanabe Takashi , Shinoda Masamichi , Sugawara Yumi , Tomata Yasutake , Yabe Yutaka , Sekiguchi Takuya , Watanabe Makoto , Osaka Ken , Sasaki Keiichi , Hagiwara Yoshihiro , Tsuji Ichiro 
Published: November 2018

AbstractObjectivesThe Great East Japan Earthquake and subsequent tsunami cause large‐scale destruction in the north‐eastern coastal areas in Japan, and forced many survivors to relocate to prefabricated temporary housing, a typical emergency accommodation. Based on the hypothesis that higher toothache prevalence among the disaster survivors is associated with postdisaster distress, we determined the impact of temporary residential environment as potential stressor on the subjective toothache prevalence.MethodsA repeated cross‐sectional health survey based on self‐reported questionnaire was conducted in 2776 disaster survivors, of whom 1446 participants underwent dental examination by dentists. Housing type was categorized into three groups including the same housing as before the earthquake, temporary housing and rented/new housing. The association of housing type with subjective toothache prevalence was examined using multivariate logistic regression analysis in all subjects and subgroup analysis in dental examination applicants. Stratified analysis by survey wave was applied with inclusion of covariates such as the socio‐demographic factors, and presence of insomnia and psychological distress. In subgroup analysis, presence of dental caries and gum problems in dental examination were included as factors of direct exposure to subjective toothache.ResultsIn the first survey wave, the participants living in the temporary housing had significantly higher odds ratio (OR) for toothache prevalence compared to the participants living in the same housing (OR: 3.76, 95% confidence interval [CI]: 1.85‐7.65, P < 0.001); whereas in all other survey waves, there was no significant difference. Subgroup analysis of dental examination applicants confirmed the presence of significant association of subjective toothache prevalence in the temporary housing group alone (OR: 3.27, 95% CI: 1.38‐7.76, P = 0.004), but not in the rented/new housing group (OR: 1.50, 95% CI: 0.57‐3.91, P = 0.411), even after adjusting for covariates related to oral findings.ConclusionTemporary housing may be a factor to increase the risk of subjective toothache among disaster survivors only at postdisaster acute phase.
A doxycycline‐treated hydroxyapatite implant surface attenuates the progression of peri‐implantitis: A radiographic and histological study in mice
Authors: Ding Lin , Zhang Peng , Wang Xin , Kasugai Shohei 
Published: November 2018

AbstractBackgroundOral rehabilitation with dental implants has become increasingly common; however, the increase of peri‐implantitis is a great concern. Doxycycline (DOX) is a widely used antibiotic that inhibits bacteria growth, inflammation, and bone resorption.ObjectivesTo evaluate the progression of peri‐implantitis of hydroxyapatite (HA)‐coated implants with (5 mg/mL, DOX group) or without (HA group) DOX treatment on the surface.Materials and MethodsThe maxillary first molars of 20 male mice were extracted. Eight weeks later, small titanium screw implants coated with thin HA and treated with or without DOX were placed at the extracted sites. Four weeks after implant placement, half of the animals in both groups were sacrificed, and ligatures were placed around the implant necks in the other half. These mice were sacrificed 4 weeks later. The bone around the implants was examined radiologically and histologically.ResultsFour weeks after the ligature placement, the radiographic measurements revealed that peri‐implant bone levels of palatal and mesial sites, and histological measurements showed that bone levels of mesial and distal sites in the DOX group were significantly higher than those in the HA group.ConclusionsThe present results indicating that the DOX‐treated HA implant surface attenuates the progression of peri‐implantitis.
IL‐2mAb reduces demyelination after focal cerebral ischemia by suppressing CD8+ T cells
Authors: Zhou Yu‐Xi , Wang Xin , Tang Dan , Li Yan , Jiao Ying‐Fu , Gan Yu , Hu Xiao‐Ming , Yang Li‐Qun , Yu Wei‐Feng , Stetler Ruth Anne , Li Pei‐Ying , Wen Da‐Xiang 
Published: November 2018

SummaryAimsDemyelination, one of the major pathological changes of white matter injury, is closely related to T‐cell–mediated immune responses. Thus, we investigate the role of an IL‐2 monoclonal antibody (IL‐2mAb, JES6‐1) in combatting demyelination during the late phase of stroke.MethodsIL‐2mAb or IgG isotype antibody (0.25 mg/kg) was injected intraperitoneally 2 and 48 hours after middle cerebral artery occlusion (MCAO) surgery. Infarct volume, peripheral immune cell infiltration, microglia activation, and myelin loss were measured by 2,3,5‐triphenyte trazoliumchloride staining, immunofluorescence staining, flow cytometry, and Western blot. Intraperitoneal CD8 neutralizing antibody (15 mg/kg) was injected 1 day before MCAO surgery to determine the role of CD8+ T cells on demyelinating lesions.ResultsIL‐2mAb treatment reduced brain infarct volume, attenuated demyelination, and improved long‐term sensorimotor functions up to 28 days after dMCAO. Brain infiltration of CD8+ T cells and peripheral activation of CD8+ T cells were both attenuated in IL‐2 mAb‐treated mice. The protection of IL‐2mAb on demyelination was abolished in mice depleted of CD8+ T cell 1 week after stroke.ConclusionsIL‐2mAb preserved white matter integrity and improved long‐term sensorimotor functions following cerebral ischemic injury. The activation and brain infiltration of CD8+ T cells are detrimental for demyelination after stroke and may be the major target of IL‐2mAb posttreatment in the protection of white matter integrity after stroke.
Temporal changes in chromium allergy in Denmark between 2002 and 2017
Authors: Alinaghi Farzad , Zachariae Claus , Thyssen Jacob P. , Johansen Jeanne D. 
Published: November 2018

BackgroundIn 2012, Danish authorities submitted a proposal to the European Chemical Agency restricting the content of hexavalent chromium to a maximum of 3 ppm in leather goods. Following its adoption, this proposal was implemented in 2015 as a directive in the EU.ObjectivesTo examine the temporal trend of chromium contact allergy in adult dermatitis patients patch tested between 2002 and 2017, and to determine clinical characteristics and causative exposures in these patients.MethodsAll adult dermatitis patients patch tested between 2002 and 2017 were included. Patch test data were reviewed retrospectively. Comparisons were performed with the χ
2 test and logistic regression analysis.ResultsA total of 13 379 adults aged 18 to 99 years were patch tested between 2002 and 2017. The overall prevalence of chromium allergy was 2.2%. An overall decreasing trend was found for the prevalence of chromium allergy (Ptrend = 0.00002). Specifically, a significant difference was found for the study periods 2010 to 2013 (Ptrend = 0.002) and 2014 to 2017 (Ptrend < 0.0001) as compared with 2002 to 2005. Leather remained the most important single cause of allergic contact dermatitis caused by chromium. The proportion of clinically relevant leather exposures increased from 42.3% during 2002 to 2009 to 54.8% during 2010 to 2017 (P = 0.04).ConclusionsThe prevalence of chromium allergy is decreasing. The EU Directive restricting the use of hexavalent chromium in leather goods is thought to be playing a central role in this change.
Emergency general surgeons, subspeciality surgeons and the future management of emergency surgery: results of a national survey
Authors: Symons N. R. A. , McArthur D. , Miller A. , Verjee A. , Senapati A. 
Published: November 2018

AbstractAimThis study aimed to survey consultants’ experience of working as or with emergency general surgery (EGS) surgeons and to investigate the role they fulfil in the management of general and subspeciality emergencies.MethodAn electronic survey, designed to capture both quantitative and qualitative data, was piloted and then circulated to members of the Association of Coloproctology of Great Britain and Ireland.ResultsTwo hundred and forty‐two responses were received from 848 recipients (a 29% response rate) covering 104 of 135 (77%) acute NHS Trusts in England. EGS surgeons were in post in 43/141 (30%) hospitals overall and 12/24 (50%) of hospitals in London. Most respondents working in units with EGS surgeons found them to be advantageous (46/63, 73%). Consultants working with EGS surgeons were significantly more likely to support their use (49/63, 78%) than those without them (83/178, 47%) (χ2 = 16.9, P < 0.001). EGS surgeons were considered to improve the delivery of EGS (78%), create time for subspecialists (70%) and provide service (73%). However, there were concerns about the quality of surgery (43%), an insufficient standard of specialist care (54%) and compromise in the training of juniors (25%). Respondents commented on a lack of job structure with a high attrition rate (21%), the insufficient quality of applicants (18%) and that subspecialization and split on‐call was preferable (17%).ConclusionRespondents were supportive of the ability of EGS surgeons to relieve pressure on subspecialists; however, there were significant concerns about the sustainability and quality of the EGS surgeon role. Emergency colorectal resections should have the input of a surgeon who performs elective colorectal resections.
Allocating structured tasks in heterogeneous agent teams
Authors: Basegio Tulio L. , Bordini Rafael H. 
Published: November 2018

AbstractTask allocation is an important aspect of multiagent coordination. However, there are many challenges in developing appropriate strategies for multiagent teams so that they operate efficiently. Real‐world scenarios such as flooding disasters usually require the use of heterogeneous robots and the execution of tasks with different structures and complexities. In this paper, we propose a decentralized task allocation mechanism considering different types of tasks for heterogeneous agent teams where agents play different roles and carry out tasks according to their own capabilities. We have run several experiments to evaluate the proposed mechanism. The results show that the proposed mechanism appears to scale well and provides near‐optimal allocations.