bluuebunny/crossref_metadata_2025 huggingface dataset:
Mental states and activities in Danish narratives: children with autism and children with language impairment
Authors: ENGBERG-PEDERSEN ELISABETH , CHRISTENSEN RIKKE VANG
Published: November 2016

This study focuses on the relationship between content elements and mental-state language in narratives from twenty-seven children with autism (ASD), twelve children with language impairment (LI), and thirty typically developing children (TD). The groups did not differ on chronological age (10;6–14;0) and non-verbal cognitive skills, and the groups with ASD and TD did not differ on language measures. The children with ASD and LI had fewer content elements of the storyline than the TD children. Compared with the TD children, the children with ASD used fewer subordinate clauses about the characters’ thoughts, and preferred talking about mental states as reported speech, especially in the form of direct speech. The children with LI did not differ from the TD children on these measures. The results are discussed in the context of difficulties with socio-cognition in children with ASD and of language difficulties in children with LI.
Effectiveness of the network of protected areas of the South Caucasus at representing terrestrial ecosystems after the dissolution of the Soviet Union
Authors: MONTALVO MANCHENO CRISTIAN S. , ZAZANASHVILI NUGZAR , BERUCHASHVILI GIORGI
Published: November 2016

Protected areas (PAs) have long been the foundation of conservation strategies to halt biodiversity losses and ecosystem degradation. In the South Caucasus (SC), coverage of PAs increased after the collapse of the Soviet Union in 1991, yet how well biodiversity is represented in them is unknown. We utilized the PA downgrading, downsizing and degazettement (PADDD) conceptual framework and the gap analysis approach to assess how changes in the PAs of Armenia, Azerbaijan and Georgia between 1991 and 2014 have affected the representation of biodiversity. Throughout this period, vegetation formations associated with high mountain ecosystems changed (≥17% representation). Colchic lowland vegetation formations which are only present in Georgia, also changed from unrepresented (0%) to under-represented (from 0% to <17%). The effect of PADDD events on biodiversity representation varied among countries depending on the amount of area gazetted after 1991. There is an inherent bias in the expansion of PAs in the SC. Our findings could be a first step towards changing the status quo by helping conservationists to strategically allocate resources towards ecosystems that are below 17% representation. Yet this will require governments in the SC to shift their views about PAs from being only national efforts to being key pieces of a larger-scale conservation strategy.
Toleration, Synthesis or Replacement? The ‘Empirical Turn’ and its Consequences for the Science of International Law
Authors: HOLTERMANN JAKOB V.H. , MADSEN MIKAEL RASK
Published: November 2016

One of the most striking trends in contemporary international law (IL) scholarship is the turn to empirical research methods. Some see this as sign of progress, whereas others call for caution or even show hostility. With a view to the future of IL scholarship, however, all sides in this at times heated debate seem to have considerable problems keeping a clear focus on the key question: What are the implications of this empirical turn in terms of philosophy of legal science, of the social understanding of IL, and, not least, of the place of doctrinal scholarship after the allegedWende? What is needed, we argue, in order to answer this question is not yet another partisan suggestion, but rather an attempt at making intelligible both the oppositions and the possibilities of synthesis between normative and empirical approaches to law.

Based on our assessment and rational reconstruction of current arguments and positions we outline a taxonomy consisting of the following three basic, ideal-types in terms of the epistemological understanding of the interface of law and empirical studies: toleration, synthesis and replacement. This tripartite model proves useful with a view to teasing out and better articulating implications of and interrelations between positions. As such the model: i) provides a framework to better situate arguments about the role of empirical studies in IL; ii) helps identify real epistemological stakes in order to overcome ‘trench wars’ – or worse: absence of dialogue and genuine argument; and iii) thus ultimately contributes to the development of a genuine basic science-of-law.
‘The greater part of jurisconsults’: On Consensus Claims and Their Footnotes in Legal Scholarship
Authors: BOER LIANNE J.M.
Published: November 2016

This article portrays the use of consensus claims, as well as their substantiation, in the debate on cyber-attacks and Article 2(4) of the UN Charter. Focusing on (re)interpretations of the prohibition on the use of force in the light of cyber-attacks, the article first shows how scholars appeal to the ‘majority opinion’ of scholars or the ‘generally accepted’ interpretation of the norm. It points out the different uses of these ‘consensus claims’, as I refer to them, and what scholars invoke exactly when referring to this elusive majority. Elaborating on this ‘elusive’ nature of consensus, I argue that the appeal of a consensus claim lies precisely in its invocation of a fairly mystical ‘out there’. Consensus, as it turns out, evaporates the moment we attempt to substantiate it, and this might be precisely where its strength lies. The second part of the article thus shifts focus to how these claims are substantiated. An empirical inquiry into the footnotes supporting consensus claims reveals that, most of the time, writers refer to the same scholars to substantiate their claims. Making use of Henry Small's idea of ‘concept symbols’, the article argues that these most-cited scholars turn into the ‘bearers’ of majority opinion. On the level of the individual academic piece, the singular reference might appear to be fairly innocent. Yet, when considered as a more widespread practice of ‘self-referentiality’, it seriously impacts who gets a say – and thus, ultimately, what we know – in international law.
International Law Scholars as Amici Curiae: An Emerging Dialogue (of the Deaf)?
Authors: KENT AVIDAN , TRINIDAD JAMIE
Published: November 2016

International law scholars frequently seek to participate in international legal proceedings as amici curiae. Often they do so by ‘piggy-backing’ onto the submissions of NGOs and other advocacy groups. Occasionally – but increasingly in recent years – they do so in their own names, purporting to offer ‘pure’ academic expertise, and generating certain expectations of scholarly neutrality. This article focuses on the latter trend, which the authors argue has the potential to re-shape the scholar-adjudicator dialogue in interesting ways. Under the traditional approach towards ‘teachings’, the decision of whether, how and with whom to engage is firmly in the hands of the adjudicators. The proliferation of academic amicus briefs threatens to disrupt this arrangement. It also brings certain benefits: the briefs are often more ‘on point’ than doctrinal writings, while openness to unsolicited academic submissions encourages plurality and reduces reliance on reputation as a measure of scholarly quality. Our survey of the emerging practice across various international courts and tribunals indicates that adjudicators tend to be reticent when it comes to the reception of unsolicited academic amicus briefs, however, we identify several instances of productive engagement. This leads us to conclude that it would be unduly gloomy to characterize the emerging practice as a ‘dialogue of the deaf’. A fairer assessment would be that the academic amicus trend is bringing about a modest adjustment in the way that international law scholars and adjudicators engage with each other.
Topological stability criteria for networking dynamical systems with Hermitian Jacobian
Authors: DO A. L. , BOCCALETTI S. , EPPERLEIN J. , SIEGMUND S. , GROSS T.
Published: November 2016

The central theme of complex systems research is to understand the emergent macroscopic properties of a system from the interplay of its microscopic constituents. The emergence of macroscopic properties is often intimately related to the structure of the microscopic interactions. Here, we present an analytical approach for deriving necessary conditions that an interaction network has to obey in order to support a given type of macroscopic behaviour. The approach is based on a graphical notation, which allows rewriting Jacobi's signature criterion in an interpretable form and which can be applied to many systems of symmetrically coupled units. The derived conditions pertain to structures on all scales, ranging from individual nodes to the interaction network as a whole. For the purpose of illustration, we consider the example of synchronization, specifically the (heterogeneous) Kuramoto model and an adaptive variant. The results complete and extend the previous analysis of Do et al. (2012Phys. Rev. Lett.108, 194102).
What kind of archaeology do we want? Introduction
Authors: Ion Alexandra , Barrett John C.
Published: November 2016

Contemporary archaeology seems to be marked by a questioning of the limits of interpretation, pushing for a radical change in the way we conceptualize our engagement with the past, the material and the world we live in: from archaeologies of affect, to new materialist approaches or calls to political engagement, practitioners seem to experiment with new questions and theoretical tools. As Artur Ribeiro points out in his contribution to the following collection of papers, ‘“new” has become the new normal’. But the question is, what are we trying to do with these experiments and what do we expect from archaeology in a world that is undergoing major changes and challenges?
The body of the martyr. Between an archival exercise and the recovery of his suffering. The need for a recovery of humanity in osteoarchaeology
Authors: Ion Alexandra
Published: November 2016

This paper addresses the limits of the methods and questions asked by osteoarchaeologists when dealing with human remains. Osteoarchaeologists seem to take for granted that through the study of such remains they can say something relevant about a past individual's identity, something about the nature of their being. Since the early 1990s various voices have questioned these assumptions, also claiming that the study and display of human remains are unethical. It is my intention to rethink the topic of ethics in osteoarchaeology by shifting the focus to the research questions and methods we employ – what kind of evidence are we looking for and what kinds of relationship are we establishing with those earlier lives? By taking as a starting point the analysis of the remains of the Greek Catholic Bishop Vasile Aftenie, killed during the Communist regime, I explore the view practitioners take as the legitimate way of framing the relationship between past and present and the transformation of bones into scientific objects. In the end I propose that such a re-evaluation, alongside an opening of our discipline towards anthropology, can contribute to a recovery of humanity as part of the academic discourse, which should be the key element in any ethical discussion.
Heritage bureaucracies and the modern nation state. Towards an ethnography of archaeological systems of government
Authors: Plets Gertjan
Published: November 2016

Drawing on examples from the West (Flanders) and developing East (Siberia, Russia), this paper investigates the subtle and often overlooked entanglements between the nation state and archaeology. Drawing on careful ethnographic assessments mapping the impact of the state on archaeological practice in Russia and Flanders, this paper illustrates that we need to transcend our traditional focus on nationalism and also look at the impact of bureaucratic procedures and documents. These at first sight benign systems of government greatly enmesh archaeologists with the nation state and its myriad of agendas, ultimately impacting both heritage management and academic research.
End-of-life care decisions using a Korean advance directive among cancer patient–caregiver dyads
Authors: Kim Shinmi , Koh Sujin , Park Kwonoh , Kim Jinshil
Published: November 2016

Objective:

The Korean advance directive (K–AD) comprises a value statement, treatment directives, preferences for cardiopulmonary resuscitation (CPR), artificial ventilation, tube feeding, and hospice care, as well as a proxy appointment. The K–AD can facilitate a patient's decision making with respect to end-of-life (EoL) care. The present study aimed to examine the extent to which patient–caregiver dyads would use the K–AD and agree on EoL care decisions.

Methods:

Using a descriptive study design, 81 cancer patients were invited to participate. The final sample consisted of 44 patient–caregiver dyads who completed survey questionnaires, including the K–AD. One patient did not complete all parts of the questionnaire, and 36 (44.4%) declined to participate. Content analysis was conducted to examine the K–AD value statements. Cohen's kappa coefficient was calculated to determine the degree of patient–caregiver dyadic agreement on K–AD treatment directives (Sudore & Fried, 2010).

Results:

Our patient participants had the following cancer diagnoses: colorectal 29.5%, breast 29.5%, and liver/biliary tract cancers, 15.9%. Half of the sample had advanced-stage disease. Spouses (70.5%) or adult children (20.4%) were the primary caregivers, with perceived bonding rated as fair (31.8%) or good (65.9%). Rejection of the K–AD was mainly due to the difficulty involved in deciding on EoL care (50%). Comfort while dying was the most common theme expressed by patients (73.8%) and caregivers (66.7%). In terms of treatment directives, dyads advocated for hospice care (66.7%) and reduced support for aggressive treatments of CPR or artificial ventilation. The use of CPR (κ = 0.43, p = 0.004) and artificial ventilation (κ = 0.28, p = 0.046) showed significantly mild to moderate concordance among the dyads. Some 16 of the 21 dyads identified their spouses as a proxy, with others designating their adult children.

Significance of results:

The degree of patient–caregiver concordance on the K–AD seemed applicable, and achieved mild to moderate concordance. Our findings are exploratory but suggest the need for EoL discussions where patient–caregiver dyads are encouraged to participate in EoL care decision making.
Analysis of crop residue use in small holder mixed farms in Ethiopia
Authors: Alkhtib Ashraf , Wamatu Jane , Kassie Girma T , Rischkowsky Barbara
Published: November 2016

Determinants of the use of cereal and pulse residue for livestock feeding and soil mulching among smallholder farmers in the mixed farming system were analyzed. Crop residue (CR) is dual purpose resources in the mixed crop–livestock systems of the Ethiopian highlands. They serve as livestock feed and inputs for soil and water conservation. They are generated predominantly from cereals and pulses. However, in view of the allocation of CR, soil conservation and livestock are two competing enterprises. Identifying the determinants of the intensity of use of cereal and pulse residue may help in designing strategies for more efficient CR utilization. Data on CR were generated and its utilization was collected in two highland regions in Ethiopia from 160 households using a structured questionnaire. The data were analyzed using the multivariate Tobit model. Results of the study showed that farmers prefer using CR from pulses over CR from cereals for livestock feeding purposes. The proportion of CR from pulses that was used as feed was positively affected by education level of the farmer, livestock extension service, number of small ruminants and CR production from the previous season. Distance of farm plots from residences of the farm households negatively affected the proportions of cereal and pulse residue used for feed. The use of pulse residue increased significantly when the women participated in decision making on CR utilization. The proportion of cereal and pulse residue used for soil mulch was positively affected by the education level of the farmer, the distance between the homestead and the cultivated land, extension service, awareness about soil mulch, the slope of cultivated land, participation in farmer-to-farmer extension and CR generated in the preceding season. In view that pulse CR have better nutritive value compared with cereal CR, better utilization of CR could be achieved by maximizing the use of pulse residue as livestock feed and optimizing the use of cereal residue as soil mulch. More livestock extension on the nutritive value of pulse residue should be provided to the farmers who cultivate sloppy plots. Encouraging the culture of labor exchange among the farmers could result in increased labor availability in the farms that would facilitate the transport and storage of pulse residue and increase its use as livestock feed. Increasing the awareness among farmers about the superiority of the pulse residue over cereal residue as feed and encouraging use of cereal residue as soil mulch could optimize the utilization of CR in the household.
Gender Differences in Negative Campaigning: The Impact of Party Environments
Authors: Ennser-Jedenastik Laurenz , Dolezal Martin , Müller Wolfgang C.
Published: November 2016

How does gender affect the attack strategies of political actors? Do men and women diverge in their propensity to go negative and in their choice of targets? Extant research has long sought to shed light on these questions (e.g., Brooks 2010; Kahn 1993; Krupnikov and Bauer 2014; Proctor, Schenck-Hamlin, and Haase 1994; Walter 2013). Among all the possible determinants of attack behavior in elections, candidate gender has been one of the most “heavily studied” (Grossmann 2012, 2). However, the relevant research focuses almost exclusively on the United States and therefore on a system with candidate-centered campaigns, weak party organizations, and winner-takes-all competitions. Notwithstanding the importance of the USA as a case and exporter of campaign techniques, such context is specific and likely to bias the results. The few pioneering studies that examine the role of gender in negative campaigning outside the U.S. (Carlson 2001, 2007; Walter 2013) have addressed this question mostly by transferring the analytical framework of U.S.-based research to other political systems. Consequently, they have barely begun to incorporate the distinctive features of multiparty systems and strong party organizations as determinants of gender differences in attack behavior. The present article provides a novel argument about the role of party environments as a crucial context factor in party-centered political systems. Specifically we argue that in party-centered campaigns the gender balance within parties influences differences in the attack behavior of male and female politicians.
Computer- und Magnetresonanztomographie sowie EUS zur Diagnostik von Pankreastumoren
Authors: Stoupis Christoforos , Wiest Reiner
Published: November 2016

Zusammenfassung. Jede optimierte Therapie basiert auf einer bestmöglichen Diagnostik. Speziell für das Pankreas kommt dabei der Bildgebung ein hoher Stellenwert zu. Die Qualität der Diagnostik wird generell gemessen als diagnostische Genauigkeit, welche von einer Vielzahl an Faktoren abhängt. Der Anwender sollte mit diesen vertraut sein, um für die jeweiligen Fragestellungen und Patienten zum gegebenen Zeitpunkt die dafür am besten geeigneten Bildmodalitäten/-verfahren wählen zu können. Zur Verfügung stehen hierbei im Wesentlichen das Computertomogramm (CT), die Magnetresonanz-Tomographie (MRT) und der endoskopische Ultraschall (EUS). Diese Verfahren werden insbesondere in Hinblick auf die Diagnostik des Pankreaskarzinoms und mit besonderem Augenmerk auf Schwierigkeiten in der Differenzierung zur autoimmunen oder chronischen Pankreatitis vorgestellt und diskutiert.
Chirurgische und Interventionelle Behandlungsmöglichkeiten beim Adenokarzinom des Pankreas
Authors: Worni Mathias , Gloor Beat
Published: November 2016

Zusammenfassung. Bei nur einer Minderheit von 20 % der Patienten mit Pankreaskarzinom wird die Erkrankung in einem noch lokal begrenzten Stadium diagnostiziert, das eine primäre onkologisch radikale Resektion erlaubt, womit ein 5-Jahres Überleben von 20 bis 25 % erreicht wird. Aber auch bei sogenannt «borderline resectable» und «locally advanced» Befunden kann eine chirurgische Behandlung eventuell kombiniert mit intraoperativer irreversibler Electroporation in ausgewählten Situationen und im Rahmen von kombinierten Behandlungskonzepten eingesetzt werden, was die Prognose deutlich verbessert. In high-volume Zentren mit entsprechender Erfahrung können auch bei Tumoren mit begrenzter Infiltration der V.portae/V.mesenterica superior durch Venenresektion und -rekonstruktion radikale Resektionen erreicht werden.
Moderne Therapie bei chronischer Pankreatitis
Authors: Angst Eliane , Malinka Thomas
Published: November 2016

Zusammenfassung. Die chronisch rezidivierenden Entzündungsschübe führen zu einem progredienten fibrotischen Umbau des Pankreasgewebes. Leitsymptom sind Schmerzen! Mögliche Folgen sind Gangstrikturen, Pankreassteine, Pseudozysten, entzündliche Schwellung (Pseudotumor) des Pankreaskopfes und Hypertrophie der vegetativen Nerven. Ziel der Therapie ist, Symptome zu lindern und Komplikationen zu behandeln. Die konservative Therapie umfasst die Schmerztherapie nach WHO-Stufenschema, Ernährung, Enzym-Substitution und die Supplementierung fettlöslicher Vitamine. Dank Fortschritten der endoskopisch interventionellen Möglichkeiten werden viele Patienten nicht primär vom Chirurgen gesehen. Ein frühes interdisziplinäres Therapiekonzept ist aber entscheidend, denn trotz häufiger endoskopischer Re-Interventionen benötigt eine Mehrheit der Patienten eine chirurgische Therapie. Endoskopische Therapien kommen bei nicht operablen Patienten und als primäre Therapie von alleinigen Gangstenosen und Pseudozysten in Frage. Chirurgische Therapien sind eine gute Option bei Nicht-Ansprechen der endoskopischen Therapien nach spätestens einem Jahr, Gallengangs- und Duodenalstenosen, infizierten Pseudozysten mit soliden Anteilen, Pseudotumoren, Tumorverdacht und obstruierenden Verkalkungen im Pankreaskopf.
Anaphylaxie im Kindes- und Jugendalter
Authors: Kerr Ute , Köhli Alice
Published: November 2016

Zusammenfassung. Die Anaphylaxie als schwerwiegendste Manifestation einer in der Regel allergischen Soforttypreaktion stellt eine potenziell lebensbedrohliche Notfallsituation dar, mit der jeder Arzt auch in der Praxis konfrontiert sein kann. Durch steigende Prävalenzzahlen gewinnt das Thema zunehmend an Bedeutung. Im folgenden Artikel beschreiben wir Auslöser, Klinik, diagnostische Hilfsmittel, Risiko- und Augmentationsfaktoren sowie medikamentöse Therapie in dieser Altersgruppe und klären die Frage, welchem Patienten Sie einen Adrenalinautoinjektor rezeptieren sollen. Daten zur Beeinträchtigung der Lebensqualität nach durchgemachter Anaphylaxie zeigen, wie wichtig die weitere Betreuung nach dem Akutereignis ist. Diagnostik zur Klärung des Auslösers, aber vor allem auch Schulung zur Selbsthilfe und Abgabe eines individualisierten Behandlungsplans können die Situation für die Betroffenen und deren Eltern vereinfachen.
Ungewöhnliche Ursache einer einseitigen schmerzhaften Wadenschwellung als Differenzialdiagnose einer tiefen Beinvenenthrombose
Authors: Jäckel Kristian , Knechtle Beat
Published: November 2016

Zusammenfassung. Wir berichten über einen 54-jährigen Mann, der sich wegen einer schmerzhaften Wadenschwellung notfallmässig in der Sprechstunde meldete. Der initiale Verdacht auf eine tiefe Venenthrombose konnte nicht bestätigt werden, es zeigte sich ein Hämatom in der Muskulatur der Wade. Die genaue Anamnese ergab, dass das Hämatom durch die Anwendung einer extrakorporalen Stosswellentherapie durch den Physiotherapeuten iatrogen bedingt war.
Reilinger Receives 2016 Paul G. Silver Award for Outstanding Scientific Service
Authors:   AGU
Published: November 2016

Robert Reilinger will receive the 2016 Paul G. Silver Award for Outstanding Scientific Service at the 2016 American Geophysical Union Fall Meeting, to be held 12–16 December in San Francisco, Calif. The award recognizes outstanding contributions to the fields of geodesy, seismology, or tectonophysics through mentoring of junior colleagues, leadership of community research initiatives, or other forms of unselfish collaboration in research.
Coeliac disease: a unique model for investigating broken tolerance in autoimmunity
Authors: Hardy Melinda Y , Tye‐Din Jason A
Published: November 2016

Coeliac disease, a prevalent immune‐mediated enteropathy driven by dietary gluten, provides an exceptional human model to dissect the genetic, environmental and immunologic factors operating in autoimmunity. Despite the causative antigen being an exogenous food protein, coeliac disease has many features in common with autoimmune disease including a strong HLA class II association and the presence of pathogenic CD4+ T cells and autoantibodies. CD8+ intraepithelial lymphocytes specifically target and destroy intestinal epithelium in response to stress signals and not a specific antigen. A unique feature of coeliac disease is the ability to remove gluten to induce disease remission and reintroduce it to trigger a memory response. This provides an unparalleled opportunity to study disease‐relevant CD4+ T cells that have been expanded in vivo. As a result, the causative peptides have been characterised at a level unprecedented for any autoimmune disease. Despite the complexity of the gluten proteome, resistance to gastrointestinal proteolysis and susceptibility to post‐translational modification by transglutaminase help shape a restricted repertoire of immunogenic gluten peptides that have high affinity for disease‐associated HLA. The critical steps in coeliac disease pathogenesis have been broadly elucidated and provide the basis for experimental therapies in pre‐clinical or clinical development. However, little is known about how and why tolerance to gluten sometimes breaks or fails to develop. Understanding the interactions between genes, the environment, gluten immunity and the microbiome may provide novel approaches for the prevention and treatment of disease.
A structure‐function approach to optimizing TLR4 ligands for human vaccines
Authors: Carter Darrick , Fox Christopher B , Day Tracey A , Guderian Jeffrey A , Liang Hong , Rolf Tom , Vergara Julie , Sagawa Zachary K , Ireton Greg , Orr Mark T , Desbien Anthony , Duthie Malcolm S , Coler Rhea N , Reed Steven G
Published: November 2016

Adjuvants are combined with vaccine antigens to enhance and modify immune responses, and have historically been primarily crude, undefined entities. Introducing toll‐like receptor (TLR) ligands has led to a new generation of adjuvants, with TLR4 ligands being the most extensively used in human vaccines. The TLR4 crystal structures demonstrate extensive contact with their ligands and provide clues as to how they discriminate a broad array of molecules and activate or attenuate innate, as well as adaptive, responses resulting from these interactions. Leveraging this discerning ability, we made subtle chemical alterations to the structure of a synthetic monophosphoryl lipid‐A molecule to produce SLA, a designer TLR4 ligand that had a number of desirable adjuvant effects. The SLA molecule stimulated human TLR4 and induced Th1 biasing cytokines and chemokines. On human cells, the activity of SLA plateaued at lower concentrations than the lipid A comparator, and induced cytokine profiles distinct from other known TLR4 agonists, indicating the potential for superior adjuvant performance. SLA was formulated in an oil‐in‐water emulsion, producing an adjuvant that elicited potent Th1‐biased adaptive responses. This was verified using a recombinant Leishmania vaccine antigen, first in mice, then in a clinical study in which the antigen‐specific Th1‐biased responses observed in mice were recapitulated in humans. These results demonstrated that using structure‐based approaches one can predictably design and produce modern adjuvant formulations for safe and effective human vaccines.
Non‐small cell lung cancer is characterised by a distinct inflammatory signature in serum compared with chronic obstructive pulmonary disease
Authors: Eide Hanne Astrid , Halvorsen Ann Rita , Sandhu Vandana , Fåne Anne , Berg Janna , Haakensen Vilde Drageset , Kure Elin H , Brustugun Odd Terje , Kiserud Cecilie Essholt , Kyte Jon Amund , Helland Åslaug
Published: November 2016

Development of lung cancer is closely related to smoking in a majority of patients. Most smokers, however, do not develop lung cancer in spite of a high mutational load accumulating in the lung tissue. Here we investigate whether a cancer‐specific footprint can be revealed by investigating circulating inflammatory markers in patients with non‐small cell lung cancer (NSCLC) compared with patients with chronic obstructive pulmonary disease (COPD), both cohorts characterised by similar smoking history. Serum concentrations of 57 cytokines and matrix metalloproteinases (MMPs) from 43 patients with advanced NSCLC were evaluated by multiplex immunoassays and compared with serum samples from 35 patients with COPD. Unsupervised hierarchical clustering and non‐parametric analyses were performed. False discovery rate was used to adjust for multiple testing. Clustering of cytokine and MMP concentrations in the serum revealed a distinct separation of the NSCLC patients from the COPD group. Individual concentrations of thymus and activation‐regulated cytokine (C‐C motif chemokine ligand 17), Gro‐b (C‐X‐C motif chemokine ligand 2 (CXCL2)), CXCL13, interleukin (IL)‐1ra, IL‐6, IL‐8 (CXCL8), IL‐16, IL‐17A, macrophage migration inhibitory factor (MIF), granulocyte colony‐stimulating factor, platelet‐derived growth factor subunit B, MMP‐2, MMP‐8 and MMP‐12 were significantly different in serum from NSCLC and COPD patients. Moreover, the interferon‐γ/IL‐10 ratio was lower in cancer patients compared with COPD patients, consistent with a cytokine milieu favouring tumour tolerance. Our results suggest that NSCLC is characterised by a distinct inflammatory signature in serum. The different cytokine profiles in NSCLC and COPD patients may represent tumour‐promoting and tumour‐suppressing immune responses developing in response to mucosal inflammation and mutations induced by smoking.
Tetrapod limb and sarcopterygian fin regeneration share a core genetic programme
Authors: Nogueira Acacio F. , Costa Carinne M. , Lorena Jamily , Moreira Rodrigo N. , Frota-Lima Gabriela N. , Furtado Carolina , Robinson Mark , Amemiya Chris T. , Darnet Sylvain , Schneider Igor
Published: November 2016

Salamanders are the only living tetrapods capable of fully regenerating limbs. The discovery of salamander lineage-specific genes (LSGs) expressed during limb regeneration suggests that this capacity is a salamander novelty. Conversely, recent paleontological evidence supports a deeper evolutionary origin, before the occurrence of salamanders in the fossil record. Here we show that lungfishes, the sister group of tetrapods, regenerate their fins through morphological steps equivalent to those seen in salamanders. Lungfishde novotranscriptome assembly and differential gene expression analysis reveal notable parallels between lungfish and salamander appendage regeneration, including strong downregulation of muscle proteins and upregulation of oncogenes, developmental genes and lungfish LSGs. MARCKS-like protein (MLP), recently discovered as a regeneration-initiating molecule in salamander, is likewise upregulated during early stages of lungfish fin regeneration. Taken together, our results lend strong support for the hypothesis that tetrapods inherited abona fidelimb regeneration programme concomitant with the fin-to-limb transition.
Turmeric powder and its derivatives from Curcuma longa rhizomes: Insecticidal effects on cabbage looper and the role of synergists
Authors: de Souza Tavares Wagner , Akhtar Yasmin , Gonçalves Gabriel Luiz Padoan , Zanuncio José Cola , Isman Murray B.
Published: November 2016

Curcuma longa has well-known insecticidal and repellent effects on insect pests, but its impact on Trichoplusia ni is unknown. In this study, the compound ar-turmerone, extracted and purified from C. longa rhizomes, was identified and its insecticidal effects, along with turmeric powder, curcuminoid pigments and crude essential oil were evaluated against this important agricultural pest. The role of natural (sesamol and piperonal) and synthetic [piperonyl butoxide (PBO)] synergists under laboratory and greenhouse conditions were also evaluated. The concentration of ar-turmerone in C. longa rhizomes harvested was 0.32% (dwt). Turmeric powder and its derivatives caused 10–20% mortality in third instar T. ni at a very low dose (10 μg/larva). Addition of PBO increased toxicity of turmeric powder and its derivatives (90–97% mortality) in most binary combinations (5 μg of turmeric powder or its derivatives +5 μg of PBO), but neither piperonal nor sesamol were active as synergists. The compound ar-turmerone alone and the combination with PBO reduced larval weight on treated Brassica oleracea in the laboratory and in greenhouse experiments, compared with the negative control. The compound ar-turmerone could be used as a low cost botanical insecticide for integrated management of cabbage looper in vegetable production.
Regulation of RNA-binding proteins affinity to export receptors enables the nuclear basket proteins to distinguish and retain aberrant mRNAs
Authors: Soheilypour M. , Mofrad M. R. K.
Published: November 2016

Export of messenger ribonucleic acids (mRNAs) into the cytoplasm is a fundamental step in gene regulation processes, which is meticulously quality controlled by highly efficient mechanisms in eukaryotic cells. Yet, it remains unclear how the aberrant mRNAs are recognized and retained inside the nucleus. Using a new modelling approach for complex systems, namely the agent-based modelling (ABM) approach, we develop a minimal model of the mRNA quality control (QC) mechanism. Our results demonstrate that regulation of the affinity of RNA-binding proteins (RBPs) to export receptors along with the weak interaction between the nuclear basket protein (Mlp1 or Tpr) and RBPs are the minimum requirements to distinguish and retain aberrant mRNAs. Our results show that the affinity between Tpr and RBPs is optimized to maximize the retention of aberrant mRNAs. In addition, we demonstrate how the length of mRNA affects the QC process. Since longer mRNAs spend more time in the nuclear basket to form a compact conformation and initiate their export, nuclear basket proteins could more easily capture and retain them inside the nucleus.
Inhomogeneous ensembles of radical pairs in chemical compasses
Authors: Procopio Maria , Ritz Thorsten
Published: November 2016

The biophysical basis for the ability of animals to detect the geomagnetic field and to use it for finding directions remains a mystery of sensory biology. One much debated hypothesis suggests that an ensemble of specialized light-induced radical pair reactions can provide the primary signal for a magnetic compass sensor. The question arises what features of such a radical pair ensemble could be optimized by evolution so as to improve the detection of the direction of weak magnetic fields. Here, we focus on the overlooked aspect of the noise arising from inhomogeneity of copies of biomolecules in a realistic biological environment. Such inhomogeneity leads to variations of the radical pair parameters, thereby deteriorating the signal arising from an ensemble and providing a source of noise. We investigate the effect of variations in hyperfine interactions between different copies of simple radical pairs on the directional response of a compass system. We find that the choice of radical pair parameters greatly influences how strongly the directional response of an ensemble is affected by inhomogeneity.
A murine model of early Pseudomonas aeruginosa lung disease with transition to chronic infection
Authors: Bayes H. K. , Ritchie N. , Irvine S. , Evans T. J.
Published: November 2016

Pseudomonas aeruginosa (PA) remains an important pathogen in patients with cystic fibrosis (CF) lung disease as well as non-CF bronchiectasis and chronic obstructive airways disease. Initial infections are cleared but chronic infection with mucoid strains ensues in the majority of CF patients and specific interventions to prevent this critical infection transition are lacking. The PA bead model has been widely used to study pulmonary P.aeruginosa infection but has limitations in animal husbandry and in accurately mimicking human disease. We have developed an adapted agar bead murine model using a clinical mucoid strain that demonstrates the key features of transition from transitory to chronic airways infection. Infected animals show very limited acute morbidity and mortality, but undergo infection-related weight loss and neutrophilic inflammation, development of anti-pseudomonal antibodies, variable bacterial clearance, endobronchial infection and microbial adaptation with PA small colony variants. We anticipate this model will allow research into the host and microbial factors governing this critical period in Pseudomonas aeruginosa pulmonary pathogenesis when transition to chronicity is occurring.
Subdiffusion in Membrane Permeation of Small Molecules
Authors: Chipot Christophe , Comer Jeffrey
Published: November 2016

Within the solubility–diffusion model of passive membrane permeation of small molecules, translocation of the permeant across the biological membrane is traditionally assumed to obey the Smoluchowski diffusion equation, which is germane for classical diffusion on an inhomogeneous free-energy and diffusivity landscape. This equation, however, cannot accommodate subdiffusive regimes, which have long been recognized in lipid bilayer dynamics, notably in the lateral diffusion of individual lipids. Through extensive biased and unbiased molecular dynamics simulations, we show that one-dimensional translocation of methanol across a pure lipid membrane remains subdiffusive on timescales approaching typical permeation times. Analysis of permeant motion within the lipid bilayer reveals that, in the absence of a net force, the mean squared displacement depends on time ast0.7, in stark contrast with the conventional model, which assumes a strictly linear dependence. We further show that an alternate model using a fractional-derivative generalization of the Smoluchowski equation provides a rigorous framework for describing the motion of the permeant molecule on the pico- to nanosecond timescale. The observed subdiffusive behavior appears to emerge from a crossover between small-scale rattling of the permeant around its present position in the membrane and larger-scale displacements precipitated by the formation of transient voids.
INO80 is Required for Osteogenic Differentiation of Human Mesenchymal Stem Cells
Authors: Zhou Chenchen , Zou Jing , Zou Shujuan , Li Xiaobing
Published: November 2016

Bone marrow derived human mesenchymal stem cells (MSC) are a great source in bone tissue engineering. However, how to improve the efficiency of MSC osteogenesis remains a big challenge in bone regenerative medicine. Here, we characterized the role of INO80 chromatin remodeling complex in osteogenic differentiation of MSC. We showed that silencing of subunits of INO80 reduced the mineral deposition of MSC in osteogenic condition. Moreover, INO80-silencing MSC cultured in osteogenic condition expressed lower mRNA levels of osteoblast-specific genes, including Runx2, Osx, Col1α1 and OCN. INO80 can interact with Wdr5 in MSC and positively regulates the canonical Wnt signaling transduction. Importantly, the mice implanted with INO80-silencing MSC displayed less bone formation. Overall, our study provides a new mechanism regarding osteogenic differentiation of MSC and could potentially be applied in clinical tissue engineering and treatment of osteoporosis.
Overexpression of soluble RAGE in mesenchymal stem cells enhances their immunoregulatory potential for cellular therapy in autoimmune arthritis
Authors: Park Min-Jung , Lee Seung Hoon , Moon Su-Jin , Lee Jung-Ah , Lee Eun-Jung , Kim Eun-Kyung , Park Jin-Sil , Lee Jennifer , Min Jun-Ki , Kim Seok Jung , Park Sung-Hwan , Cho Mi-La
Published: November 2016

Mesenchymal stem cells (MSCs) are attractive agents for cellular therapy in rheumatoid arthritis (RA). The receptor for advanced glycation end products (RAGE) serves as a pattern recognition receptor for endogenous inflammatory ligands. Soluble RAGE (sRAGE) is a truncated form of RAGE that functions as a decoy and acts as an anti-inflammatory molecule. The aim of this study was to determine whether sRAGE has therapeutic effects and the mechanisms active in sRAGE-overexpressing MSCs (sRAGE-MSCs) in an experimental model of RA. sRAGE-MSCs were generated by DNA transfection of human adipose tissue-derived MSCs (Ad-hMSCs). MSCs showed increased expression of VEGF, IL-1β, IL-6, and HMGB-1 under inflammatory conditions. However, sRAGE-MSCs showed significantly lower production of these proinflammatory molecules. Expression of immunomodulatory molecules such as IL-10, TGF-β, and indoleamine 2, 3-dioxygenase was higher in sRAGE-MSCs than in mock-MSCs. sRAGE-MSCs showed enhanced migration potential. Transplantation of sRAGE-MSCs into arthritic IL-1Ra-knockout mice markedly suppressed inflammatory arthritis, decreased Th17 cells, and reciprocally increased regulatory T cells. The differentiation of IFN-γ+CD4+ and IL-17+CD4+ cells was inhibited by incubation with sRAGE-MSCs compared with mock-MSCs. These findings suggest that sRAGE overexpression in Ad-hMSCs optimizes their immunoregulatory properties, which may be useful as a novel cellular therapy for RA.
DPDR-CPI, a server that predicts Drug Positioning and Drug Repositioning via Chemical-Protein Interactome
Authors: Luo Heng , Zhang Ping , Cao Xi Hang , Du Dizheng , Ye Hao , Huang Hui , Li Can , Qin Shengying , Wan Chunling , Shi Leming , He Lin , Yang Lun
Published: November 2016

The cost of developing a new drug has increased sharply over the past years. To ensure a reasonable return-on-investment, it is useful for drug discovery researchers in both industry and academia to identify all the possible indications for early pipeline molecules. For the first time, we propose the term computational “drug candidate positioning” or “drug positioning”, to describe the above process. It is distinct from drug repositioning, which identifies new uses for existing drugs and maximizes their value. Since many therapeutic effects are mediated by unexpected drug-protein interactions, it is reasonable to analyze the chemical-protein interactome (CPI) profiles to predict indications. Here we introduce the server DPDR-CPI, which can make real-time predictions based only on the structure of the small molecule. When a user submits a molecule, the server will dock it across 611 human proteins, generating a CPI profile of features that can be used for predictions. It can suggest the likelihood of relevance of the input molecule towards ~1,000 human diseases with top predictions listed. DPDR-CPI achieved an overall AUROC of 0.78 during 10-fold cross-validations and AUROC of 0.76 for the independent validation. The server is freely accessible via http://cpi.bio-x.cn/dpdr/.
Microbial community dynamics in the rhizosphere of a cadmium hyper-accumulator
Authors: Wood J. L. , Zhang C. , Mathews E. R. , Tang C. , Franks A. E.
Published: November 2016

Phytoextraction is influenced by the indigenous soil microbial communities during the remediation of heavy metal contaminated soils. Soil microbial communities can affect plant growth, metal availability and the performance of phytoextraction-assisting inocula. Understanding the basic ecology of indigenous soil communities associated with the phytoextraction process, including the interplay between selective pressures upon the communities, is an important step towards phytoextraction optimization. This study investigated the impact of cadmium (Cd), and the presence of a Cd-accumulating plant, Carpobrotus rossii (Haw.) Schwantes, on the structure of soil-bacterial and fungal communities using automated ribosomal intergenic spacer analysis (ARISA) and quantitative PCR (qPCR). Whilst Cd had no detectable influence upon fungal communities, bacterial communities underwent significant structural changes with no reduction in 16S rRNA copy number. The presence of C. rossii influenced the structure of all communities and increased ITS copy number. Suites of operational taxonomic units (OTUs) changed in abundance in response to either Cd or C. rossii, however we found little evidence to suggest that the two selective pressures were acting synergistically. The Cd-induced turnover in bacterial OTUs suggests that Cd alters competition dynamics within the community. Further work to understand how competition is altered could provide a deeper understanding of the microbiome-plant-environment and aid phytoextraction optimization.
Increasing trend of diabetes combined with hypertension or hypercholesterolemia: NHANES data analysis 1999–2012
Authors: Song Yongfeng , Liu Xiaoyun , Zhu Xiaolin , Zhao Bin , Hu Bo , Sheng Xia , Chen Lan , Yu Miao , Yang Tao , Zhao Jiajun
Published: November 2016

In order to prevent cardiovascular endpoints, control of diabetes, hypertension and hypercholesterolemia is a necessity as those risk factors frequently occur in combination. Prevalence trends of concurrent diabetes, hypertension and hypercholesterolemia in 36,673 subjects were obtained from the National Health and Nutrition Examination Survey (NHANES) from 1999–2012. The prevalence of concurrent diabetes, hypertension and hypercholesterolemia increased from 3% in 1999–2000 to 6.3% in 2011–2012 (P < 0.001). The diabetes with concurrent hypertension or hypercholesterolemia incidences also increased significantly, while the occurrence of concurrent hypertension and hypercholesterolemia was stable over the study period. Overall medical drug treatments for concurrent diabetes, hypertension, hypercholesterolemia were improved from 69.8% in 1999–2006, to 82.4% in 2007–2012 (P = 0.002). Treatment cost coverage rates in any combinations with diabetes were 79–82.4% and 90.7% in the subgroup of concurrent hypertension and hypercholesterolemia. General treatment goal achievement rates were <25%, the lowest rate being 14.2% in the subject groups with three combined risk factors. The treatment goal achievement rates in two subgroups with concurrent diabetes were 20.1% (with hypertension) and 17% (with hypercholesterolemia) and 24.5% in the group without diabetes. Cost coverage improved in all combinations, but the general treatment goal achievement rates were low, especially in the groups with concurrent diabetes.