bluuebunny/crossref_metadata_2025 huggingface dataset:
The confluence area of Rhine, Meuse, and Belgian rivers: Late Pliocene and Early Pleistocene fluvial history of the northern Lower Rhine Embayment
Authors: Westerhoff W.E. , Kemna H.A. , Boenigk W.
Published: April 2016

The fluvial history of the northern Lower Rhine Embayment shows interplay of three main river systems: Rhine, Meuse and smaller rivers draining the central and northern part of Belgium.

The Pliocene and Early Pleistocene (pre-)Rhine and Meuse river systems had their conjunction in the southern part of the Roer Valley Graben between Aachen and Jülich. Despite slight differences in the heavy-mineral assemblages the lithological composition of the Pliocene deposits of the three river systems shows close resemblance and therefore they cannot be mapped separately. However, due to a marked change of the petrographical composition the Upper Pliocene and Lower Pleistocene deposits of the Rhine are easily recognised and as a result Rhine and Meuse deposits can be mapped separately upstream of their confluence.

The Lower Pleistocene deposits of Rhine, Meuse and the Belgian rivers show a clear interrelationship. They are bounded by two regional well-mapable unconformities and are preserved in from west to east changing lithostratigraphical sequences. Revision of the lithostratigraphical schemes in Germany and the Netherlands and the better defined lithostratigraphical position of Meuse deposits in Germany now strongly constrain the correlation of the various fluvial deposits. As a result existing reconstructions of the fluvial deposition and tectonic history of the southern Roer Valley Graben can be evaluated and re-adjusted.

It is concluded that the main course of the Meuse was aligned through the so-called East Meuse valley during the larger part of the Early Pleistocene. Available pollen data do not conflict with this conclusion. At the same time the Rhine ceased to enter the southern part of the Roer Valley Graben. Instead, the Meuse accumulated here a series of deposits derived from the East-Meuse valley. Simultaneously, the Belgian rivers filled available accommodation space in the Roer Valley Graben of the southern Netherlands. The conclusions are based primarily on the revised lithostratigraphical framework. In general they simplify the picture of fluvial and tectonic behaviour of the area.
Oil and Democracy: Endogenous Natural Resources and the Political “Resource Curse”
Authors: Brooks Sarah M. , Kurtz Marcus J.
Published: April 2016

By the end of the twentieth century, a scholarly consensus emerged around the idea that oil fuels authoritarianism and slow growth. The natural abundance once thought to be a blessing was unconditionally, and then later only conditionally, a curse for political and economic development. We re-examine the relationship between oil wealth and political regimes, challenging the conventional wisdom that such natural resource rents lead to authoritarian outcomes. We contend that most efforts to examine the causal linkages between natural resource abundance and political regime have been complicated by the likelihood that both democracy and oil revenue are endogenous to the industrialization processes itself, particularly in its developmentalist form. Our quantitative results, based on an analysis of global data from 1970 to 2006, show that both resource endogeneity and several mechanisms of intraregional regime diffusion are powerful determinants of democratic outcomes. Qualitative evidence from the history of industrialization in Latin America yields support for our proposed causal claim. Oil wealth is not necessarily a curse and may even be a blessing with respect to democratic development.
A diachronic investigation of the vowels and fricatives in Korean: An acoustic comparison of the Seoul and South Kyungsang dialects
Authors: Lee Hyunjung , Jongman Allard
Published: April 2016

Although the segmental properties of Kyungsang Korean have been known to be distinct from those of standard Seoul Korean, the increased influence of Seoul Korean on the regional variety casts doubt on the homogeneity of the dialect. The current study investigated whether the acoustic properties of the vowels and fricatives in Kyungsang Korean are retained by both younger and older generations through a comparison with Seoul Korean. Results of acoustic analyses with 38 female Korean speakers differing in dialect (Kyungsang, Seoul) and age (older, younger) showed that the younger Kyungsang speakers did not maintain the vowel and fricative features unique to their regional dialect, but rather approximate those of standard Seoul Korean. In the acoustic study of vowels, measures of formant frequencies showed that the younger Kyungsang and Seoul speakers share seven vowels, which result from the split of /ʌ/–/ɨ/ in Kyungsang and the merger of /e/–/ε/ in Seoul Korean. In the acoustic study of fricatives, measures of fricative duration and center of gravity showed that while the two-way fricative contrast is less distinct for older Kyungsang speakers, younger speakers clearly distinguish the two fricatives similar to Seoul speakers. As a consequence of these generational changes in Kyungsang Korean, the six vowels and lack of a fricative contrast exhibited by older generations have given way to seven vowels and a clear distinction between fortis and non-fortis fricatives for younger generations. Based on the similarities in segmental properties between younger Kyungsang and Seoul speakers, it appears that the diachronic sound change is underway in South Kyungsang Korean under the influence of Seoul Korean.
Setswana (South African)
Authors: Bennett Wm. G. , Diemer Maxine , Kerford Justine , Probert Tracy , Wesi Tsholofelo
Published: April 2016

Setswana (also known as ‘Tswana’ or, more archaically, ‘Chuana’ or ‘Sechuana’) is a Bantu language (group S.30; ISO code tsn) spoken by an estimated four million people in South Africa. There are a further one million or more speakers in Botswana, where it is the dominant national language, and a smaller number of speakers in Namibia. The recordings accompanying this article were mostly produced with a 21-year-old male speaker from the area of Taung, North-West province, South Africa. Some of the accompanying recordings are of a 23-year-old female speaker from Kuruman (approximately 150 km west of Taung). The observations reported here are based on consulting with both these speakers, as well as a third speaker, from Kimberley. All three were speakers of South African Setswana varieties. For discussion of some differences between these varieties and more Northern and Eastern Setswana dialects – including those spoken in Botswana – see (Doke 1954, Cole 1955, University of Botswana 2001).
Note from the Editors
Authors: Hansson Gunnar Ólafur , Julien Marit , Miestamo Matti
Published: April 2016

This is the first issue of volume 39 of the Nordic Journal of Linguistics. NJL is the journal of the Nordic Association of Linguists. Individuals may subscribe to the Journal by joining the Nordic Association of Linguists. The NAL membership form can be found on the Cambridge University Press web site of NJL, http://journals.cambridge.org/NJL, as well as on the NAL web site, http://www.uef.fi/nal.
The Seven Ways to Find Heading
Authors: Gade Kenneth
Published: April 2016

A magnetic compass has too large a heading error for many applications, and it is often not obvious how to achieve an accurate heading, in particular for low-cost navigation systems. However, there are several different methods available for finding heading, and their feasibility depends on the given scenario. Some of the methods may seem very different, but they can all be related and categorised into a list by studying the vector that each method is using when achieving heading. A list of possible methods is very useful when ensuring that all relevant methods are being considered for a given application. For practical navigation, we have identified seven different vectors in use for heading estimation, and we define seven corresponding methods. The methods are magnetic and gyrocompass, two methods based on observations, multi-antenna Global Navigation Satellite Systems (GNSS), and two methods based on vehicle motion.
An Improved Geometry-free Three Carrier Ambiguity Resolution Method for the BeiDou Navigation Satellite System
Authors: Wang Xing , Liu Wenxiang , Sun Guangfu
Published: April 2016

BeiDou satellites transmit triple-frequency signals, which bring substantial benefits to carrier phase Ambiguity Resolution (AR). The traditional geometry-free model Three-Carrier Ambiguity Resolution (TCAR) method looks for a suitable combination of carrier phase and code-range observables by searching and comparing in the integer range, which limits the AR success probability. By analysing the error characteristics of the BeiDou triple-frequency observables, we introduce a new procedure to select the optimal combination of carrier phase and code observables to resolve the resolution of Extra-Wide-Lane (EWL) and Wide-Lane (WL) ambiguity. We also investigate a geometry-free and ionosphere-eliminated method for AR of the Medium-Lane (ML) and Narrow-Lane (NL) observables. In order to evaluate the performance of the improved TCAR method, real BeiDou triple-frequency observation data for different baseline cases were collected and processed epoch-by-epoch. The results show that the improved geometry-free TCAR method increases the single epoch AR success probability by up to 90% for short baseline and 80% for long baseline. The A perfect (100%) AR success probability can also be effortlessly achieved by averaging the float ambiguities over just tens of epochs.
Mapping the Scope of Dispute Settlement in Regional Trade Agreements: Implications for the Multilateral Governance of Trade
Authors: FROESE MARC D.
Published: April 2016

This article argues that the inclusion of provisions for the settlement of disputes in regional trade agreements enhances, rather than disrupts, the centrality of the World Trade Organization's dispute settlement system. Using a dataset that organizes exclusion clauses and special provisions for dispute settlement in regional trade agreements, the study develops a thematic typology that is used to examine the ways that disputes may be channelled between regional and multilateral dispute settlement institutions. This comparative empirical dimension offers a more accurate picture of the global contours of regionalization as they relate to the juridical aspects of trade governance, suggesting that the decentralization of dispute settlement inferred by the rapid development of regional bodies has been overstated.
RIGID ORBITS AND SHEETS IN REDUCTIVE LIE ALGEBRAS OVER FIELDS OF PRIME CHARACTERISTIC
Authors: Premet Alexander , Stewart David I.
Published: April 2016

Let$G$be a simple simply connected algebraic group over an algebraically closed field$k$of characteristic$p>0$with$\mathfrak{g}=\text{Lie}(G)$. We discuss various properties of nilpotent orbits in$\mathfrak{g}$, which have previously only been considered over$\mathbb{C}$. Using computational methods, we extend to positive characteristic various calculations of de Graaf with nilpotent orbits in exceptional Lie algebras. In particular, we classify those orbits which are reachable as well as those which satisfy a certain related condition due to Panyushev, and determine the codimension of the derived subalgebra$[\mathfrak{g}_{e},\mathfrak{g}_{e}]$in the centraliser$\mathfrak{g}_{e}$of any nilpotent element$e\in \mathfrak{g}$. Some of these calculations are used to show that the list of rigid nilpotent orbits in$\mathfrak{g}$, the classification of sheets of$\mathfrak{g}$and the distribution of the nilpotent orbits amongst them are independent of good characteristic, remaining the same as in the characteristic zero case. We also give a comprehensive account of the theory of sheets in reductive Lie algebras over algebraically closed fields of good characteristic.
TRUNCATED BARSOTTI–TATE GROUPS AND DISPLAYS
Authors: Lau Eike , Zink Thomas
Published: April 2016

We define truncated displays over rings in which a prime $p$ is nilpotent, we associate crystals to truncated displays, and we define functors from truncated displays to truncated Barsotti–Tate groups.
In Pursuit of a Single Flame? On Schubert’s Settings of Goethe’s Poems
Authors: Bodley Lorraine Byrne
Published: April 2016

Much musicological and historicist criticism has tended to ‘flatten’ Goethe by confining him to the thought-clichés of his time, and this in turn has led to an implicitly patronizing view of him as musically conservative. This article will show how Goethe proves again and again to be more musically intelligent and perceptive than scholars have given him credit for. Certain musicological questions engross the poet throughout his life: the nature of major and minor tonalities; musical identity throughout the ages; music and text; the rhetoric of attentive listening; musical language and its capacity to occlude and exclude. Yet Goethe’s thought, this article demonstrates, is anything but static; his writings keep returning to, modifying and complicating his musical preoccupations.

This article challenges the salient misconception that Goethe’s lack of musical judgement divorced him from the development of the nineteenth-century Lied and that Schubert’s settings ran counter to the poet’s intent. Two new readings of ‘Wandrers Nachtlied’ and ‘Erster Verlust’ show how Schubert is listening to the poetry and the upshot is not a song that reflects the poem but one that reflects on it.
A compact CPW-fed wideband metamaterial-inspired antenna for GSM, WLAN/Wi-Fi, and WiMAX applications
Authors: Gupta Ashish , Chaudhary Raghvendra Kumar
Published: April 2016

A compact coplanar waveguide (CPW)-fed wideband metamaterial-inspired antenna is designed and developed in this paper. The proposed structure is an asymmetric structure in which three rectangular stubs are employed between signal patch and CPW ground plane. It is demonstrated that these stubs provides lumped parameters of conventional epsilon-negative transmission line (ENG-TL). As an advantage of these stubs proposed antenna operates on 1.67–2.76 GHz with −10 dB impedance bandwidth of 49.2%. The proposed antenna having small electrical size of 0.17λ0 × 0.35λ0 × 0.01λ0 at fo = 2.21 GHz. The simulated average gain and radiation efficiency of the proposed antenna is 1.61 dB and 96.33% respectively throughout the bandwidth. Properties such as smaller electrical size, simpler design, consistent radiation characteristics, and ease of fabrication are making this antenna suitable for GSM, WLAN/Wi-Fi, Bluetooth, and WiMAX applications.
The mental health of civilians displaced by armed conflict: an ecological model of refugee distress
Authors: Miller K. E. , Rasmussen A.
Published: April 2016

Early research on the mental health of civilians displaced by armed conflict focused primarily on the direct effects of exposure to war-related violence and loss. Largely overlooked in thiswar exposure modelwere the powerful effects of ongoing stressors related to the experience of displacement itself. Anecological modelof refugee distress is proposed, drawing on research demonstrating that mental health among refugees and asylum seekers stems not only from prior war exposure, but also from a host of ongoing stressors in their social ecology, or displacement-related stressors. Implications of this model for addressing the mental health and psychosocial needs of refugees and other displaced populations are considered.
Teilhabe durch interkulturelle Öffnung
Authors: Hax-Schoppenhorst Thomas
Published: April 2016

Zusammenfassung. Die Welt ist seit geraumer Zeit massiven Veränderungsprozessen unterworfen, die es uns mitunter schwer machen, gedanklich und emotional mithalten zu können. Kriege und Bürgerkriege, Staatskrisen, Zusammenbrüche von Banken, Umweltkatastrophen und nicht zuletzt die 2015 in ganz Europa einsetzende «Flüchtlingskrise» machen unmissverständlich deutlich, dass es zu einer Bewältigung der Probleme neuer Konzepte und den Mut zu entschiedenem Handeln bedarf. Auch vor den Türen eines Krankenhauses macht diese Entwicklung keineswegs Halt!
Gesundheitliche Begleitung von Flüchtlingen in einer Notunterkunft
Authors: Ouatedem Tolsdorf Mareike
Published: April 2016

Zusammenfassung. Als mich Angelika Zegelin bat, einen Artikel für die Padua zur «Patientenedukation» durch Pflegende in Flüchtlingsunterkünften zu schreiben, willigte ich sofort ein. Sekunden später fühlte ich mich ratlos, wie sieht das aus in einem Flüchtlingsheim, in einer Notunterkunft? Gibt es das überhaupt?
Transkulturelle Pflegeanamnese und Pflegediagnostik
Authors: Georg Jürgen
Published: April 2016

Zusammenfassung. Bei Menschen, die als MigratInnen im deutschsprachigen Raum leben oder als Flüchtlinge oder Asylsuchende in die deutschsprachigen Länder gekommen sind, beeinflussen u. a. soziokulturelle Faktoren in besonderer Weise deren Pflegebedarf. Wie dieser Pflegebedarf von Menschen mit Migrationshintergrund eingeschätzt und benannt werden kann und wie Pflegende sich auf eine solche «transkulturelle Pflegeanamnese» vorbereiten können beschreibt dieser Beitrag.
«Oh Captain, mein Captain!»
Authors: Hanisch Roland , Rüster Carolin , Schnelle Denise , Sträche Kathrin , Eberhardt Doris
Published: April 2016

Zusammenfassung. Eine zentrale Aufgabe von Pflegelehrenden bzw. Praxisanleitenden ist es, die Berufsidentität der Pflegelernenden zu fördern. Doch wie steht es diesbezüglich um sie selbst? Der folgende Beitrag zeigt auf, wie Lehrende bzw. Anleitende durch spiel- und theaterpädagogische Übungen gefördert werden können, sich kritisch mit dem eigenen pädagogischen Selbstverständnis auseinanderzusetzen und ihre Identität weiterzuentwickeln. Zentraler Bezugspunkt für die vorgestellten Übungen ist der Spielfilm «Der Club der toten Dichter» aus dem auch das Zitat im Titel des Beitrags stammt.
Mündliche Examensprüfung neu gedacht
Authors: Hellbusch Lutz , Mohr Nathan
Published: April 2016

Zusammenfassung. In Wuppertal wird auch im mündlichen Examen am realen Patientenfall geprüft. Die Prüflinge bearbeiten ihren Fall, halten dazu einen Vortrag und beantworten Fragen in einem anschließenden Prüfungsgespräch. Das ermöglicht ein hohes fachliches Niveau, eine kompetenzorientierte Prüfung und reduzierten Stress für die Prüflinge.
Klassen füllen um jeden Preis?
Authors: Andreas Stefanie , Baumgarten Madlen , Ringelhan Claudia , Ayerle Gertrud
Published: April 2016

Zusammenfassung. Im Rahmen eines studentischen Forschungsprojektes an der Martin-Luther-Universität Halle/Wittenberg stellen sich die Autorinnen die Frage, wie sich die Bewerberauswahl an Pflegeschulen vor dem Hintergrund des Mangels geeigneter Bewerber/innen gestaltet und welche Auswirkungen dies auf die Ausbildung hat. Die Ergebnisse der Experteninterviews zeigten, dass die Bewerberlage für die Ausbildung der Gesundheits- und Krankenpfleger/innen vor allem in qualitativer Hinsicht ernst erscheint.
Bullying, Depression, and Suicide Risk in a Pediatric Primary Care Sample
Authors: Kodish Tamar , Herres Joanna , Shearer Annie , Atte Tita , Fein Joel , Diamond Guy
Published: April 2016

Abstract. Background: Suicide is a serious public health concern for US youth. Research has established an association between bullying and suicide risk. However, several questions remain regarding this relationship. Aims: The present study examined (a) whether experiences of verbal, physical, and cyber bullying were uniquely associated with general suicide risk; (b) whether each specific form of bullying was related to suicide attempt; and (c) whether depression moderated the relationship between each type of bullying and suicide risk. Method: The sample included medical records of 5,429 youth screened in primary care when providers had mental health concerns. Patients were screened using the Behavioral Health Screen (BHS), which assessed a range of mental health problems and behaviors, including bullying, depression, and suicide. Results: All types of bullying were associated with suicide risk, but verbal bullying was uniquely associated with suicide attempt. Depression significantly moderated the relationship between each type of bullying and suicide risk. Conclusion: The study’s limitations include the use of cross-sectional and self-data reports. When medical providers evaluate suicide risk, bullying should be considered as a possible precipitant, especially if the patient is depressed. Verbal bullying may be particularly important in understanding severity of suicide risk.
Substance Use as a Mediator of the Association Between Demographics, Suicide Attempt History, and Future Suicide Attempts in Emergency Department Patients
Authors: Arias Sarah A. , Dumas Orianne , Sullivan Ashley F. , Boudreaux Edwin D. , Miller Ivan , Camargo, Jr. Carlos A.
Published: April 2016

Abstract. Background: Identification of factors that predict and protect against attempted suicide are critical for the development of effective suicide prevention and intervention programs. Aims: To examine whether substance use mediates the association between demographic characteristics, suicide attempt history, and reports of a suicide attempt within 12 months after screening positive for active suicidal ideation or behavior during the index emergency department (ED) visit. Method: Data were collected during the first two phases of the Emergency Department Safety Assessment and Follow-up Evaluation (ED-SAFE) study. Data collection included baseline interview; 6- and 12-month chart reviews; and 6-, 12-, 24-, 36-, and 52-week telephone follow-up assessments. Structural equation modeling was used. All p values were two-tailed, with p < .05 considered statistically significant. Results: Among the 874 subjects, 195 (22%) reported a suicide attempt within 12 months after the index ED visit. Of participants reporting a suicide attempt, 59% were < 40 years old, 59% female, and 76% non-Hispanic White. Associations between race, sex, and suicide attempt 12 months after the index ED visit may be mediated by a combination of alcohol misuse and cocaine use. Conclusion: Findings from the mediation analyses provide insight into the impact of substance use on future suicide attempts in various sociodemographic groups.
Police and Suicide Prevention
Authors: Marzano Lisa , Smith Mark , Long Matthew , Kisby Charlotte , Hawton Keith
Published: April 2016

Abstract. Background: Police officers are frequently the first responders to individuals in crisis, but generally receive little training for this role. We developed and evaluated training in suicide awareness and prevention for frontline rail police in the UK. Aims: To investigate the impact of training on officers’ suicide prevention attitudes, confidence, and knowledge. Method: Fifty-three participants completed a brief questionnaire before and after undertaking training. In addition, two focus groups were conducted with 10 officers to explore in greater depth their views and experiences of the training program and the perceived impact on practice. Results: Baseline levels of suicide prevention attitudes, confidence, and knowledge were mixed but mostly positive and improved significantly after training. Such improvements were seemingly maintained over time, but there was insufficient power to test this statistically. Feedback on the course was generally excellent, notwithstanding some criticisms and suggestions for improvement. Conclusion: Training in suicide prevention appears to have been well received and to have had a beneficial impact on officers’ attitudes, confidence, and knowledge. Further research is needed to assess its longer-term effects on police attitudes, skills, and interactions with suicidal individuals, and to establish its relative effectiveness in the context of multilevel interventions.
Conformational heterogeneity of the calmodulin binding interface
Authors: Shukla Diwakar , Peck Ariana , Pande Vijay S.
Published: April 2016

Calmodulin (CaM) is a ubiquitous Ca2+ sensor and a crucial signalling hub in many pathways aberrantly activated in disease. However, the mechanistic basis of its ability to bind diverse signalling molecules including G-protein-coupled receptors, ion channels and kinases remains poorly understood. Here we harness the high resolution of molecular dynamics simulations and the analytical power of Markov state models to dissect the molecular underpinnings of CaM binding diversity. Our computational model indicates that in the absence of Ca2+, sub-states in the folded ensemble of CaM’s C-terminal domain present chemically and sterically distinct topologies that may facilitate conformational selection. Furthermore, we find that local unfolding is off-pathway for the exchange process relevant for peptide binding, in contrast to prior hypotheses that unfolding might account for binding diversity. Finally, our model predicts a novel binding interface that is well-populated in the Ca2+-bound regime and, thus, a candidate for pharmacological intervention.
A facile route to old and new cyclophanes via self-assembly and capture
Authors: Collins Mary S. , Carnes Matthew E. , Nell Bryan P. , Zakharov Lev N. , Johnson Darren W.
Published: April 2016

Cyclophanes are a venerable class of macrocyclic and/or cage compounds that often feature high strain, unusual conformations and quite surprising properties, many of which are legendary in physical organic chemistry. However, the discovery of new, diverse cyclophanes and derivatives has been hindered by syntheses that are traditionally low-yielding, requiring long reaction times, laborious purification steps and often extreme conditions. Herein, we demonstrate a new self-assembly route to a variety of discrete cyclic and caged disulfide structures, which can then be kinetically captured upon sulfur extrusion at room temperature to give a diversity of new thioether (hetera)cyclophanes in high yield. In addition to the synthesis of novel macrocycles (dimers through hexamers), this process provides an improved route to a known macrobicyclic trithiacyclophane. This technique also enables the facile isolation of a tetrahedral macrotricyclic tetrathiacyclophane in two steps at an ambient temperature.
Light-driven oxidation of polysaccharides by photosynthetic pigments and a metalloenzyme
Authors: Cannella D. , Möllers K. B. , Frigaard N.-U. , Jensen P. E. , Bjerrum M. J. , Johansen K. S. , Felby C.
Published: April 2016

Oxidative processes are essential for the degradation of plant biomass. A class of powerful and widely distributed oxidative enzymes, the lytic polysaccharide monooxygenases (LPMOs), oxidize the most recalcitrant polysaccharides and require extracellular electron donors. Here we investigated the effect of using excited photosynthetic pigments as electron donors. LPMOs combined with pigments and reducing agents were exposed to light, which resulted in a never before seen 100-fold increase in catalytic activity. In addition, LPMO substrate specificity was broadened to include both cellulose and hemicellulose. LPMO enzymes and pigment derivatives common in the environment of plant-degrading organisms thus form a highly reactive and stable light-driven system increasing the turnover rate and versatility of LPMOs. This light-driven system may find applications in biotechnology and chemical processing.
mTORC1 regulates PTHrP to coordinate chondrocyte growth, proliferation and differentiation
Authors: Yan Bo , Zhang Zhongmin , Jin Dadi , Cai Chen , Jia Chunhong , Liu Wen , Wang Ting , Li Shengfa , Zhang Haiyan , Huang Bin , Lai Pinglin , Wang Hua , Liu Anling , Zeng Chun , Cai Daozhang , Jiang Yu , Bai Xiaochun
Published: April 2016

Precise coordination of cell growth, proliferation and differentiation is essential for the development of multicellular organisms. Here, we report that although the mechanistic target of rapamycin complex 1 (mTORC1) activity is required for chondrocyte growth and proliferation, its inactivation is essential for chondrocyte differentiation. Hyperactivation of mTORC1 via TSC1 gene deletion in chondrocytes causes uncoupling of the normal proliferation and differentiation programme within the growth plate, resulting in uncontrolled cell proliferation, and blockage of differentiation and chondrodysplasia in mice. Rapamycin promotes chondrocyte differentiation and restores these defects in mutant mice. Mechanistically, mTORC1 downstream kinase S6K1 interacts with and phosphorylates Gli2, and releases Gli2 from SuFu binding, resulting in nuclear translocation of Gli2 and transcription of parathyroid hormone-related peptide (PTHrP), a key regulator of bone development. Our findings demonstrate that dynamically controlled mTORC1 activity is crucial to coordinate chondrocyte proliferation and differentiation partially through regulating Gli2/PTHrP during endochondral bone development.
CD8+ T-cell pathogenicity in Rasmussen encephalitis elucidated by large-scale T-cell receptor sequencing
Authors: Schneider-Hohendorf Tilman , Mohan Hema , Bien Christian G. , Breuer Johanna , Becker Albert , Görlich Dennis , Kuhlmann Tanja , Widman Guido , Herich Sebastian , Elpers Christiane , Melzer Nico , Dornmair Klaus , Kurlemann Gerhard , Wiendl Heinz , Schwab Nicholas
Published: April 2016

Rasmussen encephalitis (RE) is a rare paediatric epilepsy with uni-hemispheric inflammation and progressive neurological deficits. To elucidate RE immunopathology, we applied T-cell receptor (TCR) sequencing to blood (n=23), cerebrospinal fluid (n=2) and brain biopsies (n=5) of RE patients, and paediatric controls. RE patients present with peripheral CD8+ T-cell expansion and its strength correlates with disease severity. In addition, RE is the only paediatric epilepsy with prominent T-cell expansions in the CNS. Consistently, common clones are shared between RE patients, who also share MHC-I alleles. Public RE clones share Vβ genes and length of the CDR3. Rituximab/natalizumab/basiliximab treatment does not change TCR diversity, stem cell transplantation replaces the TCR repertoire with minimal overlap between donor and recipient, as observed in individual cases. Our study supports the hypothesis of an antigen-specific attack of peripherally expanded CD8+ lymphocytes against CNS structures in RE, which might be ameliorated by restricting access to the CNS.
Suppressing molecular vibrations in organic semiconductors by inducing strain
Authors: Kubo Takayoshi , Häusermann Roger , Tsurumi Junto , Soeda Junshi , Okada Yugo , Yamashita Yu , Akamatsu Norihisa , Shishido Atsushi , Mitsui Chikahiko , Okamoto Toshihiro , Yanagisawa Susumu , Matsui Hiroyuki , Takeya Jun
Published: April 2016

Organic molecular semiconductors are solution processable, enabling the growth of large-area single-crystal semiconductors. Improving the performance of organic semiconductor devices by increasing the charge mobility is an ongoing quest, which calls for novel molecular and material design, and improved processing conditions. Here we show a method to increase the charge mobility in organic single-crystal field-effect transistors, by taking advantage of the inherent softness of organic semiconductors. We compress the crystal lattice uniaxially by bending the flexible devices, leading to an improved charge transport. The mobility increases from 9.7 to 16.5 cm2 V−1 s−1 by 70% under 3% strain. In-depth analysis indicates that compressing the crystal structure directly restricts the vibration of the molecules, thus suppresses dynamic disorder, a unique mechanism in organic semiconductors. Since strain can be easily induced during the fabrication process, we expect our method to be exploited to build high-performance organic devices.
Applying medicinal chemistry strategies to understand odorant discrimination
Authors: Poivet Erwan , Peterlin Zita , Tahirova Narmin , Xu Lu , Altomare Clara , Paria Anne , Zou Dong-Jing , Firestein Stuart
Published: April 2016

Associating an odorant’s chemical structure with its percept is a long-standing challenge. One hindrance may come from the adoption of the organic chemistry scheme of molecular description and classification. Chemists classify molecules according to characteristics that are useful in synthesis or isolation, but which may be of little importance to a biological sensory system. Accordingly, we look to medicinal chemistry, which emphasizes biological function over chemical form, in an attempt to discern which among the many molecular features are most important for odour discrimination. Here we use medicinal chemistry concepts to assemble a panel of molecules to test how heteroaromatic ring substitution of the benzene ring will change the odour percept of acetophenone. This work allows us to describe an extensive rule in odorant detection by mammalian olfactory receptors. Whereas organic chemistry would have predicted the ring size and composition to be key features, our work reveals that the topological polar surface area is the key feature for the discrimination of these odorants.
Rab35 GTPase couples cell division with initiation of epithelial apico-basal polarity and lumen opening
Authors: Klinkert Kerstin , Rocancourt Murielle , Houdusse Anne , Echard Arnaud
Published: April 2016

Establishment and maintenance of apico-basal polarity in epithelial organs must be tightly coupled with cell division, but the underlying molecular mechanisms are largely unknown. Using 3D cultures of renal MDCK cells (cysts), we found that the Rab35 GTPase plays a crucial role in polarity initiation and apical lumen positioning during the first cell division of cyst development. At the molecular level, Rab35 physically couples cytokinesis with the initiation of apico-basal polarity by tethering intracellular vesicles containing key apical determinants at the cleavage site. These vesicles transport aPKC, Cdc42, Crumbs3 and the lumen-promoting factor Podocalyxin, and are tethered through a direct interaction between Rab35 and the cytoplasmic tail of Podocalyxin. Consequently, Rab35 inactivation leads to complete inversion of apico-basal polarity in 3D cysts. This novel and unconventional mode of Rab-dependent vesicle targeting provides a simple mechanism for triggering both initiation of apico-basal polarity and lumen opening at the centre of cysts.
Therapeutic activity of modified U1 core spliceosomal particles
Authors: Rogalska Malgorzata Ewa , Tajnik Mojca , Licastro Danilo , Bussani Erica , Camparini Luca , Mattioli Chiara , Pagani Franco
Published: April 2016

Modified U1 snRNAs bound to intronic sequences downstream of the 5′ splice site correct exon skipping caused by different types of mutations. Here we evaluate the therapeutic activity and structural requirements of these exon-specific U1 snRNA (ExSpeU1) particles. In a severe spinal muscular atrophy, mouse model, ExSpeU1, introduced by germline transgenesis, increases SMN2 exon 7 inclusion, SMN protein production and extends life span. In vitro, RNA mutant analysis and silencing experiments show that while U1A protein is dispensable, the 70K and stem loop IV elements mediate most of the splicing rescue activity through improvement of exon and intron definition. Our findings indicate that precise engineering of the U1 core spliceosomal RNA particle has therapeutic potential in pathologies associated with exon-skipping mutations.
Immediate ecotoxicological effects of short-lived oil spills on marine biota
Authors: Brussaard Corina P. D. , Peperzak Louis , Beggah Siham , Wick Lukas Y. , Wuerz Birgit , Weber Jan , Samuel Arey J. , van der Burg Bart , Jonas Arjen , Huisman Johannes , van der Meer Jan Roelof
Published: April 2016

Marine environments are frequently exposed to oil spills as a result of transportation, oil drilling or fuel usage. Whereas large oil spills and their effects have been widely documented, more common and recurrent small spills typically escape attention. To fill this important gap in the assessment of oil-spill effects, we performed two independent supervised full sea releases of 5 m3 of crude oil, complemented by on-board mesocosm studies and sampling of accidentally encountered slicks. Using rapid on-board biological assays, we detect high bioavailability and toxicity of dissolved and dispersed oil within 24 h after the spills, occurring fairly deep (8 m) below the slicks. Selective decline of marine plankton is observed, equally relevant for early stages of larger spills. Our results demonstrate that, contrary to common thinking, even small spills have immediate adverse biological effects and their recurrent nature is likely to affect marine ecosystem functioning.
The Bag-1 inhibitor, Thio-2, reverses an atypical 3D morphology driven by Bag-1L overexpression in a MCF-10A model of ductal carcinoma in situ
Authors: Papadakis E S , Barker C R , Syed H , Reeves T , Schwaiger S , Stuppner H , Troppmair J , Blaydes J P , Cutress R I
Published: April 2016

Mammary MCF-10A cells seeded on reconstituted basement membrane form spherical structures with a hollow central lumen, termed acini, which are a physiologically relevant model of mammary morphogenesis. Bcl-2-associated athanogene 1 (Bag-1) is a multifunctional protein overexpressed in breast cancer and ductal carcinoma in situ. When present in the nucleus Bag-1 is predictive of clinical outcome in breast cancer. Bag-1 exists as three main isoforms, which are produced by alternative translation initiation from a single mRNA. The long isoform of Bag-1, Bag-1L, contains a nuclear localisation sequence not present in the other isoforms. When present in the nucleus Bag-1L, but not the other Bag-1 isoforms, can interact with and modulate the activities of estrogen-, androgen- and vitamin D-receptors. Overexpression of Bag-1 mRNA in MCF-10A is known to produce acini with luminal filling reminiscent of ductal carcinoma in situ. As this mRNA predominantly overexpresses the short isoform of Bag-1, Bag-1S, we set out to examine whether the nuclear Bag-1L isoform is sufficient to drive premalignant change by developing a Bag-1L-overexpressing MCF-10A model. Two clones differentially overexpressing Bag-1L were grown in two-dimensional (2D) and three-dimensional (3D) cultures and compared with an established model of HER2-driven transformation. In 2D cultures, Bag-1L overexpression reduced proliferation but did not affect growth factor responsiveness or clonogenicity. Acini formed by Bag-1L-overexpressing cells exhibited reduced luminal clearing when compared with controls. An abnormal branching morphology was also observed which correlated with the level of Bag-1L overexpression, suggesting further malignant change. Treatment with Thio-2, a small-molecule inhibitor of Bag-1, reduced the level of branching. In summary, 3D cultures of MCF-10A mammary epithelial cells overexpressing Bag-1L demonstrate a premalignant phenotype with features of ductal carcinoma in situ. Using this model to test the small-molecule Bag-1 inhibitor, Thio-2, reveals its potential to reverse the atypical branched morphology of acini that characterizes this premalignant change.
CD55 is a HIF-2α marker with anti-adhesive and pro-invading properties in neuroblastoma
Authors: Cimmino F , Avitabile M , Pezone L , Scalia G , Montanaro D , Andreozzi M , Terracciano L , Iolascon A , Capasso M
Published: April 2016

CD55 has been revealed to have an important role in tumor genesis, and presence of small populations of cells with strong CD55 expression would be sufficient to predict poor prognosis of several tumors. In our study we revealed that CD55 is a novel target of hypoxia-inducible factor HIF-2α in neuroblastoma (NB) cells. We show that HIF-2α expression is sufficient to sustain stem-like features of NB cells, whereas CD55 protein upon HIF-2α expression contributes to growth of colonies and to invasion of cells, but not to stemness features. Interestingly, in NB tissues, CD55 expression is limited to quite a small population of cells that are HIF-2α positive, and the gene expression of CD55 in the NB data set reveals that the presence of CD55high affects prognosis of NB patients. The functional characterization of CD55-positive populations within heterogeneous NB monoclonal cell lines shows that CD55 has pro-invading and anti-adhesive properties that might provide the basis for the ability of solid tumors to survive as microscopic residual disease. The easy accessibility to CD55 membrane antigen will offer the possibility of a novel antibody approach in the treatment of recurrent tumors and will provide a ready target for antibody-based visualization in NB diagnosis and prognosis.
MicroRNA-206 is differentially expressed in Brca1-deficient mice and regulates epithelial and stromal cell compartments of the mouse mammary gland
Authors: Wronski A , Sandhu G K , Milevskiy M J G , Brewster B L , Bridge J A , Shewan A M , Edwards S L , French J D , Brown M A
Published: April 2016

Depletion of Brca1 leads to defects in mouse mammary gland development and mammary tumors in humans and mice. To explore the role of microRNAs (miRNAs) in this process, we examined the mammary glands of MMTV-Cre Brca1Co/Co mice for differential miRNA expression using a candidate approach. Several miRNAs were differentially expressed in mammary tissue at day 1 of lactation and in mammary epithelial cell lines in which Brca1 messenger RNA (mRNA) levels have been reduced. Functional studies revealed that several of these miRNAs regulate mammary epithelial cell function in vitro, including miR-206. Creation and analysis of MMTV-miR-206 transgenic mice showed no effect on lactational mammary development and no tumors, but indicates a role in mammary tissue remodeling in mature mice, potentially involving Igf-1 and Sfrp1. These results indicate the potential of miRNAs to mediate the consequences of Brca1 loss and suggest a novel function for miR-206.
Overconfidence, Incentives and Digit Ratio
Authors: Neyse Levent , Bosworth Steven , Ring Patrick , Schmidt Ulrich
Published: April 2016

This paper contributes to a better understanding of the biological underpinnings of overconfidence by analyzing performance predictions in the Cognitive Reflection Test with and without monetary incentives. In line with the existing literature we find that the participants are too optimistic about their performance on average; incentives lead to higher performance; and males score higher than females on this particular task. The novelty of this paper is an analysis of the relation between participants’ performance prediction accuracy and their second to fourth digit ratio. It has been reported that the digit ratio is a negatively correlated bio-marker of prenatal testosterone exposure. In the un-incentivized treatment, we find that males with low digit ratios, on average, are significantly more overconfident about their performance. In the incentivized treatment, however, we observe that males with low digit ratios, on average, are less overconfident about their performance. These effects are not observed in females. We discuss how these findings fit into the literature on testosterone and decision making and how they might help to explain seemingly opposing evidence.
BitterX: a tool for understanding bitter taste in humans
Authors: Huang Wenkang , Shen Qiancheng , Su Xubo , Ji Mingfei , Liu Xinyi , Chen Yingyi , Lu Shaoyong , Zhuang Hanyi , Zhang Jian
Published: April 2016

BitterX is an open-access tool aimed at providing a platform for identifying human bitter taste receptors, TAS2Rs, for small molecules. It predicts TAS2Rs from the molecular structures of arbitrary chemicals by integrating two individual functionalities: bitterant verification and TAS2R recognition. Using BitterX, several novel bitterants and their receptors were predicted and experimentally validated in the study. Therefore, BitterX may be an effective method for deciphering bitter taste coding and could be a useful tool for both basic bitter research in academia and new bitterant discoveries in the industry.
Aquatic vegetation in response to increased eutrophication and degraded light climate in Eastern Lake Taihu: Implications for lake ecological restoration
Authors: Zhang Yunlin , Liu Xiaohan , Qin Boqiang , Shi Kun , Deng Jianming , Zhou Yongqiang
Published: April 2016

Terrestrial and aquatic ecosystem degradation is widely recognized as a major global environmental and development problem. Although great efforts have been made to prevent aquatic ecosystem degradation, the degree, extent and impacts of this phenomenon remain controversial and unclear, such as its driving mechanisms. Here, we present results from a 17-year field investigation (1998–2014) of water quality and a 12-year remote sensing mapping (2003–2014) of the aquatic vegetation presence frequency (VPF) in Eastern Lake Taihu, a macrophyte-dominated bay of Lake Taihu in China. In the past 17 years, nutrient concentrations and water level (WL) have significantly increased, but the Secchi disk depth (SDD) has significantly decreased. These changes were associated with increased lake eutrophication and a degraded underwater light climate that further inhibited the growth of aquatic vegetation. In Eastern Lake Taihu, increased nutrients, chlorophyll a and WL, and a decreased SDD were all significantly correlated with a decreased VPF. NH4+-N concentration and SDD/WL were the most important controlling factors for VPF. Therefore, increased anthropogenic nutrient inputs and a degraded underwater light climate surely result in a decreased VPF. These results elucidate the driving mechanism of aquatic vegetation degradation and will facilitate Lake Taihu ecological restoration.
Identification of genes associated with the astrocyte-specific gene Gfap during astrocyte differentiation
Authors: Ito Kenji , Sanosaka Tsukasa , Igarashi Katsuhide , Ideta-Otsuka Maky , Aizawa Akira , Uosaki Yuichi , Noguchi Azumi , Arakawa Hirokazu , Nakashima Kinichi , Takizawa Takumi
Published: April 2016

Chromosomes and genes are non-randomly arranged within the mammalian cell nucleus and gene clustering is of great significance in transcriptional regulation. However, the relevance of gene clustering and their expression during the differentiation of neural precursor cells (NPCs) into astrocytes remains unclear. We performed a genome-wide enhanced circular chromosomal conformation capture (e4C) to screen for genes associated with the astrocyte-specific gene glial fibrillary acidic protein (Gfap) during astrocyte differentiation. We identified 18 genes that were specifically associated with Gfap and expressed in NPC-derived astrocytes. Our results provide additional evidence for the functional significance of gene clustering in transcriptional regulation during NPC differentiation.
Some pitfalls in application of functional data analysis approach to association studies
Authors: Svishcheva G. R. , Belonogova N. M. , Axenovich T. I.
Published: April 2016

One of the most effective methods for gene-based mapping employs functional data analysis, which smoothes data using standard basis functions. The full functional linear model includes a functional representation of genotypes and their effects, while the beta-smooth only model smoothes the genotype effects only. Benefits and limitations of the beta-smooth only model should be studied before using it in practice. Here we analytically compare the full and beta-smooth only models under various scenarios. We show that when the full model employs two sets of basis functions equal in type and number, genotypes smoothing is eliminated from the model and it becomes analytically equivalent to the beta-smooth only model. If the basis functions differ only in type, genotypes smoothing is also eliminated from the full model, but the type of basis functions used for smoothing genotype effects becomes redefined. This leads to misinterpretation of the results and may reduce statistical power. When basis functions differ in number, no analytical comparison of the full and beta-smooth only models is possible. However, we show that the numbers of basis functions set unequal can become equal during the analysis and the full model becomes disadvantageous.