bluuebunny/crossref_metadata_2025 huggingface dataset:
Capacitor voltage balancing method for modified modular multilevel converter
Authors: Luo Longfei , Zhang Yanbin , Jia Lixin , Yang Ningning
Published: April 2018

This paper presents a modified modular multilevel converter (MMC) topology and a simple voltage balancing scheme that consists of intra‐ and inter‐arm voltage balancing methods. Each arm of the modified MMC comprises several half‐bridge submodules (SMs), one modified full‐bridge SM, and some clamping diodes. By adding a clamping diode to each of the two adjacent SMs, the capacitor voltage of one SM will be clamped by the two neighboring SMs when the clamping diode is in operation. Based on the diode‐clamped circuit, a simplify intra‐arm voltage balancing method, which needs only two voltage sensors, is proposed, and it takes up very little time for calculation and control. Moreover, an inter‐arm voltage balancing method based on bidirectional DC–DC converter control is studied, which can regulate the voltage balancing of two arms in one phase by controlling the power transmission amount and direction between two modified full‐bridge SMs. Compared with previous works, the present design prevents the MMC common mode current component to be injected into the grid and avoids interferences with system input or output voltage and current. Finally, a modified MMC system is built by using the PSCAD/EMTDC software, and the simulation results verify the effectiveness of the proposed topology and voltage balancing methods. © 2018 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc.
Optimal Control for a Class of Infinite Dimensional Systems Involving an ‐term in the Cost Functional
Authors: Court Sébastien , Kunisch Karl , Pfeiffer Laurent
Published: April 2018

An optimal control problem with a time‐parameter is considered. The functional to be optimized includes the maximum over time‐horizon reached by a function of the state variable, and so an ‐term. In addition to the classical control function, the time at which this maximum is reached is considered as a free parameter. The problem couples the behavior of the state and the control, with this time‐parameter. A change of variable is introduced to derive first and second‐order optimality conditions. This allows the implementation of a Newton method. Numerical simulations are developed, for selected ordinary differential equations and a partial differential equation, which illustrate the influence of the additional parameter and the original motivation.
Connecting Whole Number Arithmetic Foundations to Other Parts of Mathematics: Structure and Structuring Activity
Authors: Venkat Hamsa , Beckmann Sybilla , Larsson Kerstin , Xin Yan Ping , Ramploud Alessandro , Chen Limin
Published: April 2018

In this chapter, we attend to presentation/discussion of structure and structuring activities as two key routes through which whole number arithmetic can be connected to other mathematical content areas and to central mathematical processes and products like defining/definitions and generalizing/generalization. In the body of the chapter, we use literature to distinguish between approaches focused more on the presentation of structure and those oriented towards structuring activities, before presenting an overview and discussion of studies geared more towards one or other of these approaches. We incorporate studies that have been directed towards both students’ mathematical learning and mathematical (and pedagogical) teacher learning and conclude with commentary on biases towards structure-based or structuring activity-based approaches across these contexts. Our argument is that both approaches show promise for building towards stronger connections between whole number arithmetic and other mathematical areas, with a number of examples in each category included. Given the evidence of difficulties for so many children in many parts of the world in moving beyond the terrain of whole number, our findings suggest that attention to structure and structuring can provide important routes for bridging this chasm.
Reflecting on the What and Why of Whole Number Arithmetic: A Commentary on Chapter 5
Authors: Howe Roger
Published: April 2018

This chapter discusses some matters raised by Chap. 5, both the general ideas and some specific sections. A main theme is the non-trivial nature, both of the historical development and the teaching, of the base-ten place value system. A second main theme is that the power of the system stems from its consistency with algebraic structure. A sequence of five stages of understanding of the base-ten system is reviewed, with emphasis on the importance of understanding that base-ten notation expresses each number as a sum of pieces of a special type. The value of being able to work with the pieces, for understanding the computational algorithms, and especially for discussing approximation, is reviewed. To facilitate focus on the pieces and their role, a standard name for them is called for. Also advocated is greater emphasis on understanding large numbers.
Whole Number Thinking, Learning and Development: Neuro-cognitive, Cognitive and Developmental Approaches
Authors: Mulligan Joanne , Verschaffel Lieven , Baccaglini-Frank Anna , Coles Alf , Gould Peter , He Shengqing , Ma Yunpeng , Milinković Jasmina , Obersteiner Andreas , Roberts Nicole , Sinclair Nathalie , Wang Yanling , Xie Shu , Yang Der-Ching
Published: April 2018

This chapter focuses on the neuro-cognitive, cognitive and developmental analyses of whole number arithmetic (WNA) learning. It comprises five sections. The first section provides an overview of the working group discussion. Section 7.2 reviews neuro-cognitive perspectives of learning WNA but looks beyond these to explain the transcoding of numerals to number words. In the third section, children’s early mathematics-related competencies in reasoning about quantitative relations, patterns and structures are explored from new theoretical perspectives. Studies presented and discussed in working group 2 are presented in the following section as exemplars of intervention studies. The final section examines methodologies utilized in neuro-cognitive, cognitive and developmental analyses of children’s whole number learning. It discusses study designs and their potentialities and limitations for understanding how children develop competencies with whole numbers as well as task designs in cognitive neuroscience research pertinent to number learning. The chapter concludes with implications for further research and teaching practice.
Aspects that Affect Whole Number Learning: Cultural Artefacts and Mathematical Tasks
Authors: Bartolini Bussi Maria G. , Inprasitha Maitree , Arzarello Ferdinando , Bass Hyman , Kortenkamp Ulrich , Ladel Silke , Lajoie Caroline , Ni Yujing , Rottmann Thomas , Sarungi Veronica , Soury-Lavergne Sophie , Young-Loveridge Jenny
Published: April 2018

The core of this chapter is the notion of artefact, starting from the discussion of the meaning of the word in the literature and offering a gallery of cultural artefacts from the participants’ reports and the literature. The idea of artefacts is considered in a broad sense, to include also language and texts. The use of cultural artefacts as teaching aids is addressed. A special section is devoted to the artefacts (teaching aids) from technologies (including virtual manipulatives). The issue of tasks is simply skimmed, but it is not possible to discuss about artefacts without considering the way of using artefacts with suitable tasks. Some examples of tasks are reported to elaborate about aspects that may foster learning whole number arithmetic (WNA). Artefacts and tasks appear as an inseparable pair, to be considered within a cultural and institutional context. Some future challenges are outlined concerning the issue of teacher education, in order to cope with this complex map.
SITUATING FEMINIST EPISTEMOLOGY
Authors: Ashton Natalie Alana , McKenna Robin
Published: April 2018

Feminist epistemologies hold that differences in the social locations of inquirers make for epistemic differences, for instance, in the sorts of things that inquirers are justified in believing. In this paper we situate this core idea in feminist epistemologies with respect to debates about social constructivism. We address three questions. First, are feminist epistemologies committed to a form of social constructivism about knowledge? Second, to what extent are they incompatible with traditional epistemological thinking? Third, do the answers to these questions raise serious problems for feminist epistemologies? We argue that some versions of two of the main strands in feminist epistemology – feminist standpoint theory and feminist empiricism – are committed to a form of social constructivism, which requires certain departures from traditional epistemological thinking. But we argue that these departures are less problematic than one might think. Thus, (some) feminist epistemologies provide a plausible way of understanding how (some) knowledge might be socially constructed.
On The Uniqueness of Solutions for Kawahara Type Equations
Authors: de Farias Marcos A. , Kondo Cezar I. , dos Santos Filho José Ruidival
Published: April 2018

In this paper we extend to Kawahara type equations a uniqueness result obtained by C. E. Kenig, G. Ponce, and L. Vega for KdV type equations. We prove that, under certain decay's conditions, the null solution is the unique solution.
ANALYSIS OF THE NETWORK WITH MULTIPLE CLASSES OF POSITIVE AND NEGATIVE CUSTOMERS AT A TRANSIENT REGIME
Authors: Matalytski Mikhail
Published: April 2018

This paper is devoted to the investigation of the G-network with multiple classes of positive and negative customers. The purpose of the investigation is to analyze such a network at a transient regime, to find the state probabilities of the network that depend on time. In the first part, a description of the functioning of G-networks with positive and negative customers is provided, when a negative customer when arriving to the system destroys a positive customer of its class. Streams of positive and negative customers arriving at each of the network systems are independent. Services of positive customers of all types occur in accordance with a random selection of them for service. For nonstationary probabilities of network states, a system of Kolmogorov's difference-differential equations (DDE) has been derived. A method for their finding is proposed. It is based on the use of a modified method of successive approximations, combined with the method of series. It is proved that successive approximations converge with time to a stationary probability distribution, the form of which is indicated in this paper, and the sequence of approximations converges to the unique solution of the DDE system. Any successive approximation is representable in the form of a convergent power series with an infinite radius of convergence, the coefficients of which satisfy recurrence relations, which is convenient for computer calculations. A model example illustrating the determination of the time-dependent probabilities of network states using this technique has been calculated. The obtained results can be applied in modeling the behavior of computer viruses and attacks in information and telecommunication systems and networks, for example, as a model of the impact of some file viruses on server resources. variable.
Replacement of saturated andtrans-fatty acids in the dietv.CVD risk in the light of the most recent studies
Authors: Makarewicz-Wujec Magdalena , Dworakowska Anna , Kozłowska-Wojciechowska Małgorzata
Published: April 2018

Objective

To present and discuss results of the most recent studies pertaining to the effects of consumption of different types of fatty acids on the risk of CVD. The aim was also an attempt to answer the question of whether a revision of the current recommendations is necessary.

Design

A review of prospective cohort studies, systematic reviews and meta-analyses published in 2014–2017 on the effects of SFA andtrans-fatty acid (TFA) intakes as well as various models of their replacement in the diet on CVD risk.

Results

Results of the new large prospective cohort studies pertaining to the effect of SFA consumption on CVD risk are contradictory. Similarly, the recent meta-analyses of clinical trials related to the effects of SFA substitution on CVD risk provided extremely different results, which is related to the application of different inclusion and exclusion criteria. Differences in results of randomised controlled trials may be caused by different methodologies of dietary parameter changes, varying duration of studies, as well as the time at which they were carried out.

Conclusions

It is extremely difficult to extrapolate results of recent studies to contemporary recommendations. It seems that there is a need for properly randomised studies on large groups, with good control of dietary and non-dietary parameters, which account for not only the sum of SFA and TFA, but also their source. Only such studies will allow for full evaluation of an effect of substituting SFA and TFA on cardiovascular risk.
STRATEGY AS INTELLECTUAL HISTORY
Authors: ISAAC JOEL
Published: April 2018

The world of grand strategy is not one to which intellectual historians have devoted a great deal of attention. Matters of interstate economic competition and imperial rivalry have, of course, long been at the center of histories of early modern political thought. Yet, when these currents in the history of political thought narrow into nineteenth-centuryrealpolitik, and then turn toward the professionalized contemporary discourses of international relations and war studies, intellectual historians have, for the most part, left the matter to the experts. The strategic maxims of Clausewitz and Liddell Hart may fascinate IR theorists, political scientists, and military historians, but they seldom fire the imaginations of tender-minded historians of ideas. The two books under review challenge such preconceptions. They ask us to consider the history of Cold War strategic thought in a wider conceptual frame. Buried in the history of strategy, they suggest, are some of the central themes of postwar social and political thought.
WANTED: Hillary Clinton, Suspect Citizen
Authors: Boryczka Jocelyn M.
Published: April 2018

“Lock her up! Lock her up! Lock her up!” This battle cry erupted at one Donald Trump rally after another throughout the 2016 presidential campaign. Trump even threatened to jail Hillary Rodham Clinton (HRC) if he won the election. “Crooked Hillary” emerged as Trump's disparaging nickname for his Democratic opponent. Taking a further moralistic step, Trump equated HRC with pure evil, calling her the “devil” at an August 2016 campaign rally in Pennsylvania.
Exposition aus Sicht niedergelassener Verhaltenstherapeutinnen und Verhaltenstherapeuten
Authors: Pittig Andre , Hoyer Jürgen
Published: April 2018

Zusammenfassung. Theoretischer Hintergrund: Expositionsbasierte Interventionen gehören zu den wirksamsten Methoden bei der Behandlung von Angststörungen. Dennoch legen vergangene Studien nahe, dass Exposition in der verhaltenstherapeutischen Routinepraxis nur selten eingesetzt wird. Barrieren, die eine Anwendung verhindern, wurden bisher nicht systematisch erfasst. Fragestellung und Methode: Hauptziel dieser Studie war eine praxis-orientierte Erhebung systemischer Barrieren und Veränderungswünschen bei der Anwendung von Exposition aus Sicht ambulant tätiger Verhaltenstherapeutinnen und -therapeuten. Mittels postalischer Befragung wurden diese Barrieren sowie die Anwendungshäufigkeit von expositionsbasierten Interventionen erfasst (N = 684). Ergebnisse: Gemäß Selbstbericht wurde bei weniger als der Hälfte der Behandlungen von Angststörungen eine Form der Exposition eingesetzt (46.8 %), wobei die Anwendungshäufigkeit stark zwischen den Behandelnden variierte. Exposition wurde hauptsächlich in der eigenen Praxis, durchschnittlich für eine Dauer von einer Stunde und mit einer wöchentlichen bis zweiwöchentlichen Frequenz eingesetzt. Eine häufigere Anwendung war mit jüngerem Alter, weniger Berufsjahren und mehr expositionsspezifischen Aus- und Weiterbildungsstunden assoziiert. Systemische Barrieren bezogen sich besonders auf finanzielle Aspekte und das Aufwand-Vergütungsverhältnis, Unklarheiten bezüglich Versicherungs- und Abrechnungsaspekten, sowie das begrenzte Stundenkontingent. Schlussfolgerung: Exposition bei Angststörungen scheint nicht so häufig und intensiv eingesetzt zu werden, wie in aktuellen evidenzbasierten Leitlinien empfohlen wird. Diverse systemische Barrieren erschweren die Anwendung in der ambulanten Routineversorgung.
Investigating Deviance Distraction and the Impact of the Modality of	the To-Be-Ignored Stimuli
Authors: Marsja Erik , Neely Gregory , Ljungberg Jessica K.
Published: April 2018

Abstract. It has been suggested that deviance distraction is caused by unexpected sensory events in the to-be-ignored stimuli violating the cognitive system’s predictions of incoming stimuli. The majority of research has used methods where the to-be-ignored expected (standards) and the unexpected (deviants) stimuli are presented within the same modality. Less is known about the behavioral impact of deviance distraction when the to-be-ignored stimuli are presented in different modalities (e.g., standard and deviants presented in different modalities). In three experiments using cross-modal oddball tasks with mixed-modality to-be-ignored stimuli, we examined the distractive role of unexpected auditory deviants presented in a continuous stream of expected standard vibrations. The results showed that deviance distraction seems to be dependent upon the to-be-ignored stimuli being presented within the same modality, and that the simplest omission of something expected; in this case, a standard vibration may be enough to capture attention and distract performance.
Are You Taking the Fastest Route to the RESTAURANT?
Authors: Perea Manuel , Marcet Ana , Vergara-Martínez Marta
Published: April 2018

Abstract. Most words in books and digital media are written in lowercase. The primacy of this format has been brought out by different experiments showing that common words are identified faster in lowercase (e.g., molecule) than in uppercase (MOLECULE). However, there are common words that are usually written in uppercase (street signs, billboards; e.g., STOP, PHARMACY). We conducted a lexical decision experiment to examine whether the usual letter-case configuration (uppercase vs. lowercase) of common words modulates word identification times. To this aim, we selected 78 molecule-type words and 78 PHARMACY-type words that were presented in lowercase or uppercase. For molecule-type words, the lowercase format elicited faster responses than the uppercase format, whereas this effect was absent for PHARMACY-type words. This pattern of results suggests that the usual letter configuration of common words plays an important role during visual word processing.
Remediation of adult black dental stains by phototherapy
Authors: Albelda-Bernardo M. A. , Jovani-Sancho M. del Mar , Veses V. , Sheth C. C.
Published: April 2018

Introduction and aims

This study investigates the effects of the application of antimicrobial phototherapy on black-stained tooth surfaces. Key variables were area, color and time taken to reappearance of black stain following dental prophylaxis with and without antimicrobial phototherapy. Differences in bacterial composition of black stain (specifically Aggregatibacter actinomycetemcomitans, Tannerella forsythia, and Porphyromonas gingivalis) were analyzed.

Material and methods

The phototherapy device used was GLO™ Science LLC, New York, America, emitting light at 475 nm and a power of 3 W. Light was applied in 2 cycles of 8 min on 31 volunteers. Microbial identification was carried out on DNA extracted from black plaque. This study is registered with ClinicalTrials.gov, number NCT03309748.

Results

Following antimicrobial phototherapy, 64.5% of patients displayed reduced pigmentation area. Plaque color was lighter in 48.4% of subjects. Pigmentation area and depth of color returned to normal levels during the course of the study. Colonization by the three bacterial species decreased, although the changes were not statistically significant. We report a key novel finding showing elevated levels of colonization by Tannerella forsythia (83.9%) in adult black stain.

Conclusions

Application of phototherapy results in a reduction in area, color and bacterial colonization of black plaque in adults. The changes were not found to be statistically significant, perhaps owing to the low illumination power of the home-whitening device. For the first time, we document the elevated presence of Tannerella forsythia in adult black stain. We also demonstrate the potential application of a commercially available home-whitening device for black plaque treatment.
Progress and challenges towards targeted delivery of cancer therapeutics
Authors: Rosenblum Daniel , Joshi Nitin , Tao Wei , Karp Jeffrey M. , Peer Dan
Published: April 2018

Targeted delivery approaches for cancer therapeutics have shown a steep rise over the past few decades. However, compared to the plethora of successful pre-clinical studies, only 15 passively targeted nanocarriers (NCs) have been approved for clinical use and none of the actively targeted NCs have advanced past clinical trials. Herein, we review the principles behind targeted delivery approaches to determine potential reasons for their limited clinical translation and success. We propose criteria and considerations that must be taken into account for the development of novel actively targeted NCs. We also highlight the possible directions for the development of successful tumor targeting strategies.
Somatic genome editing with the RCAS-TVA-CRISPR-Cas9 system for precision tumor modeling
Authors: Oldrini Barbara , Curiel-García Álvaro , Marques Carolina , Matia Veronica , Uluçkan Özge , Graña-Castro Osvaldo , Torres-Ruiz Raul , Rodriguez-Perales Sandra , Huse Jason T. , Squatrito Massimo
Published: April 2018

To accurately recapitulate the heterogeneity of human diseases, animal models require to recreate multiple complex genetic alterations. Here, we combine the RCAS-TVA system with the CRISPR-Cas9 genome editing tools for precise modeling of human tumors. We show that somatic deletion in neural stem cells of a variety of known tumor suppressor genes (Trp53, Cdkn2a, and Pten) leads to high-grade glioma formation. Moreover, by simultaneous delivery of pairs of guide RNAs we generate different gene fusions with oncogenic potential, either by chromosomal deletion (Bcan-Ntrk1) or by chromosomal translocation (Myb-Qk). Lastly, using homology-directed-repair, we also produce tumors carrying the homologous mutation to human BRAF V600E, frequently identified in a variety of tumors, including different types of gliomas. In summary, we have developed an extremely versatile mouse model for in vivo somatic genome editing, that will elicit the generation of more accurate cancer models particularly appropriate for pre-clinical testing.
Immiscible hydrous Fe–Ca–P melt and the origin of iron oxide-apatite ore deposits
Authors: Hou Tong , Charlier Bernard , Holtz François , Veksler Ilya , Zhang Zhaochong , Thomas Rainer , Namur Olivier
Published: April 2018

The origin of iron oxide-apatite deposits is controversial. Silicate liquid immiscibility and separation of an iron-rich melt has been invoked, but Fe–Ca–P-rich and Si-poor melts similar in composition to the ore have never been observed in natural or synthetic magmatic systems. Here we report experiments on intermediate magmas that develop liquid immiscibility at 100 MPa, 1000–1040 °C, and oxygen fugacity conditions (fO2) of ∆FMQ = 0.5–3.3 (FMQ = fayalite-magnetite-quartz equilibrium). Some of the immiscible melts are highly enriched in iron and phosphorous ± calcium, and strongly depleted in silicon (<5 wt.% SiO2). These Si-poor melts are in equilibrium with a rhyolitic conjugate and are produced under oxidized conditions (~FMQ + 3.3), high water activity (aH2O ≥ 0.7), and in fluorine-bearing systems (1 wt.%). Our results show that increasing aH2O and fO2 enlarges the two-liquid field thus allowing the Fe–Ca–P melt to separate easily from host silicic magma and produce iron oxide-apatite ores.
Publisher Correction: Unravelling the immune signature of Plasmodium falciparum transmission-reducing immunity
Authors: Stone Will J. R. , Campo Joseph J. , Ouédraogo André Lin , Meerstein-Kessel Lisette , Morlais Isabelle , Da Dari , Cohuet Anna , Nsango Sandrine , Sutherland Colin J. , van de Vegte-Bolmer Marga , Siebelink-Stoter Rianne , van Gemert Geert-Jan , Graumans Wouter , Lanke Kjerstin , Shandling Adam D. , Pablo Jozelyn V. , Teng Andy A. , Jones Sophie , de Jong Roos M. , Fabra-García Amanda , Bradley John , Roeffen Will , Lasonder Edwin , Gremo Giuliana , Schwarzer Evelin , Janse Chris J. , Singh Susheel K. , Theisen Michael , Felgner Phil , Marti Matthias , Drakeley Chris , Sauerwein Robert , Bousema Teun , Jore Matthijs M.
Published: April 2018

The original version of this Article contained errors in Fig. 3. In panel a, bars from a chart depicting the percentage of antibody-positive individuals in non-infectious and infectious groups were inadvertently included in place of bars depicting the percentage of infectious individuals, as described in the Article and figure legend. However, the p values reported in the Figure and the resulting conclusions were based on the correct dataset. The corrected Fig. 3a now shows the percentage of infectious individuals in antibody-negative and -positive groups, in both the PDF and HTML versions of the Article. The incorrect and correct versions of Figure 3a are also presented for comparison in the accompanying Publisher Correction as Figure 1.

The HTML version of the Article also omitted a link to Supplementary Data 6. The error has now been fixed and Supplementary Data 6 is available to download.
Quantitative characterization of all single amino acid variants of a viral capsid-based drug delivery vehicle
Authors: Hartman Emily C. , Jakobson Christopher M. , Favor Andrew H. , Lobba Marco J. , Álvarez-Benedicto Ester , Francis Matthew B. , Tullman-Ercek Danielle
Published: April 2018

Self-assembling proteins are critical to biological systems and industrial technologies, but predicting how mutations affect self-assembly remains a significant challenge. Here, we report a technique, termed SyMAPS (Systematic Mutation and Assembled Particle Selection), that can be used to characterize the assembly competency of all single amino acid variants of a self-assembling viral structural protein. SyMAPS studies on the MS2 bacteriophage coat protein revealed a high-resolution fitness landscape that challenges some conventional assumptions of protein engineering. An additional round of selection identified a previously unknown variant (CP[T71H]) that is stable at neutral pH but less tolerant to acidic conditions than the wild-type coat protein. The capsids formed by this variant could be more amenable to disassembly in late endosomes or early lysosomes—a feature that is advantageous for delivery applications. In addition to providing a mutability blueprint for virus-like particles, SyMAPS can be readily applied to other self-assembling proteins.
GFI1 facilitates efficient DNA repair by regulating PRMT1 dependent methylation of MRE11 and 53BP1
Authors: Vadnais Charles , Chen Riyan , Fraszczak Jennifer , Yu Zhenbao , Boulais Jonathan , Pinder Jordan , Frank Daria , Khandanpour Cyrus , Hébert Josée , Dellaire Graham , Côté Jean-François , Richard Stéphane , Orthwein Alexandre , Drobetsky Elliot , Möröy Tarik
Published: April 2018

GFI1 is a transcriptional regulator expressed in lymphoid cells, and an “oncorequisite” factor required for development and maintenance of T-lymphoid leukemia. GFI1 deletion causes hypersensitivity to ionizing radiation, for which the molecular mechanism remains unknown. Here, we demonstrate that GFI1 is required in T cells for the regulation of key DNA damage signaling and repair proteins. Specifically, GFI1 interacts with the arginine methyltransferase PRMT1 and its substrates MRE11 and 53BP1. We demonstrate that GFI1 enables PRMT1 to bind and methylate MRE11 and 53BP1, which is necessary for their function in the DNA damage response. Thus, our results provide evidence that GFI1 can adopt non-transcriptional roles, mediating the post-translational modification of proteins involved in DNA repair. These findings have direct implications for treatment responses in tumors overexpressing GFI1 and suggest that GFI1’s activity may be a therapeutic target in these malignancies.
Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways
Authors: Howard David M. , Adams Mark J. , Shirali Masoud , Clarke Toni-Kim , Marioni Riccardo E. , Davies Gail , Coleman Jonathan R. I. , Alloza Clara , Shen Xueyi , Barbu Miruna C. , Wigmore Eleanor M. , Gibson Jude ,   23andMe Research Team, Agee Michelle , Alipanahi Babak , Auton Adam , Bell Robert K. , Bryc Katarzyna , Elson Sarah L. , Fontanillas Pierre , Furlotte Nicholas A. , Hinds David A. , Huber Karen E. , Kleinman Aaron , Litterman Nadia K. , McCreight Jennifer C. , McIntyre Matthew H. , Mountain Joanna L. , Noblin Elizabeth S. , Northover Carrie A. M. , Pitts Steven J. , Sathirapongsasuti J. Fah , Sazonova Olga V. , Shelton Janie F. , Shringarpure Suyash , Tian Chao , Tung Joyce Y. , Vacic Vladimir , Wilson Catherine H. , Hagenaars Saskia P. , Lewis Cathryn M. , Ward Joey , Smith Daniel J. , Sullivan Patrick F. , Haley Chris S. , Breen Gerome , Deary Ian J. , McIntosh Andrew M.
Published: April 2018

Depression is a polygenic trait that causes extensive periods of disability. Previous genetic studies have identified common risk variants which have progressively increased in number with increasing sample sizes of the respective studies. Here, we conduct a genome-wide association study in 322,580 UK Biobank participants for three depression-related phenotypes: broad depression, probable major depressive disorder (MDD), and International Classification of Diseases (ICD, version 9 or 10)-coded MDD. We identify 17 independent loci that are significantly associated (P < 5 × 10−8) across the three phenotypes. The direction of effect of these loci is consistently replicated in an independent sample, with 14 loci likely representing novel findings. Gene sets are enriched in excitatory neurotransmission, mechanosensory behaviour, post synapse, neuron spine and dendrite functions. Our findings suggest that broad depression is the most tractable UK Biobank phenotype for discovering genes and gene sets that further our understanding of the biological pathways underlying depression.
Quantitative assessment of protein activity in orphan tissues and single cells using the metaVIPER algorithm
Authors: Ding Hongxu , Douglass Eugene F. , Sonabend Adam M. , Mela Angeliki , Bose Sayantan , Gonzalez Christian , Canoll Peter D. , Sims Peter A. , Alvarez Mariano J. , Califano Andrea
Published: April 2018

We and others have shown that transition and maintenance of biological states is controlled by master regulator proteins, which can be inferred by interrogating tissue-specific regulatory models (interactomes) with transcriptional signatures, using the VIPER algorithm. Yet, some tissues may lack molecular profiles necessary for interactome inference (orphan tissues), or, as for single cells isolated from heterogeneous samples, their tissue context may be undetermined. To address this problem, we introduce metaVIPER, an algorithm designed to assess protein activity in tissue-independent fashion by integrative analysis of multiple, non-tissue-matched interactomes. This assumes that transcriptional targets of each protein will be recapitulated by one or more available interactomes. We confirm the algorithm’s value in assessing protein dysregulation induced by somatic mutations, as well as in assessing protein activity in orphan tissues and, most critically, in single cells, thus allowing transformation of noisy and potentially biased RNA-Seq signatures into reproducible protein-activity signatures.
Release of Staphylococcus aureus extracellular vesicles and their application as a vaccine platform
Authors: Wang Xiaogang , Thompson Christopher D. , Weidenmaier Christopher , Lee Jean C.
Published: April 2018

Secretion of extracellular vesicles (EVs), a process common to eukaryotes, archae, and bacteria, represents a secretory pathway that allows cell-free intercellular communication. Microbial EVs package diverse proteins and influence the host-pathogen interaction, but the mechanisms underlying EV production in Gram-positive bacteria are poorly understood. Here we show that EVs purified from community-associated methicillin-resistant Staphylococcus aureus package cytosolic, surface, and secreted proteins, including cytolysins. Staphylococcal alpha-type phenol-soluble modulins promote EV biogenesis by disrupting the cytoplasmic membrane; whereas, peptidoglycan cross-linking and autolysin activity modulate EV production by altering the permeability of the cell wall. We demonstrate that EVs purified from a S. aureus mutant that is genetically engineered to express detoxified cytolysins are immunogenic in mice, elicit cytolysin-neutralizing antibodies, and protect the animals in a lethal sepsis model. Our study reveals mechanisms underlying S. aureus EV production and highlights the usefulness of EVs as a S. aureus vaccine platform.
Characterization of PIK3CA and PIK3R1 somatic mutations in Chinese breast cancer patients
Authors: Chen Li , Yang Liu , Yao Ling , Kuang Xia-Ying , Zuo Wen-Jia , Li Shan , Qiao Feng , Liu Yi-Rong , Cao Zhi-Gang , Zhou Shu-Ling , Zhou Xiao-Yan , Yang Wen-Tao , Shi Jin-Xiu , Huang Wei , Hu Xin , Shao Zhi-Ming
Published: April 2018

Deregulation of the phosphoinositide 3-kinase (PI3K) pathway contributes to the development and progression of tumors. Here, we determine that somatic mutations in PIK3CA (44%), PIK3R1 (17%), AKT3 (15%), and PTEN (12%) are prevalent and diverse in Chinese breast cancer patients, with 60 novel mutations identified. A high proportion of tumors harbors multiple mutations, especially PIK3CA plus PIK3R1 mutations (9.0%). Next, we develop a recombination-based mutation barcoding (ReMB) library for impactful mutations conferring clonal advantage in proliferation and drug responses. The highest-ranking PIK3CA and PIK3R1 mutations include previously reported deleterious mutations, as well as mutations with unknown significance. These PIK3CA and PIK3R1 impactful mutations exhibit a mutually exclusive pattern, leading to oncogenesis and hyperactivity of PI3K pathway. The PIK3CA impactful mutations are tightly associated with hormone receptor positivity. Collectively, these findings advance our understanding of PI3K impactful mutations in breast cancer and have important implications for PI3K-targeted therapy in precision oncology.
Computer-aided discovery of a metal–organic framework with superior oxygen uptake
Authors: Moghadam Peyman Z. , Islamoglu Timur , Goswami Subhadip , Exley Jason , Fantham Marcus , Kaminski Clemens F. , Snurr Randall Q. , Farha Omar K. , Fairen-Jimenez David
Published: April 2018

Current advances in materials science have resulted in the rapid emergence of thousands of functional adsorbent materials in recent years. This clearly creates multiple opportunities for their potential application, but it also creates the following challenge: how does one identify the most promising structures, among the thousands of possibilities, for a particular application? Here, we present a case of computer-aided material discovery, in which we complete the full cycle from computational screening of metal–organic framework materials for oxygen storage, to identification, synthesis and measurement of oxygen adsorption in the top-ranked structure. We introduce an interactive visualization concept to analyze over 1000 unique structure–property plots in five dimensions and delimit the relationships between structural properties and oxygen adsorption performance at different pressures for 2932 already-synthesized structures. We also report a world-record holding material for oxygen storage, UMCM-152, which delivers 22.5% more oxygen than the best known material to date, to the best of our knowledge.
Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program
Authors: Frye Maike , Taddei Andrea , Dierkes Cathrin , Martinez-Corral Ines , Fielden Matthew , Ortsäter Henrik , Kazenwadel Jan , Calado Dinis P. , Ostergaard Pia , Salminen Marjo , He Liqun , Harvey Natasha L. , Kiefer Friedemann , Mäkinen Taija
Published: April 2018

Tissue and vessel wall stiffening alters endothelial cell properties and contributes to vascular dysfunction. However, whether extracellular matrix (ECM) stiffness impacts vascular development is not known. Here we show that matrix stiffness controls lymphatic vascular morphogenesis. Atomic force microscopy measurements in mouse embryos reveal that venous lymphatic endothelial cell (LEC) progenitors experience a decrease in substrate stiffness upon migration out of the cardinal vein, which induces a GATA2-dependent transcriptional program required to form the first lymphatic vessels. Transcriptome analysis shows that LECs grown on a soft matrix exhibit increased GATA2 expression and a GATA2-dependent upregulation of genes involved in cell migration and lymphangiogenesis, including VEGFR3. Analyses of mouse models demonstrate a cell-autonomous function of GATA2 in regulating LEC responsiveness to VEGF-C and in controlling LEC migration and sprouting in vivo. Our study thus uncovers a mechanism by which ECM stiffness dictates the migratory behavior of LECs during early lymphatic development.
Spin-lattice decoupling in a triangular-lattice quantum spin liquid
Authors: Isono Takayuki , Sugiura Shiori , Terashima Taichi , Miyagawa Kazuya , Kanoda Kazushi , Uji Shinya
Published: April 2018

A quantum spin liquid (QSL) is an exotic state of matter in condensed-matter systems, where the electron spins are strongly correlated, but conventional magnetic orders are suppressed down to zero temperature because of strong quantum fluctuations. One of the most prominent features of a QSL is the presence of fractionalized spin excitations, called spinons. Despite extensive studies, the nature of the spinons is still highly controversial. Here we report magnetocaloric-effect measurements on an organic spin-1/2 triangular-lattice antiferromagnet, showing that electron spins are decoupled from a lattice in a QSL state. The decoupling phenomena support the gapless nature of spin excitations. We further find that as a magnetic field is applied away from a quantum critical point, the number of spin states that interact with lattice vibrations is strongly reduced, leading to weak spin–lattice coupling. The results are compared with a model of a strongly correlated QSL near a quantum critical point.
Publisher Correction: Identification of microRNAs as potential cellular monocytic biomarkers in the early phase of myocardial infarction: a pilot study
Authors: Parahuleva Mariana S. , Euler Gerhild , Mardini Amar , Parviz Behnoush , Schieffer Bernhard , Schulz Rainer , Aslam Muhammad
Published: April 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Asymmetric ommatidia count and behavioural lateralization in the ant Temnothorax albipennis
Authors: Hunt Edmund R. , Dornan Ciara , Sendova-Franks Ana B. , Franks Nigel R.
Published: April 2018

Workers of the house-hunting ant Temnothorax albipennis rely on visual edge following and landmark recognition to navigate their rocky environment, and they also exhibit a leftward turning bias when exploring unknown nest sites. We used electron microscopy to count the number of ommatidia composing the compound eyes of workers, males and queens, to make an approximate assessment of their relative sampling resolution; and to establish whether there is an asymmetry in the number of ommatidia composing the workers’ eyes, which might provide an observable, mechanistic explanation for the turning bias. We hypothesise that even small asymmetries in relative visual acuity between left and right eyes could be magnified by developmental experience into a symmetry-breaking turning preference that results in the inferior eye pointing toward the wall. Fifty-six workers were examined: 45% had more ommatidia in the right eye, 36% more in the left, and 20% an equal number. A tentative connection between relative ommatidia count for each eye and turning behaviour was identified, with a stronger assessment of behavioural lateralization before imaging and a larger sample suggested for further work. There was a clear sexual dimorphism in ommatidia counts between queens and males.
Detector-device-independent quantum secret sharing with source flaws
Authors: Yang Xiuqing , Wei Kejin , Ma Haiqiang , Liu Hongwei , Yin Zhenqiang , Cao Zhu , Wu Lingan
Published: April 2018

Measurement-device-independent entanglement witness (MDI-EW) plays an important role for detecting entanglement with untrusted measurement device. We present a double blinding-attack on a quantum secret sharing (QSS) protocol based on GHZ state. Using the MDI-EW method, we propose a QSS protocol against all detector side-channels. We allow source flaws in practical QSS system, so that Charlie can securely distribute a key between the two agents Alice and Bob over long distances. Our protocol provides condition on the extracted key rate for the secret against both external eavesdropper and arbitrary dishonest participants. A tight bound for collective attacks can provide good bounds on the practical QSS with source flaws. Then we show through numerical simulations that using single-photon source a secure QSS over 136 km can be achieved.
Higher leukocyte count predicts 3-month poor outcome of ruptured cerebral aneurysms
Authors: Yao Pei-Sen , Chen Guo-Rong , Xie Xue-Ling , Shang-Guan Huang-Cheng , Gao Jin-Zhen , Lin Yuan-Xiang , Zheng Shu-Fa , Lin Zhang-Ya , Kang De-Zhi
Published: April 2018

It is not fully established whether leukocyte can predict the poor outcome for ruptured cerebral aneurysms (CA) or not. Here, we retrospectively analyzed the clinical data of 428 patients with ruptured CA between 2010 and 2015. Patients’ demographic data, including gender, age, history of smoking, alcohol, hypertension, diabetes and hypercholesterolemia, Hunt-Hess and Fisher grade, occurrence of hydrocephalus, aneurysm location, time to surgery, delayed ischemic neurological deficit (DIND) and peak leukocyte of blood test from day 1 to 3 after aneurysmal rupture were recorded and analyzed. In the multivariable analysis model, gender, Fisher grade, time to surgery and hydrocephalus were not relevant to poor outcome. However, Hunt-Hess grade, DIND and preoperative leukocyte count (>13.84 × 109/L) were significantly associated with adverse outcome. The respective increased risks were 5.2- (OR 5.24, 95% CI 1.67–16.50, p = 0.005), 6.2-(OR 6.24, 95% CI 3.55–10.99, p < 0.001) and 10.9-fold (OR 10.93, 95% CI 5.98–19.97, p < 0.001). The study revealed that Hunt-Hess grade, DIND and preoperative leukocyte count (>13.84 × 109/L) were independent risk factors for poor outcome of ruptured CA at 3 months. Higher leukocyte count is a convenient and useful marker to predict 3-month poor outcome for ruptured CA.
A Hyphenated Preconcentrator-Infrared-Hollow-Waveguide Sensor System for N2O Sensing
Authors: da Silveira Petruci João Flavio , Wilk Andreas , Cardoso Arnaldo Alves , Mizaikoff Boris
Published: April 2018

Following the Kyoto protocol, all signatory countries must provide an annual inventory of greenhouse-gas emission including N2O. This fact associated with the wide variety of sources for N2O emissions requires appropriate sensor technologies facilitating in-situ monitoring, compact dimensions, ease of operation, and sufficient sensitivity for addressing such emission scenarios. In this contribution, we therefore describe an innovative portable mid-infrared chemical sensor system for quantifying gaseous N2O via coupling a substrate-integrated hollow waveguide (iHWG) simultaneously serving as highly miniaturized mid-infrared photon conduit and gas cell to a custom-made preconcentrator. N2O was collected onto a solid sorbent material packed into the preconcentrator unit, and then released via thermal desorption into the iHWG-MIR sensor utilizing a compact Fourier transform infrared (FTIR) spectrometer for molecularly selective spectroscopic detection with a limit of detection (LOD) at 5 ppbv. Highlighting the device flexibility in terms of sampling time, flow-rate, and iHWG design facilitates tailoring the developed preconcentrator-iHWG device towards a wide variety of application scenarios ranging from soil and aquatic emission monitoring and drone- or unmanned aerial vehicle (UAV)-mounted monitoring systems to clinical/medical analysis scenarios.
Potential Reporting Bias in Neuroimaging Studies of Sex Differences
Authors: David Sean P. , Naudet Florian , Laude Jennifer , Radua Joaquim , Fusar-Poli Paolo , Chu Isabella , Stefanick Marcia L. , Ioannidis John P. A.
Published: April 2018

Numerous functional magnetic resonance imaging (fMRI) studies have reported sex differences. To empirically evaluate for evidence of excessive significance bias in this literature, we searched for published fMRI studies of human brain to evaluate sex differences, regardless of the topic investigated, in Medline and Scopus over 10 years. We analyzed the prevalence of conclusions in favor of sex differences and the correlation between study sample sizes and number of significant foci identified. In the absence of bias, larger studies (better powered) should identify a larger number of significant foci. Across 179 papers, median sample size was n = 32 (interquartile range 23-47.5). A median of 5 foci related to sex differences were reported (interquartile range, 2-9.5). Few articles (n = 2) had titles focused on no differences or on similarities (n = 3) between sexes. Overall, 158 papers (88%) reached “positive” conclusions in their abstract and presented some foci related to sex differences. There was no statistically significant relationship between sample size and the number of foci (−0.048% increase for every 10 participants, p = 0.63). The extremely high prevalence of “positive” results and the lack of the expected relationship between sample size and the number of discovered foci reflect probable reporting bias and excess significance bias in this literature.
Up-conversion luminescence, temperature sensing properties and laser-induced heating effect of Er3+/Yb3+ co-doped YNbO4 phosphors under 1550 nm excitation
Authors: Wang Xin , Li Xiangping , Zhong Hua , Xu Sai , Cheng Lihong , Sun Jiashi , Zhang Jinsu , Li Lei , Chen Baojiu
Published: April 2018

YNbO4 phosphors with various Er3+ and Yb3+ concentrations were synthesized via a traditional high-temperature solid-state reaction method. Their crystal structure was investigated by means of X-ray diffraction (XRD) and Rietveld refinements, and it was confirmed that the obtained samples exist in monoclinic phase. The Er3+ and Yb3+ concentration-dependent up-conversion (UC) luminescence was studied under 1550 nm excitation. By inspecting the dependence of UC intensity on the laser working current, it was found that four-photon and three-photon population processes were co-existent for generating the green UC emissions in the samples with higher Yb3+ concentrations. In addition, it was observed that the temperature sensing properties of YNbO4: Er3+/Yb3+ phosphors were sensitive to both Er3+ and Yb3+ doping concentrations. Furthermore, based on the obtained temperature response of the UC luminescence phosphors, 1550 nm laser-irradiation-induced thermal effect was studied, and it was discovered that the sample temperature was very sensitive to the doping concentrations of Er3+ and Yb3+ and the excitation power.