bluuebunny/crossref_metadata_2025 huggingface dataset:
The association between cognitive function and subsequent depression: a systematic review and meta-analysis
Authors: Scult M. A. , Paulli A. R. , Mazure E. S. , Moffitt T. E. , Hariri A. R. , Strauman T. J.
Published: September 2016

Despite a growing interest in understanding the cognitive deficits associated with major depressive disorder (MDD), it is largely unknown whether such deficits exist before disorder onset or how they might influence the severity of subsequent illness. The purpose of the present study was to conduct a systematic review and meta-analysis of longitudinal datasets to determine whether cognitive function acts as a predictor of later MDD diagnosis or change in depression symptoms. Eligible studies included longitudinal designs with baseline measures of cognitive functioning, and later unipolar MDD diagnosis or symptom assessment. The systematic review identified 29 publications, representing 34 unique samples, and 121 749 participants, that met the inclusion/exclusion criteria. Quantitative meta-analysis demonstrated that higher cognitive function was associated with decreased levels of subsequent depression (r = −0.088, 95% confidence interval. −0.121 to −0.054, p < 0.001). However, sensitivity analyses revealed that this association is likely driven by concurrent depression symptoms at the time of cognitive assessment. Our review and meta-analysis indicate that the association between lower cognitive function and later depression is confounded by the presence of contemporaneous depression symptoms at the time of cognitive assessment. Thus, cognitive deficits predicting MDD likely represent deleterious effects of subclinical depression symptoms on performance rather than premorbid risk factors for disorder.
TREATMENT SWITCHING IN CANCER TRIALS: ISSUES AND PROPOSALS
Authors: Henshall Chris , Latimer Nicholas R. , Sansom Lloyd , Ward Robyn L.
Published: September 2016

Objectives:Treatment switching occurs when patients in a randomized clinical trial switch from the treatment initially assigned to them to another treatment, typically from the control to experimental treatment. This study discusses the issues this raises and possible approaches to addressing them in trials of cancer drugs.

Methods:Stakeholders from around the world were invited to a 1.5-day Workshop in Adelaide, Australia. This study attempts to capture the key points from the discussion and the perspectives of the various stakeholder groups, but is not a formal consensus statement.

Results:Treatment switching raises challenging ethical issues with arguments for and against allowing it. It is increasingly common in cancer drug trials and presents challenges for the interpretation of results by regulators, clinicians, patients, and payers. Proposals are offered for good practice in the design, management, and analysis of trials and wider development programs for cancer drugs in which treatment switching has occurred or is likely to. Recommendations are also offered for further action to improve understanding of the importance and challenges of treatment switching and to promote agreement between key stakeholders on guidelines and other steps to address these challenges.

Conclusions:The handling of treatment switching in trials is of concern to all stakeholders. On the basis of the discussions at the Adelaide International Workshop, there would appear to be common ground on approaches to addressing treatment switching in cancer trials and scope for the development of formal guidelines to inform the work of regulators, payers, industry, trial designers and other stakeholders.
COST-EFFECTIVENESS ANALYSIS OF HERPES ZOSTER VACCINATION IN ITALIAN ELDERLY PERSONS
Authors: Coretti Silvia , Codella Paola , Romano Federica , Ruggeri Matteo , Cicchetti Americo
Published: September 2016

Objectives:Herpes zoster (HZ) is characterized by a painful skin rash. Its main complication is postherpetic neuralgia (PHN), pain persisting or occurring after the rash onset. HZ treatment aims to reduce acute pain, impede the onset complications, and disease progression. The aim of this study was to assess the cost-effectiveness of HZ vaccination compared with no vaccination strategy, within the Italian context.

Methods:The natural history of HZ and PHN was mapped through a Markov model with lifetime horizon. A population of patients aged between 60 and 79 years was hypothesized. Third party payer (Italian National Health Service, I-NHS) and societal perspectives were adopted. Data were derived from literature.

Results and Conclusions:The incremental cost-effectiveness ratio of the vaccination equaled EUR 11,943 per quality-adjusted life-year (QALY) under the I-NHS perspective and EUR 11,248 per QALY under the societal perspective. Considering a cost-effectiveness threshold of EUR 30,000/QALY, the multi-way sensitivity analysis showed that vaccination is cost-effective regardless of the perspective adopted, in 99 percent of simulations.
SCIENTIFIC AND SOCIAL VALUE JUDGMENTS FOR ORPHAN DRUGS IN HEALTH TECHNOLOGY ASSESSMENT
Authors: Nicod Elena , Kanavos Panos
Published: September 2016

Objectives: We explore how broader aspects of a treatment's value and the impact of the condition on patients not captured by routine health technology assessment (HTA) methods using clinical and economic evidence, defined as “other considerations,” may influence HTA processes in different settings.

Methods: Countries included were England, Scotland, Sweden, and France. Data sources were the publicly available reports on HTA recommendations. Ten drugs with European Medicines Agency orphan designation and appraised in England were selected. Qualitative thematic analysis was used to systematically identify and code all “other considerations” based on a previously developed methodological framework, which also coded whether it was provided by stakeholders, and how it influenced the decision.

Results: A classification framework of scientific and social value judgments was developed and used throughout the study. A total of 125 “other considerations” were identified and grouped into ten subcategories based on the information provided. Eighteen to 100 percent of these, depending on the agency, were put forward as one of the main reasons for the final decision potentially contributing to accepting a higher incremental cost-effectiveness ratio or uncertain evidence. Some of these were nonquantified or nonelicited and pertained to the assessor's judgment. A taxonomy of these value judgments was created to be used in future cases. Results also contributed to better defining the determinants of social value and improving accountability for reasonableness.

Conclusions: The systematic identification of the scientific and social value judgments enables to better understanding the dimensions of value, which can be used to improve their transparency and consistent use across decisions and settings.
‘Unwomanly practices’: Poaching Crime, Gender and the Female Offender in Nineteenth-Century Britain
Authors: OSBORNE HARVEY
Published: September 2016

Studies of poaching in the nineteenth century have tended to understate the involvement of women in this archetypal rural crime. This article will suggest that female offending was both more significant and more widespread than previously assumed, but it will also highlight how in a variety of complex ways dominant conceptions of gender shaped perceptions of female poachers and often influenced their treatment before the courts. It will argue that alongside more widely effectual assumptions about appropriate male and female spheres and behaviours, the response of the authorities to female poachers was also shaped by powerful and increasingly culturally embedded notions about the sexually exclusive nature of hunting.
Economic Growth and Biological Innovation: The Development of the European Dairy Sector, 1865–1940
Authors: ADELL ISMAEL HERNÁNDEZ , PUJOL-ANDREU JOSEP
Published: September 2016

In this article we discuss an aspect of economic growth that has not been the subject of much consideration in economic and agrarian history to date: the effect of biological innovations on farming development between the mid nineteenth century and the 1930s. We have focused on dairy farming for two reasons. Firstly, dairy farming played a relevant economic role in a number of European regions during this period. Secondly, one of its products, liquid milk, was probably the most significant food during the early stages of the European nutrition transition. We present new statistical data for the evolution of dairy farming in different Northern European countries as well as Spain, and evaluate the impact of cattle population and milk yields in each case. We also link milk yields and the availability of fodder, but special attention is paid to the breeds kept and techniques for their improvement. The article shows that cattle improvement played a significant role in Central and Northern Europe from the mid nineteenth century, but that this was not the case in Spain. Improvement through inbreeding was soon discarded in Spain, absorbent crossbreeding failed, and the sector became dependent on foreign imports of bulls and cows, first from Switzerland and later from Holland. By taking these factors into consideration we can better understand why the dairy sector in Mediterranean Europe did not really begin until the late nineteenth century and why it stagnated in the wake of the First World War.
CATCH ME IF YOU LEARN: DEVELOPMENT-SPECIFIC EDUCATION AND ECONOMIC GROWTH
Authors: Cerina Fabio , Manca Fabio
Published: September 2016

This paper presents a theoretical and empirical investigation of the relationship between human capital composition and economic growth. In the theoretical analysis, we allow for nonconstant returns to scale in technological activities. Differently from previous literature, our results show that, under broad and plausible model parameterizations, the marginal growth effect of skilled workers is increasing with the distance to the frontier for sufficiently poor countries while it is decreasing (in agreement with the existing literature) only for countries close to the technological frontier. Our empirical analysis provides robust evidence for this theoretical prediction by using a 10-year panel of 85 countries for the years in between 1960 and 2000, as well as by using the System Generalized Methods of Moments (GMM) technique to address the problem of endogeneity. Results are robust to different proxies of human capital and different specifications.
Analysis of the sequence of ITS1 and ITS2 regions of Three Mentha species
Authors: Apostolova Elena , Todorov Krasimir , Dimitrova-Dyulgerova Ivanka , Stoyanov Plamen , Mladenov Rumen , Yahubyan Galina , Naimov Samir
Published: September 2016

Mentha (Nepetoideae, Lamiaceae) is a taxonomically complex genus consisting of 29 species and 11 different hybrids including a number of economically important species among them medical plants used for more than 250 years. Because of its high incidence of polyploidy, diverse morphology, high degree of chromosome number variations and interspecies hybridization, Mentha is considered to be a taxonomical challenge. In this paper, we describe cloning and sequencing of internal transcribed spacers (ITS) 1 and 2 of three mint species: Mentha aquatic L., Mentha longifolia L. (Huds) and Mentha piperita L., collected from natural habitats of Bulgaria. The applicability of ITS1 and ITS2 for molecular fingerprinting and further comparative studies, including the newly obtained ITS1 and ITS2 sequences, was tested in phylogenetic analysis of all eight Mentha species, found in Bulgarian flora.
Asymmetric cyanation of imines via dipeptide-derived organophosphine dual-reagent catalysis
Authors: Wang Hong-Yu , Zheng Chang-Wu , Chai Zhuo , Zhang Jia-Xing , Zhao Gang
Published: September 2016

Over the past few decades, enantioselective phosphine organocatalysis has evolved rapidly into a highly efficient catalytic strategy for a range of useful reactions. However, as restricted by the traditional catalytic modes, some important reactions, such as asymmetric Strecker-type reactions, have thus far been out of reach of this strategy. Reported herein is an application of enantioselective phosphine organocatalysis for asymmetric Strecker-type reactions, enabled by a dual-reagent catalyst system in which the key organophosphorus zwitterion intermediate, generated in situ by mixing a chiral dipeptide-derived multifunctional organophosphine with methyl acrylate, is used as a highly efficient chiral Lewis base catalyst. The high efficiency of this catalytic system is demonstrated in the asymmetric cyanation of isatin-derived ketimines and azomethine aldimines as well as in the kinetic resolution of racemic 3-substituted azomethines. Mechanistic studies provide experimental evidence for the intermediacy of the putative zwitterion and its role as a catalytically active Lewis base.
Observation of acceleration and deceleration in gigaelectron-volt-per-metre gradient dielectric wakefield accelerators
Authors: O’Shea B. D. , Andonian G. , Barber S. K. , Fitzmorris K. L. , Hakimi S. , Harrison J. , Hoang P. D. , Hogan M. J. , Naranjo B. , Williams O. B. , Yakimenko V. , Rosenzweig J. B.
Published: September 2016

There is urgent need to develop new acceleration techniques capable of exceeding gigaelectron-volt-per-metre (GeV m−1) gradients in order to enable future generations of both light sources and high-energy physics experiments. To address this need, short wavelength accelerators based on wakefields, where an intense relativistic electron beam radiates the demanded fields directly into the accelerator structure or medium, are currently under intense investigation. One such wakefield based accelerator, the dielectric wakefield accelerator, uses a dielectric lined-waveguide to support a wakefield used for acceleration. Here we show gradients of 1.347±0.020 GeV m−1 using a dielectric wakefield accelerator of 15 cm length, with sub-millimetre transverse aperture, by measuring changes of the kinetic state of relativistic electron beams. We follow this measurement by demonstrating accelerating gradients of 320±17 MeV m−1. Both measurements improve on previous measurements by and order of magnitude and show promise for dielectric wakefield accelerators as sources of high-energy electrons.
The electrophotonic silicon biosensor
Authors: Juan-Colás José , Parkin Alison , Dunn Katherine E. , Scullion Mark G. , Krauss Thomas F. , Johnson Steven D.
Published: September 2016

The emergence of personalized and stratified medicine requires label-free, low-cost diagnostic technology capable of monitoring multiple disease biomarkers in parallel. Silicon photonic biosensors combine high-sensitivity analysis with scalable, low-cost manufacturing, but they tend to measure only a single biomarker and provide no information about their (bio)chemical activity. Here we introduce an electrochemical silicon photonic sensor capable of highly sensitive and multiparameter profiling of biomarkers. Our electrophotonic technology consists of microring resonators optimally n-doped to support high Q resonances alongside electrochemical processes in situ. The inclusion of electrochemical control enables site-selective immobilization of different biomolecules on individual microrings within a sensor array. The combination of photonic and electrochemical characterization also provides additional quantitative information and unique insight into chemical reactivity that is unavailable with photonic detection alone. By exploiting both the photonic and the electrical properties of silicon, the sensor opens new modalities for sensing on the microscale.
Hidden lattice instabilities as origin of the conductive interface between insulating LaAlO3 and SrTiO3
Authors: Lee P. W. , Singh V. N. , Guo G. Y. , Liu H.-J. , Lin J.-C. , Chu Y.-H. , Chen C. H. , Chu M.-W.
Published: September 2016

The metallic interface between insulating LaAlO3 and SrTiO3 opens up the field of oxide electronics. With more than a decade of researches on this heterostructure, the origin of the interfacial conductivity, however, remains unsettled. Here we resolve this long-standing puzzle by atomic-scale observation of electron-gas formation for screening hidden lattice instabilities, rejuvenated near the interface by epitaxial strain. Using atomic-resolution imaging and electron spectroscopy, the generally accepted notions of polar catastrophe and cation intermixing for the metallic interface are discounted. Instead, the conductivity onset at the critical thickness of 4-unit cell LaAlO3 on SrTiO3 substrate is accompanied with head-to-head ferroelectric-like polarizations across the interface due to strain-rejuvenated ferroelectric-like instabilities in the materials. The divergent depolarization fields of the head-to-head polarizations cast the interface into an electron reservoir, forming screening electron gas in SrTiO3 with LaAlO3 hosting complementary localized holes. The ferroelectric-like polarizations and electron–hole juxtaposition reveal the cooperative nature of metallic LaAlO3/SrTiO3.
Real-time observation of DNA recognition and rejection by the RNA-guided endonuclease Cas9
Authors: Singh Digvijay , Sternberg Samuel H. , Fei Jingyi , Doudna Jennifer A. , Ha Taekjip
Published: September 2016

Binding specificity of Cas9–guide RNA complexes to DNA is important for genome-engineering applications; however, how mismatches influence target recognition/rejection kinetics is not well understood. Here we used single-molecule FRET to probe real-time interactions between Cas9–RNA and DNA targets. The bimolecular association rate is only weakly dependent on sequence; however, the dissociation rate greatly increases from <0.006 s−1 to >2 s−1 upon introduction of mismatches proximal to protospacer-adjacent motif (PAM), demonstrating that mismatches encountered early during heteroduplex formation induce rapid rejection of off-target DNA. In contrast, PAM-distal mismatches up to 11 base pairs in length, which prevent DNA cleavage, still allow formation of a stable complex (dissociation rate <0.006 s−1), suggesting that extremely slow rejection could sequester Cas9–RNA, increasing the Cas9 expression level necessary for genome-editing, thereby aggravating off-target effects. We also observed at least two different bound FRET states that may represent distinct steps in target search and proofreading.
Towards optical polarization control of laser-driven proton acceleration in foils undergoing relativistic transparency
Authors: Gonzalez-Izquierdo Bruno , King Martin , Gray Ross J. , Wilson Robbie , Dance Rachel J. , Powell Haydn , Maclellan David A. , McCreadie John , Butler Nicholas M. H. , Hawkes Steve , Green James S. , Murphy Chris D. , Stockhausen Luca C. , Carroll David C. , Booth Nicola , Scott Graeme G. , Borghesi Marco , Neely David , McKenna Paul
Published: September 2016

Control of the collective response of plasma particles to intense laser light is intrinsic to relativistic optics, the development of compact laser-driven particle and radiation sources, as well as investigations of some laboratory astrophysics phenomena. We recently demonstrated that a relativistic plasma aperture produced in an ultra-thin foil at the focus of intense laser radiation can induce diffraction, enabling polarization-based control of the collective motion of plasma electrons. Here we show that under these conditions the electron dynamics are mapped into the beam of protons accelerated via strong charge-separation-induced electrostatic fields. It is demonstrated experimentally and numerically via 3D particle-in-cell simulations that the degree of ellipticity of the laser polarization strongly influences the spatial-intensity distribution of the beam of multi-MeV protons. The influence on both sheath-accelerated and radiation pressure-accelerated protons is investigated. This approach opens up a potential new route to control laser-driven ion sources.
De novo large rare copy-number variations contribute to conotruncal heart disease in Chinese patients
Authors: Mak Christopher C Y , Chow Pak Cheong , Liu Anthony P Y , Chan Kelvin Y K , Chu Yoyo W Y , Mok Gary T K , Leung Gordon K C , Yeung Kit San , Chau Adolphus K T , Lowther Chelsea , Scherer Stephen W , Marshall Christian R , Bassett Anne S , Chung Brian H Y
Published: September 2016

Conotruncal heart anomalies (CTDs) are particularly prevalent congenital heart diseases (CHD) in Hong Kong. We surveyed large (>500 kb), rare (<1% frequency in controls) copy-number variations (CNVs) in Chinese patients with CTDs to identify potentially disease-causing variations. Adults who tested negative for 22q11.2 deletions were recruited from the adult CHD clinic in Hong Kong. Using a stringent calling criteria, high-confidence CNV calls were obtained, and a large control set comprising 3,987 Caucasian and 1,945 Singapore Chinese subjects was used to identify rare CNVs. Ten large rare CNVs were identified, and 3 in 108 individuals were confirmed to harbour de novo CNVs. All three patients were syndromic with a more complex phenotype, and each of these CNVs overlapped regions likely to be important in CHD. One was a 611 kb deletion at 17p13.3, telomeric to the Miller–Dieker syndrome (MDS) critical region, overlapping the NXN gene. Another was a 5 Mb deletion at 13q33.3, within a previously described critical region for CHD. A third CNV, previously unreported, was a large duplication at 2q22.3 overlapping the ZEB2 gene. The commonly reported 1q21.1 recurrent duplication was not observed in this Chinese cohort. We provide detailed phenotypic and genotypic descriptions of large rare genic CNVs that may represent CHD loci in the East Asian population. Larger samples of Chinese origin will be required to determine whether the genome-wide distribution differs from that found in predominantly European CHD cohorts.
P2X-mediated AMPA receptor internalization and synaptic depression is controlled by two CaMKII phosphorylation sites on GluA1 in hippocampal neurons
Authors: Pougnet Johan-Till , Compans Benjamin , Martinez Audrey , Choquet Daniel , Hosy Eric , Boué-Grabot Eric
Published: September 2016

Plasticity at excitatory synapses can be induced either by synaptic release of glutamate or the release of gliotransmitters such as ATP. Recently, we showed that postsynaptic P2X2 receptors activated by ATP released from astrocytes downregulate synaptic AMPAR, providing a novel mechanism by which glial cells modulate synaptic activity. ATP- and lNMDA-induced depression in the CA1 region of the hippocampus are additive, suggesting distinct molecular pathways. AMPARs are homo-or hetero-tetramers composed of GluA1-A4. Here, we first show that P2X2-mediated AMPAR inhibition is dependent on the subunit composition of AMPAR. GluA3 homomers are insensitive and their presence in heteromers alters P2X-mediated inhibition. Using a mutational approach, we demonstrate that the two CaMKII phosphorylation sites S567 and S831 located in the cytoplasmic Loop1 and C-terminal tail of GluA1 subunits, respectively, are critical for P2X2-mediated AMPAR inhibition recorded from co-expressing Xenopus oocytes and removal of surface AMPAR at synapses of hippocampal neurons imaged by the super-resolution dSTORM technique. Finally, using phosphorylation site-specific antibodies, we show that P2X-induced depression in hippocampal slices produces a dephosphorylation of the GluA1 subunit at S567, contrary to NMDAR-mediated LTD. These findings indicate that GluA1 phosphorylation of S567 and S831 is critical for P2X2-mediated AMPAR internalization and ATP-driven synaptic depression.
Deep brain stimulation of the subthalamic nucleus modulates sensitivity to decision outcome value in Parkinson’s disease
Authors: Seymour Ben , Barbe Michael , Dayan Peter , Shiner Tamara , Dolan Ray , Fink Gereon R.
Published: September 2016

Deep brain stimulation (DBS) of the subthalamic nucleus in Parkinson’s disease is known to cause a subtle but important adverse impact on behaviour, with impulsivity its most widely reported manifestation. However, precisely which computational components of the decision process are modulated is not fully understood. Here we probe a number of distinct subprocesses, including temporal discount, outcome utility, instrumental learning rate, instrumental outcome sensitivity, reward-loss trade-offs, and perseveration. We tested 22 Parkinson’s Disease patients both on and off subthalamic nucleus deep brain stimulation (STN-DBS), while they performed an instrumental learning task involving financial rewards and losses, and an inter-temporal choice task for financial rewards. We found that instrumental learning performance was significantly worse following stimulation, due to modulation of instrumental outcome sensitivity. Specifically, patients became less sensitive to decision values for both rewards and losses, but without any change to the learning rate or reward-loss trade-offs. However, we found no evidence that DBS modulated different components of temporal impulsivity. In conclusion, our results implicate the subthalamic nucleus in a modulation of outcome value in experience-based learning and decision-making in Parkinson’s disease, suggesting a more pervasive role of the subthalamic nucleus in the control of human decision-making than previously thought.
Erratum: Advances in mapping malaria for elimination: fine resolution modelling of Plasmodium falciparum incidence
Authors: Alegana Victor A. , Atkinson Peter M. , Lourenço Christopher , Ruktanonchai Nick W. , Bosco Claudio , Erbach-Schoenberg Elisabeth zu , Didier Bradley , Pindolia Deepa , Menach Arnaud Le , Katokele Stark , Uusiku Petrina , Tatem Andrew J.
Published: September 2016

Scientific Reports 6: Article number: 29628; published online: 13 July 2016; updated: 14 September 2016
Imaging the antimicrobial mechanism(s) of cathelicidin-2
Authors: Schneider Viktoria A. F. , Coorens Maarten , Ordonez Soledad R. , Tjeerdsma-van Bokhoven Johanna L. M. , Posthuma George , van Dijk Albert , Haagsman Henk P. , Veldhuizen Edwin J. A.
Published: September 2016

Host defence peptides (HDPs) have the potential to become alternatives to conventional antibiotics in human and veterinary medicine. The HDP chicken cathelicidin-2 (CATH-2) has immunomodulatory and direct killing activities at micromolar concentrations. In this study the mechanism of action of CATH-2 against Escherichia coli (E. coli) was investigated in great detail using a unique combination of imaging and biophysical techniques. Live-imaging with confocal fluorescence microscopy demonstrated that FITC-labelled CATH-2 mainly localized at the membrane of E. coli. Upon binding, the bacterial membrane was readily permeabilized as was shown by propidium iodide influx into the cell. Concentration- and time-dependent effects of the peptide on E. coli cells were examined by transmission electron microscopy (TEM). CATH-2 treatment was found to induce dose-dependent morphological changes in E. coli. At sub-minimal inhibitory concentrations (sub-MIC), intracellular granulation, enhanced vesicle release and wrinkled membranes were observed, while membrane breakage and cell lysis occurred at MIC values. These effects were visible within 1–5 minute of peptide exposure. Immuno-gold TEM showed CATH-2 binding to bacterial membranes. At sub-MIC values the peptide rapidly localized intracellularly without visible membrane permeabilization. It is concluded that CATH-2 has detrimental effects on E. coli at concentrations that do not immediately kill the bacteria.
TRPM4-mediated control of FcεRI-evoked Ca2+ elevation comprises enhanced plasmalemmal trafficking of TRPM4 channels in connective tissue type mast cells
Authors: Rixecker Torben , Mathar Ilka , Medert Rebekka , Mannebach Stefanie , Pfeifer Alexander , Lipp Peter , Tsvilovskyy Volodymyr , Freichel Marc
Published: September 2016

TRPM4 proteins form Ca2+-activated non selective cation (CAN) channels that affect transmembrane Ca2+-influx by determining the membrane potential. Tight control of the intracellular Ca2+ concentration is essential for mast cell responses. In this study, we analyzed the expression of TRPM4 in peritoneal mast cells (PCMC) as a model for connective tissue type mast cells with respect to FcεRI-evoked calcium changes and the subcellular localization of fluorescently labeled TRPM4 using two viral transduction systems before and following antigen stimulation. Our results show that TRPM4 is expressed in PCMCs, is an essential constituent of the endogenous CAN channels in PCMCs and regulates antigen-evoked increases in intracellular calcium that are significantly enhanced in TRPM4-deficient PCMCs. Compared to PCMCs analyzed before antigen stimulation, the cells depict a substantially increased localization of TRPM4 proteins towards the plasma membrane after FcεRI stimulation. Thus, TRPM4 functions as a limiting factor for antigen evoked calcium rise in connective tissue type mast cells and concurrent translocation of TRPM4 into the plasma membrane is part of this mechanism.
Correction: Corrigendum: Crustal movements due to Iceland’s shrinking ice caps mimic magma inflow signal at Katla volcano
Authors: Spaans Karsten , Hreinsdóttir Sigrún , Hooper Andrew , Ófeigsson Benedikt Gunnar
Published: September 2016

Scientific Reports 5: Article number: 10285; published online: 20 May 2015; updated: 14 September 2016
Multipolar, time-dynamical model for the loss compensation and lasing of a spherical plasmonic nanoparticle spaser immersed in an active gain medium
Authors: Veltri Alessandro , Chipouline Arkadi , Aradian Ashod
Published: September 2016

The plasmonic response of a metal nanoparticle in the presence of surrounding gain elements is studied, using a space and time-dependent model, which integrates a quantum formalism to describe the gain and a classical treatment for the metal. Our model fully takes into account the influence of the system geometry (nanosphere) and offers for the first time, the possibility to describe the temporal evolution of the fields and the coupling among the multipolar modes of the particle. We calculate the lasing threshold value for all multipoles of the spaser, and demonstrate that the dipolar one is lowest. The onset of the lasing instability, in the linear regime, is then studied both with and without external field forcing. We also study the behaviour of the system below the lasing threshold, with the external field, demonstrating the existence of an amplification regime where the nanoparticle’s plasmon is strongly enhanced as the threshold is approached. Finally, a qualitative discussion is provided on later, non-linear stages of the dynamics and the approach to the steady-state of the spaser; in particular, it is shown that, for the considered geometry, the spasing is necessarily multi-modal and multipolar modes are always activated.
Attention induced neural response trade-off in retinotopic cortex under load
Authors: Torralbo Ana , Kelley Todd A. , Rees Geraint , Lavie Nilli
Published: September 2016

The effects of perceptual load on visual cortex response to distractors are well established and various phenomena of ‘inattentional blindness’ associated with elimination of visual cortex response to unattended distractors, have been documented in tasks of high load. Here we tested an account for these effects in terms of a load-induced trade-off between target and distractor processing in retinotopic visual cortex. Participants were scanned using fMRI while performing a visual-search task and ignoring distractor checkerboards in the periphery. Retinotopic responses to target and distractors were assessed as a function of search load (comparing search set-sizes two, three and five). We found that increased load not only increased activity in frontoparietal network, but also had opposite effects on retinotopic responses to target and distractors. Target-related signals in areas V2–V3 linearly increased, while distractor response linearly decreased, with increased load. Critically, the slopes were equivalent for both load functions, thus demonstrating resource trade-off. Load effects were also found in displays with the same item number in the distractor hemisphere across different set sizes, thus ruling out local intrahemispheric interactions as the cause. Our findings provide new evidence for load theory proposals of attention resource sharing between target and distractor leading to inattentional blindness.
An integrative study identifies KCNC2 as a novel predisposing factor for childhood obesity and the risk of diabetes in the Korean population
Authors: Hwang Joo-Yeon , Lee Hyo Jung , Go Min Jin , Jang Han Byul , Park Sang Ick , Kim Bong-Jo , Lee Hye-Ja
Published: September 2016

Obesity is a major risk factor for type 2 diabetes. To unravel the genetic determinants of obesity-associated diabetes, we performed a genome-wide study using the 1,000 Genomes-based imputation in a Korean childhood cohort (KoCAS-1, n = 484) and carried out de novo replication in an independent population (KoCAS-2, n = 1,548). A novel variant (rs10879834) with multiple diverse associations for obesity-related traits was also found to be replicated in an adult cohort (KARE, n = 8,842). Functional annotations using integrative epigenetic analyses identified biological significance and regulatory effects with an inverse methylation-expression correlation (cg27154343 in the 5′-UTR of the KCNC2 gene), tissue-specific enhancer mark (H3K4me1), and pathway enrichment (insulin signaling). Further functional studies in cellular and mouse models demonstrated that KCNC2 is associated with anti-obesogenic effects in the regulation of obesity-induced insulin resistance. KCNC2 shRNA transfection induced endoplasmic reticulum (ER) stress and hepatic gluconeogenesis. Overproduction of KCNC2 decreased ER stress, and treatment with metformin enhanced KCNC2 expression. Taken together, these data suggest that reduction of KCNC2 is associated with modified hepatic gluconeogenesis and increased ER stress on obesity-mediated diabetic risk. An integrative multi-omics analysis might reveal new functional and clinical implications related to the control of energy and metabolic homeostasis in humans.
Doped Graphene for DNA Analysis: the Electrochemical Signal is Strongly Influenced by the Kind of Dopant and the Nucleobase Structure
Authors: Tian Huidi , Wang Lu , Sofer Zdenek , Pumera Martin , Bonanni Alessandra
Published: September 2016

Doping graphene with heteroatoms can alter the electronic and electrochemical properties of the starting material. Contrasting properties should be expected when the doping is carried out with electron donating species (n-type dopants) or with electron withdrawing species (p-type dopants). This in turn can have a profound influence on the electroanalytical performance of the doped material being used for the detection of specific probes. Here we investigate the electrochemical oxidation of DNA bases adenine, guanine, thymine and cytosine on two heteroatom-doped graphene platforms namely boron-doped graphene (p-type dopant) and nitrogen-doped graphene (n-type dopant). We found that overall, boron–doped graphene provided the best response in terms of electrochemical signal sensitivity for all bases. This is due to the electron deficiency of boron-doped graphene, which can promote the oxidation of DNA bases, as opposed to nitrogen-doped graphene which possesses an excess of electrons. Moreover, also the structure of the nucleobase was found to have significant influence on the obtained signal. Our study may open new frontiers in the electrochemical detection of DNA bases which is the first step for label-free DNA analysis.
Gene deleted live attenuated Leishmania vaccine candidates against visceral leishmaniasis elicit pro-inflammatory cytokines response in human PBMCs
Authors: Avishek Kumar , Kaushal Himanshu , Gannavaram Sreenivas , Dey Ranadhir , Selvapandiyan Angamuthu , Ramesh V. , Negi Narender Singh , Dubey Uma S. , Nakhasi Hira L. , Salotra Poonam
Published: September 2016

Currently no effective vaccine is available for human visceral leishmaniasis(VL) caused by Leishmania donovani. Previously, we showed that centrin1 and p27gene deleted live attenuated Leishmania parasites (LdCen1−/− and Ldp27−/−) are safe, immunogenic and protective in animal models. Here, to assess the correlates of protection, we evaluated immune responses induced by LdCen1−/− and Ldp27−/− in human blood samples obtained from healthy, healed VL (HVL), post kala-azar dermal leishmaniasis(PKDL) and VL subjects. Both parasites infected human macrophages, as effectively as the wild type parasites. Further, LdCen1−/− and Ldp27−/− strongly stimulated production of pro-inflammatory cytokines including, IL-12, IFN-γ, TNF-α, IL-2, IL-6 and IL-17 in the PBMCs obtained from individuals with a prior exposure to Leishmania (HVL and PKDL). There was no significant stimulation of anti-inflammatory cytokines (IL-4 and IL-10). Induction of Th1 biased immune responses was supported by a remarkable increase in IFN-γ secreting CD4+ and CD8+ T cells and IL-17 secreting CD4+ cells in PBMCs from HVL cases with no increase in IL-10 secreting T cells. Hence, LdCen1−/− and Ldp27−/− are promising as live vaccine candidates against VL since they elicit strong protective immune response in human PBMCs from HVL, similar to the wild type parasite infection, mimicking a naturally acquired protection following cure.
The enhanced atorvastatin hepatotoxicity in diabetic rats was partly attributed to the upregulated hepatic Cyp3a and SLCO1B1
Authors: Shu Nan , Hu Mengyue , Ling Zhaoli , Liu Peihua , Wang Fan , Xu Ping , Zhong Zeyu , Sun Binbin , Zhang Mian , Li Feng , Xie Qiushi , Liu Xiaodong , Liu Li
Published: September 2016

Liver injury is a common adverse effect of atorvastatin. This study aimed to investigate atorvastatin-induced hepatotoxicity in diabetic rats induced by high-fat diet combined with streptozotocin. The results showed that 40 mg/kg atorvastatin was lethal to diabetic rats, whose mean survival time was 6.2 days. Severe liver injury also occurred in diabetic rats treated with 10 mg/kg and 20 mg/kg atorvastatin. The in vitro results indicated that atorvastatin cytotoxicity in hepatocytes of diabetic rats was more severe than normal and high-fat diet feeding rats. Expressions and activities of hepatic Cyp3a and SLCO1B1 were increased in diabetic rats, which were highly correlated with hepatotoxicity. Antioxidants (glutathione and N-Acetylcysteine), Cyp3a inhibitor ketoconazole and SLCO1B1 inhibitor gemfibrozil suppressed cytotoxicity and ROS formation in primary hepatocytes of diabetic rats. In HepG2 cells, up-regulations of CYP3A4 and SLCO1B1 potentiated hepatotoxicity and ROS generation, whereas knockdowns of CYP3A4 and SLCO1B1 as well as CYP3A4/SLCO1B1 inhibitions showed the opposite effects. Phenobarbital pretreatment was used to induce hepatic Cyp3a and SLCO1B1 in rats. Phenobarbital aggravated atorvastatin-induced hepatotoxicity, while decreased plasma exposure of atorvastatin. All these findings demonstrated that the upregulations of hepatic Cyp3a and SLCO1B1 in diabetic rats potentiated atorvastatin-induced hepatotoxicity via increasing ROS formation.
Allergy-specific Phenome-Wide Association Study for Immunogenes in Turkish Children
Authors: Karaca Sefayet , Civelek Ersoy , Karaca Mehmet , Sahiner Umit M. , Ozgul Riza K. , Kocabas Can N. , Polimanti Renato , Sekerel Bülent E.
Published: September 2016

To dissect the role of immunogenetics in allergy and asthma, we performed a phenome-wide association study in 974 Turkish children selected from a cross-sectional study conducted using ISAAC (International Study of Asthma and Allergies in Children) Phase II tools. We investigated 9 loci involved in different immune functions (ADAM33, ADRB2, CD14, IL13, IL4, IL4R, MS4A2, SERPINE1, and TNF) with respect to 116 traits assessed through blood tests, hypertonic saline challenge tests, questionnaires, and skin prick tests. Multiple associations were observed for ADAM33: rs2280090 was associated with reduced MEF240% (i.e., the ratio of Mean Expiratory Flow after 240s of hypertonic saline inhalation with respect to the age- and ancestry-matched reference value) and with an increased risk of allergic bronchitis (p = 1.77*10−4 and p = 7.94*10−4, respectively); rs3918396 was associated with wheezing and eczema comorbidity (p = 3.41*10−4). IL4 rs2243250 was associated with increased FEV240 (Forced Expiratory Flow Volume after 240s of hypertonic saline inhalation; p = 4.81*10−4) and CD14 rs2569190 was associated with asthma diagnosis (p = 1.36*10−3). ADAM33 and IL4 appeared to play a role in the processes linked to allergic airway inflammation and lung function. Due to its association with wheezing and eczema comorbidity, ADAM33 may also be involved in the atopic march.
Associations of the MCM6-rs3754686 proxy for milk intake in Mediterranean and American populations with cardiovascular biomarkers, disease and mortality: Mendelian randomization
Authors: Smith Caren E. , Coltell Oscar , Sorlí Jose V. , Estruch Ramón , Martínez-González Miguel Ángel , Salas-Salvadó Jordi , Fitó Montserrat , Arós Fernando , Dashti Hassan S. , Lai Chao Q. , Miró Leticia , Serra-Majem Lluís , Gómez-Gracia Enrique , Fiol Miquel , Ros Emilio , Aslibekyan Stella , Hidalgo Bertha , Neuhouser Marian L. , Di Chongzhi , Tucker Katherine L. , Arnett Donna K. , Ordovás José M. , Corella Dolores
Published: September 2016

Controversy persists on the association between dairy products, especially milk, and cardiovascular diseases (CVD). Genetic proxies may improve dairy intake estimations, and clarify diet-disease relationships through Mendelian randomization. We meta-analytically (n ≤ 20,089) evaluated associations between a lactase persistence (LP) SNP, the minichromosome maintenance complex component 6 (MCM6)-rs3754686C>T (nonpersistence>persistence), dairy intake, and CVD biomarkers in American (Hispanics, African-American and Whites) and Mediterranean populations. Moreover, we analyzed longitudinal associations with milk, CVD and mortality in PREDIMED), a randomized Mediterranean diet (MedDiet) intervention trial (n = 7185). The MCM6-rs3754686/MCM6-rs309180 (as proxy), LP-allele (T) was strongly associated with higher milk intake, but inconsistently associated with glucose and lipids, and not associated with CVD or total mortality in the whole population. Heterogeneity analyses suggested some sex-specific associations. The T-allele was associated with higher CVD and mortality risk in women but not in men (P-sex interaction:0.005 and 0.032, respectively), mainly in the MedDiet group. However, milk intake was not associated with CVD biomarkers, CVD or mortality either generally or in sub-groups. Although MCM6-rs3754686 is a good milk intake proxy in these populations, attributing its associations with CVD and mortality in Mediterranean women to milk is unwarranted, as other factors limiting the assumption of causality in Mendelian randomization may exist.
Topological phase transition and quantum spin Hall edge states of antimony few layers
Authors: Kim Sung Hwan , Jin Kyung-Hwan , Park Joonbum , Kim Jun Sung , Jhi Seung-Hoon , Yeom Han Woong
Published: September 2016

While two-dimensional (2D) topological insulators (TI’s) initiated the field of topological materials, only very few materials were discovered to date and the direct access to their quantum spin Hall edge states has been challenging due to material issues. Here, we introduce a new 2D TI material, Sb few layer films. Electronic structures of ultrathin Sb islands grown on Bi2Te2Se are investigated by scanning tunneling microscopy. The maps of local density of states clearly identify robust edge electronic states over the thickness of three bilayers in clear contrast to thinner islands. This indicates that topological edge states emerge through a 2D topological phase transition predicted between three and four bilayer films in recent theory. The non-trivial phase transition and edge states are confirmed for epitaxial films by extensive density-functional-theory calculations. This work provides an important material platform to exploit microscopic aspects of the quantum spin Hall phase and its quantum phase transition.
Synthesis and mechanisms of action of novel harmine derivatives as potential antitumor agents
Authors: Zhang Xiao-Fei , Sun Rong-qin , Jia Yi-fan , Chen Qing , Tu Rong-Fu , Li Ke-ke , Zhang Xiao-Dong , Du Run-Lei , Cao Ri-hui
Published: September 2016

A series of novel harmine derivatives bearing a benzylindine substituent in position-1 of β-carboline ring were synthesized and evaluated as antitumor agents. The N2-benzylated β-carboline derivatives 3a–g represented the most interesting anticancer activities and compound 3c was found to be the most active agent to diverse cancer cell lines such as gastric carcinoma, melanoma and colorectal cancer. Notably, compound 3c showed low toxicity to normal cells. The treatment significantly induced cell apoptosis. Mechanistically, PI3K/AKT signaling pathway mediated compound 3c-induced apoptosis. Compound 3c inhibited phosphorylation of AKT and promoted the production of reactive oxygen species (ROS). The ROS scavenger, LNAC and GSH, could disturb the effect of compound 3c induced apoptosis and PI3K activity inhibitor LY294002 synergistically enhanced compound 3c efficacy. Moreover, the results from nude mice xenograft model showed that compound 3c treatment effectively inhibited tumor growth and decreased tumor weight. Collectively, our results demonstrated that compound 3c exerts apoptotic effect in cancer cells via suppression of phosphorylated AKT and evocation of ROS generation, which suggested that compound 3c might be served as a promising therapeutic agent for cancer treatment.
Residue Geometry Networks: A Rigidity-Based Approach to the Amino Acid Network and Evolutionary Rate Analysis
Authors: Fokas Alexander S. , Cole Daniel J. , Ahnert Sebastian E. , Chin Alex W.
Published: September 2016

Amino acid networks (AANs) abstract the protein structure by recording the amino acid contacts and can provide insight into protein function. Herein, we describe a novel AAN construction technique that employs the rigidity analysis tool, FIRST, to build the AAN, which we refer to as the residue geometry network (RGN). We show that this new construction can be combined with network theory methods to include the effects of allowed conformal motions and local chemical environments. Importantly, this is done without costly molecular dynamics simulations required by other AAN-related methods, which allows us to analyse large proteins and/or data sets. We have calculated the centrality of the residues belonging to 795 proteins. The results display a strong, negative correlation between residue centrality and the evolutionary rate. Furthermore, among residues with high closeness, those with low degree were particularly strongly conserved. Random walk simulations using the RGN were also successful in identifying allosteric residues in proteins involved in GPCR signalling. The dynamic function of these residues largely remain hidden in the traditional distance-cutoff construction technique. Despite being constructed from only the crystal structure, the results in this paper suggests that the RGN can identify residues that fulfil a dynamical function.