bluuebunny/crossref_metadata_2025 huggingface dataset:
Construction of thousands of single cell genome sequencing libraries using combinatorial indexing
Authors: Vitak Sarah A. , Torkenczy Kristof A. , Rosenkrantz Jimi L. , Fields Andrew J. , Christiansen Lena , Wong Melissa H. , Carbone Lucia , Steemers Frank J. , Adey Andrew
Published: July 2016

Single cell genome sequencing has proven to be a valuable tool for the detection of somatic variation, particularly in the context of tumor evolution and neuronal heterogeneity. Current technologies suffer from high per-cell library construction costs which restrict the number of cells that can be assessed, thus imposing limitations on the ability to quantitatively measure genomic heterogeneity within a tissue. Here, we present Single cell Combinatorial Indexed Sequencing (SCI-seq) as a means of simultaneously generating thousands of low-pass single cell libraries for the purpose of somatic copy number variant detection. In total, we constructed libraries for 16,698 single cells from a combination of cultured cell lines, frontal cortex tissue fromMacaca mulatta, and two human adenocarcinomas. This novel technology provides the opportunity for low-cost, deep characterization of somatic copy number variation in single cells, providing a foundational knowledge across both healthy and diseased tissues.
Preprocessing, normalization and integration of the Illumina HumanMethylationEPIC array
Authors: Fortin Jean-Philippe , Triche Timothy J. , Hansen Kasper D.
Published: July 2016

Theminfipackage is widely used for analyzing Illumina DNA methylation array data. Here we describe modifications to theminfipackage required to support the HumanMethylationEPIC (”EPIC”) array from Illumina. We discuss methods for the joint analysis and normalization of data from the HumanMethylation450 (”450k”) and EPIC platforms. We also introduce the single-sample Noob (ssNoob) method, a normalization procedure suitable for incremental preprocessing of individual Human-Methylation arrays. Our results recommend thessNoobmethod when integrating data from multiple generations of Infinium methylation arrays. Finally, we show how to use reference 450k datasets to estimate cell type composition of samples on EPIC arrays. The cumulative effect of these updates is to ensure thatminfiprovides the tools to best integrate existing and forthcoming Illumina methylation array data.
Numerical aspect of Predator-Pray Model
Authors: Nir Monika Justyna , Majumdar Sarangam
Published: July 2016

In a closed eco-system, there are only two types of animals: the predator and the prey. They form a simple food-chain where the predator species hunts the prey species, while the prey grazes vegetation. The size of the two populations can be described by a simple system of two nonlinear first order differential equations formally known as the Lotka-Volterra equations, which originated in the study of fish populations of the Mediterranean during and immediately after World War I. Here, we study numerically this nonlinear parabolic evolution problem and compare the result of various numerical schemes.
TelomereHunter: telomere content estimation and characterization from whole genome sequencing data
Authors: Feuerbach Lars , Sieverling Lina , Deeg Katharina I. , Ginsbach Philip , Hutter Barbara , Buchhalter Ivo , Northcott Paul A. , Lichter Peter , Pfister Stefan M. , Jones David T.W. , Rippe Karsten , Brors Benedikt
Published: July 2016

Telomere shortening plays an important role in cellular aging and tumor suppression. The availability of large next-generation sequencing cohorts of matched tumor and control samples enables a computational high-throughput analysis of changes in telomere content and composition in cancer. Here we describe a novel software tool specifically tailored for the processing of large data collections.

Availability and Implementation:

TelomereHunter is implemented as a python package. It is freely available online at:http://www.dkfz.de/en/applied-bioinformatics/telomerehunter/telomerehunter.html.
Cost-effectiveness of pharmacogenetic-guided treatment: are we there yet?
Authors: Verbelen Moira , Weale Michael E , Lewis Cathryn M
Published: July 2016

Pharmacogenetics (PGx) has the potential to personalize pharmaceutical treatments. Many relevant gene-drug associations have been discovered, but PGx guided treatment needs to be cost-effective as well as clinically beneficial to be incorporated into standard healthcare. Progress in this area can be assessed by reviewing economic evaluations to determine the cost-effectiveness of PGx testing versus standard treatment. We performed a review of economic evaluations for PGx associations listed in the US Food and Drug Administration (FDA) Table of Pharmacogenomic Biomarkers in Drug Labeling (http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm). We determined the proportion of evaluations that found PGx guided treatment to be cost-effective or dominant over the alternative strategies, and we estimated the impact on this proportion of removing the cost of genetic testing. Of the 130 PGx associations in the FDA table, 44 economic evaluations, relating to 10 drugs, were identified. Of these evaluations, 57% drew conclusions in favour of PGx testing, of which 30% were cost-effective and 27% were dominant (cost-saving). If genetic information was freely available, 75% of economic evaluations would support PGx guided treatment, of which 25% would be cost-effective and 50% would be dominant. Thus, PGx guided treatment can be a cost-effective and even cost-saving strategy. Having genetic information readily available in the clinical health record is a realistic future prospect, and would make more genetic tests economically worthwhile. However, few drugs with PGx associations have been studied and more economic evaluations are needed to underpin the uptake of genetic testing in clinical practice.
Enhanced representation of space by prefrontal neuronal ensembles and its dependence on cognitive states
Authors: Dehaqani Mohammad-Reza A. , Vahabie Abdol-Hossein , Parsa Mohammadbagher , Noudoost Behard , Soltani Alireza
Published: July 2016

Although individual neurons can be highly selective to particular stimuli and certain upcoming actions, they can provide a complex representation of stimuli and actions at the level of population. The ability to dynamically allocate neural resources is crucial for cognitive flexibility. However, it is unclear whether cognitive flexibility emerges from changes in activity at the level of individual neurons, population, or both. By applying a combination of decoding and encoding methods to simultaneously recorded neural data, we show that while maintaining their stimulus selectivity, neurons in prefrontal cortex alter their correlated activity during various cognitive states, resulting in an enhanced representation of visual space. During a task with various cognitive states, individual prefrontal neurons maintained their limited spatial sensitivity between visual encoding and saccadic target selection whereas the population selectively improved its encoding of spatial locations far from the neurons' preferred locations. This 'encoding expansion' relied on high-dimensional neural representations and was accompanied by selective reductions in noise correlation for non-preferred locations. Our results demonstrate that through recruitment of less-informative neurons and reductions of noise correlation in their activity, the representation of space by neuronal ensembles can be dynamically enhanced, and suggest that cognitive flexibility is mainly achieved by changes in neural representation at the level of population of prefrontal neurons rather than individual neurons.
Hereditary lactate dehydrogenase M‐subunit deficiency with late‐developing pustular psoriasis‐like lesions
Authors: Takeo Naoko , Fujiwara Sakuhei , Sakai Takashi , Saito‐Shono Tomoko , Ishikawa Kazushi , Hatano Yutaka
Published: July 2016

Hereditary lactate dehydrogenase (LDH) M‐subunit deficiency is very rare and we have found reports of close to a dozen cases in the published work, two of which were associated with pustular psoriasis‐like lesions. We report a third case of pustular psoriasis‐like eruptions associated with LDH M‐subunit deficiency, which occurred 24 years after the diagnosis of LDH M‐subunit deficiency. These cases indicate that abnormal activity of LDH can induce pustular psoriatic lesions in the long term. Some patients with symptoms of hereditary LDH M‐subunit deficiency have antecedent annular scaly plaque lesions, that resemble psoriatic lesions. We discuss a hypothesis to explain this scenario.
Direct and indirect genetic and fine‐scale location effects on breeding date in song sparrows
Authors: Germain Ryan R. , Wolak Matthew E. , Arcese Peter , Losdat Sylvain , Reid Jane M.
Published: July 2016

Quantifying direct and indirect genetic effects of interacting females and males on variation in jointly expressed life‐history traits is central to predicting microevolutionary dynamics. However, accurately estimating sex‐specific additive genetic variances in such traits remains difficult in wild populations, especially if related individuals inhabit similar fine‐scale environments.

Breeding date is a key life‐history trait that responds to environmental phenology and mediates individual and population responses to environmental change. However, no studies have estimated female (direct) and male (indirect) additive genetic and inbreeding effects on breeding date, and estimated the cross‐sex genetic correlation, while simultaneously accounting for fine‐scale environmental effects of breeding locations, impeding prediction of microevolutionary dynamics.

We fitted animal models to 38 years of song sparrow (Melospiza melodia) phenology and pedigree data to estimate sex‐specific additive genetic variances in breeding date, and the cross‐sex genetic correlation, thereby estimating the total additive genetic variance while simultaneously estimating sex‐specific inbreeding depression. We further fitted three forms of spatial animal model to explicitly estimate variance in breeding date attributable to breeding location, overlap among breeding locations and spatial autocorrelation. We thereby quantified fine‐scale location variances in breeding date and quantified the degree to which estimating such variances affected the estimated additive genetic variances.

The non‐spatial animal model estimated nonzero female and male additive genetic variances in breeding date (sex‐specific heritabilities: 0·07 and 0·02, respectively) and a strong, positive cross‐sex genetic correlation (0·99), creating substantial total additive genetic variance (0·18). Breeding date varied with female, but not male inbreeding coefficient, revealing direct, but not indirect, inbreeding depression. All three spatial animal models estimated small location variance in breeding date, but because relatedness and breeding location were virtually uncorrelated, modelling location variance did not alter the estimated additive genetic variances.

Our results show that sex‐specific additive genetic effects on breeding date can be strongly positively correlated, which would affect any predicted rates of microevolutionary change in response to sexually antagonistic or congruent selection. Further, we show that inbreeding effects on breeding date can also be sex specific and that genetic effects can exceed phenotypic variation stemming from fine‐scale location‐based variation within a wild population.
Intracellular movement of protein aggregates reveals heterogeneous inactivation and resuscitation dynamics in stressed populations of Escherichia coli
Authors: Govers Sander K. , Gayan Elisa , Aertsen Abram
Published: July 2016

Inactivation of bacterial pathogens is of critical importance in fields ranging from antimicrobial therapy to food preservation. The efficacy of an antimicrobial treatment is often experimentally determined through viable plate counts that inherently provide a poor focus on the mechanisms and distribution of (sub)lethal injury and subsequent inactivation or resuscitation behavior of the stressed cells, which are increasingly important features for the proper understanding and design of inactivation strategies. In this report, we employ a live cell biology approach focusing on the energy‐dependent motion of intracellular protein aggregates to investigate the heterogeneity within heat stressed Escherichia coli populations. As such, we were able to identify differential dynamics of cellular resuscitation and inactivation that are impossible to distinguish using more traditional approaches. Moreover, our data indicate the existence of late‐resuscitating cells that remain physiologically active and are able to persist in the presence of antibiotics before resuscitation.
Pediatric obesity is associated with an altered gut microbiota and discordant shifts in Firmicutes populations
Authors: Riva Alessandra , Borgo Francesca , Lassandro Carlotta , Verduci Elvira , Morace Giulia , Borghi Elisa , Berry David
Published: July 2016

An altered gut microbiota has been linked to obesity in adulthood, although little is known about childhood obesity. The aim of this study was to characterize the composition of the gut microbiota in obese (n = 42) and normal‐weight (n = 36) children aged 6 to 16. Using 16S rRNA gene‐targeted sequencing, we evaluated taxa with differential abundance according to age‐ and sex‐normalized body mass index (BMI z‐score). Obesity was associated with an altered gut microbiota characterized by elevated levels of Firmicutes and depleted levels of Bacteroidetes. Correlation network analysis revealed that the gut microbiota of obese children also had increased correlation density and clustering of operational taxonomic units (OTUs). Members of the Bacteroidetes were generally better predictors of BMI z‐score and obesity than Firmicutes, which was likely due to discordant responses of Firmicutes OTUs. In accordance with these observations, the main metabolites produced by gut bacteria, short chain fatty acids (SCFAs), were higher in obese children, suggesting elevated substrate utilisation. Multiple taxa were correlated with SCFA levels, reinforcing the tight link between the microbiota, SCFAs and obesity. Our results suggest that gut microbiota dysbiosis and elevated fermentation activity may be involved in the etiology of childhood obesity.
Identification of an iron permease, cFTR1, in cyanobacteria involved in the iron reduction/re‐oxidation uptake pathway
Authors: Xu Ning , Qiu Guo‐Wei , Lou Wen‐Jing , Li Zheng‐Ke , Jiang Hai‐Bo , Price Neil M. , Qiu Bao‐Sheng
Published: July 2016

Cyanobacteria are globally important primary producers and abundant in many iron‐limited aquatic environments. The ways in which they take up iron are largely unknown, but reduction of Fe3+ is an important step in the process. Here we report a special iron permease in Synechocystis, cFTR1, that is required for Fe3+ uptake following Fe2+ re‐oxidation. The expression of cFTR1 is induced by iron starvation, and a mutant lacking the gene is abnormally sensitive to iron starvation. The cFTR1 protein localizes to the plasma membrane and contains the iron‐binding motif “REXXE”. Point‐directed mutagenesis of the REXXE motif results in a sensitivity to Fe‐deficiency. Measurements of iron (55Fe) uptake rate show that cFTR1 takes up Fe3+ rather than Fe2+. The function of cFTR1 in Synechocystis could be genetically complemented by the iron permease, Ftr1p, of Saccharomyces cerevisiae, that is known to transport Fe3+ produced by the oxidation of Fe2+ via a multicopper oxidase. Unlike yeast Ftr1p, cyanobacterial cFTR1 probably obtains Fe3+ primarily from the oxidation of Fe2+ by oxygen. Growth assays show that the cFTR1 is required during oxygenic, photoautotrophic growth but not when oxygen production is inhibited during photoheterotrophic growth. In cyanobacteria, iron reduction/re‐oxidation uptake pathway may represent their adaptation to oxygenated environments.
Mating behavior of Psammotettix alienus (Hemiptera: Cicadellidae)
Authors: Derlink Maja , Abt Isabelle , Mabon Romain , Julian Charlotte , Virant‐Doberlet Meta , Jacquot Emmanuel
Published: July 2016

The Wheat dwarf virus, the causal agent of the wheat dwarf disease, is transmitted by leafhoppers from the genus Psammotettix and currently the main protection strategy is based on the use of insecticide treatments. Sustainable management strategies for insect vectors should include methods that are targeted to disrupt reproductive behavior and here we investigated the mating behavior of Psammotettix alineus (Dahlbom 1850) in order to determine the role of vibrational signals in intra‐specific communication and pair formation. Both genders spontaneously emit species‐ and sex‐specific calling songs that consisted of regularly repeated pulse trains and differ primarily in pulse train duration and pulse repetition time. Females preferred the conspecific male calling song. After a coordinated exchange of pulse trains, the male approached the stationary female. During the close range courtship and also immediately prior to copulatory attempts distinct male vibrational signals associated with wing flapping and wing vibrations were recorded from the substrate. In the presence of a receptive female, competing males emitted vibrational signals most likely aimed to interfere with male‐female interaction. Mated females regained sexual receptivity after they laid eggs. Although results suggest that the viruliferous status of insects may have an effect on vibrational songs, our current results did not reveal a significant effect of virus on leafhopper performance in mating behavior. However, this study also suggests, that detailed understanding of plant–vector–virus interactions relevant for vector mating behavior is essential for trying new approaches in developing future control practices against plant viruses transmitted by insect vectors.
Treatment efficacy and safety of low‐dose azathioprine in chronic active ulcerative colitis patients: A meta‐analysis and systemic review
Authors: Luan Zi Jian , Li Yue , Zhao Xin Yu , Wang Li , Sun Ying Hao , Wang Shi Yao , Qian Jia Ming
Published: July 2016

Objective

To evaluate the efficacy and safety of low‐dose azathioprine (AZA) in treating patients with chronic active ulcerative colitis (UC).

Methods

A literature search of Medline, Embase, the Cochrane Library, Web of Science, Wanfang Database, CNKI, SinoMed, VIP Chinese Science and the Technology Journals Database was conducted to identify eligible studies that evaluated the efficacy and safety of low‐dose azathioprine (AZA) in treating patients with chronic active UC published up to 15 July 2015. Data were extracted from the studies, including clinical efficacy (response rate, adverse drug reaction [ADR] rate, steroid withdrawal rate and relapse rate) and endoscopic improvement (endoscopic remission rate and mucosal healing rate).

Results

Six studies with 211 patients were eligible for the analysis. The overall response rates after 6 and 12 months of treatment were 78.0% (95% confidence interval [CI] 71.0–85.0%) and 88.0% (95% CI 80.0–96.0%), respectively. The overall ADR rate was 25.0% (95% CI 18.0–31.0%). Endoscopic response rate was around 85.0%, while the endoscopic remission rates and mucosal healing rates after 6 and 12 months of treatment were above 60.0% and 70.0%, respectively. The steroid withdrawal rate and relapse rate were in moderate to high heterogeneity. Egger's test indicated that there was no publication bias for studies regarding the 6‐month response rate and ADR rate.

Conclusions

Low‐dose AZA is effective and safe in the treatment of chronic active UC patients. However, randomized controlled trials with large sample sizes are needed to draw definitive conclusions.
FAST MRI breast screening revisited
Authors: Jain Manish , Jain Arushi , Hyzy Marek D , Werth Graziella
Published: July 2016

Introduction

Screening for breast cancer in high‐risk women takes about 40 minutes to acquire an MRI scan and is time‐intensive to report. There is recent interest in the performance of an abbreviated MRI protocol (FAST) in the screening setting. FAST scans have a reported negative predictive value of 99.8%. This study evaluates the false positive rates (FPR) and recall rates for FAST scans as compared to full diagnostic studies (FD).

Methods

A database of all screening breast MRI scans performed at our institution between 30 June 2013 and 1 July 2014 (n = 591) was created by one of the researchers, who did not subsequently analyse the MRI scans. The T1W and first post‐contrast and subtracted images from each of these scans (FAST protocol) were assessed by experienced breast MRI radiologists, blinded to the final diagnosis. The findings were then compared with the FD result.

Results

The recall rates were 6.6% for FAST scans and 5.8% for FD scans. FPR rates were 4.7% and 3.9% respectively. There is no statistically significant difference in the recall rates or FPR of FAST scans in comparison with full diagnostic studies.

Conclusions

Given the absence of statistically significant difference in the FPR and recall rates in comparison with FD, FAST scans can replace FD for screening of breast cancer.
Contesting the Divided City: Arts of Resistance in Skopje
Authors: Véron Ophélie
Published: July 2016

This paper examines issues of power and resistance in “divided cities”. Basing my analysis on fieldwork I carried out in Skopje, Macedonia, I look at how urban space may be constructed and used by hegemonic groups as a means of asserting their power and how, in turn, the city may be a place of resistance where power is contested and public space reappropriated. Drawing on Lefebvre's perspective on the production of space, I compare the conceived city to the lived city and examine how urban inhabitants may resist the division of the city and challenge hegemonic representations. I also draw on Debord's psychogeography to define an artistic, active and participatory approach to urban space through which the inhabitants may re‐conquer their right to the œuvre and to the city. I argue that the city as a lived environment may offer narratives other than division and that there are alternatives to the divided city.
Filipino Women Migrant Workers and Overseas Employment Policy: An Analysis From Women's Rights Perspective
Authors: Encinas‐Franco Jean
Published: July 2016

The Philippines is one of the world's top migrant‐sending countries. Besides financial transfers and the spread and magnitude of Filipino presence on a global scale, feminization of migration has been an important characteristic of this outmigration trend since the 1980s. Heightened globalization, lack of economic opportunities, government policies, and demographic shifts have all propelled this exodus. There is an existing policy that governs the flows of migrant workers in the Philippines as well as international commitments to safeguard the rights of migrant workers. In this Praxis feature, political scientist Jean Encinas‐Franco from the University of the Philippines evaluates to what extent has the implementation of this existing Philippine migration policy been consistent with standards and norms pertaining to women's rights, particularly against discrimination. Using a feminist perspective, Encinas‐Franco finds that some provisions of the policy are not consistent with existing international standards. She also argues that while protection against abuse and discrimination is a fundamental concern, the right of women migrant workers to travel and avail of employment opportunities that are not otherwise available in the country should also not be compromised. The Philippine experience and possible policy improvements could be instructive to other migrant‐sending countries in Asia and beyond.
Application of the integrated glucose–insulin model for cross‐study characterization of T2DM patients on metformin background treatment
Authors: Parkinson Joanna , Hamrén Bengt , Kjellsson Maria C. , Skrtic Stanko
Published: July 2016

Aim

The integrated glucose–insulin (IGI) model is a semi‐mechanistic physiological model which can describe the glucose–insulin homeostasis system following various glucose challenge settings. The aim of the present work was to apply the model to a large and diverse population of metformin‐only‐treated type 2 diabetes mellitus (T2DM) patients and identify patient‐specific covariates.

Methods

Data from four clinical studies were pooled, including glucose and insulin concentration–time profiles from T2DM patients on stable treatment with metformin alone following mixed‐meal tolerance tests. The data were collected from a wide range of patients with respect to the duration of diabetes and level of glycaemic control.

Results

The IGI model was expanded by four patient‐specific covariates. The level of glycaemic control, represented by baseline glycosylated haemoglobin was identified as a significant covariate for steady‐state glucose, insulin‐dependent glucose clearance and the magnitude of the incretin effect, while baseline body mass index was a significant covariate for steady‐state insulin levels. In addition, glucose dose was found to have an impact on glucose absorption rate. The developed model was used to simulate glucose and insulin profiles in different groups of T2DM patients, across a range of glycaemic control, and it was found accurately to characterize their response to the standard oral glucose challenge.

Conclusions

The IGI model was successfully applied to characterize differences between T2DM patients across a wide range of glycaemic control. The addition of patient‐specific covariates in the IGI model might be valuable for the future development of antidiabetic treatment and for the design and simulation of clinical studies.
Learning words and learning sounds: Advances in language development
Authors: Vihman Marilyn M.
Published: July 2016

Phonological development is sometimes seen as a process of learning sounds, or forming phonological categories, and then combining sounds to build words, with the evidence taken largely from studies demonstrating ‘perceptual narrowing’ in infant speech perception over the first year of life. In contrast, studies of early word production have long provided evidence that holistic word learning may precede the formation of phonological categories. In that account, children begin by matching their existing vocal patterns to adult words, with knowledge of the phonological system emerging from the network of related word forms. Here I review evidence from production and then consider how the implicit and explicit learning mechanisms assumed by the complementary memory systems model might be understood as reconciling the two approaches.
Somewhere I belong: Long‐term increases in adolescents’ resilience are predicted by perceived belonging to the in‐group
Authors: Scarf Damian , Moradi Saleh , McGaw Kate , Hewitt Joshua , Hayhurst Jillian G. , Boyes Mike , Ruffman Ted , Hunter John A.
Published: July 2016

This study sought to examine the role of belonging in the increases in resilience observed following an adventure education programme (AEP). First, we demonstrate that group belonging makes a significant contribution to the improvement in resilience participants’ experienced over the course of the AEP. Second, we demonstrate that this increase in resilience is maintained 9 months following the AEP and that group belonging maintained a significant contribution when controlling for participants’ initial resilience level and other psychosocial variables (i.e., centrality of identity and social support). Our findings accord well with recent research on the Social Cure or Social Identity Approach to Health and add to a growing body of work identifying the mechanisms underlying this phenomenon.
The novel late Na+ current inhibitor, GS‐6615 (eleclazine) and its anti‐arrhythmic effects in rabbit isolated heart preparations
Authors: Rajamani Sridharan , Liu Gongxin , El‐Bizri Nesrine , Guo Donglin , Li Cindy , Chen Xiao‐Liang , Kahlig Kristopher M , Mollova Nevena , Elzein Elfatih , Zablocki Jeff , Belardinelli Luiz
Published: July 2016

Background and Purpose

Enhanced late Na+ current (late INa) in the myocardium is pro‐arrhythmic. Inhibition of this current is a promising strategy to stabilize ventricular repolarization and suppress arrhythmias. Here, we describe GS‐6615, a selective inhibitor of late INa, already in clinical development for the treatment of long QT syndrome 3 (LQT3).

Experimental Approach

The effects of GS‐6615 to inhibit late INa, versus other ion currents to shorten the ventricular action potential duration (APD), monophasic APD (MAPD) and QT interval, and decrease to the incidence of ventricular arrhythmias was determined in rabbit cardiac preparations. To mimic the electrical phenotype of LQT3, late INa was increased using the sea anemone toxin (ATX‐II).

Key Results

GS‐6615 inhibited ATX‐II enhanced late INa in ventricular myocytes (IC50 = 0.7 μM), shortened the ATX‐II induced prolongation of APD, MAPD, QT interval, and decreased spatiotemporal dispersion of repolarization and ventricular arrhythmias. Inhibition by GS‐6615 of ATX‐II enhanced late INa was strongly correlated with shortening of myocyte APD and isolated heart MAPD (R2 = 0.94 and 0.98 respectively). In contrast to flecainide, GS‐6615 had the minimal effects on peak INa. GS‐6615 did not decrease the maximal upstroke velocity of the action potential (Vmax) nor widen QRS intervals.

Conclusions and Implications

GS‐6615 was a selective inhibitor of late INa, stabilizes the ventricular repolarization and suppresses arrhythmias in a model of LQT3. The concentrations at which the electrophysiological effects of GS‐6615 were observed are comparable to plasma levels associated with QTc shortening in patients with LQT3, indicating that these effects are clinically relevant.
Structure‐based virtual screening toward the discovery of novel inhibitors of the DNA repair activity of the human apurinic/apyrimidinic endonuclease 1
Authors: Guerreiro Patrícia S. , Estácio Sílvia G. , Antunes Fernando , Fernandes Ana S. , Pinheiro Pedro F. , Costa João G. , Castro Matilde , Miranda Joana P. , Guedes Rita C. , Oliveira Nuno G.
Published: July 2016

The DNA repair activity of human apurinic/apyrimidinic endonuclease 1 (APE1) has been recognized as a promising target for the development of small‐molecule inhibitors to be used in combination with anticancer agents. In an attempt to identify novel inhibitors of APE1, we present a structure‐based virtual screening (SBVS) study based on molecular docking analysis of the compounds of NCI database using the GOLD 5.1.0 (Genetic Optimization for Ligand Docking) suite of programs. Compounds selected in this screening were tested with a fluorescence‐based APE1 endonuclease activity assay. Two compounds (37 and 41) were able to inhibit the multifunctional enzyme APE1 in the micromolar range, while compound 22 showed inhibitory effects at nanomolar concentrations. These results were confirmed by a plasmid DNA nicking assay. In addition, the potential APE1 inhibitors did not affect the cell viability of non‐tumor MCF10A cells. Overall, compounds 22, 37, and 41 appear to be important scaffolds for the design of novel APE1 inhibitors and this study highlights the relevance of in silico‐based approaches as valuable tools in drug discovery.
Hydrus microstent compared to selective laser trabeculoplasty in primary open angle glaucoma: one year results
Authors: Fea Antonio M , Ahmed Iqbal Ike K , Lavia Carlo , Mittica Pietro , Consolandi Giulia , Motolese Ilaria , Pignata Giulia , Motolese Eduardo , Rolle Teresa , Frezzotti Paolo
Published: July 2016

Background

To compare the reduction of intraocular pressure (IOP) and glaucoma medications following selective laser trabeculoplasty (SLT) versus stand‐alone placement of the Hydrus microstent, a microinvasive glaucoma surgery device.

Design

Prospective interventional case‐series. University practice.

Participants

Fifty six eyes (56 patients) with uncontrolled primary open‐angle glaucoma.

Methods

Patients received either SLT (n = 25) or Hydrus implantation (n = 31) in two centres. Patients were evaluated at baseline and 1, 7 days, 1, 3, 6 and 12 months after surgery.

Main Outcome Measures

Intraocular pressure and number of glaucoma medications variations inter‐groups and intra‐groups.

Results

There were no significant differences at baseline between groups, but the mean deviation was worse in the Hydrus group (−8.43 ± 6.84 dB, confidence limits (CL)−2.8/−3.3 vs.−3.04 ± 0.65 dB, CL−6/−10.8; P < 0.001). After 12 months, there was a significant decrease in IOP and medications in the Hydrus group compared with baseline values. In the SLT group, only the decrease in IOP was significant. There was 3‐fold greater reduction in medication use in the Hydrus group compared with SLT (−1.4 ± 0.97 vs.−0.5 ± 1.05, P = 0.001). 47% of patients were medication free at 12 months in the Hydrus group (4% in the SLT group). No complications were recorded in the SLT group. In the Hydrus group, three patients experienced a temporary reduction of visual acuity post‐operatively, and two patients had post‐operative IOP spikes that resolved within one week.

Conclusions

Both SLT and Hydrus implantation reduced IOP without serious adverse events. Hydrus implantation led to a significant and further reduction in medication dependence at 12 months.
A mathematical model provides new insights into solid organ transplant‐associated acute graft‐versus‐host disease
Authors: Rashidi Armin
Published: July 2016

Solid organ transplantation‐associated acute graft‐versus‐host disease (SOT‐aGvHD) is a rare but highly fatal condition. Our poor understanding of this entity in addition to its rarity has hampered treatment progress and most patients succumb to the disease. A mechanistic mathematical model is developed to replicate and explain the complex pathogenesis of SOT‐aGvHD. The model captures a number of important features of SOT‐aGvHD including (i) the occurrence of stable and persistent mixed chimerism in some, but not all, cases, (ii) fluctuation in chimerism in some persistently mixed chimeric cases, (iii) rare occurrence of full donor chimerism, and (iv) beneficial effect of escalating immunosuppression in some cases of SOT‐aGvHD and detrimental effect in others. In addition, the model predicts the conditions under which escalation or de‐escalation of immunosuppression would be the preferred treatment strategy. In an exceedingly rare condition such as SOT‐aGvHD, where prospective trials are not feasible, mathematical modeling can provide useful insights into pathogenesis and treatment.
The Use of Fictional Stories in Science Exhibits: The Emperor Who Only Believed His Own Eyes
Authors: Murmann Mai , Avraamidou Lucy
Published: July 2016

The authors explore how fictional narratives (stories) can be used as a learning tool in the context of informal science environments and specifically science centers. They base their argument on an analysis of the theoretical, structural and epistemological properties of stories and how those can serve to establish a story as a cognitive tool. They offer an example of an application of these properties to a story‐based learning design called “The Emperor who only Believed his own Eyes” in the context of a large, public science center, and specifically an exhibition about “senses”. This paper focuses on the idea of a “hack,” a museum sanctioned strategy for exploring the potential and implications of narrative‐based design as a way to reinterpret science exhibits in a way that can engage young users in content exploration and offer recommendations for future research.
Parameterisation and validation of a resource budget model for masting using spatiotemporal flowering data of individual trees
Authors: Abe Tomoyuki , Tachiki Yuuya , Kon Hirokazu , Nagasaka Akiko , Onodera Kensuke , Minamino Kazuhiro , Han Qingmin , Satake Akiko
Published: July 2016

Synchronised and fluctuating reproduction by plant populations, called masting, is widespread in diverse taxonomic groups. Here, we propose a new method to explore the proximate mechanism of masting by combining spatiotemporal flowering data, biochemical analysis of resource allocation and mathematical modelling. Flowering data of 170 trees over 13 years showed the emergence of clustering with trees in a given cluster mutually synchronised in reproduction, which was successfully explained by resource budget models. Analysis of resources invested in the development of reproductive organs showed that parametric values used in the model are significantly different between nitrogen and carbon. Using a fully parameterised model, we showed that the observed flowering pattern is explained only when the interplay between nitrogen dynamics and climatic cues was considered. This result indicates that our approach successfully identified resource type‐specific roles on masting and that the method is suitable for a wide range of plant species.
Efficacy of vasopressin V2 receptor antagonist tolvaptan in treatment of hepatic edema
Authors: Hiramine Yasunari , Uto Hirofumi , Imamura Yasushi , Hiwaki Takuya , Kure Takeshi , Ijuin Sho , Oda Kohei , Mawatari Seiichi , Kumagai Kotaro , Tokunaga Koki , Higashi Hirofumi , Kanetsuki Ichiro , Kubozono Osamu , Maenohara Shigeho , Ido Akio
Published: July 2016

Aim

Tolvaptan, an oral active vasopressin V2 receptor antagonist, is widely used for hepatic edema in Japan, but its clinical benefits have yet to be fully clarified. The present study evaluated the efficacy of tolvaptan in hepatic edema.

Methods

The efficacy and treatment regimen of tolvaptan were evaluated in 150 patients with hepatic edema by analyzing the initial (day 14) and long‐term (day 90) responses to the drug and their predictive factors. All patients were divided into good (Child–Pugh classification B, and absent of advanced hepatocellular carcinoma) and poor hepatic condition groups, and the response rates were compared between the two groups.

Results

The initial response rate was 62%, and the long‐term response rate was 47%. The assessment of predictive factors for response to tolvaptan showed that serum creatinine and C‐reactive protein levels were important predictors of initial response, and that hepatic conditions, such as the Child–Pugh score or presence of hepatocellular carcinoma, as well as initial response, were significant predictors of long‐term response. In addition, both the initial and long‐term response rates and the cumulative survival rate were found to be higher in the good hepatic condition group than in the poor hepatic condition group, respectively (71% vs. 57%, P = 0.113; 62% vs. 39%, P = 0.009; log–rank test, P < 0.001).

Conclusion

These results suggest that tolvaptan may provide high response rates when used early in the course of hepatic edema, or when both hepatic and renal functions are still retained, leading to an improved disease prognosis.
Effect of dextran glycation on nanofibril assembly of soya β‐conglycinin at pH 2.0 and the pH stability of nanofibrils
Authors: Zou Yuan , Chen Yanqiong , Wang Mengping , Wang Jinmei , Yang Xiaoquan
Published: July 2016

In this study, we investigated the effects of dextran glycation on soya β‐conglycinin self‐assembly into nanofibrils at 85 °C and pH 2.0, as well as their stability at pH 2.0–10.0. Although the hydrolysis rate of β‐conglycinin decreased, glycation significantly increased the structural change rate in the initial stage of nanofibril formation and the growth of nanofibril. It is suggested that the glycation of three subunits (α′, α, β) in β‐conglycinin may promote fibril assembly because the extension regions of α′ and α subunits play an important role in affecting the rate of structural changes in fibril formation. At neutral pH, conjugate nanofibrils are highly dispersible and transparent and remained greater structural stability compared with mixture. The improvement stability of conjugate nanofibrils may be contributed to dextran which provides some steric hindrance to prevent the aggregation of nanofibrils; this would also facilitate the application of soya β‐conglycinin nanofibrils in food industry.
Effect of clove extract pretreatment and drying conditions on lipid oxidation and sensory discrimination of dried omena (Rastrineobola argentea) fish
Authors: Slavin Margaret , Dong Mengyi , Gewa Constance
Published: July 2016

Sun‐drying is a low‐cost, low‐technology fish preservation method frequently employed in developing areas. However, the process promotes lipid oxidation and its associated undesired flavours and odours. This study investigated low‐technology solutions for impact on lipid oxidation and sensory attributes of oven‐dried omena fish (Rastrineobola argentea). Two oven‐drying conditions and four doses of clove water extract ‘dip’ pretreatments were studied in a complete factorial design. Lipid oxidation in dried fish was assessed by TBARS, peroxide value and fatty acid analysis by GC‐FID. Results showed that soaking in 10 g L−1 clove water extract for 1 h and oven‐drying at 150 °C × 30 min significantly reduced TBARS and peroxide values in omena fish by 77% and 79%, respectively, and polyene index showed improved retention of long‐chain polyunsaturated fats, compared to original drying condition. Lastly, panellists of a triangle test were able to discriminate between biscuits made with the modified and original dried fish.
Thermal Runaway in Mold‐Assisted Flash Sintering
Authors: Dong Yanhao , Chen I.‐Wei
Published: July 2016

Analyzing the temperature evolution in pressureless mold‐assisted flash sintering, we found the same onset condition as in standard flash sintering: When sample's DC or AC Joule heating replaces environment's radiation heating as the dominant power input term, thermal runaway ensues. Various serial and parallel components connected to the sample, including the mold, insulation, and punches, can affect Joule heating and conduction heat loss, thus play an important role in successful mold‐assisted flash sintering.
Too Good to be True? An Analysis of the Options Market's Reactions to Earnings Releases
Authors: Lu Yan , Ray Sugata
Published: July 2016

Using option implied risk neutral return distributions before and after earnings announcements, we study the option market's reaction to extreme events over earnings announcements. While earnings announcements generally reduce short‐term uncertainty about the stock price, very good news does not reduce uncertainty and slightly bad news actually increases uncertainty. We also find that left tail probabilities decrease over earnings releases while right tail probabilities increase. We interpret these findings as evidence of maintained investor expectations that very good news is generally not released during earnings announcements, combined with skepticism in the form of lingering uncertainty at the release of such very good news.
Response time variability under slow and fast‐incentive conditions in children with ASD, ADHD and ASD+ADHD
Authors: Tye Charlotte , Johnson Katherine A. , Kelly Simon P. , Asherson Philip , Kuntsi Jonna , Ashwood Karen L. , Azadi Bahare , Bolton Patrick , McLoughlin Gráinne
Published: July 2016

Background

Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) show significant behavioural and genetic overlap. Both ADHD and ASD are characterised by poor performance on a range of cognitive tasks. In particular, increased response time variability (RTV) is a promising indicator of risk for both ADHD and ASD. However, it is not clear whether different indices of RTV and changes to RTV according to task conditions are able to discriminate between the two disorders.

Methods

Children with ASD (n = 19), ADHD (n = 18), ASD + ADHD (n = 29) and typically developing controls (TDC; n = 26) performed a four‐choice RT task with slow‐baseline and fast‐incentive conditions. Performance was characterised by mean RT (MRT), standard deviation of RT (SD‐RT), coefficient of variation (CV) and ex‐Gaussian distribution measures of Mu, Sigma and Tau.

Results

In the slow‐baseline condition, categorical diagnoses and trait measures converged to indicate that children with ADHD‐only and ASD + ADHD demonstrated increased MRT, SD‐RT, CV and Tau compared to TDC and ASD‐only. Importantly, greater improvement in MRT, SD‐RT and Tau was demonstrated in ADHD and ASD + ADHD from slow‐baseline to fast‐incentive conditions compared to TDC and ASD‐only.

Conclusions

Slower and more variable RTs are markers of ADHD compared to ASD and typically developing controls during slow and less rewarding conditions. Energetic factors and rewards improve task performance to a greater extent in children with ADHD compared to children with ASD. These findings suggest that RTV can be distinguished in ASD, ADHD and ASD + ADHD based on the indices of variability used and the conditions in which they are elicited. Further work identifying neural processes underlying increased RTV is warranted, in order to elucidate disorder‐specific and disorder‐convergent aetiological pathways.
Authentic leadership and followers' in‐role and extra‐role performance: The mediating role of followers' learning goal orientation
Authors: Mehmood Qaiser , Hamstra Melvyn R. W. , Nawab Samina , Vriend Tim
Published: July 2016

This study examined whether and why authentic leadership predicts followers' performance. We hypothesized that authentic leadership predicts followers' learning goal orientation (goal to develop and improve), which, in turn, predicts followers' in‐role and (civic virtue) extra‐role performance. A multilevel, multisource, time‐lagged study, conducted in telecommunications companies in Pakistan, among 115 supervisors and 345 reports supported indirect relations between authentic leadership and (1) follower in‐role and (2) extra‐role performance (civic virtue) mediated by followers' learning goal orientation.

Practitioner points

Authentic leadership is considered to promote employees' developmental focus through authenticity on the part of the leader (e.g., being aware of one's strengths and weaknesses).

We discuss and analyse authentic leadership as an approach that involves managers' modelling of a learning goal orientation to followers.

Direct supervisors' authentic leadership was found to predict employees' in‐role and extra‐role (civic virtue) performance because it may model a focus on learning goals in followers.

Hence, important organizational outcomes can be improved through authentic leadership.
Fibroblast growth factor 23 and soluble Klotho in patients with autosomal dominant polycystic kidney disease
Authors: Akiyama Kenichi , Mochizuki Toshio , Kataoka Hiroshi , Tsuchiya Ken , Nitta Kosaku
Published: July 2016

Aim

This study aimed to examine the roles of fibroblast growth factor 23 (FGF23) and soluble Klotho in phosphate metabolism in autosomal‐dominant polycystic kidney disease (ADPKD) patients.

Methods

We measured these two factors and phosphate metabolism parameters in 80 patients with ADPKD and 53 patients with non‐diabetic chronic kidney disease (CKD).

Results

The mean serum FGF23 level in the ADPKD group was significantly (twofold) higher than in the non‐diabetic CKD patients, but the mean soluble Klotho level in the ADPKD group was significantly lower in the non‐diabetic CKD group. The mean serum phosphate levels of the two groups were similar. The estimated glomerular filtration rate (eGFR) was approximately 45 mL/min per 1.73 m2 in both groups, and their serum vitamin D metabolite levels were in the normal range.

Conclusion

The serum FGF23 levels were significantly higher and soluble Klotho levels significantly lower in the ADPKD group than in the non‐diabetic CKD group matched for eGFR, and these findings may be associated with resistance of renal phosphate excretion.