bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting comorbid diseases via network endopharmacology
Authors: Aguirre-Plans Juaquim , Piñero Janet , Menche Jörg , Sanz Ferran , Furlong Laura I , Schmidt Harald H. H. W. , Oliva Baldo , Guney Emre
Published: May 2018

The traditional drug discovery paradigm has shaped around the idea of “one target, one disease”. Recently, it has become clear that not only it is hard to achieve single target specificity but also it is often more desirable to tinker the complex cellular network by targeting multiple proteins, causing a paradigm shift towards polypharmacology (multiple targets, one disease). Given the lack of clear-cut boundaries across disease (endo)phenotypes and genetic heterogeneity across patients, a natural extension to the current polypharmacology paradigm is targeting common biological pathways involved in diseases, giving rise to “endopharmacology” (multiple targets, multiple diseases). In this study, leveraging powerful network medicine tools, we describe a recipe for first, identifying common pathways pertaining to diseases and then, prioritizing drugs that target these pathways towards endopharmacology. We present proximal pathway enrichment analysis (PxEA) that uses the topology information of the network of interactions between disease genes, pathway genes, drug targets and other proteins to rank drugs for their interactome-based proximity to pathways shared across multiple diseases, providing unprecedented drug repurposing opportunities. As a proof of principle, we focus on nine autoimmune disorders and using PxEA, we show that many drugs indicated for these conditions are not necessarily specific to the condition of interest, but rather target the common biological pathways across these diseases. Finally, we provide the high scoring drug repurposing candidates that can target common mechanisms involved in type 2 diabetes and Alzheimer’s disease, two phenotypes that have recently gained attention due to the increased comorbidity among patients.
isiKnock: in silico knockouts in biochemical pathways
Authors: Scheidel Jennifer , Giese Heiko , Schweizer Börje , Amstein Leonie , Ackermann Jörg , Koch Ina
Published: May 2018

isiKnock is a new software that automatically conducts in silico knockouts for mathematical models of biochemical pathways. The software allows for the prediction of the behavior of biological systems after single or multiple knockout. The implemented algorithm applies transition invariants and the novel concept of Manatee invariants. A knockout matrix visualizes the results. The tool enables the analysis of dependencies, for example, in signal flows from the receptor activation to the cell response at steady state.

Availability and Implementation

isiKnock is an open-source tool, freely available at http://www.bioinformatik.uni-frankfurt.de/tools/isiKnock/index.php. It requires at least Java 8 and runs under Microsoft Windows, Linux, and Mac OS.

Contact

ina.koch@bioinformatik.uni-frankfurt.de
Cryptic adaptor protein interactions regulate DNA replication initiation
Authors: Matthews Lindsay A. , Simmons Lyle A.
Published: May 2018

DNA replication is a fundamental biological process that is tightly regulated in all living cells. In bacteria, the master regulator DnaA controls when and where replication begins by building a step-wise complex that loads the replicative helicase onto chromosomal DNA. In many bacteria, DnaA requires the adaptor proteins DnaD and DnaB to aid DnaA during helicase loading. How DnaA, its adaptors, and the helicase form a complex at the origin is largely unknown. In this study, we addressed this long-standing question by disassembling the initiation proteins into their individual domains and testing all possible pair-wise combinations in a bacterial two-hybrid assay. Here we report a full description of the cryptic interaction sites used by the helicase loading machinery fromBacillus subtilis. In addition, we investigated how complex formation of the helicase loading machinery is regulated by the checkpoint protein SirA, which is a potent replication inhibitor in sporulating cells. We found that SirA and the DnaD adaptor bind overlapping sites on DnaA, and therefore SirA acts as a competitive inhibitor to block initiation. The interaction between DnaA and DnaD was also mapped to the same DnaA surface in the human pathogenStaphylococcus aureus, demonstrating the broad conservation of this interface. Therefore, our approach has unveiled key protein interactions essential for initiation and is widely applicable for mapping interactions in other signaling pathways that are governed by cryptic binding surfaces.

Author Summary

In order to proliferate, bacteria must first build a step-wise protein complex on their chromosomes that determines when and where DNA replication begins. This protein complex is assembled through dynamic interactions that have been difficult to study and remain largely uncharacterized. Here we show that by deconstructing the proteins into their constituent domains, the interactions used to build the initiation complex can be readily detected and mapped to single amino acid resolution. Using this approach, we demonstrate that DNA replication is controlled through conformational changes that dictate the availability of interaction surfaces. In addition, negative regulators can also block DNA replication by influencing complex formation so that cells survive inhospitable conditions. Initiation proteins from the model organismB. subtilisand the human pathogenS. aureuswere both used to underscore the general applicability of the results to different bacterial systems. Furthermore, our general strategy for mapping dynamic protein interactions is suitable for many different signaling pathways that are controlled through cryptic interaction surfaces.
A putative human infertility allele of the meiotic recombinase DMC1 does not affect fertility in mice
Authors: Tran Tina N. , Schimenti John C.
Published: May 2018

Whole exome or genome sequencing is becoming routine in clinical situations for identifying mutations underlying presumed genetic causes of disease, including infertility. While this is a powerful approach for implicating polymorphisms or de novo mutations in genes plausibly related to the phenotype, a greater challenge is to definitively prove causality. This is a crucial requisite for treatment, especially for infertility, in which validation options are limited. In this study, we created a mouse model of a putative infertility allele,DMC1M200V.DMC1encodes a RecA homolog essential for meiotic recombination and fertility in mice. This allele was originally implicated as being responsible for sterility of a homozygous African woman, a conclusion supported by subsequent biochemical analyses of the mutant protein and by studies of yeast with the orthologous amino acid change. Here, we found thatDmc1M200V/M200Vmale and female mice are fully fertile and do not exhibit any gonadal abnormalities. Detailed immunocytological analysis of meiosis revealed no defects suggestive of compromised fertility. This study serves as a cautionary tale for making conclusions about consequences of genetic variants, especially with respect to infertility, and emphasizes the importance of conducting relevant biological assays for making accurate diagnoses in the era of genomic medicine.
Nonparametric analysis of contributions to variance in genomics and epigenomics data
Authors: Moskowitz David M. , Greenleaf William J.
Published: May 2018

Functional genomics studies, despite increasingly varied assay types and complex experimental designs, are typically analyzed by methods that are unable to identify confounding effects and that incorporate parametric assumptions particular to gene expression data. We present MAVRIC, a nonparametric method to quantify variance explained by experimental covariates and perform differential analysis on arbitrary data types. We demonstrate that MAVRIC can accurately associate covariates with underlying data variance, deliver sensitive and specific identification of genomic loci with differential counts, and provide effective noise reduction of large-scale consortium data sets.
Comparison of antioxidant activity between cyanidin-3-O-glucoside (C3G) liposome and cyanidin-3-O-glucoside (C3G) in 2D and 3D cell cultures
Authors: Liang Tisong , Guan Rongfa , Cao Guozhou , Shen Haitao , Liu Zhenfeng , Xia Qile , Wang Zhe
Published: May 2018

The 2D cell culture is the predominant in vitro model for numerous studies. However, 2D cell cultures may not accurately reflect the functions of three-dimensional (3D) tissues, which have extensive cell–cell and cell–matrix interactions; thus, using 2D cell cultures may lead to inaccurate experimental results. Therefore, to obtain adequate and detailed information about the antioxidant activity of cyanidin-3-O-glucoside (C3G) and C3G liposomes in the 2D and 3D cell culture models, we used in this study H2O2to construct the cell damage model and assess the antioxidant activity of C3G and C3G liposomes on Caco-2 cells cultured in the 3D model. We also measured the cell viability, cell morphology, and activity of glutathione (GSH), superoxide dismutase (SOD), total antioxidant capacity (T-AOC), and malondialdehyde (MDA) content of Caco-2 cells treated with H2O2, C3G, and C3G liposomes. Results showed that cells cultured in the 3D culture model formed a 3D structure and tight spheroids and showed increased cell activity and IC50. The C3G and C3G liposomes can enhance the activity of GSH, SOD, and T-AOC but decrease the MDA content. At the same time, the effect was more obvious in the 3D cell culture model than in the cells cultured in the 2D model. This study revealed that the results obtained from the 2D cell model may be inaccurate compared with the results obtained from the 3D cell model. A realistic mechanism study of antioxidant activity of C3G and C3G liposomes in the 3D cell model, which acts as an intermediate stage bridging the in vitro 2D and in vivo models, was observed.
Mosaic deletion patterns of the human antibody heavy chain gene locus as revealed by Bayesian haplotyping
Authors: Gidoni Moriah , Snir Omri , Peres Ayelet , Polak Pazit , Lindeman Ida , Mikocziova Ivana , Sarna Vikas Kumar , Lundin Knut E. A. , Clouser Christopher , Vigneault Francois , Collins Andrew M. , Sollid Ludvig M. , Yaari Gur
Published: May 2018

Analysis of antibody repertoires by high-throughput sequencing is of major importance in understanding adaptive immune responses. Our knowledge of variations in the genomic loci encoding antibody genes is incomplete, mostly due to technical difficulties in aligning short reads to these highly repetitive loci. The partial knowledge results in conflicting V-D-J gene assignments between different algorithms, and biased genotype and haplotype inference. Previous studies have shown that haplotypes can be inferred by taking advantage of IGHJ6 heterozygosity, observed in approximately one third of the population. Here, we propose a robust novel method for determining V-D-J haplotypes by adapting a Bayesian framework. Our method extends haplotype inference to IGHD- and IGHV-based analysis, thereby enabling inference of complex genetic events like deletions and copy number variations in the entire population. We generated the largest multi individual data set, to date, of naïve B-cell repertoires, and tested our method on it. We present evidence for allele usage bias, as well as a mosaic, tiled pattern of deleted and present IGHD and IGHV nearby genes, across the population. The inferred haplotypes and deletion patterns may have clinical implications for genetic predispositions to diseases. Our findings greatly expand the knowledge that can be extracted from antibody repertoire sequencing data.
Polarity sorting drives remodeling of actin-myosin networks
Authors: Wollrab Viktoria , Belmonte Julio M. , Leptin Maria , Nédeléc François , Koenderink Gijsje H.
Published: May 2018

Cytoskeletal networks of actin filaments and myosin motors drive many dynamic cell processes. A key characteristic of these networks is their contractility. Despite intense experimental and theoretical efforts, it is not clear what mechanism favors network contraction over expansion. Recent work points to a dominant role for the nonlinear mechanical response of actin filaments, which can withstand stretching but buckle upon compression. Here we present an alternative mechanism. We study how interactions between actin and myosin-2 at the single filament level translate into contraction at the network scale by performing time-lapse imaging on reconstituted quasi-2D-networks mimicking the cell cortex. We observe myosin end-dwelling after it runs processively along actin filaments. This leads to transport and clustering of actin filament ends and the formation of transiently stable bipolar structures. Further we show that myosin-driven polarity sorting leads to polar actin aster formation, which act as contractile nodes that drive contraction in crosslinked networks. Computer simulations comparing the roles of the end-dwelling mechanism and a buckling-dependent mechanism show that the relative contribution of end-dwelling contraction increases as the network mesh-size decreases.
Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors
Authors: Ratnaparkhe Manasi , Wong John , Wei Pei-Chi , Hlevnjak Mario , Kolb Thorsten , Haag Daniel , Paul Yashna , Devens Frauke , Northcott Paul , Jones David TW , Kool Marcel , Jauch Anna , Pastorczak Agata , Mlynarski Wojciech , Korshunov Andrey , Kumar Rajiv , Downing Susanna M. , Pfister Stefan M , Zapatka Marc , McKinnon Peter J , Alt Frederick W , Lichter Peter , Ernst Aurélie
Published: May 2018

Chromothripsis and chromoanasynthesis are catastrophic events leading to clustered genomic rearrangements. Whole-genome sequencing revealed frequent chromothripsis or chromoanasynthesis (n= 16/26) in brain tumors developing in mice deficient for factors involved in homologous-recombination-repair or non-homologous-end-joining. Catastrophic events were tightly linked to Myc/Mycn amplification, with increased DNA damage and inefficient apoptotic response already observable at early postnatal stages. Inhibition of repair processes and comparison of the mouse tumors with human medulloblastomas (n=68) and glioblastomas (n=32) identified chromothripsis as associated with MYC/MYCN gains and with DNA repair deficiencies, pointing towards therapeutic opportunities to target DNA repair defects in tumors with complex genomic rearrangements.
CRISPR-Cas9 interference in cassava linked to the evolution of editing-resistant geminiviruses
Authors: Mehta Devang , Stürchler Alessandra , Hirsch-Hoffmann Matthias , Gruissem Wilhelm , Vanderschuren Hervé
Published: May 2018

We used CRISPR-Cas9 in the staple food crop cassava with the aim of engineering resistance to African cassava mosaic virus, a member of a widespread and important family of plant-pathogenic DNA viruses. We found that between 33 and 48% of edited virus genomes evolved a conserved single-nucleotide mutation that confers resistance to CRISPR-Cas9 cleavage. Our study highlights the potential for virus escape from this technology. Care should be taken to design CRISPR-Cas9 experiments that minimize the risk of virus escape.
Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes
Authors: Maher Geoffrey J. , Ralph Hannah K. , Ding Zhihao , Koelling Nils , Mlcochova Hana , Giannoulatou Eleni , Dhami Pawan , Paul Dirk S. , Stricker Stefan H. , Beck Stephan , McVean Gilean , Wilkie Andrew OM , Goriely Anne
Published: May 2018

Mosaic mutations present in the germline have important implications for reproductive risk and disease transmission. We previously demonstrated a phenomenon occurring in the male germline, whereby specific mutations arising spontaneously in stem cells (spermatogonia) lead to clonal expansion, resulting in elevated mutation levels in sperm over time. This process, termed selfish spermatogonial selection, explains the high spontaneous birth prevalence and strong paternal age-effect of disorders such as achondroplasia, Apert, Noonan and Costello syndromes, with direct experimental evidence currently available for specific positions of six genes (FGFR2, FGFR3, RET, PTPN11, HRAS and KRAS). We present a discovery screen to identify novel mutations and genes showing evidence of positive selection in the male germline, by performing massively parallel simplex PCR using RainDance technology to interrogate mutational hotspots in 67 genes (51.5 kb in total) in 276 biopsies of testes from 5 men (median age: 83 years). Following ultra-deep sequencing (~16,000x), development of a low-frequency variant prioritization strategy and targeted validation, we identified 61 distinct variants present at frequencies as low as 0.06%, including 54 variants not previously directly associated with selfish selection. The majority (80%) of variants identified have previously been implicated in developmental disorders and/or oncogenesis and include mutations in six newly associated genes (BRAF, CBL, MAP2K1, MAP2K2, RAF1 and SOS1), all of which encode components of RAS-MAPK pathway and activate signaling. Our findings extend the link between mutations dysregulating the RAS-MAPK pathway and selfish selection, and show that the ageing male germline is a repository for such deleterious mutations.
Rapid olfactory discrimination learning in adult zebrafish
Authors: Namekawa Iori , Moenig Nila R. , Friedrich Rainer W.
Published: May 2018

The zebrafish is a model organism to study olfactory information processing but efficient behavioral procedures to analyze olfactory discrimination and memory are lacking. We devised an automated odor discrimination task for adult zebrafish based on olfactory conditioning of feeding behavior. Presentation of a conditioned odor (CS+), but not a neutral odor (CS-), was followed by food delivery at a specific location. Fish developed differential behavioral responses to CS+ and CS- within a few trials even when odors were similar. The behavioral response to the CS+ was complex and included components reminiscent of food search such as increased swimming speed and water surface sampling. Appetitive behavior was therefore quantified by a composite score that combined measurements of multiple behavioral parameters. Discrimination behavior was robust in different strains and learned preferences could overcome innate odor preferences. These results confirm that zebrafish can rapidly learn to make fine odor discriminations. The procedure is efficient and provides novel opportunities to dissect the neural mechanisms underlying olfactory discrimination and memory.
The suppressive cap-binding-complex factor 4EIP is required for normal differentiation
Authors: Terrao Monica , Kamanyi Marucha Kevin , Mugo Elisha , Droll Dorothea , Minia Ihor , Egler Franziska , Braun Johanna , Clayton Christine
Published: May 2018

Summary/Abstract

Trypanosoma brucei live in mammals as bloodstream forms and in the Tsetse midgut as procyclic forms. Differentiation from one form to the other proceeds via a growth-arrested stumpy form with low mRNA content and translation. The parasites have six eIF4Es and five eIF4Gs. EIF4E1 pairs with the mRNA-binding protein 4EIP but not with any EIF4G. EIF4E1 and 4EIP each inhibit expression when tethered to a reporter mRNA. The 4E-binding motif in 4EIP is required for the interaction with EIF4E1 both in vivo and in a 2-hybrid assay, but not for the suppressive activity of 4EIP when tethered. However, the suppressive activity of EIF4E1 when tethered requires 4EIP. Correspondingly, in growing bloodstream forms, 4EIP is preferentially associated with unstable mRNAs. Trypanosomes lacking 4EIP have a marginal growth disadvantage as cultured bloodstream or procyclic forms. Bloodstream forms without 4EIP cannot make differentiation-competent stumpy forms, but the defect can be complemented by a truncated 4EIP that does not interact with EIF4E1. Bloodstream forms lacking EIF4E1 have a growth defect but can differentiate. We suggest that 4EIP and EIF4E1 fine-tune mRNA levels in growing cells, and that 4EIP is required for mRNA suppression during differentiation to the stumpy form.
Polymeric perfluorocarbon nanoemulsions are ultrasound-activated wireless drug infusion catheters
Authors: Zhong Q , Yoon BC , Aryal M , Wang JB , Karthik A , Airan RD
Published: May 2018

Catheter-based intra-arterial drug therapies have proven effective for a range of oncologic, neurologic, and cardiovascular applications. However, these procedures are limited by their invasiveness, as well as the relatively broad drug spatial distribution that is achievable with selective arterial catheterization. The ideal technique for local pharmacotherapy would be noninvasive and would flexibly deliver a given drug to any region of the body. Combining polymeric perfluorocarbon nanoemulsions with existent clinical focused ultrasound systems could in principle enable noninvasive targeted drug delivery, but it has not been clear whether these nanoparticles could provide the necessary drug loading, stability, and generalizability across a range of drugs to meet these needs, beyond a few niche applications. Here, we directly address all of those challenges and fully develop polymeric perfluorocarbon nanoemulsions into a generalized platform for ultrasound-targeted drug delivery with high potential for clinical translation. We demonstrate that a wide variety of drugs may be effectively uncaged with ultrasound using these nanoparticles, with drug loading increasing with hydrophobicity. We also set the stage for clinical translation by delineating production protocols that hew to clinical standards and yield stable and optimized ultrasound-activated drug-loaded nanoemulsions. Finally, as a new potential clinical application for these nanoemulsions, we exhibit their in vivo efficacy and performance for cardiovascular applications, by achieving local vasodilation in the highest flow vessel of the body, the aorta. This work establishes the power of polymeric perfluorocarbon nanoemulsions as a clinically-translatable platform for effective noninvasive ultrasonic drug uncaging for myriad targets in the brain and body.
ShinyGO: a graphical enrichment tool for ani-mals and plants
Authors: Ge Steven Xijin , Jung Dongmin
Published: May 2018

Motivation

Gene lists are routinely produced from various genome-wide studies. Enrichment analysis can link these gene lists with underlying molecular pathways by using functional categories such as gene ontology (GO).

Results

To complement existing tools, we developed ShinyGO with several features: (1) large annotation database from GO and many other sources for over 200 plant and animal species, (2) graphical visualization of enrichment results and gene characteristics, and (3) application program interface (API) access to KEGG and STRING for the retrieval of pathway diagrams and protein-protein interaction networks. ShinyGO is an intuitive, graphical web application that can help researchers gain actionable insights from gene lists.

Availability

http://ge-lab.org/go/

Contact

gexijin@gmail.com

Supplementary information

Supplementary data are available at Bioinformatics online.
Lipid composition but not curvature is a determinant of a low molecular mobility within HIV-1 lipid envelope
Authors: Urbančič Iztok , Brun Juliane , Shrestha Dilip , Waithe Dominic , Eggeling Christian , Chojnacki Jakub
Published: May 2018

Human Immunodeficiency Virus type-1 (HIV-1) acquires its lipid membrane from the plasma membrane of the infected cell from where it buds out. Previous studies have shown that the HIV-1 envelope is a very low mobility environment with the diffusion of incorporated proteins two orders of magnitude slower than in plasma membrane. One of the reasons for this difference is thought to be due to HIV-1 membrane composition that is characterised by a high degree of rigidity and lipid packing. To further refine the model of the molecular mobility on HIV-1 surface, we here investigated the relative importance of membrane composition and curvature in Large Unilamellar Vesicles of different composition and size (0.2–1 μm) by super-resolution STED microscopy-based fluorescence correlation spectroscopy (STED-FCS) analysis. We find that lipid composition and its rigidity but not membrane curvature play an important role in the decreased molecular mobility on vesicle surface thus confirming that this factor is an essential determinant of HIV-1 low surface mobility. Our results provide further insight into the dynamic properties of the surface of individual HIV-1 particles.
Detection of Multidimensional Co-Exclusion Patterns in Microbial Communities
Authors: Albayrak Levent , Khanipov Kamil , Golovko George , Fofanov Yuriy
Published: May 2018

Motivation

Identification of complex relationships among members of microbial communities is key to understand and control the microbiota. Co-exclusion is arguably one of the most important patterns reflecting microorganisms’ intolerance to each other’s presence. Knowing these relations opens an opportunity to manipulate microbiotas, personalize anti-microbial and probiotic treatments as well as guide microbiota transplantation. The co-exclusion pattern however, cannot be appropriately described by a linear function nor its strength be estimated using covariance or (negative) Pearson and Spearman correlation coefficients. This manuscript proposes a way to quantify the strength and evaluate the statistical significance of co-exclusion patterns between two, three or more variables describing a microbiota and allows one to extend analysis beyond microorganism abundance by including other microbiome associated measurements such as, pH, temperature etc., as well as estimate the expected numbers of false positive co-exclusion patterns in a co-exclusion network.

Results

The implemented computational pipeline (CoEx) tested against 2,380 microbial profiles (samples) from The Human Microbiome Project resulted in body-site specific pairwise co-exclusion patterns.

Availability

C++ source code for calculation of the score and p-value for 2, 3, and 4 dimensional co-exclusion patterns as well as source code and executable files for the CoEx pipeline are available athttps://scsb.utmb.edu/labgroups/fofanov/co-exclusion_in_microbial_communities.asp

Contact

lealbayr@utmb.edu

Supplementary information

Supplementary data are available atbiorxivonline.
The good teacher for the twenty-first century: a “mentoring teacher” with heutagogical skills
Authors: Levy-Feldman Irit
Published: May 2018

Purpose

The purpose of this paper is to propose a new conception of the “good teacher” – that of the teacher-as-mentor, or, as the author refer to it, the “mentoring teacher,” who is equipped with heutagogical skills aimed at promoting self-determined learning through dialogic teaching. This conception appears to be better suited than current conceptions for the twenty-first century and the postmodern era.

Design/methodology/approach

The conception is based on an interpretative textual analysis of western educational philosophies and of the nature of postmodernity.

Findings

The mentoring teacher, presented to be the “good teacher” for the new era, is provided with skills associated with heutagogy: a pedagogical approach that emphasizes the individual’s need to learn autonomously and independently and that regards the capacity to do so as a basic skill for living and lifelong learning in the changing world. Using dialogic teaching, mentoring teachers equipped with heutagogical skills can navigate their teaching to promote the self-learning abilities of different learners and better prepare them to navigate the challenges of the current era.

Research limitations/implications

This paper presents one perspective on looking at the changes that have occurred in the conception of the good teacher in western society and offers one point of view of the image of the new good teacher, hoping it might stimulate new thinking on the need to reconsider the role of the teacher in contemporary western society.

Originality/value

Placing the focus on teachers’ skills as opposed to students’ needs, which is much more common, invites discussion regarding the image of the good teacher and teacher education.
Stand Up to Work: assessing the health impact of adjustable workstations
Authors: Garland Elizabeth , Watts Abigail , Doucette John , Foley Mary , Senerat Araliya , Sanchez Sadie
Published: May 2018

Purpose

Sedentary behavior is linked to health risks, and prolonged sitting is prevalent among office workers. Adjustable workstations (AWS) promote health by allowing transitions between sitting and standing. Stand Up to Work compares workers with AWS to traditional desks (TD). The paper aims to discuss these issues.

Design/methodology/approach

Employees were randomly selected from one office floor to receive AWS, two identical floors maintained TD. Participants received workplace wellness and ergonomic training, completed self-administered questionnaires, and responded to repeated micropolling at baseline (T0), 3 (T1), 6 (T2), and 12 (T3) months in Atlanta, 2015-2016. Groups were compared using two-samplet-tests and nonparametric Wilcoxon tests.

Findings

Compared to TD (n= 24), participants with AWS (n= 24) reported significantly less sedentary behavior at T1 and T2 after AWS installation (p<0.05), with a retention rate at T2 of 80 and 65 percent for the AWS and TD group, respectively. In all, 47 percent of participants with AWS reported decline in upper back, shoulder, and neck discomfort (p=0.04); 88 percent of AWS participants reported convenience to use, 65 percent reported increased productivity, and 65 percent reported positive impact outside the workplace. Individuals with normal or underweight body mass index (BMI) reported a significantly greater decline in percent of time sitting compared to participants with overweight or obese BMI at all three time points.

Originality/value

AWS are beneficial in reducing sedentary behavior in and outside the workplace. Behavioral changes were sustained over time and associated with less self-reported muscle pain, more self-reported energy, and awareness of standing. When considering total worker health, employers should include options for AWS to promote reducing sedentary behavior.
Perceptions of control legitimacy in information systems development
Authors: Cram W. Alec , Wiener Martin
Published: May 2018

Purpose

Existing studies of information systems development (ISD) control commonly examine controller-centric considerations, such as the antecedents and performance impacts of control mode choices. In contrast, little is known about the controllee-centric factors that may influence the effectiveness of control activities. Drawing on institutional theory, the purpose of this paper is to introduce the concept of control legitimacy to the ISD literature – a concept that past organizational research has linked to outcomes such as employee commitment and performance. Specifically, the authors explore how different dimensions of control activities (mode, degree, style) relate to controllee perceptions of control legitimacy in terms of justice, autonomy, group identification, and competence development.

Design/methodology/approach

Interviews were conducted with 20 practitioners across three companies. A structured data coding approach was employed and analysis was conducted within and across each case study.

Findings

The authors find that the control degree and control style can help explain control legitimacy perceptions better than control modes alone. For example, the results suggest that formal controls enacted in a bilateral style correspond with higher perceptions of justice and autonomy, when compared to formal controls enacted in a unilateral style.

Originality/value

The study results imply that ISD managers should be increasingly mindful of enacting controls in a way that is perceived to be legitimate by subordinates, thereby potentially enhancing both staff well-being and ISD performance.
The unintended emergence of a greed-led economic system
Authors: Andreff Wladimir
Published: May 2018

Purpose

This paper aims to propose a new model of economic behaviour in which activities are led by greed rather than by the traditional formal rules of capitalism.

Design/methodology/approach

This paper relies on the empirical observation of bad practices that developed in synchrony during the collapse of the former communist economic system and the rise of global financial capitalism. Both were fuelled by greedy behaviour of asset grabbing, and paved the way to an emerging greed-led economic system.

Findings

First, microeconomic individual greedy behaviours that drive asset grabbing are identified, such as rigged or corrupt privatisation drives, subprime mortgage loans, Ponzi schemes, lending to insolvent clients, bad loan securitisation, stock options, fraudulent accounting and online betting on fixed matches. Then systematic changes in the traditional formal rules of capitalism that favour those having adopted a greedy strategy are pointed at; greedy behaviour is institutionalised when these capture the state and successfully lobby for rules change. Contrary to capitalism, systemic greed uses asset grabbing, instead of capital accumulation, as its major means for wealth maximisation without constraint, in a winner-take-all economy beneficial to oligarchs.

Research limitations/implications

The implications of this new systemic behaviour have implications for further economic modelling.

Practical implications

The emergence of systemic greed will have implications for the design of regulatory systems.

Originality/value

This paper proposes that a greed-controlled economy is replacing the traditional capitalist economy.
Developing a service quality scale in context of organized grocery retail of India
Authors: Jain Prachi , Aggarwal Vijita Singh
Published: May 2018

Purpose

The purpose of this paper is to check the reliability and validity of a well-acknowledged scale developed by Pratibha A. Dabholkar (1996) in the context of Indian organized grocery retail and also to identify new aspects of service quality with respect to grocery retail from literature that have not been taken into account in earlier studies and to finally develop a new scale to measure service quality of organized retail grocery stores with consultation from several experts.

Design/methodology/approach

In order to achieve the objectives of the research, both descriptive and exploratory research designs have been employed such that a survey of 800 respondents was undertaken as part of descriptive research whereas exploratory research was conducted to add new dimensions to the existing service quality measurement model so as to develop a new comprehensive scale.

Findings

The results of the study suggest that all the five dimensions of Dabholkar’s model are not suitable to measure service quality in Indian organized grocery retail stores. Therefore, a new instrument with total four dimensions has been developed.

Practical implications

The study is of great importance for the retailers as it offers a more comprehensive and specific scale to measure service quality of organized grocery retail stores.

Originality/value

This research supports and makes contribution to the previous research on development of service quality measurement scales in Indian context.
Fluorofenidone inhibits UV‐A induced senescence in human dermal fibroblasts via the mammalian target of rapamycin‐dependent SIRT1 pathway
Authors: Lei Dan , Huang Yingxue , Xie Hongfu , Yi Yuxin , Long Juan , Lin Shangqing , Huang Chuchu , Jian Dan , Li Ji
Published: May 2018

The aim of this study was to investigate the protective effect of fluorofenidone (5‐methyl‐1‐[3‐fluorophenyl]‐2‐[1H]‐pyridone, AKF‐PD) on ultraviolet (UV)‐A‐induced senescence in human dermal fibroblasts (HDF) and examine the mechanisms involved. HDF were treated with AKF‐PD. Senescence‐associated (SA)‐β‐galactosidase level, cell viability and expression of p16 were evaluated. In addition, UV‐A‐irradiated HDF were treated with AKF‐PD, rapamycin and MHY1485; SA‐β‐galactosidase staining, 3‐(4 5‐dimethylthiazol‐2‐yl)‐2 5‐diphenyltetrazolium bromide assay and western blot for SIRT1 were performed; and phosphorylated mammalian target of rapamycin (p‐mTOR) expression and reactive oxygen species (ROS) levels were measured. Intracellular ROS was detected by the 2′,7′‐dichlorofluroescein diacetate probe. Our results showed that AKF‐PD substantially attenuated the changes of p16 expression, SA‐β‐galactosidase staining and cellular proliferation induced by UV‐A irradiation in HDF. AKF‐PD rescued the increased mTOR phosphorylation and reduced SIRT1 expression induced by UV‐A irradiation in HDF. AKF‐PD and rapamycin together had a synergistic effect on p‐mTOR reduction and SIRT1 increase. mTOR activator MHY1485 partly blocked the above effects. Moreover, intracellular ROS level induced by UV‐A irradiation could partly decrease by AKF‐PD, and MHY1485 could reduce this effect. Our results indicated that AKF‐PD could alleviate HDF senescence induced by UV‐A‐irradiation by inhibiting the p‐mTOR and increasing SIRT1. Moreover, AKF‐PD may be a potential treatment material for skin.
Pre‐ and postnatal effects of experimentally manipulated maternal corticosterone on growth, stress reactivity and survival of nestling house wrens
Authors: Weber Beth M. , Bowers E. Keith , Terrell Kimberly A. , Falcone Josephine F. , Thompson Charles F. , Sakaluk Scott K.
Published: May 2018

Corticosterone plays a central role in maintaining homeostasis, promoting energy acquisition, and regulating the stress response in birds. Exposure to elevated levels of corticosterone during development can profoundly alter offspring behaviour and physiology, but the effects of elevated maternal corticosterone on offspring development remain poorly understood.

We tested two competing hypotheses concerning the effect of maternally derived corticosterone on growth and development of free‐living house wrens: (i) elevated maternal corticosterone causes damaging effects on nestling phenotype and fitness (collateral damage hypothesis) and (ii) increased maternal corticosterone enhances offspring fitness by preparing nestlings for the environment experienced by their mother (environmental/maternal‐matching hypothesis).

We used a non‐invasive means to increase maternal corticosterone by providing females with corticosterone‐injected mealworms prior to and during egg production in the absence of any overt pre‐natal maternal stress. To disentangle pre‐ and post‐natal effects of this elevation in maternal corticosterone, we cross‐fostered young in two experiments: (i) nestlings of control and experimental females were reared by unmanipulated, natural females in a uniform maternal environment; (ii) a split‐brood design that enabled us to assess the interaction between the mother’s corticosterone treatment and that of the nestlings.

There were significant pre‐natal effects of increased maternal corticosterone on nestling growth and survival. Offspring of females experiencing experimentally increased corticosterone were heavier and larger than offspring of control females. There also was a significant interaction between maternal corticosterone treatment and the corticosterone treatment to which young were exposed within the egg in their effect on nestling survival while in the nest; experimental young exhibited greater survival than control young, but only when reared by control mothers. There was also a significant effect of maternal corticosterone treatment on nestling stress reactivity and, in both experiments, on the eventual recruitment of offspring as breeding adults in the local population.

These patterns are broadly consistent with the environmental/maternal‐matching hypothesis, and highlight the importance of disentangling pre‐ and post‐natal effects of manipulations of maternal hormone levels on offspring phenotype.

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Larval traits show temporally consistent constraints, but are decoupled from postsettlement juvenile growth, in an intertidal fish
Authors: Thia Joshua A. , Riginos Cynthia , Liggins Libby , Figueira Will F. , McGuigan Katrina
Published: May 2018

Complex life cycles may evolve to dissociate distinct developmental phases in an organism's lifetime. However, genetic or environmental factors may restrict trait independence across life stages, constraining ontogenetic trajectories. Quantifying covariance across life stages and their temporal variability is fundamental in understanding life‐history phenotypes and potential distributions and consequences for selection.

We studied developmental constraints in an intertidal fish (Bathygobius cocosensis: Gobiidae) with a discrete pelagic larval phase and benthic juvenile phase. We tested whether traits occurring earlier in life affected those expressed later, and whether larval traits were decoupled from postsettlement juvenile traits. Sampling distinct cohorts from three annual breeding seasons afforded tests of temporally variability in trait covariance.

From otoliths (fish ear stones), we measured hatch size, larval duration, pelagic growth (larval traits) and early postsettlement growth (juvenile trait) in 124 juvenile B. cocoensis. We used path analyses to model trait relationships with respect to their chronological expression, comparing models among seasons. We also modelled the effect of season and hatch date on each individual trait to quantify their inherent variability.

Our path analyses demonstrated a decoupling of larval traits on juvenile growth. Within the larval phase, longer larval durations resulted in greater pelagic growth, and larger size‐at‐settlement. There was also evidence that larger hatch size might reduce larval durations, but this effect was only marginally significant. Although pelagic and postsettlement growth were decoupled, pelagic growth had postsettlement consequences: individuals with high pelagic growth were among the largest fish at settlement, and remained among the largest early postsettlement. We observed no evidence that trait relationships varied among breeding seasons, but larval duration differed among breeding seasons, and was shorter for larvae hatching later within each season.

Overall, we demonstrate mixed support for the expectation that traits in different life stages are independent. While postsettlement growth was decoupled from larval traits, pelagic development had consequences for the size of newly settled juveniles. Temporal consistency in trait covariances implies that genetic and/or environmental factors influencing them were stable over our three‐year study. Our work highlights the importance of individual developmental experiences and temporal variability in understanding population distributions of life‐history traits.
The pricing of accruals quality in credit default swap spreads
Authors: Alam Pervaiz , Pu Xiaoling , Hettler Barry , Lin Hai
Published: May 2018

We examine the association between accounting information risk, measured with accruals quality (AQ), and credit spreads, primarily measured with credit default swap (CDS) spreads. Theoretically, AQ measures the precision with which accruals map into cash flows. Better AQ implies a more precise estimate of future cash flows and, we predict, a reduction in credit spreads due to resulting lower uncertainty regarding the ability to meet debt interest and principal payments. In support of this hypothesis, we find a negative relationship between AQ and CDS spreads whereby better AQ is associated with lower CDS spreads. Additionally, we investigate the components of total AQ and find that innate AQ is more strongly associated with CDS spreads than is discretionary AQ. We further show that AQ moderates the market's pricing of earnings: the relationship between earnings and CDS spreads weakens as AQ worsens. Together, our results indicate that accounting information risk is priced in credit spreads and that the CDS market responds not only to the level of earnings, but the quality thereof as well.
Longitudinal evaluation of clustering of chronic sinonasal and related symptoms using exploratory factor analysis
Authors: Cole M. , Bandeen‐Roche K. , Hirsch A. G. , Kuiper J. R. , Sundaresan A. S. , Tan B. K. , Schleimer R. P. , Kern R. C. , Schwartz B. S.
Published: May 2018

Background

Sinonasal symptoms are common and can have several underlying causes. When symptoms occur in specified patterns lasting 3 months or more they meet criteria for chronic rhinosinusitis (CRS). Approaches to CRS symptom measurement do not specify how to measure symptoms and treat specified sinonasal symptoms as generally interchangeable, suggesting that such symptoms should cluster on 1 or 2 latent factors.

Methods

We used questionnaire responses to 37 questions on the presence, severity, bother, and frequency of cardinal sinonasal and related symptoms lasting 3 months, from 3535 subjects at 3 time points over 16 months. We completed 5 exploratory factor analyses (EFA) to identify symptom clustering, 1 for each time point and 2 for the differences between adjacent questionnaires. The baseline EFA was used to provide factor scores that were described longitudinally and examined by CRS status.

Results

Five EFAs identified the same 5 factors (blockage and discharge, pain and pressure, asthma and cold/flu symptoms, smell loss, and ear and eye [mainly allergy] symptoms), with clustering determined by symptom frequency, severity, and degree of bother. Responses to individual questions showed changes over time but when combined into factor scores showed less longitudinal change. All symptom factor scores were progressively higher from never to past to current CRS status.

Conclusions

Although the current approaches to symptom characterization in CRS imply a single underlying latent construct, our results suggest that there are at least 3 latent constructs relevant to CRS. Further studies are needed to evaluate whether these clusters have identifiable underlying pathobiologies.
Speed Modulation of the HeartWare HVAD to Assess In Vitro Hemocompatibility of Pulsatile and Continuous Flow Regimes in a Rotary Blood Pump
Authors: Horobin Jarod T. , Simmonds Michael J. , Nandakumar Deepika , Gregory Shaun D. , Tansley Geoff , Pauls Jo P. , Girnghuber Angela , Balletti Nicoletta , Fraser John F.
Published: May 2018

Although rotary blood pumps (RBPs) sustain life, blood exposure to continuous supra‐physiological shear stress induces adverse effects (e.g., thromboembolism); thus, pulsatile flow in RBPs represents a potential solution. The present study introduced pulsatile flow to the HeartWare HVAD using a custom‐built controller and compared hemocompatibility biomarkers (i.e., platelet aggregation, concentrations for ADAMTS13, von Willebrand factor (vWf), and free‐hemoglobin in plasma (pfHb), red blood cell (RBC) deformability, and RBC‐nitric oxide synthase (NOS) activity) between continuous and pulsatile flow in a blood circulation loop over 5 h. The HeartWare HVAD was operated using a custom‐built controller, at continuous speed (3282 rev/min) or in a pulsatile mode (mean speed = 3273 rev/min, amplitude = 430 rev/min, frequency = 1 Hz) to generate a blood flow rate of 5.0 L/min, HVAD differential pressure of 90 mm Hg for continuous flow and 92 mm Hg for pulsatile flow, and systolic and diastolic pressures of 121/80 mm Hg. For both flow regimes, the current study found; (i) ADP‐ and collagen‐induced platelet aggregation, and ADAMTS13 concentration significantly decreased after 5 h (P < 0.01; P < 0.05), (ii) ristocetin‐induced platelet aggregation significantly increased after 45 min (P < 0.05), (iii) vWf concentration did not significantly differ at any time point, (iv) pfHb significantly increased after 5 h (P < 0.01), (v) RBC deformability improved during the continuous flow regime (P < 0.05) but not during pulsatile flow, and (vi) RBC‐NOS activity significantly increased during continuous flow (15 min), and pulsatile flow (5 h; P < 0.05). The current study demonstrated: (i) speed modulation does not improve hemocompatibility of the HeartWare HVAD based on no observable differences being detected for routine biomarkers, and (ii) the time‐course for increased RBC‐NOS activity observed during continuous flow may have improved RBC deformability.