bluuebunny/crossref_metadata_2025 huggingface dataset:
Modelling the distribution of white matter hyperintensities due to ageing on MRI images using Bayesian inference
Authors: Sundaresan Vaanathi , Griffanti Ludovica , Kindalova Petya , Alfaro-Almagro Fidel , Zamboni Giovanna , Rothwell Peter M. , Nichols Thomas E. , Jenkinson Mark
Published: May 2018

White matter hyperintensities (WMH), also known as white matter lesions, are localised white matter areas that appear hyperintense on MRI scans. WMH commonly occur in the ageing population, and are often associated with several factors such as cognitive disorders, cardiovascular risk factors, cerebrovascular and neurodegenerative diseases. Despite the fact that some links between lesion location and parametric factors such as age have already been established, the relationship between voxel-wise spatial distribution of lesions and these factors is not yet well understood. Hence, it would be of clinical importance to model the distribution of lesions at the population-level and quantitatively analyse the effect of various factors on the lesion distribution model.

In this work we compare various methods, including our proposed method, to generate voxel-wise distributions of WMH within a population with respect to various factors. Our proposed Bayesian spline method models the spatio-temporal distribution of WMH with respect to a parametric factor of interest, in this case age, within a population. Our probabilistic model takes as input the lesion segmentation binary maps of subjects belonging to various age groups and provides a population-level parametric lesion probability map as output. We used a spline representation to ensure a degree of smoothness in space and the dimension associated with the parameter, and formulated our model using a Bayesian framework.

We tested our algorithm output on simulated data and compared our results with those obtained using various existing methods with different levels of algorithmic and computational complexity. We then compared the better performing methods on a real dataset, consisting of 1000 subjects of the UK Biobank, divided in two groups based on hypertension diagnosis. Finally, we applied our method on a clinical dataset of patients with vascular disease.

On simulated dataset, the results from our algorithm showed a mean square error (MSE) value of 7.27 × 10−5, which was lower than the MSE value reported in the literature, with the advantage of being robust and computationally efficient. In the UK Biobank data, we found that the lesion probabilities are higher for the hypertension group compared to the non-hypertension group and further verified this finding using a statistical t-test. Finally, when applying our method on patients with vascular disease, we observed that the overall probability of lesions is significantly higher in later age groups, which is in line with the current literature.
Assessing 42 inflammatory markers in 321 control subjects and 887 major depressive disorder cases: BMI and other confounders and overall predictive ability for current depression
Authors: Powell Timothy R. , Gaspar Helena , Chung Raymond , Keohane Aoife , Gunasinghe Cerisse , Uher Rudolf , Aitchison Katherine J. , Souery Daniel , Mors Ole , Maier Wolfgang , Zobel Astrid , Rietschel Marcella , Henigsberg Neven , Dernovšek Mojca Zvezdana , Hauser Joanna , Frissa Souci , Goodwin Laura , Hotopf Matthew , Hatch Stephani L , Collier David A. , Wang Hong , Wang Hong
Published: May 2018

Inflammatory markers such as cytokines represent potential biomarkers for major depressive disorder (MDD). Many, generally small studies have examined the role of single markers and found significant associations. We assessed 42 inflammatory markers, namely cytokines, in the blood of 321 control subjects and 887 MDD cases. We tested whether individual inflammatory marker levels were significantly affected by MDD case/control status, current episode, or current depression severity, co-varying for age, sex, body mass index (BMI), smoking, current antidepressant use, ethnicity, assay batch and study effects. We further used machine learning algorithms to investigate if we could use our data to blindly discriminate MDD patients, or those in a current episode. We found broad and powerful influences of confounding factors on log-protein levels. Notably, IL-6 levels were very strongly influenced by BMI (p = 1.37 × 10−43, variance explained = 18%), while Interleukin-16 was the most significant predictor of current depressive episode (p = 0.003, variance explained = 0.9%, q < 0.1). No single inflammatory marker predicted MDD case/control status when a subject was not in a depressed episode, nor did any predict depression severity. Machine learning results revealed that using inflammatory marker data with clinical confounder information significantly increased precision for differentiating MDD patients who were in an episode. To conclude, a wide panel of inflammatory markers alongside clinical information may aid in predicting the onset of symptoms, but no single inflammatory protein is likely to represent a clinically useful biomarker for MDD diagnosis or prognosis. We note that the potential influence of physical health related and population stratification related confounders on inflammatory biomarker studies in psychiatry is considerable.
Generation and Selection of a Panel of Pan-Filovirus Single-Chain Antibodies using Cell-Free Ribosome Display
Authors: Kunamneni Adinarayana , Clarke Elizabeth C. , Ye Chunyan , Bradfute Steven B. , Durvasula Ravi
Published: May 2018

Filoviruses, which include ebolaviruses and marburgvirus, can cause outbreaks of highly lethal hemorrhagic fever. This disease causes significant morbidity and mortality in humans and non-human primates, with human fatality rates reaching 90% during some outbreaks. Currently, there are a lack of licensed vaccines or antivirals for these viruses. Since early symptoms of filovirus infection mimic more common diseases, there is a strong unmet public health and biodefense need for broad-spectrum filovirus rapid diagnostics. We have generated a panel of mouse single-chain Fv-antibodies (scFvs) to filovirus glycoproteins (GPs) using cell-free ribosome display and determined their cross-reactivity profiles to all known filovirus species. Two scFvs (4-2 and 22-1) were able to detect all known Ebolavirus and Marburgvirus species. This is the first report on ribosome display scFvs that can detect a broad set of filovirus GPs, which demonstrates their potential use in the development of a new generation of rapid diagnostic immunoassays.
TheSaccharomyces cerevisiaeHrq1 and Pif1 DNA helicases synergistically modulate telomerase activityin vitro
Authors: Nickens David G. , Rogers Cody M. , Bochman Matthew L.
Published: May 2018

Telomere length homeostasis is vital to maintaining genomic stability and is regulated by multiple factors, including telomerase activity and DNA helicases. TheSaccharomyces cerevisiaePif1 helicase was the first discovered catalytic inhibitor of telomerase, but recent experimental evidence suggests that Hrq1, the yeast homolog of the disease-linked human RecQ-like helicase 4 (RECQL4), plays a similar role via an undefined mechanism. Using yeast extracts enriched for telomerase activity and anin vitroprimer extension assay, here we determined the effects of recombinant wild-type and inactive Hrq1 and Pif1 on total telomerase activity and telomerase processivity. We found that titrations of these helicases alone have equal-but-opposite biphasic effects on telomerase, with Hrq1 stimulating activity at high concentrations. When the helicases were combined in reactions, however, they synergistically inhibited or stimulated telomerase activity depending on which helicase was catalytically active. These results suggest that Hrq1 and Pif1 interact and that their concerted activities ensure proper telomere length homeostasisin vivo. We propose a model in which Hrq1 and Pif1 cooperatively contribute to telomere length homeostasis in yeast.
Carpenter ants use diverse antennae sampling strategies to track odor trails
Authors: Draft Ryan W. , McGill Matthew R. , Kapoor Vikrant , Murthy Venkatesh N.
Published: May 2018

Directed and meaningful animal behavior depends on the ability to sense key features in the environment. Among the different environmental signals, olfactory cues are critically important for foraging, navigation, and social communication in many species, including ants. Ants use their two antennae to explore the olfactory world, but how they do so remains largely unknown. In this study, we use high resolution videography to characterize the antennae dynamics of carpenter ants (Camponotus pennsylvanicus). Antennae are highly active during both tracking and exploratory behavior. When tracking, ants used several distinct behavioral strategies with stereotyped antennae sampling patterns (which we call sinusoidal behavior, probing, and trail following). In all behaviors, left and right antennae movements were anti-correlated, and tracking ants exhibited biases in the use of left vs right antenna to sample the odor trail. These results suggest non-redundant roles for the two antennae. In one of the behavioral modules (trail following), ants used both antennae to detect trail edges and direct subsequent turns, suggesting a specialized form of tropotaxis. Lastly, removal of an antenna resulted not only in less accurate tracking but also in changes in the sampling pattern of the remaining antenna. Our quantitative characterization of odor trail tracking lays a foundation to build better models of olfactory sensory processing and sensorimotor behavior in terrestrial insects.

Summary Statement

High resolution imaging of antennae reveals distinct patterns of sampling with non-redundant roles in odor tracking.
VCPA: genomic variant calling pipeline and data management tool for Alzheimer’s Disease Sequencing Project
Authors: Leung Yuk Yee , Valladares Otto , Chou Yi-Fan , Lin Han-Jen , Kuzma Amanda B , Cantwell Laura , Qu Liming , Gangadharan Prabhakaran ,   Alzheimer’s Disease Sequencing Project (ADSP), Salerno William J , Schellenberg Gerard D. , Wang Li-San
Published: May 2018

Summary: We report VCPA, our SNP/Indel Variant Calling Pipeline and data management tool used for analysis of whole genome and exome sequencing (WGS/WES) for the Alzheimer’s Disease Sequencing Project. VCPA consists of two independent but linkable components: pipeline and tracking database. The pipeline is coded in Workflow Description Language and is fully optimized for the Amazon elastic compute cloud environment. This includes steps for processing raw sequence reads including read alignment, and all the way up to variant calling using GATK. The tracking database allows users to dynamically view the statuses of jobs running and the quality metrics reported by the pipeline. Users can thus monitor the production process and diagnose if any problem arises during the procedure. All quality metrics (>100 collected per processed genome) are stored in the database, thus facilitating users to compare, share and visualize the results. To summarize, VCPA is functional equivalent to the CCDG/TOPMed pipeline. Together with the dockerized database (also available as Amazon Machine Image), users can easily process any WGS/WES data on Amazon cloud with minimal installation.

Availability: VCPA is released under the MIT license and is available for academic and nonprofit use for free. The pipeline source code and step-by-step instructions are available from the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (http://www.niagads.org/VCPA).

Contact:yyee@pennmedicine.upenn.edu or lswang@pennmedicine.upenn.edu

Supplementary information: Supplementary data are available at Bioinformatics online.
Positive reward prediction errors strengthen incidental memory encoding
Authors: Jang Anthony I. , Nassar Matthew R. , Dillon Daniel G. , Frank Michael J.
Published: May 2018

The dopamine system is thought to provide a reward prediction error signal that facilitates reinforcement learning and reward-based choice in corticostriatal circuits. While it is believed that similar prediction error signals are also provided to temporal lobe memory systems, the impact of such signals on episodic memory encoding has not been fully characterized. Here we develop an incidental memory paradigm that allows us to 1) estimate the influence of reward prediction errors on the formation of episodic memories, 2) dissociate this influence from other factors such as surprise and uncertainty, 3) test the degree to which this influence depends on temporal correspondence between prediction error and memoranda presentation, and 4) determine the extent to which this influence is consolidation-dependent. We find that when choosing to gamble for potential rewards during a primary decision making task, people encode incidental memoranda more strongly even though they are not aware that their memory will be subsequently probed. Moreover, this strengthened encoding scales with the reward prediction error, and not overall reward, experienced selectively at the time of memoranda presentation (and not before or after). Finally, this strengthened encoding is identifiable within a few minutes and is not substantially enhanced after twenty-four hours, indicating that it is not consolidation-dependent. These results suggest a computationally and temporally specific role for putative dopaminergic reward prediction error signaling in memory formation.
Spikeling: a low-cost hardware implementation of a spiking neuron for neuroscience teaching and outreach
Authors: Baden Tom , James Ben , Zimmermann Maxime JY , Bartel Phillip , Grijseels Dorieke , Lagnado Leon , Maravall Miguel
Published: May 2018

Understanding of how neurons encode and compute information is fundamental to our study of the brain, but opportunities for hands-on experience with neurophysiological techniques on live neurons are scarce in science education. Here, we present Spikeling, an open source £25 in silico implementation of a spiking neuron that mimics a wide range of neuronal behaviours for classroom education and public neuroscience outreach. Spikeling is based on an Arduino microcontroller running the computationally efficient Izhikevich model of a spiking neuron. The microcontroller is connected to input ports that simulate synaptic excitation or inhibition, dials controlling current injection and noise levels, a photodiode that makes Spikeling light-sensitive and an LED and speaker that allows spikes to be seen and heard. Output ports provide access to variables such as membrane potential for recording in experiments or digital signals that can be used to excite other connected Spikelings. These features allow for the intuitive exploration of the function of neurons and networks. We also report our experience of using Spikeling as a teaching tool for undergraduate and graduate neuroscience education in Nigeria and the UK.
DYRK1A regulates the recruitment of 53BP1 to the sites of DNA damage in part through interaction with RNF169
Authors: Menon Vijay R. , Ananthapadmanabhan Varsha , Swanson Selene , Saini Siddharth , Sesay Fatmata , Yakovlev Vasily , Florens Laurence , DeCaprio James A. , Washburn Michael P. , Dozmorov Mikhail , Litovchick Larisa
Published: May 2018

HumanDYRK1Agene encoding Dual-specificity tyrosine (Y)- Regulated Kinase 1A (DYRK1A) is a dosage-dependent gene whereby either trisomy or haploinsufficiency result in developmental abnormalities. However, the function and regulation of this important protein kinase are not fully understood. Here we report proteomic analysis of DYRK1A in human cells that revealed a novel role of DYRK1A in the DNA double-strand break (DSB) repair signaling. This novel function of DYRK1A is mediated in part by its interaction with ubiquitin-binding protein RNF169 that regulates the choice between homologous recombination (HR) and non-homologous end joining (NHEJ) DSB repair. Accumulation of RNF169 at the DSB sites promotes homologous recombination (HR) by limiting the recruitment of the scaffold protein 53BP1 that promotes NHEJ by protecting the DNA ends from resection. Inducible overexpression of active, but not the kinase inactive, DYRK1A in U-2 OS cells inhibited accumulation of 53BP1 at the DSB sites in RNF169-dependent manner. Mutation of DYRK1A phosphorylation sites in RNF169 or pharmacological inhibition of DYRK1A using harmine decreased the ability of RNF169 to displace 53BP1 from radiation-induced DSB sites. In order to further investigate the role of DYRK1A in regulation of DNA repair, we used CRISPR-Cas9 mediated knockout of DYRK1A in human and mouse cells. Interestingly, knockout of DYRK1A also caused a defect in 53BP1 DSB recruitment that was independent of RNF169, suggesting that dosage of DYRK1A can influence the DNA repair processes through several mechanisms. U-2 OS cells devoid of DYRK1A displayed an increased DNA repair and HR efficiency, and showed a decreased sensitivity to the PARP inhibitor olaparib when compared to control cells. Given evidence of its altered expression in human cancers, DYRK1A levels could represent a significant determinant of the DNA damaging therapy response.
Dynamics of the sex ratio in Tetrahymena thermophila
Authors: Wang Guangying , Chen Kai , Zhang Jing , Ma Xuefeng , Deng Shanjun , Xiong Jie , He Xionglei , Fu Yunxin , Miao Wei
Published: May 2018

Sex is often hailed as one of the major successes in evolution, and in sexual organisms the maintenance of proper sex ratio is crucial. As a large unicellular eukaryotic lineage, ciliates exhibit tremendous variation in mating systems, especially the number of sexes and the mechanism of sex determination (SD), and yet how the populations maintain proper sex ratio is poorly understood. Here Tetrahymena thermophila, a ciliate with seven mating types (sexes) and probabilistic SD mechanism, is analyzed from the standpoint of population genetics. It is found based on a newly developed population genetics model that there are plenty of opportunities for both the co-existence of all seven sexes and the fixation of a single sex, pending on several factors, including the strength of natural selection. To test the validity of predictions, five experimental populations of T. thermophila were maintained in the laboratory so that the factors that can influence the dynamics of sex ratio could be controlled and measured. Furthermore, whole-genome sequencing was employed to examine the impact of newly arisen mutations. Overall, it is found that the experimental observations highly support theoretical predictions. It is expected that the newly established theoretical framework is applicable in principle to other multi-sex organisms to bring more insight into the understanding of the maintenance of multiple sexes in a natural population.
The Effect of Hybridization on Dosage Compensation in Member Species of theAnopheles gambiaeSpecies Complex
Authors: Deitz Kevin C. , Takken Willem , Slotman Michel A.
Published: May 2018

Dosage compensation has evolved in concert with Y-chromosome degeneration in many taxa that exhibit heterogametic sex chromosomes. Dosage compensation overcomes the biological challenge of a "half dose" of X chromosome gene transcripts in the heterogametic sex. The need to equalize gene expression of a hemizygous X with that of autosomes arises from the fact that the X chromosomes retain hundreds of functional genes that are actively transcribed in both sexes and interact with genes expressed on the autosomes. Sex determination and heterogametic sex chromosomes have evolved multiple times in Diptera, and in each case the genetic control of dosage compensation is tightly linked to sex determination. In theAnopheles gambiaespecies complex (Culicidae), maleness is conferred by the Y-chromosome geneYob, which despite its conserved role between species is polymorphic in its copy number between them. Previous work demonstrated that maleAn. gambiae s.s.males exhibit complete dosage compensation in pupal and adult stages. In the present study we have extended this analysis to three sister species in theAn. gambiaecomplex:An. coluzzii,An. arabiensis, andAn. quadriannulatus. In addition, we analyzed dosage compensation in bi-directional F1 hybrids between these species to determine if hybridization results in the mis-regulation and disruption of dosage compensation. Our results confirm that dosage compensation operates in theAn. gambiaespecies complex through the hyper-transcription of the male X chromosome. Additionally, dosage compensation in hybrid males does not differ from parental males, indicating that hybridization does not result in the mis-regulation of dosage compensation.
Searching for rewards like a child means less generalization and more directed exploration
Authors: Schulz Eric , Wu Charley M. , Ruggeri Azzurra , Meder Björn
Published: May 2018

How do children and adults differ in their search for rewards? We consider three different hypotheses that attribute developmental differences to either children’s increased random sampling, more directed exploration towards uncertain options, or narrower generalization. Using a search task in which noisy rewards are spatially correlated on a grid, we compare 55 younger children (age 7-8), 55 older children (age 9-11), and 50 adults (age 19-55) in their ability to successfully generalize about unobserved outcomes and balance the exploration-exploitation dilemma. Our results show that children explore more eagerly than adults, but obtain lower rewards. Building a predictive model of search to disentangle the unique contributions of the three hypotheses of developmental differences, we find robust and recoverable parameter estimates indicating that children generalize less and rely on directed exploration more than adults. We do not, however, find reliable differences in terms of random sampling.
Reproductive longevity predicts mutation rates in primates
Authors: Thomas Gregg W.C. , Wang Richard J. , Puri Arthi , Harris R. Alan , Raveendran Muthuswamy , Hughes Daniel , Murali Shwetha , Williams Lawrence , Doddapaneni Harsha , Muzny Donna , Gibbs Richard , Abee Christian , Galinski Mary R. , Worley Kim C. , Rogers Jeffrey , Radivojac Predrag , Hahn Matthew W.
Published: May 2018

Mutation rates vary between species across several orders of magnitude, with larger organisms having the highest per-generation mutation rates. Hypotheses for this pattern typically invoke physiological or population-genetic constraints imposed on the molecular machinery preventing mutations1. However, continuing germline cell division in multicellular eukaryotes means that organisms with longer generation times and of larger size will leave more mutations to their offspring simply as a by-product of their increased lifespan2,3. Here, we deeply sequence the genomes of 30 owl monkeys (Aotus nancymaae) from 6 multi-generation pedigrees to demonstrate that paternal age is the major factor determining the number of de novo mutations in this species. We find that owl monkeys have an average mutation rate of 0.81 × 10−8 per site per generation, roughly 32% lower than the estimate in humans. Based on a simple model of reproductive longevity that does not require any changes to the mutational machinery, we show that this is the expected mutation rate in owl monkeys. We further demonstrate that our model predicts species-specific mutation rates in other primates, including study-specific mutation rates in humans based on the average paternal age. Our results suggest that variation in life history traits alone can explain variation in the per-generation mutation rate among primates, and perhaps among a wide range of multicellular organisms.
Transition State Interactions in a Promiscuous Enzyme: Sulfate and Phosphate Monoester Hydrolysis byPseudomonas aeruginosaArylsulfatase
Authors: van Loo Bert , Berry Ryan , Boonyuen Usa , Mohamed Mark F. , Golicnik Marko , Hengge Alvan C. , Hollfelder Florian
Published: May 2018

Pseudomonas aeruginosaarylsulfatase (PAS) hydrolyses sulfate and, promiscuously, phosphate monoesters. Enzyme-catalyzed sulfate transfer is crucial to a wide variety of biological processes, but detailed studies of the mechanistic contributions to its catalysis are lacking. We present an investigation based on linear free energy relationships (LFERs) and kinetic isotope effects (KIEs) of PAS and active site mutants that suggest a key role for leaving group (LG) stabilization. In LFERs wild type PAS has a much less negative Br0nsted coefficient (βleaving groupobs-Enz= −0.33) than the uncatalyzed reaction (βleavingroupobs= −1.81). This situation is diminished when cationic active site groups are exchanged for alanine. The considerable degree of bond breaking during the TS is evidenced by an18ObridgeKIE of 1.0088. LFER and KIE data for several active site mutants point to leaving group stabilization by active-site lysine K375, in cooperation with histidine H211.15N KIEs combined with an increased sensitivity to leaving group ability of the sulfatase activity in neat D2O (Δβleaving groupH-D= +0.06) suggest that the mechanism for S-Obridgebond fission shifts, with decreasing leaving group ability, from charge compensation via Lewis acid interactions towards direct proton donation.18OnonbridgeKIEs indicate that the TS for PAS-catalyzed sulfate monoester hydrolysis has a significantly more associative character compared to the uncatalyzed reaction, while PAS-catalyzed phosphate monoester hydrolysis does not show this shift. This difference in enzyme-catalyzed TSs appears to be the major factor favoring specificity toward sulfate over phosphate in this promiscuous hydrolase, since other features are either too similar (uncatalyzed TS) or inherently favor phosphate (charge).
Bayesian analysis of isothermal titration calorimetry for binding thermodynamics
Authors: Nguyen Trung Hai , Rustenburg Ariën S. , Krimmer Stefan G. , Zhang Hexi , Clark John D. , Novick Paul A. , Branson Kim , Pande Vijay S. , Chodera John D. , Minh David D. L.
Published: May 2018

Isothermal titration calorimetry (ITC) is the only technique able to determine both the enthalpy and entropy of noncovalent association in a single experiment. The standard data analysis method based on nonlinear regression, however, provides unrealistically small uncertainty estimates due to its neglect of dominant sources of error. Here, we present a Bayesian framework for sampling from the posterior distribution of all thermodynamic parameters and other quantities of interest from one or more ITC experiments, allowing uncertainties and correlations to be quantitatively assessed. For a series of ITC measurements on metal:chelator and protein:ligand systems, the Bayesian approach yields uncertainties which represent the variability from experiment to experiment more accurately than the standard data analysis. In some datasets, the median enthalpy of binding is shifted by as much as 1.5 kcal/mol. A Python implementation suitable for analysis of data generated by MicroCal instruments (and adaptable to other calorimeters) is freely available online.
Circulating proteomic patterns in AF related left atrial remodeling indicate involvement of coagulation and complement cascade
Authors: Kornej Jelena , Büttner Petra , Hammer Elke , Engelmann Beatrice , Dinov Borislav , Sommer Philipp , Husser Daniela , Hindricks Gerhard , Völker Uwe , Bollmann Andreas
Published: May 2018

Background

Left atrial (LA) electro-anatomical remodeling and diameter increase in atrial fibrillation (AF) indicates disease progression and is associated with poor therapeutic success. Furthermore, AF leads to a hypercoagulable state, which in turn promotes the development of a substrate for AF and disease progression in the experimental setting. The aim of this study was to identify pathways associated with LA remodeling in AF patients using untargeted proteomics approach.

Methods

Peripheral blood samples of 48 patients (62±10 years, 63% males, 59% persistent AF) undergoing AF catheter ablation were collected before ablation. 24 patients with left atrial low voltage areas (LVA), defined as <0.5 mV, and 24 patients without LVA were matched for age, gender and CHA2DS2-VASc score. Untargeted proteome analysis was performed using LC-ESI-Tandem mass spectrometry in a label free intensity based workflow. Significantly different abundant proteins were identified and used for pathway analysis and protein-protein interaction analysis.

Results

Analysis covered 280 non-redundant circulating plasma proteins. The presence of LVA correlated with 30 differentially abundant proteins of coagulation and complement cascade (q<0.05).

Conclusions

This pilot proteomic study identified plasma protein candidates associated with electro-anatomical remodeling in AF and pointed towards an imbalance in coagulation and complement pathway, tissue remodeling and inflammation
Discovery of gene regulatory elements through a new bioinformatics analysis of haploid genetic screens
Authors: Patel Bhaven B. , Lebensohn Andres M. , Carette Jan E. , Salzman Julia , Rohatgi Rajat
Published: May 2018

The systematic identification of regulatory elements that control gene expression remains a challenge. Genetic screens that use untargeted mutagenesis have the potential to identify protein-coding genes, non-coding RNAs and regulatory elements, but their analysis has mainly focused on identifying the former two. To identify regulatory elements, we conducted a new bioinformatics analysis of insertional mutagenesis screens interrogating WNT signaling in haploid human cells. We searched for specific patterns of retroviral gene trap integrations (used as mutagens in haploid screens) in short genomic intervals overlapping with introns and regions upstream of genes. We uncovered atypical patterns of gene trap insertions that were not predicted to disrupt coding sequences, but caused changes in the expression of two key regulators of WNT signaling, suggesting the presence of cis-regulatory elements. Our methodology extends the scope of haploid genetic screens by enabling the identification of regulatory elements that control gene expression.
Impact of MMP-2 and MMP-9 activation on wound healing, tumor growth and RACPP cleavage
Authors: Hingorani Dina V. , Lippert Csilla N. , Crisp Jessica L. , Savariar Elamprakash N. , Hasselmann Jonathan P.C. , Kuo Christopher , Nguyen Quyen T. , Tsien Roger Y. , Whitney Michael A. , Ellies Lesley G.
Published: May 2018

Matrix metalloproteinases-2 and -9 (MMP-2/-9) are key tissue remodeling enzymes that have multiple overlapping activities critical for wound healing and tumor progressionin vivo. To overcome issues of redundancy, we created MMP-2/-9 double knockout (DKO) mice in the C57BL/6 background to examine wound healing. We then bred the DKO mice into the polyomavirus middle T (PyVmT) model of breast cancer to analyze the role of these enzymes in tumorigenesis. Breeding analyses indicated that significantly fewer DKO mice were born than predicted by Mendelian genetics and weaned DKO mice were growth compromised compared with wild type (WT) cohorts. Epithelial wound healing was dramatically delayed in adult DKO mice and when the DKO was combined with the PyVmT oncogene, we found that the biologically related process of mammary tumorigenesis was inhibited in a site-specific manner. To further examine the role of MMP-2/-9 in tumor progression, tumor cells derived from WT or DKO PyVmT transgenic tumors were grown in WT or DKO mice. Ratiometric activatable cell penetrating peptides (RACPPs) previously used to image cancer based on MMP-2/-9 activity were used to understand differences in MMP activity in WT or knockout syngeneic tumors in WT and KO animals. Analysis of an MMP-2 selective RACPP in WT or DKO mice bearing WT and DKO PyVmT tumor cells indicated that the genotype of the tumor cells was more important than the host stromal genotype in promoting MMP-2/-9 activity in the tumors in this model system. Additional complexities were revealed as the recruitment of host macrophages by the tumor cells was found to be the source of the tumor MMP-2/-9 activity and it is evident that MMP-2/-9 from both host and tumor is required for maximum signal using RACPP imaging for detection. We conclude that in the PyVmT model, the majority of MMP-2/-9 activity in mammary tumors is associated with host macrophages recruited into the tumor rather than that produced by the tumor cells themselves. Thus therapies that target tumor-associated macrophage functions have the potential to slow tumor progression.
Insights from a distinguished scholar’s literary contribution
Authors: Popoola Ifeoluwa Tobi
Published: May 2018

Purpose

The purpose of this paper is to reflect on the varied themes of Professor Steve Evans contributions to Accounting Auditing and Accountability Journal (AAAJ) as Literary Editor between 2009 and 2011.

Design/methodology/approach

Methodology takes the form of a prose article and accompanying fictional poem.

Findings

Literary editors provide different themes when publishing submitted and accepted literary works. However, there might be similarities in the themes provided.

Research limitations/implications

The manuscript encourages use of creative expression as a way of representing areas of inquiry and research.

Originality/value

A review of Professor Evans’ contribution to AAAJ, as contained in the Journal’s Literature and Insights, is structured in a cento variant and prose.
Tone disclosure and financial performance: evidence from Egypt
Authors: Aly Doaa , El-Halaby Sherif , Hussainey Khaled
Published: May 2018

Purpose

This paper aims to examine the extent to which financial performance (FP) represents one of the main determinants for tone disclosure (TD) in Egyptian annual reports. The authors also measure the bidirectional relationship between TD and FP.

Design/methodology/approach

The manual content analysis is used to measure the levels of TD in annual reports for a sample of 105 firms listed on the Egyptian stock market. The sample covers a three-year period (2011-2013).

Findings

The descriptive analysis in this paper shows that Egyptian firms disclose more good news than bad news. Therefore, the net news disclosure, or net variances, between good/bad is positive. The empirical analysis shows a positive association between the narrative disclosure of good/bad news and FP based on return on assets. The authors also find a highly significant association between the auditor, profitability, leverage, firm growth and financial reporting of good/bad news information. Finally, the results of the ordinary least squares regression show that the causality between the two endogenous variables runs from FP to TD. Thus, TD is determined by FP.

Originality/value

This study offers a novel contribution to disclosure studies by being the first study to examine TD in one of the developing countries.
An experimental investigation of dimensional precision in uncertainty disclosures related to revenue recognition
Authors: Du Ning , Whittington Ray
Published: May 2018

Purpose

The purpose of this paper is to investigate how managerial disclosure of imprecise information about revenue recognition affects investors’ perceptions of corporate and management performance. Specifically, the authors focus on how outcome and probability dimensions and their respective (im) precision interact with each other and jointly affect investors’ judgments and decision-making.

Design/methodology/approach

The authors conducted an experiment where the dimensions are manipulated (outcome vs probability) of disclosed revenue recognition information and its related precision (a point vs a range estimate).

Findings

Results from this study suggest that participants are sensitive to specific dimensions of uncertainty disclosure: participants were highly aware of the (im)precision in outcome information, were more likely to invest when both dimensions were vague and expected higher revenue when dimensional precision was consistent.

Practical implications

The results imply that dimensional precision is an important component in uncertainty disclosure and may have a significant impact on investors’ judgments and decision making. Regulators and managers should consider dimensional imprecision when they develop and implement disclosure strategy regarding revenue recognition.

Social implications

The results have practical value for regulators/managers, who are in the process of developing/implementing disclosure strategy regarding revenue recognition.

Originality/value

This is the first study to examine the interaction of dimensions of uncertainty in revenue disclosures.
Opportunities for Lean Six Sigma in public sector municipalities
Authors: Fletcher Jeffrey
Published: May 2018

Purpose

The purpose of this study is to investigate awareness and opportunities for Lean Six Sigma in public sector municipalities striving to become more efficient and effective in the quality and delivery of services and goods leading to increased citizen satisfaction and budget savings.

Design/methodology/approach

Lean Six Sigma is a quality improvement methodology widely implemented in the for-profit sectors and, now, is expanding into the public sector. This study includes a literature review on Lean Six Sigma, supported by results from interviews with public sector officials, and includes recommendations for how public sector entities can utilize Lean Six Sigma.

Findings

Based on results from interviews with a sample of public sector officials, this study uncovered that overall there exists a keen interest in Lean Six Sigma and how it can be applied to streamline and improve organizational processes, produce cost-savings, improve organizational culture and improve the quality of goods and services. This study also discovers that there are plenty of opportunities for Lean Six Sigma in the public sector and municipalities can, in fact, incorporate its philosophy and methodology to streamline and improve organizational processes, produce cost-savings, improve organizational culture and improve the quality of goods and services.

Originality/value

Abundant literature exists on Lean Six Sigma and the private sector. This study includes a review of the literature supported by interview results of public sector officials and suggests techniques for how public sector municipalities can utilize the Lean Six Sigma methodology. In a twenty-first-century economy, public sector officials are looking for ways to maximize their tax dollars while increasing the quality of their goods and services; Lean Six Sigma is a framework that can make these objectives become a reality.
Impact of athletic star power on product consumption
Authors: McCormick Karla
Published: May 2018

Purpose

The purpose of this paper is to determine if the star power of an athletic endorser influenced consumers’ consumption of the advertised product. Specifically, does the amount of star power an athlete is thought to have impact consumers’ direct consumption of the advertised product and media consumption of the athlete? Moreover, the components of star power, along with congruency measures, were examined to determine which components of star power influenced both direct and media consumption.

Design/methodology/approach

Four advertisements were created that used an athlete with high star power and an athlete with low star power. Respondents viewed two of the advertisements, but did not know which athlete had high star power or low star power. They were asked to answer a questionnaire that contained questions pertaining to the components of star power (source attractiveness, source credibility, professional trustworthiness, likeable personality and character style), congruency of the athlete and product, direct consumption of the advertised product and media consumption of the athlete.

Findings

Results indicated that overall star power increased the direct consumption of the advertised product and the media consumption of the athlete, however not each component was found to be significant. Character style was the only component that was consistently significant across all four advertisements. The congruency between the athlete and product was also found to be significant across all four advertisements.

Research limitations/implications

First, this study only looked at two athletes; others may generate different results. Second, the products used in the study were fashion related; other categories of products may also generate different relationships. Third, only two brands were used. It was also assumed that the respondents knew the athlete in the advertisement. Finally, the questions used to measure direct consumption did not distinguish between buying the brand in the store or online.

Originality/value

This study has the potential to contribute theoretically by analyzing how and which components of star power affect consumption of endorsed products, as well as which components influence consumers. Moreover, adding a congruency measure will aide in strengthening the measurement of endorser effectiveness. The justification of the present study lies in the need to determine how the dimensions of star power an athlete possesses contribute to the consumption behaviors of consumers.
The applicability of credit scoring models in emerging economies: an evidence from Jordan
Authors: Ala’raj Maher , Abbod Maysam , Radi Mohammed
Published: May 2018

Purpose

The purpose of this study is to propose an objective and efficient method for assessing credit risk by introducing and investigating to a greater extent the applicability of credit scoring models in the Jordanian banks and to what range they can be used to achieve their strategic and business objectives.

Design/methodology/approach

The research methodology comprises two phases. The first phase is the model development. Three modeling techniques are used to build the scoring models, namely, logistic regression (LR), artificial neural network (NN) and support vector machine (SVM), and the best performing model is selected for next stage. The second phase is two-fold: linking the credit expert knowledge in a way that can enhance the outcomes of the scoring model and a profitability test to explore if the selected model is efficient in meeting banks’ strategic and business objectives.

Findings

The findings showed that LR model outperformed both ANN and SVM across various performance indicators. The LR model also fits best with achieving the bank’s strategic and business objectives.

Originality/value

To the best of the authors’ knowledge, this study is the first that applied several modeling and classification techniques for Jordanian banks and calibrated the best model in terms of its strategic and business objectives. Furthermore, credit experts’ knowledge was engaged with the scoring model to determine its efficiency and reliability against the sole use of an automated scoring model in the hope to encourage the application of credit scoring models as an advisory tool for credit decisions.
Self-exploitation or successful entrepreneurship? The effects of personal capital on variable outcomes from self-employment
Authors: Atherton Andrew , Wu Dongxu , Wu Zhongmin
Published: May 2018

Purpose

The purpose of this paper is to understand whether the personal capital of the entrepreneur positively or negatively affects outcomes from self-employment.

Design/methodology/approach

Data from the UK’s longitudinal household surveys (BHPS, UKLHS) between 1991 and 2014 were analysed. Relationships between age, education, health and family status, income earned and hours worked were tested.

Findings

Entrepreneurs with higher levels of personal capital enjoyed higher incomes. However, those with lower levels of personal capital were more likely to have negative returns from self-employment, and so experience it as “self-exploitation”.

Research limitations/implications

A basis for understanding different outcomes from self-employment was developed and tested.

Practical implications

Specific characteristics of continuing and new entrepreneurs were identified that are positively associated with beneficial outcomes from self-employment.

Originality/value

Positive and negative outcomes from self-employment are explained. The notion of personal capital is developed as an explanatory framework for variable outcomes from self-employment.
Japanese Dermatological Association Guidelines: Guidelines for the treatment of acne vulgaris 2017
Authors: Hayashi Nobukazu , Akamatsu Hirohiko , Iwatsuki Keiji , Shimada‐Omori Ryoko , Kaminaka Chikako , Kurokawa Ichiro , Kono Takeshi , Kobayashi Miwa , Tanioka Miki , Furukawa Fukumi , Furumura Minao , Yamasaki Osamu , Yamasaki Kenshi , Yamamoto Yuki , Miyachi Yoshiki , Kawashima Makoto
Published: May 2018

The Guidelines for the Treatment of Acne Vulgaris of the Japanese Dermatological Association was first published in Japanese in 2008 and revised in 2016 and 2017. These guidelines (GL) indicate the standard acne treatments in Japan and address pharmaceutical drugs and treatments applicable or in use in Japan. In theseGL, the strength of the recommendation is based on clinical evidences as well as availability in Japanese medical institutions. In the 2016 and 2017GL, some of the clinical questions were revised, and other questions were added in accordance with approval of topical medicines containing benzoyl peroxide (BPO). Rather than monotherapies of antibiotics, the 2017GLmore strongly recommend combination therapies, especially fixed‐dose combination gels includingBPOin the aspects of pharmacological actions and compliance in the acute inflammatory phase to achieve earlier and better improvements. The 2017GLalso indicate to limit the antimicrobial treatments for the acute inflammatory phase up to approximately 3 months and recommendBPO, adapalene, and a fixed‐dose combination gel of 0.1% adapalene and 2.5%BPOfor the maintenance phase to avoid the emergence of antimicrobial‐resistantPropionibacterium acnes. The 2017GLalso discuss rosacea, which requires discrimination from acne and a different treatment plan.