bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

SummaryHumanDYRK1Agene 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

AbstractSex 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

AbstractDosage 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

AbstractHow 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

AbstractMutation 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

ABSTRACTPseudomonas 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

AbstractIsothermal 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

AbstractBackgroundLeft 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.MethodsPeripheral 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.ResultsAnalysis 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).ConclusionsThis 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

AbstractThe 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

AbstractMatrix 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

PurposeThe 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/approachThe 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).FindingsResults 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 implicationsThe 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 implicationsThe results have practical value for regulators/managers, who are in the process of developing/implementing disclosure strategy regarding revenue recognition.Originality/valueThis 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.