bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative analysis of large-scale loss-of-function screens identifies robust cancer-associated genetic interactions
Authors: Lord Christopher J. , Quinn Niall , Ryan Colm J. 
Published: May 2019

AbstractGenetic interactions, such as synthetic lethal effects, can now be systematically identified in cancer cell lines using high-throughput genetic perturbation screens. Despite this advance, few genetic interactions have been reproduced across multiple studies and many appear highly context-specific. Understanding which genetic interactions are robust in the face of the molecular heterogeneity observed in tumours and what factors influence this robustness could streamline the identification of therapeutic targets. Here, we develop a computational approach to identify robust genetic interactions that can be reproduced across independent experiments and across non-overlapping cell line panels. We used this approach to evaluate >140,000 potential genetic interactions involving cancer driver genes and identified 1,520 that are significant in at least one study but only 220 that reproduce across multiple studies. Analysis of these interactions demonstrated that: (i) oncogene addiction effects are more robust than oncogene-related synthetic lethal effects; and (ii) robust genetic interactions in cancer are enriched for gene pairs whose protein products physically interact. This suggests that protein-protein interactions can be used not only to understand the mechanistic basis of genetic interaction effects, but also to prioritise robust targets for further development. To explore the utility of this approach, we used a protein-protein interaction network to guide the search for robust synthetic lethal interactions associated with passenger gene alterations and validated two novel robust synthetic lethalities.
AEGIS: An In Silico Tool to model Genome Evolution in Age-Structured Populations
Authors: Bradshaw William J. , Šajina Arian , Valenzano Dario Riccardo 
Published: May 2019

AbstractAEGIS (Ageing of Evolving Genomes In Silico) is a versatile population-genetics numerical-simulation tool that enables the evolution of life history trajectories under sexual and asexual reproduction and a wide variety of evolutionary constraints. By encoding age-specific survival and reproduction probabilities as discrete genomic elements, AEGIS allows these probabilities to evolve freely and independently over time. Simulation of population evolution with AEGIS demonstrates that ageing-like phenotypes evolve in stable environments under a wide range of conditions, that life history trajectories depend heavily on mutation rates, and that sexual populations are better able to accumulate high levels of beneficial mutations affecting early-life survival and reproduction. AEGIS is free and open-source, and aims to become a standard reference tool in the study of life-history evolution and the evolutionary biology of ageing.
A novel inhibitor of complement C5 provides structural insights into activation
Authors: Reichhardt Martin P. , Johnson Steven , Tang Terence , Morgan Thomas , Tebeka Nchimunya , Popitsch Niko , Deme Justin C. , Jore Matthijs M. , Lea Susan M. 
Published: May 2019

AbstractThe complement system is a crucial part of innate immune defences against invading pathogens. The blood-meal of thetick Rhipicephalus pulchelluslasts for days, and the tick must therefore rely on inhibitors to counter complement activation. We have identified a novel class of inhibitors from tick saliva, the CirpT family, and generated detailed structural data revealing their mechanism of action. We show direct binding of a CirpT to complement C5 and have determined the structure of the C5-CirpT complex by cryo-electron microscopy. This reveals an interaction with the peripheral macro globulin domain 4 (C5_MG4) of C5. To achieve higher resolution detail, the structure of the C5_MG4-CirpT complex was solved by X-ray crystallography (at 2.7 Å). We thus present the novel fold of the CirpT protein family, and provide detailed mechanistic insights into its inhibitory function. Analysis of the binding interface reveals a novel mechanism of C5 inhibition, and provides information to expand our biological understanding of the activation of C5, and thus the terminal complement pathway.
Phenotypic and genotypic consequences of CRISPR/Cas9 editing of the replication origins in the rDNA of Saccharomyces cerevisiae
Authors: Sanchez Joseph C. , Ollodart Anja , Large Christopher R. L. , Clough Courtnee , Alvino Gina M. , Tsuchiya Mitsuhiro , Crane Matthew , Kwan Elizabeth X. , Kaeberlein Matt , Dunham Maitreya J. , Raghuraman M. K. , Brewer Bonita J. 
Published: May 2019

AbstractThe complex structure and repetitive nature of eukaryotic ribosomal DNA (rDNA) is a challenge for genome assembly, and thus, the consequences of sequence variation in rDNA remain unexplored. However, renewed interest in the role that rDNA variation may play in diverse cellular functions, aside from ribosome production, highlights the need for a method that would permit genetic manipulation of the rDNA. Here, we describe a CRISPR/Cas9 based strategy to edit the rDNA locus in the budding yeast Saccharomyces cerevisiae. Using this approach, we modified the endogenous rDNA origin of replication in each repeat by deleting or replacing its consensus sequence. We characterized the transformants that have successfully modified their rDNA locus and propose a mechanism for how CRISPR/Cas9 mediated editing of the rDNA occurs. In addition, we carried out extended growth and life span experiments to investigate the long-term consequences that altering the rDNA origin of replication has on cellular health. We find that long-term growth of the edited clones results in faster growing suppressors that have acquired segmental aneusomy of the rDNA containing region of chr XII or aneuploidy of chromosomes XII, II, or IV. Furthermore, we find that all edited isolates suffer a reduced life span, irrespective of their levels of extrachromosomal rDNA circles. Our work demonstrates that it is possible to quickly, efficiently and homogeneously edit the rDNA locus via CRISPR/Cas9. It serves as a model for modifying other parts of the rDNA and, more generally, for editing other tandemly repeated sequences in higher eukaryotes.
The Firre locus produces a trans-acting RNA molecule that functions in hematopoiesis
Authors: Lewandowski Jordan P. , Lee James C. , Hwang Taeyoung , Sunwoo Hongjae , Goldstein Jill M. , Groff Abigail F. , Chang Nydia , Mallard William , Williams Adam , Henao-Meija Jorge , Flavell Richard A. , Lee Jeannie T. , Gerhardinger Chiara , Wagers Amy J. , Rinn John L. 
Published: May 2019

ABSTRACTRNA has been classically known to play central roles in biology, including maintaining telomeres1, protein synthesis2, and in sex chromosome compensation in certain species3,4. At the center of these important biological systems are noncoding RNAs. While thousands of long noncoding RNAs (lncRNAs) have been identified in mammalian genomes5–8, attributing RNA-based roles to lncRNA loci requires an assessment of whether the observed effect could be due to DNA regulatory elements, the act of transcription, or the lncRNA transcript. Here, we use the syntenically conserved lncRNA locus, Functional intergenic repeating RNA element (Firre), that is located on the X chromosome as a model to discriminate between DNA- and RNA-mediated effects in vivo. To this end, we generated genetically defined loss-of-function, gain-of-function, and rescue mouse models for Firre and provide genetic evidence that the Firre locus produces a trans-acting RNA. We report that: (i) Firre mutant mice have cell-specific defects during hematopoiesis and changes in gene expression that can be rescued by induction of Firre RNA from a transgene in the Firre knockout background, (ii) mice overexpressing Firre from a transgene exhibit increased levels of pro-inflammatory cytokines and impaired survival upon exposure to lipopolysaccharide, and (iii) deletion of the Firre locus did not result in changes in local gene expression on the X chromosome in 9 different biological contexts, suggesting that Firre does not function by cis-acting RNA or DNA elements. Together, our results provide genetic evidence that the Firre locus produces a trans-acting lncRNA that has physiological roles in hematopoiesis and immune function.
Cis-regulatory basis of sister cell type divergence in the vertebrate retina
Authors: Murphy Daniel , Hughes Andrew. E.O. , Lawrence Karen A. , Myers Connie A. , Corbo Joseph C. 
Published: May 2019

AbstractMulticellular organisms evolved via repeated functional divergence of transcriptionally related sister cell types, but the mechanisms underlying sister cell type divergence are not well understood. Here, we study a canonical pair of sister cell types, retinal photoreceptors and bipolar cells, to identify the key cis-regulatory features that distinguish them. By comparing open chromatin maps and transcriptomic profiles, we found that while photoreceptor and bipolar cells have divergent transcriptomes, they share remarkably similar cis-regulatory grammars, marked by enrichment of K50 homeodomain binding sites. However, cell class-specific enhancers are distinguished by enrichment of E-box motifs in bipolar cells, and Q50 homeodomain motifs in photoreceptors. We show that converting K50 motifs to Q50 motifs represses reporter expression in bipolar cells, while photoreceptor expression is maintained. These findings suggest that partitioning of Q50 motifs within cell type-specific cis-regulatory elements was a critical step in the divergence of the bipolar transcriptome from that of photoreceptors.
The Prevalence and Patterns of Combined Psychotropic Polypharmacy among Acute Care Hospitals in Japan
Authors: Shimizu Sayuri , Okumura Yasuyuki , Ishikawa Koichi B. , Matsuda Shinya , Ito Hiroto , Fushimi Kiyohide 
Published: May 2019

ABSTRACTPurposeTo evaluate the prescribing patterns of psychotropic polypharmacy for inpatients of acute care hospitals in Japan.MethodsAdministrative data on 2,639,885 patients admitted to acute care hospitals in Japan between July and December of 2008 were analyzed retrospectively. We defined psychotropic medications as antipsychotics, antidepressants, benzodiazepines, and other sedatives/hypnotics and studied their prescription patterns during the hospitalization of patients with stroke, acute cardiac infarction, cancer, and diabetes mellitus.ResultsAt least one psychotropic drug was prescribed in 35.9% of all cases. Two-drug combinations of antipsychotic drugs were prescribed for stroke patients in 14,615 cases (1.4%), more than 2 in 3,132 cases (0.3%), and 22.4% of cases were prescribed 2 or more psychotropic drugs in addition to antipsychotic drugs. Amongst upper gastrointestinal cancer patients, 7.7% were prescribed a combination of 2 or more drugs, including benzodiazepines. Of the upper gastrointestinal cancer patients who were prescribed benzodiazepines, 20.3% were also prescribed 2 or more psychotropic drugs. Amongst stroke and upper gastrointestinal cancer patients, 36.6% and 35.6%, respectively, were treated with combination therapy using drugs of this class and others.ConclusionThere is a pattern of polypharmacy that combines benzodiazepines and other sedatives/hypnotics with antidepressants or antipsychotic drugs, and this study provides a detailed analysis of this within acute care hospitals. Our results indicate the need for additional research into the efficacy of polypharmacy for inpatients in non-psychiatric settings.
Transcriptional bursts explain autosomal random monoallelic expression and affect allelic imbalance
Authors: Larsson Anton J.M. , Reinius Björn , Jacob Tina , Dalessandri Tim , Hendriks Gert-Jan , Kasper Maria , Sandberg Rickard 
Published: May 2019

AbstractTranscriptional bursts render substantial biological noise in cellular transcriptomes. Here, we investigated the theoretical extent of monoallelic expression resulting from transcriptional bursting and how it compared to the amounts of monoallelic expression of autosomal genes observed in single-cell RNA-sequencing (scRNA-seq) data. We found that transcriptional bursting can explain frequent observations of autosomal monoallelic gene expression in cells. Importantly, the burst frequency largely determined the fraction of cells with monoallelic expression, whereas both burst frequency and size contributed to allelic imbalance. Allelic observations deviate from the expected when analysed across heterogeneous groups of cells, suggesting that allelic modelling can provide an unbiased assessment of heterogeneity within cells. Finally, large numbers of cells are required for analyses of allelic imbalance to avoid confounding observations from transcriptional bursting. Altogether, our results shed light on the implications of transcriptional burst kinetics on allelic expression patterns and phenotypic variation between cells.
Regional tourism at the farmers’ market: consumers’ preferences for local food products
Authors: Garner Benjamin , Ayala Cesar 
Published: May 2019

PurposeThe purpose of this paper is to examine farmers’ market consumer behavior through a regional food and culinary tourism lens to see the ways these festive and atmospheric markets can be used to develop a regional brand or identity surrounding food production.Design/methodology/approachThis study was based on a survey of 270 participants in a farmers’ market in the USA. A combination of descriptive and statistical analyses was used to analyze consumer habits and spending.FindingsThe findings in this study suggest that while most of the customers live in a town where the market is located, a significant number of customers come from other locations, with some traveling significant distances, to participate in this market, particularly for the Saturday market. Many of the customers come to purchase organic and local foods.Research limitations/implicationsThis work is limited, in that it is a case study at one farmers’ market in the USA, and the work is exploratory in nature.Practical implicationsThis work has implications for market managers seeking to increase their consumer base. Markets that want to increase their reach would do well to promote their events to a wider geographic area. The results presented here showed that consumers are willing to drive upward of 40 miles to attend a high-quality market.Originality/valueThis work expands our conceptualization of farmers’ markets by suggesting that these markets have the potential to form the backbone of a region is food identity through the creation of a food destination.
The patterns of the numbers used in occupational fraud schemes
Authors: Nigrini Mark J. 
Published: May 2019

Purpose
This study aims to classify the numbers used in recent financial statement, corruption and asset misappropriation fraud schemes in such a way that these classes can be used to design effective proactive analytics-based fraud detection tests.

Design/methodology/approach
The data sources for the classification scheme include the court records of fraud prosecutions, investigative reports and research papers related to fraud cases.

Findings
Fraudulent numbers are most often amounts that are round, have a strong period-over-period growth, are just above or below internal control thresholds or other targets, are deviations from Benford’s Law, are purposeful duplicates of authentic transactions, are outliers due to being excessively large and are excessively rounded up or down. The study includes several examples of fraudulent numbers.

Research limitations/implications
The fraudulent number types are based on a sample of fraud-related court documents, and the sample might not be representative of the population of detected and undetected frauds. Further research is needed into the detection of corruption/bribery schemes.

Practical implications
The results are important for auditors and forensic accountants running proactive fraud detection tests. The discussions emphasize that the analysis should include refining and rerunning the tests, and then using groupings and filtering to deal with false positives. The importance of an effective audit of the notable transactions is stressed in the concluding section.

Originality/value
The study is an original in-depth coverage of the patterns found in fraudulent numbers. The discussion sections review implementation issues and considerations for future research.
Optimism-pessimism effects on money demand: theory and evidence
Authors: Karpetis Christos , Papadamou Stephanos , Spyromitros Eleftherios , Varelas Erotokritos 
Published: May 2019

PurposeThe purpose of this paper is to investigate, both theoretically and empirically, the relationship between optimism (pessimism) – as reflected by animal spirits – and money demand by taking into account transaction costs.Design/methodology/approachInspired by the theoretical model of money demand by Teleset al.(2016) the authors incorporate the optimism (pessimism) effects in the money demand. Then, using the consumers’ confidence indicator as a proxy indicator of optimism/pessimism, they estimate the money demand in a panel data framework.FindingsThe theoretical framework suggests that the optimism (pessimism) effects on money demand are positive (negative). Empirical evidence for 11 Eurozone countries divided in two groups (i.e. core and periphery) confirms the theoretical considerations.Practical implicationsIt appears that periphery countries with a higher sensitivity to the recent financial crisis present lower real money demand sensitivity to consumption expenditures and higher real money demand sensitivity to consumer confidence index. Moreover, in such countries, money demand changes present higher persistence over time. Thus, the authors observe differing attitudes concerning money demand across Eurozone citizens that should be taken into account by monetary policymakers (i.e. the ECB).Originality/valueThe authors introduce, in the vast literature on money demand, both theoretically and empirically the role of optimism (pessimism). Differences across core and periphery Eurozone countries identified.
Insider Information: The Ethicality of the High Frequency Trading Industry
Authors: Sobolev Daphne 
Published: May 2019

AbstractThis study explores the ethical perceptions of employees in the financial industry. Focusing on the high frequency trading (HFT) industry, it analyses a series of interviews with HFT employees (managers, computer programmers and traders). It shows that regulations and firm rules profoundly affect HFT practices. However, they do not provide employees with answers for their ethical questions. To judge the ethicality of HFT, employees choose reference stakeholder groups and assess the way HFT impacts them. The perception that HFT has a positive effect on stakeholder groups is associated with moral satisfaction, whereas the perception that it has a negative effect is related to emotional detachment, sense of meaninglessness and turnover intent. The high variance in employees’ choices of stakeholder reference groups emphasizes the subjectivity and uncertainty that HFT ethicality entails. Therefore, this study suggests that the financial industry may lack moral leadership. It makes empirical and theoretical contributions to the ‘business ethics as practice’ theory and examines management and regulatory applications.
Experiences of Urban Militarism: Spatial Stigma, Ruins and Everyday Life
Authors: Pasquetti Silvia 
Published: May 2019

AbstractA key question in urban sociology is how people interpret the urban environment. At a time when cities are increasingly militarized, this question is particularly important for understanding how militarism impacts urban life. However, urban sociologists have not addressed how people experience militarized environments. This article turns to this question by considering the case of Lydda‐Lod, an Israeli city that has been demographically and physically transformed by war, displacement and securitization. Drawing on Wacquant's sociology of spatial stigma and adding insights from works on emotions in (post‐)conflict cities, I examine how poor Palestinians think and feel about the surveilled districts where they live within the city's broader landscape of ruins. I show how the Israeli military, security and policing agencies have collectively produced spatial stigmatization of these districts. I discuss how Palestinians respond to this spatial stigma by attaching a sense of worthlessness to their districts. However, this reproduction of spatial stigma is punctuated by expressions of care for the built environment and by a desire to revalorize collective Palestinian life in the city. I conclude by discussing how a perspective on militarized cities focused on everyday responses to militarism and attentive to marginalities enriches urban sociology and urban studies more generally.
Complexation of Amylosucrase‐Modified Waxy Corn Starch with Fatty Acids: Determination of Their Physicochemical Properties and Digestibilities
Authors: Lim Joo Hee , Kim Ha Ram , Choi Seung Jun , Park Cheon‐Seok , Moon Tae Wha 
Published: May 2019

AbstractIn this study, starch–lipid complexes were prepared using normal corn starch (NC) and amylosucrase‐modified waxy corn starch (ASWC) with myristic acid (C14:0) and palmitic acid (C16:0). The amylosucrase modification elongated branch chains in waxy corn starch leading to an increase of apparent amylose content (29.7%) similar to that of NC (29.0%). The X‐ray diffraction of starch–lipid complexes revealed a V‐type pattern, a clear indication of complex formation. The ability of the ASWC to complex with fatty acids was greater than that of NC. Interestingly, the changes in relative crystallinity, thermal parameters, and digestion properties according to the complexation showed opposite patterns in NC and ASWC. This study found that the structure of ASWC contributes to the formation of starch–fatty acid complexes and suggested that the ASWC can be preferred over NC in a delivery system.Practical ApplicationAmylopectin has been considered to be incapable of forming complexes with fatty acids due to its short chain length and steric hindrance. Through this study, an appropriate enzymatic modification of the molecular structures of waxy starches could make a complexation of waxy starches with fatty acids possible. The findings of this study suggest a promising perspective for utilization of waxy starch as a carrier material of lipophilic molecules.