bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct life histories impact dikaryotic genome evolution in the rust fungus Puccinia striiformis causing stripe rust in wheat
Authors: Schwessinger Benjamin , Chen Yan-Jun , Tien Richard , Vogt Josef Korbinian , Sperschneider Jana , Nagar Ramawatar , McMullan Mark , Sicheritz-Ponten Thomas , Sørensen Chris K. , Hovmøller Mogens Støvring , Rathjen John P. , Justesen Annemarie Fejer 
Published: December 2019

AbstractStripe rust of wheat, caused by the obligate biotrophic fungus Puccinia striiformis f. sp. tritici, is a major threat to wheat production world-wide with an estimated yearly loss of US $1 billion. The recent advances in long-read sequencing technologies and tailored-assembly algorithms enabled us to disentangle the two haploid genomes of Pst. This provides us with haplotype-specific information at a whole-genome level. Exploiting this novel information, we perform whole genome comparative genomics of two P. striiformis f. sp. tritici isolates with contrasting life histories. We compare one isolate of the old European lineage (PstS0), which has been asexual for over 50 years, and a Warrior isolate (PstS7 lineage) from a novel incursion into Europe in 2011 from a sexual population in the Himalayan region. This comparison provides evidence that long-term asexual evolution leads to genome expansion, accumulation of transposable elements, and increased heterozygosity at the single nucleotide, structural and allele levels. At the whole genome level, candidate effectors are not compartmentalized and do not exhibit reduced levels of synteny. Yet we were able to identify two subsets of candidate effector populations. About 70% of candidate effectors are invariant between the two isolates while 30% are hypervariable. The latter might be involved in host adaptation on wheat and explain the different phenotypes of the two isolates. Overall this detailed comparative analysis of two haplotype-aware assemblies of P. striiformis f. sp. tritici are the first steps in understanding the evolution of dikaryotic rust fungi at a whole genome level.
TORC1 regulates the transcriptional response to glucose and developmental cycle via the Tap42-Sit4-Rrd1/2 pathway in Saccharomyces cerevisiae
Authors: Alfatah Mohammad , Wong Jin Huei , Krishnan Vidhya Gomathi , Lee Yong Cheow , Sin Quan Feng , Goh Corinna Jie Hui , Kong Kiat Whye , Hoon Shawn , Arumugam Prakash 
Published: December 2019

AbstractTarget of Rapamycin Complex 1 (TORC1) is a highly conserved eukaryotic protein complex that couples the presence of growth factors and nutrients in the environment with cellular proliferation. TORC1 is primarily implicated in linking amino acid levels with cellular growth in yeast and mammals. Although glucose deprivation has been shown to cause TORC1 inactivation in yeast, the precise role of TORC1 in glucose signaling and the underlying mechanisms remain unclear. In this paper, we demonstrate that the presence of glucose in the growth medium is both necessary and sufficient for TORC1 activation. TORC1 activity increases upon addition of glucose to yeast cells growing in a non-fermentable carbon source. Conversely, shifting yeast cells from glucose to a non-fermentable carbon source reduces TORC1 activity. Analysis of transcriptomic data revealed that glucose and TORC1 co-regulate about 27% (1668/6004) of yeast genes. We demonstrate that TORC1 orchestrates the expression of glucose-response genes mainly via the Tap42-Sit4-Rrd1/Rrd2 pathway. To confirm TORC1’s role in glucose-signaling, we tested its role in spore germination, a glucose-dependent developmental state transition in yeast. TORC1 regulates the glucose-responsive genes during spore germination and inhibition of TORC1 blocks spore germination. We propose that a regulatory loop that involves activation of TORC1 by glucose and regulation of glucose-responsive genes by TORC1, mediates nutritional control of growth and development in yeast.
Stepwise autophosphorylation regulates biased agonism of the insulin receptor
Authors: Yunn Na-Oh , Park Mangeun , Noh Jungeun , Ryu Sung Ho 
Published: December 2019

SummaryInsulin is a key regulator of energy metabolism in peripheral tissues but also functions as a growth factor. Insulin binding to the insulin receptor (IR) leads to autophosphorylation of intracellular tyrosine residues, which simultaneously initiates a multitude of signals and functions. In contrast, some artificial (non-insulin) ligands for the IR result in biased agonism, selectively activating the PI3K/AKT pathway and metabolic effects without activating mitogen-activated protein kinase (MAPK) pathway and mitogenic effects. However, the precise mechanism of biased agonism at the receptor level remains unclear. The biased agonist IR-A48 aptamer selectively induces mono-phosphorylation of Tyr1150 residue (m-pY1150) in the kinase domain of IR. Hence, we hypothesized that IR autophosphorylation is a stepwise process in which formation of m-pY1150 represents an intermediate step. To explore this idea, we used hybrid receptors in which insulin can bind only one of the two binding sites of the dimeric receptor. Asymmetric insulin binding selectively induced symmetric m-pY1150 in both kinase domains. Moreover, the juxtamembrane domain, which interacts with the kinase domain, restricted the full activation of IR, and symmetric m-pY1150 played a crucial role in the rearrangement of intracellular domains to release this restriction. Our findings demonstrate that the symmetry of insulin binding to a dimeric receptor determines the stepwise autophosphorylation of IR. Furthermore, considering that the degree of ligand symmetry on a receptor depends mainly on ligand concentration, our results suggest that IR may play metabolic-biased roles in peripheral tissues dependent on local insulin concentrations.
Pan-organ model integration of metabolic and regulatory processes in type 1 diabetes
Authors: Ben Guebila Marouen , Thiele Ines 
Published: December 2019

SummaryType 1 diabetes mellitus (T1D) is a systemic disease triggered by a local autoimmune inflammatory reaction in insulin-producing cells that disrupts the glucose-insulin-glucagon system and induces organ-wide, long-term effects on glycolytic and nonglycolytic processes. Mathematical modeling of the whole-body regulatory bihormonal system has helped to identify intervention points to ensure better control of T1D but was limited to a coarse-grained representation of metabolism. To extend the depiction of T1D, we developed a whole-body model using a novel integrative modeling framework that links organ-specific regulation and metabolism. The developed framework allowed the correct prediction of disrupted metabolic processes in T1D, highlighted pathophysiological processes common with neurodegenerative disorders, and suggested calcium channel blockers as potential adjuvants for diabetes control. Additionally, the model predicted the occurrence of insulin-dependent rewiring of interorgan crosstalk. Moreover, a simulation of a population of virtual patients allowed an assessment of the impact of inter and intraindividual variability on insulin treatment and the implications for clinical outcomes. In particular, GLUT4 was suggested as a potential pharmacogenomic regulator of intraindividual insulin efficacy. Taken together, the organ-resolved, dynamic model may pave the way for a better understanding of human pathology and model-based design of precise allopathic strategies.
Experimental and stochastic models of melanoma T-cell therapy define impact of subclone fitness on selection of antigen loss variants
Authors: Glodde Nicole , Kraut Anna , van den Boorn-Konijnenberg Debby , Vadder Saskia , Kreten Florian , Schmid-Burgk Jonathan L. , Aymans Pia , Echelmeyer Kai , Rumpf Martin , Landsberg Jennifer , Bald Tobias , Tüting Thomas , Bovier Anton , Hölzel Michael 
Published: December 2019

SummaryAntigen loss is a key mechanism how tumor cells escape from T-cell immunotherapy. Using a mouse model of melanoma we directly compared antigen downregulation by phenotypic adaptation with genetically hardwired antigen loss. Unexpectedly, genetic ablation of Pmel, the melanocyte differentiation antigen targeted by adoptively transferred CD8+T-cells, impaired melanoma cell growth in untreated tumors due to competitive pressure exerted by the bulk wild-type population. This established an evolutionary scenario, where T-cell immunotherapy imposed a dynamic fitness switch on wild-type melanoma cells and antigen loss variants, which resulted in highly variable enrichment of the latter in recurrent tumors. Stochastic simulations by an individual-based continuous-time Markov process suggested variable fitness of subclones within the antigen loss variant population as the most likely cause, which was validated experimentally. In summary, we provide a framework to better understand how subclone heterogeneity in tumors influences immune selection of genetic antigen loss variants through stochastic events.
Predicting cancer origins with a DNA methylation-based deep neural network model
Authors: Zheng Chunlei , Xu Rong 
Published: December 2019

AbstractCancer origin determination combined with site-specific treatment of metastatic cancer patients is critical to improve patient outcomes. Existing pathology and gene expression-based techniques often have limited performance. In this study, we developed a deep neural network (DNN)-based classifier for cancer origin prediction using DNA methylation data of 7,339 patients of 18 different cancer origins from The Cancer Genome Atlas (TCGA). This DNN model was evaluated using four strategies: (1) when evaluated by 10-fold cross-validation, it achieved an overall specificity of 99.72% (95% CI 99.69%-99.75%) and sensitivity of 92.59% (95% CI 91.87%-93.30%); (2) when tested on hold-out testing data of 1,468 patients, the model had an overall specificity of 99.83% and sensitivity of 95.95%; (3) when tested on 143 metastasized cancer patients (12 cancer origins), the model achieved an overall specificity of 99.47% and sensitivity of 95.95%; and (4) when tested on an independent dataset of 581 samples (10 cancer origins), the model achieved overall specificity of 99.91% and sensitivity of 93.43%. Compared to existing pathology and gene expression-based techniques, the DNA methylation-based DNN classifier showed higher performance and had the unique advantage of easy implementation in clinical settings.
Detecting Operons in Bacterial Genomes via Visual Representation Learning
Authors: Assaf Rida , Xia Fangfang , Stevens Rick 
Published: December 2019

ABSTRACTContiguous genes in prokaryotes are often arranged into operons. Detecting operons plays a critical role in inferring gene functionality and regulatory networks. Human experts annotate operons by visually inspecting gene neighborhoods across pileups of related genomes. These visual representations capture the inter-genic distance, strand direction, gene size, functional relatedness, and gene neighborhood conservation, which are the most prominent operon features mentioned in the literature. By studying these features, an expert can then decide whether a genomic region is part of an operon. We propose a deep learning based method named Operon Hunter that uses visual representations of genomic fragments to make operon predictions. Using transfer learning and data augmentation techniques facilitates leveraging the powerful neural networks trained on image datasets by re-training them on a more limited dataset of extensively validated operons. Our method outperforms the previously reported state-of-the-art tools, especially when it comes to predicting full operons and their boundaries accurately. Furthermore, our approach makes it possible to visually identify the features influencing the network’s decisions to be subsequently cross-checked by human experts.
Identifying Novel Targets by using Drug-binding Site Signature: A Case Study of Kinase Inhibitors
Authors: Naveed Hammad , Reglin Corinna , Schubert Thomas , Gao Xin , Arold Stefan T. , Maitland Michael L. 
Published: December 2019

AbstractCurrent FDA-approved kinase inhibitors cause diverse adverse effects, some of which are due to the mechanism-independent effects of these drugs. Identifying these mechanism-independent interactions could improve drug safety and support drug repurposing. We have developed “iDTPnd”, a computational approach for large-scale discovery of novel targets for known drugs. For a given drug, we construct a positive and a negative structural signature that captures the weakly conserved structural features of drug binding sites. To facilitate assessment of unintended targets iDTPnd also provides a docking-based interaction score and its statistical significance. We were able to confirm the interaction of sorafenib, imatinib, dasatinib, sunitinib, and pazopanib with their known targets at a sensitivity and specificity of 52% and 55% respectively. We have validated 10 predicted novel targets, usingin vitroexperiments. Our results suggest that proteins other than kinases, such as nuclear receptors, cytochrome P450 or MHC Class I molecules can also be physiologically relevant targets of kinase inhibitors. Our method is general and broadly applicable for the identification of protein-small molecule interactions, when sufficient drug-target 3D data are available.
Airline safety management system issues: a practitioner’s perspective
Authors: Chaves Filipe 
Published: December 2019

Purpose
This study aims to introduce the reader to some problems faced by safety practitioners operating within an airline safety department, particularly risk assessment subjectivity, and processing of flight data monitoring events. In doing so, it attempts to propose solutions to these issues.

Design/methodology/approach
Quality management tools, including six sigma, in combination with flight data monitoring, are proposed as a solution to the issues identified.

Findings
The proposed solutions reduce the subjectivity of some risk assessments and help airlines to efficiently process flight data monitoring events.

Research limitations/implications
This paper presents a two-part case study of how these issues have been dealt with by an airline. However, as demonstrated by the literature review, there seems to exist further advanced methods, some of them still in a developmental stage, to deal more effectively with the problems discussed.

Originality/value
This study is particularly directed and more valuable to small-scale airlines. These are more susceptible to the lack of resources needed to implement advanced approaches into the safety management system, but still want to adopt a systematic way of conducting business. Furthermore, it highlights common issues faced by safety practitioners in airlines and should hopefully stimulate the discussion around the topic and promote other academics/practitioners to share viable solutions.
A comprehensive assessment process for children with autism spectrum disorders
Authors: Di Renzo Magda , Guerriero Viviana , Petrillo Massimiliano , Racinaro Lidia , Vanadia Elena , Bianchi di Castelbianco Federico 
Published: December 2019

Purpose
The assessment of Autism Spectrum Disorders (ASD) in childhood has two essential aspects: the identification of the risk (under 30 months of age) and the definition of a diagnosis that takes into account its core areas as well as further non-specific aspects. The purpose of this paper is to present an approach that considers the combination of clinical evaluation with the use of tools that analyse the various levels of the child’s functioning as fundamental.

Design/methodology/approach
The comprehensive assessment at the Institute of Ortofonologia in Rome provides the ADOS-2 and the Leiter-R for the evaluation of the symptomatology, the severity level, the non-verbal cognitive functioning and the fluid reasoning; the TCE and the UOI are used to identify, respectively, the child’s emotional skills and the ability to understand the intentions of others, as precursors of the theory of mind. Within this assessment, the Brief-P, the Short Sensory Profile and the RBS are also included for the evaluation of executive functions, sensory pattern and of restricted and repetitive behaviours, as observed by parents.

Findings
How to define a reliable development profile, which allows to plan a specific intervention calibrated on the potential of the child and on his development trajectory, is described. Two clinical cases are also presented.

Originality/value
The entire process is aimed both at a detailed assessment of the child’s functioning and at identifying a specific therapeutic project and predictive factors for achieving an optimal outcome.
Mining the treasure of palm leaf manuscripts through information retrieval techniques
Authors: Singh Bhupendra , Ahuja Neelu Jyoti 
Published: December 2019

Purpose
This paper aims to popularize information retrieval from palm leaf manuscripts among computer scientists to make available the guidance of the age-old heritage in shaping the future.

Design/methodology/approach
With computer technology penetrating every aspect of life, information retrieval algorithms can be exploited to help build a system which can dig into the ocean of knowledge from these manuscripts.

Findings
The knowledge in them covers all aspects of life. Be it religious beliefs, literature, science, mathematics, or any other. However, due to discontinuation of practice of copying their content on fresh leaves, they now possess a fragile life which needs to be preserved at the earliest. The modern means of digitization can help in their preservation.

Research limitations
The Government of India and other organizations are doing commendable job of preserving and safeguarding country’s heritage and age-old knowledge system through the movement of digitization. In the years to come, the agonizing problem of manuscripts degradation will be eradicated completely. However, next when it will come to mining the knowledge treasure out of these manuscripts, we would be confronted with another helpless situation.

Practical implications
The digitization process would capture the manuscripts from present physical palm leaf to digital image form by clicking high-quality pictures. All the text in a palm leaf will be available in the form of images, but on these images, a simple search for any word would not be possible.

Originality/value
Working towards mining the treasure of knowledge from the palm leaf manuscripts, hordes of challenges have been outlined. Over and above the problem of preventing decay to palm leaf manuscripts is the challenge of deciphering text, image analysis, information retrieval and search. Search is further associated with issues of meaningful and useful extraction through semantic analysis. This paper advocates the dire need for systematic research to be undertaken in this field opening up avenues for past knowledge to guide future prospects in several domains.
Gaps between competence and importance of employability skills: evidence from Malaysia
Authors: Kenayathulla Husaina Banu , Ahmad Nor Aziah , Idris Abdul Rahman 
Published: December 2019

PurposeThe purpose of this paper is to identify the gaps between the importance perceived and the competence gained by the hospitality students in terms of the employability skills.Design/methodology/approachQuestionnaires were distributed to 841 hospitality students in five regions in Malaysia. Descriptive and inferential statistics were used to analyze the data.FindingsThe findings show that there are significant differences between importance perceived and competence attained in teamwork, leadership, basic, technical skills and ethical skills. Additionally, the finding of this study indicates that the culinary and bakery students perceive that they are not given adequate exposure to possess such skills. It is important to ensure that graduates are equipped with the twenty-first century skills such as problem solving and analytic, decision making, organization and time management, risk taking and communication.Research limitations/implicationsThe findings provide insights to curriculum developers and policy makers on the appropriate interventions that need to be taken to improve the employability skills of the graduates.Originality/valueAn original contribution is made by linking employability model to TVET sector.
“Does your walk match your talk?” Analyzing IPSASs diffusion in developing and developed countries
Authors: Polzer Tobias , Gårseth-Nesbakk Levi , Adhikari Pawan 
Published: December 2019

Purpose
The purpose of this paper is to provide a global overview of the adoption status of International Public Sector Accounting Standards (IPSASs) in the different contexts of developed and developing countries on central government level, particularly delineating key reform issues and attempts to overcome these.

Design/methodology/approach
Drawing on an analytical framework that combines neo-institutional theory with diffusion theory, prior research and official documents were re-analysed.

Findings
There are substantial differences regarding whether countries acknowledge having experienced large implementation challenges and the extent to which the reform benefits have been achieved. The study sheds light on the (institutional) underpinnings of these differences.

Research limitations/implications
First, the analysis could be extended to regional and local governments, as well as social funds. Both qualitative and quantitative strategies are suggested. Second, the implementation of the conceptual framework deserves further attention. Third, further research should more thoroughly scrutinise cost-benefit analyses used for justifying the (non)implementation of IPSASs, and in particular the assumptions that are being made in such analyses.

Practical implications
The paper informs policymakers and standard setters by delineating the areas and issues complicating the widespread adoption of IPSASs across countries, including pointing out directions to overcome these.

Social implications
Substantial amounts of public money are invested internationally to converge accounting standards and translate them into native languages. A close(r) monitoring is needed to ensure that these efforts obtain sufficient value for money.

Originality/value
This study is original as it applies an analytical framework that combines neo-institutional theory and diffusion theory to examine public sector accounting convergence issues internationally. Such an approach explicitly puts a focus on decoupling between reform “talk” (decision) and “walk” (implementation) and helps to analyse the reasons for this decoupling.