bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prediction of the Effect of Naturally Occurring Missense Mutations on CellularN-Acetyl-GlucosaminidaseEnzymatic Activity
Authors: Ford Colby T. , Uppal Aneeta , Nodzak Conor M. , Shi Xinghua 
Published: April 2019

ABSTRACTIn 2015, the Critical Assessment of Genome Interpretation (CAGI) proposed a challenge to devise a computational method for predicting the phenotypic consequences of genetic variants of a lysosomal hydrolase enzyme known asα-N-acetylglucosaminidase (NAGLU). In 2014, the Human Gene Mutation Database released that 153 NAGLU mutations associated with MPS IIIB and 90 of them are missense mutations. The ExAC dataset catalogued 189 missense mutations NAGLU based on exome sequence data from about 60,000 individual and 24 of them are known to be disease associated. Biotechnology company, BioMarin, has quantified the relative functionality of NAGLU for the remaining subset of 165 missense mutations. For this particular challenge, we examined the subset missense mutations within the ExAC dataset and predicted the probability of a given mutation being deleterious and relating this measure to the capacity of enzymatic activity. In doing so, we hoped to learn the degree to which changes in amino acid physicochemical properties are tolerable for NAGLU function.Amino acid substitution (AAS) prediction methods are mainly based on the sequence and structure information. Simple comparisons between different AAS methods are not only difficult, but also irrational because each method was tested on various datasets and based on varied versions of databases. Currently, several AAS prediction methods have been introduced. PolyPhen-2, an updated version of PolyPhen, is a tool used to predict possible impacts of an amino acid substitution on the structure and function. Users are required to provide protein or SNP identifiers, protein sequences, substitution positions, etc. A score is provided, ranging from 0 to 1, corresponding to the probability of a mutation resulting in no functionality for the enzymeOnce the probability scores were generated, the dataset was then run through multiple machine learning algorithms to generate an applicable model for predicting the enzymatic activity of MPS IIIB-related mutations. This prediction was generated using the PolyPhen-2 probability score and other information about the mutation (amino acid type, location, allele frequency, etc.) as input feature variables. This generated a predicted aggregate score for each mutation, which was then reported back to CAGI. The results of the analysis are significant enough to hold confidence that the scores are decent predictors of enzymatic activity given a mutation in the NAGLU amino acid sequence.
Allele-specific expression changes dynamically during T cell activation in HLA and other autoimmune loci
Authors: Gutierrez-Arcelus Maria , Baglaenko Yuriy , Arora Jatin , Hannes Susan , Luo Yang , Amariuta Tiffany , Teslovich Nikola , Rao Deepak A. , Ermann Joerg , Jonsson Helena , Naverrete Cristina , Gregersen Peter K. , Esko Tonu , Brenner Michael B. , Raychaudhuri Soumya 
Published: April 2019

AbstractUnderstanding how genetic regulatory variation affects gene expression in different T cell states is essential to deciphering autoimmunity. We conducted a high-resolution RNA-seq time course analysis of stimulated memory CD4+T cells from 24 healthy individuals. We identified 186 genes with dynamic allele-specific expression, where the balance of alleles changes over time. These genes were four fold enriched in autoimmune loci. We found pervasive dynamic regulatory effects within six HLA genes, particularly for a major autoimmune risk gene,HLA-DQB1. EachHLA-DQB1allele had one of three distinct transcriptional regulatory programs. Using CRISPR/Cas9 genomic editing we demonstrated that a single nucleotide variant at the promoter is causal for T cell-specific control ofHLA-DQB1expression. Our study in CD4+T cells shows that genetic variation incisregulatory elements may affect gene expression in a lymphocyte activation status-dependent manner contributing to the inter-individual complexity of immune responses.
Integrated RNA and metabolite profiling of urine liquid biopsies for prostate cancer biomarker discovery
Authors: Lee Bongyong , Mahmud Iqbal , Marchica John , Dereziński Paweł , Qi Feng , Wang Fubo , Joshi Piyush , Valerio Felipe , Rivera Inoel , Patel Vipul , Pavlovich Christian P. , Garrett Timothy , Schroth Gary P. , Sun Yinghao , Perera Ranjan J. 
Published: April 2019

AbstractSensitive and specific diagnostic and prognostic biomarkers for prostate cancer (PCa) are urgently needed. Urine samples are a non-invasive means to obtain abundant and readily accessible “liquid biopsies”. Herein we used urine liquid biopsies to identify and characterize a novel group of urine-enriched RNAs and metabolites in PCa patients and normal individuals with or without benign prostatic disease. Differentially expressed RNAs were identified in urine samples by deep sequencing and metabolites in urine were measured by mass spectrometry. The mRNA and metabolite profiles were distinct in patients with benign and malignant disease. Integrated analysis of urinary gene expression and metabolite signatures unveiled an aberrant glutamate metabolism and tricarboxylic acid (TCA) cycle node in prostate cancer-derived cells. Functional validation supports a role for glutamate metabolism and glutamate oxaloacetate transaminase 1 (GOT1)-dependent redox balance in prostate cancer, which can be exploited for novel biomarkers and therapies.
Improved bacteria population structure analysis on thousands of genomes using unsupervised methods
Authors: Schlum Katrina , Jun Se-Ran , Udaondo Zulema , Ussery David W. , Emrich Scott J. 
Published: April 2019

AbstractOver ten thousand genomes ofEscherichia coliare now available, and this number will continue to grow for this and other important microbial species. The first approach often used to better understand microbes is phylogenetic group analysis followed by pan-genome analysis of highly related genomes. Here, we combine sequence-based features with unsupervised clustering on up to 2,231E. coligenomes and a total of 1,367Clostridium difficilegenomes. We show that Non-negative Matrix Factorization (NMF) can identify “mixed”/cryptic genomes, and can better determine inter-related genome groups and their distinguishing features (genes) relative to prior methods.
Spatial density estimates of Eurasian lynx (Lynx lynx) in the French Jura and Vosges Mountains
Authors: Gimenez Olivier , Gatti Sylvain , Duchamp Christophe , Germain Estelle , Laurent Alain , Zimmermann Fridolin , Marboutin Eric 
Published: April 2019

AbstractObtaining estimates of animal population density is a key step in providing sound conservation and management strategies for wildlife. For many large carnivores however, estimating density is difficult because these species are elusive and wide-ranging. Here, we focus on providing the first density estimates of the Eurasian lynx (Lynx lynx) in the French Jura and Vosges mountains. We sampled a total of 413 camera trapping sites (with 2 cameras per site) between January 2011 and April 2016 in seven study areas across seven counties of the French Jura and Vosges mountains. We obtained 592 lynx detections over 19,035 trap days in the Jura mountain and 0 detection over 6,804 trap days in the Vosges mountain. Based on coat patterns, we identified a total number of 92 unique individuals from photographs, including 16 females, 13 males and 63 individuals of unknown sex. Using spatial capture-recapture (SCR) models, we estimated abundance in the study areas between 5 (SE = 0.1) and 29 (0.2) lynx and density between 0.24 (SE = 0.02) and 0.91 (SE = 0.03) lynx per 100 km2. We also provide a comparison with non-spatial density estimates and discuss the expected discrepancies. Our study is yet another example of the advantage of combining SCR methods and non-invasive sampling techniques to estimate density for elusive and wide-ranging species, like large carnivores. While the estimated densities in the French Jura mountain are comparable to other lynx populations in Europe, the fact that we detected no lynx in the Vosges mountain is alarming. Connectivity should be encouraged between the French Jura mountain, the Vosges mountain and the Palatinate Forest in Germany where a reintroduction program is currently ongoing. Our density estimates will help in setting a baseline conservation status for the lynx population in France.
Quality control of large genome datasets using genome fingerprints
Authors: Robinson Max , Joshi Arpita , Vidyarthi Ansh , Maccoun Mary , Rangavajjhala Sanjay , Glusman Gustavo 
Published: April 2019

AbstractThe 1000 Genomes Project (TGP) is a foundational resource which serves the biomedical community as a standard reference cohort for human genetic variation. There are now seven public versions of these genomes. The TGP Consortium produced the first by mapping its final data release against human reference sequence GRCh37, then “lifted over’’ these genomes to the improved reference sequence (GRCh38) when it was released, and remapped the original data to GRCh38 with two similar pipelines. As ‘best practice’ quality validation, the pipelines that generated these versions were benchmarked against the Genome In A Bottle Consortium’s ‘platinum quality’ genome (NA12878). The New York Genome Center recently released the results of independently resequencing the cohort at greater depth (30X), a phased version informed by the inclusion of related individuals, and independently remapped the original variant calls to GRCh38. We evaluated all seven versions using genome fingerprinting, which supports ultrafast genome comparison even across reference versions. We noted multiple issues including discrepancies in cohort membership, disagreement on the overall level of variation, evidence of substandard pipeline performance on specific genomes and in specific regions of the genome, cryptic relationships between individuals, inconsistent phasing, and annotation distortions caused by the history of the reference genome itself. We therefore recommend global quality assessment by rapid genome comparisons, using genome fingerprints and other metrics, alongside benchmarking as part of ‘best practice’ quality assessment of large genome datasets. Our observations also help inform the decision of which version to use, to support analyses by individual researchers.
SUPPRESSOR OF MAX2 1-LIKE 5 promotes secondary phloem formation during radial stem growth
Authors: Wallner Eva-Sophie , Jouannet Virginie , Greb Thomas 
Published: April 2019

ABSTRACTAs a prerequisite for constant growth, plants can produce vascular tissues at different sites in their postembryonic body. In particular, the formation of vascular tissues during longitudinal and radial expansion of growth axes differs fundamentally with respect to its anatomical configuration. This raises the question to which level regulatory mechanisms of vascular tissue formation are shared throughout plant development. Here, we show that, similar as primary phloem formation during longitudinal growth, the cambium-based formation of secondary phloem depends on the function of SMXL genes. Using promoter reporter lines, we observe that SMXL4 and SMXL5 activities are associated with different stages of secondary phloem formation in Arabidopsis stems and the specific loss of SMXL5 function results in the absence of secondary phloem. Interestingly, the additional disruption of SMXL4 activity increases cell proliferation rates in the cambium region without that secondary phloem is formed. Based on genome-wide transcriptional profiling and expression analyses of phloem-related markers we conclude that early steps of phloem formation are impaired in smxl4;smxl5 double mutants and that additional cambium-derived cells fail in establishing any phloem-related feature. Our results show that molecular mechanisms determining primary and secondary phloem share important features but differ slightly with SMXL5 playing a more dominant role in the formation of secondary phloem.
Electric-induced reversal of morphogenesis inHydra
Authors: Braun Erez , Ori Hillel 
Published: April 2019

ABSTRACTMorphogenesis involves the dynamic interplay of biochemical, mechanical and electrical processes. Here we ask: to what extent can the course of morphogenesis be modulated and controlled by an external electric field? We show that above a critical amplitude, an external electric field can halt morphogenesis inHydraregeneration. Moreover, above this critical amplitude, the electric field can even lead to reversal dynamics: a fully developedHydrafolds back into its incipient spheroid morphology. The potential to renew morphogenesis is re-exposed when the field is reduced back to amplitudes below criticality. These dynamics are accompanied by modulations of theWnt3activity, a central component of the head organizer inHydra. Reversal of morphogenesis is shown to be triggered by enhanced epithelial electrical excitations, accompanied by intensified calcium activity, indicating that electrical processes play an instructive role to a level that can direct developmental trajectories. Reversal of morphogenesis by external fields, calls for extending its framework beyond programmatic, forward-driven, hierarchical processes.
Extensive Ribosome and RF2 Rearrangements during Translation Termination
Authors: Svidritskiy Egor , Demo Gabriel , Loveland Anna B. , Xu Chen , Korostelev Andrei A. 
Published: April 2019

AbstractProtein synthesis ends when a ribosome reaches an mRNA stop codon. Release factors (RFs) decode the stop codon, hydrolyze peptidyl-tRNA to release the nascent protein, and then dissociate to allow ribosome recycling. To visualize termination by RF2, we resolved a cryo-EM ensemble of E. coli 70S•RF2 structures at up to 3.3 Å in a single sample. Five structures suggest a highly dynamic termination pathway. Upon peptidyl-tRNA hydrolysis, the CCA end of deacyl-tRNA departs from the peptidyl transferase center. The catalytic GGQ loop of RF2 is rearranged into a long β-hairpin that plugs the peptide tunnel, biasing a nascent protein toward the ribosome exit. Ribosomal intersubunit rotation destabilizes the catalytic RF2 domain on the 50S subunit and disassembles the central intersubunit bridge B2a, resulting in RF2 departure. Our structures visualize how local rearrangements and spontaneous inter-subunit rotation poise the newly-made protein and RF2 to dissociate in preparation for ribosome recycling.
Conformational catalysis of cataract-associated aggregation in a human eye lens crystallin occurs via interface stealing
Authors: Serebryany Eugene , Jacobs William M. , Razban Rostam M. , Shakhnovich Eugene I. 
Published: April 2019

AbstractHuman γD-crystallin (HγD) is an abundant and highly stable two-domain protein in the core region of the eye lens. Destabilizing mutations and post-translational modifications in this protein are linked to onset of aggregation that causes cataract disease (lens turbidity). Wild-type HγD greatly accelerates aggregation of the cataract-related W42Q variant, without itself aggregating. The mechanism of this “inverse prion” catalysis of aggregation remained unknown. Here we provide evidence that an early unfolding intermediate with an opened domain interface enables transient dimerization of the C-terminal domains of wild-type and mutant, or mutant and mutant, HγD molecules, which deprives the mutant’s N-terminal domain of intramolecular stabilization by the native domain interface and thus accelerates its misfolding to a distinct, aggregation-prone intermediate. A detailed kinetic model predicts universal power-law scaling relationships for lag time and rate of the resulting aggregation, which are in excellent agreement with the data. The mechanism reported here, which we term interface stealing, can be generalized to explain how common domain-domain interactions can have surprising consequences, such as conformational catalysis of unfolding, in multidomain proteins.SignificanceMost known proteins in nature consist of multiple domains. Interactions between domains may lead to unexpected folding and misfolding phenomena. This study of human γD-crystallin, a two-domain protein in the eye lens, revealed one such surprise: conformational catalysis of misfolding via intermolecular domain interface “stealing.” An intermolecular interface between the more stable domains outcompetes the native intramolecular domain interface. Loss of the native interface in turn promotes misfolding and subsequent aggregation, especially in cataract-related γD-crystallin variants. This phenomenon is likely a contributing factor in the development of cataract disease, the leading worldwide cause of blindness. However, interface stealing likely occurs in many proteins composed of two or more interacting domains.
Crystal structure of fac-aqua[(E)-4-(benzo[d]thiazol-2-yl)-N-(pyridin-2-ylmethylidene)aniline-κ2
N,N′]tricarbonylrhenium(I) hexafluoridophosphate methanol monosolvate
Authors: Roupa Ioanna , Kaplanis Michael , Raptopoulou Catherine , Pelecanou Maria , Pirmettis Ioannis , Papadopoulos Minas , Psycharis Vassilis 
Published: April 2019

In the title compound, fac-[Re(C19H13N3S)(CO)3(H2O)]PF6·CH3OH, the coordination environment of the ReI atom is octahedral with a C3N2O coordination set. In this molecule, the N,N′ bidentate ligand, (E)-4-(benzo[d]thiazol-2-yl)-N-(pyridin-2-ylmethylidene)aniline, and the monodentate aqua ligand occupy the three available coordination sites of the [Re(CO)3]+ core, generating a `2 + 1' mixed-ligand complex. In this complex, the Re—C bonds of the carbonyl ligands trans to the coordinating N,N′ atoms of the bidentate ligand are longer than the Re—C bond of the carbonyl group trans to the aqua ligand, in accordance with the intensity of their trans effects. The complex is positively charged with PF6
− as the counter-ion. In the structure, the complexes form dimers through π–π intermolecular interactions. O—H...O and O—H...N hydrogen bonds lead to the formation of stacks parallel to the a axis, which further extend into layers parallel to (0\overline{1}1). Through O—H...F hydrogen bonds between the complexes and the PF6
−counter-anions, a three-dimensional network is established.
Fast high fidelity CFD/CSM fluid structure interaction using RBF mesh morphing and modal superposition method
Authors: Groth Corrado , Cella Ubaldo , Costa Emiliano , Biancolini Marco Evangelos 
Published: April 2019

Purpose
This paper aims to present a fast and effective approach to tackle complex fluid structure interaction problems that are relevant for the aeronautical design.

Design/methodology/approach
High fidelity computer-aided engineering models (computational fluid dynamics [CFD] and computational structural mechanics) are coupled by embedding modal shapes into the CFD solver using RBF mesh morphing.

Findings
The theoretical framework is first explained and its use is then demonstrated with a review of applications including both steady and unsteady cases. Different flow and structural solvers are considered to showcase the portability of the concept.

Practical implications
The method is flexible and can be used for the simulation of complex scenarios, including components vibrations induced by external devices, as in the case of flapping wings.

Originality/value
The computation mesh of the CFD model becomes parametric with respect to the modal shape and, so, capable to self-adapt to the loads exerted by the surrounding fluid both for steady and transient numerical studies.
Owner and contractor solution strategies for industrial commissioning
Authors: Mock Brant , O’Connor James T. 
Published: April 2019

PurposeThe purpose of this study is to discover which solution strategies to common industrial commissioning and startup (CSU) problems (Hot Spots) owner and contractor organizations identify as most effective and to identify which strategies are identified by one or both organization types.Design/methodology/approachRatings for the relative value provided by strategies, and the effort required to implement strategies were solicited from CSU industry experts employed by owner or contractor organizations via a survey. Quantitative modelling using the Possible, Implement, Challenge, Kill (PICK) chart method distinguished high-value, low-effort strategies from other strategies.FindingsOwners and contractors identify distinct sets of CSU solution strategies as high value and low effort, with some overlap. Of 178 total strategies, 40 (22.5 per cent) were identified by owners and 34 (19.1 per cent) by contractors, with 19 (10.7 per cent) of those strategies in common. Strategies with the greatest differences in opinions between owners and contractors are also identified.Research limitations/implicationsResearch findings are limited to industrial-type, operational systems-intensive facilities. Similarities may exist with other systems-intensive project types, such as some commercial or infrastructure projects. The survey sample size is relatively small (n= 35), but close to that of other CSU-related surveys. The majority of survey participants were based in North America at the time of participation. Further, the number of contractor and owner participants differed slightly.Practical implicationsCSU managers and personnel should consider using high-value, low-effort strategies before resorting to other less effective strategies, as applicable on their projects. Depending on which organization is executing CSU, or if both organization types share CSU responsibilities, different solution strategies may be most effective.Originality/valueDifferences in owner and contractor perspectives and opinions have been noted in other aspects of the project lifecycle but never for CSU solution strategies. Use of the strategies identified will support more effective CSU execution.
CEO inside debt, market competition and corporate risk taking
Authors: Sheikh Shahbaz 
Published: April 2019

Purpose
The purpose of this paper is to investigate the effect of market competition on the relation between CEO inside debt and corporate risk-taking.

Design/methodology/approach
Ordinary least squares regressions are used to estimate the relation between CEO inside debt and firm risk. Additionally, instrumental variable (IV-GMM) regressions are used to check the robustness of the results.

Findings
The results of this paper indicate that CEO inside debt is negatively associated with the measures of future risk. However, this negative association is influenced by market competition. Specifically, CEO inside debt results in lower levels of firm risk when market competition is high. When market competition is low, inside debt has no effect on firm risk. Additional results show that CEOs with large inside debt tend to decrease R&D investments and financial leverage and increase firm cash holdings and working capital only when market competition is high. Overall, these results suggest that market competition significantly influences the effect of CEO inside debt on corporate risk-taking by changing the strength of incentives from inside debt.

Practical implications
CEO inside debt could be used to provide incentives to CEOs to manage corporate risk-taking.

Social implications
The empirical results in this paper provide a practical tool to the boards of corporations to manage corporate risk-taking. The results suggest that boards can reduce excessive risk-taking by increasing the level of debt type compensation incentives. However, this strategy is effective only when market competition is high because in such markets inside debt provides the strongest incentives to reduce corporate risk. When competition is low, incentives from inside debt are ineffective in managing corporate risk-taking.

Originality/value
This is the first study that shows that the negative association between CEO inside debt and corporate risk-taking critically depends on the intensity of market competition.