bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reactivity of O
2
versus H
2
O
2
with polysaccharide monooxygenases
Authors: Hangasky John A. , Iavarone Anthony T. , Marletta Michael A. 
Published: April 2018

Significance
Since the discovery of polysaccharide monooxygenases (PMOs), attention has focused on structure, function, and mechanism. The PMO copper active site can utilize oxygen or hydrogen peroxide to catalyze substrate oxidation. Although oxygen has been considered to be the physiologically relevant cosubstrate in the reaction, recent reports have focused on hydrogen peroxide. While oxygen is acknowledged as the cosubstrate utilized for other biological copper-dependent hydroxylations, there is no reason to rule out hydrogen peroxide for PMOs. This paper provides a detailed kinetic analysis and characterization of PMO reactivity with each cosubstrate. PMOs are capable of using either cosubstrate to oxidize the glycosidic linkage of cellulosic substrates, but different molecular mechanisms are accessed that affect enzyme activity and the products formed.
Neuronal activity regulates neurotransmitter switching in the adult brain following light-induced stress
Authors: Meng Da , Li Hui-quan , Deisseroth Karl , Leutgeb Stefan , Spitzer Nicholas C. 
Published: April 2018

Significance
The discovery that neurotransmitter identity is regulated by activity in the adult mammalian brain during a stress response raises questions about the extent and function of this plasticity. Specific synapses are associated with the release of a particular neurotransmitter or transmitters on the basis of evidence obtained under a single set of conditions. Transmitter switching endows the connectome with greater plasticity: Activity-dependent revision of signaling provides another dimension of flexibility to regulate normal behavior. Changes in transmitter identity are also positioned to contribute to diseases of the nervous system. Neurotransmitter imbalance has long been implicated in common neurological and psychiatric disorders, provoking interest in transmitter switching as a therapeutic tool for patients.
Syntactic alternation research
Authors: Gries Stefan Th. 
Published: April 2018

AbstractOver the last 20 or so years, research on syntactic alternations has made great strides in both theoretical and methodological ways. On the theoretical side, much of the research on syntactic alternations was restricted to generative linguistics debating how near synonymous constructions differed slightly in meaning and/or how one (and which one) was derived from the other (transformationally). On the methodological side, much research consisted of monofactorial studies based on relatively simple text counts. By now, however, syntactic alternation research has become much more functional (in a broad sense of the term) and much more methodologically sophisticated: Much work is now motivated/interpreted psycholinguistically or in a broadly usage-based/cognitive linguistic framework and much work has now adopted a regression-based analytical strategy. These attractive developments notwithstanding, much remains to be done and, in this paper, I sketch some recent developments in (largely) separate alternation studies that I would like the field to adopt more broadly. These developments can be heuristically grouped into ones that have to do with (i) the statistical analysis of corpus-based and experimental alternation data, (ii) new predictors that explain typically unexplored aspects of variability in alternations.
CTDquerier: a bioconductor R package for Comparative Toxicogenomics DatabaseTM data extraction, visualization and enrichment of environmental and toxicological studies
Authors: Hernandez-Ferrer Carles , Gonzalez Juan R 
Published: April 2018

Abstract

Summary
Biomedical studies currently include a large volume of genomic and environmental factors for studying the etiology of human diseases. R/Bioconductor projects provide several tools for performing enrichment analysis at gene-pathway level, allowing researchers to develop novel hypotheses. However, there is a need to perform similar analyses at the chemicals-genes or chemicals-diseases levels to provide complementary knowledge of the causal path between chemicals and diseases. While the Comparative Toxicogenomics DatabaseTM (CTD) provides information about these relationships, there is no software for integrating it into R/Bioconductor analysis pipelines. CTDquerier helps users to easily download CTD data and integrate it in the R/Bioconductor framework. The package also contains functions for visualizing CTD data and performing enrichment analyses. We illustrate how to use the package with a real data analysis of asthma-related genes. CTDquerier is a flexible and easy-to-use Bioconductor package that provides novel hypothesis about the relationships between chemicals and diseases.

Availability and implementation
CTDquerier R package is available through Bioconductor and its development version at https://github.com/isglobal-brge/CTDquerier.

Supplementary information
Supplementary data are available at Bioinformatics online.
Two-phase differential expression analysis for single cell RNA-seq
Authors: Wu Zhijin , Zhang Yi , Stitzel Michael L , Wu Hao 
Published: April 2018

AbstractMotivationSingle-cell RNA-sequencing (scRNA-seq) has brought the study of the transcriptome to higher resolution and makes it possible for scientists to provide answers with more clarity to the question of ‘differential expression’. However, most computational methods still stick with the old mentality of viewing differential expression as a simple ‘up or down’ phenomenon. We advocate that we should fully embrace the features of single cell data, which allows us to observe binary (from Off to On) as well as continuous (the amount of expression) regulations.ResultsWe develop a method, termed SC2P, that first identifies the phase of expression a gene is in, by taking into account of both cell- and gene-specific contexts, in a model-based and data-driven fashion. We then identify two forms of transcription regulation: phase transition, and magnitude tuning. We demonstrate that compared with existing methods, SC2P provides substantial improvement in sensitivity without sacrificing the control of false discovery, as well as better robustness. Furthermore, the analysis provides better interpretation of the nature of regulation types in different genes.Availability and implementationSC2P is implemented as an open source R package publicly available at https://github.com/haowulab/SC2P.Supplementary informationSupplementary data are available at Bioinformatics online.
MetaBridge: enabling network-based integrative analysis via direct protein interactors of metabolites
Authors: Hinshaw Samuel J , H Y Lee Amy , Gill Erin E , E W Hancock Robert 
Published: April 2018

Abstract

Summary
Here, we present MetaBridge, a tool that collates protein interactors (curated metabolite-enzyme interactions) that influence the levels of specific metabolites including both biosynthetic and degradative enzymes. This enables network-based integrative analysis of metabolomics data with other omics data types. MetaBridge is designed to complement a systems-biology approach to analysis, pairing well with network analysis tools such as NetworkAnalyst.ca, but can be used in any bioinformatics workflow.

Availability and implementation
MetaBridge has been implemented as a web tool at https://www.metabridge.org, and the source code is available at https://github.com/samhinshaw/metabridge_shiny (GNU GPLv3).
PheProb: probabilistic phenotyping using diagnosis codes to improve power for genetic association studies
Authors: Sinnott Jennifer A , Cai Fiona , Yu Sheng , Hejblum Boris P , Hong Chuan , Kohane Isaac S , Liao Katherine P 
Published: April 2018

AbstractObjectiveStandard approaches for large scale phenotypic screens using electronic health record (EHR) data apply thresholds, such as ≥2 diagnosis codes, to define subjects as having a phenotype. However, the variation in the accuracy of diagnosis codes can impair the power of such screens. Our objective was to develop and evaluate an approach which converts diagnosis codes into a probability of a phenotype (PheProb). We hypothesized that this alternate approach for defining phenotypes would improve power for genetic association studies.MethodsThe PheProb approach employs unsupervised clustering to separate patients into 2 groups based on diagnosis codes. Subjects are assigned a probability of having the phenotype based on the number of diagnosis codes. This approach was developed using simulated EHR data and tested in a real world EHR cohort. In the latter, we tested the association between low density lipoprotein cholesterol (LDL-C) genetic risk alleles known for association with hyperlipidemia and hyperlipidemia codes (ICD-9 272.x). PheProb and thresholding approaches were compared.ResultsAmong n = 1462 subjects in the real world EHR cohort, the threshold-based p-values for association between the genetic risk score (GRS) and hyperlipidemia were 0.126 (≥1 code), 0.123 (≥2 codes), and 0.142 (≥3 codes). The PheProb approach produced the expected significant association between the GRS and hyperlipidemia: p = .001.ConclusionsPheProb improves statistical power for association studies relative to standard thresholding approaches by leveraging information about the phenotype in the billing code counts. The PheProb approach has direct applications where efficient approaches are required, such as in Phenome-Wide Association Studies.
Informed Trading in Business Groups
Authors: Pedraza Alvaro 
Published: April 2018

Abstract
Business groups, which are collections of legally independent companies with a significant amount of common ownership, dominate private sector activity in developing countries. This paper studies information flows within these groups by examining the trading performance of institutional investors in firms that belong to the same group. Using a novel dataset with complete transaction records in Colombia, this paper estimates the difference in returns between trades of asset managers in group-affiliated companies and trades of non-affiliated managers in the same stocks during the same period. The data show that affiliated managers display superior timing ability and that their trades outperform those of non-affiliated managers by 0.85 percent per month. The evidence suggests that institutional investors with group affiliation access information that is only available to members of the group. In order to limit the use of private information, financial authorities might need to expand their disclosure rules to monitor the trades of group-affiliated investors.
Isoform-selective HDAC1/6/8 inhibitors with an imidazo-ketopiperazine cap containing stereochemical diversity
Authors: Lecointre Bertrand , Narozny Remy , Borrello Maria Teresa , Senger Johanna , Chakrabarti Alokta , Jung Manfred , Marek Martin , Romier Christophe , Melesina Jelena , Sippl Wolfgang , Bischoff Laurent , Ganesan A. 
Published: April 2018

A series of hydroxamic acids linked by different lengths to a chiral imidazo-ketopiperazine scaffold were synthesized. The compounds with linker lengths of 6 and 7 carbon atoms were the most potent in histone deacetylase (HDAC) inhibition, and were specific submicromolar inhibitors of the HDAC1, HDAC6 and HDAC8 isoforms. A docking model for the binding mode predicts binding of the hydroxamic acid to the active site zinc cation and additional interactions between the imidazo-ketopiperazine and the enzyme rim. The compounds were micromolar inhibitors of the MV4-11, THP-1 and U937 cancer cell lines. Increased levels of histone H3 and tubulin acetylation support a cellular mechanism of action through HDAC inhibition.
This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.
De novo protein structure prediction using ultra-fast molecular dynamics simulation
Authors: Cheung Ngaam J. , Yu Wookyung 
Published: April 2018

ABSTRACTModern genomics sequencing techniques have provided a massive amount of protein sequences, but experimental endeavor in determining protein structures is largely lagging far behind the vast and unexplored sequences. Apparently, computational biology is playing a more important role in protein structure prediction than ever. Here, we present a system of de novo predictor, termed NiDelta, building on a deep convolutional neural network and statistical potential enabling molecular dynamics simulation for modeling protein tertiary structure. Combining with evolutionary-based residue-contacts, the presented predictor can predict the tertiary structures of a number of target proteins with remarkable accuracy. The proposed approach is demonstrated by calculations on a set of eighteen large proteins from different fold classes. The results show that the ultra-fast molecular dynamics simulation could dramatically reduce the gap between the sequence and its structure at atom level, and it could also present high efficiency in protein structure determination if sparse experimental data is available.
A weighted burden test using logistic regression for integrated analysis of sequence variants, copy number variants and polygenic risk score
Authors: Curtis David 
Published: April 2018

AbstractPreviously described methods of analysis allow variants in a gene to be weighted more highly according to rarity and/or predicted function and then for the variant contributions to be summed into a gene-wise risk score which can be compared between cases and controls using a t test. However this does not allow incorporating covariates into the analysis. Schizophrenia is an example of an illness where there is evidence that different kinds of genetic variation can contribute to risk, including common variants contributing to a polygenic risk score (PRS), very rare copy number variants (CNVs) and sequence variants. A logistic regression approach has been implemented to compare the gene-wise risk scores between cases and controls while incorporating as covariates population principal components, the PRS and the presence of pathogenic CNVs and sequence variants. A likelihood ratio test is performed comparing the likelihoods of logistic regression models with and without this score. The method was applied to an ethnically heterogeneous exome-sequenced sample of 6000 controls and 5000 schizophrenia cases. In the raw analysis the test statistic is inflated but inclusion of principal components satisfactorily controls for this. In this dataset the inclusion of the PRS and effect from CNVs and sequence variants had only small effects. The set of genes which are FMRP targets showed some evidence for enrichment of rare, functional variants among cases (p=0.0005). This approach can be applied to any disease in which different kinds of genetic and non-genetic risk factors make contributions to risk.
High Resolution Single Particle Cryo-Electron Microscopy using Beam-Image Shift
Authors: Cheng Anchi , Eng Edward T. , Alink Lambertus , Rice William J. , Jordan Kelsey D. , Kim Laura Y. , Potter Clinton S. , Carragher Bridget 
Published: April 2018

AbstractAutomated data acquisition is now used widely for the single-particle averaging approach to reconstruction of three-dimensional (3D) volumes of biological complexes preserved in vitreous ice and imaged in a transmission electron microscope (cryo-EM). Automation has become integral to this method because of the very large number of particle images required to be averaged in order to overcome the typically low signal-to-noise ratio of these images.For optimal efficiency, all automated data acquisition software packages employ some degree of beam-image shift because this method is fast and accurate (+/− 0.1 μm). Relocation to a targeted area under low-dose conditions can only be achieved using stage movements in combination with multiple iterations or long relaxation times, both reducing efficiency. It is, however, well known that applying beam-image shift induces beam-tilt and hence structure phase error. A π/4 phase error is considered as the worst that can be accepted, and is used as an argument against the use of any beam-image shift for high resolution data collection.In this study, we performed cryo-EM single-particle reconstructions on a T20S proteasome sample using applied beam-image shifts corresponding to beam tilts from 0 to 10 mrad. To evaluate the results we compared the FSC values, and examined the water density peaks in the 3D map. We conclude that the π/4 phase error does not limit the validity of the 3D reconstruction from single-particle averaging beyond the π/4 resolution limit.
LONP1 is required for maturation of a subset of mitochondrial proteins and its loss elicits an integrated stress response
Authors: Rendón Olga Zurita , Shoubridge Eric A. 
Published: April 2018

AbstractLONP1, a AAA+ mitochondrial protease, is implicated in protein quality control, but its substrates and precise role in this process remain poorly understood. Here we have investigated the role of human LONP1 in mitochondrial gene expression and proteostasis. Depletion of LONP1 resulted in partial loss of mtDNA, complete suppression of mitochondrial translation, a marked increase in the levels of a distinct subset of mitochondrial matrix proteins (SSBP1, MTERFD3, FASTKD2 and CLPX), and the accumulation of their unprocessed forms, with intact mitochondrial targeting sequences, in an insoluble protein fraction. Depletion of LONP1 produced massive matrix protein aggregates and activated the Integrated Stress Response (ISR) pathway. These results demonstrate that LONP1 is required for maturation of a subset of its client proteins and for maintenance of mitochondrial gene expression.
Dynamics of Allosteric Transitions in Dynein
Authors: Goldtzvik Yonathan , Mugnai Mauro L. , Thirumalai D. 
Published: April 2018

1SummaryCytoplasmic Dynein, a motor with an unusual architecture made up of a motor domain belonging to the AAA+ family, walks on microtubule towards the minus end. Prompted by the availability of structures in different nucleotide states, we performed simulations based on a new coarse-grained model to illustrate the molecular details of the dynamics of allosteric transitions in the motor. The simulations show that binding of ATP results in the closure of the cleft between the AAA1 and AAA2, which in turn triggers conformational changes in the rest of the motor domain, thus poising dynein in the pre-power stroke state. Interactions with the microtubule, which are modeled implicitly, substantially enhances the rate of ADP release, and formation of the post-power stroke state. The dynamics associated with the key mechanical element, the linker (LN) domain, which changes from a straight to a bent state and vice versa, are highly heterogeneous suggestive of multiple routes in the pre power stroke to post power stroke transition. We show that persistent interactions between the LN and the insert loops in the AAA2 domain prevent the formation of pre-power stroke state when ATP is bound to AAA3, thus locking dynein in a non-functional repressed state. Motility in such a state may be rescued by applying mechanical force to the LN domain. Taken together, these results show how the intricate signaling dynamics within the motor domain facilitate the stepping of dynein.
Engagement in help-seeking of dual diagnosed mothers at a low-threshold service: grasping life through co-created opportunities
Authors: Sorsa Minna A. , Kiikkala Irma , Åstedt-Kurki Päivi 
Published: April 2018

Purpose
Mothers with a dual diagnosis (mental ill health and substance use) have delays in accessing services, or their care may be interrupted prior to therapeutic relationships being formed. The purpose of this paper is to explore and describe how engagement merges in the context of mothers with a dual diagnosis.

Design/methodology/approach
This is a qualitative, focused ethnographic study at a low-threshold service for substance abusing families. The data contain interviews, observations, field notes, and reflections. The analysis followed several systematic steps.

Findings
Engagement is the co-creation of possibilities between workplace staff and the client in different interfaces. It is not a single act, emotion, or verbal communication, but a complex intertwined system of events that can awaken or enable the client to get a grasp on life. The sensitivity of the worker is one tool for engaging the client in manifold ways in different interfaces: even the smallest events with connection are viewed as valuable. Engagement involves the intentional client in the process of interaction: the client needs to participate and become an acting and sensing part of the change, which occurs on an experiential level. The process is described with the metaphor of a seed.

Originality/value
Engagement as inner involvement challenges the current working methods, and requires sensitivity, because the mothers with a dual diagnosis may not have verbalisable goals when arriving to the services.
Operationalizing business ethics in organizations
Authors: Singh Jang B. , Wood Greg , Callaghan Michael , Svensson Goran , Andersson Svante 
Published: April 2018

PurposeCodes of ethics have become the mainstay of the ethics programs of corporations. Many studies have explored their contents, but few have examined what makes them effective. This international study aims to identify the measures viewed as being important by top executives in determining the worth to their organizations of corporate codes of ethics.Design/methodology/approachData were collected by questionnaires sent to the top 500 companies ranked by revenue operating in the private sectors in Australia, Canada and Sweden. By analyzing the survey results from the top corporate executives in these countries, the research team was able to test for a number of determinants of effectiveness for codes of ethics.FindingsIn a statistically significant model, it was found that four factors related to the internal management of the corporation are positively correlated to executives’ perceptions of the value of their corporate codes of ethics.Research limitations/implicationsFuture research may seek to address features of this study that limit its generalizability, as it was conducted on the largest of companies in each country and thus this sample may not reflect the way that business ethics are managed in smaller organizations in those countries.Originality/valueIf executives see particular items as important to their business ethics success, one could postulate that this has arisen from a perception that implementing these measures has been effective for their organizations. This provides guidance to other organizations on what items could enhance the effectiveness of their codes of ethics.