bluuebunny/crossref_metadata_2025 huggingface dataset:
Häufigkeit und Vorkommen multiresistenter gramnegativer Erreger: 3MRGN/4MRGN
Authors: Hamprecht Axel , Göttig Stephan
Published: April 2018

The increase of multidrug-resistant Gram-negative bacilli (MRGN) is a great threat for both the health system and patients. Challenges of MRGN for physicians are limited therapeutic options, the need of infection control measures and the danger of outbreaks. In this article, the prevalence of MRGN, risk factors, the background and definitions of multidrug-resistant organisms are presented.
Dysphagie aus gastroenterologischer Sicht
Authors: Hollenbach Marcus , Feisthammel Jürgen , Mössner Joachim , Hoffmeister Albrecht
Published: April 2018

Swallowing disorders (dysphagia) comprise a common cause of medical consultation and are defined as a subjective sensation of difficulty or abnormality of swallowing. In the initial step, a clear differentiation of dysphagia from odynophagia and globus sensation for further diagnostic procedures is mandatory. The careful questioning of patients symptoms and complaints is often helpful for the differentiation of oropharyngeal and esophageal dysphagia. Oropharyngeal dysphagia is mainly caused by neurological disorders (cerebral ischemia, Parkinson’s disease, dementia) or local compression of malignancies, thyroid gland or lymph nodes. In contrast, stenosis of the tubular esophagus (peptic stricture, rings and webs, diverticula, malignancies, infections) can lead to esophageal dysphagia, mostly only after ingestion of solids. Esophageal dysphagia after ingestion of solids and liquids is often caused by motility disorders of the esophagus (achalasia, hypertensive or hypercontractile esophagus). Important diagnostic procedures comprise endoscopy, barium swallow and high-resolution manometry. Overlap syndromes are frequent and need to be supervised interdisciplinary. The diagnostic algorithm and interpretation of exam results is complex. If the results are ambiguous, a reevaluation and, when appropriate, repetition of diagnostics are recommended. Whereas oropharyngeal dysphagia is treated by neurologists or ENT physicians, diagnostic and treatment of esophageal dysphagia is a challenging role for gastroenterologists.
Simultaneous measurement of the dynamic emissivity and the radiance of the shocked Al/LiF interface in the near-infrared wavelength
Authors: Liu Shenggang , Li Jiabo , Li Jun , Xue Tao , Tao Tianjiong , Ma Heli , Wang Xiang , Weng Jidong , Li Zeren
Published: April 2018

A novel method based on signal superimposing has been presented to simultaneously measure the dynamic emissivity and the radiance of a shocked sample/window interface in the near-infrared wavelength. In this method, we have used three rectangle laser pulses to illuminate the sample/window interface via an integrating sphere and expect that the reflected laser pulses from the sample/window interface can be superimposed on its thermal radiation at the shocked steady state by time precision synchronization. In the two proving trials, the second laser pulse reflected from the Al/LiF interface has been successfully superimposed on its thermal radiation despite large flyer velocity uncertainty. The dynamic emissivity and the radiance at 1064 nm have been obtained simultaneously from the superimposing signals. The obtained interface temperatures are 1842 ± 82 K and 1666 ± 154 K, respectively, the corresponding release pressures are 65.7 GPa and 62.6 GPa, and the deduced Hugonoit temperatures are consistent with the theoretical calculations. In comparison, the fitting temperatures from the gray body model are 300–500 K higher than our experimental measurement results and the theoretical calculations.
Extension of the thermal porosimetry method to high gas pressure for nanoporosimetry estimation
Authors: Jannot Y. , Degiovanni A. , Camus M.
Published: April 2018

Standard pore size determination methods like mercury porosimetry, nitrogen sorption, microscopy, or X-ray tomography are not suited to highly porous, low density, and thus very fragile materials. For this kind of materials, a method based on thermal characterization has been developed in a previous study. This method has been used with air pressure varying from 10−1 to 105 Pa for materials having a thermal conductivity less than 0.05 W m−1 K−1 at atmospheric pressure. It enables the estimation of pore size distribution between 100 nm and 1 mm. In this paper, we present a new experimental device enabling thermal conductivity measurement under gas pressure up to 106 Pa, enabling the estimation of the volume fraction of pores having a 10 nm diameter. It is also demonstrated that the main thermal conductivity models (parallel, series, Maxwell, Bruggeman, self-consistent) lead to the same estimation of the pore size distribution as the extended parallel model (EPM) presented in this paper and then used to process the experimental data. Three materials with thermal conductivities at atmospheric pressure ranging from 0.014 W m−1 K−1 to 0.04 W m−1 K−1 are studied. The thermal conductivity measurement results obtained with the three materials are presented, and the corresponding pore size distributions between 10 nm and 1 mm are presented and discussed.
Control of the Urbach band tail and interband dephasing time with post-growth annealing in low-temperature-grown GaAs
Authors: Webber D. , Liu X. , Dobrowolska M. , Furdyna J. K. , Hall K. C.
Published: April 2018

Femtosecond four-wave mixing experiments on low-temperature-grown (LT-) GaAs for a range of post-growth annealing temperatures indicate that the Urbach band tail abruptly diminishes above 550°C due to the conversion of As-related point defects to As clusters and that the interband dephasing time is limited by scattering with As point defects for annealing temperatures below 550°C. In addition, we observe a complex interplay of polarization source terms associated with the exciton and Urbach band tail for annealing temperatures below 550°C. These experiments shed light on the carrier dynamics and ultrafast nonlinear optical properties of LT-GaAs.
Proton conductance and dielectric relaxation in hydrated graphite oxide, studied with impedance spectroscopy
Authors: Yu Ji , Lian Yadong , Xu Wei , Wang Chenglong , Chang Xueling , Tang Tong B. , Gu Min
Published: April 2018

Hydrated graphite oxide samples containing different concentrations of functional groups were investigated with a range of experimental techniques including complex impedance spectroscopy. The activation energies in their conductivities increase with their epoxide concentrations and closely match those in dielectric relaxation. They appear to conduct by a Grotthuss mechanism, involving the exchange of protons between neighboring water molecules and the rotation of water. In the region below room temperature, this conductance is not limited by proton hopping but by water rotation about its hydrogen bond to an epoxide group attached to a graphene plane.
Dynamical analysis of cigarette smoking model with a saturated incidence rate
Authors: Zeb Anwar , Bano Ayesha , Alzahrani Ebraheem , Zaman Gul
Published: April 2018

In this paper, we consider a delayed smoking model in which the potential smokers are assumed to satisfy the logistic equation. We discuss the dynamical behavior of our proposed model in the form of Delayed Differential Equations (DDEs) and show conditions for asymptotic stability of the model in steady state. We also discuss the Hopf bifurcation analysis of considered model. Finally, we use the nonstandard finite difference (NSFD) scheme to show the results graphically with help of MATLAB.
Environmental selection during the last ice age on the mother-to-infant transmission of vitamin D and fatty acids through breast milk
Authors: Hlusko Leslea J. , Carlson Joshua P. , Chaplin George , Elias Scott A. , Hoffecker John F. , Huffman Michaela , Jablonski Nina G. , Monson Tesla A. , O’Rourke Dennis H. , Pilloud Marin A. , Scott G. Richard
Published: April 2018

Significance

The frequency of the human-specificEDAR V370Aisoform is highly elevated in North and East Asian populations. The gene is known to have several pleiotropic effects, among which are sweat gland density and ductal branching in the mammary gland. The former has led some geneticists to argue that the near-fixation of this allele was caused by selection for modulation of thermoregulatory sweating. We provide an alternative hypothesis, that selection instead acted on the allele’s effect of increasing ductal branching in the mammary gland, thereby amplifying the transfer of critical nutrients to infants via mother’s milk. This is likely to have occurred during the Last Glacial Maximum when a human population was genetically isolated in the high-latitude environment of the Beringia.
Lifetime of muscarinic receptor–G-protein complexes determines coupling efficiency and G-protein subtype selectivity
Authors: Ilyaskina Olga S. , Lemoine Horst , Bünemann Moritz
Published: April 2018

Significance

The family of G-protein–coupled receptors (GPCRs) is the largest receptor family, and each member detects specific ligands, which in turn, activate selected members of one or more G-protein families. We developed a broadly applicable assay to study the specificity of GPCR–G-protein interaction in a subtype selective manner. We were able to quantitatively measure both association and dissociation rates of G proteins from agonist-activated GPCRs. We found that the stability of the receptor–G-protein complex is an inherent property of both interaction partners independent on the agonist used. Furthermore, its lifetime correlated closely with the ability of the receptor to activate the corresponding G-protein subtype.
Recurrent structural variation, clustered sites of selection, and disease risk for the complement factor H (
CFH
) gene family
Authors: Cantsilieris Stuart , Nelson Bradley J. , Huddleston John , Baker Carl , Harshman Lana , Penewit Kelsi , Munson Katherine M. , Sorensen Melanie , Welch AnneMarie E. , Dang Vy , Grassmann Felix , Richardson Andrea J. , Guymer Robyn H. , Graves-Lindsay Tina A. , Wilson Richard K. , Weber Bernhard H. F. , Baird Paul N. , Allikmets Rando , Eichler Evan E.
Published: April 2018

Significance

Genetic variation of the complement factor H (
CFH
) gene family is associated with several complex diseases. Here, we have performed both long- and short-read sequencing of multiple humans and nonhuman primates in an effort to understand its complex evolutionary history. We find that this locus has evolved predominantly through incomplete segmental duplication and identify recurrent reuse of donor and acceptor duplications leading to
CFHR
fusion genes with diverse functions. Investigation of a large cohort of patients with age-related macular degeneration revealed multiple structural variation breakpoints and mutational burdens that cluster in specific domains of the CFH protein. These domains overlap sites showing signatures of natural selection, providing strong evidence for the shared role of selective pressure on diversity and disease.
Interdependent and separable functions of
Caenorhabditis elegans
MRN-C complex members couple formation and repair of meiotic DSBs
Authors: Girard Chloe , Roelens Baptiste , Zawadzki Karl A. , Villeneuve Anne M.
Published: April 2018

Significance

Double-strand breaks (DSBs) are deleterious DNA lesions, and impairment of the DSB repair machinery can lead to devastating diseases, such as Nijmegen Breakage Syndrome (NBS). During meiosis, DSBs represent a “necessary evil”: they are required to promote formation of crossovers between homologous chromosomes. Crossovers, in turn, ensure correct chromosome inheritance during gamete formation, which is essential for viability and normal development of embryos. During meiosis, numerous DSBs are actively created, so meiotic cells must ensure that all breaks are properly repaired to ensure crossover formation and restore genomic integrity. Here, we identify
Caenorhabditis elegans
NBS-1 as essential to properly process meiotic DSBs to both promote crossover formation and antagonize an error-prone DSB repair pathway, thereby ensuring faithful chromosome inheritance.
Efficient models of polymerization applied to FtsZ ring assembly in
Escherichia coli
Authors: Ruiz-Martínez Álvaro , Bartol Thomas M. , Sejnowski Terrence J. , Tartakovsky Daniel M.
Published: April 2018

Significance

Our modeling framework yields accurate and computationally efficient quantitative predictions of complex kinetics of polymerization processes in biological systems. The resulting model consists of 10 differential equations, regardless of the total concentration of proteins. This is in contrast to previous polymerization models, in which the number of equations increases with the total concentrations, reaching into the thousands. Consequently, our model is orders of magnitude faster than its existing alternatives. It can be used to predict polymerization kinetics at high concentrations characteristic of in vivo processes and, especially, their compartmentalized and spatially distributed representations.
Abscisic acid-induced degradation of
Arabidopsis
guanine nucleotide exchange factor requires calcium-dependent protein kinases
Authors: Li Zixing , Takahashi Yohei , Scavo Alexander , Brandt Benjamin , Nguyen Desiree , Rieu Philippe , Schroeder Julian I.
Published: April 2018

Significance

Arabidopsis
RopGEF1 acts as a negative regulator of signal transduction by the plant hormone abscisic acid (ABA). In turn, ABA treatment causes subcellular translocation and degradation of RopGEF1 protein. Interestingly, PP2C protein phosphatases, the core negative regulators of ABA signal transduction, protect RopGEF1 from degradation. This suggests that protein kinases may be involved in RopGEF1 protein removal. We find that calcium-dependent protein kinases (CPKs) including CPK4 phosphorylate RopGEF1. CPK4 promotes RopGEF1 degradation in
Arabidopsis
. CPK4 also negatively regulates RopGEF1 activities in root hair development. Furthermore, phosphorylation of serine residues at the N terminus of RopGEF1 is important for RopGEF1 degradation. We further discuss possible abiotic stress-triggered repression of plant growth via CPK-mediated removal of RopGEF.
Sporadic sampling, not climatic forcing, drives observed early hominin diversity
Authors: Maxwell Simon J. , Hopley Philip J. , Upchurch Paul , Soligo Christophe
Published: April 2018

Significance

Paleoanthropologists have long been intrigued by the observed patterns of human evolution, including species diversity, and often invoked climatic change as the principal driver of evolutionary change. Here, we investigate whether the early hominin fossil record is of suitable quality to test these climate-forcing hypotheses. Specifically, we compare early hominin diversity to sampling metrics that quantify changes in fossil preservation and sampling intensity between 7 and 1 million years ago. We find that observed diversity patterns are governed by sporadic sampling and do not yield a genuine evolutionary signal. Many more fossil discoveries are required before existing hypotheses linking climate and evolution can be meaningfully tested.
Protection from cytomegalovirus viremia following glycoprotein B vaccination is not dependent on neutralizing antibodies
Authors: Baraniak Ilona , Kropff Barbara , Ambrose Lyn , McIntosh Megan , McLean Gary R. , Pichon Sylvie , Atkinson Claire , Milne Richard S. B. , Mach Michael , Griffiths Paul D. , Reeves Matthew B.
Published: April 2018

Significance

Conventionally, vaccines are screened for induction of a neutralizing antibody response in human volunteers before proceeding to late-stage clinical trials. We present results from a human cytomegalovirus (HCMV) challenge study suggesting that this paradigm may not apply universally to all viruses. Instead, viruses like HCMV, which establish lifelong infections and grow both cell-free and cell-associated, may be controlled independently of a potent neutralizing antibody response. Our results suggest that more detailed laboratory studies are required to identify correlates of immune protection for such viruses and that failure of a vaccine to induce a neutralizing antibody response should not necessarily be considered as a key go-no-go decision point in the design of future vaccine studies.
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

Over 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

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

Motivation

Single-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.

Results

We 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 implementation

SC2P is implemented as an open source R package publicly available at https://github.com/haowulab/SC2P.

Supplementary information

Supplementary 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

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

Objective

Standard 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.

Methods

The 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.

Results

Among 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.

Conclusions

PheProb 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

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.
Inhibitors of both the
N
-methyl lysyl- and arginyl-demethylase activities of the JmjC oxygenases
Authors: Bonnici Joanna , Tumber Anthony , Kawamura Akane , Schofield Christopher J.
Published: April 2018

The Jumonji C (JmjC) family of 2-oxoglutarate (2OG)-dependent oxygenases have established roles in the regulation of transcription via the catalysis of demethylation of
N
ε
-
methylated lysine residues in histone tails, especially the N
-
terminal tail of histone H3. Most human JmjC
N

ɛ

-methyl lysine demethylases (KDMs) are complex enzymes, with ‘reader domains’ in addition to their catalytic domains. Recent biochemical evidence has shown that some, but not all, JmjC KDMs also have
N
ω
-
methyl arginyl demethylase (RDM) activity. JmjC KDM activity has been linked to multiple cancers and some JmjC proteins are therapeutic targets. It is, therefore, important to test not only whether compounds in development inhibit the KDM activity of targeted JmjC demethylases, but also whether they inhibit other activities of these proteins. Here we report biochemical studies on the potential dual inhibition of JmjC KDM and RDM activities using a model JmjC demethylase, KDM4E (JMJD2E). The results reveal that all of the tested compounds inhibit both the KDM and RDM activities, raising questions about the
in vivo
effects of the inhibitors.

This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.
Selective recognition of
N
4-methylcytosine in DNA by engineered transcription-activator-like effectors
Authors: Rathi Preeti , Maurer Sara , Summerer Daniel
Published: April 2018

The epigenetic DNA nucleobases 5-methylcytosine (5mC) and
N
4-methylcytosine (4mC) coexist in bacterial genomes and have important functions in host defence and transcription regulation. To better understand the individual biological roles of both methylated nucleobases, analytical strategies for distinguishing unmodified cytosine (C) from 4mC and 5mC are required. Transcription-activator-like effectors (TALEs) are programmable DNA-binding repeat proteins, which can be re-engineered for the direct detection of epigenetic nucleobases in user-defined DNA sequences. We here report the natural, cytosine-binding TALE repeat to not strongly differentiate between 5mC and 4mC. To engineer repeats with selectivity in the context of C, 5mC and 4mC, we developed a homogeneous fluorescence assay and screened a library of size-reduced TALE repeats for binding to all three nucleobases. This provided insights into the requirements of size-reduced TALE repeats for 4mC binding and revealed a single mutant repeat as a selective binder of 4mC. Employment of a TALE with this repeat in affinity enrichment enabled the isolation of a user-defined DNA sequence containing a single 4mC but not C or 5mC from the background of a bacterial genome. Comparative enrichments with TALEs bearing this or the natural C-binding repeat provides an approach for the complete, programmable decoding of all cytosine nucleobases found in bacterial genomes.

This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.
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

Modern 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

Previously 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

Automated 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

LONP1, 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

1

Cytoplasmic 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.
Single-cell phenotyping and RNA sequencing reveal novel patterns of gene expression heterogeneity and regulation during growth and stress adaptation in a unicellular eukaryote
Authors: Saint Malika , Bertaux François , Tang Wenhao , Sun Xi-Ming , Game Laurence , Köferle Anna , Bähler Jürg , Shahrezaei Vahid , Marguerat Samuel
Published: April 2018

Cell-to-cell variability is central for microbial populations and contributes to cell function, stress adaptation and drug resistance. Gene-expression heterogeneity underpins this variability, but has been challenging to study genome-wide. Here, we report an integrated approach for imaging of individual fission yeast cells followed by single-cell RNA sequencing (scRNA-seq) and novel Bayesian normalisation. We analyse >2000 single cells and >700 matching RNA controls in various environmental conditions and identify sets of highly variable genes. Combining scRNA-seq with cell-size measurements provides unique insights into genes regulated during cell growth and division in single cells, including genes whose expression does not scale with cell size. We further analyse the heterogeneity and dynamics of gene expression during adaptive and acute responses to changing environments. Entry into stationary phase is preceded by a gradual, synchronised adaptation in gene regulation, followed by highly variable gene expression when growth decreases. Conversely, a sudden and acute heat-shock leads to a stronger and coordinated response and adaptation across cells. This analysis reveals that the extent and dynamics of global gene-expression heterogeneity is regulated in response to different physiological conditions within populations of a unicellular eukaryote. In summary, this works illustrates the potential of combined transcriptomics and imaging analysis in single cells to provide comprehensive and unbiased mechanistic understanding of cell-to-cell variability in microbial communities.
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

Purpose

Codes 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/approach

Data 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.

Findings

In 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/implications

Future 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/value

If 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.
Post-diagnostic support for dementia
Authors: Levin Kate Ann , Lithgow Stephen , Miller Martine , Carson Jill
Published: April 2018

Purpose

The purpose of this paper is to examine three interpretations of post-diagnostic support (PDS) for dementia, to understand how best to support people recently diagnosed with dementia.

Design/methodology/approach

A sequential mixed-method approach was used which included analysis of the data collected by each sector, a focus group and interviews with PDS linkworkers and other staff.

Findings

All three sectors used a mix of supported self-management workshops and one-to-one PDS, however sectors varied by linkworker’s affiliation, caseload management and client group. Caseload varied greatly between sectors. Stage of disease and socioeconomic make-up of the local population were raised as factors determining the form of PDS offered. Some pillars appeared to be more easily achieved than others. There was a general agreement among all staff that “caseload” was misleading and that a measurement of workload would be preferable. Agile/mobile working was preferred by linkworkers. Even within teams there was variation in perceptions of PDS; some felt the linkworker role to be one of signposting, while others felt more involved with their client group, and for longer than 12 months.

Practical implications

Guidance at the outset of the PDS programme was sparse. The findings of this study should inform future development of the PDS model and a supporting guidance framework.

Originality/value

There is a growing interest in PDS for dementia. However, little is known about what a model of PDS should look like. This study attempts to capture the most important aspects of PDS delivery.
Recursive least squares identification for piecewise affine Hammerstein models
Authors: Hong Wang Jian , Wang Daobo
Published: April 2018

Purpose

The purpose of this paper is to probe the recursive identification of piecewise affine Hammerstein models directly by using input-output data. To explain the identification process of a parametric piecewise affine nonlinear function, the authors prove that the inverse function corresponding to the given piecewise affine nonlinear function is also an equivalent piecewise affine form. Based on this equivalent property, during the detailed identification process with respect to piecewise affine function and linear dynamical system, three recursive least squares methods are proposed to identify those unknown parameters under the probabilistic description or bounded property of noise.

Design/methodology/approach

First, the basic recursive least squares method is used to identify those unknown parameters under the probabilistic description of noise. Second, multi-innovation recursive least squares method is proposed to improve the efficiency lacked in basic recursive least squares method. Third, to relax the strict probabilistic description on noise, the authors provide a projection algorithm with a dead zone in the presence of bounded noise and analyze its two properties.

Findings

Based on complex mathematical derivation, the inverse function of a given piecewise affine nonlinear function is also an equivalent piecewise affine form. As the least squares method is suited under one condition that the considered noise may be a zero mean random signal, a projection algorithm with a dead zone in the presence of bounded noise can enhance the robustness in the parameter update equation.

Originality/value

To the best knowledge of the authors, this is the first attempt at identifying piecewise affine Hammerstein models, which combine a piecewise affine function and a linear dynamical system. In the presence of bounded noise, the modified recursive least squares methods are efficient in identifying two kinds of unknown parameters, so that the common set membership method can be replaced by the proposed methods.