bluuebunny/crossref_metadata_2025 huggingface dataset:
Food Insecurity in Vulnerable Populations: Coping with Food Price Shocks in Afghanistan
Authors: D'Souza Anna , Jolliffe Dean
Published: December 2013

Based on data from Afghanistan collected prior to and during the 2007‐2008 food price crisis, this paper illustrates that caloric intake is an ineffectual indicator for monitoring the onset of food insecurity. Unconditional Quantile Regression estimates indicate that the most vulnerable of households, which cannot afford to make substantial cuts to calories, exhibit no decline in caloric intake in response to increasing wheat prices. In contrast, households with high‐calorie diets experience large declines. The estimates also reveal declines in dietary diversity across the entire distribution of households. The most vulnerable households may be sacrificing diet quality to maintain calories, with the potential for serious and long‐term health consequences.
ChAMP: 450k Chip Analysis Methylation Pipeline
Authors: Morris Tiffany J. , Butcher Lee M. , Feber Andrew , Teschendorff Andrew E. , Chakravarthy Ankur R. , Wojdacz Tomasz K. , Beck Stephan
Published: December 2013

The Illumina Infinium HumanMethylation450 BeadChip is a new platform for high-throughput DNA methylation analysis. Several methods for normalization and processing of these data have been published recently. Here we present an integrated analysis pipeline offering a choice of the most popular normalization methods while also introducing new methods for calling differentially methylated regions and detecting copy number aberrations.

Availability and implementation: ChAMP is implemented as a Bioconductor package in R. The package and the vignette can be downloaded at bioconductor.org

Contact:  tiffany.morris@ucl.ac.uk
Genes related to differentiation are correlated with the gene regulatory network structure
Authors: Bodaker Matan , Meshorer Eran , Mitrani Eduardo , Louzoun Yoram
Published: December 2013

Motivation: Many secondary messengers, receptors and transcription factors are related to cell differentiation. Their role in cell differentiation can be affected by their position in the gene regulatory network. Here, we test whether the properties of the gene regulatory network can highlight which genes and proteins are associated with cell differentiation. We use a previously developed purely theoretical algorithm built to detect nodes that can induce a state change in Boolean gene regulatory networks, and show that most genes predicted to participate in differentiation in the theoretical framework are also experimentally known to be associated with such differentiation. These results show that genes related to differentiation are associated with specific features of the genetic regulatory network. The proposed algorithm produces a better classification than simple network measures such as the nodes degree or centrality. Boolean networks were used in many previous theoretical models. Here, we show a direct application of such networks to the detection of genes and subnetworks related to differentiation. The subnetwork emerging from the genes and edges that are predicted to be associated with differentiation are the most active molecular pathways experimentally described to be involved in cell differentiation.

Availability and implementation:  http://peptibase.cs.biu.ac.il/homepage/Boolean_network_conversion_code.zip.

Contact:  louzouy@math.biu.ac.il

Supplementary information:  Supplementary data are available at Bioinformatics online.
Causal analysis approaches in Ingenuity Pathway Analysis
Authors: Krämer Andreas , Green Jeff , Pollard Jack , Tugendreich Stuart
Published: December 2013

Motivation: Prior biological knowledge greatly facilitates the meaningful interpretation of gene-expression data. Causal networks constructed from individual relationships curated from the literature are particularly suited for this task, since they create mechanistic hypotheses that explain the expression changes observed in datasets.

Results: We present and discuss a suite of algorithms and tools for inferring and scoring regulator networks upstream of gene-expression data based on a large-scale causal network derived from the Ingenuity Knowledge Base. We extend the method to predict downstream effects on biological functions and diseases and demonstrate the validity of our approach by applying it to example datasets.

Availability: The causal analytics tools ‘Upstream Regulator Analysis', ‘Mechanistic Networks', ‘Causal Network Analysis' and ‘Downstream Effects Analysis' are implemented and available within Ingenuity Pathway Analysis (IPA, http://www.ingenuity.com).

Supplementary information:  Supplementary material is available at Bioinformatics online.
HAMMER: automated operation of mass frontier to construct in silico mass spectral fragmentation libraries
Authors: Zhou Jiarui , Weber Ralf J. M. , Allwood J. William , Mistrik Robert , Zhu Zexuan , Ji Zhen , Chen Siping , Dunn Warwick B. , He Shan , Viant Mark R.
Published: December 2013

Summary: Experimental MSn mass spectral libraries currently do not adequately cover chemical space. This limits the robust annotation of metabolites in metabolomics studies of complex biological samples. In silico fragmentation libraries would improve the identification of compounds from experimental multistage fragmentation data when experimental reference data are unavailable. Here, we present a freely available software package to automatically control Mass Frontier software to construct in silico mass spectral libraries and to perform spectral matching. Based on two case studies, we have demonstrated that high-throughput automation of Mass Frontier allows researchers to generate in silico mass spectral libraries in an automated and high-throughput fashion with little or no human intervention required.

Availability and implementation: Documentation, examples, results and source code are available at http://www.biosciences-labs.bham.ac.uk/viant/hammer/.

Contact:  m.viant@bham.ac.uk

Supplementary information:  Supplementary data are available at Bioinformatics online.
Sequence-based Gaussian network model for protein dynamics
Authors: Zhang Hua , Kurgan Lukasz
Published: December 2013

Motivation: Gaussian network model (GNM) is widely adopted to analyze and understand protein dynamics, function and conformational changes. The existing GNM-based approaches require atomic coordinates of the corresponding protein and cannot be used when only the sequence is known.

Results: We report, first of its kind, GNM model that allows modeling using the sequence. Our linear regression-based, parameter-free, sequence-derived GNM (L-pfSeqGNM) uses contact maps predicted from the sequence and models local, in the sequence, contact neighborhoods with the linear regression. Empirical benchmarking shows relatively high correlations between the native and the predicted with L-pfSeqGNM B-factors and between the cross-correlations of residue fluctuations derived from the structure- and the sequence-based GNM models. Our results demonstrate that L-pfSeqGNM is an attractive platform to explore protein dynamics. In contrast to the highly used GNMs that require protein structures that number in thousands, our model can be used to study motions for the millions of the readily available sequences, which finds applications in modeling conformational changes, protein–protein interactions and protein functions.

Contact:  zerozhua@126.com

Supplementary information:  Supplementary data are available at Bioinformatics online.
BETASEQ: a powerful novel method to control type-I error inflation in partially sequenced data for rare variant association testing
Authors: Yan Song , Li Yun
Published: December 2013

Summary: Despite its great capability to detect rare variant associations, next-generation sequencing is still prohibitively expensive when applied to large samples. In case-control studies, it is thus appealing to sequence only a subset of cases to discover variants and genotype the identified variants in controls and the remaining cases under the reasonable assumption that causal variants are usually enriched among cases. However, this approach leads to inflated type-I error if analyzed naively for rare variant association. Several methods have been proposed in recent literature to control type-I error at the cost of either excluding some sequenced cases or correcting the genotypes of discovered rare variants. All of these approaches thus suffer from certain extent of information loss and thus are underpowered. We propose a novel method (BETASEQ), which corrects inflation of type-I error by supplementing pseudo-variants while keeps the original sequence and genotype data intact. Extensive simulations and real data analysis demonstrate that, in most practical situations, BETASEQ leads to higher testing powers than existing approaches with guaranteed (controlled or conservative) type-I error.

Availability and implementation: BETASEQ and associated R files, including documentation, examples, are available at http://www.unc.edu/∼yunmli/betaseq

Contact:  songyan@unc.edu or yunli@med.unc.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
VIRAPOPS: a forward simulator dedicated to rapidly evolved viral populations
Authors: Petitjean Michel , Vanet Anne
Published: December 2013

Summary: Daily, mutability and recombination of RNA viruses result in the production of million variants. All these rapid genomic changes directly influence the functional sites of the protein, its 3D structure or its drug resistances. Therefore, it is important to simulate these drastic switches to determine their effects on virus populations. Many computer programs are able to simulate specific variations in DNA genomes, but are generally non-adapted to RNA viruses. They simulate site-specific selection pressures, but rarely pressures on covariant or on higher order correlated sites and no at all on synthetic lethal groups. That is why we felt it important to create VIRAPOPS, a forward simulator that models specific RNA virus functions. It was designed for computational biologists, biologists and virologists.

Availability and implementation: Free binaries are available through a software repository at http://petitjeanmichel.free.fr/itoweb.petitjean.freeware.html.

Contact: anne.vanet@univ-paris-diderot.fr
Timing variations in the secondary eclipse of NN Ser
Authors: Parsons S. G. , Marsh T. R. , Bours M. C. P. , Littlefair S. P. , Copperwheat C. M. , Dhillon V. S. , Breedt E. , Caceres C. , Schreiber M. R.
Published: December 2013

The eclipsing white dwarf plus main-sequence binary NN Serpentis provides one of the most convincing cases for the existence of circumbinary planets around evolved binaries. The exquisite timing precision provided by the deep eclipse of the white dwarf has revealed complex variations in the eclipse arrival times over the last few decades. These variations have been interpreted as the influence of two planets in orbit around the binary. Recent studies have proved that such a system is dynamically stable over the current lifetime of the binary. However, the existence of such planets is by no means proven and several alternative mechanisms have been proposed that could drive similar variations. One of these is apsidal precession, which causes the eclipse times of eccentric binaries to vary sinusoidally on many year time-scales. In this Letter, we present timing data for the secondary eclipse of NN Ser and show that they follow the same trend seen in the primary eclipse times, ruling out apsidal precession as a possible cause for the variations. This result leaves no alternatives to the planetary interpretation for the observed period variations, although we still do not consider their existence as proven. Our data limit the eccentricity of NN Ser to e < 10−3. We also detect a 3.3 ± 1.0 s delay in the arrival times of the secondary eclipses relative to the best planetary model. This delay is consistent with the expected 2.84 ± 0.04 s Rømer delay of the binary, and is the first time this effect has been detected in a white dwarf plus M dwarf system.
Systematic discovery and characterization of regulatory motifs in ENCODE TF binding experiments
Authors: Kheradpour Pouya , Kellis Manolis
Published: December 2013

Recent advances in technology have led to a dramatic increase in the number of available transcription factor ChIP-seq and ChIP-chip data sets. Understanding the motif content of these data sets is an important step in understanding the underlying mechanisms of regulation. Here we provide a systematic motif analysis for 427 human ChIP-seq data sets using motifs curated from the literature and also discovered de novo using five established motif discovery tools. We use a systematic pipeline for calculating motif enrichment in each data set, providing a principled way for choosing between motif variants found in the literature and for flagging potentially problematic data sets. Our analysis confirms the known specificity of 41 of the 56 analyzed factor groups and reveals motifs of potential cofactors. We also use cell type-specific binding to find factors active in specific conditions. The resource we provide is accessible both for browsing a small number of factors and for performing large-scale systematic analyses. We provide motif matrices, instances and enrichments in each of the ENCODE data sets. The motifs discovered here have been used in parallel studies to validate the specificity of antibodies, understand cooperativity between data sets and measure the variation of motif binding across individuals and species.
Glycogen synthase kinase 3 beta inhibits microRNA-183-96-182 cluster via the β-Catenin/TCF/LEF-1 pathway in gastric cancer cells
Authors: Tang Xiaoli , Zheng Dong , Hu Ping , Zeng Zongyue , Li Ming , Tucker Lynne , Monahan Renee , Resnick Murray B. , Liu Manran , Ramratnam Bharat
Published: December 2013

Glycogen synthase kinase 3 beta (GSK3β) is a critical protein kinase that phosphorylates numerous proteins in cells and thereby impacts multiple pathways including the β-Catenin/TCF/LEF-1 pathway. MicroRNAs (miRs) are a class of noncoding small RNAs of ∼22 nucleotides in length. Both GSK3β and miR play myriad roles in cell functions including stem cell development, apoptosis, embryogenesis and tumorigenesis. Here we show that GSK3β inhibits the expression of miR-96, miR-182 and miR-183 through the β-Catenin/TCF/LEF-1 pathway. Knockout of GSK3β in mouse embryonic fibroblast cells increases expression of miR-96, miR-182 and miR-183, coinciding with increases in the protein level and nuclear translocation of β-Catenin. In addition, overexpression of β-Catenin enhances the expression of miR-96, miR-182 and miR-183 in human gastric cancer AGS cells. GSK3β protein levels are decreased in human gastric cancer tissue compared with surrounding normal gastric tissue, coinciding with increases of β-Catenin protein, miR-96, miR-182, miR-183 and primary miR-183-96-182 cluster (pri-miR-183). Furthermore, suppression of miR-183-96-182 cluster with miRCURY LNA miR inhibitors decreases the proliferation and migration of AGS cells. Knockdown of GSK3β with siRNA increases the proliferation of AGS cells. Mechanistically, we show that β-Catenin/TCF/LEF-1 binds to the promoter of miR-183-96-182 cluster gene and thereby activates the transcription of the cluster. In summary, our findings identify a novel role for GSK3β in the regulation of miR-183-96-182 biogenesis through β-Catenin/TCF/LEF-1 pathway in gastric cancer cells.
Identification of novel methyltransferases, Bmt5 and Bmt6, responsible for the m3U methylations of 25S rRNA in Saccharomyces cerevisiae
Authors: Sharma Sunny , Yang Jun , Düttmann Simon , Watzinger Peter , Kötter Peter , Entian Karl-Dieter
Published: December 2013

RNA contains various chemical modifications that expand its otherwise limited repertoire to mediate complex processes like translation and gene regulation. 25S rRNA of the large subunit of ribosome contains eight base methylations. Except for the methylation of uridine residues, methyltransferases for all other known base methylations have been recently identified. Here we report the identification of BMT5 (YIL096C) and BMT6 (YLR063W), two previously uncharacterized genes, to be responsible for m3U2634 and m3U2843 methylation of the 25S rRNA, respectively. These genes were identified by RP-HPLC screening of all deletion mutants of putative RNA methyltransferases and were confirmed by gene complementation and phenotypic characterization. Both proteins belong to Rossmann-fold–like methyltransferases and the point mutations in the S-adenosyl-l-methionine binding pocket abolish the methylation reaction. Bmt5 localizes in the nucleolus, whereas Bmt6 is localized predominantly in the cytoplasm. Furthermore, we showed that 25S rRNA of yeast does not contain any m5U residues as previously predicted. With Bmt5 and Bmt6, all base methyltransferases of the 25S rRNA have been identified. This will facilitate the analyses of the significance of these modifications in ribosome function and cellular physiology.
A Tale of Two Hypotheses: Genetics and the Ethnogenesis of Ashkenazi Jewry
Authors: Aram Yardumian M.A.
Published: December 2013

The debate over the ethnogenesis of Ashkenazi Jewry is longstanding, and has been hampered by a lack of Jewish historiographical work between the Biblical and the early Modern eras. Most historians, as well as geneticists, situate them as the descendants of Israelite tribes whose presence in Europe is owed to deportations during the Roman conquest of Palestine, as well as migration from Babylonia, and eventual settlement along the Rhine. By contrast, a few historians and other writers, most famously Arthur Koestler, have looked to migrations following the decline of the little-understood Medieval Jewish kingdom of Khazaria as the main source for Ashkenazi Jewry. A recent study of genetic variation in southeastern European populations (Elhaik 2012) also proposed a Khazarian origin for Ashkenazi Jews, eliciting considerable criticism from other scholars investigating Jewish ancestry who favor a Near Eastern origin of Ashkenazi populations. This paper re-examines the genetic data and analytical approaches used in these studies of Jewish ancestry, and situates them in the context of historical, linguistic, and archaeological evidence from the Caucasus, Europe and the Near East. Based on this reanalysis, it appears not only that the Khazar Hypothesis per se is without serious merit, but also the veracity of the ‘Rhineland Hypothesis’ may also be questionable.
Accurate detection ofde novoand transmitted INDELs within exome-capture data using micro-assembly
Authors: Narzisi Giuseppe , O’Rawe Jason A. , Iossifov Ivan , Fang Han , Lee Yoon-ha , Wang Zihua , Wu Yiyang , Lyon Gholson J. , Wigler Michael , Schatz Michael C.
Published: December 2013

We present a new open-source algorithm, Scalpel, for sensitive and specific discovery of INDELs in exome-capture data. By combining the power of mapping and assembly, Scalpel carefully searches the de Bruijn graph for sequence paths that span each exon. A detailed repeat analysis coupled with a self-tuningk-mer strategy allows Scalpel to outperform other state-of-the-art approaches for INDEL discovery. We extensively compared Scalpel with a battery of >10000 simulated and >1000 experimentally validated INDELs against two recent algorithms: GATK HaplotypeCaller and SOAPindel. We report anomalies for these tools to detect INDELs in regions containing near-perfect repeats. We also present a large-scale application of Scalpel for detectingde novoand transmitted INDELs in 593 families from the Simons Simplex Collection. Scalpel demonstrates enhanced power to detect long (≥20bp) transmitted events, and strengthens previous reports of enrichment forde novolikely gene-disrupting INDELs in autistic children with many new candidate genes.
Parametric inference in the large data limit using maximally informative models
Authors: Kinney Justin B. , Atwal Gurinder S.
Published: December 2013

Motivated by data-rich experiments in transcriptional regulation and sensory neuro-science, we consider the following general problem in statistical inference. When exposed to a high-dimensional signalS, a system of interest computes a representationRof that signal which is then observed through a noisy measurementM. From a large number of signals and measurements, we wish to infer the “filter” that mapsStoR. However, the standard method for solving such problems, likelihood-based inference, requires perfecta prioriknowledge of the “noise function” mappingRtoM. In practice such noise functions are usually known only approximately, if at all, and using an incorrect noise function will typically bias the inferred filter. Here we show that, in the large data limit, this need for a pre-characterized noise function can be circumvented by searching for filters that instead maximize the mutual informationI[M;R] between observed measurements and predicted representations. Moreover, if the correct filter lies within the space of filters being explored, maximizing mutual information becomes equivalent to simultaneously maximizing every dependence measure that satisfies the Data Processing Inequality. It is important to note that maximizing mutual information will typically leave a small number of directions in parameter space unconstrained. We term these directions “diffeomorphic modes” and present an equation that allows these modes to be derived systematically. The presence of diffeomorphic modes reflects a fundamental and nontrivial substructure within parameter space, one that is obscured by standard likelihood-based inference.
Cold-Induced Cysts of the Photosynthetic DinoflagellateLingulodinium polyedrumHave an Arrested Circadian Bioluminescence Rhythm and Lower Levels of Protein Phosphorylation
Authors: Roy Sougata , Letourneau Louis , Morse David
Published: December 2013

Dinoflagellates are microscopic, eukaryotic, and primarily marine plankton. Temporary cyst formation is a well-known physiological response of dinoflagellate cells to environmental stresses. However, the molecular underpinnings of cold-induced cyst physiology have never been described. Cultures of the photosynthetic dinoflagellate Lingulodinium polyedrum readily form temporary cysts when placed at low (8°C ± 1°C) temperature and excyst to form normal motile cells following a return to normal temperature (18°C ± 1°C). The normal circadian bioluminescence rhythm and the expected changes in Luciferin Binding Protein abundance were arrested in L. polyedrum cysts. Furthermore, after excystment, the bioluminescence rhythm initiates at a time corresponding to zeitgeber 12, independent of the time when the cells encysted. Phosphoprotein staining after two-dimensional polyacrylamide gel electrophoresis, as well as column-based phosphoprotein enrichment followed by liquid chromatography tandem mass spectrometry, showed cyst proteins are hypophosphorylated when compared with those from motile cells, with the most marked decreases found for predicted Casein Kinase2 target sites. In contrast to the phosphoproteome, the cyst proteome is not markedly different from motile cells, as assessed by two-dimensional polyacrylamide gel electrophoresis. In addition to changes in the phosphoproteome, RNA sequencing revealed that cysts show a significant decrease in the levels of 132 RNAs. Of the 42 RNAs that were identified by sequence analysis, 21 correspond to plastid-encoded gene products and 11 to nuclear-encoded cell wall/plasma membrane components. Our data are consistent with a model in which the highly reduced metabolism in cysts is achieved primarily by alterations in the phosphoproteome. The stalling of the circadian rhythm suggests temporary cysts may provide an interesting model to address the circadian system of dinoflagellates.
Specificity of the Cyanobacterial Orange Carotenoid Protein: Influences of Orange Carotenoid Protein and Phycobilisome Structures
Authors: Jallet Denis , Thurotte Adrien , Leverenz Ryan L. , Perreau François , Kerfeld Cheryl A. , Kirilovsky Diana
Published: December 2013

Cyanobacteria have developed a photoprotective mechanism that decreases the energy arriving at the reaction centers by increasing thermal energy dissipation at the level of the phycobilisome (PB), the extramembranous light-harvesting antenna. This mechanism is triggered by the photoactive Orange Carotenoid Protein (OCP), which acts both as the photosensor and the energy quencher. The OCP binds the core of the PB. The structure of this core differs in diverse cyanobacterial strains. Here, using two isolated OCPs and four classes of PBs, we demonstrated that differences exist between OCPs related to PB binding, photoactivity, and carotenoid binding. Synechocystis PCC 6803 (hereafter Synechocystis) OCP, but not Arthrospira platensis PCC 7345 (hereafter Arthrospira) OCP, can attach echinenone in addition to hydroxyechinenone. Arthrospira OCP binds more strongly than Synechocystis OCP to all types of PBs. Synechocystis OCP can strongly bind only its own PB in 0.8 m potassium phosphate. However, if the Synechocystis OCP binds to the PB at very high phosphate concentrations (approximately 1.4 m), it is able to quench the fluorescence of any type of PB, even those isolated from strains that lack the OCP-mediated photoprotective mechanism. Thus, the determining step for the induction of photoprotection is the binding of the OCP to PBs. Our results also indicated that the structure of PBs, at least in vitro, significantly influences OCP binding and the stabilization of OCP-PB complexes. Finally, the fact that the OCP induced large fluorescence quenching even in the two-cylinder core of Synechococcus elongatus  PBs strongly suggested that OCP binds to one of the basal allophycocyanin cylinders.
Poly[[chlorido(1,10-phenanthroline-κ2N,N′)copper(II)]-μ3-1,1,3,3-tetracyano-2-ethoxypropenido-κ3N:N′:N′′]: coordination polymer sheets linked into bilayers by hydrogen bonds
Authors: Setifi Zouaoui , Setifi Fatima , El Ammari Lahcen , El-Ghozzi Malika , Sopková-de Oliveira Santos Jana , Merazig Hocine , Glidewell Christopher
Published: December 2013

In the title compound, [Cu(C9H5N4O)Cl(C12H8N2)]nor [Cu(tcnoet)Cl(phen)]n, where phen is 1,10-phenanthroline and tcnoet is 1,1,3,3-tetracyano-2-ethoxypropenide, the axially elongated (4 + 2) coordination polyhedron around the CuIIcentre contains N atoms from three different tcnoet ligands. The resulting coordination polymer takes the form of sheets which are linked in pairs by a single C—H...N hydrogen bond to form bilayers. The bond lengths provide evidence for significant bond fixation in the phen ligand and extensive electronic delocalization in the tcnoet ligand, where the two –C(CN)2units are rotated, in conrotatory fashion, out of the plane of the central C3O fragment.
Anisotropic permeability in fractured reservoirs from frequency‐dependent seismic Amplitude Versus Angle and Azimuth data
Authors: Ali Aamir , Jakobsen Morten
Published: December 2013

Attempts have previously been made to predict anisotropic permeability in fractured reservoirs from seismic Amplitude Versus Angle and Azimuth data on the basis of a consistent permeability‐stiffness model and the anisotropic Gassmann relations of Brown and Korringa. However, these attempts were not very successful, mainly because the effective stiffness tensor of a fractured porous medium under saturated (drained) conditions is much less sensitive to the aperture of the fractures than the corresponding permeability tensor. We here show that one can obtain information about the fracture aperture as well as the fracture density and orientation (which determines the effective permeability) from frequency‐dependent seismic Amplitude Versus Angle and Azimuth data. Our workflow is based on a unified stiffness‐permeability model, which takes into account seismic attenuation by wave‐induced fluid flow. Synthetic seismic Amplitude Versus Angle and Azimuth data are generated by using a combination of a dynamic effective medium theory with Rüger's approximations for PP reflection coefficients in Horizontally Transversely Isotropic media. A Monte Carlo method is used to perform a Bayesian inversion of these synthetic seismic Amplitude Versus Angle and Azimuth data with respect to the parameters of the fractures. An effective permeability model is then used to construct the corresponding probability density functions for the different components of the effective permeability constants. The results suggest that an improved characterization of fractured reservoirs can indeed be obtained from frequency‐dependent seismic Amplitude Versus Angle and Azimuth data, provided that a dynamic effective medium model is used in the inversion process and a priori information about the fracture length is available.
Political Connections and the Cost of Bank Loans
Authors: HOUSTON JOEL F. , JIANG LIANGLIANG , LIN CHEN , MA YUE
Published: December 2013

This paper analyzes whether the political connections of listed firms in the United States affect the cost and terms of loan contracts. Using a hand‐collected data set of the political connections of S&P 500 companies over the 2003–2008 time period, we find that the cost of bank loans is significantly lower for companies that have board members with political ties. We consider two possible explanations for these findings: a Borrower Channel in which lenders charge lower rates because they recognize that connections enhance the borrower's credit worthiness and a Bank Channel in which banks assign greater value to connected loans to enhance their own relationships with key politicians. After employing a series of tests to distinguish between these two channels, we find strong support for the Borrower Channel but no direct evidence supporting the Bank Channel. Finally, we demonstrate that political connections reduce the likelihood of a capital expenditure restriction or liquidity requirement commanded by banks at the origination of the loan. Taken together, our results suggest that political connections increase the value of U.S. companies and reduce monitoring costs and credit risk faced by banks, which, in turn, reduces the borrower's cost of debt.
Determination of Acetamiprid and IM‐1‐2 in PostMortem Human Blood, Liver, Stomach Contents by HPLC‐DAD
Authors: Yeter Oya , Aydın Adnan
Published: December 2013

An HPLC‐DAD method was developed to detect and quantify a neonicotinoid insecticide acetamiprid (ATP) and its metabolite IM‐1‐2 in autopsy samples of a fatal intoxication case. The postmortem blood and tissue distribution of ATP and IM‐1‐2 was determined for the first time. The method showed acceptable precisions and recoveries with relative standard deviations of <10% for ATP level and 1.38 % for IM‐1‐2. The detection and quantification limits for ATP were 0.015 μg/mL and 0.030 μg/mL for blood and were 0.035 μg/g and 0.050 μg/g for liver samples, respectively. The mean contents of ATP were 0.79 μg/g in the liver, 47.35 μg/g in the stomach contents and 2.7 μg/mL in the blood. IM‐1‐2 content was 17.0 μg/g in the stomach contents. ATP and IM‐1‐2 were not detected in the urine. The presence of ATP and IM‐1‐2 in the samples was confirmed by GC‐MS. The method can be exploited in future forensic casework.
Impact of peer‐led group education on the quality of life in patients with ankylosing spondylitis
Authors: Kaya Taciser , Goksel Karatepe Altinay , Atici Ozturk Pinar , Gunaydin Rezzan
Published: December 2013

Objectives

To determine the effect of peer‐led group education on the quality of life and depression in patients with ankylosing spondylitis (AS).

Methods

Eighty patients with definite AS were allocated randomly to either the education or control group. The education group (n = 40) was subjected to a peer‐led group education program about disease and was given an educational booklet, while the control group (n = 40) was given the educational booklet only. Levels of quality of life and depression were measured at baseline, immediately after education (fourth week) and at 6 months in both groups.

Results

The results are based on 56 (n = 27, education group; n = 29, control group) patients. The level of quality of life and depressive symptoms were not changed except for a deterioration in the social functioning subgroup of Short From (SF)‐36 in both groups. When the groups were compared, there were no significant differences between changes in social functioning scores.

Conclusions

Peer‐led education did not alter quality of life levels and depression scores. However, because of the maintainance of quality of life levels, this type of intervention may be considered as a supplementary intervention to the standard medical care for management of AS.
Clinical courses and predictors of outcomes in patients with monoarthritis: a retrospective study of 171 cases
Authors: Jeong Hyemin , Kim Ah Yeong , Yoon Hyun Jung , Park Eun‐Jung , Hwang Jiwon , Kim Hyungjin , Ahn Joong Kyong , Lee Jaejoon , Koh Eun‐Mi , Cha Hoon‐Suk
Published: December 2013

Objectives

To evaluate the clinical courses and outcomes of patients with monoarthritis and to investigate the predictive factors of clinical outcomes.

Methods

A retrospective analysis was performed of 171 patients with chronic monoarthritis at a single tertiary hospital between January 2001 and January 2011. Baseline characteristics, radiographic findings and the clinical course were reviewed.

Results

The most commonly involved joints were the knees (24.0%), followed by the wrists (22.8%) and ankles (18.7%). A final diagnosis was established in 74 (43.3%) patients. Thirty‐one (18.1%) patients were diagnosed with rheumatoid arthritis (RA), 23 (13.5%) with peripheral spondyloarthritis (SpA), and 19 (11.1%) with Behçet's disease (BD). Among 108 patients who were initially undiagnosed, 85 (78.7%) patients remained with undiagnosed monoarthritis, with relatively shorter symptom durations and requiring less treatment. The initially involved joint was a predictive factor for the final diagnosis: the wrist joint for RA (odds ratio [OR] 11.58, P < 0.001), the ankle joint for SpA (OR 6.19, P < 0.001), and the knee joint for BD (OR 3.43, P = 0.014). Bony erosion at baseline was associated with progression to oligo‐ or polyarthritis (OR 2.88, P = 0.030) and with radiographic progression.

Conclusions

In patients presenting with monoarthritis, a final diagnosis was established in less than half of the patients, and a majority of undiagnosed patients showed benign clinical courses. The initially involved joint and the presence of erosion at baseline were predictors of the final diagnosis and of clinical outcomes.
To read or not to read: decoding Synthetic Phonics
Authors: Davis Andrew
Published: December 2013

In England, current government policy on children's reading is strongly prescriptive, insisting on the delivery of a pure and exclusive form of synthetic phonics, where letter sounds are learned and blended in order to ‘read’ text. A universally imposed phonics ‘check’ is taken by all five year olds and the results are widely reported.

These policies are underpinned by the claim that research has shown systematic synthetic phonics to be the most effective way of teaching children to read. Andrew Davis argues that there is a basic problem with this claim. Whatever it is that empirical researchers take themselves to be doing when they investigate synthetic phonics, they are not investigating a specifiable method of teaching reading. This is for two reasons. First, there are no such things as specifiable methods of teaching. Teaching is a vastly complex human activity involving contextual and reactive practical judgments that are responsive to the myriad contingencies of classroom life. The idea that teachers might proceed by way of prescribed methods rather than practical judgments is simply a fantasy.

Second, teaching children to correlate letter combinations with sounds, and to blend sounds into sequences, is not teaching them to read. Reading is a matter of grasping meaning conveyed by text. While sustained attention to letter‐sound correspondences can be helpful to some novice readers, we should neither assume that it is helpful to all nor confuse mastery of such correspondences with the ability to read.

Davis's challenge to government policy on the teaching of reading, and to the empirical research that supposedly underpins it, is timely, radical and compelling. The zeal with which synthetic phonics is championed by its advocates has been remarkably effective in pushing it to the top of the educational agenda; but we should not mistake zeal for warrant.
Effectiveness of different intracanal irrigation techniques in removing intracanal paste medicaments
Authors: Chou Kenny , George Roy , Walsh Laurence J.
Published: December 2013

This study aimed to compare the effectiveness of different intracanal irrigation techniques in removing intracanal medicaments prior to obturation. A total of 168 single roots were prepared with ProTaper® rotary files and medicament pastes applied (Ledermix®, Odontopaste®, Doxypaste and Pulpdent®), left in for 2 weeks, then removed using filing followed by one of four methods: irrigation with an open‐ended notched irrigation needle (Appli‐Vac) either at the working length or 5 mm from the canal orifice, or the Max‐I‐probe or EndoActivator® at the working length. Following the removal of medicaments, the roots were split into two and the internal surfaces photographed, for digital image analysis of the overall percentage of residual medicament. With the exception of canals irrigated 5 mm apical to the root canal orifice, all four irrigation techniques achieved an average of 95% for removal of Ledermix®, Odontopaste® and Doxypaste. Calcium hydroxide paste was the most difficult medicament to remove, with no difference between irrigation techniques. Up to 27% of the Pulpdent® material remained after irrigation. No irrigation technique could completely remove all traces of medicaments. The position of the irrigational needle and the type of medicament used are key factors, which influence the effectiveness of irrigation in removing medicaments.
Medication Errors Outside Healthcare Facilities: A National Poison Centre Perspective
Authors: Lavon Ophir , Ben‐Zeev Adi , Bentur Yedidia
Published: December 2013

Medication errors (ME) are a major concern to healthcare systems. Most studies evaluated ME occurring in healthcare facilities; only few focused on ME outside them. The objective was to characterise ME occurring outside healthcare facilities. A prospective observational follow‐up study evaluating all ME occurring outside healthcare facilities reported to a national poison information centre during a 5‐month period. For each ME case, a detailed questionnaire was filled and a follow‐up call was made within 7 days. The collected data included demographics, circumstances, type of error and outcome. Of 1381 consecutive ME cases were included; 97.8% involved a single incident and 88.3% one drug. The main characteristics of the ME were as follows: children younger than 6 years old (58.9%), parents responsible for 55.6% of cases, wrong dose 34.5% and different medication 30.1%. Analgesics (27.4%) and antimicrobials (12.2%) were the most common pharmaceuticals. The main reasons for the ME were look‐alike packaging (31.4%) and misunderstood instructions (28%). Most followed up patients (97.1%) were asymptomatic or mildly affected; there was one severe case and no mortality. Most ME occurring outside healthcare facilities are single incidents, involving young children who were administered a wrong dose or medication due to look‐alike packaging or misunderstood instructions with asymptomatic or mild outcome. Improved packaging, labelling and patient education are suggested to reduce ME.
Huntington's Disease (HD): Degeneration of Select Nuclei, Widespread Occurrence of Neuronal Nuclear and Axonal Inclusions in the Brainstem
Authors: Rüb Udo , Hentschel Matthias , Stratmann Katharina , Brunt Ewout , Heinsen Helmut , Seidel Kay , Bouzrou Mohamed , Auburger Georg , Paulson Henry , Vonsattel Jean‐Paul , Lange Herwig , Korf Horst‐Werner , den Dunnen Wilfred
Published: December 2013

Huntington's disease (HD) is a progressive polyglutamine disease that leads to a severe striatal and layer‐specific neuronal loss in the cerebral neo‐and allocortex. As some of the clinical symptoms (eg, oculomotor dysfunctions) suggested a degeneration of select brainstem nuclei, we performed a systematic investigation of the brainstem of eight clinically diagnosed and genetically confirmed HD patients. This post‐mortem investigation revealed a consistent neuronal loss in the substantia nigra, pontine nuclei, reticulotegmental nucleus of the pons, superior and inferior olives, in the area of the excitatory burst neurons for horizontal saccades, raphe interpositus nucleus and vestibular nuclei. Immunoreactive intranuclear neuronal inclusions were present in all degenerated and apparently spared brainstem nuclei and immunoreactive axonal inclusions were observed in all brainstem fiber tracts of the HD patients. Degeneration of brainstem nuclei can account for a number of less well‐understood clinical HD symptoms (ie, cerebellar, oculomotor and vestibular symptoms), while the formation of axonal aggregates may represent a crucial event in the cascades of pathological events leading to neurodegeneration in HD.
The tail wags the dog: possible mechanism for reverse allosteric control of ligand‐activated channels
Authors: Vardy E , Kenakin T
Published: December 2013

In this issue of the British Journal of Pharmacology, a new article by Kozuska et al. discusses the multiple salt bridges in the intracellular domain of the 5HT3A receptor. These interactions increase the overall rigidity of the receptor, stabilize its low conducting state and affect the ligand cooperativity. The authors suggest that the allosteric effects of these regions on the receptor may be involved in a possible ‘reverse’ allosteric modulation of 5HT3 receptors.

Linked Article

This article is a Commentary on Kozuska et al., pp. 1617–1628 volume 171 issue 7. To view this paper visit http://dx.doi.org/10.1111/bph.12536
Investigation of connexin 43 uncoupling and prolongation of the cardiac QRS complex in preclinical and marketed drugs
Authors: Burnham M P , Sharpe P M , Garner C , Hughes R , Pollard C E , Bowes J
Published: December 2013

Background and Purpose

Prolongation of the cardiac QRS complex is linked to increased mortality and may result from drug‐induced inhibition of cardiac sodium channels (hNaV1.5). There has been no systematic evaluation of preclinical and marketed drugs for their additional potential to cause QRS prolongation via gap junction uncoupling.

Experimental Approach

Using the human cardiac gap junction connexin 43 (hCx43), a dye transfer ‘parachute’ assay to determine IC50 values for compound ranking was validated with compounds known to uncouple gap junctions. Uncoupling activity (and hNaV1.5 inhibition by automated patch clamp) was determined in a set of marketed drugs and preclinical candidate drugs, each with information regarding propensity to prolong QRS.

Key Results

The potency of known gap junction uncouplers to uncouple hCx43 was ranked (according to IC50) as phorbol ester>digoxin>meclofenamic acid>carbenoxolone>heptanol. Among the drugs associated with QRS prolongation, 29% were found to uncouple hCx43 (IC50 < 50 μM), whereas no uncoupling activity was observed in drugs not associated with QRS prolongation. In preclinical candidate drugs, hCx43 and hNaV1.5 IC50 values were similar (within threefold). No consistent margin over preclinical Cmax (free) was apparent for QRS prolongation associated with Cx43 inhibition. However, instances were found of QRS prolonging compounds that uncoupled hCx43 with significantly less activity at hNaV1.5.

Conclusion and Implications

These results demonstrate that off‐target uncoupling activity is apparent in drug and drug‐like molecules. Although the full ramifications of Cx inhibition remain to be established, screening for hCx43 off‐target activity could reduce the likelihood of developing candidate drugs with a risk of causing QRS prolongation.
Antihyperalgesic effects of imidazoline I2 receptor ligands in rat models of inflammatory and neuropathic pain
Authors: Li Jun‐Xu , Thorn David A , Qiu Yanyan , Peng Bi‐Wen , Zhang Yanan
Published: December 2013

Background and Purpose

A new imidazoline I2 receptor ligand, CR4056, is effective for chronic inflammatory pain and diabetic neuropathy. However, it is unclear whether other I2 receptor ligands have similar effects and whether antinociceptive tolerance develops with repeated treatment.

Experimental Approach

The Von Frey filament test was used to measure mechanical hyperalgesia and the plantar test to measure thermal hyperalgesia in rats injected with complete Freund's adjuvant (CFA) treatment or had undergone surgery to induce chronic constriction injury (CCI), models of inflammatory pain and peripheral neuropathic pain respectively. The effects of morphine and I2 receptor ligands, 2‐BFI, BU224, tracizoline and CR4056, 3.2–32 mg·kg−1, i.p., on hyperalgesia or affective pain (as measured by a place escape/avoidance paradigm) were studied in separate experiments.

Key Results

Morphine and the I2 receptor ligands (2‐BFI, BU224 and tracizoline) all dose‐dependently attenuated mechanical and thermal hyperalgesia in CFA‐treated rats. The anti‐hyperalgesic effects of 2‐BFI in CFA‐treated and CCI rats were attenuated by the I2 receptor antagonist idazoxan. The combination of 2‐BFI and morphine produced additive effects against mechanical hyperalgesia in CFA‐treated rats. Repeated treatment (daily for 7–9 days) with 2‐BFI or CR4056 did not produce antinociceptive tolerance in CFA‐treated or CCI rats. Morphine and the I2 receptor ligands (2‐BFI, BU224 and CR4056) were all effective at attenuating place escape/avoidance behaviour in CFA‐treated rats.

Conclusions and Implications

Imidazoline I2 receptor ligands have antihyperalgesic effects in rat models of inflammatory and neuropathic pain and may represent a new class of pharmacotherapeutics for the management of chronic pain.
Bortezomib therapy‐related lung disease in Japanese patients with multiple myeloma: Incidence, mortality and clinical characterization
Authors: Yoshizawa Kazutake , Mukai Harumi Y. , Miyazawa Michiko , Miyao Makiko , Ogawa Yoshimasa , Ohyashiki Kazuma , Katoh Takao , Kusumoto Masahiko , Gemma Akihiko , Sakai Fumikazu , Sugiyama Yukihiko , Hatake Kiyohiko , Fukuda Yuh , Kudoh Shoji
Published: December 2013

Because of the potentially high mortality rate (6.5%) associated with bortezomib‐induced lung disease (BILD) in Japanese patients with relapsed or refractory multiple myeloma, we evaluated the incidence, mortality and clinical features of BILD in a Japanese population. This study was conducted under the Risk Minimization Action Plan (RMAP), which was collaboratively developed by the pharmaceutical industry and public health authority. The RMAP consisted of an intensive dissemination of risk information and a recommended countermeasure to health‐care professionals. All patients treated with bortezomib were consecutively registered in the study within 1 year and monitored for emerging BILD. Of the 1010 patients registered, 45 (4.5%) developed BILD, 5 (0.50%) of whom had fatal cases. The median time to BILD onset from the first bortezomib dose was 14.5 days, and most of the patients responded well to corticosteroid therapy. A retrospective review by the Lung Injury Medical Expert Panel revealed that the types with capillary leak syndrome and hypoxia without infiltrative shadows were uniquely and frequently observed in patients with BILD compared with those with conditions associated with other molecular‐targeted anticancer drugs. The incidence rate of BILD in Japan remains high compared with that reported in other countries, but the incidence and mortality rates are lower than expected before the introduction of bortezomib in Japan. This study describes the radiographic pattern and clinical characterization of BILD in the Japanese population. The RMAP seemed clinically effective in minimizing the BILD risk among our Japanese population.