bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of proteasomal degradation rescues a pathogenic variant of mitochondrial Respiratory chain assembly 1 factor
Authors: Mohanraj Karthik , Wasilewski Michal , Benincá Cristiane , Cysewski Dominik , Poznanski Jarosław , Sakowska Paulina , Deckers Markus , Dennerlein Sven , Fernandez-Vizarra Erika , Rehling Peter , Dadlez Michal , Zeviani Massimo , Chacinska Agnieszka
Published: July 2018

Nuclear and mitochondrial genome mutations lead to various mitochondrial diseases, many of which affect the mitochondrial respiratory chain. The proteome of the intermembrane space (IMS) of mitochondria consists of several important assembly factors that participate in the biogenesis of mitochondrial respiratory chain complexes. The present study comprehensively analyzed a recently identified IMS protein, RESpiratory chain Assembly 1 (RESA1) factor, or cytochrome c oxidase assembly factor 7 (COA7) that is associated with a rare form of mitochondrial leukoencephalopathy and complex IV deficiency. We found that RESA1 requires the mitochondrial IMS import and assembly (MIA) pathway for efficient accumulation in the IMS. We also found that pathogenic mutant versions of RESA1 are imported slower than the wild type protein, and mislocalized mutant proteins are degraded in the cytosol by proteasome machinery. Interestingly, proteasome inhibition rescued both the mitochondrial localization of mutant RESA1 and complex IV activity in patient-derived fibroblasts. We propose that proteasome inhibition is a novel therapeutic approach for a broad range of mitochondrial pathologies that are associated with the excessive degradation of mitochondrial proteins that is caused by genetic mutations or biogenesis defects.
Guanabenz treatment improves Oculopharyngeal muscular dystrophy phenotype
Authors: Malerba Alberto , Roth Fanny , Harish Pradeep , Dhiab Jamila , Lu-Nguyen Ngoc , Cappellari Ornella , Jarmin Susan , Mahoudeau Alexandrine , Ythier Victor , Lainé Jeanne , Negroni Elisa , Abgueguen Emmanuelle , Simonelig Martine , Guedat Philippe , Mouly Vincent , Butler-Browne Gillian , Voisset Cécile , Dickson George , Trollet Capucine
Published: July 2018

Oculopharyngeal muscular dystrophy (OPMD) is a rare late onset genetic disease affecting most profoundly eyelid and pharyngeal muscles, leading respectively to ptosis and dysphagia, and proximal limb muscles at later stages. A short abnormal (GCG) triplet expansion in the polyA– binding protein nuclear 1 (PABPN1) gene leads to PABPN1-containing aggregates in the muscles of OPMD patients. It is commonly accepted that aggregates themselves, the aggregation process and/or the early oligomeric species of PABPN1 are toxic in OPMD. Decreasing PABPN1 aggregate load in animal models of OPMD ameliorates the muscle phenotype. In order to identify a potential therapeutic molecule that would prevent and reduce aggregates, we tested guanabenz acetate (GA), an FDA-approved antihypertensive drug, in OPMD cells as well as in the A17 OPMD mouse model. We demonstrate that treating mice with GA reduces the size and number of nuclear aggregates, improves muscle force, protects myofibres from the pathology-derived turnover and decreases fibrosis. GA is known to target various cell processes, including the unfolded protein response (UPR), which acts to attenuate endoplasmic reticulum (ER) stress. Here we used a cellular model of OPMD to demonstrate that GA increases both the phosphorylation of the eukaryotic translation initiator factor 2α subunit (eIF2α) and the splicing of Xbp1, key components of the UPR. Altogether these data suggest that modulation of protein folding regulation can be beneficial for OPMD and support the further development of guanabenz or its derivatives for treatment of OPMD in humans.

Significance Statement

Oculopharyngeal muscular dystrophy (OPMD) is a rare late onset incurable genetic disease characterized by the formation of insoluble aggregates in skeletal muscles. It has been shown that the reduction of aggregates correlates with an improvement of the disease. Here we used a mouse model of OPMD to show that Guanabenz acetate, the active constituent of a marketed but recently discontinued drug for hypertension, decreases the number and the size of aggregates after systemic delivery and improves many aspects of the disease. We also describe experimental evidences explaining the mechanism behind the efficacy of such compound for OPMD.
Improving the diagnostic yield of exome-sequencing, by predicting gene-phenotype associations using large-scale gene expression analysis
Authors: Deelen Patrick , Dam Sipko van , Herkert Johanna C. , Karjalainen Juha M. , Brugge Harm , Abbott Kristin M. , van Diemen Cleo C. , der Zwaag Paul A. van , Gerkes Erica H. , Folkertsma Pytrik , Gillett Tessa , der Velde K. Joeri van , Kanninga Roan , den Akker Peter C. van , Jan Sabrina Z. , Hoorntje Edgar T. , te Rijdt Wouter P. , Vos Yvonne J. , Jongbloed Jan D.H. , van Ravenswaaij-Arts Conny M.A. , Sinke Richard , Sikkema-Raddatz Birgit , Kerstjens-Frederikse Wilhelmina S. , Swertz Morris A. , Franke Lude
Published: July 2018

Clinical interpretation of exome and genome sequencing data remains challenging and time consuming, with many variants with unknown effects found in genes with unknown functions. Automated prioritization of these variants can improve the speed of current diagnostics and identify previously unknown disease genes. Here, we used 31,499 RNA-seq samples to predict the phenotypic consequences of variants in genes. We developed GeneNetwork Assisted Diagnostic Optimization (GADO), a tool that uses these predictions in combination with a patient’s phenotype, denoted using HPO terms, to prioritize identified variants and ease interpretation. GADO is unique because it does not rely on existing knowledge of a gene and can therefore prioritize variants missed by tools that rely on existing annotations or pathway membership. In a validation trial on patients with a known genetic diagnosis, GADO prioritized the causative gene within the top 3 for 41% of the cases. Applying GADO to a cohort of 38 patients without genetic diagnosis, yielded new candidate genes for seven cases. Our results highlight the added value of GADO (www.genenetwork.nl) for increasing diagnostic yield and for implicating previously unknown disease-causing genes.
The Site Frequency Spectrum under Finite and Time-Varying Mutation Rates
Authors: Melfi Andrew , Viswanath Divakar
Published: July 2018

The diversity in genomes is due to the accumulation of mutations and the site frequency spectrum (SFS) is a popular statistic for summarizing genomic data. The current coalescent algorithm for calculating the SFS for a given demography assumes theμ→ 0 limit, whereμis the mutation probability (or rate) per base pair per generation. The algorithm is applicable whenμN,Nbeing the haploid population size, is negligible. We derive a coalescent based algorithm for calculating the SFS that allows the mutation rateμ(t) as well as the population sizeN(t) to vary arbitrarily as a function of time. That algorithm shows that the probability of two mutations in the genealogy becomes noticeable already forμ= 10-8for samples ofn= 105haploid human genomes and increases rapidly withμ. Our algorithm calculates the SFS under the assumption of a single mutation in the genealogy, and the part of the SFS due to a single mutation depends only mildly on the finiteness ofμ. However, the dependence of the SFS on variation inμcan be substantial for evenn= 100 samples. In addition, increasing and decreasing mutation rates alter the SFS in different ways and to different extents.
Multiscale analysis of 3D nuclear morphology reveals new insights into growth plate organization in mice
Authors: Rubin Sarah , Stern Tomer , Villoutreix Paul , Stegmaier Johannes , Addadi Yoseph , Zelzer Elazar
Published: July 2018

The shape of the nucleus is tightly associated with cell morphology, the mechanical environment, and differentiation and transcriptional states. Yet, imaging of nuclei in three dimensions while preserving the spatial context of the tissue has been highly challenging. Here, using the embryonic tibial growth plate as a model for cell differentiation, we study nuclear morphology by imaging cleared samples by light-sheet fluorescence microscopy. Next, we quickly segmented tens of thousands of nuclei using several open-source tools including machine learning. Finally, segmented nuclei underwent morphometric analysis and 3D spatial reconstruction using newly designed algorithms. Our method revealed differences in nuclear morphology between chondrocytes at different differentiation stages. Additionally, we identified different morphological patterns in opposing growth plates, such as gradients of volume and surface area, as well as features characteristic of specific growth plate zones, such as sphericity and orientation. Altogether, this work supports a link between nuclear morphology and cell differentiation. Moreover, it demonstrates the suitability of our approach for studying the relationships between nuclear morphology and organ development.

Author summary

There has been a growing interest in the relationship between nuclear morphology and its regulation of gene expression. However, to study global patterns of nuclear morphology within a tissue we must address the problem of acquiring and analyzing multiscale data, ranging from the tissue level through to subcellular resolution. We have established a new pipeline that enables acquisition and segmentation of hundreds of thousands of nuclei at a resolution that allows quantitative analysis. Moreover we have developed new algorithms that allow superimposing morphological aspects of hundreds of thousands of nuclei onto a visual representation of the entire tissue, allowing us to study nuclear morphology at an organ level. Using mouse growth plates as a model for the relationship between nuclear morphology and tissue differentiation, we show that nuclei change different aspects of their morphology during chondrocyte differentiation. Growth plates are usually described generically in the literature, suggesting they lack unique characteristics. We challenge this dogma by showing that morphological features such as volume distribute differently in opposing growth plates. Altogether, this work highlights the possible role of nuclear shape in the regulation of cell differentiation and demonstrates that our approach enables the study of nuclear morphology patterns within a tissue.
Vertical transmission of Zika virus in orally-infected Aedes aegypti produces infectious adult progeny
Authors: Comeau Genevieve , Zinna Robert A. , Scott Taylor , Ernst Kacey , Walker Kathleen , Carrière Yves , Riehle Michael A.
Published: July 2018

Vertical transmission, or pathogen transfer from mother to offspring, can facilitate persistence of emerging arboviruses, such as Zika virus (ZIKV), in mosquito populations. Understanding vertical transmission and the different environmental and temporal conditions that affect it is important to assess whether new outbreaks could occur without reintroduction of the virus. To determine the rate of vertical transmission for ZIKV, Aedes aegypti females were fed on ZIKV infected blood, maintained under three temperature conditions (27°C, 30°C, and 33°C), and allowed to oviposit three times. Progeny were tested for virus presence at 3, 7, and 14 days after adult emergence. The overall vertical transmission rate was 6.5% (3.9 - 9.9). Vertical transmission was observed across all maternal temperature conditions and was detected in adult progeny as young as 3 days and as late as 14 days post-emergence. In total, 3.4% (1.6 - 6.2) of adult progeny produced saliva with detectable ZIKV, indicating their capacity to transmit ZIKV to humans. To our knowledge, this is the first evidence that vertical transmission occurs from orally-infected female Aedes aegypti to their adult progeny at a range of temperatures, and proof that Zika virus can persist in the saliva of those progeny throughout their lifetimes. These results suggest that the virus may be maintained in Ae. aegypti populations without a vertebrate host, allowing for human infections to occur without consistent re-introductions of ZIKV.

Author Summary

In 2015, Zika virus spread to over 50 countries. However, it is not known whether the virus persisted in the outbreak areas or became locally extinct. One way mosquito-borne viruses, like Zika, could become established is by transferring directly between mosquito generations rather than circulating between mosquitoes and humans. This is known as vertical transmission, and happens when the virus infects the developing eggs of infected maternal mosquitoes. As with other mosquito-borne diseases, like dengue, in order to infect humans the virus must be present in the saliva of infected mosquito progeny during blood feeding. We found vertical transmission occurred throughout the infected mother’s reproductive lifetime and across a range of temperature conditions. Vertically infected progeny had Zika virus in their saliva as early as three days after adult emergence, implying that they could infect a person even during their first bloodmeal. Importantly, this work indicates that Zika virus could establish itself in the mosquito population even when human to mosquito transmission is not actively occurring.
High-density linkage map and QTLs for growth in snapper (Chrysophrys auratus)
Authors: Ashton David T. , Ritchie Peter A. , Wellenreuther Maren
Published: July 2018

Characterizing the genetic variation underlying phenotypic traits is a central objective in biological research. This research has been hampered in the past by the limited genomic resources available for most non-model species. However, recent advances in sequencing technology and related genotyping methods are rapidly changing this. Here we report the use of genome-wide SNP data from the ecologically and commercially important marine fish species Chrysophrys auratus (snapper) to 1) construct the first linkage map for this species, 2) scan for growth QTLs, and 3) search for candidate genes in the surrounding QTL regions. The newly constructed linkage map contained ~11K SNP markers and is the densest map to date in the fish family Sparidae. Comparisons with available genome scaffolds indicated that overall marker placement was strongly correlated between the scaffolds and linkage map (R = 0.7), but at fine scales (< 5 cM) there were some precision limitations. Of the 24 linkage groups, which reflect the 24 chromosomes of this species, three were found to contain QTLs with genome-wide significance for growth-related traits. A scan for 13 known candidate growth genes located the genes for growth hormone, parvalbumin, and myogenin within 13.2, 2.6, and 5.0 cM of these genome-wide significant QTLs, respectively. The linkage map and QTLs found in this study will advance the investigation of genome structure and selective breeding in snapper.
Transcription promotes the interaction of the FAcilitates Chromatin Transactions (FACT) complex with nucleosomes inS. cerevisiae
Authors: Martin Benjamin J.E. , Chruscicki Adam T. , Howe LeAnn J.
Published: July 2018

The FACT (FAcilitates Chromatin Transactions) complex is enriched on highly expressed genes, where it facilitates transcription while maintaining chromatin structure. How it is targeted to these regions is unknown. In vitro, FACT binds destabilized nucleosomes, supporting the hypothesis that FACT is targeted to transcribed chromatin through recognition of RNA polymerase-disrupted nucleosomes. In this study, we used high resolution analysis of FACT occupancy inS. cerevisiaeto test this hypothesis. We demonstrate that FACT interacts with unstable nucleosomesin vivoand its interaction with chromatin is dependent on transcription by any of the three RNA polymerases. Deep sequencing of micrococcal nuclease-resistant fragments shows that FACT-bound nucleosomes exhibit differences in micrococcal nuclease sensitivity compared to bulk chromatin, consistent with a modified nucleosome structure being the preferred ligand for this complex. While the presence of altered nucleosomes associated with FACT can also be explained by the known ability of this complex to modulate nucleosome structure, transcription inhibition alleviates this effect indicating that it is not due to FACT interaction alone. Collectively these results suggest that FACT is targeted to transcribed genes through preferential interaction with RNA polymerase disrupted nucleosomes.
Glucose intake hampers PKA-regulated HSP90 chaperone activity
Authors: Chen Yu-Chen , Jiang Pei-Heng , Chen Hsuan-Ming , Chen Chang-Han , Wang Yi-Ting , Chen Yu-Ju , Yu Chia-Jung , Teng Shu-Chun
Published: July 2018

Aging is an intricate phenomenon associated with the gradual loss of physiological functions, and both nutrient sensing and proteostasis control lifespan. Although multiple approaches have facilitated the identification of candidate genes that govern longevity, the molecular mechanisms that link aging pathways are still elusive. Here, we conducted a quantitative mass spectrometry screen and identified all phosphorylation/dephosphorylation sites on yeast proteins that significantly responded to calorie restriction, a well-established approach to extend lifespan. Functional screening of 135 potential regulators uncovered that Ids2 is activated by PP2C under CR and inactivated by PKA under glucose intake.ids2Δorids2phosphomimetic cells displayed heat sensitivity and lifespan shortening. Ids2 serves as a co-chaperone to form a complex with Hsc82 or the redundant Hsp82, and phosphorylation of Ids2 impedes its association with chaperone HSP90. Thus, PP2C and PKA orchestrate glucose sensing and protein folding to enable cells to maintain protein quality for sustained longevity.
Bed nucleus of the stria terminalis regulates fear to unpredictable threat signals
Authors: Goode Travis D. , Ressler Reed L. , Acca Gillian M. , Miles Olivia W. , Maren Stephen
Published: July 2018

The bed nucleus of the stria terminalis (BNST) has been implicated in conditioned fear and anxiety, but the specific factors that engage the BNST in defensive behaviors are unclear. Here we examined whether the BNST mediates freezing to conditioned stimuli (CSs) that poorly predict the onset of aversive unconditioned stimuli (USs) in rats. Reversible inactivation of the BNST selectively reduced freezing to CSs that poorly signaled US onset (e.g., a backward CS that followed the US), but did not eliminate freezing to forward CSs even when they predicted USs of variable intensity. Additionally, backward (but not forward) CSs selectively increased Fos in the ventral BNST and in BNST-projecting neurons in the infralimbic region of the medial prefrontal cortex (mPFC), but not in the hippocampus or amygdala. These data reveal that BNST circuits regulate fear to unpredictable threats, which may be critical to the etiology and expression of anxiety.

IMPACT STATEMENT

The bed nucleus of the stria terminalis (BNST) is required for the expression of defensive behavior to unpredictable threats, a function that may be central to pathological anxiety.
RNA polymerase mapping in plants identifies enhancers enriched in causal variants
Authors: Lozano Roberto , Booth Gregory T. , Omar Bilan Yonis , Li Bo , Buckler Edward S. , Lis John T. , Jannink Jean-Luc , del Carpio Dunia Pino
Published: July 2018

Promoter-proximal pausing and divergent transcription at promoters and enhancers, which are prominent features in animals, have been reported to be absent in plants based on a study of Arabidopsis thaliana. Here, our PRO-Seq analysis in cassava (Manihot esculenta) identified peaks of transcriptionally-engaged RNA polymerase II (Pol2) at both 5’ and 3’ ends of genes, consistent with paused or slowly-moving Pol2, and divergent transcription at potential intragenic enhancers. A full genome search for bi-directional transcription using an algorithm for enhancer detection developed in mammals (dREG) identified many enhancer candidates. These sites show distinct patterns of methylation and nucleotide variation based on genomic evolutionary rate profiling characteristic of active enhancers. Maize GRO-Seq data showed RNA polymerase occupancy at promoters and enhancers consistent with cassava but not Arabidopsis. Furthermore, putative enhancers in maize identified by dREG significantly overlapped with sites previously identified on the basis of open chromatin, histone marks, and methylation. We show that SNPs within these divergently transcribed intergenic regions predict significantly more variation in fitness and root composition than SNPs in chromosomal segments randomly ascertained from the same intergenic distribution, suggesting a functional importance of these sites on cassava. The findings shed new light on plant transcription regulation and its impact on development and plasticity.
Deregulation of the G1/S-phase transition is the proximal cause of mortality in old yeast mother cells
Authors: Neurohr Gabriel E. , Terry Rachel L. , Sandikci Arzu , Zou Ke , Li Hao , Amon Angelika
Published: July 2018

Budding yeast cells produce a finite number of daughter cells before they die. Why old yeast cells stop dividing and die is unclear. We found that age-induced accumulation of the G1/S-phase inhibitor Whi5 and defects in G1/S cyclin transcription cause cell cycle delays and genomic instability that result in cell death. We further identified extrachromosomal rDNA (ribosomal DNA) circles (ERCs) to cause the G1/S cyclin expression defect in old cells. Spontaneous segregation of Whi5 and ERCs into daughter cells rejuvenates old mothers, but daughters that inherit these aging factors die rapidly. Our results identify deregulation of the G1/S-phase transition as the proximal cause of age-induced proliferation decline and cell death in budding yeast.
Synthesis and crystal structure of an M
4
L
6 tetrahedral cage with outward-facing pockets from a substituted pyrazolyl–pyridine ligand
Authors: Al Rasbi Nawal K. , Ward Michael D.
Published: July 2018

The self-assembly of metal–polydentate ligands to give supramolecular tetrahedral complexes is of considerable current interest. A new ligand, 4-benzyl-2-[1-(2-{[3-(4-benzylpyridin-2-yl)-1H-pyrazol-1-yl]methyl}benzyl)-1H-pyrazol-3-yl]pyridine (L), with chelating pyrazolyl–pyridine units substituted on the 4-position of the pyridyl ring with benzyl units, has been synthesized and fully characterized. The self-assembly of L with cobalt(II) gave rise to a tetrahedral cage (hexakis{μ-4-benzyl-2-[1-(2-{[3-(4-benzylpyridin-2-yl)-1H-pyrazol-1-yl]methyl}benzyl)-1H-pyrazol-3-yl]pyridine}perchloratotetracobalt(II) octakis(perchlorate) acetonitrile undecasolvate, [Co4(ClO4)(C38H32N6)6](ClO4)7·11CH3CN) with approximate T symmetry. The X-ray crystal structure of the cage, i.e. [Co4
L
6\subsetClO4](ClO4)7, shows that the substituted benzyl groups are oriented away from the centres of their respective ligands towards the CoII vertices, making small outward-facing pockets from three benzyl rings at the corners of the tetrahedron.
Crystal structures of 2-bromo-1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane and 2-bromo-1,1,1,3,3,3-hexaisopropyl-2-(triisopropylsilyl)trisilane
Authors: Gulotty Eva M. , Staples Richard J. , Biros Shannon M. , Gaspar Peter P. , Rath Nigam P. , Winchester William R.
Published: July 2018

The synthesis and crystal structures of two tris(trialkylsilyl)silyl bromide compounds, C9H27BrSi4 (I, HypSiBr) and C27H63BrSi4 (II, TipSiBr), are described. Compound I was prepared in 85% yield by free-radical bromination of 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane using bromobutane and 2,2′-azobis(2-methylpropionitrile) as a radical initiator at 333 K. The molecule possesses threefold rotational symmetry, with the central Si atom and the Br atom being located on the threefold rotation axis. The Si—Br bond distance is 2.2990 (12) Å and the Si—Si bond lengths are 2.3477 (8) Å. The Br—Si—Si bond angles are 104.83 (3)° and the Si—Si—Si bond angles are 113.69 (2)°, reflecting the steric hindrance inherent in the three trimethylsilyl groups attached to the central Si atom. Compound II was prepared in 55% yield by free-radical bromination of 1,1,1,3,3,3-hexaisopropyl-2-(triisopropylsilyl)trisilane using N-bromosuccinimide and 2,2′-azobis(2-methylpropionitrile) as a radical initiator at 353 K. Here the Si—Br bond length is 2.3185 (7) Å and the Si—Si bond lengths range from 2.443 (1) to 2.4628 (9) Å. The Br—Si—Si bond angles range from 98.44 (3) to 103.77 (3)°, indicating steric hindrance between the three triisopropylsilyl groups.
The crystal structure ofProteus vulgaristryptophan indole-lyase complexed with oxindolyl-L-alanine: implications for the reaction mechanism
Authors: Phillips Robert S. , Buisman Adriaan A. , Choi Sarah , Hussaini Anusha , Wood Zachary A.
Published: July 2018

Tryptophan indole-lyase (TIL) is a bacterial enzyme which catalyzes the reversible formation of indole and ammonium pyruvate from L-tryptophan. Oxindolyl-L-alanine (OIA) is an inhibitor of TIL, with aKivalue of about 5 µM. The crystal structure of the complex ofProteus vulgarisTIL with OIA has now been determined at 2.1 Å resolution. The ligand forms a closed quinonoid complex with the pyridoxal 5′-phosphate (PLP) cofactor. The small domain rotates about 10° to close the active site, bringing His458 into position to donate a hydrogen bond to Asp133, which also accepts a hydrogen bond from the heterocyclic NH of the inhibitor. This brings Phe37 and Phe459 into van der Waals contact with the aromatic ring of OIA. Mutation of the homologous Phe464 inEscherichia coliTIL to Ala results in a 500-fold decrease inkcat/Kmfor L-tryptophan, with less effect on the reaction of other nonphysiological β-elimination substrates. Stopped-flow kinetic experiments of F464A TIL show that the mutation has no effect on the formation of quinonoid intermediates. An aminoacrylate intermediate is observed in the reaction of F464A TIL withS-ethyl-L-cysteine and benzimidazole. A model of the L-tryptophan quinonoid complex with PLP in the active site ofP. vulgarisTIL shows that there would be a severe clash of Phe459 (∼1.5 Å apart) and Phe37 (∼2 Å apart) with the benzene ring of the substrate. It is proposed that this creates distortion of the substrate aromatic ring out of plane and moves the substrate upwards on the reaction coordinate towards the transition state, thus reducing the activation energy and accelerating the enzymatic reaction.
Evaluation of models determined by neutron diffraction and proposed improvements to their validation and deposition
Authors: Liebschner Dorothee , Afonine Pavel V. , Moriarty Nigel W. , Langan Paul , Adams Paul D.
Published: July 2018

The Protein Data Bank (PDB) contains a growing number of models that have been determined using neutron diffraction or a hybrid method that combines X-ray and neutron diffraction. The advantage of neutron diffraction experiments is that the positions of all atoms can be determined, including H atoms, which are hardly detectable by X-ray diffraction. This allows the determination of protonation states and the assignment of H atoms to water molecules. Because neutrons are scattered differently by hydrogen and its isotope deuterium, neutron diffraction in combination with H/D exchange can provide information on accessibility, dynamics and chemical lability. In this study, the deposited data, models and model-to-data fit for all PDB entries that used neutron diffraction as the source of experimental data have been analysed. In many cases, the reported R
work and R
free values were not reproducible. In such cases, the model and data files were analysed to identify the reasons for this mismatch. The issues responsible for the discrepancies are summarized and explained. The analysis unveiled limitations to the annotation, deposition and validation of models and data, and a lack of community-wide accepted standards for the description of neutron models and data, as well as deficiencies in current model refinement tools. Most of the issues identified concern the handling of H atoms. Since the primary use of neutron macromolecular crystallography is to locate and directly visualize H atoms, it is important to address these issues, so that the deposited neutron models allow the retrieval of the maximum amount of information with the smallest effort of manual intervention. A path forward to improving the annotation, validation and deposition of neutron models and hybrid X-ray and neutron models is suggested.
Impact of disputed tax litigation risk on firm performance: evidence from India
Authors: Dash Saumya Ranjan , Raithatha Mehul
Published: July 2018

Purpose

The purpose of this study is to investigate the impact of disputed tax litigation risk on firm performance and stock return behavior using a sample of Indian listed firms.

Design/methodology/approach

The authors use disputed tax liability, reported as a contingent liability by the listed firms, as a proxy for the disputed tax litigation risk. To examine the impact of disputed tax litigation risk on firm performance (measured by accounting and market-based measures), the empirical approach used in this study focusses on the panel estimation technique. A portfolio-based approach using alternative asset pricing models examines the cross-sectional return variation because of the influence of disputed tax litigation risk.

Findings

The results of this study show a negative relationship between firm performance measures and disputed tax litigation risk. Cross-sectional test results reveal that higher disputed tax litigation risk is associated with higher expected returns.

Research limitations/implications

This study focusses on disputed tax reported under the heading of contingent liability as a proxy for litigation risk. The study will help investors and portfolio managers to consider disputed tax litigation risk as an important parameter in the evaluation of firm performance. This study will also help regulators to get feedback on tax related policies and improve the dispute resolution process.

Originality/value

This study adds to the existing literature on the relationship between litigation risk and firm performance. In the context of emerging market, this study is the first-of-its-kind study, which focusses on disputed tax as a litigation risk proxy and examines its possible impact on firm performance and stock return behavior.
The determinants of voluntary strategy disclosure: an international comparison
Authors: Morris Richard D. , Tronnes Per Christen
Published: July 2018

Purpose

The purpose of this paper is to examine the roles of country-level characteristics versus firm-level characteristics in explaining variations in firms’ voluntary strategy disclosures.

Design/methodology/approach

Strategy disclosure in annual reports is measured using an index of 40 items derived from the strategy literature. The sample is 204 large companies from 12 Asian and European countries in 2005. The disclosure index is subdivided into four underlying latent constructs using principal components analysis. The authors then use OLS regression to test whether total disclosure score, and the latent constructs are associated with country-level characteristics and firm-level characteristics.

Findings

The authors find that total strategy disclosures are more prevalent in stakeholder-oriented countries, in countries with greater levels of financial transparency, but are less prevalent in countries with a culture of secrecy, and strategy disclosures are more likely to occur in companies with greater economic incentives to disclose, with a Big 4 auditor or which are listed in New York. These findings also occur but not as consistently with the four latent constructs.

Research limitations/implications

The sample used in this paper comprises large public companies, so the findings may not be generalisable to all companies. Nevertheless, the findings demonstrate that both country- and firm-level variables matter in explaining voluntary strategy disclosure.

Practical implications

The IASB released an IFRS Practice Statement in 2010, which recommends, but does not require, disclosure of information about corporate strategy in Management Commentary statements. The findings of this paper may help inform the issue of whether regulators should make strategy disclosures mandatory.

Originality/value

The paper contains the first detailed examination of the roles of country-level characteristics versus firm-level characteristics in explaining variations in corporate voluntary strategy disclosures.
Web-based system for Japanese local political documents
Authors: Ototake Hokuto , Sakaji Hiroki , Takamaru Keiichi , Kobayashi Akio , Uchida Yuzu , Kimura Yasutomo
Published: July 2018

Purpose

This paper aims to propose a Web-based system for visualizing local politics in Japan. Although many local governments in Japan provide public access to political documents, researchers and scientists cannot take full advantage of them because they consist only of raw text. Therefore, there is a need for these to be converted into panel data and to visualize differences by region or over time. For ordinary citizens, visualizing differences between the topics discussed by assembly members can be useful in assessing their characteristics. The proposed system aims to provide a complete solution that meets all of these requirements.

Design/methodology/approach

The system has five main functions: full-text search for political documents, showing keywords in context, map and time-series visualization, cross-tabulation and political keyword extraction. Although three existing systems offer some of these functions, the proposed system integrates all the five necessary functions and provides a complete solution that meets all of the requirements.

Findings

The proposed system is demonstrated to be a complete solution for the requirements based on the comparisons with the existing systems and use cases.

Originality/value

The proposed system, which integrates all the five necessary functions and even adds a new cross-tabulation function, meets all the requirements and is a complete solution for researchers, scientists and ordinary citizens.
Is there room for another hedonic model?
Authors: Cajias Marcelo
Published: July 2018

Purpose

This paper aims to explore the in-sample explanatory and out-of-sample forecasting accuracy of the generalized additive model for location, scale and shape (GAMLSS) model in contrast to the GAM method in Munich’s residential market.

Design/methodology/approach

The paper explores the in-sample explanatory results via comparison of coefficients and a graphical analysis of non-linear effects. The out-of-sample forecasting accuracy focusses on 50 loops of three models excluding 10 per cent of the observations randomly. Afterwards, it obtains the predicted functional forms and predicts the remaining 10 per cent. The forecasting performance is measured via error variance, root mean squared error, mean absolute error and the mean percentage error.

Findings

The results show that the complexity of asking rents in Munich is more accurately captured by the GAMLSS approach than the GAM as shown by an outperformance in the in-sample explanatory accuracy. The results further show that the theoretical and empirical complexities do pay off in view of the increased out-of-sample forecasting power of the GAMLSS approach.

Research limitations/implications

The computational requirements necessary to estimate GAMLSS models in terms of number of cores and RAM are high and might constitute one of the limiting factors for (institutional) researchers. Moreover, large and detailed knowledge on statistical inference and programming is necessary.

Practical implications

The usage of the GAMLSS approach would lead policymakers to better understand the local factors affecting rents. Institutional researchers, instead, would clearly aim at calibrating the forecasting accuracy of the model to better forecast rents in investment strategies. Finally, future researchers are encouraged to exploit the large potential of the GAMLSS framework and its modelling flexibility.

Originality/value

The GAMLSS approach is widely recognised and used by international institutions such as the World Health Organisation, the International Monetary Fund and the European Commission. This is the first study to the best of the author’s knowledge to assess the properties of the GAMLSS approach in applied real estate research from a statistical asymptotic perspective by using a unique data basis with more than 38,000 observations.
Auditor choice as a commitment device
Authors: Noda Akihiro
Published: July 2018

Purpose

This study aims to examine how firms choose an auditor in the presence of bilateral information asymmetry between insiders and outsiders regarding firms’ economic performance.

Design/methodology/approach

This study presents a one-period reporting bias game with a firm’s risk-neutral manager and investors in the capital market, in which a manager with private information chooses an auditor and reports earnings to investors who acquire their own information. The analysis focuses on the possibility that the manager engages an auditor to constrain earnings management as a commitment device to minimize reporting error cost.

Findings

The results show that the manager’s optimal auditor choice is determined based on investor sensitivity to the earnings report, and managerial incentives for earnings management, discounted by the uncertainty of reporting errors. The results for optimal auditor choice are counterintuitive: engaging a higher-quality auditor could seemingly be associated with aggressive earnings management.

Originality/value

This study advances the understanding of the theoretical basis of firms’ auditor choice in the context of market investors’ information acquisition when auditors exercise their discretion in reporting. This issue has received limited attention in the extant literature.
Dry‐season decline in tree sapflux is correlated with leaf turgor loss point in a tropical rainforest
Authors: Maréchaux Isabelle , Bonal Damien , Bartlett Megan K. , Burban Benoît , Coste Sabrina , Courtois Elodie A. , Dulormne Maguy , Goret Jean‐Yves , Mira Eléonore , Mirabel Ariane , Sack Lawren , Stahl Clément , Chave Jérôme
Published: July 2018

Water availability is a key determinant of forest ecosystem function and tree species distributions. While droughts are increasing in frequency in many ecosystems, including in the tropics, plant responses to water supply vary with species and drought intensity and are therefore difficult to model. Based on physiological first principles, we hypothesized that trees with a lower turgor loss point (πtlp), that is, a more negative leaf water potential at wilting, would maintain water transport for longer into a dry season.

We measured sapflux density of 22 mature trees of 10 species during a dry season in an Amazonian rainforest, quantified sapflux decline as soil water content decreased and tested its relationship to tree πtlp, size and leaf predawn and midday water potentials measured after the onset of the dry season.

The measured trees varied strongly in the response of water use to the seasonal drought, with sapflux at the end of the dry season ranging from 37 to 117% (on average 83 ± 5 %) of that at the beginning of the dry season. The decline of water transport as soil dried was correlated with tree πtlp (Spearman’s ρ ≥ 0.63), but not with tree size or predawn and midday water potentials. Thus, trees with more drought‐tolerant leaves better maintained water transport during the seasonal drought.

Our study provides an explicit correlation between a trait, measurable at the leaf level, and whole‐plant performance under drying conditions. Physiological traits such as πtlp can be used to assess and model higher scale processes in response to drying conditions.

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Relationship between perceived social support and patient‐reported communication outcomes across communication disorders: a systematic review
Authors: Eadie Tanya , Kapsner‐Smith Mara , Bolt Susan , Sauder Cara , Yorkston Kathryn , Baylor Carolyn
Published: July 2018

Background

Beyond the severity of voice, speech and language impairments, one potential predictor of communication success across adult populations with communication disorders may be perceived social support: the expectation that others will provide support if needed. Despite the preponderance of intervention approaches that assume a positive relationship between perceived social support and patient‐reported communication success, the evidence base for these relationships is limited.

Aims

The aim of this systematic review is to explore relationships between measures of perceived social support and patient‐reported communication outcomes in adult populations with communication disorders.

Methods & Procedures

The PRISMA guidelines were followed in the conduct and reporting of this review. Electronic databases including PubMed, PsychINFO and CINAHL were systematically searched up to 19 May 2017. Additional data were obtained for two studies. All the included studies were appraised using the Critical Appraisal Skills Program (CASP) tools. Given the heterogeneous nature of the studies, data synthesis was narrative for the quantitative studies. A meta‐ethnographic approach was used to synthesize qualitative data.

Outcomes & Results

Eight quantitative and four qualitative studies met eligibility criteria. All quantitative studies met eight of eight quality criteria. For the qualitative studies, one study met nine of nine quality criteria; the remaining three studies met three, seven and eight quality criteria. Of the eight included quantitative studies, six independent data sets were used. Results revealed no significant relationships between perceived social support and communication outcomes in three studies (two aphasia with one data set, one Parkinson's disease), while perceived social support was a weak, but significant predictor in two studies (one multiple sclerosis, one head and neck cancer). Three additional studies (two aphasia with one data set; one Parkinson's disease) found that relationships were initially weak, but strengthened over time to become moderate. Results from qualitative studies (one head and neck cancer, two aphasia, one multiple sclerosis) revealed that perceived social support acted as a facilitator, and absent or misguided support acted as a barrier to communication outcomes. Skilful, responsive family members were able to facilitate better quality of communicative interactions, whereas lack of social support, or negative attitudes and behaviours of other people, were barriers.

Conclusions & Implications

While perceived social support may affect communication outcomes in adults with communication disorders, current measures may not adequately capture these constructs. Results have implications for future research and interventions for speech and language therapists.
Leader–follower guanxi: an invisible hand of cronyism in Chinese management
Authors: Zhang Jiarui , Gill Carol
Published: July 2018

Guanxi social networks are part of the fabric of Chinese society and central to every aspect of Chinese life including work. The relationship between guanxi and cronyism has been researched and discussed by scholars in supervisor–subordinate guanxi (SSG) studies. However, SSG cannot explain the full extent of cronyism in Chinese management, which usually encompasses a network of actors including a supervisor, a subordinate, a third party (called ‘leader’) who has a higher ranking than a subordinate, and possibly an intermediary between a leader and a supervisor in the same organization. Consequently, this paper develops a new construct leader–follower guanxi (LFG) to explain cronyism in Chinese management. LFG is defined as the existence of direct particularistic (ingroup) ties associated with a particular set of differentiated behavioral obligations based on social norms between a leader and a follower in the same organization. We examine the relationship between LFG and cronyism in Chinese organizations and propose that LFG will be positively associated with cronyism. We then use Chinese ‘face’ theory (mianzi and lian) to illustrate how LFG engenders cronyism in Chinese management. We assert that LFG serves as an invisible hand of cronyism in Chinese organizations. Finally, we consider how to develop leadership and HR practices that prevent cronyism in Chinese organizations.
Clinical efficacy and safety of golimumab in biologically experienced and naive patients with active ulcerative colitis: A real‐life experience from two Italian IBD centers
Authors: Orlandini Beatrice , Dragoni Gabriele , Variola Angela , Massella Arianna , Bagnoli Siro , Campi Riccardo , Rogai Francesca
Published: July 2018

OBJECTIVE

To evaluate the efficacy and safety of golimumab in biological naive and experienced patients with moderately to severely active ulcerative colitis (UC) treated at two Italian IBD centers.

METHODS

We retrospectively reviewed our prospectively maintained UC database from March 2015 to March 2017. Patients received golimumab 200 mg at week 0, 100 mg at week 2, then 50 mg or 100 mg every 4 weeks. Follow‐up was recorded at 12 and 24 weeks and in March 2017, with a median follow‐up of 64 weeks. The main outcomes evaluated were clinical remission (CR) and adverse event rates.

RESULTS

Of the 59 patients (44% naive and 56% experienced), CR rate was 47% at 12‐week follow‐up, 55% (among the 49 patients on treatment) at 24‐week follow‐up and 49% (among 35 patients on treatment) at the last follow‐up visit. Median treatment duration was 52 weeks (interquartile range 30–64 weeks) among patients treated for >6 months. Overall, 10 (17%) patients experienced adverse events, of whom 50% discontinued treatment. The most frequent adverse events were infections. Biological naive and experienced patients did not differ in terms of CR and adverse event rates.

CONCLUSIONS

Our real‐life experience showed that CR decreased over time and was achieved by almost one‐third of the cohort at the last follow‐up visit. Golimumab showed an overall favorable safety profile and the results were not different between biological naive and experienced patients. Future research is needed to confirm our results and to identify criteria to select patients most likely to respond.
Expert consensus on image‐guided radiofrequency ablation of pulmonary tumors: 2018 edition
Authors: Liu Bao‐Dong , Ye Xin , Fan Wei‐Jun , Li Xiao‐Guang , Feng Wei‐Jian , Lu Qiang , Mao Yu , Lin Zheng‐Yu , Li Lu , Zhuang Yi‐Ping , Ni Xu‐Dong , Shen Jia‐Lin , Fu Yi‐Li , Han Jian‐Jun , Li Chen‐Rui , Liu Chen , Yang Wu‐Wei , Su Zhi‐Yong , Wu Zhi‐Yuan , Liu Lei
Published: July 2018

Lung cancer ranks first in incidence and mortality in China. Surgery is the primary method to cure cancer, but only 20–30% of patients are eligible for curative resection. In recent years, in addition to surgery, other local therapies have been developed for patients with numerous localized primary and metastatic pulmonary tumors, including stereotactic body radiation therapy and thermal ablative therapies through percutaneously inserted applicators. Percutaneous thermal ablation of pulmonary tumors is minimally invasive, conformal, repeatable, feasible, cheap, has a shorter recovery time, and offers reduced morbidity and mortality. Radiofrequency ablation (RFA), the most commonly used thermal ablation technique, has a reported 80–90% rate of complete ablation, with the best results obtained in tumors < 3 cm in diameter. Because the clinical efficacy of RFA of pulmonary tumors has not yet been determined, this clinical guideline describes the techniques used in the treatment of localized primary and metastatic pulmonary tumors in nonsurgical candidates, including mechanism of action, devices, indications, techniques, potential complications, clinical outcomes, post‐ablation surveillance, and use in combination with other therapies. In the future, the role of RFA in the treatment of localized pulmonary tumors should ultimately be determined by evidence from prospective randomized controlled trials comparing sublobar resection or stereotactic body radiation therapy.