bluuebunny/crossref_metadata_2025_split huggingface dataset:
Actomyosin Contractility Drives Bile Regurgitation as an Early Homeostatic Response to Increased Biliary Pressure in Obstructive Cholestasis
Authors: Gupta Kapish , Li Qiushi , Fan Jun Jun , Shan Fong Eliza Li , Song Ziwei , Mo Shupei , Tang Haoyu , Ng Inn Chuan , Ng Chan Way , Pawijit Pornteera , Zhuo Shuangmu , Dong Chen-Yuan , Low Boon Chuan , Wee Aileen , Dan Yock Young , Kanchanawong Pakorn , So Peter , Viasnoff Virgile , Yu Hanry 
Published: September 2016

AbstractA wide range of liver diseases manifest as biliary obstruction, or cholestasis. However, the sequence of molecular events triggered as part of the early hepatocellular homeostatic response to abnormal elevations in biliary pressure remains poorly elucidated. Bile canaliculi are dynamic luminal structures that undergo actomyosin-mediated periodic contractions to propel secreted bile. Additionally, pericanalicular actin is accumulated during obstructive cholestasis. Therefore, we hypothesize that the pericanalicular actin cortex undergoes significant remodeling as a regulatory response against increased biliary pressure. Here, we report that, actomyosin contractility induces transient deformations along the canalicular membrane, a process we have termed inward blebbing. We show that these membrane intrusions are initiated by local ruptures in the pericanalicular actin cortex, and they typically retract following repair by actin polymerization and actomyosin contraction. However, above a certain osmotic pressure threshold, these inward blebs pinch away from the canalicular membrane into the hepatocyte cytoplasm as large vesicles (2-8 µm). Importantly, we show that these vesicles aid in the regurgitation of bile from the canalicular system. Conclusion: Actomyosin contractility induces the formation of bile-regurgitative vesicles, thus serving as an early homeostatic mechanism against increased biliary pressure during cholestasis.
An International Inter-Laboratory Digital PCR Study Demonstrates High Reproducibility for the Measurement of a Rare Sequence Variant
Authors: Whale Alexandra S. , Devonshire Alison S. , Karlin-Neumann George , Regan Jack , Javier Leanne , Cowen Simon , Fernandez-Gonzalez Ana , Jones Gerwyn M. , Redshaw Nicholas , Beck Julia , Berger Andreas W. , Combaret Valérie , Kjersgaard Nina Dahl , Davis Lisa , Fina Frederic , Forshew Tim , Andersen Rikke Fredslund , Galbiati Silvia , Hernández Álvaro González , Haynes Charles A. , Janku Filip , Lacave Roger , Lee Justin , Mistry Vilas , Pender Alexandra , Pradines Anne , Proudhon Charlotte , Saal Lao , Stieglitz Elliot , Ulrich Bryan , Foy Carole A. , Parkes Helen , Tzonev Svilen , Huggett Jim F. 
Published: September 2016

AbstractThis study tested the claim that digital PCR (dPCR) can offer highly reproducible quantitative measurements in disparate labs. Twenty-one laboratories measured four blinded samples containing different quantities of aKRASfragment encoding G12D, an important genetic marker for guiding therapy of certain cancers. This marker is challenging to quantify reproducibly using qPCR or NGS due to the presence of competing wild type sequences and the need for calibration. Using dPCR, eighteen laboratories were able to quantify the G12D marker within 12% of each other in all samples. Three laboratories appeared to measure consistently outlying results; however, proper application of a follow-up analysis recommendation rectified their data. Our findings show that dPCR has demonstrable reproducibility across a large number of laboratories without calibration and could enable the reproducible application of molecular stratification to guide therapy, and potentially for molecular diagnostics.SIGNIFICANCE STATEMENTThe poor reproducibility of molecular diagnostic methods limits their application in part due to the challenges associated with calibration of what are relative measurement approaches. In this study we investigate the performance of one of the only absolute measurement methods available today, digital PCR (dPCR), and demonstrated that when compared across twenty-one laboratories, dPCR has unprecedented reproducibility. These results were achieved when measuring a challenging single nucleotide variant and without calibration to any reference samples. This opens the possibility for dPCR to offer a method to transform reproducibility in the molecular diagnostic field, both by direct use as well as in support of other currently used clinical methods.
Blockwise Site Frequency Spectra for Inferring Complex Population Histories and Recombination
Authors: Beeravolu Champak R. , Hickerson Michael J. , Frantz Laurent A.F. , Lohse Konrad 
Published: September 2016

AbstractWe introduce ABLE (Approximate Blockwise Likelihood Estimation), a novel composite likelihood framework based on a recently introduced summary of sequence variation: the blockwise site frequency spectrum (bSFS). This simulation-based framework uses the the frequencies of bSFS configurations to jointly model demographic history and recombination and is explicitly designed to make inference using multiple whole genomes or genome-wide multi-locus data (e.g.RADSeq) catering to the needs of researchers studying model or non-model organisms respectively. The flexible nature of our method further allows for arbitrarily complex population histories using unphased and unpolarized whole genome sequences.In silicoexperiments demonstrate accurate parameter estimates across a range of divergence models with increasing complexity, and as a proof of principle, we infer the demographic history of the two species of orangutan from multiple genome sequences (over 160 Mbp in length) from each species. Our results indicate that the two orangutan species split approximately 650-950 thousand years ago but experienced a pulse of secondary contact much more recently, most likely during a period of low sea-level South East Asia (∼300,000 years ago). Unlike previous analyses we can reject a history of continuous gene flow and co-estimate genome-wide recombination. ABLE is available for download athttps://github.com/champost/ABLE.
Proper modelling of ligand binding requires an ensemble of bound and unbound states
Authors: Pearce Nicholas M , von Delft Frank 
Published: September 2016

SynopsisWe emphasise and demonstrate the importance of modelling the superpositions of ligand-bound and unbound states that commonly occur in crystallographic datasets. Generation of an ensemble that describes not only the dominant state in the crystal is important for the high-quality refinement of low-occupancy ligands, as well as to present a model that explains all of the observed density.AbstractSmall molecules bind to only a fraction of the proteins in the crystal lattice, but occupancy refinement of ligands is often avoided by convention; occupancies are set to unity, assuming that the error will be adequately modelled by the B-factors, and weak ligand density is generally ignored or attributed to disorder. Where occupancy refinementisperformed, the superposed atomic state is rarely modelled. We show here that these modelling approaches lead to a degradation of the quality of the ligand model, and potentially affect the interpretation of the interactions between the bound ligand and the protein. Instead, superior accuracy is achieved by modelling the ligand as partially occupied and superposed on a ligand-free “ground-state” solvent model. Explicit modelling of the superposed unbound fraction of the crystal using a reference dataset allows constrained refinement of the occupancy of the ligand with minimal fear of over-fitting. Better representation of the crystal also leads to more meaningful refined atomic parameters such as the B-factor, allowing more insight into dynamics in the crystal. We present a simple approach and simple guidelines for generating the ensemble of bound and unbound states, assuming that datasets representing the unbound states (the ground state) are available. Judged by various electron density metrics, ensemble models are consistently better than corresponding single-state models. Furthermore, local modelling of the superposed ground state is found to be generally more important for the quality of the ligand model than convergence of the overall phases.
Evolutionary and Functional Implications of Hypervariable Loci Within the Skin Virome
Authors: Hannigan Geoffrey D. , Zheng Qi , Meisel Jacquelyn S. , Minot Samuel , Bushman Frederick D. , Grice Elizabeth A. 
Published: September 2016

ABSTRACTLocalized genomic variability is crucial for the ongoing conflicts between infectious microbes and their hosts. An understanding of evolutionary and adaptive patterns associated with genomic variability will help guide development of vaccines and anti-microbial agents. While most analyses of the human microbiome have focused on taxonomic classification and gene annotation, we investigated genomic variation of skin-associated viral communities. We evaluated patterns of viral genomic variation across 16 healthy human volunteers. HPV andStaphylococcusphages contained 106 and 465 regions of diversification, or hypervariable loci, respectively.Propionibacteriumphage genomes were minimally divergent and contained no hypervariable loci. Genes containing hypervariable loci were involved in functions including host tropism and immune evasion. HPV andStaphylococcusphage hypervariable loci were associated with purifying selection. Amino acid substitution patterns were virus dependent, as were predictions of their phenotypic effects. We identified diversity generating retroelements as one likely mechanism driving hypervariability. We validated these findings in an independently collected skin metagenomic sequence dataset, suggesting that these features of skin virome genomic variability are widespread. Our results highlight the genomic variation landscape of the skin virome and provide a foundation for better understanding community viral evolution and the functional implications of genomic diversification of skin viruses.
Protein Kinase C and the stress response pathways are required for kinetochore homeostasis
Authors: Ledesma-Fernández Elena , Herrero Eva , Ólafsson Guðjón , Thorpe Peter H 
Published: September 2016

AbstractKinetochores serve both a structural role linking chromosomes to the mitotic spindle and a regulatory role, controlling the timing of mitosis via the spindle assembly checkpoint. To identify proteins that regulate the kinetochore we used a genome-wide fluorescence microscopy approach. We combined an array of mutants of either non-essential gene deletions or essential temperature-sensitive alleles with fluorescently tagged spindle pole bodies (centrosome) and outer kinetochores. Quantitative and qualitative analysis revealed mutants that affect the levels and distribution of kinetochores respectively. These mutants are enriched for those involved in mRNA processing, chromatin organization, DNA replication/repair and mitosis. Our data show that the Pkc1 kinase maintains the kinetochore focus via its ability to prevent cell stress and this phenotype is rescued by an osmotic stabilizer. These data support the notion that kinetochore and microtubule homeostasis are perturbed by the stress response pathways. Hence this observation provides a candidate mechanism for extracellular stress leading to chromosome segregation defects.
Assessing the Relationship Between Vegetation Structure and Harvestmen Assemblage in an Amazonian Upland Forest
Authors: Colmenares Pío , Baccaro Fabrício B. , Tourinho Ana Lúcia 
Published: September 2016

Abstract1. Arthropod diversity and non-flying arthropod food web are strongly influenced by habitat components related to plant architecture and habitat structural complexity. However, we still poorly understand the relationship between arthropod diversity and the vegetation structure at different spatial scales. Here, we examined how harvestmen assemblages are distributed across six local scale habitats (trees, dead trunks, palms, bushes, herbs and litter), and along three proxies of vegetation structure (number of palms, number of trees and litter depth) at mesoscale.2. We collected harvestmen using cryptic manual search in 30 permanent plots of 250 m at Reserva Ducke, Amazonas, Brazil. The 30 plots cover approximately 25 km2of upland forests. At a local scale, harvestmen were most diverse and abundant on trees. The likely preference of trees by harvestmen may be related to the variety of local microhabitats offered by large trees. However, despite the strong link between number of harvestman species and individuals with large trees, only harvestmen assemblages composition were related with number of trees and with number of palms, at mesoscale.3. Harvestman richness and abundance were not related with any vegetation structure predictor at mesoscale. Therefore, areas ofuplandforest in the central Amazon with large trees and palms do not harbor more harvestman species nor individuals, but are suitable to maintain different harvestmen assemblages.
A phylogenetic codon substitution model for antibody lineages
Authors: Hoehn Kenneth B , Lunter Gerton , Pybus Oliver G 
Published: September 2016

AbstractPhylogenetic methods have shown promise in understanding the development of broadly neutralizing antibody lineages (bNAbs). However, the mutational process that generates these lineages – somatic hypermutation (SHM) – is biased by hotspot motifs, which violates important assumptions in most phylogenetic substitution models. Here, we develop a modified GY94-type substitution model that partially accounts for this context-dependency while preserving independence of sites during calculation. This model shows a substantially better fit to three well-characterized bNAb lineages than the standard GY94 model. We show through simulations that accounting for hotspot motifs can lead to reduced bias of other substitution parameters, and more accurate ancestral state reconstructions. We also demonstrate how our model can be used to test hypotheses concerning the roles of different hotspot and coldspot motifs in the evolution of B-cell lineages. Further, we explore the consequences of the idea that the number of hotspot motifs – and perhaps the mutation rate in general – is expected to decay over time in individual bNAb lineages.
Alignment of governance and senior executive perceptions of culture
Authors: Looi Evelyn Suk Yi , Greatbanks Richard , Everett André M. 
Published: September 2016

PurposeThe purpose of this paper is to examine the alignment of perceived organizational culture between Health Board chairs and Board members with that of their respective senior executive teams. It compares the degree of alignment between these two groups, and analyses them against District Health Board (DHB) performance using the New Zealand Ministry of Health’s national measure “shorter stays in Emergency Departments.”Design/methodology/approachPrimary survey data were collected across eight DHBs using a modified version of the Organizational Culture Assessment Instrument and utilizes a sample of both higher and lower performing DHBs as defined by the “shorter stays” measure.FindingsMany health organizations cite Ovseiko and Buchan’s (2012) preferred culture as an ideal model. However, this study’s findings indicate that most DHBs scored higher than the preferred score for “Hierarchical” and “Rational” cultures, and lower for “Clan” and “Developmental” cultures, and therefore calls into question the validity of this organizational profile as the “preferred” cultural state.Research limitations/implicationsThis research considers perceived organizational culture from the perspective of the Board members and their respective senior executive teams. It uses a relatively small sample size and excludes potential interactions of national culture.Practical implicationsThe findings indicate that healthcare organizations should de-emphasize the dominant “Hierarchical” and “Rational” cultures, and promote “Clan” and “Developmental” cultures within their organizations as a means of potentially improving healthcare performance.Originality/valueOrganizational culture has been highlighted as a major component of performance within healthcare organizations, yet very few studies examine how organizational culture is perceived by governance and executive groups. This study empirically counters prevailing knowledge regarding the most appropriate organizational cultures for healthcare organizations.
Measuring distributed leadership agency in a hospital context
Authors: Jønsson Thomas , Unterrainer Christine , Jeppesen Hans-Jeppe , Jain Ajay Kumar 
Published: September 2016

Purpose
The purpose of this paper is to develop and validate an instrument that can measure distributed leadership (DL) as employees’ active participation in DL tasks. The authors designate this as the distributed leadership agency (DLA).

Design/methodology/approach
Data were collected throughout all departments and occupational groups at a merged centralized hospital setting in Denmark. A total of 1,774 employees from 24 hospital departments and 16 occupational groups completed our survey. Structural equation model and confirmatory factor analyses were applied to identify appropriate items and a test for measurement invariance, predictive, discriminant and convergent validity, and ANOVAs were applied to analyse group differences in DLA.

Findings
The identified unidimensional questionnaire consists of seven items, as it is different from, but associated with, empowering leadership, organizational influence, attitude to participation and trust in management. As theoretically predicted, DLA is positively related to self-efficacy, job satisfaction and innovative behaviour. Chief physicians, permanent employees and employee representatives scored higher on the scale than the rest of their respective counterparts.

Practical implications
The survey offers a method to assess a distribution of leadership agency in hospital organizations. Such assessment may provide a basis for organizational and leadership development.

Originality/value
The present study provides a reliable and valid quantitative instrument that measures how much employees at all hierarchical levels are involved in concrete leadership activities in the hospital context. Taking a normative perspective the authors could show that DL – measured with the DLA-questionnaire – has positive effects on employees’ behaviour.
Process redesign for time-based emergency admission targets
Authors: G. Leggat Sandra , Gough Richard , Bartram Timothy , Stanton Pauline , Bamber Greg J. , Ballardie Ruth , Sohal Amrik 
Published: September 2016

PurposeHospitals have used process redesign to increase the efficiency of the emergency department (ED) to cope with increasing demand. While there are published studies suggesting a positive outcome, recent reviews have reported that it is difficult to conclude that these approaches are effective as a result of substandard research methodology. The purpose of this paper is to explore the perceptions of hospital staff on the impact of a process redesign initiative on quality of care.Design/methodology/approachA retrospective qualitative case study examining a Lean Six Sigma (LSS) initiative in a large metropolitan hospital from 2009 to 2010. Non-probability sampling identified interview subjects who, through their participation in the redesign initiative, had a detailed understanding of the implementation and outcomes of the initiative. Between April 2012 and January 2013 26 in-depth semi-structured interviews were conducted and analysed with thematic content analysis.FindingsThere were four important findings. First, when asked to comment on the impact of the LSS implementation, without prompting the staff spoke of quality of care. Second, there was little agreement among the participants as to whether the project had been successful. Third, despite the recognition of the need for a coordinated effort across the hospital to improve ED access, the redesign process was not successful in reducing existing divides among clinicians and among managers and clinicians. Finally, staff expressed tension between production processes to move patients more quickly and their duty of care to their patients as individuals.Originality/valueOne of the first studies to explore the impact of process redesign through in-depth interviews with participating staff, this study adds further evidence that organisations implementing process redesign must ensure the supporting management practices are in place.
What factors determine the choice of public engagement undertaken by health technology assessment decision-making organizations?
Authors: Wortley Sally , Street Jackie , Lipworth Wendy , Howard Kirsten 
Published: September 2016

Purpose
Public engagement in health technology assessment (HTA) is increasingly considered crucial for good decision making. Determining the “right” type of engagement activity is key in achieving the appropriate consideration of public values. Little is known about the factors that determine how HTA organizations (HTAOs) decide on their method of public engagement, and there are a number of possible factors that might shape these decisions. The purpose of this paper is to understand the potential drivers of public engagement from an organizational perspective.

Design/methodology/approach
The published HTA literature is reviewed alongside existing frameworks of public engagement in order to elucidate key factors influencing the choice of public engagement process undertaken by HTAOs. A conceptual framework is then developed to illustrate the factors identified from the literature that appear to influence public engagement choice.

Findings
Determining the type of public engagement undertaken in HTA is based on multiple factors, some of which are not always explicitly acknowledged. These factors included the: perceived complexity of the policy-making issue, perceived impact of the decision, transparency and opportunities for public involvement in governance, as well as time and resource constraints. The influences of these factors vary depending on the context, indicating that a one size fits all approach to public engagement may not be effective.

Originality/value
Awareness of the various factors that might influence the type of public engagement undertaken would enable decision makers to reflect on their choices and be more accountable and transparent about their choice of engagement process in eliciting public values and preferences in a HTAO.