bluuebunny/crossref_metadata_2025 huggingface dataset:
Dual bioluminescence and near-infrared fluorescence monitoring to evaluate spherical nucleic acid nanoconjugate activity in vivo
Authors: Sita Timothy L. , Kouri Fotini M. , Hurley Lisa A. , Merkel Timothy J. , Chalastanis Alexandra , May Jasmine L. , Ghelfi Serena T. , Cole Lisa E. , Cayton Thomas C. , Barnaby Stacey N. , Sprangers Anthony J. , Savalia Nikunjkumar , James Charles David , Lee Andrew , Mirkin Chad A. , Stegh Alexander H.
Published: April 2017

Significance

Small interfering (si) and micro (mi)RNA-carrying nanomaterials emerged as a new class of anticancer therapeutics. To enable quantification of intratumoral gene expression in response to RNAi nanoconjugate treatment in vivo, we developed a dual reporter glioblastoma xenograft model using cell lines that stably coexpress optical reporters for luciferase and a near-infrared fluorescent protein (iRFP670). We generated orthotopic glioblastoma multiforme tumors expressing an iRFP670-O
6
-methylguanine-DNA-methyltransferase (MGMT) fusion protein for real-time assessment of MGMT-targeting spherical nucleic acids (i.e., gold-based nanoconjugates functionalized with siRNA oligonucleotides targeted to MGMT). We demonstrate that dual noninvasive bioluminescence and fluorescence imaging can determine intratumoral protein expression in response to systemic spherical nucleic acid treatment and represents an in vivo testing platform to facilitate preclinical investigations of nanoscale gene silencing therapeutics.
Modeling Otolith Weight using Fish Age and Length: Applications to Age Determination
Authors: Hanson S. Dale , Stafford Craig P.
Published: April 2017

Relationships among otolith weight and age have been explored widely as cost‐effective means to predict age. However, otolith weight is influenced by both fish age and somatic growth, making it necessary to partition these confounding effects to best use otolith weight to predict age. We used several hatchery strains of Lake Trout Salvelinus namaycush that varied in capture season, year, location, and mean size at stocking to develop a maximum likelihood model of otolith weight as complementary but independent functions of age (mg/year) and fish length (mg/mm). Once these relationships were established, we determined age probabilities for each fish based on their measurements. Our best model included age and somatic growth components, with cumulative mean temperature as a variable to scale for seasonal differences in otolith accretion. For fish between 3 and 19 years of age, otolith weight increased by 1.16 mg/year, with an additional somatic growth component of 0.62 × exp(fish length × 0.0038) mg/mm. We correctly assigned age to 60% of the age‐3 fish, but this decreased to about 10% among the oldest age‐classes; however, predicted age residuals approximated normal distributions within each age‐class. The model was robust to seasonal and annual variation, but somatic growth differences among some strain and stocking‐size groupings resulted in modal aging biases of ±1 year. Given the stability in otolith weight components arising from fish age and somatic growth, we suggest that modeling otolith weight using reader age estimates offers a new quality assurance/quality control tool to assess whether reader ages support the widely documented properties of otolith growth. When otolith weight and fish length are more informative of age, our model may also be useful in estimating age composition data similar to an age–length key.

Received December 19, 2016; accepted March 20, 2017 Published online May 26, 2017
Severe asthma
Authors: Shah Anand , Menzies-Gow Andrew
Published: April 2017

Poorly controlled asthma is a common reason for referral to the respiratory clinic, and the majority of cases can be managed effectively by ensuring the correct diagnosis and ensuring good compliance with inhaled therapy. However, severe asthma affects up to 10% of patients with asthma and is associated with substantial morbidity and mortality, along with significant health-care costs from both inpatient treatment and lost work days. This chapter covers two cases of difficult-to-control asthma and highlights the role of detailed investigations when asthma control is not straightforward. It will cover the diagnostic criteria for allergic bronchopulmonary aspergillosis and severe asthma with fungal sensitization and discuss the role of omalizumab in managing severe asthma.
Chronic obstructive pulmonary disease
Authors: Jaffer Amina , Patel Anant , Hurst John
Published: April 2017

This chapter discusses the case of a 70-year-old man with his first presentation of chronic obstructive pulmonary disease. This case is used as a basis to explore and describe the diagnosis, investigation, and management of this condition. The chapter includes the evidence base and relative guidelines that support current practice, as well as highlighting useful learning points and providing expert opinion. The role of lung volume reduction surgery is discussed, and its potential benefits in selected patients highlighted. Phenotypic variability within chronic obstructive pulmonary disease is increasingly recognized, and this is discussed, including the implications on current management and future research.
Intensive care unit and ventilation
Authors: Garner Justin , Treacher David
Published: April 2017

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by rapidly developing hypoxaemic respiratory failure and bilateral pulmonary infiltrates on chest X-ray. ALI/ARDS are a relatively frequent diagnosis in protracted-stay patients in the intensive care unit. The pathology is a non-specific response to a wide variety of insults. Impaired gas exchange, ventilation-perfusion mismatch, and reduced compliance ensue. Mechanical ventilation is the mainstay of management, along with treatment of the underlying cause. Mortality remains very high at around 40%. The condition is challenging to treat. Injury to the lungs, indistinguishable from that of ARDS, has been attributed to the use of excessive tidal volumes, pressures, and repeated opening and collapsing of alveoli. Lung-protective strategies aim to minimize the effects of ventilator-induced lung injury. Use of low tidal volume ventilation has been shown to improve mortality. Emerging ventilatory therapies include high-frequency oscillatory ventilation and extracorporeal membrane oxygenation.
Narcolepsy: still sleepy on CPAP
Authors: Walder Dave , Reading Paul
Published: April 2017

Sleep disorders are an increasingly common reason for referral to the respiratory clinic, and our understanding of the different aetiologies is increasing. The commonest sleep disorder is sleep apnoea, but other sleep disorders can cause similar symptoms. Narcolepsy is a neurological disorder that affects the brain’s ability to regulate the normal sleep-wake cycle and often presents with similar symptoms to obstructive sleep apnoea, daytime hypersomnolence, and disturbed night-time sleeping but is largely underdiagnosed. This chapter discusses a patient who presented with symptoms of daytime somnolence and witnessed apnoeas and details the investigations required for a diagnosis of narcolepsy. It covers the more specialized sleep studies required for a clinical diagnosis and the treatment options available for patients with this condition.
Pulmonary disease caused by non-tuberculous mycobacteria
Authors: Stowell Janet , Breen Ronan
Published: April 2017

This chapter describes a case of Mycobacterium malmoense in a male ex-smoker with chronic obstructive pulmonary disease. The approaches to a diagnosis of pulmonary non-tuberculous mycobacterial disease are discussed, including key laboratory features and associated radiological changes. The factors influencing the decision to treat and treatment regimen selected are reviewed, along with evidence from landmark trials regarding drug combinations and the role of surgery in managing non-tuberculous mycobacterial disease. This case was complicated by a secondary diagnosis of invasive aspergillosis, and the challenges of treating non-tuberculous mycobacteria and Aspergillus concurrently are highlighted. Non-tuberculous mycobacterial infection in HIV-positive patients can behave differently to non-tuberculous mycobacterial disease in immunocompetent individuals. Restoring immunocompetence is key to the success of non-tuberculous mycobacterial treatment in these individuals, but beware Mycobacterium avium complex-related immune restoration inflammatory syndrome.
Swine ‘flu’ in pregnancy
Authors: Almond Mark H , Griffiths Mark J
Published: April 2017

Influenza viruses are a significant cause of morbidity and mortality globally, resulting in severe illness in 3-5 million people and death in up to 500,000 during epidemic years. In March 2009, a novel H1N1 virus emerged in Mexico, spreading rapidly around the globe and achieving pandemic status within 3 months. Although it is now generally considered that the 2009 pandemic resulted in mild disease in most individuals, serious complications still occurred, with 12,000 deaths by mid-February 2010 in the United States alone. Risk factors for severe disease included asthma, cardiac disease, immunosuppression, pregnancy, diabetes mellitus, and obesity. The chapter outlines the case of a young pregnant female who presented with an influenza-like illness and subsequently developed acute respiratory distress syndrome requiring extracorporeal membrane oxygenation. The origins, presentation, diagnosis, complications, and management of pandemic influenza are discussed, in addition to a summary of the pulmonary physiology and pathology of pregnancy.
Transplant
Authors: Barrett Jessica , Carby Martin
Published: April 2017

Since the first successful lung transplant in 1981, tens of thousands of operations have been performed across the world. Yet despite significant technical advances, mortality is the highest of any solid organ transplant. Most patients will have a major complication within the first 5 years of the operation. These are best managed in transplant centres. However, a working knowledge of the presentation and initial management is essential for a respiratory physician. Although the rate of complications remains high, more than 80% of patients with surviving transplants report no limitation of activity at 1, 3, and 5 years. Developments in surgical technique have reduced immediate complications, and immunosuppressive regimens continue to improve. However, the incidence of obliterative bronchiolitis remains high and is responsible for the majority of graft failures.
Conflicting Effects of Climate and Vector Behavior on the Spread of a Plant Pathogen
Authors: Daugherty Matthew P. , Zeilinger Adam R. , Almeida Rodrigo P. P.
Published: April 2017

Local climatic conditions are important determinants of disease dynamics through effects on vector population performance or distribution. Yet, climate may also be epidemiologically significant due to effects on host−pathogen infection dynamics. We developed a model to explore interactive effects between climate-mediated acceleration in disease phenology (i.e., faster incubation or symptom onset) and vector preference based on host symptom status. Higher incubation rates favored pathogen outbreaks, but more rapid symptom onset may constrain spread if vectors avoid symptomatic hosts. Next, we tested whether warmer conditions favored greater spread of the plant pathogen, Xylella fastidiosa, by its leafhopper vector, Graphocephala atropunctata. Inoculated and healthy plants were reared in two temperature-controlled greenhouses. At six times postinoculation, a healthy and inoculated plant were exposed to noninfective vectors, after which pathogen spread was evaluated. Incubation rate and symptom onset in infected hosts was significantly accelerated at higher temperature. Although there was a tendency for greater pathogen spread at higher temperature, the effect depended on time since inoculation. In later introductions, after disease symptoms manifest, vectors were more likely to be found on healthy hosts. Vector avoidance of symptoms, particularly for hosts reared at higher temperature, constrained pathogen spread at later introductions. These results indicate that climate and vector behavior may mediate interactively pathogen spread. Further consideration of such epidemiological complexities is needed to predict adequately the consequences of climate change for disease dynamics.
The molten glass sewing machine
Authors: Brun P.-T. , Inamura Chikara , Lizardo Daniel , Franchin Giorgia , Stern Michael , Houk Peter , Oxman Neri
Published: April 2017

We present a fluid-instability-based approach for digitally fabricating geometrically complex uniformly sized structures in molten glass. Formed by mathematically defined and physically characterized instability patterns, such structures are produced via the additive manufacturing of optically transparent glass, and result from the coiling of an extruded glass thread. We propose a minimal geometrical model—and a methodology—to reliably control the morphology of patterns, so that these building blocks can be assembled into larger structures with tailored functionally and optically tunable properties.

This article is part of the themed issue ‘Patterning through instabilities in complex media: theory and applications’.
Wrinkling of a thin circular sheet bonded to a spherical substrate
Authors: Bella Peter , Kohn Robert V.
Published: April 2017

We consider a disc-shaped thin elastic sheet bonded to a compliant sphere. (Our sheet can slip along the sphere; the bonding controls only its normal displacement.) If the bonding is stiff (but not too stiff), the geometry of the sphere makes the sheet wrinkle to avoid azimuthal compression. The total energy of this system is the elastic energy of the sheet plus a (Winkler-type) substrate energy. Treating the thickness of the sheet
h
as a small parameter, we determine the leading-order behaviour of the energy as
h
tends to zero, and we give (almost matching) upper and lower bounds for the next-order correction. Our analysis of the leading-order behaviour determines the macroscopic deformation of the sheet; in particular, it determines the extent of the wrinkled region, and predicts the (non-trivial) radial strain of the sheet. The leading-order behaviour also provides insight about the length scale of the wrinkling, showing that it must be approximately independent of the distance
r
from the centre of the sheet (so that the number of wrinkles must increase with
r
). Our results on the next-order correction provide insight about how the wrinkling pattern should vary with
r
. Roughly speaking, they suggest that the length scale of wrinkling should
not
be exactly constant—rather, it should vary slightly, so that the number of wrinkles at radius
r
can be approximately piecewise constant in its dependence on
r
, taking values that are integer multiples of
h

−
a

with

.

This article is part of the themed issue ‘Patterning through instabilities in complex media: theory and applications’.
Oblique wrinkles
Authors: Carfagna M. , Destrade M. , Gower A. L. , Grillo A.
Published: April 2017

We prove theoretically that when a soft solid is subjected to an extreme deformation, wrinkles can form on its surface at an angle that is oblique to a principal direction of stretch. These oblique wrinkles occur for a strain that is smaller than the one required to obtain wrinkles normal to the direction of greatest compression. We go on to explain why they will probably never be observed in real-world experiments.

This article is part of the themed issue ‘Patterning through instabilities in complex media: theory and applications.’
The dynamics of folding instability in a constrained Cosserat medium
Authors: Gourgiotis Panos A. , Bigoni Davide
Published: April 2017

Different from Cauchy elastic materials, generalized continua, and in particular constrained Cosserat materials, can be designed to possess extreme (near a failure of ellipticity) orthotropy properties and in this way to model folding in a three-dimensional solid. Following this approach, folding, which is a narrow zone of highly localized bending, spontaneously emerges as a deformation pattern occurring in a strongly anisotropic solid. How this peculiar pattern interacts with wave propagation in the time-harmonic domain is revealed through the derivation of an antiplane, infinite-body Green’s function, which opens the way to integral techniques for anisotropic constrained Cosserat continua. Viewed as a perturbing agent, the Green’s function shows that folding, emerging near a steadily pulsating source in the limit of failure of ellipticity, is transformed into a disturbance with wavefronts parallel to the folding itself. The results of the presented study introduce the possibility of exploiting constrained Cosserat solids for propagating waves in materials displaying origami patterns of deformation.

This article is part of the themed issue ‘Patterning through instabilities in complex media: theory and applications.’
Wrinkling instabilities in soft bilayered systems
Authors: Budday Silvia , Andres Sebastian , Walter Bastian , Steinmann Paul , Kuhl Ellen
Published: April 2017

Wrinkling phenomena control the surface morphology of many technical and biological systems. While primary wrinkling has been extensively studied, experimentally, analytically and computationally, higher-order instabilities remain insufficiently understood, especially in systems with stiffness contrasts well below 100. Here, we use the model system of an elastomeric bilayer to experimentally characterize primary and secondary wrinkling at moderate stiffness contrasts. We systematically vary the film thickness and substrate prestretch to explore which parameters modulate the emergence of secondary instabilities, including period-doubling, period-tripling and wrinkle-to-fold transitions. Our experiments suggest that period-doubling is the favourable secondary instability mode and that period-tripling can emerge under disturbed boundary conditions. High substrate prestretch can suppress period-doubling and primary wrinkles immediately transform into folds. We combine analytical models with computational simulations to predict the onset of primary wrinkling, the post-buckling behaviour, secondary bifurcations and the wrinkle-to-fold transition. Understanding the mechanisms of pattern selection and identifying the critical control parameters of wrinkling will allow us to fabricate smart surfaces with tunable properties and to control undesired surface patterns like in the asthmatic airway.

This article is part of the themed issue ‘Patterning through instabilities in complex media: theory and applications.’
On the buckling of elastic rings by external confinement
Authors: Hazel Andrew L. , Mullin Tom
Published: April 2017

We report the results of an experimental and numerical investigation into the buckling of thin elastic rings confined within containers of circular or regular polygonal cross section. The rings float on the surface of water held in the container and controlled removal of the fluid increases the confinement of the ring. The increased compressive forces can cause the ring to buckle into a variety of shapes. For the circular container, finite perturbations are required to induce buckling, whereas in polygonal containers the buckling occurs through a linear instability that is closely related to the canonical Euler column buckling. A model based on Kirchhoff–Love beam theory is developed and solved numerically, showing good agreement with the experiments and revealing that in polygons increasing the number of sides means that buckling occurs at reduced levels of confinement.

This article is part of the themed issue ‘Patterning through instabilities in complex media: theory and applications.’
Detecting Drug-Target Binding in Cells using Fluorescence Activated Cell Sorting Coupled with Mass Spectrometry Analysis
Authors: Wilson Kris , Webster Scott P , Iredale John P , Zheng Xiaozhong , Homer Natalie Z , Pham Nhan , Auer Manfred , Mole Damian J
Published: April 2017

The assessment of drug-target engagement for determining the efficacy of a compound inside cells remains challenging, particularly for difficult target proteins. Existing techniques are more suited to soluble protein targets. Difficult target proteins include those with challenging in vitro solubility, stability or purification properties that preclude target isolation. Here, we report a novel technique that measures intracellular compound-target complex formation, as well as cellular permeability, specificity and cytotoxicity - the Toxicity-Affinity-Permeability-Selectivity (TAPS) technique. The TAPS assay is exemplified here using human kynurenine 3-monooxygenase (KMO), a challenging intracellular membrane protein target of significant current interest. TAPS confirmed target binding of known KMO inhibitors inside cells. We conclude that the TAPS assay can be used to facilitate intracellular hit validation on most, if not all intracellular drug targets.
De novoVariants in Neurodevelopmental Disorders with Epilepsy
Authors: Heyne Henrike O. , Singh Tarjinder , Stamberger Hannah , Jamra Rami Abou , Caglayan Hande , Craiu Dana , Jonghe Peter De , Guerrini Renzo , Helbig Katherine L. , Koeleman Bobby P. C. , Kosmicki Jack A. , Linnankivi Tarja , May Patrick , Muhle Hiltrud , Møller Rikke S. , Neubauer Bernd A. , Palotie Aarno , Pendziwiat Manuela , Striano Pasquale , Tang Sha , Wu Sitao ,   EuroEPINOMICS RES Consortium, Poduri Annapurna , Weber Yvonne G. , Weckhuysen Sarah , Sisodiya Sanjay M. , Daly Mark , Helbig Ingo , Lal Dennis , Lemke Johannes R.
Published: April 2017

Epilepsy is a frequent feature of neurodevelopmental disorders (NDD) but little is known about genetic differences between NDD with and without epilepsy. We analyzedde novovariants (DNV) in 6753 parent-offspring trios ascertained for different NDD. In the subset of 1942 individuals with NDD with epilepsy, we identified 33 genes with a significant excess of DNV, of whichSNAP25andGABRB2had previously only limited evidence for disease association. Joint analysis of all individuals with NDD also implicatedCACNA1Eas a novel disease gene. Comparing NDD with and without epilepsy, we found missense DNV, DNV in specific genes, age of recruitment and severity of intellectual disability to be associated with epilepsy. We further demonstrate to what extent our results impact current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDD with epilepsy.
Meta-analysis of liver and heart transcriptomic data for functional annotation transfer in mammalian orthologs
Authors: Loren Reyes Pía Francesca , Michoel Tom , Joshi Anagha , Devailly Guillaume
Published: April 2017

Functional annotation transfer across multi-gene family orthologs can lead to functional misannotations. We hypothesised that co-expression network will help predict functional orthologs amongst complex homologous gene families. To explore the use of transcriptomic data available in public domain to identify functionally equivalent ones from all predicted orthologs, we collected genome wide expression data in mouse and rat liver from over 1500 experiments with varied treatments. We used a hyper-graph clustering method to identify clusters of orthologous genes co-expressed in both mouse and rat. We validated these clusters by analysing expression profiles in each species separately, and demonstrating a high overlap. We then focused on genes in 18 homology groups with one-to-many or many-to-many relationships between two species, to discriminate between functionally equivalent and non-equivalent orthologs. Finally, we further applied our method by collecting heart transcriptomic data (over 1400 experiments) in rat and mouse to validate the method in an independent tissue.
blkbox: Integration of multiple machine learning approaches to identify disease biomarkers
Authors: Guennewig Boris , Davies Zachary , Pinese Mark , Cooper Antony A
Published: April 2017

Motivation

Machine learning (ML) is a powerful tool to create supervised models that can distinguish between classes and facilitate biomarker selection in high-dimensional datasets, including RNA Sequencing (RNA-Seq). However, it is variable as to which is the best performing ML algorithm(s) for a specific dataset, and identifying the optimal match is time consuming. blkbox is a software package including a shiny frontend, that integrates nine ML algorithms to select the best performing classifier for a specific dataset. blkbox accepts a simple abundance matrix as input, includes extensive visualization, and also provides an easy to use feature selection step to enable convenient and rapid potential biomarker selection, all without requiring parameter optimization.

Results

Feature selection makes blkbox computationally inexpensive while multi-functionality, including nested cross-fold validation (NCV), ensures robust results. blkbox identified algorithms that outperformed prior published ML results. Applying NCV identifies features, which are utilized to gain high accuracy.

Availability

The software is available as a CRAN R package and as a developer version with extended functionality on github (https://github.com/gboris/blkbox).

Contact

b.guennewig@garvan.org.au
Modelling Theta-Band Connectivity Between Occipital and Frontal Lobes: A Methodological MEG Study
Authors: Price Darren , Brookes Matthew J. , Liddle Elizabeth B. , Liddle Peter F. , Palaniyappan Lena , Morris Peter G.
Published: April 2017

Measuring functional connectivity between cortical regions of the human brain has become an important area of research. Modern theory suggests that brain networks exhibit non-stationarity, constantly forming and reforming depending on task demands. A robust means of determining effective connectivity in the short-lived neural responses that occur in event related paradigms would allow the investigation of event related cortico-cortical dynamics. We present such a mathematical model of wave propagation, motivated by current neuroscience literature, and demonstrate the utility of the method in a clinical sample of schizophrenia patients. MEG data were acquired in 10 patients with schizophrenia and 12 healthy controls during a relevance modulation task. Data were filtered into the theta band (4-8Hz) and source localised using a beamformer. The model was implemented using Fourier analysis methods which uncovered an event related travelling wave moving from the visual to frontal cortices. The model was validated using Monte Carlo phase randomisation and compared with another plausible model of wave propagation in the cortex. Results from the clinical sample revealed that wave speed was modulated by task condition and patients were found to have less difference between conditions (ANOVA revealing a significant interaction between group and condition, p<0.05). In conclusion, our method provides a simple and robust means to investigate event related cortico-cortical brain dynamics in individuals and groups in the task positive state.
Dynamic post-transcriptional regulation during embryonic stem cell differentiation
Authors: van den Berg Patrick R. , Budnik Bogdan , Slavov Nikolai , Semrau Stefan
Published: April 2017

Duringin vitrodifferentiation, pluripotent stem cells undergo extensive remodeling of their gene expression profile. While studied extensively at the transcriptome level, much less is known about protein dynamics. Here, we measured mRNA and protein levels of 7459 genes during differentiation of embryonic stem cells (ESCs). This comprehensive data set revealed pervasive discordance between mRNA and protein. The high temporal resolution of the data made it possible to determine protein turnover rates genome-wide by fitting a kinetic model. This model further enabled us to systematically identify dynamic post-transcriptional regulation. Moreover, we linked different modes of regulation to the function of specific gene sets. Finally, we showed that the kinetic model can be applied to singlecell transcriptomics data to predict protein levels in differentiated cell types. In conclusion, our comprehensive data set, easily accessible through a web application, is a valuable resource for the discovery of post-transcriptional regulation in ESC differentiation.
HiPiler: Visual Exploration of Large Genome Interaction Matrices with Interactive Small Multiples
Authors: Lekschas Fritz , Bach Benjamin , Kerpedjiev Peter , Gehlenborg Nils , Pfister Hanspeter
Published: April 2017

This paper presents an interactive visualization interface—HiPiler—for the exploration and visualization of regions-of-interest in large genome interaction matrices. Genome interaction matrices approximate the physical distance of pairs of regions on the genome to each other and can contain up to 3 million rows and columns with many sparse regions.Regions of interest(ROIs) can be defined, e.g., by sets of adjacent rows and columns, or by specific visual patterns in the matrix. However, traditional matrix aggregation or pan-and-zoom interfaces fail in supporting search, inspection, and comparison of ROIs in such large matrices. In HiPiler, ROIs are first-class objects, represented as thumbnail-like “snippets”. Snippets can be interactively explored and grouped or laid out automatically in scatterplots, or through dimension reduction methods. Snippets are linked to the entire navigable genome interaction matrix through brushing and linking. The design of HiPiler is based on a series of semi-structured interviews with 10 domain experts involved in the analysis and interpretation of genome interaction matrices. We describe six exploration tasks that are crucial for analysis of interaction matrices and demonstrate how HiPiler supports these tasks. We report on a user study with a series of data exploration sessions with domain experts to assess the usability of HiPiler as well as to demonstrate respective findings in the data.
Structures of partition protein ParA with nonspecific DNA and ParB effector reveal molecular insights into principles governing Walker-box DNA segregation
Authors: Zhang Hengshan , Schumacher Maria A.
Published: April 2017

Walker-box partition systems are ubiquitous in nature and mediate the segregation of bacterial and archaeal DNA. Well-studied plasmid Walker-box partition modules require ParA, centromere–DNA, and a centromere-binding protein, ParB. In these systems, ParA–ATP binds nucleoid DNA and uses it as a substratum to deliver ParB-attached cargo DNA, and ParB drives ParA dynamics, allowing ParA progression along the nucleoid. How ParA–ATP binds nonspecific DNA and is regulated by ParB is unclear. Also under debate is whether ParA polymerizes on DNA to mediate segregation. Here we describe structures of key ParA segregation complexes. The ParA–β,γ-imidoadenosine 5′-triphosphate (AMPPNP)–DNA structure revealed no polymers. Instead, ParA–AMPPNP dimerization creates a multifaceted DNA-binding surface, allowing it to preferentially bind high-density DNA regions (HDRs). DNA-bound ParA–AMPPNP adopts a dimer conformation distinct from the ATP sandwich dimer, optimized for DNA association. Our ParA–AMPPNP–ParB structure reveals that ParB binds at the ParA dimer interface, stabilizing the ATPase-competent ATP sandwich dimer, ultimately driving ParA DNA dissociation. Thus, the data indicate how harnessing a conformationally adaptive dimer can drive large-scale cargo movement without the requirement for polymers and suggest a segregation mechanism by which ParA–ATP dimers equilibrate to HDRs shown to be localized near cell poles of dividing chromosomes, thus mediating equipartition of attached ParB–DNA substrates.
Single-molecule sequencing resolves the detailed structure of complex satellite DNA loci in Drosophila melanogaster
Authors: Khost Daniel E. , Eickbush Danna G. , Larracuente Amanda M.
Published: April 2017

Highly repetitive satellite DNA (satDNA) repeats are found in most eukaryotic genomes. SatDNAs are rapidly evolving and have roles in genome stability and chromosome segregation. Their repetitive nature poses a challenge for genome assembly and makes progress on the detailed study of satDNA structure difficult. Here, we use single-molecule sequencing long reads from Pacific Biosciences (PacBio) to determine the detailed structure of all major autosomal complex satDNA loci in Drosophila melanogaster, with a particular focus on the 260-bp and Responder satellites. We determine the optimal de novo assembly methods and parameter combinations required to produce a high-quality assembly of these previously unassembled satDNA loci and validate this assembly using molecular and computational approaches. We determined that the computationally intensive PBcR-BLASR assembly pipeline yielded better assemblies than the faster and more efficient pipelines based on the MHAP hashing algorithm, and it is essential to validate assemblies of repetitive loci. The assemblies reveal that satDNA repeats are organized into large arrays interrupted by transposable elements. The repeats in the center of the array tend to be homogenized in sequence, suggesting that gene conversion and unequal crossovers lead to repeat homogenization through concerted evolution, although the degree of unequal crossing over may differ among complex satellite loci. We find evidence for higher-order structure within satDNA arrays that suggest recent structural rearrangements. These assemblies provide a platform for the evolutionary and functional genomics of satDNAs in pericentric heterochromatin.
Moving beyond Bermuda: sharing data to build a medical information commons
Authors: Cook-Deegan Robert , McGuire Amy L.
Published: April 2017

The ubiquity of DNA sequencing and the advent of medical imaging, electronic health records, and “omics” technologies have produced a deluge of data. Making meaning of those data—creating scientific knowledge and useful clinical information—will vastly exceed the capacity of even the largest institutions. Data must be shared to achieve the promises of genomic science and precision medicine.
Crystal structure of the 1:2 adduct of bis(piperidinium) sulfate and 1,3-dimethylthiourea
Authors: Döring Cindy , Lueck Julian F. D. , Jones Peter G.
Published: April 2017

In the title compound, 2C5H12N+·SO4
2−·2C3H8N2S, the C=S groups of the two independent 1,3-dimethylurea molecules and the sulfur atom of the anion lie on twofold axes. The packing is centred on bis(piperidinium) sulfate ribbons parallel to the c axis; the cations are hydrogen bonded to the sulfate by N—H...O and C—H...O interactions. The 1,3-dimethylurea molecules are also hydrogen bonded to sulfate O atoms, and project outwards from the ribbon parallel to the b axis.
Crystal structures of the polymer precursors 3-(2,5-dimethoxy-3,4,6-trimethylphenyl)propyl methacrylate and 3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)propyl methacrylate
Authors: Goswami Shailesh K. , Hanton Lyall R. , McAdam C. John , Moratti Stephen C. , Simpson Jim
Published: April 2017

The closely related title compounds, 3-(2,5-dimethoxy-3,4,6-trimethylphenyl)propyl methacrylate, C18H26O4 (I), and 3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)propyl methacrylate, C16H20O4 (II), are monomers suitable for the preparation of redox polymers. They consist of a propylmethacrylate group and three methyl substituents on dimethoxybenzene and quinone cores, respectively. Both crystal structures feature weak C—H...O hydrogen bonds and C—H...π(ring) contacts between methyl groups and the six-membered rings.
Crystal structure of (1Z,4Z)-2,4-dimethyl-3H-benzo[b][1,4]diazepine
Authors: Nieto Carla I. , Claramunt Rosa M. , Torralba M. Carmen , Torres M. Rosario , Elguero Jose
Published: April 2017

The title compound, C11H12N2, is not planar due to the folding of the seven-membered ring. In the crystal, molecules are packed opposite each other to minimize the electronic repulsion but the long intermolecular distances indicate that no directional contacts are found.
Une surstructure de α-Ge, type diamant, induite par un dopage d'antimoine
Authors: Herrero Adrian Gómez , Hammoudi Lamia , Kars Mohammed , Roisnel Thierry , Otero-Diáz L. Carlos
Published: April 2017

Single crystals of antimony-doped germanium, Ge1–xSbx+0.01(x≃ 0.0625), were grown by chemical transport reaction. The alloy crystallizes as a superstructure of diamond-type α-Ge. All atoms in the asymmetric unit lie on special positions and are characterized by strong covalent bonds. The antimony atoms substitute for one germanium atom at full occupancy at Wyckoff position 4a(site symmetry -43m), and are also at an adjacent tetrahedral interstitial site with partially occupation (16%) at position 4c(or 4d) (site symmetry -43m). The structural model does not show close Sb...Sb contacts, and suggests that the interstitial antimony atoms move between the two adjacent tetrahedral sites.
(3β,5α,25R)-12-(Hydroxyimino)spirostan-3-yl acetate
Authors: Carrasco-Carballo Alan , Guerrero-Luna Gabriel , Hernández Linares María-Guadalupe , Bernès Sylvain
Published: April 2017

The title steroid, C29H45NO5, obtained by condensation of hecogenin acetate [systematic name: (3β,5α,25R)-12-oxospirostan-3-yl acetate] with NH2OH, has the oxime group substituting the C-12 site on theCring of the steroid nucleus. The introduction of this functional group allows the formation of chain motifs, using the oxime OH group as a donor and the O atom of theEring as an acceptor. TheC(8) chains formed by this intermolecular hydrogen bond are oriented parallel to the short cell axisa. The structural features of this compound are very close to those of C29H43NO5, the derivative with a C14=C15 double bond in theDring, which crystallizes in the same space group and with similar unit-cell parameters.
Methyl 3-(2,5-dimethoxy-3,4,6-trimethylphenyl)propanoate
Authors: Goswami Shailesh K. , Hanton Lyall R. , McAdam C. John , Moratti Stephen C. , Simpson Jim
Published: April 2017

In the title compound, C15H22O4, the fully substituted benzene ring carries a methyl propanoate, two methoxy and three methyl substituents. Both methoxy substituents are almost orthogonal to the benzene ring plane. The methyl propanoate group is almost planar, r.m.s. deviation 0.0138 Å, and is inclined to the benzene ring plane by 80.26 (14)°. In the crystal, C—H...O hydrogen bonds form head-to-tail chains of molecules along theb-axis direction that are supported by very weak C—H...π(ring) contacts.
Audience development: a cross-national comparison
Authors: Cuenca-Amigo Macarena , Makua Amaia
Published: April 2017

Purpose

The purpose of this paper is to review the concept of audience development, analysing differences between a number of countries and identifying common elements that underlie the concept regardless of the context.

Design/methodology/approach

In addition to the literature review, fieldwork has been conducted in the UK, Denmark, Italy, and Spain applying qualitative methodology. The study has been structured in two phases. The first phase comprised 26 in-depth interviews with European experts in audience development while the second phase consisted of six focus groups with European experts.

Findings

The paper reveals differences between countries, ranging from the definition of the term audience development to the approach undertaken. Despite this, a number of aspects, independent of the context and considered key to a successful audience development, are identified. These aspects are related to the consideration of the development of audiences as a transversal long-term strategy supported by the top management of the organisation.

Originality/value

The value provided is twofold. First, thanks to the empirical data used, the paper analyses the socio-cultural aspects that affect the emergence of country-specific approaches to audience development and it individuates general features and ideas that contribute to the better understanding of the concept itself. Second, it is one of the few academic works carried out in Spain on this issue.
Effects of human capital on the relationship between export and firm innovation
Authors: Liu Guangqiang , Pang Lirang , Kong Dongmin
Published: April 2017

Purpose

This study aims to examine the effects of human capital, such as top managers and employees, on the relationship between export and firm innovation. Although the issue of how firms remain creative and competitive in international markets is important both in practice and in research, little attention has been devoted to the internal mechanism through which export affects innovation.

Design/methodology/approach

Using a hand-collected data set of human capital on the overseas experiences of managers and educational levels of employees as the basis, this study utilizes Chinese A-share listed firms from 2006 to 2015 to test the research questions through regression analyses.

Findings

First, export significantly enhances firm innovation. Second, different types of human capital exhibit different moderating and mediating effects. Specifically, returnee managers play positive moderating and mediating roles on the relationship between export and innovation, whereas highly educated employees exhibit negative moderating effects and no mediating effect. Third, to address potential endogeneity, the authors construct novel instrumental variables of export and human capital and use the two-stage least-squares method to identify causality.

Originality/value

This study provides direct policy implications by showing the roles of export and human capital in innovation, thereby guiding the management practices of firms and talent policies of governments.
Performance aspiration, industrial search and R&D investment among chinese firms
Authors: Su Yiyi , Su Taoyong
Published: April 2017

Purpose

This paper aims to examine the behavioral determinants of firm research and development (R&D) investment in China by looking into the interaction between performance aspiration and industrial search.

Design/methodology/approach

The author argues that the performance aspiration effect is strengthened in R&D-intensive industries based on the isomorphism rationale, whereas it is weakened by high industry R&D intensity owing to the differentiation rationale. Deriving from the isomorphism and differentiation rationales, the author developed a set of competitive hypotheses and empirically tested them by using a large panel data of 6,539 company-years from China for the period 2001-2003.

Findings

First, R&D intensity is positively related to the deviation of firm performance from aspiration. Second, industry R&D intensity negatively moderates the relationship between performance aspiration and firm R&D intensity for firms performing above aspiration. Therefore, the results provide support for the differentiation rationale.

Originality/value

The study contributes to the ongoing research that provides and tests the behavioral explanations for R&D and innovation. By delving into the moderating role of industry R&D intensity, the author advocate the need for contextualizing performance aspiration in industrial environments. The study informs policymakers and business leaders about the interaction between the external environment and internal decision process in R&D investment decision.
The effects of organizational isomorphism on innovation performance through knowledge search in industrial cluster
Authors: Zhang Hui , Hu Baoliang
Published: April 2017

Purpose

This paper aims to identify the relationships of both organizational isomorphism and knowledge search with the innovation performance of cluster enterprises. It also specifies the mechanism by which organizational isomorphism affects innovation performance, through knowledge search.

Design/methodology/approach

Firm-level data were collected with questionnaires distributed to cluster enterprises in Zhejiang Province, China, which produced 165 usable responses for the analysis. Both multiple regression analyses and structural equation modelling were used to test the hypotheses.

Findings

Normative isomorphism and mimetic isomorphism have inverse U-shaped effects on the innovation performance of cluster enterprises, as does exploratory knowledge search. Exploitative knowledge search and the balance between two types of knowledge search have positive effects on the innovation performance of cluster enterprises; exploratory and exploitative knowledge searches exert partial mediation effects between the organizational isomorphism and innovation performance of cluster enterprises. The mediating effect of knowledge search transforms the inverse U-shaped effect of normative isomorphism and mimetic isomorphism on innovation performance into a positive effect.

Originality/value

This study provides new insights into the effects of organizational isomorphism on innovation performance by showing the indirect influence of organizational isomorphism in clusters. The study proposes a strategic logic of moderate isomorphism, clarifies the innovative effect of different knowledge search modes and reveals the construction and management mechanisms of organizational isomorphism and knowledge search strategy of firms in clusters.
Do outside directors matter? the impact of prestigious CEOs on firm performance
Authors: Zhang Liang , Zhang Zhe , Jia Ming , Ren Yeyao
Published: April 2017

Purpose

The effect of prestigious CEOs on firm performance is not clear. By integrating resource dependence and agency theories, this paper aims to focus on how prestigious CEOs affect firm performance and how informal relations between the CEO and outside directors affect agency costs and resource benefits associated with prestigious CEOs.

Design/methodology/approach

The authors use ordinary least squares (OLS) regression to analyze their data set, which is conducted by a sample of 4,226 Chinese listed firms from 2009 to 2013. The authors also use OLS regression to assess the sensitivity and robustness of their findings.

Findings

The findings indicate that prestigious CEOs are significantly and positively associated with firm performance. Moreover, the authors find the effect of prestigious CEOs on firm performance is more pronounced when prestigious outside directors interact with prestigious CEOs.Guanxi– a Chinese concept similar to camaraderie – attenuates this association, particularly when the CEO and outside directors share the same surname.

Research limitations/implications

Future research should consider whether there is a mediating link between prestigious affiliates (i.e. CEOs) and firm performance.

Practical/implications

This paper provides two practical implications. First, China Securities Regulatory Commission policymakers should pay more attention to outside directors’ quality and ability and their informalguanxiwith the CEO. Second, prestigious CEOs may also have potential costs.

Originality/value

This study contributes to corporate governance literature and CEO-board relations literature by shedding light on how resource dependence and agency theories apply to corporate governance.