bluuebunny/crossref_metadata_2025 huggingface dataset:
Beyond the 3 Rs to a More Comprehensive Framework of Principles for Animal Research Ethics
Authors: DeGrazia David , Beauchamp Tom L
Published: July 2019

We have produced a framework of general moral principles for animal research ethics in a book, Principles of Animal Research Ethics, which is forthcoming with Oxford University Press in fall 2019. This book includes a detailed statement and defense of our framework along with critical commentaries on our work from seven eminent scholars: Larry Carbone, Frans de Waal, Rebecca Dresser, Joseph Garner, Brian Hare, Margaret Landi, and Julian Savulescu. In the present paper, we explain the motivation for our project and present our framework of principles. The first section explains why a new framework is both needed and timely, on the basis of six important developments in recent decades. The second section challenges assertions of an unbridgeable gulf dividing the animal-research and animal-protection communities on the issue of animal research. It does so, first, by indicating common ground in the core values of social benefit and animal welfare and, then, by presenting and briefly defending our framework: three principles of social benefit and three principles of animal welfare. These six principles, we argue, constitute a more suitable framework than any other that is currently available, including the canonical 3 Rs advanced in 1959 by William M. S. Russell and Rex L. Burch.
Reproducibility and Rigor in Animal-Based Research
Authors: Macleod Malcolm , Mohan Swapna
Published: July 2019

Increasing focus on issues of research reproducibility affords us the opportunity to review some of the key issues related in vivo research. First, we set out some key definitions, to guide the reader through the rest of the paper. Next we consider issues of epistemology, of how animal experiments lead to changes in our understanding of biomedicine and, potentially, to the development of new therapeutics. Here we consider the meaning of statistical significance; the importance of understanding whether findings have general truth; and the advances in knowledge which can result from ‘failed’ replication. Then, we consider weaknesses in the design, conduct and reporting of experiments, and review evidence for this from systematic reviews and from experimental studies addressing these issues. We consider the impact that these weaknesses have on the development of new treatments for human disease, and reflect on the response to these issues from the biomedical research community. Finally, we consider strategies for improvement including increased use of brief, pre-registered study protocols; pre-registration, open publication and open data; and the central importance of education in improving research performance.
Multi-directed Graph Complexes and Quasi-isomorphisms Between Them II: Sourced Graphs
Authors: Živković Marko
Published: July 2019

We prove that the projection from graph complex with at least one source to oriented graph complex is a quasi-isomorphism, showing that homology of the “sourced” graph complex is also equal to the homology of standard Kontsevich’s graph complex. This result may have applications in theory of multi-vector fields $T_{\textrm{poly}}^{\geq 1}$ of degree at least one, and to the hairy graph complex that computes the rational homotopy of the space of long knots. The result is generalized to multi-directed graph complexes, showing that all such graph complexes are quasi-isomorphic. These complexes play a key role in the deformation theory of multi-oriented props recently invented by Sergei Merkulov. We also develop a theory of graph complexes with arbitrary edge types.
Genetic parameters of meat quality, carcass composition, and growth traits in commercial swine
Authors: Khanal Piush , Maltecca Christian , Schwab Clint , Gray Kent , Tiezzi Francesco
Published: July 2019

Swine industry breeding goals are mostly directed towards meat quality and carcass traits due to their high economic value. Yet, studies on meat quality and carcass traits including both phenotypic and genotypic information remain limited, particularly in commercial crossbred swine. The objectives of this study were to estimate the heritabilities for different carcass composition traits and meat quality traits and to estimate the genetic and phenotypic correlations between meat quality, carcass composition, and growth traits in 2 large commercial swine populations: The Maschhoffs LLC (TML) and Smithfield Premium Genetics (SPG), using genotypes and phenotypes data. The TML data set consists of 1,254 crossbred pigs genotyped with 60K SNP chip and phenotyped for meat quality, carcass composition, and growth traits. The SPG population included over 35,000 crossbred pigs phenotyped for meat quality, carcass composition, and growth traits. For TML data sets, the model included fixed effects of dam line, contemporary group (CG), gender, as well as random additive genetic effect and pen nested within CG. For the SPG data set, fixed effects included parity, gender, and CG, as well as random additive genetic effect and harvest group. Analyses were conducted using BLUPF90 suite of programs. Univariate and bivariate analyses were implemented to estimate heritabilities and correlations among traits. Primal yield traits were uniquely created in this study. Heritabilities [high posterior density interval] of meat quality traits ranged from 0.08 [0.03, 0.16] for pH and 0.08 [0.03, 0.1] for Minolta b* to 0.27 [0.22, 0.32] for marbling score, except intramuscular fat with the highest estimate of 0.52 [0.40, 0.62]. Heritabilities of primal yield traits were higher than that of primal weight traits and ranged from 0.17 [0.13, 0.25] for butt yield to 0.45 [0.36, 0.55] for ham yield. The genetic correlations of meat quality and carcass composition traits with growth traits ranged from moderate to high in both directions. High genetic correlations were observed for male and female for all traits except pH. The genetic parameter estimates of this study indicate that a multitrait approach should be considered for selection programs aimed at meat quality and carcass composition in commercial swine populations.
Genetic Diversity and Population Structure of Wild Sunflower (Helianthus annuus L.) in Argentina: Reconstructing Its Invasion History
Authors: Hernández Fernando , Presotto Alejandro , Poverene Mónica , Mandel Jennifer R
Published: July 2019

Studying the levels and patterns of genetic diversity of invasive populations is important to understand the evolutionary and ecological factors promoting invasions and for better designing preventive and control strategies. Wild sunflower (Helianthus annuus L.) is native to North America and was introduced, and has become invasive, in several countries, including Argentina (ARG). Here, using classical population genetic analyses and approximate Bayesian computation (ABC) modeling, we studied the invasion history of wild sunflower in ARG. We analyzed 115 individuals belonging to 15 populations from ARG (invasive range) and United States (US, native range) at 14 nuclear and 3 chloroplast simple sequence repeat markers along with 23 phenotypic variables. Populations from ARG showed similar levels of nuclear genetic diversity to US populations and higher genetic diversity in the chloroplast genome, indicating no severe genetic bottlenecks during the invasion process. Bayesian clustering analysis, based on nuclear markers, suggests the presence of 3 genetic clusters, all present in both US and ARG. Discriminant analysis of principal components (DAPC) detected an overall low population structure between central US and ARG populations but separated 2 invasive populations from the rest. ABC modeling supports multiple introductions but also a southward dispersal within ARG. Genetic and phenotypic data support the central US as a source of introduction while the source of secondary introductions could not be resolved. Finally, using genetic markers from the chloroplast genome, we found lower population structure in ARG when compared with US populations, suggesting a role for seed-mediated gene flow in Argentina.
German Constitutional Law
Authors: Christian Bumke , Andreas Voßkuhle
Published: July 2019

This book provides a comprehensive summary of German constitutional law, in particular the case law of the German Federal Constitutional Court. It provides first-hand insight into the complex principles of the Basic Law, or Grundgesetz (GG), and an authoritative introduction to the history of the German constitution, the Basic Law, and the methodology of the Federal Constitutional Court. As well as an analysis of the general principles of German constitutional law, the book covers the salient articles of the German constitution and offers relevant extracts of the Court's most important decisions on the provisions of the Basic Law. It provides notes and discussions of landmark cases to illustrate their legal and historical context and give the reader a clear understanding of the principles governing German constitutional law. The book covers the fundamental rights catalogue of the Basic Law and offers a comprehensive account of its intellectual moorings. It includes landmark jurisprudence on the equal treatment of same-sex couples, life imprisonment, the legal structure of property, the right to assembly, and the right to informational self-presentation. The book also covers the provisions and respective case law governing the state structure of Germany, for instance the recent decisions on the prohibition of the far-right German nationalist party, and the Court's jurisprudence on European integration, including the most recent decisions on the OMT program of the European Central Bank.
6 Art. 5 GG: Freedom of Communication and Art
Authors: Christian Bumke , Andreas Voßkuhle
Published: July 2019

This chapter discusses Art. 5 of the Grundgesetz (GG), which guarantees freedom of communication, art and science. It first considers the jurisprudence of the Federal Constitutional Court concerning the scope of protection for freedom of opinion, focussing on the importance of such freedom in a democratic community, consequences flowing from the importance of freedom of opinion, and limits on the protective scope of freedom of opinion. The chapter then examines the scope of protection for freedom of information, freedom of the press and freedom of broadcast before analysing the limits on the reservation of the fundamental rights protected in Art. 5 GG, with emphasis on the problematic nature of limits imposed by general laws, the doctrine of reciprocity and the principle of proportionality, and the balancing of interests between freedom of opinion and a protected legal interest. Finally, the chapter describes the scope of protection for artistic freedom.
16 Arts. 16 and 16a GG: Protection from Extradition and Deprivation of Citizenship, and Asylum Law
Authors: Christian Bumke , Andreas Voßkuhle
Published: July 2019

This chapter examines the three fundamental rights guaranteed under Art. 16 and 16a of the Grundgesetz (GG): a prohibition on the deprivation of citizenship and limits on the loss of German citizenship, a ban on the extradition of Germans, and the right to political asylum. It begins with a discussion of the Federal Constitutional Court's jurisprudence regarding protection of citizenship, more specifically revocation of fraudulently obtained citizenship and the provision allowing agencies to challenge official acknowledgements of paternity by German men. It then considers cases relating to protection against the extradition of Germans before analysing the asylum law, with particular emphasis on political persecution, the concepts of ‘safe third countries’ and ‘secure country of origin’, and limitations on the right of asylum.
26 Art. 33 GG: Equal Citizenship, Civil Service
Authors: Christian Bumke , Andreas Voßkuhle
Published: July 2019

This chapter deals with equal access to civil service which is guaranteed by Art. 33 of the Grundgesetz (GG). It first examines the Federal Constitutional Court's jurisprudence regarding the importance of the civil service to a democratic state founded on the rule of law before addressing the question of access to civil service, with emphasis on the performance principle and the procedures which safeguard it. It then analyses the Court's so-called ‘Radicals decision’, in which it ruled that the duty of political loyalty was one of the traditional principles of the professional civil service, and the scope of the functional reservation of Art. 33 para. 4 GG. It also explains the prohibition of strikes by civil servants, along with the traditional principles of the professional civil service. Finally, it describes the traditional principles of the civil service as individual rights comparable to fundamental rights.
Introduction
Authors: Bielekova Bibiana , Birnbaum Gary , Lisak Robert P.
Published: July 2019

The opening chapter provides a short introduction to the rest of the book. It outlines the purpose of the book, which is to introduce the rapidly expanding field of neuroimmunology, the discipline that deals with neurologic diseases in which the immune system plays a dominant, or at least preponderant, role in pathogenesis.
CIDP and Related Variants and Overlap Disorders
Authors: Allen Jeffrey A.
Published: July 2019

This chapter begins with a history of chronic immunological neuropathies. It then looks in particular at chronic inflammatory demyelinating polyneuropathy (CIDP), which is an immune-mediated peripheral nerve disorder characterized by progressive or relapsing motor or sensory symptoms. It then considers the epidemiology, clinical manifestations, and electrophysiology of CIDP. The chapter examines diagnostic data and diagnostic criteria for CIDP. It then looks at other neuropathies with clinical and electrophysiologic features that are shared with CIDP. Particular attention is given to neuropathy associated with monoclonal gammopathy including IgM associated neuropathy and POEMS syndrome, polyneuropathies associated with specific autoantibodies including antibodies that target nodal and paranodal structures, and multifocal motor neuropathy. For each condition diagnostic data, pathophysiology and treatment are discussed.
Symptomatic therapy
Authors: Glassock Richard J
Published: July 2019

Patients with glomerular diseases develop a wide variety of biochemical disturbances and pathophysiologic alterations leading to overt clinical manifestations. Collectively, these abnormalities give rise to the classical syndromes of glomerular disease. The clinical abnormalities resulting from these disturbances in renal pathophysiology require management in order to minimize or avoid disabling symptoms, often referred to as symptomatic therapy. This chapter provides an introduction to and overview of these abnormalities. It then covers therapies for a variety of manifestations of primary glomerular diseases, including haematuria, oedema, hypertension, hyperlipidaemia (e.g. hypercholesterolaemia), the ‘hypercoagulable’ or ‘thrombophilic’ state, non-disease-specific strategies designed to retard the progression of renal disease (loss of glomerular filtration rate, GFR), and more.
The pharmacology of old and new agents for specific therapy of primary glomerular diseases
Authors: Ponticelli Claudio , Glassock Richard J
Published: July 2019

A wide variety of pharmacologic agents having diverse mechanisms of action and potential adverse events are widely used in treatment of primary glomerular diseases. However, the indications for treating specific disease entities still represent a matter of controversy and discussion among nephrologists. Indeed, randomized controlled trials are relatively few in number and are often small, underpowered, and of short duration. Conversely, drugs such as glucocorticoids (GCs) and cytotoxic agents may exert beneficial effects in some glomerular diseases, but may also be responsible for disquieting adverse events that can discourage their use in patients with indolent glomerulonephritis. Recently, a number of biological agents have been developed to spare the use of potentially toxic agents while targeting the immune cells implicated in the pathogenesis of glomerular diseases. Thus far, however, many of them have failed to find a role in the clinical management of glomerular diseases. This chapter reports the main characteristics of the pharmacological classes of immunosuppressive agents that may be used in primary glomerular diseases.
Minimal change disease
Authors: Ponticelli Claudio , Glassock Richard J , Coppo Rosanna
Published: July 2019

This chapter discusses minimal change disease (MCD), which is chiefly characterized clinically by episodes of nephrotic syndrome (NS) and presents with massive proteinuria, hypo-albuminaemia, hyperlipidaemia, and generalized oedema, Morphologically, it is characterized by no or only minimal glomerular abnormalities in a renal biopsy examined by light microscopy and immunofluorescence, while there is diffuse effacement of the podocyte foot process by electron microscopy. MCD is the most common cause of NS in children but it may also develop at any age, including in the elderly. This chapter covers the pathology, presentation, and treatment of MCD, including practical tips for the practitioner.
Historical and conceptual aspects
Authors: Berrios German E.
Published: July 2019

‘Inpatient treatment’ in psychiatry names a cluster of therapeutic activities whose meaning and justification have changed throughout history. Currently, an emphasis on the success of neurobiological treatment tends to give the impression that the spaces of care themselves are little more than short-term containers. This would be wrong. Best considered as dynamic environments, spaces of care have always had a profound effect on the bodies and minds of their occupants. Whether such affects have been negative or positive has depended upon the sociopolitical, economic, and theoretical factors governing their organization. To understand and improve these spaces of care it is important to realize that they sit at the intersection of various dimensions: container versus dynamic, physical versus social, custodial versus interventionistic, intramural versus extramural, institutional versus rehabilitatory, and communitarian versus societal. Throughout the centuries, a variety of therapeutic interventions have been offered within these spaces. Because their nature, ethics, and rationale have repeatedly changed, it may be more sensible to consider the current state of inpatient psychiatry not as the final stage in the evolution of the ‘science of psychiatry’ but as a mere moment in the evolution of a never-ending interpretative process about the meaning of madness.
Mental Health Legislation
Authors: Chalmers Julie
Published: July 2019

This chapter gives an overview of the mental health legislation of England and Wales as it applies to inpatient psychiatric wards, discusses some key concepts such as capacity and deprivation of liberty, and highlights the principles underpinning the Human Rights Act 1998, the Mental Capacity Act 2005, and the Mental Health Act 1983. The use of legislation at the point of admission and in the provision of treatment particularly in the absence of consent will be considered. The safeguards protecting the patient detained under the Mental Health Act will be highlighted and the use of community treatment orders on leaving hospital will be briefly touched upon. Finally, governance of the use of the Mental Health Act and some future challenges to the basis of legislation will be discussed.
Physical health care
Authors: Toynbee Mark , Frighi Valeria
Published: July 2019

This chapter explores the impact of physical health comorbidities on morbidity and mortality in individuals with psychiatric illnesses. There is a significant and enduring disparity in the life expectancy of the general population and people with severe mental illness (SMI). The majority of this inequality is due to preventable physical illness, particularly cardiovascular disease, respiratory disorders, and diabetes mellitus. Risk factors for these disorders such as smoking, obesity, and lack of physical activity are disproportionately represented in SMI populations and some psychotropic medications also contribute. Physical ill health impacts negatively on mental health outcomes. Psychiatric inpatient admissions represent a unique opportunity to address many of these illnesses and risk factors. Physical health care is the business of all professionals involved in inpatient care.
Adverse reactions to medication
Authors: Bajorek Tomasz , Hafferty Jonathan
Published: July 2019

Adverse reactions to medication represent a major issue in inpatient psychiatry. This chapter systematically explores the most relevant, concerning, and problematic adverse effects routinely encountered in an inpatient setting. It describes the typical presentation, pathophysiology, incidence, and practical management of these problems. Extrapyramidal side effects including acute dystonia, drug-induced parkinsonism, akathisia, and tardive dyskinesia are considered before the chapter explores the rare but potentially life-threatening condition of neuroleptic malignant syndrome. Other adverse effects common to antipsychotics that are described include hyperprolactinaemia and psychotropic-induced arrhythmias including QTc prolongation. Sexual dysfunction is an under-recognized and undertreated adverse effect common to several classes of psychotropic medication and is also considered. Focusing on antidepressants, the chapter reviews the frequently encountered issue of hyponatraemia as well as serotonin syndrome and selective serotonin reuptake inhibitor-induced bleeding risk. Finally, the chapter addresses perinatal considerations for psychotropic drugs.
Assessment and management of vulnerable patients
Authors: Behrman Sophie , Dan-Cooke Dorcas
Published: July 2019

Staff working on mental health wards are well accustomed to assessing and managing vulnerable patients. With the current organization of mental health care in the UK, where only 5.7% of patients in contact with mental health services received inpatient care in a year, only the most unwell and/or complex patients are seen on mental health wards. These patients may well have numerous vulnerabilities, which require assessment and management as part of the holistic treatment of the patient during their admission and for discharge planning. This chapter discusses who these particularly vulnerable patients are, examines what sort of vulnerabilities patients might experience, and suggests possible management strategies.
Diversity in inpatient care
Authors: Mbayiwa Michelle
Published: July 2019

Diversity in inpatient care is important for a number of reasons. This chapter discusses the protected characteristics of race, disability, gender reassignment, age, religion or belief, sex, and sexual orientation, and how the way in which they are approached impacts the assessment and treatment of patients within an inpatient setting. It also highlights the importance of challenging and addressing these issues, and suggests some points of best practice. Diversity is a complex issue and organizations are required to improve their services for patients and staff that fit the protected characteristics. Services and professionals must continue working towards inclusivity and promotion of diversity.
Psychiatric intensive care
Authors: Rule Ashley
Published: July 2019

A psychiatric intensive care unit (PICU) represents the frontline of acute psychiatric services, and the purpose of a PICU is to provide safe and effective care to the most challenging patients in the acute psychiatric population. PICU psychiatry concerns the management of acute psychiatric illness, usually of a manic and/or psychotic nature, associated with behavioural disturbance. Such disturbance often involves violence and aggression towards others. The basic principles of PICU psychiatry involve the provision of a less stimulating, safe environment for the patient; consideration of physical, procedural, and relational security; and the possible use of restrictive practices such as seclusion/isolation, restraint, and rapid tranquilization.
Survival of molecular gas in a stellar feedback-driven outflow witnessed with the MUSE TIMER project and ALMA
Authors: Leaman Ryan , Fragkoudi Francesca , Querejeta Miguel , Leung Gigi Y C , Gadotti Dimitri A , Husemann Bernd , Falcón-Barroso Jesus , Sánchez-Blázquez Patricia , van de Ven Glenn , Kim Taehyun , Coelho Paula , Lyubenova Mariya , de Lorenzo-Cáceres Adriana , Martig Marie , Martinez-Valpuesta Inma , Neumann Justus , Pérez Isabel , Seidel Marja
Published: July 2019

Stellar feedback plays a significant role in modulating star formation, redistributing metals, and shaping the baryonic and dark structure of galaxies – however, the efficiency of its energy deposition to the interstellar medium is challenging to constrain observationally. Here we leverage HST and ALMA imaging of a molecular gas and dust shell ($M_{\mathrm{ H}_2} \sim 2\times 10^{5}\, {\rm M}_{\odot }$) in an outflow from the nuclear star-forming ring of the galaxy NGC 3351, to serve as a boundary condition for a dynamical and energetic analysis of the outflowing ionized gas seen in our MUSE TIMER survey. We use starburst99 models and prescriptions for feedback from simulations to demonstrate that the observed star formation energetics can reproduce the ionized and molecular gas dynamics – provided a dominant component of the momentum injection comes from direct photon pressure from young stars, on top of supernovae, photoionization heating, and stellar winds. The mechanical energy budget from these sources is comparable to low luminosity active galactic neuclei, suggesting that stellar feedback can be a relevant driver of bulk gas motions in galaxy centres – although here ≲10−3 of the ionized gas mass is escaping the galaxy. We test several scenarios for the survival/formation of the cold gas in the outflow, including in situ condensation and cooling. Interestingly, the geometry of the molecular gas shell, observed magnetic field strengths and emission line diagnostics are consistent with a scenario where magnetic field lines aided survival of the dusty ISM as it was initially launched (with mass-loading factor ≲1) from the ring by stellar feedback. This system’s unique feedback-driven morphology can hopefully serve as a useful litmus test for feedback prescriptions in magnetohydrodynamical galaxy simulations.
Modelling pulsed gamma-ray emissions from millisecond pulsars with double peaks
Authors: Chang Shan , Zhang Li , Li Xiang , Jiang Zejun
Published: July 2019

Pulsed γ-ray properties of 22 millisecond pulsars (MSPs) with double peaks are studied in the revised versions of the outer gap (OG) and the stripped wind (SW) models. The major differences between these two models are magnetic field structures, γ-ray production sites, and radiation mechanisms. In the models, γ-ray light curves of these MSPs are calculated through a Markov chain Monte Carlo (MCMC) method to pick best-fitting model parameters. Our results indicate that (1) both models can reproduce observed double-peak structures of the MSPs well, for most MSPs, a relatively large magnetic inclination angle (α ∼ 50°–90°) and small viewing angle (ζ ∼ 30°–90°) are obtained in the OG model, but a relatively small α ∈ (20°, 60°) and large ζ ∈ (70°, 150°) in the SW model; (2) phase-averaged spectra, cut-off energy, and γ-ray luminosity calculated in both models are consistent with observed those by Fermi-Large Area Telescope (LAT). Therefore, it may be concluded that the OG and the SW models for describing high-energy emissions of MSPs cannot be ruled out at present, and further studies are required.
Localization of binary black hole mergers with known inclination
Authors: Corley K Rainer , Bartos Imre , Singer Leo P , Williamson Andrew R , Haiman Zoltán , Kocsis Bence , Nissanke Samaya , Márka Zsuzsa , Márka Szabolcs
Published: July 2019

The localization of stellar-mass binary black hole mergers using gravitational waves is critical in understanding the properties of the binaries’ host galaxies, observing possible electromagnetic emission from the mergers, or using them as a cosmological distance ladder. The precision of this localization can be substantially increased with prior astrophysical information about the binary system. In particular, constraining the inclination of the binary can reduce the distance uncertainty of the source. Here, we present the first realistic set of localizations for binary black hole mergers, including different prior constraints on the binaries’ inclinations. We find that prior information on the inclination can reduce the localization volume by a factor of 3. We discuss two astrophysical scenarios of interest: (i) follow-up searches for beamed electromagnetic/neutrino counterparts and (ii) mergers in the accretion discs of active galactic nuclei.
Two families of elliptical plasma lenses
Authors: Er Xinzhong , Rogers Adam
Published: July 2019

Plasma lensing is the refraction of low-frequency electromagnetic rays due to free electrons in the interstellar medium. Although the phenomenon has a distinct similarity to gravitational lensing, particularly in its mathematical description, plasma lensing introduces other additional features, such as wavelength dependence, radial rather than tangential image distortions, and strong demagnification of background sources. Axisymmetrical models of plasma lenses have been well studied in the literature, but density distributions with more complicated shapes can provide new and exotic image configurations and increase the richness of the magnification properties. As a first step towards non-axisymmetrical distributions, we study two families of elliptical plasma lens, softened power law, and exponential plasma distributions. We perform numerical studies on each lens model, and present them over a parameter space. In addition to deriving elliptical plasma lens formulae, we also investigate the number of critical curves that the lens can produce by studying the lens parameter space, in particular the dependence on the lensing ellipticity. We find that the introduction of ellipticity into the plasma distribution can enhance the lensing effects as well as the complexity of the magnification map.
Subaru narrow-band imaging search for Lyman continuum from galaxies at z > 3 in the GOODS-N field
Authors: Iwata Ikuru , Inoue Akio K , Micheva Genoveva , Matsuda Yuichi , Yamada Toru
Published: July 2019

We report results of a search for galaxies at z > 3 with Lyman continuum (LyC) emission using a narrow-band filter NB359  with Subaru/Suprime-Cam in an ∼800 arcmin2 blank field around the GOODS-N. We use 103 star-forming galaxies (SFGs) and 8 active galactic nuclei (AGNs) with spectroscopic redshifts in a range between 3.06 and 3.5 and 157 photometrically selected z = 3.1 Lyman α emitter (LAE) candidates as the targets. After removing galaxies spectroscopically confirmed to be contaminated by foreground sources, we found two SFGs and one AGN as candidate LyC-emitting sources among the targets with spectroscopic redshifts. Among LAE candidates, five sources are detected in the NB359 image, and three among them may be contaminated by foreground sources. We compare the sample galaxies in the GOODS-N with those in the SSA22, where a prominent protocluster at z = 3.1 is known and an LyC search using the same NB359 filter has been made. The frequency of galaxies with LyC leakage in the SSA22 field may be about two times higher than that of galaxies in the GOODS-N with the sample ultraviolet (UV) magnitude range, although the numbers of LyC detections in these fields are too small to make a statistically significant conclusion. By combining the sample galaxies in these fields, we place the 3σ upper limits of the observed LyC-to-UV flux density ratio and LyC escape fraction for galaxies at z = 3.1 with absolute UV magnitude MUV < −18.8 as (fLyC/fUV)obs < 0.036 and $f_\mathrm{esc}^\mathrm{abs}\,\lt\, 8$ per cent, respectively.
Globular clusters as a probe for Weyl conformal gravity
Authors: Islam Tousif
Published: July 2019

Eventual flattening of velocity dispersion profiles of some galactic globular clusters (GCs) in the Milky Way cannot be explained in the framework of Newtonian gravity and hence in general theory of relativity in the weak field limit, without resorting to the occurrence of tidal effects. We explore the possibility of explaining such deviation from expected Keplerian fall-off in dispersion profiles within the context of Weyl conformal gravity. We choose a set of 20 GCs for which recent kinematic measurements are available. We model the GCs with approximate Hernquist mass profiles and choose a constant mass-to-light ratio throughout the cluster as the only free parameter in the model. Our analysis finds reasonable Weyl gravity fits to the observed dispersion profiles, exhibiting both Keplerian decline and eventual flattening, with acceptable mass-to-light ratios. We further recover a Tully–Fisher-like scaling relation in GCs through Weyl gravity.
A ‘poly-transfection’ method for rapid, one-pot characterization and optimization of genetic systems
Authors: Gam Jeremy J , DiAndreth Breanna , Jones Ross D , Huh Jin , Weiss Ron
Published: July 2019

Biological research is relying on increasingly complex genetic systems and circuits to perform sophisticated operations in living cells. Performing these operations often requires simultaneous delivery of many genes, and optimizing the stoichiometry of these genes can yield drastic improvements in performance. However, sufficiently sampling the large design space of gene expression stoichiometries in mammalian cells using current methods is cumbersome, complex, or expensive. We present a ‘poly-transfection’ method as a simple yet high-throughput alternative that enables comprehensive evaluation of genetic systems in a single, readily-prepared transfection sample. Each cell in a poly-transfection represents an independent measurement at a distinct gene expression stoichiometry, fully leveraging the single-cell nature of transfection experiments. We first benchmark poly-transfection against co-transfection, showing that titration curves for commonly-used regulators agree between the two methods. We then use poly-transfections to efficiently generate new insights, for example in CRISPRa and synthetic miRNA systems. Finally, we use poly-transfection to rapidly engineer a difficult-to-optimize miRNA-based cell classifier for discriminating cancerous cells. One-pot evaluation enabled by poly-transfection accelerates and simplifies the design of genetic systems, providing a new high-information strategy for interrogating biology.
PPARβ/δ recruits NCOR and regulates transcription reinitiation of ANGPTL4
Authors: Legrand Nathalie , Bretscher Clemens L , Zielke Svenja , Wilke Bernhard , Daude Michael , Fritz Barbara , Diederich Wibke E , Adhikary Till
Published: July 2019

In the absence of ligands, the nuclear receptor PPARβ/δ recruits the NCOR and SMRT corepressors, which form complexes with HDAC3, to canonical target genes. Agonistic ligands cause dissociation of corepressors and enable enhanced transcription. Vice versa, synthetic inverse agonists augment corepressor recruitment and repression. Both basal repression of the target gene ANGPTL4 and reinforced repression elicited by inverse agonists are partially insensitive to HDAC inhibition. This raises the question how PPARβ/δ represses transcription mechanistically. We show that the PPARβ/δ inverse agonist PT-S264 impairs transcription initiation by decreasing recruitment of activating Mediator subunits, RNA polymerase II, and TFIIB, but not of TFIIA, to the ANGPTL4 promoter. Mass spectrometry identifies NCOR as the main PT-S264-dependent interactor of PPARβ/δ. Reconstitution of knockout cells with PPARβ/δ mutants deficient in basal repression results in diminished recruitment of NCOR, SMRT, and HDAC3 to PPAR target genes, while occupancy by RNA polymerase II is increased. PT-S264 restores binding of NCOR, SMRT, and HDAC3 to the mutants, resulting in reduced polymerase II occupancy. Our findings corroborate deacetylase-dependent and -independent repressive functions of HDAC3-containing complexes, which act in parallel to downregulate transcription.
Circularization of flavivirus genomic RNA inhibits de novo translation initiation
Authors: Sanford Thomas J , Mears Harriet V , Fajardo Teodoro , Locker Nicolas , Sweeney Trevor R
Published: July 2019

Members of the Flaviviridae family, including dengue virus (DENV) and yellow fever virus, cause serious disease in humans, whilst maternal infection with Zika virus (ZIKV) can induce microcephaly in newborns. Following infection, flaviviral RNA genomes are translated to produce the viral replication machinery but must then serve as a template for the transcription of new genomes. However, the ribosome and viral polymerase proceed in opposite directions along the RNA, risking collisions and abortive replication. Whilst generally linear, flavivirus genomes can adopt a circular conformation facilitated by long-range RNA–RNA interactions, shown to be essential for replication. Using an in vitro reconstitution approach, we demonstrate that circularization inhibits de novo translation initiation on ZIKV and DENV RNA, whilst the linear conformation is translation-competent. Our results provide a mechanism to clear the viral RNA of ribosomes in order to promote efficient replication and, therefore, define opposing roles for linear and circular conformations of the flavivirus genome.
Targeted broad-based genetic testing by next-generation sequencing informs diagnosis and facilitates management in patients with kidney diseases
Authors: Mansilla M Adela , Sompallae Ramakrishna R , Nishimura Carla J , Kwitek Anne E , Kimble Mycah J , Freese Margaret E , Campbell Colleen A , Smith Richard J , Thomas Christie P
Published: July 2019

Background

The clinical diagnosis of genetic renal diseases may be limited by the overlapping spectrum of manifestations between diseases or by the advancement of disease where clues to the original process are absent. The objective of this study was to determine whether genetic testing informs diagnosis and facilitates management of kidney disease patients.

Methods

We developed a comprehensive genetic testing panel (KidneySeq) to evaluate patients with various phenotypes including cystic diseases, congenital anomalies of the kidney and urinary tract (CAKUT), tubulointerstitial diseases, transport disorders and glomerular diseases. We evaluated this panel in 127 consecutive patients ranging in age from newborns to 81 years who had samples sent in for genetic testing.

Results

The performance of the sequencing pipeline for single-nucleotide variants was validated using CEPH (Centre de’Etude du Polymorphism) controls and for indels using Genome-in-a-Bottle. To test the reliability of the copy number variant (CNV) analysis, positive samples were re-sequenced and analyzed. For patient samples, a multidisciplinary review board interpreted genetic results in the context of clinical data. A genetic diagnosis was made in 54 (43%) patients and ranged from 54% for CAKUT, 53% for ciliopathies/tubulointerstitial diseases, 45% for transport disorders to 33% for glomerulopathies. Pathogenic and likely pathogenic variants included 46% missense, 11% nonsense, 6% splice site variants, 23% insertion–deletions and 14% CNVs. In 13 cases, the genetic result changed the clinical diagnosis.

Conclusion

Broad genetic testing should be considered in the evaluation of renal patients as it complements other tests and provides insight into the underlying disease and its management.
The Experimental Tobacco Marketplace: Demand and Substitutability as a Function of Cigarette Taxes and e-Liquid Subsidies
Authors: Pope Derek A , Poe Lindsey , Stein Jeffrey S , Kaplan Brent A , DeHart William B , Mellis Alexandra M , Heckman Bryan W , Epstein Leonard H , Chaloupka Frank J , Bickel Warren K
Published: July 2019

Introduction

The experimental tobacco marketplace (ETM) approximates real-world situations by estimating the effects of several, concurrently available products and policies on budgeted purchasing. Although the effects of increasing cigarette price on potentially less harmful substitutability are well documented, the effects of other, nuanced pricing policies remain speculative. This study used the ETM as a tool to assess the effects of two pricing policies, conventional cigarette taxation and e-liquid subsidization, on demand and substitutability.

Methods

During sampling periods, participants were provided 2-day samples of 24 mg/mL e-liquid, after which ETM purchase sessions occurred. Across two ETM sessions, conventional cigarettes were taxed or e-liquid was subsidized in combination with increasing cigarette price. The other four available products were always price constant and not taxed or subsidized.

Results

E-liquid functioned as a substitute for conventional cigarettes across all conditions. Increasing cigarette taxation and e-liquid subsidization increased the number of participants for which e-liquid functioned as a substitute. Cigarette taxation decreased cigarette demand, by decreasing demand intensity, and marginally increased the initial intensity of e-liquid substitution, but did not affect the functions’ slopes (substitutability). E-liquid subsidization resulted in large increases in the initial intensity of e-liquid substitution, but did not affect e-liquid substitutability nor cigarette demand.

Implications

24 mg/mL e-cigarette e-liquid was the only product to significantly substitute for cigarettes in at least one condition throughout the experiment; it functioned as a significant substitute throughout all four tax and all four subsidy conditions. Increasing cigarette taxes decreased cigarette demand through decreases in demand intensity but did not affect e-cigarette substitution. Increasing e-liquid subsidies increased e-liquid initial intensity of substitution but did not affect cigarette demand.

Conclusions

This study extended research on the behavioral economics of conventional cigarette demand and e-liquid substitutability in a complex marketplace. The results suggest that the most efficacious method to decrease conventional cigarette purchasing and increase e-liquid purchasing may involve greatly increasing cigarette taxes while also increasing the value of e-liquid through potentially less harmful product subsidization or differential taxation.
Economic Evaluation of Five Tobacco Control Policies Across Seven European Countries
Authors: Leão Teresa , Perelman Julian , Clancy Luke , Mlinarić Martin , Kinnunen Jaana M , Nuyts Paulien A W , Mélard Nora , Rimpelä Arja , Lorant Vincent , Kunst Anton E
Published: July 2019

Introduction

Economic evaluations of tobacco control policies targeting adolescents are scarce. Few take into account real-world, large-scale implementation costs; few compare cost-effectiveness of different policies across different countries. We assessed the cost-effectiveness of five tobacco control policies (nonschool bans, including bans on sales to minors, bans on smoking in public places, bans on advertising at points-of-sale, school smoke-free bans, and school education programs), implemented in 2016 in Finland, Ireland, the Netherlands, Belgium, Germany, Italy, and Portugal.

Methods

Cost-effectiveness estimates were calculated per country and per policy, from the State perspective. Costs were collected by combining quantitative questionnaires with semi-structured interviews on how policies were implemented in each setting, in real practice. Short-term effectiveness was based on the literature, and long-term effectiveness was modeled using the DYNAMO-HIA tool. Discount rates of 3.5% were used for costs and effectiveness. Sensitivity analyses considered 1%–50% short-term effectiveness estimates, highest cost estimates, and undiscounted effectiveness.

Findings

Nonschool bans cost up to €253.23 per healthy life year, school smoking bans up to €91.87 per healthy life year, and school education programs up to €481.35 per healthy life year. Cost-effectiveness depended on the costs of implementation, short-term effectiveness, initial smoking rates, dimension of the target population, and weight of smoking in overall mortality and morbidity.

Conclusions

All five policies were highly cost-effective in all countries according to the World Health Organization thresholds for public health interventions. Cost-effectiveness was preserved even when using the highest costs and most conservative effectiveness estimates.

Implications

Economic evaluations using real-world data on tobacco control policies implemented at a large scale are scarce, especially considering nonschool bans targeting adolescents. We assessed the cost-effectiveness of five tobacco control policies implemented in 2016 in Finland, Ireland, the Netherlands, Belgium, Germany, Italy, and Portugal. This study shows that all five policies were highly cost-effective considering the World Health Organization threshold, even when considering the highest costs and most conservative effectiveness estimates.
The Territorial Select Committees, 40 Years On
Authors: Torrance David , Evans Adam
Published: July 2019

The territorial departmental select committees have largely escaped academic scrutiny since their establishment in 1979 (for Scotland and Wales) and 1994 (Northern Ireland). This article charts the history of territorial representation in Westminster, including the creation of grand committees for Scotland and Wales and a Northern Ireland Standing Committee, before explaining the forces that led to the creation of territorial departmental select committees. The article then explores the work of these committees after their formation, and explores how they have responded to the devolution dispensations in their respective nations. A key theme of this article is the influence of constitutional developments in Scotland, Wales and Northern Ireland on territorial committees at Westminster. Indeed, as this article highlights, the different timings of establishment, the asymmetric levels of (in)stability in the various devolution dispensations and prolonged suspensions of devolution in Northern Ireland have had an impact on the role of the respective territorial select committees.
Inhibition of Pre-mRNA Splicing Promotes Root Hair Development in Arabidopsis thaliana
Authors: Ishizawa Miku , Hashimoto Kayo , Ohtani Misato , Sano Ryosuke , Kurihara Yukio , Kusano Hiroaki , Demura Taku , Matsui Minami , Sato-Nara Kumi
Published: July 2019

Root hairs protruding from epidermal cells increase the surface area for water absorption and nutrient uptake. Various environmental factors including light, oxygen concentration, carbon dioxide concentration, calcium and mycorrhizal associations promote root hair formation in Arabidopsis thaliana. Light regulates the expression of a large number of genes at the transcriptional and post-transcriptional levels; however, there is little information linking the light response to root hair development. In this study, we describe a novel mutant, light-sensitive root-hair development 1 (lrh1), that displays enhanced root hair development in response to light. Hypocotyl and root elongation was inhibited in the lrh1 mutant, which had a late flowering phenotype. We identified the gene encoding the p14 protein, a putative component of the splicing factor 3b complex essential for pre-mRNA splicing, as being responsible for the lrh1 phenotype. Indeed, regulation of alternative splicing was affected in lrh1 mutants and treatment with a splicing inhibitor mimicked the lrh1 phenotype. Genome-wide alterations in pre-mRNA splicing patterns including differential splicing events of light signaling- and circadian clock-related genes were found in lrh1 as well as a difference in transcriptional regulation of multiple genes including upregulation of essential genes for root hair development. These results suggest that pre-mRNA splicing is the key mechanism regulating root hair development in response to light signals.