bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

AbstractMembers 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

AbstractBackgroundThe 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.MethodsWe 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.ResultsThe 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.ConclusionBroad 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

AbstractIntroductionThe 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.MethodsDuring 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.ResultsE-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.Implications24 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.ConclusionsThis 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

Abstract

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

AbstractThe 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

Abstract
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.
Attention for the Inattentive: Positive Effects of Negative Financial Shocks*
Authors: Ouimet Paige , Tate Geoffrey 
Published: July 2019

Abstract
Using unique data on employee ownership plans, we find that negative shocks lead to changes in portfolio choices among previously inattentive investors. Employees within employee ownership plans did not actively select into ownership, but instead received grants upon employment. Many employees remain initially passive within these plans. However, following the 2008 Financial Crisis, they become more likely to exercise options, sell restricted stock, and participate in an Employee Stock Purchase Plan (ESPP). These changes likely improve welfare. For example, nonparticipation in an ESPP leaves money on the table. Our results improve our understanding of how investors’ personal return experiences affect investment choices. Negative shocks can increase attention among previously passive investors, yielding decisions that are closer to the optimum.
Involvement of Populus CLEL peptides in root development
Authors: Tian Dongdong , Liu Yueyuan , Tian Lidan , Wan Mengjie , Zheng Bo , Shi Xueping 
Published: July 2019

Abstract
As one of the major groups of small post-translationally modified peptides, the CLV3/EMBRYO SURROUNDING REGION-RELATED (CLE)-like (CLEL) peptide family has been reported to regulate root growth, lateral root development and plant gravitropic responses in Arabidopsis thaliana. In this study, we identified 12 CLEL genes in Populus trichocarpa and performed a comprehensive bioinformatics analysis on these genes. Among them, five P. trichocarpa CLELs (PtrCLELs) were revised with new gene models. All of these PtrCLEL proteins were structurally similar to the A. thaliana CLELs (AtCLELs), including an N-terminal signal peptide, a conserved C-terminal 13-amino-acid CLEL motif and a variable intermediate region. In silico and quantitative real-time PCR analyses showed that PtrCLELs were widely expressed in various tissues, including roots, leaves, buds and stems. Exogenous application of chemically synthesized PtrCLEL peptides resulted in wavy or curly roots and reduced lateral root formation in A. thaliana. Moreover, germinating Populus deltoides seedlings on a growth medium containing these peptides caused the roots to thicken and to form abnormal lateral roots, in many cases in clusters. Anatomical and histological changes in thickened roots were further investigated by treating Populus 717 cuttings with the PtrCLEL10 peptide. We observed that root thickening was mainly due to an increased number of cells in the epidermis, hypodermis and cortex. The results of our study suggested that PtrCLEL and AtCLEL genes encode proteins with similar protein structures, sequences of peptide motif and peptide activities on developing roots. The activities of PtrCLEL peptides in root development were species-dependent.
Periodontal bacteria and the rheumatoid arthritis-related antigen RA-A47: the cross-reactivity potential
Authors: Lucchese Alberta 
Published: July 2019

Purpose of review
The purpose of this review is to evaluate the mechanisms that underlie the association between periodontal pathogens and rheumatoid arthritis (RA).

Recent findings
This review focuses on the cross-reactivity hypothesis as a mechanism that might contribute to explain the pathologic evolution of periodontal infections from periodontitis to RA. The scientific rationale is that immune reactions following infection by periodontal bacteria might cross-react with RA autoantigens, in this way eventually leading to autoimmunity.

Summary
Using the rheumatoid antigen associated with RA-A47 arthritis as an antigen model and analyzing five periodontal bacteria (eg, Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Treponema denticola, Tannerella forsythia and Prevotella intermedia), an extremely varied pattern of peptide sharing was found. In the context of the cross-reactivity hypothesis, the data allow us to glimpse the possibility of distinguishing the periodontal bacteria capable of attacking the periodontal tissue from those that are additionally equipped with a rheumatologic potential by virtue of the sharing of peptide sequences with RA antigens.
Early Operative Versus Nonoperative Treatment of Fragility Fractures of the Pelvis: A Propensity-Matched Multicenter Study
Authors: Osterhoff Georg , Noser Jonas , Held Ulrike , Werner Clément M. L. , Pape Hans-Christoph , Dietrich Michael 
Published: July 2019

Objective:
To compare early operative treatment with nonoperative treatment of fragility fractures of the pelvis regarding mortality and functional outcome.

Design:
Retrospective.

Setting:
Two trauma centers.

Patients and Methods:
Two hundred thirty consecutive patients 60 years of age or older with an isolated low-energy fracture of the pelvis and with a follow-up of at least 24 months. In center 1, treatment consisted of a nonoperative attempt and early operative fixation if mobilization was not possible. In center 2, all patients were treated nonoperatively.

Main Outcome Measurements:
Primary outcome was mortality. Secondary outcomes were in-hospital complications. Patients who survived were contacted by phone, and a modified Majeed score was obtained to assess functional outcome at the final follow-up.

Results:
At the final follow-up (mean 61 months, SD 24), 105/230 (45.7%) patients had died. One year after the initial hospitalization, 34/148 patients [23%, 95% confidence interval (CI): 17%–31%] of the early operative group and 14/82 patients (17%, 95% CI: 10%–27%) of the nonoperative group had died (P = 0.294). Nonoperative treatment had a protective effect on survival during the first 2 years (hazard ratio of the nonlinear effect: 2.86, 95% CI: 1.38–5.94, P < 0.001). Patients in the early operative treatment group who survived the first 2 years had a better long-term survival. The functional outcome at the end of follow-up as measured by a modified Majeed score was not different between the 2 groups (early operative: 66.1, SD 12.6 vs. nonoperative: 65.7, SD 12.5, P = 0.910).

Conclusion:
Early operative fixation of patients who cannot be mobilized within 3–5 days was associated with a higher mortality rate and complication rate at 1 year but with a better long-term survival after more than 2 years. Hence, patients with a life expectancy of less than 2 years may not benefit from surgery with regard to survival.

Level of Evidence:
Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Percutaneous Decannulation Instead of Surgical Removal for Weaning After Venoarterial Extracorporeal Membrane Oxygenation—A Crossed Perclose ProGlide Closure Device Technique Using a Hemostasis Valve Y Connector
Authors: Lüsebrink Enzo , Stremmel Christopher , Stark Konstantin , Petzold Tobias , Hein-Rothweiler Ralph , Scherer Clemens , Schüttler Dominik , Massberg Steffen , Orban Martin 
Published: July 2019

Objectives:
Improvements in cannula removal techniques, and in particular a standardized decannulation technique with a suitable closure device, are needed to further improve patients’ outcomes after percutaneous cannulation. The decannulation techniques described so far are neither sufficiently standardized nor proven enough to be used in the large group of venoarterial extracorporeal membrane oxygenation patients. To meet this challenge, we have established a highly standardized and safe decannulation technique based on the Perclose ProGlide closure system (Abbott Vascular, Lake Bluff, IL).

Design:
Establishment of a highly standardized and safe decannulation technique based on the Perclose ProGlide closure system, which is described in detail with comprehensive instructions for the executive clinician and first application in the context of a pilot study.

Measurements and Main Results:
So far our technique has already been used successfully in seven patients since January 2019 as a standard procedure on our ICU with only one minor complication occurred after the first procedure, that is, a small pseudoaneurysm likely originating from antegrade perfusion puncture site which was sealed by thrombin injection.

Conclusions:
Our crossed ProGlide technique using a hemostasis valve Y connector ensuring no blood loss seems to be a very promising decannulation technique.
Role of Caspase 1 in Ischemia/Reperfusion Injury of the Myocardium
Authors: Rauf Ali , Shah Mo , Yellon Derek M. , Davidson Sean M. 
Published: July 2019

Abstract:
Acute occlusion of a coronary artery can result in myocardial infarction—a leading cause of premature death. Prompt restoration of blood flow to the myocardium can prevent excessive death of cardiomyocytes and improve clinical outcome. Although the major mechanism of cell death after reperfusion is necrosis, it is now recognized that many other cell death pathways may be involved in ischemia–reperfusion (I/R) injury. Pyroptosis is one such cell death pathway that is caspase-1–dependent and induced in response to cellular insult. The activated caspase-1 protease cleaves and activates specific cellular targets including gasdermin D and the proinflammatory cytokines interleukin-1β and interleukin-18. The N-terminal fragment of gasdermin D forms plasma membrane pores resulting in cytosolic leakage and cell rupture, releasing interleukin-1β and interleukin-18. Evidence suggests that inflammation induced by I/R through the pyroptotic pathway contributes to cardiomyocyte death, excessive scar formation, and poor ventricular remodeling. For this reason, there is growing interest in targeting components of the pyroptotic pathway as a means of reducing I/R injury.