bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autoinhibitory properties of the parent but not of the N‐oxide metabolite contribute to infusion rate‐dependent voriconazole pharmacokinetics
Authors: Hohmann Nicolas , Kreuter Rebecca , Blank Antje , Weiss Johanna , Burhenne Jürgen , Haefeli Walter E. , Mikus Gerd 
Published: March 2017

AimsThe pharmacokinetics of voriconazole show a nonlinear dose–exposure relationship caused by inhibition of its own CYP3A‐dependent metabolism. Because the magnitude of autoinhibition also depends on voriconazole concentrations, infusion rate might modulate voriconazole exposure. The impact of four different infusion rates on voriconazole pharmacokinetics was investigated.MethodsTwelve healthy participants received 100 mg voriconazole intravenous over 4 h, 400 mg over 6 h, 4 h, and 2 h in a crossover design. Oral midazolam (3 μg) was given at the end of infusion. Blood and urine samples were collected up to 48 h. Voriconazole and its N‐oxide metabolite were quantified using high‐performance liquid chromatography coupled to tandem mass spectrometry. Midazolam estimated metabolic clearance (eCLmet) was calculated using a limited sampling strategy. Voriconazole‐N‐oxide inhibition of cytochrome P450 (CYP) isoforms 2C19 and 3A4 were assessed with the P450‐Glo luminescence assay.ResultsArea under the concentration–time curve for 400 mg intravenous voriconazole was 16% (90% confidence interval: 12–20%) lower when administered over 6 h compared to 2 h infusion. Dose‐corrected area under the concentration–time curve for 100 mg over 4 h was 34% lower compared to 400 mg over 4 h. Midazolam eCLmet was 516 ml min–1 (420–640) following 100 mg 4 h–1 voriconazole, 152 ml min–1 (139–166) for 400 mg 6 h–1, 192 ml min–1 (167–220) for 400 mg 4 h−1, and 202 ml min–1 (189–217) for 400 mg 2 h–1. Concentration giving 50% CYP inhibition of voriconazole N‐oxide was 146 ± 23 μmol l–1 for CYP3A4, and 40.2 ± 4.2 μmol l–1 for CYP2C19.ConclusionsVoriconazole pharmacokinetics is modulated by infusion rate, an autoinhibitory contribution voriconazole metabolism by CYP3A and 2C19 and to a lesser extent its main N‐oxide metabolite for CYP2C19. To avoid reduced exposure, the infusion rate should be 2 h.
Cost‐effectiveness of a new urinary biomarker‐based risk score compared to standard of care in prostate cancer diagnostics – a decision analytical model
Authors: Dijkstra Siebren , Govers Tim M. , Hendriks Rianne J. , Schalken Jack A. , Van Criekinge Wim , Van Neste Leander , Grutters Janneke P.C. , Sedelaar John P. Michiel , van Oort Inge M. 
Published: March 2017

ObjectiveTo assess the cost‐effectiveness of a new urinary biomarker‐based risk score (SelectMDx; MDxHealth, Inc., Irvine, CA, USA) to identify patients for transrectal ultrasonography (TRUS)‐guided biopsy and to compare this with the current standard of care (SOC), using only prostate‐specific antigen (PSA) to select for TRUS‐guided biopsy.Materials and MethodsA decision tree and Markov model were developed to evaluate the cost‐effectiveness of SelectMDx as a reflex test vs SOC in men with a PSA level of >3 ng/mL. Transition probabilities, utilities and costs were derived from the literature and expert opinion. Cost‐effectiveness was expressed in quality‐adjusted life years (QALYs) and healthcare costs of both diagnostic strategies, simulating the course of patients over a time horizon representing 18 years. Deterministic sensitivity analyses were performed to address uncertainty in assumptions.ResultsA diagnostic strategy including SelectMDx with a cut‐off chosen at a sensitivity of 95.7% for high‐grade prostate cancer resulted in savings of €128 and a gain of 0.025 QALY per patient compared to the SOC strategy. The sensitivity analyses showed that the disutility assigned to active surveillance had a high impact on the QALYs gained and the disutility attributed to TRUS‐guided biopsy only slightly influenced the outcome of the model.ConclusionBased on the currently available evidence, the reduction of over diagnosis and overtreatment due to the use of the SelectMDx test in men with PSA levels of >3 ng/mL may lead to a reduction in total costs per patient and a gain in QALYs.
The available intravenous iron formulations: History, efficacy, and toxicology
Authors: Auerbach Michael , Macdougall Iain 
Published: March 2017

AbstractA number of intravenous iron formulations have been developed over the past 65 years which rely on dextran or other compounds to prevent uncontrolled release of free iron to the circulation. High molecular weight dextran was associated with a number of serious adverse reactions and was removed from markets worldwide in 2009. The preponderance of published evidence suggests that the formulations of parenteral iron currently available in the United States, including low molecular weight iron dextran, are all safe and effective and there are no major, clinically important differences among them in terms of either efficacy or safety. For patients with chemotherapy induced anemia or with anemia of end stage renal disease who are being treated with hemodialysis, it is reasonable to use any of the iron formulations, including iron sucrose and ferric gluconate, as frequent patient encounters with health caregivers are a routine part of care and the need to administer multiple low doses of IV iron is not a major disadvantage. However, a single infusion of a total iron dose is as effective and safe when giving iron preparations containing low molecular weight iron dextran, ferumoxytol, iron isomaltoside, or ferric carboxymaltose. Use of a single total dose infusion results in a decreased number of intravenous infusions with a lower cumulative risk for infusion reactions or extravasations, a reduced need for multiple office visits and repeated utilization of medical staff, and increased convenience for physicians and patients.
High cover of forest increases the abundance of most grassland butterflies in boreal farmland
Authors: Toivonen Marjaana , Peltonen Aino , Herzon Irina , Heliölä Janne , Leikola Niko , Kuussaari Mikko 
Published: March 2017

Abstract

High cover of forest in the landscape matrix has been shown to weaken the negative effects of habitat fragmentation on grassland butterflies. No studies have however focused on examining species‐specific responses of grassland butterflies to forest.

The data from 3 years of butterfly monitoring in Southern Finland were used to test whether the amount of forest cover in the surrounding landscape affected the abundance of grassland butterfly species in semi‐natural grasslands, field margins, and forest edges.

More than half of the studied species benefitted from high cover of forest. Species with the strongest preference for forested landscapes were Lycaena virgaureae, Argynnis adippe, Argynnis aglaja, and Boloria selene, which probably find suitable resources in herbaceous habitats at forest edges and clearings.

Several small‐sized species were positively affected by surrounding forest cover in field margins but not in the other habitat types. Although field margins are suboptimal habitats for grassland butterflies, they provide important corridors for dispersal. High cover of forest in the landscape matrix may enhance butterfly dispersal along field margins by reducing windiness, which is likely to be most important for small‐sized species with poor dispersal capacity.

The most abundant grassland species showed little or no preference for forested landscapes.

Our results suggest that high cover of forest enhances the persistence of most grassland butterflies, including declining species, in boreal agricultural landscapes. The responses to forest are however strongly dependent on species‐specific properties and habitat types.
Being as Iconic: Aquinas on ‘He Who Is’ as the Name for God
Authors: Rooney James Dominic 
Published: March 2017

AbstractAquinas claims that ‘He Who Is’ is the most proper of the names we have for God. But this attempt to ‘describe’ God with a philosophical concept like ‘being’ can seem dangerously close to creating a false conception based on our limited understanding – an idol. A dominant criticism of Aquinas’ use of this term is that any attempt to use ‘being’ to describe God will inevitably make him merely some object in our ontology alongside other beings, unacceptably mitigating God's radical transcendence and otherness. I will argue that Aquinas has a very creative response to this charge: ‘being’ stands in a unique relationship as the only concept that can ensure we do not draw God under some particular creaturely limit and thus use divine names to create an ‘idol’. In other words, ‘being’ is a special paradigm concept/term which ensures that we preserve humility in our attempts to name God.
Fixed Odds Bookmaking with Stochastic Betting Demands
Authors: Hodges Stewart , Lin Hao , Liu Lan 
Published: March 2017

AbstractThis paper studies fixed odds bookmaking in the market for bets in a British horse race. The bookmaker faces the risk of unbalanced liability exposures. Even random shocks in the noisy betting demands are costly to the bookmaker since his book could become less balanced. In our model, the bookmaker sets appropriate odds to influence the betting flow to mitigate the risk. The stylised fact of the favourite‐longshot bias only arises from the model under specific assumptions. Our model offers insights into the complexity of managing a series of state contingent exposures such as options.
Feeding biomechanics of Late Triassic metoposaurids (Amphibia: Temnospondyli): a 3D finite element analysis approach
Authors: Fortuny Josep , Marcé‐Nogué Jordi , Konietzko‐Meier Dorota 
Published: March 2017

AbstractThe Late Triassic freshwater ecosystems were occupied by different tetrapod groups including large‐sized anamniotes, such as metoposaurids. Most members of this group of temnospondyls acquired gigantic sizes (up to 5 m long) with a nearly worldwide distribution. The paleoecology of metoposaurids is controversial; they have been historically considered passive, bottom‐dwelling animals, waiting for prey on the bottom of rivers and lakes, or they have been suggested to be active mid‐water feeders. The present study aims to expand upon the paleoecological interpretations of these animals using 3D finite element analyses (FEA). Skulls from two taxa, Metoposaurus krasiejowensis, a gigantic taxon from Europe, and Apachesaurus gregorii, a non‐gigantic taxon from North America, were analyzed under different biomechanical scenarios. Both 3D models of the skulls were scaled to allow comparisons between them and reveal that the general stress distribution pattern found in both taxa is clearly similar in all scenarios. In light of our results, both previous hypotheses about the paleoecology of these animals can be partly merged: metoposaurids probably were ambush and active predators, but not the top predators of these aquatic environments. The FEA results demonstrate that they were particularly efficient at bilateral biting, and together with their characteristically anteropositioned orbits, optimal for an ambush strategy. Nonetheless, the results also show that these animals were capable of lateral strikes of the head, suggesting active hunting of prey. Regarding the important skull size differences between the taxa analyzed, our results suggest that the size reduction in the North American taxon could be related to drastic environmental changes or the increase of competitors. The size reduction might have helped them expand into new ecological niches, but they likely remained fully aquatic, as are all other metoposaurids.
Induction of the pho regulon and polyphosphate synthesis against spermine stress in Pseudomonas aeruginosa
Authors: Peng Yu‐Chih , Lu ChienYi , Li Guoqing , Eichenbaum Zehava , Lu Chung‐Dar 
Published: March 2017

SummaryGrowth of Pseudomonas aeruginosa on spermine requires a functional γ‐glutamylpolyamine synthetase PauA2. Not only subjected to growth inhibition by spermine, the pauA2 mutant became more sensitive to β‐lactam antibiotics in human serum. To explore PauA2 as a potential target of drug development, suppressors of the pauA2 mutant, which alleviated toxicity, were isolated from selection plates containing spermine. These suppressors share common phenotypic changes including delayed growth rate, retarded swarming motility, and pyocyanin overproduction. Genome resequencing of a representative suppressor revealed a unique C599T mutation at the phoU gene that results in Ser200Leu substitution and a constitutive expression of the Pho regulon. Identical phenotypes were also observed in a ΔpauA2ΔphoU double knockout mutant and complemented by the wild‐type phoU gene. Accumulation of polyphosphate granules and spermine resistance in the suppressor were reversed concomitantly when expressing exopolyphosphatase PPX from a recombinant plasmid, or by the introduction of deletion alleles in pstS pstC for phosphate uptake, phoB for Pho regulation, and ppk for polyphosphate synthesis. In conclusion, this study identifies polyphosphate accumulation due to an activated Pho regulon and phosphate uptake by the phoU mutation as a potential protection mechanism against spermine toxicity.
The HCPro from thePotyviridaefamily: an enviable multitasking Helper Component that every virus would like to have
Authors: Valli Adrián A. , Gallo Araiz , Rodamilans Bernardo , López‐Moya Juan José , García Juan Antonio 
Published: March 2017

SummaryRNA viruses have very compact genomes and so provide a unique opportunity to study how evolution works to optimize the use of very limited genomic information. A widespread viral strategy to solve this issue concerning the coding space relies on the expression of proteins with multiple functions. Members of the familyPotyviridae, the most abundant group of RNA viruses in plants, offer several attractive examples of viral factors which play roles in diverse infection‐related pathways. The Helper Component Proteinase (HCPro) is an essential and well‐characterized multitasking protein for which at least three independent functions have been described: (i) viral plant‐to‐plant transmission; (ii) polyprotein maturation; and (iii) RNA silencing suppression. Moreover, multitudes of host factors have been found to interact with HCPro. Intriguingly, most of these partners have not been ascribed to any of the HCPro roles during the infectious cycle, supporting the idea that this protein might play even more roles than those already established. In this comprehensive review, we attempt to summarize our current knowledge about HCPro and its already attributed and putative novel roles, and to discuss the similarities and differences regarding this factor in members of this important viral family.
The importance of hydraulic architecture to the distribution patterns of trees in a central Amazonian forest
Authors: Cosme Luiza H. M. , Schietti Juliana , Costa Flávia R. C. , Oliveira Rafael S. 
Published: March 2017

Summary

Species distributions and assemblage composition may be the result of trait selection through environmental filters. Here, we ask whether filtering of species at the local scale could be attributed to their hydraulic architectural traits, revealing the basis of hydrological microhabitat partitioning in a Central Amazonian forest.

We analyzed the hydraulic characteristics at tissue (anatomical traits, wood specific gravity (WSG)), organ (leaf area, specific leaf area (SLA), leaf area : sapwood area ratio) and whole‐plant (height) levels for 28 pairs of congeneric species from 14 genera restricted to either valleys or plateaus of a terra‐firme forest in Central Amazonia.

On plateaus, species had higher WSG, but lower mean vessel area, mean vessel hydraulic diameter, sapwood area and SLA than in valleys; traits commonly associated with hydraulic safety. Mean vessel hydraulic diameter and mean vessel area increased with height for both habitats, but leaf area and leaf area : sapwood area ratio investments with tree height declined in valley vs plateau species. [Correction added after online publication 29 March 2017: the preceding sentence has been reworded.] Two strategies for either efficiency or safety were detected, based on vessel size or allocation to sapwood.

In conclusion, contrasting hydrological conditions act as environmental filters, generating differences in species composition at the local scale. This has important implications for the prediction of species distributions under future climate change scenarios.
Objective Bayes Covariate‐Adjusted Sparse Graphical Model Selection
Authors: Consonni Guido , La Rocca Luca , Peluso Stefano 
Published: March 2017

AbstractWe present an objective Bayes method for covariance selection in Gaussian multivariate regression models having a sparse regression and covariance structure, the latter being Markov with respect to a directed acyclic graph (DAG). Our procedure can be easily complemented with a variable selection step, so that variable and graphical model selection can be performed jointly. In this way, we offer a solution to a problem of growing importance especially in the area of genetical genomics (eQTL analysis). The input of our method is a single default prior, essentially involving no subjective elicitation, while its output is a closed form marginal likelihood for every covariate‐adjusted DAG model, which is constant over each class of Markov equivalent DAGs; our procedure thus naturally encompasses covariate‐adjusted decomposable graphical models. In realistic experimental studies, our method is highly competitive, especially when the number of responses is large relative to the sample size.
WRI1‐1, ABI5, NF‐YA3 and NF‐YC2 increase oil biosynthesis in coordination with hormonal signaling during fruit development in oil palm
Authors: Yeap Wan‐Chin , Lee Fong‐Chin , Shabari Shan Dilip Kumar , Musa Hamidah , Appleton David Ross , Kulaveerasingam Harikrishna 
Published: March 2017

SummaryThe oil biosynthesis pathway must be tightly controlled to maximize oil yield. Oil palm accumulates exceptionally high oil content in its mesocarp, suggesting the existence of a unique fruit‐specific fatty acid metabolism transcriptional network. We report the complex fruit‐specific network of transcription factors responsible for modulation of oil biosynthesis genes in oil palm mesocarp. Transcriptional activation of EgWRI1‐1 encoding a key master regulator that activates expression of oil biosynthesis genes, is activated by three ABA‐responsive transcription factors, EgNF‐YA3, EgNF‐YC2 and EgABI5. Overexpression of EgWRI1‐1 and its activators in Arabidopsis accelerated flowering, increased seed size and oil content, and altered expression levels of oil biosynthesis genes. Protein–protein interaction experiments demonstrated that EgNF‐YA3 interacts directly with EgWRI1‐1, forming a transcription complex with EgNF‐YC2 and EgABI5 to modulate transcription of oil biosynthesis pathway genes. Furthermore, EgABI5 acts downstream of EgWRKY40, a repressor that interacts with EgWRKY2 to inhibit the transcription of oil biosynthesis genes. We showed that expression of these activators and repressors in oil biosynthesis can be induced by phytohormones coordinating fruit development in oil palm. We propose a model highlighting a hormone signaling network coordinating fruit development and fatty acid biosynthesis.
SpxA1 and SpxA2 Act Coordinately To Fine-Tune Stress Responses and Virulence in
Streptococcus pyogenes
Authors: Port Gary C. , Cusumano Zachary T. , Tumminello Paul R. , Caparon Michael G. 
Published: March 2017

ABSTRACT

SpxA is a unique transcriptional regulator highly conserved among members of the phylum
Firmicutes
that binds RNA polymerase and can act as an antiactivator. Why some
Firmicutes
members have two highly similar SpxA paralogs is not understood. Here, we show that the SpxA paralogs of the pathogen
Streptococcus pyogenes
, SpxA1 and SpxA2, act coordinately to regulate virulence by fine-tuning toxin expression and stress resistance. Construction and analysis of mutants revealed that SpxA1
−
mutants were defective for growth under aerobic conditions, while SpxA2
−
mutants had severely attenuated responses to multiple stresses, including thermal and oxidative stresses. SpxA1
−
mutants had enhanced resistance to the cationic antimicrobial molecule polymyxin B, while SpxA2
−
mutants were more sensitive. In a murine model of soft tissue infection, a SpxA1
−
mutant was highly attenuated. In contrast, the highly stress-sensitive SpxA2
−
mutant was hypervirulent, exhibiting more extensive tissue damage and a greater bacterial burden than the wild-type strain. SpxA1
−
attenuation was associated with reduced expression of several toxins, including the SpeB cysteine protease. In contrast, SpxA2
−
hypervirulence correlated with toxin overexpression and could be suppressed to wild-type levels by deletion of
speB
. These data show that SpxA1 and SpxA2 have opposing roles in virulence and stress resistance, suggesting that they act coordinately to fine-tune toxin expression in response to stress. SpxA2
−
hypervirulence also shows that stress resistance is not always essential for
S. pyogenes
pathogenesis in soft tissue.

IMPORTANCE
For many pathogens, it is generally assumed that stress resistance is essential for pathogenesis. For
Streptococcus pyogenes
, environmental stress is also used as a signal to alter toxin expression. The amount of stress likely informs the bacterium of the strength of the host’s defense response, allowing it to adjust its toxin expression to produce the ideal amount of tissue damage, balancing between too little damage, which will result in its elimination, and too much damage, which will debilitate the host. Here we identify components of a genetic circuit involved in stress resistance and toxin expression that has a fine-tuning function in tissue damage. The circuit consists of two versions of the protein SpxA that regulate transcription and are highly similar but have opposing effects on the severity of soft tissue damage. These results will help us understand how virulence is fine-tuned in other pathogens that have two SpxA proteins.