bluuebunny/crossref_metadata_2025_split huggingface dataset:
Levels of interleukin (IL)‐6 and IL‐8 are elevated in serum and bronchoalveolar lavage fluid of haematological patients with invasive pulmonary aspergillosis
Authors: Heldt Sven , Eigl Susanne , Prattes Juergen , Flick Holger , Rabensteiner Jasmin , Prüller Florian , Niedrist Tobias , Neumeister Peter , Wölfler Albert , Strohmaier Heimo , Krause Robert , Hoenigl Martin 
Published: September 2017

SummaryAspergillus spp. have been shown to induce T‐helper cell (Th) 1 and Th17 subsets resulting in elevated levels of several cytokines. The objective of this study was to analyse a bundle of cytokines in serum and bronchoalveolar lavage fluid (BALF) in patients with and without invasive pulmonary aspergillosis (IPA). This nested case‐control analysis included 10 patients with probable/proven IPA and 20 matched controls without evidence of IPA, out of a pool of prospectively enrolled (2014‐2017) adult cases with underlying haematological malignancies and suspected pulmonary infection. Serum samples were collected within 24 hours of BALF sampling. All samples were stored at −70°C for retrospective determination of cytokines. IL‐6 and IL‐8 were significantly associated with IPA in both serum (P = .011 and P = .028) and BALF (P = .006 and P = .012, respectively), and a trend was observed for serum IL‐10 (P = .059). In multivariate conditional logistic regression analysis, IL‐10 remained a significant predictor of IPA in serum and IL‐8 among BALF cytokines. In conclusion, levels of IL‐6 and IL‐8 were significantly associated with probable/proven IPA, and a similar trend was observed for serum IL‐10. Future cohort studies should determine the diagnostic potential of these cytokines for IPA, and evaluate combinations with other IPA biomarkers/diagnostic tests.
Capital–Skill Complementarity: Does Capital Composition Matter?
Authors: Correa Juan A. , Lorca Miguel , Parro Francisco 
Published: September 2017

AbstractWe estimate the effect of capital composition on the size of capital–skill complementarity and the skill wage premium. Disaggregating the capital stock into different types according to technological content, we find that: capital is more of a q‐complement to skilled labor than to unskilled labor; the higher the technological component of capital, the larger the size of the relative q‐complementarity between capital and skilled labor; and replacing non‐technological with technological capital might increase the skill wage premium by about 9 percent. Our results highlight that changes in capital composition matter for understanding changes in the skill wage premium.
Pathogen reduction of whole blood: utility and feasibility
Authors: Allain J.‐P. , Goodrich R. 
Published: September 2017

SUMMARYObjectivesTo collect information on pathogen reduction applied to whole blood.BackgroundPathogen reduction (PR) of blood components has been developed over the past two decades, and pathogen‐reduced fresh‐frozen plasma and platelet concentrates are currently in clinical use. High cost and incomplete coverage of components make PR out of reach for low‐ and middle‐income countries (LMIC). However, should PR become applicable to whole blood (WB), the main product transfused in sub‐Saharan Africa, and be compatible with the preparation of clinically suitable components, cost would be minimised, and a range of safety measures in place at high cost in developed areas would become redundant.MethodsAll articles called with “pathogen reduction”, “pathogen inactivation” and “whole blood” were retrieved from Medline. References in articles were utilised.ResultsOne such PR technology (PRT) applied to WB has been developed and has shown efficacious against viruses, bacteria and parasites in vitro; and has been able to inactivate nucleated blood cells whilst retaining the ability to prepare components with acceptable characteristics.The efficacy of this WB PRT has been demonstrated in vivo using the inactivation of Plasmodium falciparum as a model and showing a high degree of correlation between in vitro and in vivo data. Obtaining further evidence of efficacy on other suitable targets is warranted. Shortening of the process, which is currently around 50 min, or increasing the number of units simultaneously processed would be necessary to make PRT WB conducive to LMIC blood services' needs.ConclusionsEven if not 100% effective against agents that are present in high pathogen load titres, WB PRT could massively impact blood safety in LMIC by providing safer products at an affordable cost.
Subinhibitory Dalbavancin Attenuates Exotoxin Production from Methicillin-Sensitive and Methicillin-Resistant Staphylococcus aureusIn Vitro
Authors: Hobdey Sarah E. , Katahira Eva J. , Dockstader Pamela , Davidson Stephen M. , Bond Laura , Bolz Devin D. , Bryant Amy E. , Stevens Dennis L. 
Published: September 2017

ABSTRACTThis study investigated the effects of subinhibitory doses of the lipoglycopeptide antibiotic dalbavancin onStaphylococcus aureustoxin productionin vitro.S. aureustoxin production levels were compared to those seen with the natural glycopeptide antibiotic vancomycin and with representative beta-lactam and oxazolidinone antibiotics. While neither dalbavancin nor vancomycin adversely affected toxin production, of these glycopeptide antibiotics, only dalbavancin significantly attenuated toxin production at subinhibitory concentrations. These findings support the recent success of dalbavancin for treatment of staphylococcal infections.
Transcriptional and Mutational Profiling of an Aminoglycoside-Resistant Pseudomonas aeruginosa Small-Colony Variant
Authors: Schniederjans Monika , Koska Michal , Häussler Susanne 
Published: September 2017

ABSTRACT

Pseudomonas aeruginosa
is a major causative agent of both acute and chronic infections. Although aminoglycoside antibiotics are very potent drugs against such infections, antibiotic failure is steadily increasing mainly because of increasing resistance of the bacteria. Many molecular mechanisms that determine resistance, such as acquisition of genes encoding aminoglycoside-inactivating enzymes or overexpression of efflux pumps, have been elucidated. However, there are additional, less well-described mechanisms of aminoglycoside resistance. In this study, we profiled a clinical tobramycin-resistant
P. aeruginosa
strain that exhibited a small-colony variant (SCV) phenotype. Both the resistance and colony morphology phenotypes were lost upon passage of the isolate under rich medium conditions. Transcriptional and mutational profiling revealed that the SCV harbored activating mutations in the two-component systems AmgRS and PmrAB. Introduction of these mutations individually into type strain PA14 conferred tobramycin and colistin resistance, respectively. However, their combined introduction had an additive effect on the tobramycin resistance phenotype. Activation of the AmgRS system slightly reduced the colony size of wild-type PA14, whereas the simultaneous overexpression of
gacA
, the response regulator of the GacSA two-component system, further reduced colony size. In conclusion, we uncovered combinatorial influences of two-component systems on clinically relevant phenotypes such as resistance and the expression of the SCV phenotype. Our results clearly demonstrate that the combined activation of
P. aeruginosa
two-component systems has pleiotropic effects with unforeseen consequences.
Antagonism between Front-Line Antibiotics Clarithromycin and Amikacin in the Treatment of Mycobacterium abscessus Infections Is Mediated by the
whiB7
Gene
Authors: Pryjma Mark , Burian Ján , Kuchinski Kevin , Thompson Charles J. 
Published: September 2017

ABSTRACT

Combinations of antibiotics, each individually effective against
Mycobacterium abscessus
, are routinely coadministered based on the concept that this minimizes the spread of antibiotic resistance. However, our
in vitro
data contradict this assumption and instead document antagonistic interactions between two antibiotics (clarithromycin and amikacin) used to treat
M. abscessus
infections. Clinically relevant concentrations of clarithromycin induced increased resistance to both amikacin and itself. The induction of resistance was dependent on
whiB7
, a transcriptional activator of intrinsic antibiotic resistance that is induced by exposure to many different antibiotics. In
M. abscessus
, the deletion of
whiB7
(MAB_3508c) resulted in increased sensitivity to a broad range of antibiotics. WhiB7 was required for transcriptional activation of genes that confer resistance to three commonly used anti-
M. abscessus
drugs: clarithromycin, amikacin, and tigecycline. The
whiB7
-dependent gene that conferred macrolide resistance was identified as
erm
(41) (MAB_2297), which encodes a ribosomal methyltransferase. The
whiB7
-dependent gene contributing to amikacin resistance was
eis2
(MAB_4532c), which encodes a Gcn5-related
N
-acetyltransferase (GNAT). Transcription of
whiB7
and the resistance genes in its regulon was inducible by subinhibitory concentrations of clarithromycin but not by amikacin. Thus, exposure to clarithromycin, or likely any
whiB7
-inducing antibiotic, may antagonize the activities of amikacin and other drugs. This has important implications for the management of
M. abscessus
infections, both in cystic fibrosis (CF) and non-CF patients.
Multiple Modes of Action of a Monoclonal Antibody against Multidrug-Resistant Escherichia coli Sequence Type 131-H30
Authors: Guachalla Luis M. , Hartl Katharina , Varga Cecília , Stulik Lukas , Mirkina Irina , Malafa Stefan , Nagy Eszter , Nagy Gábor , Szijártó Valéria 
Published: September 2017

ABSTRACTThe multidrug-resistantH30 subclone of extraintestinal pathogenicEscherichia colisequence type 131 (ST131-H30) has spread worldwide. This clone expresses a conserved lipopolysaccharide (LPS) O antigen, O25b. Previously, we described monoclonal antibodies (MAbs) specific to the O25b antigen and characterized them as diagnostic and therapeutic tools. In this study, evidence is provided that besides the previously shown complement-mediated bactericidal effect, an O25b-specific humanized MAb, A1124, also enhances opsonophagocytic uptake by the murine macrophage cell line RAW 264.7. Both phagocyte-dependent killing and phagocyte-independent killing, triggered by A1124, were confirmed in human whole blood. Furthermore, A1124 was shown to neutralize endotoxin activity of purified LPS of clinical isolates. This activity was demonstratedin vitrousing both RAW 264.7 cells and a human Toll-like receptor 4 (TLR4) reporter cell line, as well as in a murine model of endotoxemia using purified LPS for challenge. Significant protective efficacy of A1124 at low doses (<1 mg/kg of body weight) was shown in murine and rat models of bacteremia. The contribution of the bactericidal and anti-inflammatory effects was dissected in the mouse bacteremia model through depletion of complement with cobra venom factor (CVF). Protective efficacy was lost in complement-depleted mice, suggesting the essential role of complement-mediated activities for protection in this model. These data suggest that A1124 exhibits different mechanisms of action, namely, direct complement-mediated and opsonophagocytic killing as well as endotoxin neutralization in various challenge models. Which of these activities are the most relevant in a clinical setting will need to be addressed by future translational studies.
Structure and Dynamics of FosA-Mediated Fosfomycin Resistance in Klebsiella pneumoniae and Escherichia coli
Authors: Klontz Erik H. , Tomich Adam D. , Günther Sebastian , Lemkul Justin A. , Deredge Daniel , Silverstein Zach , Shaw JoAnna F. , McElheny Christi , Doi Yohei , Wintrode Patrick L. , MacKerell Alexander D. , Sluis-Cremer Nicolas , Sundberg Eric J. 
Published: September 2017

ABSTRACTFosfomycin exhibits broad-spectrum antibacterial activity and is being reevaluated for the treatment of extensively drug-resistant pathogens. Its activity in Gram-negative organisms, however, can be compromised by expression of FosA, a metal-dependent transferase that catalyzes the conjugation of glutathione to fosfomycin, rendering the antibiotic inactive. In this study, we solved the crystal structures of two of the most clinically relevant FosA enzymes: plasmid-encoded FosA3 fromEscherichia coliand chromosomally encoded FosA fromKlebsiella pneumoniae(FosAKP). The structure, molecular dynamics, catalytic activity, and fosfomycin resistance of FosA3 and FosAKPwere also compared to those of FosA fromPseudomonas aeruginosa(FosAPA), for which prior crystal structures exist.E. coliTOP10 transformants expressing FosA3 and FosAKPconferred significantly greater fosfomycin resistance (MIC, >1,024 μg/ml) than those expressing FosAPA(MIC, 16 μg/ml), which could be explained in part by the higher catalytic efficiencies of the FosA3 and FosAKPenzymes. Interestingly, these differences in enzyme activity could not be attributed to structural differences at their active sites. Instead, molecular dynamics simulations and hydrogen-deuterium exchange experiments with FosAKPrevealed dynamic interconnectivity between its active sites and a loop structure that extends from the active site of each monomer and traverses the dimer interface. This dimer interface loop is longer and more extended in FosAKPand FosA3 than in FosAPA, and kinetic analyses of FosAKPand FosAPAloop-swapped chimeric enzymes highlighted its importance in FosA activity. Collectively, these data yield novel insights into fosfomycin resistance that could be leveraged to develop new strategies to inhibit FosA and potentiate fosfomycin activity.
An Evolutionarily Conserved Pathway Essential for Orsay Virus Infection of
Caenorhabditis elegans
Authors: Jiang Hongbing , Chen Kevin , Sandoval Luis E. , Leung Christian , Wang David 
Published: September 2017

ABSTRACT

Many fundamental biological discoveries have been made in
Caenorhabditis elegans
. The discovery of Orsay virus has enabled studies of host-virus interactions in this model organism. To identify host factors critical for Orsay virus infection, we designed a forward genetic screen that utilizes a virally induced green fluorescent protein (GFP) reporter. Following chemical mutagenesis, two Viro (
v
irus
i
nduced
r
eporter
o
ff) mutants that failed to express GFP were mapped to
sid-3
, a nonreceptor tyrosine kinase, and B0280.13 (renamed
viro-2
), an ortholog of human Wiskott-Aldrich syndrome protein (WASP). Both mutants yielded Orsay virus RNA levels comparable to that of the residual input virus, suggesting that they are not permissive for Orsay virus replication. In addition, we demonstrated that both genes affect an early prereplication stage of Orsay virus infection. Furthermore, it is known that the human ortholog of SID-3, activated CDC42-associated kinase (ACK1/TNK2), is capable of phosphorylating human WASP, suggesting that VIRO-2 may be a substrate for SID-3 in
C. elegans
. A targeted RNA interference (RNAi) knockdown screen further identified the
C. elegans
gene
nck-1
, which has a human ortholog that interacts with TNK2 and WASP, as required for Orsay virus infection. Thus, genetic screening in
C. elegans
identified critical roles in virus infection for evolutionarily conserved genes in a known human pathway.

IMPORTANCE
Orsay virus is the only known virus capable of naturally infecting the model organism
Caenorhabditis elegans
, which shares many evolutionarily conserved genes with humans. We exploited the robust genetic tractability of
C. elegans
to identify three host genes,
sid-3
,
viro-2
, and
nck-1
, which are essential for Orsay virus infection. Mutant animals that lack these three genes are highly defective in viral replication. Strikingly, the human orthologs of these three genes, activated CDC42-associated kinase (TNK2), Wiskott-Aldrich syndrome protein (WASP), and noncatalytic region of tyrosine kinase adaptor protein 1 (NCK1) are part of a known signaling pathway in mammals. These results suggest that TNK2, WASP, and NCK1 may play important roles in mammalian virus infection.
Therapeutic endoscopy-related GI bleeding and thromboembolic events in patients using warfarin or direct oral anticoagulants: results from a large nationwide database analysis
Authors: Nagata Naoyoshi , Yasunaga Hideo , Matsui Hiroki , Fushimi Kiyohide , Watanabe Kazuhiro , Akiyama Junichi , Uemura Naomi , Niikura Ryota 
Published: September 2017

Objective
To compare the risks of postendoscopy outcomes associated with warfarin with direct oral anticoagulants (DOACs), taking into account heparin bridging and various types of endoscopic procedures.

Design
Using the Japanese Diagnosis Procedure Combination database, we identified 16 977 patients who underwent 13 types of high-risk endoscopic procedures and took preoperative warfarin or DOACs from 2014 to 2015. One-to-one propensity score matching was performed to compare postendoscopy GI bleeding and thromboembolism between the warfarin and DOAC groups.

Results
In the propensity score-matched analysis involving 5046 pairs, the warfarin group had a significantly higher proportion of GI bleeding than the DOAC group (12.0% vs 9.9%; p=0.002). No significant difference was observed in thromboembolism (5.4% vs 4.7%) or in-hospital mortality (5.4% vs 4.7%). The risks of GI bleeding and thromboembolism were greater in patients treated with warfarin plus heparin bridging or DOACs plus bridging than in patients treated with DOACs alone. Compared with percutaneous endoscopic gastrostomy, patients who underwent endoscopic submucosal dissection, endoscopic mucosal resection and haemostatic procedures including endoscopic variceal ligation or endoscopic injection sclerotherapy were at the highest risk of GI bleeding among the 13 types of endoscopic procedures, whereas those who underwent lower polypectomy endoscopic sphincterotomy or endoscopic ultrasound-guided fine needle aspiration were at moderate risk.

Conclusion
The risk of postendoscopy GI bleeding was higher in warfarin than DOAC users. Heparin bridging was associated with an increased risk of bleeding and did not prevent thromboembolism. The bleeding risk varied by the type of endoscopic procedure.
The study of the structure stability of hexagonal Bi(PO4)(H2O)0.67 under high pressure
Authors: Zhang Jun , Yuan Zhen , Zhao Jian-Fa , Li Wen-Min , Jia Ya-Ting , Liu Ying , Deng Zheng , Zhang Si-Jia , Feng Shao-Min , Liu Qing-Qing , Wang Xian-Cheng , Jin Chang-Qin 
Published: September 2017

In this work, the structure stability of hexagonal Bi(PO[Formula: see text](H2O)[Formula: see text] has been investigated by high-pressure synchrotron X-ray diffraction measurements. The results show that the structure is stable within the pressure up to 18.3 GPa. The diffraction data are refined and the lattice constants [Formula: see text] and [Formula: see text] are determined, which is compressed by 6.3(7)% and 3.5(0)% within the experimental pressure, respectively. By fitting the pressure dependence of [Formula: see text] (unit cell volume divided by that at ambient pressure) with the second-order Birch equation of state, the bulk modulus [Formula: see text] is given to be about 87.1(0) GPa.
Panascleroticoxylon crystallosa gen. et sp. nov.: a new Miocene malpighialean tree from Panama
Authors: Rodriguez-Reyes Oris , Gasson Peter , Thornton Carolyn , Falcon-Lang Howard J. , Jud Nathan A. 
Published: September 2017

ABSTRACTWe report fossil wood specimens from two Miocene sites in Panama, Central America: Hodges Hill (Cucaracha Formation; Burdigalian, c. 19 Ma) and Lago Alajuela (Alajuela Formation; Tortonian, c. 10 Ma), where material is preserved as calcic and silicic permineralizations, respectively. The fossils show an unusual combination of features: diffuse porous vessel arrangement, simple perforation plates, alternate intervessel pitting, vessel–ray parenchyma pits either with much reduced borders or similar to the intervessel pits, abundant sclerotic tyloses, rays markedly heterocellular with long uniseriate tails, and rare to absent axial parenchyma. This combination of features allows assignment of the fossils to Malpighiales, and we note similarities with four predominantly tropical families: Salicaceae, Achariaceae, and especially, Phyllanthaceae, and Euphorbiaceae. These findings improve our knowledge of Miocene neotropical diversity and highlight the importance of Malpighiales in the forests of Panama prior to the collision of the Americas.
The 2016 RANZCP Guidelines for the Management of Schizophrenia and Related Disorders – what’s next?
Authors: Jablensky Assen , Castle David J , Dark Frances , Humberstone Verity , Killackey Eoin , Kulkarni Jayashri , McGorry Patrick , Morgan Vera A , Nielssen Olav , Tran Nga , Galletly Cherrie 
Published: September 2017

Objectives: The recently published RANZCP guidelines for schizophrenia and related disorders reviewed recent scientific evidence, and, where lacking, referred to clinical expertise to supply a template for raising the standard of care. This paper builds on the guidelines and recommends how they might be used to improve outcomes. Methods: The guidelines call for evidence-based mental health policies, inclusive of mobilising affected families, communities and the public in support of policies that ensure better care and protect the wellbeing of people with severe mental disorders. The process of preparing the guidelines highlighted the limits of our scientific understanding of schizophrenia and shortcomings in the care currently provided. Results: Writing the guidelines evinced the need for a culture of measuring outcomes and response to treatment, and harnessing such data to monitoring and optimising patient care. Conclusions: We recommend creation of a national case cohort for mental health research involving a collaborative network of clinical research centres, using the guidelines and generating scientific evidence for translation into clinical practice protocols that enable personalised treatment plans for patients and criteria for the performance of clinical services.
Psychiatric advance directives in Australian mental-health legislation
Authors: Ouliaris Calina , Kealy-Bateman Warren 
Published: September 2017

Objective: Following the recent widespread reform of mental-health legislation in Australia, psychiatric advance directives (PADs) have now been incorporated in four jurisdictions. We contextualise the potential role for PADs within the Australian legal framework and note their varying introduction across jurisdictions, with a focus on progressive legislation in the Australian Capital Territory (ACT). Conclusion: The formal recognition of PADs effectively shifts the trajectory of mental-health law towards a stronger recognition of consumer autonomy, albeit to varying degrees across jurisdictions. The most inspiring of these changes may be seen in the ACT Act, where an innovative framing of PAD provisions creates a safe space for clinicians and patients to engage, build therapeutic alliances and develop appropriate frameworks for further change.