bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Effects of Lapatinib Revealed in the African Trypanosome by Using Hypothesis-Generating Proteomics and Chemical Biology Strategies
Authors: Guyett Paul J. , Behera Ranjan , Ogata Yuko , Pollastri Michael , Mensa-Wilmot Kojo 
Published: November 2016

ABSTRACT

Human African trypanosomiasis is a neglected tropical disease caused by the protozoan parasite
Trypanosoma brucei
. Lapatinib, a human epidermal growth factor receptor (EGFR) inhibitor, can cure 25% of trypanosome-infected mice, although the parasite lacks EGFR-like tyrosine kinases. Four trypanosome protein kinases associate with lapatinib, suggesting that the drug may be a multitargeted inhibitor of phosphoprotein signaling in the bloodstream trypanosome. Phosphoprotein signaling pathways in
T. brucei
have diverged significantly from those in humans. As a first step in the evaluation of the polypharmacology of lapatinib in
T. brucei
, we performed a proteome-wide phosphopeptide analysis before and after drug addition to cells. Lapatinib caused dephosphorylation of Ser/Thr sites on proteins predicted to be involved in scaffolding, gene expression, and intracellular vesicle trafficking. To explore the perturbation of phosphotyrosine (pTyr)-dependent signaling by lapatinib, proteins in lapatinib-susceptible pTyr complexes were identified by affinity chromatography; they included BILBO-1, MORN, and paraflagellar rod (PFR) proteins PFR1 and PFR2. These data led us to hypothesize that lapatinib disrupts PFR functions and/or endocytosis in the trypanosome. In direct chemical biology tests of these speculations, lapatinib-treated trypanosomes (i) lost segments of the PFR inside the flagellum, (ii) were inhibited in the endocytosis of transferrin, and (iii) changed morphology from long and slender to rounded. Thus, our hypothesis-generating phosphoproteomics strategy predicted novel physiological pathways perturbed by lapatinib, which were verified experimentally. General implications of this workflow for identifying signaling pathways perturbed by drug hits discovered in phenotypic screens are discussed.
Polymyxin B in Combination with Rifampin and Meropenem against Polymyxin B-Resistant KPC-Producing Klebsiella pneumoniae
Authors: Diep John K. , Jacobs David M. , Sharma Rajnikant , Covelli Jenna , Bowers Dana R. , Russo Thomas A. , Rao Gauri G. 
Published: November 2016

ABSTRACT

Safe and effective therapies are urgently needed to treat polymyxin-resistant KPC-producing
Klebsiella pneumoniae
infections and suppress the emergence of resistance. We investigated the pharmacodynamics of polymyxin B, rifampin, and meropenem alone and as polymyxin B-based double and triple combinations against KPC-producing
K. pneumoniae
isolates. The rates and extents of killing with polymyxin B (1 to 128 mg/liter), rifampin (2 to 16 mg/liter), and meropenem (10 to 120 mg/liter) were evaluated against polymyxin B-susceptible (PB
s
) and polymyxin B-resistant (PB
r
) clinical isolates using 48-h static time-kill studies. Additionally, humanized triple-drug regimens of polymyxin B (concentration at steady state [
C
ss
] values of 0.5, 1, and 2 mg/liter), 600 mg rifampin every 12 or 8 h, and 1 or 2 g meropenem every 8 h dosed as an extended 3-h infusion were simulated over 48 h by using a one-compartment
in vitro
dynamic infection model. Serial bacterial counts were performed to quantify the pharmacodynamic effect. Population analysis profiles (PAPs) were used to assess the emergence of polymyxin B resistance. Monotherapy was ineffective against both isolates. Polymyxin B with rifampin demonstrated early bactericidal activity against the PB
s
isolate, followed by regrowth by 48 h. Bactericidal activity was sustained at all polymyxin B concentrations of ≥2 mg/liter in combination with meropenem. No two-drug combinations were effective against the PB
r
isolate, but all simulated triple-drug regimens showed early bactericidal activity against both strains by 8 h that was sustained over 48 h. PAPs did not reveal the emergence of resistant subpopulations. The triple-drug combination of polymyxin B, rifampin, and meropenem may be a viable consideration for the treatment of PB
r
KPC-producing
K. pneumoniae
infections. Further investigation is warranted to optimize triple-combination therapy.
Missense Mutations in the Unfoldase ClpC1 of the Caseinolytic Protease Complex Are Associated with Pyrazinamide Resistance in Mycobacterium tuberculosis
Authors: Yee Michelle , Gopal Pooja , Dick Thomas 
Published: November 2016

ABSTRACT

Previously, we showed that mutations in
Mycobacterium tuberculosis
panD
, involved in coenzyme A biosynthesis, cause resistance against pyrazinoic acid, the bioactive component of the prodrug pyrazinamide. To identify additional resistance mechanisms, we isolated mutants resistant against pyrazinoic acid and subjected
panD
wild-type strains to whole-genome sequencing. Eight of the nine resistant strains harbored missense mutations in the unfoldase ClpC1 associated with the caseinolytic protease complex.
The Type III Effector NleD from Enteropathogenic Escherichia coli Differentiates between Host Substrates p38 and JNK
Authors: Creuzburg Kristina , Giogha Cristina , Wong Fok Lung Tania , Scott Nichollas E. , Mühlen Sabrina , Hartland Elizabeth L. , Pearson Jaclyn S. 
Published: November 2016

ABSTRACT

Enteropathogenic
Escherichia coli
(EPEC) is a gastrointestinal pathogen that utilizes a type III secretion system (T3SS) to inject an array of virulence effector proteins into host enterocytes to subvert numerous cellular processes for successful colonization and dissemination. The T3SS effector NleD is a 26-kDa zinc metalloprotease that is translocated into host enterocytes, where it directly cleaves and inactivates the mitogen-activated protein kinase signaling proteins JNK and p38. Here a library of 91 random transposon-based, in-frame, linker insertion mutants of NleD were tested for their ability to cleave JNK and p38 during transient transfection of cultured epithelial cells. Immunoblot analysis of p38 and JNK cleavage showed that 7 mutant derivatives of NleD no longer cleaved p38 but maintained the ability to cleave JNK. Site-directed mutation of specific regions surrounding the insertion sites within NleD revealed that a single amino acid, R203, was essential for cleavage of p38 but not JNK in a direct
in vitro
cleavage assay, in transiently transfected cells, or in EPEC-infected cells. Mass spectrometry analysis narrowed the cleavage region to within residues 187 and 213 of p38. Mutation of residue R203 within NleD to a glutamate residue abolished the cleavage of p38 and impaired the ability of NleD to inhibit AP-1-dependent gene transcription of a luciferase reporter. Furthermore, the R203 mutation abrogated the ability of NleD to dampen interleukin-6 production in EPEC-infected cells. Overall, this work provides greater insight into substrate recognition and specificity by the type III effector NleD.
Flagellin-Mediated Protection against Intestinal Yersinia pseudotuberculosis Infection Does Not Require Interleukin-22
Authors: Porte Rémi , Van Maele Laurye , Muñoz-Wolf Natalia , Foligné Benoit , Dumoutier Laure , Tabareau Julien , Cayet Delphine , Gosset Pierre , Jonckheere Nicolas , Van Seuningen Isabelle , Chabalgoity José A. , Simonet Michel , Lamkanfi Mohamed , Renauld Jean-Christophe , Sirard Jean-Claude , Carnoy Christophe 
Published: November 2016

ABSTRACT

Signaling through Toll-like receptors (TLRs), the main receptors in innate immunity, is essential for the defense of mucosal surfaces. It was previously shown that systemic TLR5 stimulation by bacterial flagellin induces an immediate, transient interleukin-22 (IL-22)-dependent antimicrobial response to bacterial or viral infections of the mucosa. This process was dependent on the activation of type 3 innate lymphoid cells (ILCs). The objective of the present study was to analyze the effects of flagellin treatment in a murine model of oral infection with
Yersinia pseudotuberculosis
(an invasive, Gram-negative, enteropathogenic bacterium that targets the small intestine). We found that systemic administration of flagellin significantly increased the survival rate after intestinal infection (but not systemic infection) by
Y. pseudotuberculosis
. This protection was associated with a low bacterial count in the gut and the spleen. In contrast, no protection was afforded by administration of the TLR4 agonist lipopolysaccharide, suggesting the presence of a flagellin-specific effect. Lastly, we found that TLR5- and MyD88-mediated signaling was required for the protective effects of flagellin, whereas neither lymphoid cells nor IL-22 was involved.
An
ompR-envZ
Two-Component System Ortholog Regulates Phase Variation, Osmotic Tolerance, Motility, and Virulence in Acinetobacter baumannii Strain AB5075
Authors: Tipton Kyle A. , Rather Philip N. 
Published: November 2016

ABSTRACT

Recently, a novel phase-variable colony opacity phenotype was discovered in
Acinetobacter baumannii
strain AB5075, where colonies interconvert between opaque and translucent variants. Opaque colonies become mottled or sectored after 24 h of growth due to translucent variants arising within the colony. This easily distinguishable opaque-colony phenotype was used to screen for random transposon insertions that increased the frequency of sectoring at a time point when wild-type colonies were uniformly opaque. A colony was identified that contained multiple papillae of translucent variants, and the insertion in this mutant mapped to an ortholog of the two-component system response regulator
ompR
. Subsequent investigation of in-frame deletions of
ompR
and the sensor kinase
envZ
(located adjacent to
ompR
) showed that the switching frequency from opaque to translucent was increased 401- and 281-fold, respectively. The
ompR
mutant also exhibited sensitivity to sodium chloride in growth medium, whereas the
envZ
mutation did not elicit sensitivity to sodium chloride. Mutation of either gene reduced motility in
A. baumannii
strain AB5075, but a mutation in both
ompR
and
envZ
produced a more profound effect. The
ompR
and
envZ
genes were cotranscribed but were not subject to autoregulation by OmpR. Both
ompR
and
envZ
mutant opaque variants were attenuated in virulence in the
Galleria mellonella
infection model, whereas mutation of
ompR
had no effect on the virulence of the translucent variant.

IMPORTANCE
Acinetobacter baumannii
is a well-known antibiotic-resistant pathogen; many clinical isolates can only be treated by a very small number of antibiotics (including colistin), while some exhibit panresistance. The current antimicrobial arsenal is nearing futility in the treatment of
Acinetobacter
infections, and new avenues of treatment are profoundly needed. Since phase variation controls the transition between opaque (virulent) and translucent (avirulent) states in
A. baumannii
, this may represent an “Achilles' heel” that can be targeted via the development of small molecules that lock cells in the translucent state and allow the host immune system to clear the infection. A better understanding of how phase variation is regulated may allow for the development of methods to target this process. The
ompR-envZ
two-component system ortholog negatively regulates phase variation in
A. baumannii
, and perturbation of this system leads to the attenuation of virulence in an invertebrate infection model.
High-precision time-space correlation through coupled apatite and zircon tephrochronology: An example from the Permian-Triassic boundary in South China
Authors: Baresel Björn , d’Abzac François-Xavier , Bucher Hugo , Schaltegger Urs 
Published: November 2016

Abstract
Accurate and precise dating of individual volcanogenic beds that spread across multiple sedimentary successions is a powerful tool to untangle stratigraphic age contradictions, since these horizons are deposited synchronously. In this study, we show that combining apatite chemistry with zircon age, Th/U ratio, and Hf isotope composition leads to reliable lateral correlation of volcanic horizons across sections representing disparate biological, chemical, and physical paleoenvironments. We correlate two volcanogenic horizons across six sedimentary sections straddling the Permian-Triassic boundary (PTB) in the Nanpanjiang Basin (South China), including the last Permian bed below the unconformity in shallow-water sections of the Luolou Platform. We place the PTB in our sections at the marked lithological change in order to avoid the difficulties that arise from the diachronism of the index conodont Hindeodus parvus, the first occurrence of which defines the PTB at the Global Stratotype Section and Point at Meishan. Our new data demonstrate that these volcanogenic beds are contemporaneous and cogenetic, allowing us to pool high-precision U-Pb zircon ages from the same horizon across several sections, and dating the last Permian volcanic event in this basin at 252.048 ± 0.033 Ma. We show that the mineral chemistry of apatite and zircon of intra- and interbasin-wide volcanogenic beds provides tie points against which biozones, carbon isotopes, astronomic cycles, and geomagnetic polarity time series can be stringently tested.
40Ar/39Ar dating and thermal modeling of adularia to constrain the timing of hydrothermal activity in magmatic settings
Authors: Oze Christopher , Cattell Hamish , Grove Marty 
Published: November 2016

Abstract
Hydrothermal systems develop via interspersed thermal events over tens to hundreds of thousands of years. The timing of how these systems evolve is commonly established via application of geochronology to a variety of phases and/or the indirect correlation of dated stratigraphy. Here we report 40Ar/39Ar results from adularia extracted from a single mineralized fracture in the late Quaternary Tauhara geothermal system of New Zealand. By utilizing both the age and Ar diffusion properties, we demonstrate how adularia can provide reliable temporal and thermal constraints on the evolution of geologically youthful and active geothermal systems. Our results indicate that adularia formation occurred after 30 ka (mean age 15 ± 10 ka), possibly resulting from subsurface fracturing induced by a 25.4 ka hydrothermal eruption. Simulation of transient heat effects upon Ar retention in adularia with respect to the thermal history of the Tauhara geothermal system confirm that this age is consistent with the time of adularia crystallization. Overall, 40Ar/39Ar dating on geologically young hydrothermal adularia with respect to its thermal history may be used to assess the timing and potential events (e.g., eruptions and fracturing) related to hydrothermal system evolution.
First direct evidence for natural occurrence of colloidal silica in chalcedony-hosted vacuoles and implications for ore-forming processes
Authors: Prokofiev Vsevolod Yu. , Kamenetsky Vadim S. , Selektor Sofia L. , Rodemann Thomas , Kovalenker Vladimir A. , Vatsadze Sergey Z. 
Published: November 2016

Abstract
Different forms of abundant silica (e.g., quartz and chalcedony) are closely associated with many types of ore deposits in igneous, metamorphic, and sedimentary environments. Occurrence of quartz and metal-bearing minerals together strongly indicates that silica is an important component in hydrothermal fluids transporting and concentrating economic metals to the ore grade, however chemical and physical characteristics of such ore-forming media remain debated. Understanding of the environment in which chalcedony forms is largely hampered by the lack of chalcedony-hosted fluid inclusions. Our study reports for the first time fortuitously preserved, large-sized (up to 150 μm) fluid inclusions in chalcedony from the Gonchak deposit of optical calcite in the Early Triassic basalts belonging to the Siberian large igneous province. The application of microthermometric methods, scanning electron microscopy with cathodoluminescence, and laser Raman spectroscopy to the fluid inclusions and their host chalcedony recognized the formation of chalcedony from a colloidal suspension. The fluid inclusions represent a gel-like saline aqueous fluid that is residual after precipitation of spherulitic chalcedony aggregates with numerous H2O-bearing and H2O-poor layers. We propose that the colloidal nature of fluids forming chalcedony lends strong support to the natural existence of experimentally predicted “silicothermal fluids”. Such fluids can be instrumental in mobilizing and transporting large quantities of both silica and nano- and micro-particles of ore minerals, followed by efficient separation of the latter from coagulating silica gel into ore-rich zones and bodies.
Too much detention? Street Triage and detentions under Section 136 Mental Health Act in the North-East of England: a descriptive study of the effects of a Street Triage intervention
Authors: Keown Patrick , French Jo , Gibson Graham , Newton Eddy , Cull Steve , Brown Paul , Parry Jo , Lyons Diana , McKinnon Iain 
Published: November 2016

ObjectivesTo describe the impact of Street Triage (ST) on the number and rate of Section 136 Mental Health Act (S136) detentions in one NHS Mental Health and Disability Trust (Northumberland, Tyne and Wear (NTW)).DesignComparative descriptive study of numbers and rates of S136 detentions prior to and following the introduction of ST in NTW. More detailed data were obtained from one local authority in the NTW area.SettingNTW, a secondary care NHS Foundation Trust providing mental health and disability services in the north-east of England, in conjunction with Northumbria Police Service.ParticipantsPeople being detained under S136 Mental Health Act (MHA). Routine data on S136 detentions and ST interventions were obtained from NTW, Northumbria Police, Sunderland Hospitals NHS Foundation Trust and Sunderland Local Authority.InterventionsIntroduction of a ST service in NTW. The main outcome measures were routinely collected data on the number and rate of ST interventions as well as patterns of the numbers and rates of S136 detentions. These were collected retrospectively.ResultsThe annual rate of S136 detentions reduced by 56% in the first year of ST (from 59.8 per 100 000 population to 26.4 per 100 000). There was a linear relationship between the rate of ST in each locality and the reduction in rate of S136 detentions. There were 1623 ST contacts in the first 3 localities to have a ST service during its first year; there were also 403 fewer S136 detentions. Data from Sunderland indicate a 78% reduction in S136 use and a significant reduction in the number and proportion of adult admissions that originated from S136 detentions.ConclusionsThere is evidence to support the hypothesis that ST decreases the rate of s136 detention. When operating across the whole of NTW, ST resulted in 50 fewer S136 detentions a month, which represents a substantial reduction.
Does integrated care reduce hospital activity for patients with chronic diseases? An umbrella review of systematic reviews
Authors: Damery Sarah , Flanagan Sarah , Combes Gill 
Published: November 2016

ObjectiveTo summarise the evidence regarding the effectiveness of integrated care interventions in reducing hospital activity.DesignUmbrella review of systematic reviews and meta-analyses.SettingInterventions must have delivered care crossing the boundary between at least two health and/or social care settings.ParticipantsAdult patients with one or more chronic diseases.Data sourcesMEDLINE, Embase, ASSIA, PsycINFO, HMIC, CINAHL, Cochrane Library (HTA database, DARE, Cochrane Database of Systematic Reviews), EPPI-Centre, TRIP, HEED, manual screening of references.Outcome measuresAny measure of hospital admission or readmission, length of stay (LoS), accident and emergency use, healthcare costs.Results50 reviews were included. Interventions focused on case management (n=8), chronic care model (CCM) (n=9), discharge management (n=15), complex interventions (n=3), multidisciplinary teams (MDT) (n=10) and self-management (n=5). 29 reviews reported statistically significant improvements in at least one outcome. 11/21 reviews reported significantly reduced emergency admissions (15–50%); 11/24 showed significant reductions in all-cause (10–30%) or condition-specific (15–50%) readmissions; 9/16 reported LoS reductions of 1–7 days and 4/9 showed significantly lower A&E use (30–40%). 10/25 reviews reported significant cost reductions but provided little robust evidence. Effective interventions included discharge management with postdischarge support, MDT care with teams that include condition-specific expertise, specialist nurses and/or pharmacists and self-management as an adjunct to broader interventions. Interventions were most effective when targeting single conditions such as heart failure, and when care was provided in patients’ homes.ConclusionsAlthough all outcomes showed some significant reductions, and a number of potentially effective interventions were found, interventions rarely demonstrated unequivocally positive effects. Despite the centrality of integrated care to current policy, questions remain about whether the magnitude of potentially achievable gains is enough to satisfy national targets for reductions in hospital activity.Trial registration numberCRD42015016458.
Efficacy of intravenous nicorandil for fractional flow reserve assessment: study protocol for a crossover randomised trial
Authors: Nishi Takeshi , Kitahara Hideki , Fujimoto Yoshihide , Nakayama Takashi , Sugimoto Kazumasa , Nagashima Kengo , Hanaoka Hideki , Kobayashi Yoshio 
Published: November 2016

IntroductionNicorandil has vasodilatory effects on both the epicardial coronary arteries and the coronary microvasculature, thereby increasing coronary blood flow. Intravenous administration of nicorandil can be applicable for fractional flow reserve (FFR) measurement as a hyperaemic agent and a possible alternative to adenosine. However, the effectiveness of intravenous nicorandil infusion for FFR measurement is largely unclear.Methods and analysisThis crossover randomised study is being performed to investigate the efficacy of intravenous administration of nicorandil for FFR measurement. Patients with an intermediate coronary artery stenosis who satisfy the eligibility criteria undergo FFR measurement with a consecutive randomised order of patient-blind infusions of continuous intravenous administration of adenosine and a single bolus intravenous administration of nicorandil. The primary end point of the study is the agreement between the FFR values obtained by the intravenous nicorandil and those obtained by the intravenous adenosine. Recruitment of this trial started in November 2015 and will end in March 2017, or until a total of 50 participants have been recruited.Ethics and disseminationThe protocol was approved by the Institutional Review Board at Chiba University Hospital. Study findings will be published in peer-reviewed journals.Trial registration numberUMIN000019309; Pre-results.