bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vitro
Susceptibility of Pythium insidiosum Isolates to Aminoglycoside Antibiotics and Tigecycline
Authors: Mahl Deise Luiza , de Jesus Francielli Pantella Kunz , Loreto Érico Silva , Zanette Régis Adriel , Ferreiro Laerte , Pilotto Maiara Ben , Alves Sydney Hartz , Santurio Janio Morais 
Published: April 2012

ABSTRACT

This study evaluated the
in vitro
activity of aminoglycoside antibiotics and tigecycline against
Pythium insidiosum
. The susceptibility tests were carried out using the broth microdilution method in accordance with the CLSI document M38-A2. MIC values for gentamicin, neomycin, paromomycin, and streptomycin ranged from 32 to 64 mg/liter, and the minimal fungicidal concentration (MFC) ranged from 32 to 128 mg/liter, which are incompatible with safe concentrations of these drugs in plasma
in vivo
. Tigecycline showed the lowest MIC (0.25 to 2 mg/liter) and MFC (1 to 8 mg/liter) range values. The
in vitro
susceptibility observed to tigecycline makes this drug a good option in future tests
in vitro
and
in vivo
for the management of pythiosis.
The Antidepressant Sertraline Provides a Promising Therapeutic Option for Neurotropic Cryptococcal Infections
Authors: Zhai Bing , Wu Cheng , Wang Linqi , Sachs Matthew S. , Lin Xiaorong 
Published: April 2012

ABSTRACT

Therapeutic treatment for systemic mycoses is severely hampered by the extremely limited number of antifungals. The difficulty of treatment of fungal infections in the central nervous system is further compounded by the poor central nervous system (CNS) penetration of most antifungals due to the blood-brain barrier. Only a few fungistatic azole drugs, such as fluconazole, show reasonable CNS penetration. Here we demonstrate that sertraline (Zoloft), the most frequently prescribed antidepressant, displays potent antifungal activity against
Cryptococcus neoformans
, the major causative agent of fungal meningitis. In
in vitro
assays, this neurotropic drug is fungicidal to all natural
Cryptococcus
isolates tested at clinically relevant concentrations. Furthermore, sertraline interacts synergistically or additively with fluconazole against
Cryptococcus
. Importantly, consistent with our
in vitro
observations, sertraline used alone reduces the brain fungal burden at an efficacy comparable to that of fluconazole in a murine model of systemic cryptococcosis. It works synergistically with fluconazole in reducing the fungal burden in brain, kidney, and spleen. In contrast to its potency against
Cryptococcus
, sertraline is less effective against strains of
Candida
species and its interactions with fluconazole against
Candida
strains are often antagonistic. Therefore, our data suggest the unique application of sertraline against cryptococcosis. To understand the antifungal mechanisms of sertraline, we screened a whole-genome deletion collection of
Saccharomyces cerevisiae
for altered sertraline susceptibility. Gene ontology analyses of selected mutations suggest that sertraline perturbs translation.
In vitro
translation assays using fungal cell extracts show that sertraline inhibits protein synthesis. Taken together, our findings indicate the potential of adopting this antidepressant in treating cryptococcal meningitis.
UC781 Microbicide Gel Retains Anti-HIV Activity in Cervicovaginal Lavage Fluids Collected following Twice-Daily Vaginal Application
Authors: Haaland Richard E. , Evans-Strickfaden Tammy , Holder Angela , Pau Chou-Pong , McNicholl Janet M. , Chaikummao Supraporn , Chonwattana Wannee , Hart Clyde E. 
Published: April 2012

ABSTRACTThe potent nonnucleoside reverse transcriptase inhibitor UC781 has been safety tested as a vaginal microbicide gel formulation for prevention of HIV-1 sexual transmission. To investigate whether UC781 retained anti-infective activity following exposure to the female genital tract, we conducted anex vivoanalysis of the UC781 levels and antiviral activity in cervicovaginal lavage (CVL) fluids from 25 Thai women enrolled in a 14-day safety trial of twice-daily vaginal application of two concentrations of the UC781 microbicide gel. CVL samples were collected from women in the 0.1% (n= 5), 0.25% (n= 15), and placebo (n= 5) gel arms following the first application of gel (T15 min) and 8 to 24 h after the final application (T8-24 h) and separated into cell-free (CVL-s) and pelletable (CVL-p) fractions. As UC781 is highly hydrophobic, there were significantly higher levels of UC781 in the CVL-p samples than in the CVL-s samples for the UC781 gel arms. InT8-24 hCVL-p samples, 2/5 and 13/15 samples collected from the 0.1% and 0.25% UC781 gel arms, respectively, efficiently blocked infection with ≥4 log1050% tissue culture infective dose (TCID50) of a CCR5-tropic CRF01_AE HIV-1 virus stock. Independent of the arm, the 11 CVL-p samples with UC781 levels of ≥5 μg/CVL sample reduced infectious HIV by ≥4 log10TCID50. Our results suggest that the levels and anti-infective activities of UC781 gel formulations are likely to be associated with a cellular or pelletable component in CVL samples. Therefore, cellular and pelletable fractions should be assayed for drug levels and anti-infective activity in preclinical studies of candidate microbicides.
The Anthelmintic Triclabendazole and Its Metabolites Inhibit the Membrane Transporter ABCG2/BCRP
Authors: Barrera Borja , Otero Jon A. , Egido Estefanía , Prieto Julio G. , Seelig Anna , Álvarez Ana I. , Merino Gracia 
Published: April 2012

ABSTRACT

ABCG2/BCRP is an ATP-binding cassette transporter that extrudes compounds from cells in the intestine, liver, kidney, and other organs, such as the mammary gland, affecting pharmacokinetics and milk secretion of antibiotics, anticancer drugs, and other compounds and mediating drug-drug interactions. In addition, ABCG2 expression in cancer cells may directly cause resistance by active efflux of anticancer drugs. The development of ABCG2 modulators is critical in order to improve drug pharmacokinetic properties, reduce milk secretion of xenotoxins, and/or increase the effective intracellular concentrations of substrates. Our purpose was to determine whether the anthelmintic triclabendazole (TCBZ) and its main plasma metabolites triclabendazole sulfoxide (TCBZSO) and triclabendazole sulfone (TCBZSO
2
) inhibit ABCG2 activity. ATPase assays using human ABCG2-enriched membranes demonstrated a clear ABCG2 inhibition exerted by these compounds. Mitoxantrone accumulation assays using murine Abcg2- and human ABCG2-transduced MDCK-II cells confirmed that TCBZSO and TCBZSO
2
are ABCG2 inhibitors, reaching inhibitory potencies between 40 and 55% for a concentration range from 5 to 25 μM. Transepithelial transport assays of ABCG2 substrates in the presence of both TCBZ metabolites at 15 μM showed very efficient inhibition of the Abcg2/ABCG2-mediated transport of the antibacterial agents nitrofurantoin and danofloxacin. TCBZSO administration also inhibited nitrofurantoin Abcg2-mediated secretion into milk by more than 2-fold and increased plasma levels of the sulfonamide sulfasalazine by more than 1.5-fold in mice. These results support the potential role of TCBZSO and TCBZSO
2
as ABCG2 inhibitors to participate in drug interactions and modulate ABCG2-mediated pharmacokinetic processes.
In Vitro
Reconstitution of the Complete Clostridium thermocellum Cellulosome and Synergistic Activity on Crystalline Cellulose
Authors: Krauss Jan , Zverlov Vladimir V. , Schwarz Wolfgang H. 
Published: April 2012

ABSTRACT

Artificial cellulase complexes active on crystalline cellulose were reconstituted
in vitro
from a native mix of cellulosomal enzymes and CipA scaffoldin. Enzymes containing dockerin modules for binding to the corresponding cohesin modules were prepared from culture supernatants of a
C. thermocellum cipA
mutant. They were reassociated to cellulosomes via dockerin-cohesin interaction. Recombinantly produced mini-CipA proteins with one to three cohesins either with or without the carbohydrate-binding module (CBM) and the complete CipA protein were used as the cellulosomal backbone. The binding between cohesins and dockerins occurred spontaneously. The hydrolytic activity against soluble and crystalline cellulosic compounds showed that the composition of the complex does not seem to be dependent on which CipA-derived cohesin was used for reconstitution. Binding did not seem to have an obvious local preference (equal binding to Coh1 and Coh6). The synergism on crystalline cellulose increased with an increasing number of cohesins in the scaffoldin. The
in vitro
-formed complex showed a 12-fold synergism on the crystalline substrate (compared to the uncomplexed components). The activity of reconstituted cellulosomes with full-size CipA reached 80% of that of native cellulosomes. Complexation on the surface of nanoparticles retained the activity of protein complexes and enhanced their stability. Partial supplementation of the native cellulosome components with three selected recombinant cellulases enhanced the activity on crystalline cellulose and reached that of the native cellulosome. This opens possibilities for
in vitro
complex reconstitution, which is an important step toward the creation of highly efficient engineered cellulases.
The Spx Regulator Modulates Stress Responses and Virulence in Enterococcus faecalis
Authors: Kajfasz Jessica K. , Mendoza Jorge E. , Gaca Anthony O. , Miller James H. , Koselny Kristy A. , Giambiagi-deMarval Marcia , Wellington Melanie , Abranches Jacqueline , Lemos José A. 
Published: April 2012

ABSTRACT

The ability to cope with endogenous or host-generated reactive oxygen species is considered a key virulence attribute of the opportunistic pathogen
Enterococcus faecalis
, a leading cause of hospital-acquired infections. In this study, we used
in silico
and mutational analyses to identify and characterize the role of the Spx global regulator in oxidative stress tolerance and virulence in
E. faecalis
. While the Δ
spx
strain grew as well as the wild-type strain under anaerobic conditions, the mutant strain exhibited impaired growth under aerobic conditions and was highly sensitive to oxidative stress agents. The
spx
mutant strain was also sensitive to a variety of other stressful conditions, including antibiotic stress and killing by the mouse-derived macrophage cell line J774. Using a murine model of foreign body-associated peritonitis, we demonstrated that the ability of the Δ
spx
strain to colonize the peritoneum and disseminate in the bloodstream was significantly reduced compared to that of the parent strain. Transcriptional analysis revealed that a large number of known oxidative stress genes are under positive control by Spx. Collectively, our results show that Spx is a major stress gene regulator and is implicated in the pathophysiology of
E. faecalis
. The relationship of Spx to other oxidative stress regulators is also discussed.
Enhanced involvement of general practitioners in cancer rehabilitation: a randomised controlled trial
Authors: Bergholdt Stinne Holm , Larsen Pia Veldt , Kragstrup Jakob , Søndergaard Jens , Hansen Dorte Gilså 
Published: April 2012

ObjectiveTo test the hypothesis that a multimodal intervention giving the general practitioner (GP) an enhanced role in cancer rehabilitation improves patients' health-related quality of life and psychological distress.DesignCluster randomised controlled trial. All general practices in Denmark were randomised to an intervention group or to a control group. Patients were subsequently allocated to intervention or control (usual procedures) based on the randomisation status of their GP.SettingAll clinical departments at a public regional hospital treating cancer patients and all general practices in Denmark.ParticipantsAdult patients treated for incident cancer at Vejle Hospital, Denmark, between 12 May 2008 and 28 February 2009. A total of 955 patients (486 to the intervention group and 469 to the control group) registered with 323 general practices were included.InterventionThe intervention included an interview about rehabilitation needs with a rehabilitation coordinator at the regional hospital, information from the hospital to the GP about individual needs for rehabilitation and an encouragement of the GP to contact the patient to offer his support with rehabilitation.Main outcome measuresThe primary outcome was health-related quality of life measured 6 months after inclusion using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Secondary outcomes included quality of life at 14 months and additional subscales of the EORTC QLQ-C30 at 6 and 14 months and psychological distress at 14 months using the Profile of Mood States Scale.ResultsNo effect of the intervention was observed on primary and/or secondary outcomes after 6 and 14 months.ConclusionA multimodal intervention aiming to give the GP an enhanced role in cancer patients' rehabilitation did not improve quality of life or psychological distress.Trial registrationClinicalTrials.gov, registration ID numberNCT01021371.
Do adverts increase the probability of finding online cognitive behavioural therapy for depression? Cross-sectional study
Authors: Jones Ray B , Goldsmith Lesley , Hewson Paul , Kamel Boulos Maged N , Williams Christopher J 
Published: April 2012

ObjectiveTo estimate the effect of online adverts on the probability of finding online cognitive behavioural therapy (CBT) for depression.DesignExploratory online cross-sectional study of search experience of people in the UK with depression in 2011. (1) The authors identified the search terms over 6 months entered by users who subsequently clicked on the advert for online help for depression. (2) A panel of volunteers across the UK recorded websites presented by normal Google search for the term ‘depression’. (iii) The authors examined these websites to estimate probabilities of knowledgeable and naive internet users finding online CBT and the improved probability by addition of a Google advert.Participants(1) 3868 internet users entering search terms related to depression into Google. (2) Panel, recruited online, of 12 UK participants with an interest in depression.Main outcome measuresProbability of finding online CBT for depression with/without an advert.ResultsThe 3868 users entered 1748 different search terms but the single keyword ‘depression’ resulted in two-thirds of the presentations of, and over half the ‘clicks’ on, the advert. In total, 14 different websites were presented to our panel in the first page of Google results for ‘depression’. Four of the 14 websites had links enabling access to online CBT in three clicks for knowledgeable users. Extending this approach to the 10 most frequent search terms, the authors estimated probabilities of finding online CBT as 0.29 for knowledgeable users and 0.006 for naive users, making it unlikely CBT would be found. Adding adverts that linked directly to online CBT increased the probabilities to 0.31 (knowledgeable) and 0.02 (naive).ConclusionsIn this case, online CBT was not easy to find and online adverts substantially increased the chance for naive users. Others could use this approach to explore additional impact before committing to long-term Google AdWords advertising budgets.Trial registrationThis exploratory case study was a substudy within a cluster randomised trial, registered onhttp://www.clinicaltrials.gov(reference:NCT01469689). (The trial will be reported subsequently).
TGF-β1 Induces Endothelial Cell Apoptosis by Shifting VEGF Activation of p38MAPK from the Prosurvival p38β to Proapoptotic p38α
Authors: Ferrari Giovanni , Terushkin Vitaly , Wolff Martin J. , Zhang Xiaodong , Valacca Cristina , Poggio Paolo , Pintucci Giuseppe , Mignatti Paolo 
Published: April 2012

Abstract
TGF-β1 and VEGF, both angiogenesis inducers, have opposing effects on vascular endothelial cells. TGF-β1 induces apoptosis; VEGF induces survival. We have previously shown that TGF-β1 induces endothelial cell expression of VEGF, which mediates TGF-β1 induction of apoptosis through activation of p38 mitogen-activated protein kinase (MAPK). Because VEGF activates p38MAPK but protects the cells from apoptosis, this finding suggested that TGF-β1 converts p38MAPK signaling from prosurvival to proapoptotic. Four isoforms of p38MAPK —α, β, γ, and δ—have been identified. Therefore, we hypothesized that different p38MAPK isoforms control endothelial cell apoptosis or survival, and that TGF-β1 directs VEGF activation of p38MAPK from a prosurvival to a proapoptotic isoform. Here, we report that cultured endothelial cells express p38α, β, and γ. VEGF activates p38β, whereas TGF-β1 activates p38α. TGF-β1 treatment rapidly induces p38α activation and apoptosis. Subsequently, p38α activation is downregulated, p38β is activated, and the surviving cells become refractory to TGF-β1 induction of apoptosis and proliferate. Gene silencing of p38α blocks TGF-β1 induction of apoptosis, whereas downregulation of p38β or p38γ expression results in massive apoptosis. Thus, in endothelial cells p38α mediates apoptotic signaling, whereas p38β and p38γ transduce survival signaling. TGF-β1 activation of p38α is mediated by VEGF, which in the absence of TGF-β1 activates p38β. Therefore, these results show that TGF-β1 induces endothelial cell apoptosis by shifting VEGF signaling from the prosurvival p38β to the proapoptotic p38α. Mol Cancer Res; 10(5); 605–14. ©2012 AACR.
A Pacific Centennial Oscillation Predicted by Coupled GCMs*
Authors: Karnauskas Kristopher B. , Smerdon Jason E. , Seager Richard , González-Rouco Jesús Fidel 
Published: April 2012

Abstract
Internal climate variability at the centennial time scale is investigated using long control integrations from three state-of-the-art global coupled general circulation models. In the absence of external forcing, all three models produce centennial variability in the mean zonal sea surface temperature (SST) and sea level pressure (SLP) gradients in the equatorial Pacific with counterparts in the extratropics. The centennial pattern in the tropical Pacific is dissimilar to that of the interannual El Niño–Southern Oscillation (ENSO), in that the most prominent expression in temperature is found beneath the surface of the western Pacific warm pool. Some global repercussions nevertheless are analogous, such as a hemispherically symmetric atmospheric wave pattern of alternating highs and lows. Centennial variability in western equatorial Pacific SST is a result of the strong asymmetry of interannual ocean heat content anomalies, while the eastern equatorial Pacific exhibits a lagged, Bjerknes-like response to temperature and convection in the west. The extratropical counterpart is shown to be a flux-driven response to the hemispherically symmetric circulation anomalies emanating from the tropical Pacific.
Significant centennial-length trends in the zonal SST and SLP gradients rivaling those estimated from observations and model simulations forced with increasing CO2 appear to be inherent features of the internal climate dynamics simulated by all three models. Unforced variability and trends on the centennial time scale therefore need to be addressed in estimated uncertainties, beyond more traditional signal-to-noise estimates that do not account for natural variability on the centennial time scale.
Influence of the Tropics on the Southern Annular Mode
Authors: Ding Qinghua , Steig Eric J. , Battisti David S. , Wallace John M. 
Published: April 2012

Abstract
Perturbations in the southern annular mode (SAM) are shown to be significantly correlated with SST anomalies in the central tropical Pacific during austral winter and SST anomalies in the eastern tropical Pacific during austral summer. The SAM signature in the Pacific sector resembles a tropically forced Rossby wave train, the so-called Pacific–South American pattern, while the signature in the Indian Ocean sector is a zonally elongated meridional dipole. Thus, the SAM contains strong zonally asymmetric variability and tends to behave differently in the Eastern and Western Hemispheres, with internal dynamics prevailing in the Indian Ocean sector and the forced response to tropical SST anomalies exerting a strong influence in the Pacific sector. The tropically forced component of the SAM in the Pacific sector is related to a geographically fixed active Rossby wave source to the east of Australia within the core of the subtropical jet. In addition to the well-documented positive trend in summer, the SAM also exhibits a negative wintertime trend since 1979, characterized by prominent geopotential height increases over the high latitudes. In both seasons, SAM trends are closely linked to long-term trends in tropical Pacific SST that are independent of the canonical eastern Pacific ENSO variability. Although the SAM is an intrinsic pattern of high-latitude variability, the SAM index reflects the superposition of both high-latitude and tropically forced variability.
A Zonal Wavenumber 3 Pattern of Northern Hemisphere Wintertime Planetary Wave Variability at High Latitudes
Authors: Teng Haiyan , Branstator Grant 
Published: April 2012

Abstract
A prominent pattern of variability of the Northern Hemisphere wintertime tropospheric planetary waves, referred to here as the Wave3 pattern, is identified from the NCEP–NCAR reanalysis. It is worthy of attention because its structure is similar to the linear trend pattern as well as the leading pattern of multidecadal variability of the planetary waves during the past half century. The Wave3 pattern is defined as the second empirical orthogonal function (EOF) of detrended December–February mean 300-hPa meridional wind V300 and denotes a zonal shift of the ridges and troughs of the climatological flow. Although its interannual variance is roughly comparable to that of EOF1 of V300, which represents the Pacific–North America (PNA) pattern, its multidecadal variance is nearly twice as large as that of the PNA. Wave3 is not completely structurally or temporally distinct from the northern annular mode (NAM) but, for some attributes, the linkage of the observed trend to Wave3 is clearer than to NAM. The prominence of the Wave3 pattern is further supported by attributes of many climate models that participated in phase 3 of the Coupled Model Intercomparison Project (CMIP3). In particular, in the Community Climate System Model, version 3 (CCSM3), the Wave3 pattern is present as EOF3 of V300 in both a fully coupled integration and a stand-alone atmospheric integration forced by climatological sea surface temperatures. Its existence in the latter experiment indicates that the pattern can be produced by atmospheric processes alone.