bluuebunny/crossref_metadata_2025_split huggingface dataset:
Surotomycin Demonstrates Low
In Vitro
Frequency of Resistance and Rapid Bactericidal Activity in Clostridium difficile, Enterococcus faecalis, and Enterococcus faecium
Authors: Mascio Carmela T. M. , Chesnel Laurent , Thorne Grace , Silverman Jared A. 
Published: May 2014

ABSTRACT

Surotomycin (CB-183,315) is an orally administered, minimally absorbed, selective bactericidal cyclic lipopeptide in phase 3 development for the treatment of
Clostridium difficile
-associated diarrhea. The aim of this study was to evaluate the emergence of resistance in
C. difficile
(ATCC 700057 and three recent clinical isolates from the restriction endonuclease analysis groups BI, BK, and K), vancomycin-susceptible (VS)
Enterococcus faecalis
(ATCC 49452), vancomycin-resistant (VR)
E. faecalis
(ATCC 700802), VS
Enterococcus faecium
(ATCC 6569), and VR
E. faecium
(ATCC 51559) under anaerobic conditions. The rate of spontaneous resistance was below the limit of detection (<10
−8
to <10
−9
) for surotomycin at 16 and 32× the MIC for all isolates tested. Under selective pressure by serial passage,
C. difficile
grew in a maximum of 4 μg/ml surotomycin (final MICs of 2 to 8 μg/ml [4- to 16-fold higher than those of the naive control]) at day 15, with the exception of the
C. difficile
BK strain, which grew in 16 to 32 μg/ml (final MICs of 8 to 32 μg/ml [16- to 64-fold higher than those of the naive control]). Enterococci remained relatively unchanged over 15 days, growing in a maximum of 8 μg/ml surotomycin (final MICs of 2 to 16 μg/ml [8- to 64-fold higher than those of the naive control]). Of the isolates tested, no cross-resistance to vancomycin, rifampin, ampicillin, metronidazole, or moxifloxacin was observed. Surotomycin at 20× MIC demonstrated equally rapid bactericidal activity (≥3-log-unit reduction in CFU/ml in ≤8 h) against naive and reduced-susceptibility isolates of
C. difficile
, VS
Enterococcus
(VSE), and VR
Enterococcus
(VRE), except for
C. difficile
BK (2.6-log-unit reductions for both). These results suggest that emergence of resistance to surotomycin against
C. difficile
,
E. faecalis
, and
E. faecium
is likely to be rare.
Screening for Inhibition of Vibrio cholerae VipA-VipB Interaction Identifies Small-Molecule Compounds Active against Type VI Secretion
Authors: Sun Kun , Bröms Jeanette , Lavander Moa , Gurram Bharat Kumar , Enquist Per-Anders , Andersson C. David , Elofsson Mikael , Sjöstedt Anders 
Published: May 2014

ABSTRACT

The type VI secretion system (T6SS) is the most prevalent bacterial secretion system and an important virulence mechanism utilized by Gram-negative bacteria, either to target eukaryotic cells or to combat other microbes. The components show much variability, but some appear essential for the function, and two homologues, denoted VipA and VipB in
Vibrio cholerae
, have been identified in all T6SSs described so far. Secretion is dependent on binding of an α-helical region of VipA to VipB, and in the absence of this binding, both components are degraded within minutes and secretion is ceased. The aim of the study was to investigate if this interaction could be blocked, and we hypothesized that such inhibition would lead to abrogation of T6S. A library of 9,600 small-molecule compounds was screened for their ability to block the binding of VipA-VipB in a bacterial two-hybrid system (B2H). After excluding compounds that showed cytotoxicity toward eukaryotic cells, that inhibited growth of
Vibrio
, or that inhibited an unrelated B2H interaction, 34 compounds were further investigated for effects on the T6SS-dependent secretion of hemolysin-coregulated protein (Hcp) or of phospholipase A
1
activity. Two compounds, KS100 and KS200, showed intermediate or strong effects in both assays. Analogues were obtained, and compounds with potent inhibitory effects in the assays and desirable physicochemical properties as predicted by
in silico
analysis were identified. Since the compounds specifically target a virulence mechanism without affecting bacterial replication, they have the potential to mitigate the virulence with minimal risk for development of resistance.
Linezolid-Induced Lactic Acidosis in Two Liver Transplant Patients with the Mitochondrial DNA A2706G Polymorphism
Authors: Del Pozo J. L. , Fernández-Ros N. , Sáez E. , Herrero J. I. , Yuste J. R. , Banales J. M. 
Published: May 2014

ABSTRACT
Mitochondrial toxicity has been recently suggested to be the underlying mechanism of long-term linezolid-associated toxicity in patients with 16S rRNA genetic polymorphisms. Here, we report for the first time two cases of lactic acidosis due to long-term linezolid exposure in liver transplant recipients who presented an A2706G mitochondrial DNA polymorphism.
Effector CD8+T Cells Are Generated in Response to an Immunodominant Epitope in Type III Effector YopE during Primary Yersinia pseudotuberculosis Infection
Authors: Zhang Yue , Mena Patricio , Romanov Galina , Bliska James B. 
Published: May 2014

ABSTRACTYopE is a virulence factor that is secreted into host cells infected byYersiniaspecies. The YopE C-terminal domain has GTPase-activating protein (GAP) activity. The YopE N-terminal domain contains an epitope that is an immunodominant CD8+T cell antigen during primary infection of C57BL/6 mice withYersinia pseudotuberculosis. The characteristics of the CD8+T cells generated in response to the epitope, which comprises YopE amino acid residues 69 to 77 (YopE69–77), and the features of YopE that are important for antigenicity during primary infection, are unknown. Following intravenous infection of naïve C57BL/6 mice with ayopEGAP mutant (the R144A mutant), flow cytometry analysis of splenocytes by tetramer and intracellular cytokine staining over a time course showed that YopE69–77-specific CD8+T cells producing gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) were generated by day 7, with a peak at day 14. In addition, ∼80% of YopE69–77-specific CD8+T cells were positive for KLRG1, a memory phenotype marker, at day 21. To determine if residues that regulate YopE activity by ubiquitination or membrane localization affect the antigenicity of YopE69–77, mice were infected with ayopEubiquitination or membrane localization mutant (the R62K or L55N I59N L63N mutant, respectively). These mutants elicited YopE69–77-specific CD8+T cells producing IFN-γ and TNF-α with kinetics and magnitudes similar to those of the parental R144A strain, indicating that primary infection primes effector CD8+T cells independently of the ubiquitination or membrane localization of YopE. Additionally, at day 7, there was an unexpected positive correlation between the numbers of YopE69–77-specific CD8+T cells and CD11b+cells, but not between the numbers of YopE69–77-specific CD8+T cells and bacterial cells, in spleens, suggesting that the innate immune response contributes to the immunodominance of YopE69–77.
Phenotypic Differences of Cryptococcus Molecular Types and Their Implications for Virulence in a Drosophila Model of Infection
Authors: Thompson George R. , Albert Nathaniel , Hodge Greg , Wilson Machelle D. , Sykes Jane E. , Bays Derek J. , Firacative Carolina , Meyer Wieland , Kontoyiannis Dimitrios P. 
Published: May 2014

ABSTRACTCompared toCryptococcus neoformans, little is known about the virulence of the molecular types inCryptococcus gattii. We comparedin vitrovirulence factor production and survival data using aDrosophilamodel of infection to further characterize the phenotypic features of different cryptococcal molecular types. Forty-nine different isolates were inoculated into wild-type flies and followed for survival.In vitro, isolates were assessed for growth at 30 and 37°C, melanin production, capsule size, resistance to H2O2, and antifungal susceptibility. A mediator model was used to assess molecular type and virulence characteristics as predictors of survival in the fly model. VGIII was the most virulent molecular type in flies (P< 0.001). At 30°C, VGIII isolates grew most rapidly; at 37°C, VNI isolates grew best.C. gattiicapsules were larger than those ofC. neoformans(P< 0.001). Mediator model analysis found a strong correlation ofDrosophilasurvival with molecular type and with growth at 30°C. We found molecular-type-specific differences inC. gattiiin growth at different temperatures, melanin production, capsule size, ability to resist hydrogen peroxide, and antifungal susceptibility, while growth at 30°C and the VGIII molecular type were strongly associated with virulence in aDrosophilamodel of infection.
Cytadherence of Mycoplasma pneumoniae Induces Inflammatory Responses through Autophagy and Toll-Like Receptor 4
Authors: Shimizu Takashi , Kimura Yui , Kida Yutaka , Kuwano Koichi , Tachibana Masato , Hashino Masanori , Watarai Masahisa 
Published: May 2014

ABSTRACTMycoplasma pneumoniaecauses pneumonia, tracheobronchitis, pharyngitis, and asthma in humans. The pathogenesis ofM. pneumoniaeinfection is attributed to excessive immune responses. We previously demonstrated thatM. pneumoniaelipoproteins induced inflammatory responses through Toll-like receptor 2 (TLR2). In the present study, we demonstrated thatM. pneumoniaeinduced strong inflammatory responses in macrophages derived from TLR2 knockout (KO) mice. Cytokine production in TLR2 KO macrophages was increased compared with that in the macrophages of wild-type (WT) mice. Heat-killed, antibiotic-treated, and overgrownM. pneumoniaefailed to induce inflammatory responses in TLR2 KO macrophages. 3-Methyladenine and chloroquine, inhibitors of autophagy, decreased the induction of inflammatory responses in TLR2 KO macrophages. These inflammatory responses were also inhibited in macrophages treated with the TLR4 inhibitor VIPER and those obtained from TLR2 and TLR4 (TLR2/4) double-KO mice. Two mutants that lacked the ability to induce inflammatory responses in TLR2 KO macrophages were obtained by transposon mutagenesis. The transposons were inserted inatpCencoding an ATP synthase F0F1 ε subunit andF10_orf750encoding hypothetical protein MPN333. These mutants showed deficiencies in cytadherence. These results suggest that cytadherence ofM. pneumoniaeinduces inflammatory responses through TLR4 and autophagy.
Enhanced Alpha-oscillations in Visual Cortex during Anticipation of Self-generated Visual Stimulation
Authors: Stenner Max-Philipp , Bauer Markus , Haggard Patrick , Heinze Hans-Jochen , Dolan Ray 
Published: May 2014

Abstract
The perceived intensity of sensory stimuli is reduced when these stimuli are caused by the observer's actions. This phenomenon is traditionally explained by forward models of sensory action–outcome, which arise from motor processing. Although these forward models critically predict anticipatory modulation of sensory neural processing, neurophysiological evidence for anticipatory modulation is sparse and has not been linked to perceptual data showing sensory attenuation. By combining a psychophysical task involving contrast discrimination with source-level time–frequency analysis of MEG data, we demonstrate that the amplitude of alpha-oscillations in visual cortex is enhanced before the onset of a visual stimulus when the identity and onset of the stimulus are controlled by participants' motor actions. Critically, this prestimulus enhancement of alpha-amplitude is paralleled by psychophysical judgments of a reduced contrast for this stimulus. We suggest that alpha-oscillations in visual cortex preceding self-generated visual stimulation are a likely neurophysiological signature of motor-induced sensory anticipation and mediate sensory attenuation. We discuss our results in relation to proposals that attribute generic inhibitory functions to alpha-oscillations in prioritizing and gating sensory information via top–down control.
Functional Reorganization of the Visual Dorsal Stream as Probed by 3-D Visual Coherence in Williams Syndrome
Authors: Bernardino Inês , Rebola José , Farivar Reza , Silva Eduardo , Castelo-Branco Miguel 
Published: May 2014

Abstract
Object and depth perception from motion cues involves the recruitment of visual dorsal stream brain areas. In 3-D structure-from-motion (SFM) perception, motion and depth information are first extracted in this visual stream to allow object categorization, which is in turn mediated by the ventral visual stream. Such interplay justifies the use of SFM paradigms to understand dorsal–ventral integration of visual information. The nature of such processing is particularly interesting to be investigated in a neurological model of cognitive dissociation between dorsal (impaired) and ventral stream (relatively preserved) processing, Williams syndrome (WS). In the current fMRI study, we assessed dorsal versus ventral stream processing by using a performance-matched 3-D SFM object categorization task. We found evidence for substantial reorganization of the dorsal stream in WS as assessed by whole-brain ANOVA random effects analysis, with subtle differences in ventral activation. Dorsal reorganization was expressed by larger medial recruitment in WS (cuneus, precuneus, and retrosplenial cortex) in contrast with controls, which showed the expected dorsolateral pattern (caudal intraparietal sulcus and lateral occipital cortex). In summary, we found a substantial reorganization of dorsal stream regions in WS in response to simple visual categories and 3-D SFM perception, with less affected ventral stream. Our results corroborate the existence of a medial dorsal pathway that provides the substrate for information rerouting and reorganization in the presence of lateral dorsal stream vulnerability. This interpretation is consistent with recent findings suggesting parallel routing of information in medial and lateral parts of dorsal stream.
The assessment of the effect of binary homogeneous nucleation on wet steam energy loss in a low pressure steam turbine
Authors: Petr Vaclav , Kolovratnik Michal 
Published: May 2014

The objective of the paper was to recognize the possible effect of a low concentration of chemical impurity (NaCl) present in the inlet steam (2.27 ppb) in the assessment of the wet steam energy loss occurring in a 1000 MW nuclear low pressure steam turbine. The presented analysis suggests that the used binary nucleation model, accounting for the electrolytic nature of the droplets, predicts a reduced wet steam energy loss of order –9 %, in comparison with the unary pure steam droplet nucleation model. This minor difference, considering the uncertainties of the existing measurements and the incomplete knowledge of the real droplet nucleation conditions in the steam of the turbine (primarily in relation to the necessary input data of chemical impurities), suggests that unary pure steam droplet nucleation (Becker–Döring) is an acceptable approximation at the current state of knowledge.
A review of the use of tadalafil in the treatment of benign prostatic hyperplasia in men with and without erectile dysfunction
Authors: Hatzimouratidis Konstantinos 
Published: May 2014

Epidemiological data link erectile dysfunction (ED) and benign prostatic hyperplasia (BPH)-associated lower urinary tract symptoms (LUTS), two highly prevalent conditions in aging men, assuming common pathophysiological pathways. Tadalafil 5 mg once daily has been approved for the treatment of men with LUTS with or without comorbid ED. The aim of this review is to provide an overview of current knowledge on the epidemiological and pathophysiological links between ED and LUTS and to focus on tadalafil as a new treatment option in men with BPH-associated LUTS. A Medline search was completed using the Medical Subject Headings (MESH® keywords) ‘prostatic hyperplasia’ and ‘phosphodiesterase inhibitors’. This search revealed 125 relevant references (entire Medline database up to 11 March 2014). The efficacy of tadalafil 5 mg once daily for the treatment of LUTS has been reported by several well-designed studies. Tadalafil improves significantly the total International Prostate Symptom Score (IPSS), the voiding and storage subscores, the IPSS Quality of Life (QoL) and the BPH Impact Index (BII). Its efficacy is irrelevant to the erectile function status of the patients. However, in the majority of these studies tadalafil is not associated with improvement in maximum urine flow or post-void residual volume (PVR). Its safety profile is well established and no new or unexpected adverse events other than those reported in ED studies have been recorded. Tadalafil is today a new treatment alternative to other established drugs for LUTS such as the α-adrenergic antagonists or 5α-reductase inhibitors. However, it is not just an alternative, since sexual adverse events associated with these drugs are avoided and tadalafil is the only drug that can treat both ED and LUTS at the same time.
A transgenic mouse model demonstrating the oncogenic role of mutations in the polycomb-group gene EZH2 in lymphomagenesis
Authors: Berg Tobias , Thoene Silvia , Yap Damian , Wee Tracee , Schoeler Nathalie , Rosten Patty , Lim Emilia , Bilenky Misha , Mungall Andrew J. , Oellerich Thomas , Lee Sherry , Lai Courteney K. , Umlandt Patricia , Salmi Anisa , Chang Harry , Yue Lisa , Lai David , Cheng S.-W. Grace , Morin Ryan D. , Hirst Martin , Serve Hubert , Marra Marco A. , Morin Gregg B. , Gascoyne Randy D. , Aparicio Samuel A. , Humphries R. Keith 
Published: May 2014

Key Points
A functional demonstration of the oncogenic role of mutated EZH2 in a mouse model is presented. The global effects of mutated EZH2 on expression and epigenome have been characterized.
Implementing tobacco dependence treatment during clinical consultations: a qualitative study of clinicians’ experiences, perceptions and behaviours in a South African primary health care setting
Authors: Omole Olufemi B , Ayo-Yusuf Olalekan A , Ngobale Kabilabe NW 
Published: May 2014

Abstract

Background
Evidence suggests that healthcare providers (HCPs) in South Africa do not consistently offer tobacco dependence treatment (TDT) during clinical consultations. In order to understand and explain this behaviour in a South African context, we conducted a qualitative exploration of HCPs’ experiences, perceptions and behaviours regarding TDT.

Methods
Individual qualitative interviews were conducted with physicians and nurses who were purposively selected. Themes were identified from interview transcripts using content analysis. Findings were triangulated and peer-reviewed, and were also verified by the participants.

Results
Fifteen physicians and four nurses were interviewed, none of whom used tobacco. These participants perceived TDT as an important task, but could not consistently implement it during clinical consultations due to health systems constraints (time-constraints because of patient-overload, the unavailability of cessation medications and a lack of support for referrals), misperceptions and misconceptions (negative outcome expectations about the effectiveness and feasibility of TDT), socio-cultural barriers (counselling older persons was perceived as challenging) and personal limitations (perceived low self-efficacy, poor knowledge and skills on implementing any evidence-based TDT framework). Patients are therefore selectively screened based on clinical relevance and offered only prescriptive brief advice. Participants recommended several systems changes, including academic detailing of tobacco status, training HCPs and incorporating tobacco cessation medications in the Essential Drug List.

Conclusion
The reported selective screening and limited TDT interventions offered by HCPs are related to interactions between health systems constraints, personal limitations, and misperceptions and misconceptions about the effectiveness and feasibility of TDT during clinical consultation. Implementing the recommended systems changes has the potential to improve the implementation of TDT in South African primary health care (PHC).
Fabrication of nanochannels with ladder nanostructure at the bottom using AFM nanoscratching method
Authors: Yan Yongda , Geng Yanquan , Hu Zhenjiang , Zhao Xuesen , Yu Bowen , Zhang Qi 
Published: May 2014

Abstract
This letter presents a novel atomic force microscopy (AFM)-based nanomanufacturing method combining the tip scanning with the high-precision stage movement to fabricate nanochannels with ladder nanostructure at the bottom by continuous scanning with a fixed scan size. Different structures can be obtained according to the matching relation of the tip feeding velocity and the precision stage moving velocity. This relationship was first studied in detail to achieve nanochannels with different ladder nanostructures at the bottom. Machining experiments were then performed to fabricate nanochannels on an aluminum alloy surface to demonstrate the capability of this AFM-based fabrication method presented in this study. Results show that the feed value and the tip orientation in the removing action play important roles in this method which has a significant effect on the machined surfaces. Finally, the capacity of this method to fabricate a large-scale nanochannel was also demonstrated. This method has the potential to advance the existing AFM tip-based nanomanufacturing technique of the formation these complex structures by increasing the removal speed, simplifying the processing procedure and achieving the large-scale nanofabrication.
Coupled best proximity points in ordered metric spaces
Authors: Kumam P , Pragadeeswarar V , Marudai M , Sitthithakerngkiet K 
Published: May 2014

Abstract
In this paper, we prove the existence and uniqueness of a coupled best proximity point for mappings satisfying the proximally coupled contraction condition in a complete ordered metric space. Further, our result provides an extension of a result due to Luong and Thuan (Comput. Math. Appl. 62(11):4238-4248, 2011; Nonlinear Anal. 74:983-992, 2011).

MSC:41A65, 90C30, 47H10.
Existence of solutions of a second-order impulsive differential equation
Authors: Luo Zhiguo , Xie Jingli , Chen Guoping 
Published: May 2014

Abstract
This paper is concerned with the existence of solutions of a second-order impulsive differential equation with mixed boundary condition. We obtain sufficient conditions for the existence of a unique solution, at least one solution, at least two solutions and infinitely many solutions, respectively, by using critical point theorems. The main results are also demonstrated with examples.

MSC:34B15, 34B18, 34B37, 58E30.
Exact finite-difference scheme and nonstandard finite-difference scheme for coupled Burgers equation
Authors: Zhang Lei , Wang Lisha , Ding Xiaohua 
Published: May 2014

Abstract
This work develops exact finite-difference schemes for the two-dimensional nonlinear coupled viscous Burgers equation using the analytic solution. We extend the explicit nonstandard finite-difference schemes on the basis of the exact finite-difference schemes to solve the coupled Burgers equation. Numerical examples are presented to verify the efficiency and accuracy of the methods.

MSC:39A10, 65L12, 74H15.
Large time behavior of solutions for the porous medium equation with a nonlinear gradient source
Authors: Li Nan , Zheng Pan , Mu Chunlai , Ahmed Iftikhar 
Published: May 2014

Abstract
This paper deals with the large time behavior of non-negative solutions for the porous medium equation with a nonlinear gradient source

u
t

=
Δ

u
m

+

|
∇

u
l

|

q

,

(
x
,
t
)
∈
Ω
×
(
0
,
∞
)

, where

l
≥
m
>
1

and

1
≤
q
<
2

. When

l
q
=
m

, we prove that the global solution converges to the separate variable solution

t

−

1

m
−
1

f
(
x
)

. While

m
<
l
q
≤
m
+
1

, we note that the global solution converges to the separate variable solution

t

−

1

m
−
1

f
0

(
x
)

. Moreover, when

l
q
>
m
+
1

, we show that the global solution also converges to the separate variable solution

t

−

1

m
−
1

f
0

(
x
)

for the small initial data

u
0

(
x
)

, and we find that the solution

u
(
x
,
t
)

blows up in finite time for the large initial data

u
0

(
x
)

.

MSC:35K55, 35K65, 35B40.