bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antiviral Activity and Mode of Action of TMC647078, a Novel Nucleoside Inhibitor of the Hepatitis C Virus NS5B Polymerase
Authors: Berke Jan Martin , Vijgen Leen , Lachau-Durand Sophie , Powdrill Megan H. , Rawe Svea , Sjuvarsson Elena , Eriksson Staffan , Götte Matthias , Fransen Els , Dehertogh Pascale , Van den Eynde Christel , Leclercq Laurent , Jonckers Tim H. M. , Raboisson Pierre , Nilsson Magnus , Samuelsson Bertil , Rosenquist Åsa , Fanning Gregory C. , Lin Tse-I 
Published: May 2011

ABSTRACT

Chronic infection with hepatitis C virus (HCV) is a major global health burden and is associated with an increased risk of liver cirrhosis and hepatocellular carcinoma. Current therapy for HCV infection has limited efficacy, particularly against genotype 1 virus, and is hampered by a range of adverse effects. Therefore, there is a clear unmet medical need for efficacious and safe direct antiviral drugs for use in combination with current treatments to increase cure rates and shorten treatment times. The broad genotypic coverage achievable with nucleosides or nucleotides and the high genetic barrier to resistance of these compounds observed
in vitro
and
in vivo
suggest that this class of inhibitors could be a valuable component of future therapeutic regimens. Here, we report the
in vitro
inhibitory activity and mode of action of 2′-deoxy-2′-spirocyclopropylcytidine (TMC647078), a novel and potent nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase that causes chain termination of the nascent HCV RNA chain.
In vitro
combination studies with a protease inhibitor resulted in additive efficacy in the suppression of HCV RNA replication, highlighting the potential for the combination of these two classes in the treatment of chronic HCV infection. No cytotoxic effects were observed in various cell lines. Biochemical studies indicated that TMC647078 is phosphorylated mainly by deoxycytidine kinase (dCK) without inhibiting the phosphorylation of the natural substrate, and high levels of triphosphate were observed in Huh7 cells and in primary hepatocytes
in vitro
. TMC647078 is a potent novel nucleoside inhibitor of HCV replication with a promising
in vitro
virology and biology profile.
Antimicrobial Properties of MX-2401, an Expanded-Spectrum Lipopeptide Active in the Presence of Lung Surfactant
Authors: Dugourd Dominique , Yang Haiyan , Elliott Melissa , Siu Raymond , Clement Jacob J. , Straus Suzana K. , Hancock Robert E. W. , Rubinchik Evelina 
Published: May 2011

ABSTRACT

MX-2401 is an expanded-spectrum lipopeptide antibiotic selective for Gram-positive bacteria that is a semisynthetic analog of the naturally occurring lipopeptide amphomycin. It was active against
Enterococcus
spp., including vancomycin-sensitive
Enterococcus
(VSE),
vanA
-,
vanB
-, and
vanC
-positive vancomycin-resistant
Enterococcus
(VRE), linezolid- and quinupristin-dalfopristin-resistant isolates (MIC
90
of 4 μg/ml), methicillin-resistant
Staphylococcus aureus
(MRSA) and methicillin-sensitive
S. aureus
(MSSA) (MIC
90
of 2 μg/ml), coagulase-negative staphylococci, including methicillin-sensitive
Staphylococcus epidermidis
(MSSE) and methicillin-resistant
S. epidermidis
(MRSE) (MIC
90
of 2 μg/ml), and
Streptococcus
spp. including viridans group streptococci, and penicillin-resistant, penicillin-sensitive, penicillin-intermediate and macrolide-resistant isolates of
Streptococcus pneumoniae
(MIC
90
of 2 μg/ml). MX-2401 demonstrated a dose-dependent postantibiotic effect varying from 1.5 to 2.4 h. Furthermore, MX-2401 was rapidly bactericidal at 4 times the MIC against
S. aureus
and
Enterococcus faecalis
, with more than 99.9% reduction in viable bacterial attained at 4 and 24 h, respectively. The MICs of MX-2401 against MRSA, MSSA, VSE, and VRE strains serially exposed for 15 passages to sub- to supra-MICs of MX-2401 remained within three dilutions of the original MIC. In contrast to that of the lipopeptide daptomycin, the antibacterial activity of MX-2401 was not affected
in vitro
by the presence of lung surfactant, and MX-2401 was active
in vivo
in the bronchial-alveolar pneumonia mouse model, in which daptomycin failed to show any activity. Moreover, the activity of MX-2401 was not as strongly dependent on the Ca
2+
concentration as is the activity of daptomycin. In conclusion, MX-2401 is a promising new-generation lipopeptide for the treatment of serious infections with Gram-positive bacteria, including hospital-acquired pneumonia.
Moraxella catarrhalis
Outer Membrane Vesicles Carry β-Lactamase and Promote Survival of
Streptococcus pneumoniae
and
Haemophilus influenzae
by Inactivating Amoxicillin
Authors: Schaar Viveka , Nordström Therése , Mörgelin Matthias , Riesbeck Kristian 
Published: May 2011

ABSTRACT

Moraxella catarrhalis
is a common pathogen found in children with upper respiratory tract infections and in patients with chronic obstructive pulmonary disease during exacerbations. The bacterial species is often isolated together with
Streptococcus pneumoniae
and
Haemophilus influenzae
. Outer membrane vesicles (OMVs) are released by
M. catarrhalis
and contain phospholipids, adhesins, and immunomodulatory compounds such as lipooligosaccharide. We have recently shown that
M. catarrhalis
OMVs exist in patients upon nasopharyngeal colonization. As virtually all
M. catarrhalis
isolates are β-lactamase positive, the goal of this study was to investigate whether
M. catarrhalis
OMVs carry β-lactamase and to analyze if OMV consequently can prevent amoxicillin-induced killing. Recombinant β-lactamase was produced and antibodies were raised in rabbits. Transmission electron microscopy, flow cytometry, and Western blotting verified that OMVs carried β-lactamase. Moreover, enzyme assays revealed that
M. catarrhalis
OMVs contained active β-lactamase. OMVs (25 μg/ml) incubated with amoxicillin for 1 h completely hydrolyzed amoxicillin at concentrations up to 2.5 μg/ml. In functional experiments, preincubation of amoxicillin (10× MIC) with
M. catarrhalis
OMVs fully rescued amoxicillin-susceptible
M. catarrhalis
,
S. pneumoniae
, and type b or nontypeable
H. influenzae
from β-lactam-induced killing. Our results suggest that the presence of amoxicillin-resistant
M. catarrhalis
originating from β-lactamase-containing OMVs may pave the way for respiratory pathogens that by definition are susceptible to β-lactam antibiotics.
New Fks Hot Spot for Acquired Echinocandin Resistance in
Saccharomyces cerevisiae
and Its Contribution to Intrinsic Resistance of
Scedosporium
Species
Authors: Johnson Michael E. , Katiyar Santosh K. , Edlind Thomas D. 
Published: May 2011

ABSTRACT

Echinocandins represent a new antifungal group with potent activity against
Candida
species. These lipopeptides inhibit the synthesis of β-1,3-glucan, the major cell wall polysaccharide. Acquired resistance or reduced echinocandin susceptibility (RES) is rare and associated with mutations in two “hot spot” regions of Fks1 or Fks2, the probable β-1,3-glucan synthases. In contrast, many fungi demonstrate intrinsic RES for reasons that remain unclear. We are using
Saccharomyces cerevisiae
to understand the basis for RES by modeling echinocandin-Fks interaction. Previously characterized mutations confer cross-RES; we screened for mutations conferring differential RES, implying direct interaction of that Fks residue with a variable echinocandin side chain. One mutant (in an
fks1
Δ background) exhibited ≥16-fold micafungin and anidulafungin versus caspofungin RES. Sequencing identified a novel Fks2 mutation, W714L/Y715N. Equivalent W695L/Y696N and related W695L/F/C mutations in Fks1 generated by site-directed mutagenesis and the isolation of a W695L-equivalent mutation in
Candida glabrata
confirmed the role of the new “hot spot 3” in RES. Further mutagenesis expanded hot spot 3 to Fks1 residues 690 to 700, yielding phenotypes ranging from cross-RES to differential hypersusceptibility. Fks1 sequences from intrinsically RES
Scedosporium
species revealed W695F-equivalent substitutions; Fks1 hybrids expressing
Scedosporium prolificans
hot spot 3 confirmed that this substitution imparts RES.
Requirement for Invariant Chain in Macrophages for Mycobacterium tuberculosis Replication and CD1d Antigen Presentation
Authors: Sillé Fenna C. M. , Martin Constance , Jayaraman Pushpa , Rothchild Alissa , Fortune Sarah , Besra Gurdyal S. , Behar Samuel M. , Boes Marianne 
Published: May 2011

ABSTRACTMycobacterium tuberculosisis an intracellular bacterium that persists in phagosomes of myeloid cells.M. tuberculosis-encoded factors support pathogen survival and reduce fusion of phagosomes with bactericidal lysosomal compartments. It is, however, not entirely understood if host factors that mediate endosomal fusion affectM. tuberculosisintracellular localization and survival. Neither is it known if endosomal fusion influences induction of host immune reactivity byM. tuberculosis-infected cells. Lysosomal degradation ofM. tuberculosisappears to be pivotal for making available lipid substrates for assembly into lipid-CD1d complexes to allow activation of CD1d-restricted invariant natural killer T (iNKT) cells. To clarify the role for endosomal fusion inM. tuberculosissurvival and induction of host CD1d-mediated immune defense, we focused our studies on the invariant chain (Ii). Ii regulates endosome docking and fusion and thereby controls endosomal transport. Through direct binding, Ii also directs intracellular transport of the class II major histocompatibility complex and CD1d. Our findings demonstrate that upon infection of Ii-knockout (Ii−/−) macrophages,M. tuberculosisis initially retained in early endosomal antigen 1-positive lysosomal-associated membrane protein 1-negative phagosomes, which results in slightly impaired pathogen replication. The absence of Ii did not affect the ability of uninfected and infected macrophages to produce nitric oxide, tumor necrosis factor alpha, or interleukin-12. However, induction of cell surface CD1d was impaired in infected Ii−/−macrophages, and CD1d-restricted iNKT cells were unable to suppress bacterial replication when they were cocultured withM. tuberculosis-infected Ii−/−macrophages. Thus, while the host factor Ii is not essential for the formation of theM. tuberculosis-containing vacuole, its presence is crucial for iNKT cell recognition of infected macrophages.
Attenuated Nephritis in Inducible Nitric Oxide Synthase Knockout C57BL/6 Mice and Pulmonary Hemorrhage in CB17 SCID and Recombination Activating Gene 1 Knockout C57BL/6 Mice Infected with Leptospira interrogans
Authors: Bandeira Maurício , Santos Cleiton S. , de Azevedo Everton C. , Soares Luciane Marieta , Macedo Júlio O. , Marchi Samyra , da Silva Caroline Luane R. , Chagas-Junior Adenizar D. , McBride Alan J. A. , McBride Flávia W. C. , Reis Mitermayer G. , Athanazio Daniel A. 
Published: May 2011

ABSTRACT

The aims of this study were to investigate the frequency of pulmonary hemorrhage (PH) in mice unable to produce functional B and T lymphocytes and to explore the effect of an inducible nitric oxide synthase gene (
Inos
) knockout (KO) on the frequency/severity of interstitial nephritis
in vivo
. We studied the outcome of infection by the virulent
Leptospira interrogans
serovar Copenhageni strain Cop. The animals used were
Inos
KO mice, recombination activating gene 1 (
Rag1
) KO mice, CB17 severe combined immunodeficiency (SCID) mice, and the respective wild-type (WT) C57BL/6 and BALB/c controls. The
Inos
KO and WT mice survived with no clinical symptoms of leptospirosis. The frequency and severity of nephritis was significantly lower in the
Inos
KO mice. All of the
Rag1
KO and SCID animals died of acute leptospirosis, whereas all of the WT mice survived. PH was observed in 57 and 94% of
Rag1
KO mice and in 83 and 100% of SCID mice, using inoculum doses of 10
7
and 10
6
leptospires, respectively. There was no evidence of PH in the WT controls. In conclusion, the loss of the
Inos
gene had a negligible effect on the outcome of leptospiral infection, although we observed a reduced susceptibility for interstitial nephritis in this group. Of note, the absence of functional B- and T-cell lymphocytes did not preclude the occurrence of PH. These data provide evidence that PH in leptospirosis may not be related only to autoimmune mechanisms.
Expression of the Type 1 Pneumococcal Pilus Is Bistable and Negatively Regulated by the Structural Component RrgA
Authors: Basset Alan , Turner Keith H. , Boush Elizabeth , Sayeed Sabina , Dove Simon L. , Malley Richard 
Published: May 2011

ABSTRACT

The pneumococcal type 1 pilus, which is present in 25 to 30% of clinical isolates, has been associated with increased adherence and inflammatory responses and is being evaluated as a potential vaccine candidate. Here we show that expression of the pilus is bistable as a result of the molecular interaction between the transcription activator RrlA and a structural component of the pilus called RrgA. Sampling various clinical pneumococcal isolates that harbor the type 1 pilus-encoding islet, we show that distinct populations of cells can be identified with either undetectable or prominent pilus expression. When these two populations are separated and regrown in liquid medium, they are phenotypically different: the nonexpressing population reverts to the previous bimodal distribution, whereas the expressing population retains the same high level of pilus expression. Controlled exogenous expression of the regulatory pilus gene
rlrA
in a strain from which the endogenous version has been deleted increases pilus expression steadily, suggesting that the bistable expression of the pilus observed in wild-type cells is dependent on the native
rlrA
promoter. Finally, we demonstrate that RrgA is a negative regulator of pilus expression and that this repression is likely mediated through direct interaction with RlrA. We conclude that type 1 pilus expression in pneumococcus exhibits a bistable phenotype, which is dependent upon the molecular interplay between the RlrA and RrgA proteins. We suggest that this flexibility in expression may assist adaptation to a range of immune conditions, such as evasion of antipilus antibodies, within potential hosts.
A Novel Zinc Binding System, ZevAB, Is Critical for Survival of Nontypeable Haemophilus influenzae in a Murine Lung Infection Model
Authors: Rosadini Charles V. , Gawronski Jeffrey D. , Raimunda Daniel , Argüello José M. , Akerley Brian J. 
Published: May 2011

ABSTRACT

Nontypeable
Haemophilus influenzae
(NTHI) is a Gram-negative bacterial pathogen that causes upper and lower respiratory infections. Factors required for pulmonary infection by NTHI are not well understood. Previously, using high-throughput insertion tracking by deep sequencing (HITS), putative lung colonization factors were identified. Also, previous research indicates that secreted disulfide-dependent factors are important for virulence of
H. influenzae
. In the present study, HITS data were compared with an informatics-based list of putative substrates of the periplasmic oxidoreductase DsbA to find and characterize secreted virulence factors. This analysis resulted in identification of the “
z
inc binding
e
ssential for
v
irulence” (
zev
) locus consisting of
zevA
(HI1249) and
zevB
(HI1248). NTHI mutants of
zevA
and
zevB
grew normally in rich medium but were defective for colonization in a mouse lung model. Mutants also exhibited severe growth defects in medium containing EDTA and were rescued by supplementation with zinc. Additionally, purified recombinant ZevA was found to bind to zinc with high affinity. Together, these data demonstrate that
zevAB
is a novel virulence factor important for zinc utilization of
H. influenzae
under conditions where zinc is limiting. Furthermore, evidence presented here suggests that zinc limitation is likely an important mechanism for host defense against pathogens during lung infection.
Mitochondrial genome sequences of representatives of three families of scorpionflies (Order Mecoptera) and evolution in a major duplication of coding sequence
Authors: Beckenbach Andrew T 
Published: May 2011

The complete mitochondrial DNA sequences of a hangingfly, Bittacus pilicornis (Mecoptera: Bittacidae), a snow scorpion fly, Boreus elegans (Mecoptera: Boreidae), and a nearly complete sequence from another scorpionfly species, Microchorista philpotti (Mecoptera: Nannochoristidae) were determined. The coding sequence of all three genomes includes the 37 genes normally found in insect mtDNAs, in the same gene order as first described in Drosophila. In addition to the standard set of genes, the Microchorista sequence includes a large duplication of the coding region. The duplication is at least 4 kb (and may be much larger) and includes the remnants of three protein-coding genes and seven tRNA genes. The duplication evidently arose as a single event, and the duplicated region can be aligned in its entirety with the corresponding region of the functional genome. Although most of the genes contain defects that render them nonfunctional, analysis shows that the protein-coding genes in the duplicated region evolved for a considerable period under constraints expected of functional protein-coding genes. It is evident, therefore, that for a period two copies of some of the mitochondrial genes were functional in this species, including genes coding for proteins.
CENTRAL LIMIT THEOREM FOR DIMENSION OF GIBBS MEASURES IN HYPERBOLIC DYNAMICS
Authors: LEPLAIDEUR RENAUD , SAUSSOL BENOÎT 
Published: May 2011

For an equilibrium measure of a Hölder potential, we prove an analogue of the Central Limit Theorem for the fluctuations of the logarithm of the measure of balls as the radius goes to zero. A noticeable consequence is that when this measure is not absolutely continuous, the probability that a ball of radius ε chosen at random have a measure smaller (or larger) than εδ is asymptotically equal to 1/2, where δ is the Hausdorff dimension of the measure. Our method applies to a class of non-conformal expanding maps on the d-dimensional torus. It also applies to conformal repellers and Axiom A surface diffeomorphisms and possibly to a class of one-dimensional non-uniformly expanding maps. These generalizations are presented at the end of the paper.
Agile management and development of software projects based on collaborative environments
Authors: Franky María Consuelo 
Published: May 2011

We've heard of Agile methodologies for several years, but software projects have still delays and failures in planning and management. How then automate the processes of the development of software projects following agile methodologies?
In this paper we try to answer this question by proposing an appropriate use of collaborative environments for software development that effectively translated into action the principles and practices of Agile methodologies. The appropriate use of these collaborative environments leads to a truly agile management, where the project manager achieves the vision and the continuous monitoring of the project, and the participants become adapted to an agile and productive discipline imposed by the environment, regardless if they are geographically dispersed. To ensure that appropriate use, this paper proposes a methodological guide to achieve an agile management of software projects by relying on a particular collaborative environment.
Editor's introduction
Authors: Conitzer Vincent 
Published: May 2011

I am very happy to introduce Issue 8.2 of SIGecom Exchanges.
The first four contributions concern game theory. The first contribution is a full-length paper by Demaine, Hajiaghayi, Mahini, and Zadimoghaddam, titled "The Price of Anarchy in Cooperative Network Creation Games." In it, they study network creation games, in which the nodes of a graph decide which edges to create. They study "collaborative equilibrium" in which coalitions do not want to change their collective strategy on a single edge, and analyze the price of anarchy in this model. In "Computing Shapley's Saddles," Brandt, Brill, Fischer, Harrenstein, and Hoffmann discuss the computational complexity of saddles, an ordinal, set-valued solution concept defined by Shapley. In "A Prescriptive Approach for Playing Games," Feldman gives an overview of two recent papers on two-player zero-sum games: one of these papers considers a model in which the randomization phase of a randomized strategy is not completely private, and the other considers repeated symmetric games in which one player never observes a single payoff (but does observe the opponent's play). Finally, Pita, Bellamane, Jain, Kiekintveld, Tsai, Ordóñez, and Tambe consider some real-world applications of game theory at Los Angeles International Airport and the US Federal Air Marshals, and discuss some of the challenges in applying game theory to practice, in their letter "Security Applications: Lessons of Real-World Deployment".
New Strategies in Non–Small Cell Lung Cancer: Improving Outcomes in Chemoradiotherapy for Locally Advanced Disease
Authors: Rengan Ramesh , Maity Amit M. , Stevenson James P. , Hahn Stephen M. 
Published: May 2011

AbstractThe past decade has seen significant breakthroughs in our knowledge of the tumor biology of non–small cell lung cancer (NSCLC). Signaling pathways that are vital for tumor growth have been identified and have been effectively targeted for pharmacologic intervention. Furthermore, advances in imaging and treatment delivery have allowed radiation oncologists to deliver therapy more precisely to mobile tumors, while minimizing the dose to surrounding critical structures. This article summarizes the implications of these advances for the patient with unresectable locally advanced NSCLC and highlights ongoing work to improve clinical outcomes in this disease. Clin Cancer Res; 17(13); 4192–9. ©2011 AACR.
Application of an Exercise Intervention on the Evolution of Diastolic Dysfunction in Patients With Diabetes Mellitus
Authors: Hare James L. , Hordern Matthew D. , Leano Rodel , Stanton Tony , Prins Johannes B. , Marwick Thomas H. 
Published: May 2011

Background—
Diastolic dysfunction (DD) is associated with adverse cardiovascular outcomes. We studied the impact of an exercise-based lifestyle intervention on the evolution of DD in patients with type 2 diabetes mellitus (T2DM) and prospectively investigated the clinical correlates of DD progression.

Methods and Results—

A total of 223 outpatients with T2DM were randomized to supervised exercise-based lifestyle intervention (initial gym-based program and lifestyle and diet advice followed by telephone-guided supervision) or usual care. Patients underwent echocardiographic assessment of diastolic function and metabolic and clinical evaluation at baseline and 3 years. Changes in prevalence and evolution of DD were assessed and correlations sought with clinical and metabolic variables. DD was present in 50% of patients at baseline and 54% at 3 years, with no difference between the usual care and intervention groups (60% versus 48%,
P
=0.10). Abnormal DD at the final visit was independently associated with older age and a decrease in peak oxygen consumption over time (
P
<0.05). There was no impact on glycemic control or exercise capacity. In a subanalysis restricted to patients who finished the full 3-year follow-up, control subjects were independently associated with DD at 3 years (β=0.90; odds ratio, 2.46;
P
=0.034), with the only other independent correlate being older age (β=0.05; odds ratio, 1.06;
P
=0.019).

Conclusions—
Despite being efficacious in the subgroup who completed 3 years of exercise-based lifestyle intervention, randomization to this program was not effective in reducing progression of subclinical DD in patients with T2DM, which may reflect the recognized difficulty of adherence to prolonged exercise intervention.

Clinical Trial Registration—

URL:
http://www.anzctr.org.au
. Unique identifier: ACTRN12607000060448.