bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antimalarial Activity of Tigecycline, a Novel Glycylcycline Antibiotic
Authors: Starzengruber P. , Thriemer K. , Haque R. , Khan W. A. , Fuehrer H. P. , Siedl A. , Hofecker V. , Ley B. , Wernsdorfer W. H. , Noedl H. 
Published: July 2009

ABSTRACT

Tigecycline is a novel glycylcycline antibiotic with a broad antibacterial spectrum. Tigecycline was tested with 66 clinical isolates of
Plasmodium falciparum
from Bangladesh using the histidine-rich protein 2 in vitro drug susceptibility assay. The 50% and 90% inhibitory concentrations of tigecycline were 699 (95% confidence interval, 496 to 986) and 5,905 nM (4,344 to 8,028). Tigecycline shows no activity correlation with traditional antimalarials and has substantial antimalarial activity on its own.
Anti-Human Immunodeficiency Virus Activity, Cross-Resistance, Cytotoxicity, and Intracellular Pharmacology of the 3′-Azido-2′,3′-Dideoxypurine Nucleosides
Authors: Sluis-Cremer Nicolas , Koontz Dianna , Bassit Leda , Hernandez-Santiago Brenda I. , Detorio Mervi , Rapp Kim L. , Amblard Franck , Bondada Lavanya , Grier Jason , Coats Steven J. , Schinazi Raymond F. , Mellors John W. 
Published: July 2009

ABSTRACT

Although the approved nucleoside reverse transcriptase (RT) inhibitors (NRTI) are integral components of therapy for human immunodeficiency virus type 1 (HIV-1) infection, they can have significant limitations, including the selection of NRTI-resistant HIV-1 and cellular toxicity. Accordingly, there is a critical need to develop new NRTI that have excellent activity and safety profiles and exhibit little or no cross-resistance with existing drugs. In this study, we report that the 3′-azido-2′,3′-dideoxypurine nucleosides (ADPNs) 3′-azido-2′,3′-dideoxyadenosine (3′-azido-ddA) and 3′-azido-2′,3′-dideoxyguanosine (3′-azido-ddG) exert potent antiviral activity in primary human lymphocytes and HeLa and T-cell lines (50% inhibitory concentrations [IC
50
s] range from 0.19 to 2.1 μM for 3′-azido-ddG and from 0.36 to 10 μM for 3′-azido-ddA) and that their triphosphate forms are incorporated as efficiently as the natural dGTP or dATP substrates by HIV-1 RT. Importantly, both 3′-azido-ddA and 3′-azido-ddG retain activity against viruses containing K65R, L74V, or M184V (IC
50
change of <2.0-fold) and against those containing three or more thymidine analog mutations (IC
50
change of <3.5-fold). In addition, 3′-azido-ddG does not exhibit cytotoxicity in primary lymphocytes or epithelial or T-cell lines and does not decrease the mitochondrial DNA content of HepG2 cells. Furthermore, 3′-azido-ddG is efficiently phosphorylated to 3′-azido-ddGTP in human lymphocytes, with an intracellular half-life of the nucleoside triphosphate of 9 h. The present data suggest that additional preclinical studies are warranted to assess the potential of ADPNs for treatment of HIV-1 infection.
Differential Expression of
ccrA
in Methicillin-Resistant
Staphylococcus aureus
Strains Carrying Staphylococcal Cassette Chromosome
mec
Type II and IVa Elements
Authors: Higgins Paul G. , Rosato Adriana E. , Seifert Harald , Archer Gordon L. , Wisplinghoff Hilmar 
Published: July 2009

ABSTRACT

Excision of staphylococcal cassette chromosome
mec
(SCC
mec
) is mediated through the
ccrA
- and -
B
-encoded recombinases. We investigated the effects of different antimicrobial agents on
ccrA
expression by using a
ccrA
::
lacZ
fusion and reverse transcription-PCR with methicillin (meticillin)-resistant
Staphylococcus aureus
strains MW2 (SCC
mec
IVa) and N315 (SCC
mec
II). Upregulation of
ccrA
was observed upon exposure to β-lactam antibiotics. Vancomycin increased
ccrA
expression in MW2 but had no effect on N315. Vancomycin may contribute to the transfer of SCC
mec
IVa but have no effect in SCC
mec
II.
Staphylococcus aureus
Mutant Screen Reveals Interaction of the Human Antimicrobial Peptide Dermcidin with Membrane Phospholipids
Authors: Li Min , Rigby Kevin , Lai Yuping , Nair Vinod , Peschel Andreas , Schittek Birgit , Otto Michael 
Published: July 2009

ABSTRACT

Antimicrobial peptides (AMPs) form an important part of the innate host defense. In contrast to most AMPs, human dermcidin has an anionic net charge. To investigate whether bacteria have developed specific mechanisms of resistance to dermcidin, we screened for mutants of the leading human pathogen,
Staphylococcus aureus
, with altered resistance to dermcidin. To that end, we constructed a plasmid for use in mariner-based transposon mutagenesis and developed a high-throughput cell viability screening method based on luminescence. In a large screen, we did not find mutants with strongly increased susceptibility to dermcidin, indicating that
S. aureus
has no specific mechanism of resistance to this AMP. Furthermore, we detected a mutation in a gene of unknown function that resulted in significantly increased resistance to dermcidin. The mutant strain had an altered membrane phospholipid pattern and showed decreased binding of dermcidin to the bacterial surface, indicating that dermcidin interacts with membrane phospholipids. The mode of this interaction was direct, as shown by assays of dermcidin binding to phospholipid preparations, and specific, as the resistance to other AMPs was not affected. Our findings indicate that dermcidin has an exceptional value for the human innate host defense and lend support to the idea that it evolved to evade bacterial resistance mechanisms targeted at the cationic character of most AMPs. Moreover, they suggest that the antimicrobial activity of dermcidin is dependent on the interaction with the bacterial membrane and might thus assist with the determination of the yet unknown mode of action of this important human AMP.
Effect of β-1,6-Glucan Inhibitors on the Invasion Process of
Candida albicans
: Potential Mechanism of Their In Vivo Efficacy
Authors: Kitamura Akihiro , Higuchi Saito , Hata Masato , Kawakami Katsuhiro , Yoshida Kumi , Namba Kenji , Nakajima Ryohei 
Published: July 2009

ABSTRACT

β-1,6-Glucan is a fungus-specific cell wall component that is essential for the retention of many cell wall proteins. We recently reported the discovery of a small molecule inhibitor of β-1,6-glucan biosynthesis in yeasts. In the course of our study of its derivatives, we found a unique feature in their antifungal profile. D21-6076, one of these compounds, exhibited potent in vitro and in vivo antifungal activities against
Candida glabrata
. Interestingly, although it only weakly reduced the growth of
Candida albicans
in conventional media, it significantly prolonged the survival of mice infected by the pathogen. Biochemical evaluation of D21-6076 indicated that it inhibited β-1,6-glucan synthesis of
C. albicans
, leading the cell wall proteins, which play a critical role in its virulence, to be released from the cell. Correspondingly, adhesion of
C. albicans
cells to mammalian cells and their hyphal elongation were strongly reduced by the drug treatment. The results of the experiment using an in vitro model of vaginal candidiasis showed that D21-6076 strongly inhibited the invasion process of
C. albicans
without a significant reduction in its growth in the medium. These evidences suggested that D21-6076 probably exhibited in vivo efficacy against
C. albicans
by inhibiting its invasion process.
Improved Murine Model of Malaria UsingPlasmodium falciparumCompetent Strains and Non-Myelodepleted NOD-scid IL2RγnullMice Engrafted with Human Erythrocytes
Authors: Jiménez-Díaz María Belén , Mulet Teresa , Viera Sara , Gómez Vanessa , Garuti Helen , Ibáñez Javier , Alvarez-Doval Angela , Shultz Leonard D. , Martínez Antonio , Gargallo-Viola Domingo , Angulo-Barturen Iñigo 
Published: July 2009

ABSTRACTMurine models ofPlasmodium falciparummalaria may become crucial tools in drug discovery. Here we show that non-myelodepleted NOD-scid IL2Rγnullmice engrafted with human erythrocytes support an infectious burden up to tenfold higher than that supported by engrafted NOD-scid β2microglobulinnullmice. The new model was validated for drug discovery and was used to assess the therapeutic efficacy of 4-pyridones, selective inhibitors ofP. falciparumcytochromebc1.
In Vitro Activities of Trioxaquines against
Schistosoma mansoni
Authors: Boissier Jérôme , Coslédan Frédéric , Robert Anne , Meunier Bernard 
Published: July 2009

ABSTRACT
We report the in vitro activities of trioxaquines against larval and adult-stage schistosomes at 5 and 50 μg/ml, respectively. Such activities are equivalent to that of praziquantel, the major and rather unique drug currently used for the treatment of schistosomiasis. In this range of concentrations, artemisinin derivatives (artesunate and artemether) have no activity.
Anidulafungin in Combination with Amphotericin B against
Aspergillus fumigatus
Authors: Spreghini Elisabetta , Orlando Fiorenza , Santinelli Alfredo , Pisa Eleonora , Loretelli Cristian , Manso Esther , Milici Maria Eleonara , Scalise Giorgio , Barchiesi Francesco 
Published: July 2009

ABSTRACT

We investigated the effects of anidulafungin alone and in combination with amphotericin B against
Aspergillus fumigatus
. Indifference was the only type of interaction observed in vitro. Anidulafungin at 1 and 5 mg/kg of body weight/day, amphotericin B at 1 mg/kg/day, and combination therapy prolonged the survival of mice with invasive aspergillosis. Anidulafungin at 5 mg/kg/day, alone and in combination with amphotericin B, reduced the kidney fungal burden. Overall, the combination was not superior to the most active single drug.
Pharmacodynamics of Vancomycin at Simulated Epithelial Lining Fluid Concentrations against Methicillin-Resistant
Staphylococcus aureus
(MRSA): Implications for Dosing in MRSA Pneumonia
Authors: Harigaya Yoriko , Bulitta Jürgen B. , Forrest Alan , Sakoulas George , Lesse Alan J. , Mylotte Joseph M. , Tsuji Brian T. 
Published: July 2009

ABSTRACT

Little is known regarding killing activity of vancomycin against methicillin (meticillin)-resistant
Staphylococcus aureus
(MRSA) in pneumonia since the extent of vancomycin penetration into epithelial lining fluid (ELF) has not been definitively established. We evaluated the impact of the extent of ELF penetration on bacterial killing and resistance by simulating a range of vancomycin exposures (24-h free drug area under the concentration-time curve [ƒAUC
24
]/MIC) using an in vitro pharmacodynamic model and population-based mathematical modeling. A high-dose, 1.5-g-every-12-h vancomycin regimen according to American Thoracic Society/Infectious Diseases Society of America guidelines (trough concentration, 15 mg/liter) with simulated ELF/plasma penetration of 0, 20, 40, 60, 80, or 100% (ƒAUC
24
/MIC of 0, 70, 140, 210, 280, or 350) was evaluated against two
agr
-functional, group II MRSA clinical isolates obtained from patients with a bloodstream infection (MIC = 1.0 mg/liter) at a high inoculum of 10
8
CFU/ml. Despite high vancomycin exposures and 100% penetration, all regimens up to a ƒAUC
24
/MIC of 350 did not achieve bactericidal activity. At regimens of ≤60% penetration (ƒAUC
24
/MIC ≤ 210), stasis and regrowth occurred, amplifying the development of intermediately resistant subpopulations. Regimens simulating ≥80% penetration (ƒAUC
24
/MIC ≥ 280) suppressed development of resistance. Resistant mutants amplified by suboptimal vancomycin exposure displayed reduced rates of autolysis (Triton X-100) at 72 h. Bacterial growth and death were well characterized by a Hill-type model (
r
2
≥ 0.984) and a population pharmacodynamic model with a resistant and susceptible subpopulation (
r
2
≥ 0.965). Due to the emergence of vancomycin-intermediate resistance at a ƒAUC
24
/MIC of ≤210, exceeding this exposure breakpoint in ELF may help to guide optimal dosage regimens in the treatment of MRSA pneumonia.
The RD1 Locus in the
Mycobacterium tuberculosis
Genome Contributes to Activation of Caspase-1 via Induction of Potassium Ion Efflux in Infected Macrophages
Authors: Kurenuma Takeshi , Kawamura Ikuo , Hara Hideki , Uchiyama Ryosuke , Daim Sylvia , Dewamitta Sita Ramyamali , Sakai Shunsuke , Tsuchiya Kohsuke , Nomura Takamasa , Mitsuyama Masao 
Published: July 2009

ABSTRACT

A genomic locus called “region of difference 1” (RD1) in
Mycobacterium tuberculosis
has been shown to contribute to the generation of host protective immunity as well as to the virulence of the bacterium. To gain insight into the molecular mechanism, we investigated the difference in the cytokine-inducing ability between H37Rv and a mutant strain deficient for RD1 (ΔRD1). We found that RD1 is implicated in the production of caspase-1-dependent cytokines, interleukin-18 (IL-18) and IL-1β, from infected macrophages. The expression of these cytokines was similarly induced after infection with H37Rv and ΔRD1. However, the activation of caspase-1 was observed only in H37Rv-infected macrophages. The cytokine production and caspase-1 activation were induced independently of type I interferon receptor signaling events. We also found that the activation of caspase-1 was markedly inhibited with increasing concentrations of extracellular KCl. Furthermore, the production of IL-18 and IL-1β and caspase-1 activation were induced independently of a P2X7 purinergic receptor, and the inability of ΔRD1 in caspase-1 activation was compensated for by nigericin, an agent inducing the potassium ion efflux. Based on these results, we concluded that RD1 participates in caspase-1-dependent cytokine production via induction of the potassium ion efflux in infected macrophages.
Anaplasma phagocytophilum
Dense-Cored Organisms Mediate Cellular Adherence through Recognition of Human P-Selectin Glycoprotein Ligand 1
Authors: Troese Matthew J. , Carlyon Jason A. 
Published: July 2009

ABSTRACT

Anaplasma phagocytophilum
is an obligate intracellular bacterium that infects granulocytes to cause human granulocytic anaplasmosis. The susceptibilities of human neutrophils and promyelocytic HL-60 cells to
A. phagocytophilum
are linked to bacterial usage of P-selectin glycoprotein ligand 1 (PSGL-1) as a receptor for adhesion and entry.
A. phagocytophilum
undergoes a biphasic developmental cycle, transitioning between a smaller electron dense-cored cell (DC), which has a dense nucleoid, and a larger, pleomorphic electron lucent reticulate cell (RC), which has a dispersed nucleoid. The pathobiological roles of each form have not been elucidated. To ascertain the role of each form, we used electron microscopy to monitor bacterial binding, entry, and intracellular development within HL-60 cells. Only DCs were observed binding to and inducing uptake by HL-60 cells. By 12 h, internalized DCs had transitioned to RCs, which had initiated replication. By 24 h, large RC numbers were observed within individual inclusions. Reinfection had occurred by 36 h, as individual, vacuole-enclosed DCs and RCs were again observed. The abilities of DC- and RC-enriched
A. phagocytophilum
populations to bind and/or infect HL-60 cells or Chinese hamster ovary cells transfected to express PSGL-1 (PSGL-1 CHO) were compared. Only DCs bound PSGL-1 CHO cells and did so in a PSGL-1-blocking antibody-inhibitable manner. These results demonstrate that the respective roles of
A. phagocytophilum
DCs and RCs are consistent with analogous forms of other obligate intracellular pathogens that undergo biphasic development and hint that the PSGL-1-targeting adhesin(s) may be upregulated or optimally posttranslationally modified on DCs.
Shiga Toxin 1-Induced Proinflammatory Cytokine Production Is Regulated by the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Signaling Pathway
Authors: Cherla Rama P. , Lee Sang-Yun , Mulder Renée A. , Lee Moo-Seung , Tesh Vernon L. 
Published: July 2009

ABSTRACT

Shiga toxin 1 (Stx1) transiently increases the expression of proinflammatory cytokines by macrophage-like THP-1 cells in vitro. Increased cytokine production is partly due to activation of the translation initiation factor eIF4E through a mitogen-activated protein kinase (MAPK)- and Mnk1-dependent pathway. eIF4E availability for translation initiation is regulated by association with eIF4E binding proteins (4E-BP). In this study, we showed that Stx1 transiently induced 4E-BP hyperphosphorylation, which may release eIF4E for translation initiation. Phosphorylation of 4E-BP at priming sites T37 and T46 was not altered by Stx1 but was transiently increased at S65, concomitant with increased cytokine expression. Using kinase inhibitors, we showed that 4E-BP phosphorylation was dependent on phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR) activation but did not require MAPKs. Stx1 treatment resulted in increased levels of cytosolic Ca
2+
. PI3K and Akt activation led to the phosphorylation and inactivation of the positive cytokine regulator glycogen synthase kinase 3α/β (GSK-3α/β). PI3K, Akt, and mTOR inhibitors and small interfering RNA knockdown of Akt expression all increased, whereas a GSK-3α/β inhibitor decreased, Stx1-induced soluble tumor necrosis factor alpha and interleukin-1β production. Overall, these findings suggest that despite transient activation of 4E-BP, the PI3K/Akt/mTOR pathway negatively influences cytokine induction by inactivating the positive regulator GSK-3α/β.
Cannabinoid receptor 1 is a potential drug target for treatment of translocation-positive rhabdomyosarcoma
Authors: Oesch Susanne , Walter Dagmar , Wachtel Marco , Pretre Kathya , Salazar Maria , Guzmán Manuel , Velasco Guillermo , Schäfer Beat W. 
Published: July 2009

Abstract
Gene expression profiling has revealed that the gene coding for cannabinoid receptor 1 (CB1) is highly up-regulated in rhabdomyosarcoma biopsies bearing the typical chromosomal translocations PAX3/FKHR or PAX7/FKHR. Because cannabinoid receptor agonists are capable of reducing proliferation and inducing apoptosis in diverse cancer cells such as glioma, breast cancer, and melanoma, we evaluated whether CB1 is a potential drug target in rhabdomyosarcoma. Our study shows that treatment with the cannabinoid receptor agonists HU210 and Δ9-tetrahydrocannabinol lowers the viability of translocation-positive rhabdomyosarcoma cells through the induction of apoptosis. This effect relies on inhibition of AKT signaling and induction of the stress-associated transcription factor p8 because small interfering RNA–mediated down-regulation of p8 rescued cell viability upon cannabinoid treatment. Finally, treatment of xenografts with HU210 led to a significant suppression of tumor growth in vivo. These results support the notion that cannabinoid receptor agonists could represent a novel targeted approach for treatment of translocation-positive rhabdomyosarcoma. [Mol Cancer Ther 2009;8(7):1838–45]
Identification and preclinical characterization of AZ-23, a novel, selective, and orally bioavailable inhibitor of the Trk kinase pathway
Authors: Thress Kenneth , MacIntyre Terry , Wang Haiyun , Whitston Dave , Liu Zhong-Ying , Hoffmann Ethan , Wang Tao , Brown Jeffrey L. , Webster Kevin , Omer Charles , Zage Peter E. , Zeng Lizhi , Zweidler-McKay Patrick A. 
Published: July 2009

Abstract
Tropomyosin-related kinases (TrkA, TrkB, and TrkC) are receptor tyrosine kinases that, along with their ligands, the neurotrophins, are involved in neuronal cell growth, development, and survival. The Trk-neurotrophin pathway may also play a role in tumorigenesis through oncogenic fusions, mutations, and autocrine signaling, prompting the development of novel Trk inhibitors as agents for cancer therapy. This report describes the identification of AZ-23, a novel, potent, and selective Trk kinase inhibitor. In vitro studies with AZ-23 showed improved selectivity over previous compounds and inhibition of Trk kinase activity in cells at low nanomolar concentrations. AZ-23 showed in vivo TrkA kinase inhibition and efficacy in mice following oral administration in a TrkA-driven allograft model and significant tumor growth inhibition in a Trk-expressing xenograft model of neuroblastoma. AZ-23 represents a potent and selective Trk kinase inhibitor from a novel series with the potential for use as a treatment for cancer. [Mol Cancer Ther 2009;8(7):1818–27]
The Quest for Hizbut Tahrir in Indonesia
Authors: Muhtadi Burhanuddin 
Published: July 2009

AbstractThis article describes the nature of Hizbut Tahrir Indonesia (HTI) in the post-Suharto era and its views on the resurrection of the global Islamic caliphate, its opposition to the notions of democracy and nation-state. In the aftermath of Suharto's fall in 1998, HTI has seized the opportunity to promise the establishment of a fair society under a global Islamic caliphate. The rapid rise of HTI has, more so than most other Islamist groups, been accentuated by the growing public dissatisfaction with the post-Suharto or reformasi period. There is an increasing perception in larger society that political, economic, and law reforms introduced in the reformasi era has had no significant impact to improve people's daily lives. This deteriorating condition under post-Suharto regimes has successfully justified the HTI's claims that Indonesia needs a radical and comprehensive system, or what HTI coined as al-khalifah al-Islamiyyah (Islamic caliphate). Looking at HTI's grand narrative of the global Islamic caliphate and its refutation of the ideas of democracy and nation-state, it is clear that HTI has taken a number of negative steps in the direction of democratic consolidation in Indonesia.
'. . . And the Truth Shall Set You Free': Confessional Trade-Offs and Community Reconciliation in East Timor
Authors: Larke Ben 
Published: July 2009

AbstractIn East Timor, as with many nations dealing with the legacies of colonisation and occupation, divisions and allegiances forged in the past are combining with other contemporary factors to destabilising effect. The civil unrest of 2006/2007 provides the most recent example of the propensity for violence to escalate rapidly in such a climate. In this context, past experience in promoting and facilitating re-integration following the mass displacement in 1999 in East Timor may offer lessons for those seeking to address social cohesion in the wake of more recent displacement. This paper assesses the work of the Community Reconciliation Process implemented by the Commission of Reception, Truth and Reconciliation (Commonly known by the Portuguese acronym CAVR) in order to provide a reflection on what was achieved and highlight some of the shortcomings that might similarly befall current, and future, attempts. In doing so, the process, and particularly the use of narrative, is considered in terms of its performative elements: the circumstances in which the scripts were written; the stage on which they were acted out; the actors who voiced them, and the audience who listened. It is argued that the Community Reconciliation Process, through its mechanism that synthesised customary reconciliation procedures and elements of the formal justice system, facilitated a reintegrative process that had at its core the exchange of confession, apology and shaming for the right to re-enter the social group from which perpetrators had been excluded. This process, however, may have occurred at the expense of the competing needs of those who had been victimised.
Social and Intercultural Relations in Nineteenth-Century Zanzibar: Dressed Identity
Authors: Vander biesen Ivan 
Published: July 2009

AbstractStarting from the nineteenth century descriptive literatures on Zanzibar by authors such as Sir Richard Burton and Charles Guillain, and Salima bint Said-Ruete's autobiography, we can draw a rather detailed picture of the relationship between the different social layers, cultures and genders on Zanzibar. Describing and differentiating the complexity of Zanzibar society in the nineteenth century is the main aim of this paper. The focus is on clothing in order to sketch the social organization of the society and to highlight the cultural relations between the different groups in Zanzibar. The evidence obtained from the description of clothing is used as an eye-opener for the Zanzibar society and this evidence is supported by nineteenth century literature and photography on Zanzibar.