bluuebunny/crossref_metadata_2025_split huggingface dataset:
Arithmetically defined dense subgroups of Morava stabilizer groups
Authors: Naumann Niko 
Published: January 2008

AbstractFor every prime p and integer n≥3 we explicitly construct an abelian variety $A/\mathbb {F}_{p^n}$ of dimension n such that for a suitable prime l the group of quasi-isogenies of $A/\mathbb {F}_{p^n}$ of l-power degree is canonically a dense subgroup of the nth Morava stabilizer group at p. We also give a variant of this result taking into account a polarization. This is motivated by the recent construction by Behrens and Lawson of topological automorphic forms which generalizes topological modular forms. For this, we prove some arithmetic results of independent interest: a result about approximation of local units in maximal orders of global skew fields which also gives a precise solution to the problem of extending automorphisms of the p-divisible group of a simple abelian variety over a finite field to quasi-isogenies of the abelian variety of degree divisible by as few primes as possible.
Stratifications with respect to actions of real reductive groups
Authors: Heinzner Peter , Schwarz Gerald W. , Stötzel Henrik 
Published: January 2008

AbstractWe study the action of a real reductive group G on a real submanifold X of a Kähler manifold Z. We suppose that the action of G extends holomorphically to an action of the complexified group $G^{\mathbb {C}}$ and that with respect to a compatible maximal compact subgroup U of $G^{\mathbb {C}}$ the action on Z is Hamiltonian. There is a corresponding gradient map $\mu _{\mathfrak {p}}\colon X\to \mathfrak {p}^*$ where $\mathfrak {g}=\mathfrak {k}\oplus \mathfrak {p}$ is a Cartan decomposition of $\mathfrak {g}$. We obtain a Morse-like function $\eta _{\mathfrak {p}}:=\Vert \mu _{\mathfrak {p}}\Vert ^2$ on X. Associated with critical points of $\eta _{\mathfrak {p}}$ are various sets of semistable points which we study in great detail. In particular, we have G-stable submanifolds Sβ of X which are called pre-strata. In cases where $\mu _{\mathfrak {p}}$ is proper, the pre-strata form a decomposition of X and in cases where X is compact they are the strata of a Morse-type stratification of X. Our results are generalizations of results of Kirwan obtained in the case where $G=U^{\mathbb {C}}$ and X=Z is compact.
Effect of 14-Membered-Ring Macrolides on Production of Interleukin-8 Mediated by Protease-Activated Receptor 2 in Human Keratinocytes
Authors: Tsuda Tatsuya , Ishikawa Chika , Konishi Hiroe , Hayashi Yoshiaki , Nakagawa Noboru , Matsuki Masato , Mizutani Hitoshi , Yamanishi Kiyofumi 
Published: January 2008

ABSTRACT
The production of interleukin-8 induced by the activation of protease-activated receptor 2 and its synergism with interleukin-1β were modulated by 14-membered-ring macrolides, namely, roxithromycin, erythromycin, and clarithromycin, in cultured normal human epidermal keratinocytes. Those macrolides may attenuate the protease-activated receptor 2-interleukin-8 axis and thereby modulate proinflammatory responses in the skin.
Drosomycin-Like Defensin, a Human Homologue ofDrosophila melanogasterDrosomycin with Antifungal Activity
Authors: Simon Anna , Kullberg Bart Jan , Tripet Brian , Boerman Otto C. , Zeeuwen Patrick , van der Ven-Jongekrijg Johanna , Verweij Paul , Schalkwijk Joost , Hodges Robert , van der Meer Jos W. M. , Netea Mihai G. 
Published: January 2008

ABSTRACTInnate antifungal defense inDrosophila melanogasterrelies on the activation of the Toll molecule and the release of drosomycin, a defensin-like molecule with antifungal properties. Ten human homologues of Toll have been described, with central roles in activation of the innate host defense. In the present study, we report a putative human homologue of theDrosophila-derived drosomycin, designated drosomycin-like defensin (DLD). Synthetic DLD displays a broad spectrum of activity againstAspergillusspp. and other clinically relevant filamentous fungi. These effects are specific for filamentous fungi; no activity has been found against yeasts or gram-positive or gram-negative bacteria. Synthetic DLD also displays immunomodulatory effects onAspergillus-stimulated cytokine production. In addition, we show the expression of DLD mRNA in several human tissues, particularly in the skin, consistent with its putative role as a defensin against invading microorganisms. This is the first indication of an endogenous human peptide with specific antifungal activity, which is probably central in the defense against infections with molds.
Potent Antimalarial Activity of Histone Deacetylase Inhibitor Analogues
Authors: Andrews K. T. , Tran T. N. , Lucke A. J. , Kahnberg P. , Le G. T. , Boyle G. M. , Gardiner D. L. , Skinner-Adams T. S. , Fairlie D. P. 
Published: January 2008

ABSTRACT

The malaria parasite
Plasmodium falciparum
has at least five putative histone deacetylase (HDAC) enzymes, which have been proposed as new antimalarial drug targets and may play roles in regulating gene transcription, like the better-known and more intensively studied human HDACs (hHDACs). Fourteen new compounds derived from
l
-cysteine or 2-aminosuberic acid were designed to inhibit
P. falciparum
HDAC-1 (PfHDAC-1) based on homology modeling with human class I and class II HDAC enzymes. The compounds displayed highly potent antiproliferative activity against drug-resistant (Dd2) or drug sensitive (3D7) strains of
P. falciparum
in vitro (50% inhibitory concentration of 13 to 334 nM). Unlike known hHDAC inhibitors, some of these new compounds were significantly more toxic to
P. falciparum
parasites than to mammalian cells. The compounds inhibited
P. falciparum
growth in erythrocytes at both the early and late stages of the parasite's life cycle and caused altered histone acetylation patterns (hyperacetylation), which is a marker of HDAC inhibition in mammalian cells. These results support PfHDAC enzymes as being promising targets for new antimalarial drugs.
New Active Drugs against Liver Stages of
Plasmodium
Predicted by Molecular Topology
Authors: Mahmoudi Nassira , Garcia-Domenech Ramon , Galvez Jorge , Farhati Khemais , Franetich Jean-François , Sauerwein Robert , Hannoun Laurent , Derouin Francis , Danis Martin , Mazier Dominique 
Published: January 2008

ABSTRACT

We conducted a quantitative structure-activity relationship (QSAR) study based on a database of 127 compounds previously tested against the liver stage of
Plasmodium yoelii
in order to develop a model capable of predicting the in vitro antimalarial activities of new compounds. Topological indices were used as structural descriptors, and their relation to antimalarial activity was determined by using linear discriminant analysis. A topological model consisting of two discriminant functions was created. The first function discriminated between active and inactive compounds, and the second identified the most active among the active compounds. The model was then applied sequentially to a large database of compounds with unknown activity against liver stages of
Plasmodium
. Seventeen drugs that were predicted to be active or inactive were selected for testing against the hepatic stage of
P. yoelii
in vitro. Antiretroviral, antifungal, and cardiotonic drugs were found to be highly active (nanomolar 50% inhibitory concentration values), and two ionophores completely inhibited parasite development. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed on hepatocyte cultures for all compounds, and none of these compounds were toxic in vitro. For both ionophores, the same in vitro assay as those for
P. yoelii
has confirmed their in vitro activities on
Plasmodium falciparum
. A similar topological model was used to estimate the octanol/water partition of each compound. These results demonstrate the utility of the QSAR and molecular topology approaches for identifying new drugs that are active against the hepatic stage of malaria parasites. We also show the remarkable efficacy of some drugs that were not previously reported to have antiparasitic activity.
Linezolid Resistance in
Staphylococcus aureus
: Gene Dosage Effect, Stability, Fitness Costs, and Cross-Resistances
Authors: Besier Silke , Ludwig Albrecht , Zander Johannes , Brade Volker , Wichelhaus Thomas A. 
Published: January 2008

ABSTRACT

Linezolid resistance in
Staphylococcus aureus
is typically associated with mutations in the 23S rRNA gene. Here we show that the accumulation of a single point mutation, G2576T, in the different copies of this gene causes stepwise increases in resistance, impairment of the biological fitness, and cross-resistance to quinupristin-dalfopristin and chloramphenicol.
In Vitro Susceptibility of Various Genotypic Strains of
Toxoplasma gondii
to Pyrimethamine, Sulfadiazine, and Atovaquone
Authors: Meneceur Pascale , Bouldouyre Marie-Anne , Aubert Dominique , Villena Isabelle , Menotti Jean , Sauvage Virginie , Garin Jean-François , Derouin Francis 
Published: January 2008

ABSTRACT

Sulfadiazine, pyrimethamine, and atovaquone are widely used for the treatment of severe toxoplasmosis. Their in vitro activities have been almost exclusively demonstrated on laboratory strains belonging to genotype I. We determined the in vitro activities of these drugs against 17 strains of
Toxoplasma gondii
belonging to various genotypes and examined the correlations among 50% inhibitory concentrations (IC
50
s), growth kinetics, strain genotypes, and mutations on drug target genes. Growth kinetics were determined in THP-1 cell cultures using real-time PCR. IC
50
s were determined in MRC-5 cell cultures using a
T. gondii
-specific enzyme-linked immunosorbent assay performed on cultures. Mutations in dihydrofolate reductase (DHFR), dihydropteroate synthase (DHPS), and cytochrome
b
genes were determined by sequencing. Pyrimethamine IC
50
s ranged between 0.07 and 0.39 mg/liter, with no correlation with the strain genotype but a significant correlation with growth kinetics. Several mutations found on the DHFR gene were not linked to lower susceptibility. Atovaquone IC
50
s were in a narrow range of concentrations (mean, 0.06 ± 0.02 mg/liter); no mutation was found on the cytochrome
b
gene. IC
50
s for sulfadiazine ranged between 3 and 18.9 mg/liter for 13 strains and were >50 mg/liter for three strains. High IC
50
s were not correlated to strain genotypes or growth kinetics. A new mutation of the DHPS gene was demonstrated in one of these strains. In conclusion, we found variability in the susceptibilities of
T. gondii
strains to pyrimethamine and atovaquone, with no evidence of drug resistance. A higher variability was found for sulfadiazine, with a possible resistance of three strains. No relationship was found between drug susceptibility and strain genotype.
Structure-Function Correlations of Two Highly Conserved Motifs inSaccharomyces cerevisiaeSqualene Epoxidase
Authors: Ruckenstuhl Christoph , Poschenel Andrea , Possert Reinhard , Baral Pravas Kumar , Gruber Karl , Turnowsky Friederike 
Published: January 2008

ABSTRACTSaccharomyces cerevisiaesqualene epoxidase contains two highly conserved motifs, 1 and 2, of unknown function. Amino acid substitutions in both regions reduce enzyme activity and/or alter allylamine sensitivity. In the homology model, these motifs flank the flavin adenine dinucleotide cofactor and form part of the interface between cofactor and substrate binding domains.
In Vitro Activity of the New Azole Isavuconazole (BAL4815) Compared with Six Other Antifungal Agents against 162
Cryptococcus neoformans
Isolates from Cuba
Authors: Illnait-Zaragozi Maria-Teresa , Martínez Gerardo F. , Curfs-Breuker Ilse , Fernández Carlos M. , Boekhout Teun , Meis Jacques F. 
Published: January 2008

ABSTRACT

Cuban
Cryptococcus
isolates (
n
= 165) were tested in vitro against amphotericin B, flucytosine, fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole, giving MIC
90
values of 0.25, 8, 4, 0.25, 0.125, 0.016, and 0.016 μg/ml, respectively. Isavuconazole and posaconazole seem to be potentially active drugs for treating cryptococcal infections.
Treatment of Scedosporiosis with Voriconazole: Clinical Experience with 107 Patients
Authors: Troke Peter , Aguirrebengoa Koldo , Arteaga Carmen , Ellis David , Heath Christopher H. , Lutsar Irja , Rovira Montserrat , Nguyen Quoc , Slavin Monica , Chen Sharon C. A. 
Published: January 2008

ABSTRACT

The efficacy of voriconazole in 107 patients with scedosporiosis was analyzed. Principal infection sites were the lungs/sinuses (24%), central nervous system (CNS) (20%), and bone (18%), while 21% of patients had disseminated infection. Solid organ transplantation (22%), hematological malignancy (21%), and surgery/trauma (15%) were the predominant underlying conditions. A successful therapeutic response was achieved in 57% of patients (median, 103 therapy days), with >98% of those responding receiving ≥28 days of therapy. Patients receiving primary therapy showed a 61% response versus 56% for the others. The best therapeutic responses were seen for skin/subcutaneous (91%) or bone (79%) infections, and the lowest for CNS infections (43%). Patients without major immune suppression (72%) or those with solid organ transplantation (63%) or various hematological conditions (60%) showed the best responses by underlying condition. Median known survival time was 133 days (therapy successes, 252 days; failures, 21 days). In all, 43 (40%) patients died, 73% due to scedosporiosis. Patients with
Scedosporium prolificans
infection had significantly reduced survival times (
P
= 0.0259) and were more likely to die from fungal infection (
P
= 0.002) than were
Scedosporium apiospermum
-infected patients. In a subset of 43 patients where voriconazole baseline MICs were available, response to voriconazole was higher for
S. apiospermum
-infected patients (54% response; MIC
50
, 0.25 μg/ml) than for
S. prolificans
-infected patients (40% response; MIC
50
, 4.0 μg/ml). Voriconazole demonstrated clinically useful activity in the treatment of both
S. apiospermum
and
S. prolificans
infections and was well tolerated.
Genomewide Screening for Genes Associated with Gliotoxin Resistance and Sensitivity in
Saccharomyces cerevisiae
Authors: Chamilos Georgios , Lewis Russell E. , Lamaris Gregory A. , Albert Nathaniel D. , Kontoyiannis Dimitrios P. 
Published: January 2008

ABSTRACT

Gliotoxin (GT) is a secondary fungal metabolite with pleiotropic immunosuppressive properties that have been implicated in
Aspergillus
virulence. However, the mechanisms of GT cytotoxicity and its molecular targets in eukaryotic cells have not been fully characterized. We screened a haploid library of
Saccharomyces cerevisiae
single-gene deletion mutants (4,787 strains in EUROSCARF) to identify nonessential genes associated with GT increased resistance (GT-IR) and increased sensitivity (GT-IS). The susceptibility of the wild-type parental strain BY4741 to GT was initially assessed by broth microdilution methods using different media. GT-IR and GT-IS were defined as a fourfold increase and decrease, respectively, in MIC, and this was additionally confirmed by susceptibility testing on agar yeast extract-peptone-glucose plates. The specificity of GT-IR and GT-IS mutants exhibiting normal growth compared with the wild-type strain was further tested in studies of their susceptibility to conventional antifungal agents, cycloheximide, and H
2
O
2
. GT-IR was associated with the disruption of genes acting in general metabolism (
OPI1
,
SNF1
,
IFA38
), mitochondrial function (
RTG2
), DNA damage repair (
RAD18
), and vesicular transport (
APL2
) and genes of unknown function (
YGL235W
,
YOR345C
,
YLR456W
,
YGL072C
). The disruption of three genes encoding transsulfuration (
CYS3
), mitochondrial function (
MEF2
), and an unknown function (
YKL037W
) led to GT-IS. Specificity for GT-IR and GT-IS was observed in all mutants. Importantly, the majority (69%) of genes implicated in GT-IR (6/10) and GT-IS (2/3) have human homologs. We identified novel
Saccharomyces
genes specifically implicated in GT-IR or GT-IS. Because most of these genes are evolutionarily conserved, further characterization of their function could improve our understanding of GT cytotoxicity mechanisms in humans.
In Vitro Antifungal Activities of Isavuconazole (BAL4815), Voriconazole, and Fluconazole against 1,007 Isolates of Zygomycete,
Candida
,
Aspergillus
,
Fusarium
, and
Scedosporium
Species
Authors: Guinea Jesús , Peláez Teresa , Recio Sandra , Torres-Narbona Marta , Bouza Emilio 
Published: January 2008

ABSTRACT

Isavuconazole (BAL4815) is a promising novel broad-spectrum triazole in late-stage clinical development that has proven active in vitro against
Aspergillus
and
Candida
species. We compared the in vitro activities of this agent with those of voriconazole and fluconazole by the CLSI (formerly NCCLS) M38-A and M27-A2 procedures against a large collection of 1,007 relevant opportunistic fungi collected from 1986 to 2007:
Aspergillus
spp. (
n
= 702),
Candida
spp. (
n
= 218), Zygomycetes (
n
= 45),
Scedosporium
spp. (
n
= 22), and
Fusarium
spp. (
n
= 20). All
Candida
isolates were from patients with candidemia. For isavuconazole, these techniques were also compared with the Etest. Isavuconazole and voriconazole had MICs at which 50% and 90% of isolates were inhibited (MIC
50
and MIC
90
), respectively, of 1 and 1 μg/ml and 0.5 and 1 μg/ml against
Aspergillus
spp. and of 0.015 and 0.03 μg/ml and 0.25 and 0.125 μg/ml against
Candida
spp. (including fluconazole-resistant strains). The MIC
50
partial and complete inhibition end points of isavuconazole and voriconazole against the non-
Aspergillus
molds were as follows: 1 and 2 μg/ml and 16 and >16 μg/ml against Zygomycetes; 1 and 4 μg/ml and 0.25 and 0.5 μg/ml against
Scedosporium apiospermum
; 4 to 16 and >16 μg/ml and 4 to 8 and 16 to >16 μg/ml (ranges) against
Scedosporium prolificans
; and 16 and 16 μg/ml and 4 and 4 μg/ml against
Fusarium
spp. Isavuconazole showed minimal fungicidal concentrations for 50% and 90% of the isolates of 1 and 1 μg/ml against
Aspergillus
, 16 and >16 μg/ml against
Candida
, and 4 and >16 μg/ml against Zygomycetes, respectively, and >16 μg/ml against the remaining molds. The Etest proved to be a suitable alternative method for determining the antifungal activities of isavuconazole against
Aspergillus
and
Candida
; the Etest results showed 96% and 93% agreement with the results of the CLSI M38-A and M27-A2 methods, respectively.
Analysis of the Protective Capacity of ThreeStreptococcus suisProteins Induced under Divalent-Cation-Limited Conditions
Authors: Aranda Jesús , Garrido Maria Elena , Cortés Pilar , Llagostera Montserrat , Barbé Jordi 
Published: January 2008

ABSTRACTStreptococcus suisis a gram-positive pathogen that causes serious diseases in pigs and, in some cases, humans. Three genes of the virulentS. suis89/1591 strain, encoding putative divalent-cation-binding lipoproteins, were isolated based on information obtained from the draft annotation files of this organism's genome. The products of these genes, which are inducible by divalent-cation deprivation, were subsequently purified, and their immunogenic and protective abilities were analyzed. All three proteins (SsuiDRAFT 0103, SsuiDRAFT 0174, and SsuiDRAFT 1237) were found to be immunogenic, but only one of them (SsuiDRAFT 0103) induced a significant protective response (87.5%,P= 0.01) against the sameS. suisstrain. Furthermore, theS. suisssuiDRAFT 1240 gene (adcR), which encodes a predicted regulator of Zn2+and/or Mn2+uptake in streptococci, was cloned, and its protein product was purified. Electrophoretic mobility shift assays with purifiedS. suisAdcR protein showed experimentally, for the first time, that the AdcR DNA-binding sequence corresponds to the TTAACNRGTTAA motif. In addition, a requirement for either Zn2+or Mn2+, but not Fe2+, to establish in vitro binding of AdcR to its target sequence and the ability of AdcR to bind the ssuiDRAFT 0103 and ssuiDRAFT 1237 gene promoters but not the promoter of the ssuiDRAFT 0174 gene were demonstrated. Taken together, these data suggest that SsuiDRAFT 0103 is a good candidate for vaccines againstS. suisand support preliminary results indicating that bacterial envelope proteins involved in the uptake of divalent cations other than iron may be useful for protective purposes.
Tumor Necrosis Factor Blockade in Chronic Murine Tuberculosis Enhances Granulomatous Inflammation and Disorganizes Granulomas in the Lungs
Authors: Chakravarty Soumya D. , Zhu Guofeng , Tsai Ming C. , Mohan Vellore P. , Marino Simeone , Kirschner Denise E. , Huang Luqi , Flynn JoAnne , Chan John 
Published: January 2008

ABSTRACTTumor necrosis factor (TNF) is a prototypic proinflammatory cytokine that contributes significantly to the development of immunopathology in various disease states. A complication of TNF blockade therapy, which is used increasingly for the treatment of chronic inflammatory diseases, is the reactivation of latent tuberculosis. This study used a low-dose aerogenic model of murine tuberculosis to analyze the effect of TNF neutralization on disease progression in mice with chronic tuberculous infections. Histological, immunohistochemical, and flow cytometric analyses ofMycobacterium tuberculosis-infected lung tissues revealed that the neutralization of TNF results in marked disorganization of the tuberculous granuloma, as demonstrated by the dissolution of the previously described B-cell-macrophage unit in granulomatous tissues as well as by increased inflammatory cell infiltration. Quantitative gene expression studies using laser capture microdissected granulomatous lung tissues revealed that TNF blockade in mice chronically infected withM. tuberculosisleads to the enhanced expression of specific proinflammatory molecules. Collectively, these studies have provided evidence suggesting that in the chronic phase ofM. tuberculosisinfection, TNF is essential for maintaining the structure of the tuberculous granuloma and may regulate the granulomatous response by exerting an anti-inflammatory effect through modulation of the expression of proinflammatory mediators.
Contribution of Type IV Pili to the Virulence of
Aeromonas salmonicida
subsp.
salmonicida
in Atlantic Salmon (
Salmo salar
L.)
Authors: Boyd Jessica M. , Dacanay Andrew , Knickle Leah C. , Touhami Ahmed , Brown Laura L. , Jericho Manfred H. , Johnson Stewart C. , Reith Michael 
Published: January 2008

ABSTRACT

Aeromonas salmonicida
subsp.
salmonicida
, a bacterial pathogen of Atlantic salmon, has no visible pili, yet its genome contains genes for three type IV pilus systems. One system, Tap, is similar to the
Pseudomonas aeruginosa
Pil system, and a second, Flp, resembles the
Actinobacillus actinomycetemcomitans
Flp pilus, while the third has homology to the mannose-sensitive hemagglutinin pilus of
Vibrio cholerae
. The latter system is likely nonfunctional since eight genes, including the gene encoding the main pilin subunit, are deleted compared with the orthologous
V. cholerae
locus. The first two systems were characterized to investigate their expression and role in pathogenesis. The pili of
A. salmonicida
subsp.
salmonicida
were imaged using atomic force microscopy and Tap- and Flp-overexpressing strains. The Tap pili appeared to be polar, while the Flp pili appeared to be peritrichous. Strains deficient in
tap
and/or
flp
were used in live bacterial challenges of Atlantic salmon, which showed that the Tap pilus made a moderate contribution to virulence, while the Flp pilus made little or no contribution. Delivery of the
tap
mutant by immersion resulted in reduced cumulative morbidity compared with the cumulative morbidity observed with the wild-type strain; however, delivery by intraperitoneal injection resulted in cumulative morbidity similar to that of the wild type. Unlike the pili of other piliated bacterial pathogens,
A. salmonicida
subsp.
salmonicida
type IV pili are not absolutely required for virulence in Atlantic salmon. Significant differences in the behavior of the two mutant strains indicated that the two pilus systems are not redundant.