bluuebunny/crossref_metadata_2025 huggingface dataset:
The debt of nations and the distribution of ecological impacts from human activities
Authors: Srinivasan U. Thara , Carey Susan P. , Hallstein Eric , Higgins Paul A. T. , Kerr Amber C. , Koteen Laura E. , Smith Adam B. , Watson Reg , Harte John , Norgaard Richard B.
Published: January 2008

As human impacts to the environment accelerate, disparities in the distribution of damages between rich and poor nations mount. Globally, environmental change is dramatically affecting the flow of ecosystem services, but the distribution of ecological damages and their driving forces has not been estimated. Here, we conservatively estimate the environmental costs of human activities over 1961–2000 in six major categories (climate change, stratospheric ozone depletion, agricultural intensification and expansion, deforestation, overfishing, and mangrove conversion), quantitatively connecting costs borne by poor, middle-income, and rich nations to specific activities by each of these groups. Adjusting impact valuations for different standards of living across the groups as commonly practiced, we find striking imbalances. Climate change and ozone depletion impacts predicted for low-income nations have been overwhelmingly driven by emissions from the other two groups, a pattern also observed for overfishing damages indirectly driven by the consumption of fishery products. Indeed, through disproportionate emissions of greenhouse gases alone, the rich group may have imposed climate damages on the poor group greater than the latter's current foreign debt. Our analysis provides
prima facie
evidence for an uneven distribution pattern of damages across income groups. Moreover, our estimates of each group's share in various damaging activities are independent from controversies in environmental valuation methods. In a world increasingly connected ecologically and economically, our analysis is thus an early step toward reframing issues of environmental responsibility, development, and globalization in accordance with ecological costs.
SAP expression in T cells, not in B cells, is required for humoral immunity
Authors: Veillette André , Zhang Shaohua , Shi Xiaochu , Dong Zhongjun , Davidson Dominique , Zhong Ming-Chao
Published: January 2008

SAP (also named SH2D1A) is an intracellular adaptor molecule expressed in T cells, natural killer (NK) cells, and some B cells. TheSAPgene is mutated in X-linked lymphoproliferative (XLP) disease, a human immunodeficiency characterized by a faulty immune response to Epstein–Barr virus infection. Previous reports documented severe defects in antibody production and germinal center (GC) formation in SAP-deficient humans and mice genetically engineered to lack SAP expression. However,in vitrostudies and adoptive transfer experiments provided conflicting data as to whether this phenotype is caused by a functional defect resulting from SAP deficiency in T cells, B cells, or both. Here, we ascertained which cell types are responsible for this humoral immunity defect by using a conditional gene targeting approach. We also thoroughly examined the expression pattern of SAP in normal immune cells by using intracellular flow cytometry. The results showed that expression of SAP in T cells, but not in B cells or NK cells, is required and sufficient for SAP-dependent antibody production and GC formation. These data provide a critical insight into the mechanism by which SAP regulates humoral immunity. They also help elucidate the basis of a severe human immunodeficiency.
High-throughput biochemical analysis of in vivo location data reveals novel distinct classes of POU5F1(Oct4)/DNA complexes
Authors: Tantin Dean , Gemberling Matthew , Callister Catherine , Fairbrother William
Published: January 2008

The transcription factor POU5F1 is a key regulator of embryonic stem (ES) cell pluripotency and a known oncoprotein. We have developed a novel high-throughput binding assay called MEGAshift (microarray evaluation of genomic aptamers by shift) that we use to pinpoint the exact location, affinity, and stoichiometry of the DNA–protein complexes identified by chromatin immunoprecipitation studies. We consider all genomic regions identified as POU5F1-ChIP–enriched in both human and mouse. Compared with regions that are ChIP-enriched in a single species, we find these regions more likely to be near actively transcribed genes in ES cells. We resynthesize these genomic regions as a pool of tiled 35-mers. This oligonucleotide pool is then assayed for binding to recombinant POU5F1 by gel shift. The degree of binding for each oligonucleotide is accurately measured on a custom oligonucleotide microarray. We explore the relationship between experimentally determined and computationally predicted binding strengths, find many novel functional combinations of POU5F1 half sites, and demonstrate efficient motif discovery by incorporating binding information into a motif finding algorithm. In addition to further refining location studies for transcription factors, this method holds promise for the high-throughput screening of promoters, SNP regions, and epigenetic modifications for factor binding.
Un résultat de connexité pour les variétés analytiques p-adiques: privilège et noethérianité
Authors: Poineau Jérôme
Published: January 2008

Let k be a non-Archimedean field, let X be a k-affinoid space and let f1,…,fn, with $n\in \mathbb {N}^*$, be analytic functions over X. If X is irreducible, we prove that the analytic domain $\bigcup _{1\le j\le n} \{x\in X\mid |f_{j}(x)|\ge \varepsilon _{j}\}$ is still irreducible, provided that $(\varepsilon _{1},\ldots ,\varepsilon _{n}) \in \mathbb {R}_{+}^n$ is small enough. Then, for a general X, we precisely describe how the geometric connected components of the spaces $\{x\in X\mid |f(x)|\ge \varepsilon \}$ behave with regards to ε. Finally, we obtain a result concerning privileged neighbourhoods and adapt a theorem from complex analytic geometry about Noetherianity for germs of analytic functions.
Stability conditions for generic K3 categories
Authors: Huybrechts Daniel , Macrì Emanuele , Stellari Paolo
Published: January 2008

A K3 category is by definition a Calabi–Yau category of dimension two. Geometrically K3 categories occur as bounded derived categories of (twisted) coherent sheaves on K3 or abelian surfaces. A K3 category is generic if there are no spherical objects (or just one up to shift). We study stability conditions on K3 categories as introduced by Bridgeland and prove his conjecture about the topology of the stability manifold and the autoequivalences group for generic twisted projective K3, abelian surfaces, and K3 surfaces with trivial Picard group.
Utilisation d’une cohomologie étale équivariante en topologie arithmétique
Authors: Morin Baptiste
Published: January 2008

Sikora has given results which confirm the analogy between number fields and 3-manifolds. However, he has given proofs of his results which are very different in the arithmetic and in the topological case. In this paper, we show how to provide a unified approach to the results in the two cases. For this we introduce an equivariant cohomology which satisfies a localization theorem. In particular, we obtain a satisfactory explanation for the coincidences between Sikora’s formulas which leads us to clarify and to extend the dictionary of arithmetic topology.
Arithmetically defined dense subgroups of Morava stabilizer groups
Authors: Naumann Niko
Published: January 2008

For 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

We 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.
Destabilization of Laminar Wall Jet Flow and Relaminarization of the Turbulent Confined Jet Flow in Axially Rotating Circular Pipe
Authors: Majumder Snehamoy , Sanyal Dipankar
Published: January 2008

Destabilization and relaminarization phenomena have been investigated in an axially rotating circular duct. Standard k-ε model with modification for streamline curvature has been used in the numerical study. The laminar and turbulent velocity distributions at inlet have been observed to become turbulent and laminar, respectively, toward the exit of the pipe. A local velocity profile with parabolic or nearly uniform variation has been considered as the characteristic of laminarlike or turbulent flow, respectively, and changeover of flow from former to the later variation or vice versa has been taken to characterize destabilization and relaminarization, respectively. The predicted azimuthal velocity component was found to be reasonably accurate near the wall and not so encouraging in the core region of the swirling flow. The recirculation bubble generated by a central jet flow at the wall has been observed to reduce in size due to rotation of the pipe confirming the relaminarization phenomenon, whereas with laminar wall jet waspredicted recirculation bubble growing with rotation rate manifesting the destabilization effects.
Incipience of Liquid Entrainment From a Stratified Gas-Liquid Region in Multiple Discharging Branches
Authors: Bowden R. C. , Hassan I. G.
Published: January 2008

The onset of liquid entrainment in discharging branches, from a stratified gas-liquid region, has implications in industrial applications where safety is of concern. The onset criterion was characterized by the critical height, the vertical distance from the discharge inlet to the gas-liquid interface, and was shown to be a function of the Froude number. The critical height signified a transition in the discharging flow quality from a single phase gas to a two-phase gas-liquid mixture. The onset of liquid entrainment with multiple discharging branches, and a stratified gas-liquid region, was experimentally investigated using air and water. A test section with a semicircular cross section and three discharging branches at 0deg, 45deg, and 90deg was used. The critical height was recorded using both increasing and decreasing liquid level methods, thereby demonstrating surface tension and wetness effects. A total of eight cases were investigated for single, dual, and triple discharges, with onset occurring in the branch closest to and above the gas-liquid interface. Wall curvature effects were discussed through comparison with previous flat wall studies. Agreement between previously developed analytical models and the decreasing liquid level results was found.
Numerical Simulation of Cavitation Around a Hydrofoil and Evaluation of a RNG κ-ε Model
Authors: Zhou Lingjiu , Wang Zhengwei
Published: January 2008

Cavitating flow around a hydrofoil was simulated using a transport equation-based model with consideration of the influence of noncondensable gases. The cavity length and the pressure distributions on the suction side can be well predicted for stable cavities using the standard renormalization-group (RNG) κ-ε turbulence model with proper noncondensable gas mass fraction. The unstable cavity shedding at lower cavitation numbers was not well predicted by the standard RNG κ-ε turbulence model. A modified RNG κ-ε turbulence model was evaluated by comparing the calculated spatial-temporal pressure distributions on the suction wall with experimental data. The results showed that the predicted cavity growth and shedding cycle and its frequency agree well with the experimental data. However, the pressure increase caused by interaction of the reentrant flow and the cavity interface is overestimated, which caused the time-averaged pressure on the front part of the hydrofoil to be overestimated. The time-averaged pressure on the rear of the hydrofoil was low because the small cavity shedding on the rear part of the cavity was not predicted.
PIV Study of Turbulent Flow in Asymmetric Converging and Diverging Channels
Authors: Shah M. K. , Tachie M. F.
Published: January 2008

An experimental investigation of turbulent flow subjected to variable adverse and favorable pressure gradients in two-dimensional asymmetric channels is reported. The floors of the diverging and converging channels were flat while the roofs of the channels were curved. Adverse pressure gradient flows at Reh=27,050 and 12,450 and favorable pressure gradient flow at Reh=19,280 were studied. A particle image velocimetry was used to conduct detailed measurements at several planes upstream, within the variable section and within the downstream sections. The boundary layer parameters were obtained in the upper and lower boundary layers to study the effects of pressure gradients on the development of the mean flow on the floor and roof of the channels. The profiles of the mean velocities, turbulence intensities, Reynolds shear stress, mixing length, eddy viscosity, and turbulence production were also obtained to document the salient features of pressure gradient turbulent flows in asymmetric converging and diverging channels.
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

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

Innate 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

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

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

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

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

Saccharomyces 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

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

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

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

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

Streptococcus 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

Tumor 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

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.
Duration of Naturally Acquired Antibody Responses to Blood-StagePlasmodium falciparumIs Age Dependent and Antigen Specific
Authors: Akpogheneta Onome J. , Duah Nancy O. , Tetteh Kevin K. A. , Dunyo Samuel , Lanar David E. , Pinder Margaret , Conway David J.
Published: January 2008

Naturally acquired antibody responses provide partial protection from clinical malaria, and blood-stage parasite vaccines under development aim to prime such responses. To investigate the determinants of antibody response longevity, immunoglobulin G (IgG) antibodies to several blood-stage vaccine candidate antigens in the sera of two cohorts of children of up to 6 years of age during the dry seasons of 2003 and 2004 in The Gambia were examined. The first cohort showed that most antibodies were lost within less than 4 months of the first sampling if a persistent infection was not present, so the study of the second-year cohort involved collecting samples from individuals every 2 weeks over a 3-month period. Antibody responses in the second cohort were also influenced by persistent malaria infection, so analysis focused particularly on children in whom parasites were not detected after the first time point. Antibodies to most antigens declined more slowly in children in the oldest age group (>5 years old) and more rapidly in children in the youngest group (<3 years old). However, antibodies to merozoite surface protein 2 were shorter lived than antibodies to other antigens and were not more persistent in older children. The age-specific and antigen-specific differences were not explained by different IgG subclass response profiles, indicating the probable importance of differential longevities of plasma cell populations rather than antibody molecules. It is likely that young children mostly have short-lived plasma cells and thus experience rapid declines in antibody levels but that older children have longer-lasting antibody responses that depend on long-lived plasma cells.
Identification of an HLA-A*0201-Restricted T-Cell Epitope on the MPT51 Protein, a Major Secreted Protein Derived fromMycobacterium tuberculosis, by MPT51 Overlapping Peptide Screening
Authors: Aoshi Taiki , Nagata Toshi , Suzuki Mina , Uchijima Masato , Hashimoto Dai , Rafiei Alireza , Suda Takafumi , Chida Kingo , Koide Yukio
Published: January 2008

CD8+T cells play a pivotal role in protection againstMycobacterium tuberculosisinfection. We identified a novel HLA-A*0201-restricted CD8+T-cell epitope on a dominant secreted antigen ofM. tuberculosis, MPT51, in HLA-A*0201 transgenic HHD mice. HHD mice were immunized with plasmid DNA encoding MPT51 with gene gun bombardment, and gamma interferon (IFN-γ) production by the immune splenocytes was analyzed. In response to overlapping synthetic peptides covering the mature MPT51 sequence, the splenocytes were stimulated to produce IFN-γ by only one peptide, p51-70. Three-color flow cytometric analysis of intracellular IFN-γ and cell surface CD4 and CD8 staining revealed that the MPT51 p51-70 peptide contains an immunodominant CD8+T-cell epitope. Further analysis using computer algorithms permitted identification of a bona fide T-cell epitope, p53-62. A major histocompatibility complex class I stabilization assay using T2 cells confirmed that this epitope binds to HLA-A*0201. The T cells were capable of lysing MPT51 p53-62 peptide-pulsed T2 cells. In addition, MPT51 p53-62-specific memory CD8+T cells were found in tuberculin skin test-positive HLA-A*0201+healthy individuals. Use of this HLA-A*0201-restricted CD8+T-cell epitope for analysis of the role of MPT51-specific T cells inM. tuberculosisinfection and for design of vaccines against tuberculosis is feasible.
A Variable-Length PCR Target Protein of
Ehrlichia chaffeensis
Contains Major Species-Specific Antibody Epitopes in Acidic Serine-Rich Tandem Repeats
Authors: Luo Tian , Zhang Xiaofeng , Wakeel Abdul , Popov Vsevolod L. , McBride Jere W.
Published: January 2008

Ehrlichia chaffeensis
and
E. canis
have a small subset of tandem repeat (TR)-containing proteins that elicit strong host immune responses and are associated with host-pathogen interactions. In a previous study, we molecularly characterized a highly conserved 19-kDa major immunoreactive protein (gp19) of
E. canis
and identified the corresponding TR-containing ortholog variable-length PCR target (VLPT) protein in
E. chaffeensis
. In this study, the native 32-kDa VLPT protein was identified and the immunodeterminants defined in order to further understand the molecular basis of the host immune response to
E. chaffeensis
. Synthetic and/or recombinant polypeptides corresponding to various regions of VLPT were used to localize major antibody epitopes to the TR-containing region. Major antibody epitopes were identified in three nonidentical repeats (R2, R3, and R4), which reacted strongly with antibodies in sera from an
E. chaffeensis
-infected dog and human monocytotropic ehrlichiosis patients. VLPT-R3 and VLPT-R2 reacted most strongly with antibody, and the epitope was further localized to a nearly identical proximal 17-amino-acid region common between these repeats that was species specific. The epitope in R4 was distinct from that of R2 and R3 and was found to have conformational dependence. VLPT was detected in supernatants from infected cells, indicating that the protein was secreted. VLPT was localized on both reticulate and dense-core cells, and it was found extracellularly in the morula fibrillar matrix and associated with the morula membrane.
Externally assessed psychosocial work characteristics and diagnoses of anxiety and depression
Authors: Waldenström K , Ahlberg G , Bergman P , Forsell Y , Stoetzer U , Waldenström M , Lundberg I
Published: January 2008

Background:

Interpretations of relationships between work characteristics and psychiatric disorders may be biased by over-reporting of unfavourable work characteristics among those with psychiatric disorders. This study attempts to account for this bias by using external assessments of work characteristics.

Methods:

Psychiatric symptoms were assessed in an interview and psychiatric diagnoses were established according to DSM-IV. Current work characteristics and work characteristics three years ago were assessed in an interview with predetermined criteria and included cognitive requirements, possibility of influence, and required conformance to schedule, time pressure, and hindrances concerning goals, resources and instrumental support. Deterioration in work characteristics during the study period was also assessed. The sample consisted of 672 employed men and women in different occupations.

Results:

Lack of instrumental support from colleagues and supervisors (OR 6.4, 95% CI 2.6 to 15.8) assessed as a hindrance to work performance, and deterioration in work characteristics during the study period (OR 2.8, 95% CI 1.3 to 6.1) were associated with increased odds ratios for depression after adjustment for confounding factors, including symptoms of mental illness at baseline. Findings for anxiety were similar but not statistically significant.

Conclusion:

Externally assessed lack of instrumental social support at work and deteriorating work characteristics were associated with an increased risk for depression.
The life history and feeding habits of Sialis cornuta Ross in a series of abandoned beaver ponds (Insecta; Megaloptera)
Authors: Pritchard G. , Leischner T. G.
Published: January 2008

Sialis cornuta is being studied in a series of abandoned beaver ponds in the Rocky Mountains 80 km west of Calgary, Alberta. The species has a 2-year life cycle in this area. Eggs are laid mainly on the undersides of uprooted trees; each egg mass contains a mean of 585 eggs which are susceptible to heavy parasitism by Trichogramma semblidis. Most eggs are laid during late June, they hatch in 7 to 21 days, and most larvae attain the fifth or sixth instar by the first winter. In the laboratory there are between 7 and 10 instars before pupation, but in the field the number appears to be more constant at 10. Sexual dimorphism and possibly a larval diapause complicate the separation of instars and the translation of laboratory data to the field. Between May and mid-June of their second year larvae leave the water and pupate in the soil a short distance from the water's edge and adults emerge through June and the first half of July.Larvae feed on benthic invertebrates in approximate proportion to their abundance provided they are not too large. Chironomid larvae, tubificid worms, and ostracods form the bulk of the food.Information is given on mating, oviposition, and feeding behavior, and comparisons are made with the life history features of S. californica and S. rotunda in Oregon.
The role of plerocercoids in the biology of Proteocephalus ambloplitis (Cestoda) maturing in smallmouth bass
Authors: Fischer Hartwig , Freeman Reino S.
Published: January 2008

Plerocercoids of Proteocephalus ambloplitis removed from parenteral sites and the enteron of smallmouth bass, or parenteral sites in other fish from Lake Opeongo, were fed to bass which were either laboratory-reared or captured from the lake and treated with the anthelmintic di-n-butyl tin oxide. The experiments demonstrate that, following growth to plerocercoid I in copepods, plerocercoid II passes through three physiologically distinct levels of development in fish. "Initial" growth may be parenteral in bass or other fish; "middle" growth can be completed only while parenteral in bass; "terminal" growth of plerocercoid II precedes sexual maturation in the gut lumen of bass. Plerocercoids commonly enter the gut of bass by direct entry from parenteral sites in the same fish, and only rarely following ingestion of an infected bass, since cannibalism is rare in Lake Opeongo. Plerocercoids from parenteral sites in fish other than bass are, therefore, an essential reservoir, and most "middle" plerocercoid II in bass develop from "initial" plerocercoid II from parenteral sites in other species of infected fish that bass ingest.
The distribution and tissue retention of mercury-203 in the goldfish (Carassius auratus)
Authors: Weisbart Melvin
Published: January 2008

Goldfish injected intraperitoneally with 203Hg(NO3)2 lost mercury at an apparent constant rate resulting in a biological half-life of 568 h. Correlated with this loss was a linear increase in the amount of mercury in the water.The mercury-203 content in the tissues displayed four different responses.(1) Gall bladder, gonad, and spleen tissues showed no significant regressions.(2) Eye, kidney, and intestinal tissue manifested significant losses of mercury, but the rate of loss was not significantly different from that of the body as a whole.(3) Gill, heart, skin, and swim bladder tissues lost mercury at rates faster than the body as a whole.(4) Brain, liver, muscle, and head kidney tissues showed no significant losses of mercury.