bluuebunny/crossref_metadata_2025_split huggingface dataset:
First‐Person Methodologies: A View From Outside the Phenomenological Tradition
Authors: Georgalis Nicholas 
Published: March 2010

AbstractIt is argued that results from first‐person methodologies are unacceptable for incorporation into a fundamental philosophical theory of the mind unless they satisfy a necessary condition, which I introduce and defend. I also describe a narrow,nonphenomenal, first‐person concept that I callminimal contentthat satisfies this condition.Minimal content is irreducible to third‐person concepts, but it is required for an adequate account of intentionality, representation, and language. Consequently, consciousness is implicated in these as strongly — but differently — than it is in our phenomenal states. Minimal content provides a foundation for an objective philosophical theory of the mind and language. (Some support for these claims is given here. They are extensively argued for in myThe Primacy of the Subjective.)
A Biological Alternative to Moral Explanations
Authors: Millum Joseph 
Published: March 2010

AbstractSome moral realists claim that moral facts are a species of natural fact, amenable to scientific investigation. They argue that these moral facts are needed in the best explanations of certain phenomena and that this is evidence that they are real. In this paper I present part of a biological account of the function of morality. The account allows the identification of a plausible natural kind that could play the explanatory role that a moral kind would play in naturalist realist theories. It is therefore a candidate for being the moral kind. I argue, however, that it will underdetermine the morally good, that is, identifying the kind is not sufficient to identify what is good. Hence this is not a natural moral kind. Its explanatory usefulness, however, means that we do not have to postulate any further (moral) facts to provide moral explanations. Hence there is no reason to believe that there are any natural moral kinds.
Puzzles about Trust
Authors: Smolkin Doran 
Published: March 2010

AbstractThis article is an attempt to deepen our understanding of trust. To this end, several elements frequently present in trust‐relationships are first identified, and then three underappreciated puzzles about trust are described. Next, it is argued that certain leading analyses of trust are unsatisfactory, in part, because they are unable to solve these puzzles succesfully. Finally, an alternative way of thinking about trust is proposed. It is agued that this new way of thinking about trust is both independently plausible and better able to solve these puzzles about trust.
A Euthyphronic Problem for Kitcher's Epistemology of Science
Authors: Roland Jeffrey W. 
Published: March 2010

AbstractPhilip Kitcher has advanced an epistemology of science that purports to be naturalistic. For Kitcher, this entails that his epistemology of science must explain the correctness of belief‐regulating norms while endorsing a realist notion of truth. This paper concerns whether or not Kitcher's epistemology of science is naturalistic on these terms. I find that it is not but that by supplementing the account we can secure its naturalistic standing.
Passing‐over: The Death of the Author in Hegel's Philosophy
Authors: Berthold Daniel 
Published: March 2010

AbstractCriticism of Hegel has been a central preoccupation of “postmodern” philosophy, from critical theory and deconstruction to Lacanian psychoanalytic theory and Foucauldian “archaeology.” One of the most frequent criticisms is that Hegel's invocation of “absolute knowledge” installs him in a position of authorial arrogance, of God‐like authority, leaving the reader in a position of subservience to the Sage's perfect wisdom. The argument of this article is that this sort of criticism is profoundly ironic, since Hegel's construction of the role of the Sage possessing absolute knowledge is in fact an elaborate mask covering over a radical project of disappearance of the author by which it becomes the reader who is left to author the text. The article explores Hegel's commitment to his own death as an author in his invention of a new method of demonstration, his epistemology, his philosophy of language, his theory of desire, and even in the seemingly least likely place of all, his portrait of “absolute knowledge.”
A New Kantian Solution to the Third Antinomy of Pure Reason and to the Free Will Problem
Authors: Vaida Iuliana Corina 
Published: March 2010

AbstractThe goal of this paper is to articulate a new solution to Kant's third antinomy of pure reason, one that establishes the possibility of incompatibilist freedom—the freedom presupposed by our traditional conceptions of moral responsibility, moral worth, and justice—without relying on the doctrine of transcendental idealism (TI). A discussion of Henry Allison's “two‐aspect” interpretation of Kant's TI allows me both to criticize one of the best defenses of TI today and to advance my own TI‐free solution to the third antinomy by appeal to a thesis of epistemic modesty based on Paul Guyer's realist interpretation of Kant's theory of experience. According to this interpretation, the a priori forms of our sensibility and understanding are not forms that the mind imposes on a material whose real properties are unknowable to us but are instead forms that limit or filter the kinds of things we can experience and know. In particular, being causally determined is a real feature of things as they are in themselves, but the necessity and universality of our deterministic claims are relative, restricted to the objects of possible experience. Consequently, though a causally determined event cannot be free, the necessity and universality of determinism does not entail that free events (choices) cannot exist but that they cannot constitute objects of possible experience. After arguing that freedom is possible, I outline an argument for the reality of freedom, based on the requirements of morality. Finally, I argue that my view, though opposed to metaphysical naturalism, is consistent with scientific realism and methodological naturalism.
Efflux Pumps, OprD Porin, AmpC β-Lactamase, and Multiresistance in
Pseudomonas aeruginosa
Isolates from Cystic Fibrosis Patients
Authors: Tomás Maria , Doumith Michel , Warner Marina , Turton Jane F. , Beceiro Alejandro , Bou German , Livermore David M. , Woodford Neil 
Published: March 2010

ABSTRACT

Expression of
ampC
,
oprD
,
mexA
,
mexC
,
mexE
, and
mexX
was studied in 25
Pseudomonas aeruginosa
isolates from cystic fibrosis patients, including 14 isolates of the Liverpool epidemic strain. Overexpressed
mexA
or
ampC
and reduced
oprD
were associated with β-lactam resistance. A specific combination of
mexR
,
nalC
, and
nalD
mutations occurred in 11 Liverpool strain isolates, including 7 with upregulated
mexA
.
3-Hydroxyphthalic Anhydride-Modified Chicken Ovalbumin Exhibits Potent and Broad Anti-HIV-1 Activity: a Potential Microbicide for Preventing Sexual Transmission of HIV-1
Authors: Li Lin , He Lili , Tan Suiyi , Guo Xinhua , Lu Hong , Qi Zhi , Pan Chungen , An Xiuli , Jiang Shibo , Liu Shuwen 
Published: March 2010

ABSTRACTHeterosexual transmission is the primary route by which women acquire human immunodeficiency virus (HIV)/AIDS. Thus, development of woman-controlled topical microbicides for prevention of sexual transmission of HIV is urgently needed. Here we report that 3-hydroxyphthalic anhydride-modified chicken ovalbumin (HP-OVA) exhibits potent antiviral activity against a broad spectrum of human immunodeficiency virus type 1 (HIV-1) isolates with different genotypes and biotypes. Its antiviral activity is correlated with the percentages of the chemically modified and unmodified lysines and arginines in OVA. HP-OVA inhibits HIV-1 fusion and entry through multiple mechanisms of action, including (i) blocking gp120 binding to CD4 and (ii) interfering with gp41 six-helix bundle formation. Because of the widespread availability and established safety profile of OVA, HP-OVA has good potential to be developed as an effective, safe, and affordable microbicide for prevention of HIV sexual transmission.
Antiviral Properties, Metabolism, and Pharmacokinetics of a Novel Azolo-1,2,4-Triazine-Derived Inhibitor of Influenza A and B Virus Replication
Authors: Karpenko Inna , Deev Sergey , Kiselev Oleg , Charushin Valerey , Rusinov Vladimir , Ulomsky Eugeney , Deeva Ella , Yanvarev Dmitry , Ivanov Alexander , Smirnova Olga , Kochetkov Sergey , Chupakhin Oleg , Kukhanova Marina 
Published: March 2010

ABSTRACT

Influenza viruses of types A and B cause periodic pandemics in the human population. The antiviral drugs approved to combat influenza virus infections are currently limited. We have investigated an effective novel inhibitor of human influenza A and B viruses, triazavirine {2-methylthio-6-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazine-7(4Í)-one} (TZV). TZV suppressed the replication of influenza virus in cell culture and in chicken chorioallantoic membranes, and it protected mice from death caused by type A and B influenza viruses. TZV was also effective against a rimantadine-resistant influenza virus strain and against avian influenza A virus H5N1 strains. The pharmacokinetic parameters and bioavailability of TZV were calculated after the administration of TZV to rabbits. The TZV metabolite AMTZV {2-methylthio-6-amino-1,2,4-triazolo[5,1-
s
]-1,2,4-triazin(e)-7(4Í)-one} was discovered in ÍÅK 293T and Huh7 cell cultures, a liver homogenate, and rabbit blood after intragastric administration of TZV. AMTZV was nontoxic and inactive as an inhibitor of influenza virus in cell culture. Most likely, this metabolite is a product of TZV elimination.
Skin Concentrations and Pharmacokinetics of Posaconazole after Oral Administration
Authors: Krishna Gopal , Beresford Eric , Ma Lei , Vickery Donna , Martinho Monika , Yu Xin , Komjathy Steven , Tavakkol Amir 
Published: March 2010

ABSTRACT

A randomized, single-center, open-label study of posaconazole (POS) was performed to determine the concentration of POS in the skin of 30 healthy adult human subjects receiving 400 mg POS oral suspension twice daily for 8 days with a high-fat meal. Blood samples for plasma POS level determination were collected at prespecified times on day 1 and day 8. From each subject, two 4-mm skin punch biopsy samples were obtained, one immediately before or after both the first and last doses of POS. A MIC
90
value of 250 ng/ml, which encompasses the majority of common dermatophytes, was used to calculate the time above the MIC
90
in plasma and skin. On days 1 and 8, POS attained peak plasma concentrations at median times of 8 and 5 h, respectively. On days 1 and 8, POS peak skin concentrations were attained at 12 and 3 h, respectively; peak skin concentrations were produced from a single composite profile. On day 8, POS concentrations in skin and plasma for the entire dosing interval were severalfold higher than the MIC
90
. POS dosed at 400 mg twice daily per os was well tolerated in healthy subjects. Two subjects reported increased alanine aminotransferase (ALT) levels. The findings of this study demonstrate adequate skin penetration and have certain implications for the treatment of dermatophytic skin and nail infections.
Interaction of
Candida albicans
Biofilms with Antifungals: Transcriptional Response and Binding of Antifungals to Beta-Glucans
Authors: Vediyappan Govindsamy , Rossignol Tristan , d'Enfert Christophe 
Published: March 2010

ABSTRACT

Candida albicans
can form biofilms that exhibit elevated intrinsic resistance to various antifungal agents, in particular azoles and polyenes. The molecular mechanisms involved in the antifungal resistance of biofilms remain poorly understood. We have used transcript profiling to explore the early transcriptional responses of mature
C. albicans
biofilms exposed to various antifungal agents. Mature
C. albicans
biofilms grown under continuous flow were exposed for as long as 2 h to concentrations of fluconazole (FLU), amphotericin B (AMB), and caspofungin (CAS) that, while lethal for planktonic cells, were not lethal for biofilms. Interestingly, FLU-exposed biofilms showed no significant changes in gene expression over the course of the experiment. In AMB-exposed biofilms, 2.7% of the genes showed altered expression, while in CAS-exposed biofilms, 13.0% of the genes had their expression modified. In particular, exposure to CAS resulted in the upregulation of hypha-specific genes known to play a role in biofilm formation, such as
ALS3
and
HWP1
. There was little overlap between AMB- or CAS-responsive genes in biofilms and those that have been identified as AMB, FLU, or CAS responsive in
C. albicans
planktonic cultures. These results suggested that the resistance of
C. albicans
biofilms to azoles or polyenes was due not to the activation of specific mechanisms in response to exposure to these antifungals but rather to the intrinsic properties of the mature biofilms. In this regard, our study led us to observe that AMB physically bound
C. albicans
biofilms and beta-glucans, which have been proposed to be major constituents of the biofilm extracellular matrix and to prevent azoles from reaching biofilm cells. Thus, enhanced extracellular matrix or beta-glucan synthesis during biofilm growth might prevent antifungals, such as azoles and polyenes, from reaching biofilm cells, thus limiting their toxicity to these cells and the associated transcriptional responses.
Use of a High-Resolution Melt Assay To Characterize Codon 54 of the
cyp51A
Gene of
Aspergillus fumigatus
on a Rotor-Gene 6000 Instrument
Authors: Tuohy M. J. , Reja V. , Park S. , Perlin D. S. , Wnek M. , Procop G. W. , Yen-Lieberman B. 
Published: March 2010

ABSTRACT

A high-resolution melt (HRM) assay using a Rotor-Gene 6000 instrument was developed to characterize the codon for glycine 54 in the
cyp51A
genes from 13 reference isolates and 12 clinical isolates of
Aspergillus fumigatus
. Mutations in this codon confer reduced susceptibility to itraconazole and posaconazole. The assay is simple to perform, and a result of “wild type” or “mutant” is available after approximately 1 h following DNA extraction using commercially available reagents and conventional primers.
Mechanism of the Synergistic Effect of Amiodarone and Fluconazole in
Candida albicans
Authors: Gamarra Soledad , Rocha Elousa Maria F. , Zhang Yong-Qiang , Park Steven , Rao Rajini , Perlin David S. 
Published: March 2010

ABSTRACT

The antiarrhythmic drug amiodarone has been found to have fungicidal activity. In
Saccharomyces cerevisiae
, its antifungal activity is mediated by calcium overload stress, which leads to a rapid nuclear accumulation of the calcineurin-regulated transcription factor
CRZ1
. In addition, low doses of amiodarone have been reported to be synergistic with fluconazole in fluconazole-resistant
Candida albicans
. To establish its mechanism of toxicity in
C. albicans
, we used expression profiling of key pathway genes to examine cellular responses to amiodarone alone and in combination with fluconazole. Gene expression profiling of 59 genes was done in five
C. albicans
strains (three fluconazole-susceptible strains and two fluconazole-resistant strains) after amiodarone and/or fluconazole exposure. Of the 59 genes, 27 analyzed showed a significant change (>2-fold) in expression levels after amiodarone exposure. The up- or downregulated genes included genes involved in Ca
2+
homeostasis, cell wall synthesis, vacuolar/lysosomal transport, diverse pathway regulation, stress response, and pseudohyphal morphogenesis. As expected, fluconazole induces an increase in ergosterol pathway genes expression levels. The combination treatment significantly dampened the transcriptional response to either drug, suggesting that synergism was due to an inhibition of compensatory response pathways. This dampening resulted in a decrease in total ergosterol levels and decreased pseudohyphal formation, a finding consistent with decreased virulence in a murine candidiasis model.
Evaluation of Nucleoside Hydrolase Inhibitors for Treatment of African Trypanosomiasis
Authors: Berg Maya , Kohl Linda , Van der Veken Pieter , Joossens Jurgen , Al-Salabi Mohammed I. , Castagna Valeria , Giannese Francesca , Cos Paul , Versées Wim , Steyaert Jan , Grellier Philippe , Haemers Achiel , Degano Massimo , Maes Louis , de Koning Harry P. , Augustyns Koen 
Published: March 2010

ABSTRACT

In this paper, we present the biochemical and biological evaluation of
N
-arylmethyl-substituted iminoribitol derivatives as potential chemotherapeutic agents against trypanosomiasis. Previously, a library of 52 compounds was designed and synthesized as potent and selective inhibitors of
Trypanosoma vivax
inosine-adenosine-guanosine nucleoside hydrolase (IAG-NH). However, when the compounds were tested against bloodstream-form
Trypanosoma brucei brucei
, only one inhibitor,
N
-(9-deaza-adenin-9-yl)methyl-1,4-dideoxy-1,4-imino-
d
-ribitol (UAMC-00363), displayed significant activity (mean 50% inhibitory concentration [IC
50
] ± standard error, 0.49 ± 0.31 μM). Validation in an
in vivo
model of African trypanosomiasis showed promising results for this compound. Several experiments were performed to investigate why only UAMC-00363 showed antiparasitic activity. First, the compound library was screened against
T. b. brucei
IAG-NH and inosine-guanosine nucleoside hydrolase (IG-NH) to confirm the previously demonstrated inhibitory effects of the compounds on
T. vivax
IAG-NH. Second, to verify the uptake of these compounds by
T. b. brucei
, their affinities for the nucleoside P1 and nucleoside/nucleobase P2 transporters of
T. b. brucei
were tested. Only UAMC-00363 displayed significant affinity for the P2 transporter. It was also shown that UAMC-00363 is concentrated in the cell via at least one additional transporter, since P2 knockout mutants of
T. b. brucei
displayed no resistance to the compound. Consequently, no cross-resistance to the diamidine or the melaminophenyl arsenical classes of trypanocides is expected. Third, three enzymes of the purine salvage pathway of procyclic
T. b. brucei
(IAG-NH, IG-NH, and methylthioadenosine phosphorylase [MTAP]) were investigated using RNA interference. The findings from all these studies showed that it is probably not sufficient to target only the nucleoside hydrolase activity to block the purine salvage pathway of
T. b. brucei
and that, therefore, it is possible that UAMC-00363 acts on an additional target.
Disruption of theRickettsia rickettsiiSca2 Autotransporter Inhibits Actin-Based Motility
Authors: Kleba Betsy , Clark Tina R. , Lutter Erika I. , Ellison Damon W. , Hackstadt Ted 
Published: March 2010

ABSTRACTRickettsii rickettsii, the etiologic agent of Rocky Mountain spotted fever, replicates within the cytosol of infected cells and uses actin-based motility to spread inter- and intracellularly. Although the ultrastructure of the actin tail and host proteins associated with it are distinct from those ofListeriaorShigella, comparatively little is known regarding the rickettsial proteins involved in its organization. Here, we have used random transposon mutagenesis ofR. rickettsiito generate a small-plaque mutant that is defective in actin-based motility and does not spread directly from cell to cell as is characteristic of spotted fever group rickettsiae. The transposon insertion site of this mutant strain was within Sca2, a member of a family of large autotransporter proteins. Sca2 exhibits several features suggestive of its apparent role in actin-based motility. It displays an N-terminal secretory signal peptide, a C-terminal predicted autotransporter domain, up to four predicted Wasp homology 2 (WH2) domains, and two proline-rich domains, one with similarity to eukaryotic formins. In a guinea pig model of infection, the Sca2 mutant did not elicit fever, suggesting that Sca2 and actin-based motility are virulence factors of spotted fever group rickettsiae.
Interaction of Pneumococcal Histidine Triad Proteins with Human Complement
Authors: Melin Merit , Di Paolo Emmanuel , Tikkanen Leena , Jarva Hanna , Neyt Cecile , Käyhty Helena , Meri Seppo , Poolman Jan , Väkeväinen Merja 
Published: March 2010

ABSTRACTThe pneumococcal histidine triad (Pht) proteins PhtA, PhtB, PhtD, and PhtE form a group of conserved pneumococcal surface proteins. Humans produce antibodies to Pht proteins upon exposure to pneumococcus, and immunization of mice has provided protective immunity against sepsis and pneumonia and reduced nasopharyngeal colonization. Pht proteins are candidates for inclusion in multicomponent pneumococcal protein vaccines. Their biological function in pneumococcal infections is not clear, but a role in complement inhibition has been suggested. We measured complement deposition on wild-type and Pht mutant strains in four genetic backgrounds:Streptococcus pneumoniaeD39 (serotype 2) and R36A (unencapsulated derivative of D39) and strains of serotypes 3, 4, and 19F. PspA and PspC single and double mutants were compared to the wild-type and Pht-deficient D39 strains. Factor H binding was measured to bacterial cells, lysates, and protein antigens. Deletion of all four Pht proteins (Pht−) resulted in increased C3 deposition on the serotype 4 strain but not on the other strains. Pht antigens did not bind factor H, and deletion of Pht proteins did not affect factor H binding by bacterial lysates. The Pht−mutant serotype 4 strain bound slightly less factor H than the wild-type strain when binding was measured by flow cytometry. Pht proteins may play a role in immune evasion, but the mechanism of function is unlikely to be mediated by factor H binding. The relative contribution of Pht proteins to the inhibition of complement deposition is likely to be affected by the presence of other pneumococcal proteins and to depend on the genetic background.
Salmonella entericaSerovar Typhimurium-Induced Placental Inflammation and Not Bacterial Burden Correlates with Pathology and Fatal Maternal Disease
Authors: Chattopadhyay Anindita , Robinson Nirmal , Sandhu Jagdeep K. , Finlay B. Brett , Sad Subash , Krishnan Lakshmi 
Published: March 2010

ABSTRACTFood-borne infections caused bySalmonella entericaspecies are increasing globally, and pregnancy poses a high risk. Pregnant mice rapidly succumb toS. entericaserovar Typhimurium infection. To determine the mechanisms involved, we addressed the role of inflammation and bacterial burden in causing placental and systemic disease.In vitro, choriocarcinoma cells were a highly conducive niche for intracellularS.Typhimurium proliferation. While infection of mice withS.Typhimurium wild-type (WT) and mutant (ΔaroAand ΔinvA) strains led to profound pathogen proliferation and massive burden within placental cells, only the virulent WTS.Typhimurium infection evoked total fetal loss and adverse host outcome. This correlated with substantial placental expression of granulocyte colony-stimulating factor (G-CSF), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) and increased serum inflammatory cytokines/chemokines, such as G-CSF, IL-6, CCL1, and KC, evoked by WTS.Typhimurium infection. In contrast, infection with high doses ofS.Typhimurium ΔaroA, despite causing massive placental infection, resulted in reduced inflammatory cellular and cytokine response. WhileS.Typhimurium WT bacteria were dispersed in large numbers across all regions of the placenta, including the deeper labyrinth trophoblast,S.Typhimurium ΔaroAbacteria localized primarily to the decidua. This correlated with the widespread placental necrosis accompanied by neutrophil infiltration evoked by theS.Typhimurium WT bacteria. Thus, the ability ofSalmonellato localize to deeper layers of the placenta and the nature of inflammation triggered by the pathogen, rather than bacterial burden, profoundly influenced placental integrity and host survival.