bluuebunny/crossref_metadata_2025_split huggingface dataset:
Administration at the Supreme Court of Canada: Challenges and change in the Charter era
Authors: Macfarlane Emmett 
Published: April 2009

Abstract:This article presents a descriptive account of administration at the Supreme Court of Canada. Since 1975, the Court has gained considerable control over its docket, attained administrative independence from the federal Department of Justice and seen its role transformed following the enactment of the Charter of Rights. This new context has brought a host of challenges, requiring procedural reforms and adaptation to technological developments to ensure institutional efficiency. The institution's role under the Charter has also enhanced its public prominence, placing normative pressure on the Court to enact measures to increase transparency, particularly with regards to its relationship with the media. Drawing on interviews with former justices and Court staff members, as well as secondary material, this article examines these changes and their implications.Sommaire :Cet article décrit l'administration de la Cour Suprême du Canada. Depuis 1975, la Cour a considérablement augmenté le contrôle de son registre, a acquis une indépendance administrative par rapport au ministère fédéral de la Justice et a vu son rôle se transformer suite à l'adoption de la Charte des droits et libertés. Ce nouveau contexte a apporté pléthore de défis, exigeant à la fois des réformes procédurales et une adaptation aux changements technologiques afin d'assurer son efficacité institutionnelle. L'adoption de la Charte a aussi augmenté le profil de la Cour auprès de la population, en exerçant une pression normative et en l'obligeant à adopter des mesures supplémentaires pour accroître sa transparence, en particulier en ce qui concerne son rapport avec les médias. En s'appuyant sur des entrevues avec d'anciens juges et membres du personnel de la Cour et d'autres documents, cet article examine ces changements et leurs implications.
Wittgenstein's Rule‐Following Considerations and Moral Particularism
Authors: LOTFI SHIDAN 
Published: April 2009

AbstractMoral particularists have seen Wittgenstein as a close ally. One of the main reasons for this is that particularists such as Jonathan Dancy and John McDowell have argued that Wittgenstein's so‐called “rule‐following considerations” (RFCs) provide support for their skepticism about the existence and/or role of rules and principles in ethics. In this paper, I show that while Wittgenstein's RFCs challenge the notion that competence with language, i.e., the ability to apply concepts properly, is like mechanically following a rule, he does not reject the idea that there are rules that govern proper use of language. I then argue that while the RFCs may, at best, support a weak form of particularism that denies that moral competence is dependent on an explicit grasp of rules, they do not support a stronger version of particularism that denies that there are any true rules or principles in ethics.
Epistemic Supervenience and Internalism: A Trilemma
Authors: RULOFF COLIN 
Published: April 2009

AbstractEpistemic Internalism (EI) is the claim that an agent S is justified in believing that p at a time t iff S has either an actual or potential direct awareness of the grounds or properties that confer justification on p at t. In this paper I argue that EI does not provide the proponent of EI with an intuitively clear analysis of epistemic justification. More exactly, after identifying two different versions of EI – a weak version and a strong version – I offer some general considerations for thinking that neither the weak version nor the strong version provides the proponent of EI with a plausible analysis of epistemic justification and conclude, therefore, that EI itself cannot be considered a plausible analysis of epistemic justification.
Nonhuman Primates Are Protected from Smallpox Virus or Monkeypox Virus Challenges by the Antiviral Drug ST-246
Authors: Huggins John , Goff Arthur , Hensley Lisa , Mucker Eric , Shamblin Josh , Wlazlowski Carly , Johnson Wendy , Chapman Jennifer , Larsen Tom , Twenhafel Nancy , Karem Kevin , Damon Inger K. , Byrd Chelsea M. , Bolken Tove' C. , Jordan Robert , Hruby Dennis 
Published: April 2009

ABSTRACT
ST-246, a potent orthopoxvirus egress inhibitor, is safe and effective at preventing disease and death in studies of small-animal models involving challenge by several different pathogenic poxviruses. In this report, the antiviral efficacy of ST-246 in treatment of nonhuman primates infected with variola virus or monkeypox virus was assessed. The data indicate that oral dosing once per day with ST-246 protects animals from poxvirus disease, as measured by reductions in viral load and numbers of lesions and enhancement of survival.
Assessment of Malaria In Vitro Drug Combination Screening and Mixed-Strain Infections Using the Malaria Sybr Green I-Based Fluorescence Assay
Authors: Co Edgie-Mark A. , Dennull Richard A. , Reinbold Drew D. , Waters Norman C. , Johnson Jacob D. 
Published: April 2009

ABSTRACT

Several drug development strategies, including optimization of new antimalarial drug combinations, have been used to counter malaria drug resistance. We evaluated the malaria Sybr green I-based fluorescence (MSF) assay for its use in in vitro drug combination sensitivity assays. Drug combinations of previously published synergistic (atovaquone and proguanil), indifferent (chloroquine and azithromycin), and antagonistic (chloroquine and atovaquone) antimalarial drug interactions were tested against
Plasmodium falciparum
strains D6 and W2 using the MSF assay. Fifty percent inhibitory concentrations (IC
50
s) were calculated for individual drugs and in fixed ratio combinations relative to their individual IC
50
s. Subsequent isobologram analysis and fractional inhibitory concentration determinations demonstrated the expected drug interaction pattern for each combination tested. Furthermore, we explored the ability of the MSF assay to examine mixed parasite population dynamics, which are commonly seen in malaria patient isolates. Specifically, the capacity of the MSF assay to discern between single and mixed parasite populations was determined. To simulate mixed infections in vitro, fixed ratios of D6 and W2 strains were cocultured with antimalarial drugs and IC
50
s were determined using the MSF assay. Dichotomous concentration curves indicated that the sensitive and resistant parasites composing the genetically heterogeneous population were detectable. Biphasic analysis was performed to obtain subpopulation IC
50
s for comparison to those obtained for the individual malaria strains alone. In conclusion, the MSF assay allows for reliable antimalarial drug combination screening and provides an important method to discern between homogenous and heterogeneous parasite populations.
High-Throughput Screening Identifies Novel Inhibitors of the Acetyltransferase Activity of
Escherichia coli
GlmU
Authors: Pereira Mark P. , Blanchard Jan E. , Murphy Cecilia , Roderick Steven L. , Brown Eric D. 
Published: April 2009

ABSTRACT

The bifunctional GlmU protein catalyzes the formation of UDP-
N
-acetylglucosamine in a two-step reaction using the substrates glucosamine-1-phosphate, acetyl coenzyme A, and UTP. This metabolite is a common precursor to the synthesis of bacterial cell surface carbohydrate polymers, such as peptidoglycan, lipopolysaccharide, and wall teichoic acid that are involved in the maintenance of cell shape, permeability, and virulence. The C-terminal acetyltransferase domain of GlmU exhibits structural and mechanistic features unique to bacterial UDP-
N
-acetylglucosamine synthases, making it an excellent target for antibacterial design. In the work described here, we have developed an absorbance-based assay to screen diverse chemical libraries in high throughput for inhibitors to the acetyltransferase reaction of
Escherichia coli
GlmU. The primary screen of 50,000 drug-like small molecules identified 63 hits, 37 of which were specific to acetyltransferase activity of GlmU. Secondary screening and mode-of-inhibition studies identified potent inhibitors where compound binding within the acetyltransferase active site was requisite on the presence of glucosamine-1-phosphate and were competitive with the substrate acetyl coenzyme A. These molecules may represent novel chemical scaffolds for future antimicrobial drug discovery. In addition, this work outlines the utility of catalytic variants in targeting specific activities of bifunctional enzymes in high-throughput screens.
Pharmacokinetics of Nikkomycin Z after Single Rising Oral Doses
Authors: Nix David E. , Swezey Robert R. , Hector Richard , Galgiani John N. 
Published: April 2009

ABSTRACT

Nikkomycin Z is an antifungal drug that inhibits chitin synthase. This agent is under development as an orphan product for treatment of coccidioidomycosis. Safety and pharmacokinetics of nikkomycin Z were evaluated in healthy male subjects following single, rising oral doses ranging from 250 mg to 2,000 mg. A total of 12 subjects were recruited and divided into two groups. Group 1 (
n
= 6) received two out of three doses of 250 mg, 1,000 mg, or 1,750 mg and a placebo randomly in place of one of the doses. Group 2 (
n
= 6) received two out of three doses of 500 mg, 1,500 mg, or 2,000 mg and a placebo in place of one of the doses. Subjects were confined to the study unit overnight prior to dosing, and 12 blood samples were collected over 24 h postdosing while subjects were confined. Subjects returned for additional blood samples and safety evaluations at 48 h and 72 h after each dose. There was a 2-week washout period between doses. Plasma drug concentrations were determined using a validated high-performance liquid chromatography method. Nikkomycin Z was absorbed after oral administration, reaching a maximum concentration in serum of 2.21 μg/ml at 2 h postdose and an area under the concentration-time curve from 0 h to infinity of 11.3 μg·h/ml for the 250-mg dose. Pharmacokinetics appeared linear over the range of 250 to 500 mg; however, relative bioavailability was about 62 to 70% for the 1,000-mg dose and 42 to 47% for doses between 1,500 and 2,000 mg. The mean terminal half-life ranged from 2.1 to 2.5 h and was independent of dose. No serious or dose-related adverse events were observed. This study provides a basis for pharmacokinetic simulations and continued studies of nikkomycin Z administered in multiple doses.
Susceptibility of Highly Pathogenic H5N1 Influenza Viruses to the Neuraminidase Inhibitor Oseltamivir Differs In Vitro and in a Mouse Model
Authors: Govorkova Elena A. , Ilyushina Natalia A. , McClaren Jennifer L. , Naipospos Tri S. P. , Douangngeun Bounlom , Webster Robert G. 
Published: April 2009

ABSTRACTWhile the neuraminidase (NA) inhibitor oseltamivir is currently our first line of defense against a pandemic threat, there is little information about whether in vitro testing can predict the in vivo effectiveness of antiviral treatment. Using a panel of five H5N1 influenza viruses (H5 clades 1 and 2), we determined that four viruses were susceptible to the drug in vitro (mean 50% inhibitory concentration [IC50], 0.1 to 4.9 nM), and A/Turkey/65-1242/06 virus was slightly less susceptible (mean IC50, 10.8 nM). Two avian viruses showed significantly greater NA enzymatic activity (Vmax) than the human viruses, and the five viruses varied in their affinity for the NA substrate MUNANA (Km, 64 to 300 μM) and for oseltamivir carboxylate (Ki, 0.1 to 7.9 nM). The protection of mice provided by a standard oseltamivir regimen (20 mg/kg/day for 5 days) also varied among the viruses used. We observed (i) complete protection against the less virulent A/chicken/Jogjakarta/BBVET/IX/04 virus; (ii) moderate protection (60 to 80% survival) against three viruses, two of which are neurotropic; and (iii) no protection against A/Turkey/65-1242/06 virus, which induced high pulmonary expression of proinflammatory mediators (interleukin-1α [IL-1α], IL-6, alpha interferon, and monocyte chemotactic protein 1) and contained a minor subpopulation of drug-resistant clones (I117V and E119A NA mutations). We found no correlation between in vitro susceptibility and in vivo protection (Spearman rank correlation coefficient ρ = −0.1;P> 0.05). Therefore, the in vivo efficacy of oseltamivir against highly pathogenic H5N1 influenza viruses cannot be reliably predicted by susceptibility testing, and more prognostic ways to evaluate anti-influenza compounds must be developed. Multiple viral and host factors modulate the effectiveness of NA inhibitor regimens against such viruses and new, more consistently effective treatment options, including combination therapies, are needed.
Genome-Scale Model of
Streptococcus thermophilus
LMG18311 for Metabolic Comparison of Lactic Acid Bacteria
Authors: Pastink Margreet I. , Teusink Bas , Hols Pascal , Visser Sanne , de Vos Willem M. , Hugenholtz Jeroen 
Published: April 2009

ABSTRACT

In this report, we describe the amino acid metabolism and amino acid dependency of the dairy bacterium
Streptococcus thermophilus
LMG18311 and compare them with those of two other characterized lactic acid bacteria,
Lactococcus lactis
and
Lactobacillus plantarum
. Through the construction of a genome-scale metabolic model of
S. thermophilus
, the metabolic differences between the three bacteria were visualized by direct projection on a metabolic map. The comparative analysis revealed the minimal amino acid auxotrophy (only histidine and methionine or cysteine) of
S. thermophilus
LMG18311 and the broad variety of volatiles produced from amino acids compared to the other two bacteria. It also revealed the limited number of pyruvate branches, forcing this strain to use the homofermentative metabolism for growth optimization. In addition, some industrially relevant features could be identified in
S. thermophilus
, such as the unique pathway for acetaldehyde (yogurt flavor) production and the absence of a complete pentose phosphate pathway.
Phenotypic Diversity of Infectious Red Sea Bream Iridovirus Isolates from Cultured Fish in Japan
Authors: Shinmoto Hajime , Taniguchi Ken , Ikawa Takuya , Kawai Kenji , Oshima Syun-ichirou 
Published: April 2009

ABSTRACT

Megalocytivirus
is causing economically serious mass mortality by infecting fish in and around the Pacific region of Asia. The recent emergence of many new iridoviruses has drawn attention to the marked taxonomic variation within this virus family. Most studies of these viruses have not included extensive study of these emergent species. We explored the emergence of red sea bream iridovirus (RSIV) on a fish farm in Japan, and we specifically endeavored to quantify genetic and phenotypic differences between RSIV isolates using in vitro and in vivo methods. The three isolates had identical major capsid protein sequences, and they were closely related to Korean RSIV isolates. In vitro studies revealed that the isolates differed in replication rate, which was determined by real-time quantitative PCR of viral genomes in infected cells and cell culture supernatant, and in cell viability, estimated by the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay for infected cells. In vivo studies showed that the isolates exhibit different virulence characteristics: infected red sea bream showed either acute death or subacute death according to infection with different isolates. Significant differences were seen in the antigenicity of isolates by a formalin-inactivated vaccine test. These results revealed that variant characteristics exist in the same phylogenetic location in emergent iridoviruses. We suggest that this strain variation would expand the host range in iridoviral epidemics.
Diversity and Distribution of
Anaeromyxobacter
Strains in a Uranium-Contaminated Subsurface Environment with a Nonuniform Groundwater Flow
Authors: Thomas Sara H. , Padilla-Crespo Elizabeth , Jardine Phillip M. , Sanford Robert A. , Löffler Frank E. 
Published: April 2009

ABSTRACT

Versaphilic
Anaeromyxobacter dehalogenans
strains implicated in hexavalent uranium reduction and immobilization are present in the fractured saprolite subsurface environment at the U.S. Department of Energy Integrated Field-Scale Subsurface Research Challenge (IFC) site near Oak Ridge, TN. To provide insight into the in situ distribution of
Anaeromyxobacter
strains in this system with a nonuniform groundwater flow, 16S rRNA gene-targeted primers and linear hybridization (TaqMan) probes were designed for Oak Ridge IFC
Anaeromyxobacter
isolates FRC-D1 and FRC-W, along with an
Anaeromyxobacter
genus-targeted probe and primer set. Multiplex quantitative real-time PCR (mqPCR) was applied to samples collected from Oak Ridge IFC site areas 1 and 3, which are not connected by the primary groundwater flow paths; however, transport between them through cross-plane fractures is hypothesized. Strain FRC-W accounted for more than 10% of the total quantifiable
Anaeromyxobacter
community in area 1 soils, while strain FRC-D1 was not detected. In FeOOH-amended enrichment cultures derived from area 1 site materials, strain FRC-D1 accounted for 30 to 90% of the total
Anaeromyxobacter
community, demonstrating that this strain was present in situ in area 1. The area 3 total
Anaeromyxobacter
abundance exceeded that of area 1 by 3 to 5 orders of magnitude, but neither strain FRC-W- nor FRC-D1-like sequences were quantifiable in any of the 33 area 3 groundwater or sediment samples tested. The
Anaeromyxobacter
community in area 3 increased from <10
5
cells/g sediment outside the ethanol biostimulation treatment zone to 10
8
cells/g sediment near the injection well, and 16S rRNA gene clone library analysis revealed that representatives of a novel phylogenetic cluster dominated the area 3
Anaeromyxobacter
community inside the treatment loop. The combined applications of genus- and strain-level mqPCR approaches along with clone libraries provided novel information on patterns of microbial variability within a bacterial group relevant to uranium bioremediation.
Insect-Specific Polyketide Synthases (PKSs), Potential PKS-Nonribosomal Peptide Synthetase Hybrids, and Novel PKS Clades in Tropical Fungi
Authors: Amnuaykanjanasin Alongkorn , Phonghanpot Suranat , Sengpanich Nattapong , Cheevadhanarak Supapon , Tanticharoen Morakot 
Published: April 2009

ABSTRACT

Polyketides draw much attention because of their potential use in pharmaceutical and biotechnological applications. This study identifies an abundant pool of polyketide synthase (PKS) genes from local isolates of tropical fungi found in Thailand in three different ecological niches: insect pathogens, marine inhabitants, and lichen mutualists. We detected 149 PKS genes from 48 fungi using PCR with PKS-specific degenerate primers. We identified and classified 283 additional PKS genes from 13 fungal genomes. Phylogenetic analysis of all these PKS sequences the comprising ketosynthase (KS) conserved region and the KS-acyltransferase interdomain region yielded results very similar to those for phylogenies of the KS domain and suggested a number of remarkable points. (i) Twelve PKS genes amplified from 12 different insect-pathogenic fungi form a tight cluster, although along with two PKS genes extracted from genomes of
Aspergillus niger
and
Aspergillus terreus
, in reducing clade III. Some of these insect-specific fungal PKSs are nearly identical. (ii) We identified 38 new PKS-nonribosomal peptide synthetase hybrid genes in reducing clade II. (iii) Four distinct clades were discovered with more than 75% bootstrap support. We propose to designate the novel clade D1 with 100% bootstrap support “reducing clade V.” The newly cloned PKS genes from these tropical fungi should provide useful and diverse genetic resources for future research on the characterization of polyketide compounds synthesized by these enzymes.
Gene Expression Induced in
Escherichia coli
O157:H7 upon Exposure to Model Apple Juice
Authors: Bergholz Teresa M. , Vanaja Sivapriya Kailasan , Whittam Thomas S. 
Published: April 2009

ABSTRACT

Escherichia coli
O157:H7 has caused serious outbreaks of food-borne illness via transmission in a variety of food vehicles, including unpasteurized apple juice, dried salami, and spinach. To understand how this pathogen responds to the multiple stresses of the food environment, we compared global transcription patterns before and after exposure to model apple juice. Transcriptomes of mid-exponential- and stationary-phase cells were evaluated after 10 min in model apple juice (pH 3.5) using microarrays probing 4,886 open reading frames. A total of 331 genes were significantly induced upon exposure of cells to model apple juice, including genes involved in the acid, osmotic, and oxidative stress responses as well as the envelope stress response. Acid and osmotic stress response genes, including
asr, osmC, osmB
, and
osmY
, were significantly induced in response to model apple juice. Multiple envelope stress responses were activated as evidenced by increased expression of CpxR and Rcs phosphorelay-controlled genes. Genes controlled by CpxR (
cpxP, degP
, and
htpX
) were significantly induced 2- to 15-fold upon exposure to apple juice. Inactivation of CpxRA resulted in a significant decrease in survival of O157:H7 in model apple juice compared to the isogenic parent strain. Of the 331 genes induced in model apple juice, 104 are O157-specific genes, including those encoding type three secretion effectors (
espJ, espB, espM2, espL3
, and
espZ
). Elucidating the response of O157:H7 to acidic foods provides insight into how this pathogen is able to survive in food matrices and how exposure to foods influences subsequent transmission and virulence.
Bacillus anthracisEdema Toxin Impairs Neutrophil Actin-Based Motility
Authors: Szarowicz Sarah E. , During Russell L. , Li Wei , Quinn Conrad P. , Tang Wei-Jen , Southwick Frederick S. 
Published: April 2009

ABSTRACTInhalation anthrax results in high-grade bacteremia and is accompanied by a delay in the rise of the peripheral polymorphonuclear neutrophil (PMN) count and a paucity of PMNs in the infected pleural fluid and mediastinum. Edema toxin (ET) is one of the majorBacillus anthracisvirulence factors and consists of the adenylate cyclase edema factor (EF) and protective antigen (PA). Relatively low concentrations of ET (100 to 500 ng/ml of PA and EF) significantly impair human PMN chemokinesis, chemotaxis, and ability to polarize. These changes are accompanied by a reduction in chemoattractant-stimulated PMN actin assembly. ET also causes a significant decrease inListeria monocytogenesintracellular actin-based motility within HeLa cells. These defects in actin assembly are accompanied by a >50-fold increase in intracellular cyclic AMP and a >4-fold increase in the phosphorylation of protein kinase A. We have previously shown that anthrax lethal toxin (LT) also impairs neutrophil actin-based motility (R. L. During, W. Li, B. Hao, J. M. Koenig, D. S. Stephens, C. P. Quinn, and F. S. Southwick, J. Infect. Dis. 192:837-845, 2005), and we now find that LT combined with ET causes an additive inhibition of PMN chemokinesis, polarization, chemotaxis, and FMLP (N-formyl-met-leu-phe)-induced actin assembly. We conclude that ET alone or combined with LT impairs PMN actin assembly, resulting in paralysis of PMN chemotaxis.