bluuebunny/crossref_metadata_2025_split huggingface dataset:
Public‐service values and ethics: Dead end or strong foundation?
Authors: Heintzman Ralph 
Published: March 2008

Abstract: In the Winter 2004 issue of this journal, John Langford pronounced a negative verdict on the concern for public‐service values, which has been a feature of public‐service reform over the past decade. This article reconsiders Langford's arguments. It suggests that public‐service renewal requires ongoing attention to public‐service values but also a widening of perspectives. It is now necessary to give more attention to the organizational, professional and institutional conditions for sound individual behaviour. Renewed attention to public‐service values did not seek to supplant traditional approaches to individual decision‐making but rather to re‐frame them, grounded in the principles without which they cannot make sense of the world. The research literature on values and ethics contradicts the critique's main contentions. The critique is also based on a mistaken premise, false dichotomies, and inadequate and contradictory assumptions about the nature of individual decision‐making. Three points that are useful contributions to the ongoing dialogue on public‐service values and ethics are noted. But an individual perspective must now be augmented by a focus on organizational performance. Far from being a “dead end,” public‐service values remain the strong foundation – the only possible foundation – for the public service of the future.Sommaire: Le présent article réexamine celui de John Langford, publié dans le numéro d'hiver 2004, dans lequel il prononqait un verdict négatif sur la préoccupation au sujet des valeurs du service public qui a été un élément de la réforme de la fonction publique au cours de la dernière décennie. Une nouvelle attention portée aux valeurs du service public n'a pas cherchéà remplacer les approches traditionnelles concernant la prise de décisions, mais plutôt à les recadrer, à les faire reposer sur des principes sans lesquels le monde n'a pas de sens. La littérature de recherche sur les valeurs et l'éthique conrredit les principales allégations du critique et est également fondée sur des assomptions erronées et contradictoires au sujet de la nature de la prise de décision individuelle. Trois points qui représentent des contributions utiles au dialogue actuel sur les valeurs et l'éthique du service public sont mentionnés. Mais la perspective individuelle doit aussi avoir pour objectif la performance organisarionnelle. Loin d'être une « voie sans issue », les valeurs du service public restent le fondement solide – et en fait le seul fondement possible – du service public de l'avenir.
A Morpholino Oligomer Targeting Highly Conserved Internal Ribosome Entry Site Sequence Is Able To Inhibit Multiple Species of Picornavirus
Authors: Stone Jeffrey K. , Rijnbrand Rene , Stein David A. , Ma Yinghong , Yang Yan , Iversen Patrick L. , Andino Raul 
Published: March 2008

ABSTRACT

Members of the genera
Enterovirus
and
Rhinovirus
(family
Picornaviridae
) cause a wide range of human diseases. An established vaccine is available only for poliovirus, and no effective therapy is available for the treatment of infections caused by any pathogenic picornavirus. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) are single-stranded DNA-like antisense agents that readily enter cells. A panel of PPMO was tested for their antiviral activities against various picornaviruses. PPMO targeting conserved internal ribosome entry site (IRES) sequence were highly active against human rhinovirus type 14, coxsackievirus type B2, and poliovirus type 1 (PV1), reducing PV1 titers by up to 6 log
10
in cell cultures. Comparative sequence analysis led us to design a PPMO (EnteroX) targeting 22 nucleotides of IRES sequence that are perfectly conserved across greater than 99% of all human enteroviruses and rhinoviruses. EnteroX reduced PV1 replication in cell culture to an extent similar to that of other IRES-specific PPMO. Resistant PV1 arose in cell cultures after 12 passages in the presence of EnteroX and were found to have two mutations within the EnteroX target sequence. Nevertheless, cPVR transgenic mice treated once daily by intraperitoneal (i.p.) injection with EnteroX before and/or after i.p. infection with 3 × 10
8
PFU (three times the 50% lethal dose) of PV1 had an approximately 80% higher rate of survival than the controls. The viral titer in tissues taken at day 5 postinfection showed that animals in the EnteroX-treated group averaged over 3, 4, and 5 log
10
less virus in the small intestine, spinal cord, and brain, respectively, than the amount in the control animals. These results suggest that EnteroX may have broad therapeutic potential against entero- and rhinoviruses.
Phase I Dose-Escalation Study of a Monovalent Heat Shock Protein 70-Herpes Simplex Virus Type 2 (HSV-2) Peptide-Based Vaccine Designed To Prime or Boost CD8 T-Cell Responses in HSV-Naïve and HSV-2-Infected Subjects
Authors: Koelle David M. , Magaret Amalia , McClurkan Christopher L. , Remington Michael L. , Warren Terri , Teofilovici Florentina , Wald Anna 
Published: March 2008

ABSTRACTThis was a phase I study to assess the safety, tolerability, and immunogenicity of escalating doses of AG-702, a noncovalent complex of an HLA A*0201-restricted epitope in the glycoprotein B protein of herpes simplex virus type 2 (gB2) and truncated human constitutive heat shock protein 70. Similar vaccines have been immunogenic in animals. Three injections of 10 to 250 μg were administered intradermally to HLA A*0201-bearing subjects who were either herpes simplex virus type 2 (HSV-2)-infected or HSV uninfected. Sixty-two participants received the vaccine, 60 completed the protocol, and T-cell data were accrued for 56 subjects. The vaccine was safe and well tolerated. New or boosted responses to the HSV-2 CD8 epitope were not detected. Baseline responses to an epitope in virion proteins 13/14 were higher than responses to the gB2 epitope. A heat shock protein vaccine with an HSV-2 peptide appears to be safe at the doses studied in healthy adults with or without HSV infection. Modifications of the dose, adjuvant, route, schedule, or HSV antigen may be required to improve responses.
A Neutralizing Antibody to the A Chain of Abrin Inhibits Abrin Toxicity both In Vitro and In Vivo
Authors: Surendranath Kalpana , Karande Anjali A. 
Published: March 2008

ABSTRACTPlant ribosome-inactivating proteins (RIPs) are RNA N-glycosidases that inhibit protein synthesis in cells. Abrin, a type II RIP, is an AB type toxin, which is one of the most lethal types of toxin known. The B chain facilitates the entry of the molecule into the cell, whereas the A chain exerts the toxic effect. We have generated hybridomas secreting antibodies of the immunoglobulin G class specific to the recombinant A chain of abrin. One monoclonal antibody, namely, D6F10, rescued cells from abrin toxicity. Importantly, the antibody also protected mice from lethal doses of the toxin. The neutralizing effect of the antibody was shown to be due to interference with abrin attachment to the cell surface.
Kinesin Motor Domain ofLeishmania donovanias a Future Vaccine Candidate
Authors: Dey Ayan , Sharma Pawan , Redhu Naresh Singh , Singh Sarman 
Published: March 2008

ABSTRACTVisceral leishmaniasis (VL) is one of the important parasitic diseases, with approximately 350 million people at risk. Due to the nonavailability of an ideal drug, development of a safe, effective, and affordable vaccine could be a solution for control and prevention of this disease. The present study was carried out to examine the immunological potential of kinesin protein from the microtubule locus ofLeishmania donovanias a suitable vaccine candidate. In silico analysis of this region revealed clusters of major histocompatibility complex class I and II binding epitopes in its motor domain region. A recombinant protein was expressed from this region and named rLvacc. The antigenicity and immunogenicity studies of this protein by Western blot analysis revealed that rLvacc is strongly recognized by sera from acute VL patients. To evaluate its immunogenicity, peripheral blood mononuclear cells from cured VL patients were separated, and a lymphocyte proliferation assay was carried out in the presence of rLvacc. After lymphocyte proliferation, the pooled culture supernatant was assayed for anti-rLvacc antibody titers using an enzyme-linked immunosorbent assay. The results showed that immunoglobulin G2 (IgG2) subtype antibodies were predominant, while IgG1 subtype antibodies were produced in very low titers. On the basis of these ex vivo preliminary findings, its immunogenicity was studied in BALB/c mice. Vaccination with the DNA construct generated a good cellular immune response with significant increases in gamma interferon and interleukin-2 (IL-2) cytokine levels (Th1), but no increase in IL-4 levels (Th2). Taken together, our findings suggest the kinesin motor domain region ofL. donovanias a potential vaccine candidate against visceral leishmaniasis.
EmaA, a Potential Virulence Determinant of
Aggregatibacter actinomycetemcomitans
in Infective Endocarditis
Authors: Tang Gaoyan , Kitten Todd , Munro Cindy L. , Wellman George C. , Mintz Keith P. 
Published: March 2008

ABSTRACT

The gram-negative fastidious human oropharyngeal
Aggregatibacter actinomycetemcomitans
is implicated in the etiology of infective endocarditis. EmaA, an oligomeric coiled-coil adhesin homologous to YadA of
Yersinia enterocolitica
, was hypothesized to mediate the interaction of
A. actinomycetemcomitans
with collagen. Collagen, the most abundant protein in human bodies and the main component of extracellular matrix (ECM), predominates in the supporting tissue of cardiac valves. To extend our earlier studies using purified collagen to determine bacterial binding activities, we developed a tissue model using rabbit cardiac valves to investigate the interaction of
A. actinomycetemcomitans
with native collagen. The resected mitral valves, with or without removal of the endothelium, were incubated with equivalent numbers of the wild type and the isogenic
emaA
mutant defective in collagen binding. There was no difference in binding between the wild-type and the mutant strains when the endothelium remained intact. However, the
emaA
mutant was fivefold less effective than the wild-type strain in colonizing the exposed ECM. A 10-fold increase in the binding of the wild-type strain to ECM was observed compared with the intact endothelium. Similar observations were replicated in an in vivo endocarditis rabbit model; the
emaA
mutant was 10-fold less effective in the initial infection of the traumatized aortic valve. Colocalization studies indicated that
A. actinomycetemcomitans
bound to type I collagen.
A. actinomycetemcomitans
preferentially colonized the ECM and, together with the evidence that EmaA interacts with the native collagen, suggested that the adhesin is likely a potential virulence determinant of the bacterium in the initiation of infective endocarditis.
Staphylococcus aureus
CcpA Affects Biofilm Formation
Authors: Seidl Kati , Goerke Christiane , Wolz Christiane , Mack Dietrich , Berger-Bächi Brigitte , Bischoff Markus 
Published: March 2008

ABSTRACT

Biofilm formation in
Staphylococcus aureus
under in vitro growth conditions is generally promoted by high concentrations of sugar and/or salts. The addition of glucose to routinely used complex growth media triggered biofilm formation in
S. aureus
strain SA113. Deletion of
ccpA
, coding for the catabolite control protein A (CcpA), which regulates gene expression in response to the carbon source, abolished the capacity of SA113 to form a biofilm under static and flow conditions, while still allowing primary attachment to polystyrene surfaces. This suggested that CcpA mainly affects biofilm accumulation and intercellular aggregation.
trans
-Complementation of the mutant with the wild-type
ccpA
allele fully restored the biofilm formation. The biofilm produced by SA113 was susceptible to sodium metaperiodate, DNase I, and proteinase K treatment, indicating the presence of polysaccharide intercellular adhesin (PIA), protein factors, and extracellular DNA (eDNA). The investigation of several factors which were reported to influence biofilm formation in
S. aureus
(
arlRS
,
mgrA
,
rbf
,
sarA
,
atl
,
ica
,
citZ
,
citB
, and
cidABC
) showed that CcpA up-regulated the transcription of
cidA
, which was recently shown to contribute to eDNA production. Moreover, we showed that CcpA increased
icaA
expression and PIA production, presumably over the down-regulation of the tricarboxylic acid cycle genes
citB
and
citZ
.
TheChlamydia trachomatisPlasmid Is a Transcriptional Regulator of Chromosomal Genes and a Virulence Factor
Authors: Carlson John H. , Whitmire William M. , Crane Deborah D. , Wicke Luke , Virtaneva Kimmo , Sturdevant Daniel E. , Kupko John J. , Porcella Stephen F. , Martinez-Orengo Neysha , Heinzen Robert A. , Kari Laszlo , Caldwell Harlan D. 
Published: March 2008

ABSTRACTChlamydia trachomatispossesses a cryptic 7.5-kb plasmid of unknown function. Here, we describe a comprehensive molecular and biological characterization of the naturally occurring plasmidless humanC. trachomatisstrain L2(25667R). We found that despite minimal chromosomal polymorphisms, the LGV strain L2(25667R) was indistinguishable from plasmid-positive strain L2(434) with regard to its in vitro infectivity characteristics such as growth kinetics, plaquing efficiency, and plaque size. The only in vitro phenotypic differences between L2(434) and L2(25667R) were the accumulation of glycogen granules in the inclusion matrix and the lack of the typical intrainclusion Brownian-like movement characteristic ofC. trachomatisstrains. Conversely, we observed a marked difference between the two strains in their abilities to colonize and infect the female mouse genital tract. The 50% infective dose of plasmidless strain L2(25667R) was 400-fold greater (4 × 106inclusion-forming units [IFU]) than that of plasmid-bearing strain L2(434) (1 × 104IFU). Transcriptome analysis of the two strains demonstrated a decrease in the transcript levels of a subset of chromosomal genes for strain L2(25667R). Among those genes wasglgA, encoding glycogen synthase, a finding consistent with the failure of L2(25667R) to accumulate glycogen granules. These findings support a primary role for the plasmid in in vivo infectivity and suggest that virulence is controlled, at least in part, by the plasmid's ability to regulate the expression of chromosomal genes. Our findings have important implications in understanding a role for the plasmid in the pathogenesis of human infection and disease.
Burkholderia pseudomallei
Infection of T Cells Leads to T-Cell Costimulation Partially Provided by Flagellin
Authors: Ye Zhiyong , Lee Cheryl Mei Ling , Sun Guang Wen , Gan Yunn-Hwen 
Published: March 2008

ABSTRACT

Burkholderia pseudomallei
is the causative agent of melioidosis. While adaptive immunity has been shown to be important for host resistance to
B. pseudomallei
, the direct interaction of the bacteria with adaptive immune cells such as T and B cells is not well known. To address this question, we infected Jurkat T cells, as well as human primary CD4
+
and CD8
+
T cells, with live
B. pseudomallei
. We found that live bacterial infection could costimulate T cells to produce interleukin-2 (IL-2) and gamma interferon (IFN-γ) in the presence of anti-CD3 cross-linking antibodies. Bacterial supernatant could also costimulate T cells, and this was due to the presence of flagellin in the supernatant. However, T cells infected with bacterial mutants lacking flagellin showed strong impairment in IL-2 but only a slight impairment in IFN-γ production. When cross-linking of CD3 is replaced by IL-2, live bacterial infection was still able to costimulate human primary T cells to produce IFN-γ and flagellin is only a minor ligand contributing to this costimulation. Thus, live
B. pseudomallei
could potentially costimulate T cells not only in an antigen-specific manner but also in a nonspecific manner through bystander activation via IL-2.
Dominant Role of Paraoxonases in Inactivation of the
Pseudomonas aeruginosa
Quorum-Sensing Signal
N
-(3-Oxododecanoyl)-
l
-Homoserine Lactone
Authors: Teiber John F. , Horke Sven , Haines Donovan C. , Chowdhary Puneet K. , Xiao Junhui , Kramer Gerald L. , Haley Robert W. , Draganov Dragomir I. 
Published: March 2008

ABSTRACT

The pathogenic bacterium
Pseudomonas aeruginosa
causes serious infections in immunocompromised patients.
N
-(3-Oxododecanoyl)-
l
-homoserine lactone (3OC12-HSL) is a key component of
P
.
aeruginosa
's quorum-sensing system and regulates the expression of many virulence factors. 3OC12-HSL was previously shown to be hydrolytically inactivated by the paraoxonase (PON) family of calcium-dependent esterases, consisting of PON1, PON2, and PON3. Here we determined the specific activities of purified human PONs for 3OC12-HSL hydrolysis, including the common PON1 polymorphic forms, and found they were in the following order: PON2 ≫ PON1
192R
> PON1
192Q
> PON3. PON2 exhibited a high specific activity of 7.6 ± 0.4 μmols/min/mg at 10 μM 3OC12-HSL, making it the best PON2 substrate identified to date. By use of class-specific inhibitors, approximately 85 and 95% of the 3OC12-HSL lactonase activity were attributable to PON1 in mouse and human sera, respectively. In mouse liver homogenates, the activity was metal dependent, with magnesium- and manganese-dependent lactonase activities comprising 10 to 15% of the calcium-dependent activity. In mouse lung homogenates, all of the activity was calcium dependent. The calcium-dependent activities were irreversibly inhibited by extended EDTA treatment, implicating PONs as the major enzymes inactivating 3OC12-HSL. In human HepG2 and EA.hy 926 cell lysates, the 3OC12-HSL lactonase activity closely paralleled the PON2 protein levels after PON2 knockdown by small interfering RNA treatment of the cells. These findings suggest that PONs, particularly PON2, could be an important mechanism by which 3OC12-HSL is inactivated in mammals.
Optimizing Screening for Acute Human Immunodeficiency Virus Infection with Pooled Nucleic Acid Amplification Tests
Authors: Westreich Daniel J. , Hudgens Michael G. , Fiscus Susan A. , Pilcher Christopher D. 
Published: March 2008

ABSTRACT
Recent studies have shown the public health importance of identifying individuals with acute human immunodeficiency virus infection (AHI); however, the cost of nucleic acid amplification testing (NAAT) makes individual testing of at-risk individuals prohibitively expensive in many settings. Pooled NAAT (or group testing) can improve efficiency and test performance of testing for AHI, but optimizing the pooling algorithm can be difficult. We developed simple, flexible biostatistical models of specimen pooling with NAAT for the identification of AHI cases; these models incorporate group testing theory, operating characteristics of biological assays, and a model of viral dynamics during AHI. Pooling algorithm sensitivity, efficiency (test kits used per individual specimen evaluated), and positive predictive value (PPV) were modeled and compared for three simple pooling algorithms: two-stage minipools (D2), three-stage hierarchical pools (D3), and square arrays with master pools (A2m). We confirmed the results by stochastic simulation and produced reference tables and a Web calculator to facilitate pooling by investigators without specific biostatistical expertise. All three pooling strategies demonstrated improved efficiency and PPV for AHI case detection compared to individual NAAT. D3 and A2m algorithms generally provided better efficiency and PPV than D2; additionally, A2m generally exhibited better PPV than D3. Used selectively and carefully, the simple models developed here can guide the selection of a pooling algorithm for the detection of AHI cases in a wide variety of settings.
Assessing Proficiency of Interpretation of Rapid Human Immunodeficiency Virus Assays in Nonlaboratory Settings: Ensuring Quality of Testing
Authors: Learmonth Kate M. , McPhee Dale A. , Jardine Darren K. , Walker Sandy K. , Aye Thein-Thein , Dax Elizabeth M. 
Published: March 2008

ABSTRACT

Rapid antibody tests for the detection of human immunodeficiency virus (HIV) offer an effective means of providing a timely result of HIV serostatus to individuals. The increased use of rapid HIV antibody tests outside the laboratory has highlighted the need for new, cost-effective quality assurance methods to be developed for use in nonlaboratory-based and resource-limited settings. Photographed rapid HIV test results were used in a modified external quality assessment scheme to assess the interpretation proficiency and, therefore, to assess the feasibility of using this method as a basis for a quality assessment program for nonlaboratory-based testing. Participants (
n
= 148), both experienced and inexperienced in the performance and interpretation of rapid HIV testing, interpreted the photographed results of five rapid HIV assays. These were scored according to the degree of technical discordance. Error scores were grouped according to each participant's technical experience. The accuracy of interpretation for four of the five assays was between 80 and 97%, indicating that the photographed results of samples, including those difficult to read or borderline difficult to read, can be used to assess the proficiency of test operators in interpreting results. Participants had greater difficulty in interpreting samples of weak reactivity; this was consistent across the five assays. Experience played an important role in accurate interpretation, with experienced laboratory participants exhibiting greater proficiency (
P
< 0.05) in interpreting the results of three of the five rapid HIV assays. It was established that photographed results of rapid HIV assays could be interpreted with accuracy and demonstrated that prior experience resulted in a more accurate interpretation performance.
Automated and Manual Methods of DNA Extraction for
Aspergillus fumigatus
and
Rhizopus oryzae
Analyzed by Quantitative Real-Time PCR
Authors: Francesconi Andrea , Kasai Miki , Harrington Susan M. , Beveridge Mara G. , Petraitiene Ruta , Petraitis Vidmantas , Schaufele Robert L. , Walsh Thomas J. 
Published: March 2008

ABSTRACT

Quantitative real-time PCR (qPCR) may improve the detection of fungal pathogens. Extraction of DNA from fungal pathogens is fundamental to optimization of qPCR; however, the loss of fungal DNA during the extraction process is a major limitation to molecular diagnostic tools for pathogenic fungi. We therefore studied representative automated and manual extraction methods for
Aspergillus fumigatus
and
Rhizopus oryzae
. Both were analyzed by qPCR for their ability to extract DNA from propagules and germinated hyphal elements (GHE). The limit of detection of
A. fumigatus
and
R. oryzae
GHE in bronchoalveolar lavage (BAL) fluid with either extraction method was 1 GHE/ml. Both methods efficiently extracted DNA from
A. fumigatus
, with a limit of detection of 1 × 10
2
conidia. Extraction of
R. oryzae
by the manual method resulted in a limit of detection of 1 × 10
3
sporangiospores. However, extraction with the automated method resulted in a limit of detection of 1 × 10
1
sporangiospores. The amount of time to process 24 samples by the automated method was 2.5 h prior to transferring for automation, 1.3 h of automation, and 10 min postautomation, resulting in a total time of 4 h. The total time required for the manual method was 5.25 h. The automated and manual methods were similar in sensitivity for DNA extraction from
A. fumigatus
conidia and GHE. For
R. oryzae
, the automated method was more sensitive for DNA extraction of sporangiospores, while the manual method was more sensitive for GHE in BAL fluid.