bluuebunny/crossref_metadata_2025 huggingface dataset:
Management Control Systems in a Non‐Enterprise Network: The Greenhouse Gas Protocol Initiative
Authors: Sundin Heidi , Brown David , Wakefield James , Ranganathan Janet
Published: May 2009

This article is based on the action research project of a multi‐stakeholder collaboration formed to produce the Greenhouse Gas Protocol. This non‐enterprise cross‐sector collaboration had two sets of problems: the first being the ideological differences of the stakeholders, who had differing interests and agendas regarding the production of standards. The second set relates to the practical problems of enabling 300 people from different organisations and time zones, with different levels of resource access and no clear financial goal or endpoint, to work together. To overcome these issues three types of management control systems were developed: strong planning processes, administrative and governance structures, and socio‐ideological controls. The result of the collaboration is a set of greenhouse gas accounting standards that have widespread acceptance internationally. This study contributes to both practice and research on management control systems (MCS) by outlining how alternative forms of MCS can be designed for non‐enterprise cross‐sector collaboration.
Controlling International Joint Ventures: An Investigation of Australian Parent Partners
Authors: Giacobbe Francesco , Booth Peter
Published: May 2009

International joint ventures (IJVs) are an important modern organisational form, with their complexity presenting significant management and control issues. Our research uses a cross‐sectional survey of Australian parent partners of IJVs to provide insights into the characteristics of Australian companies and their IJVs, performance outcomes and choices of parent partners management control systems (MCS) design in terms of operational areas they seek to control (focus), the extent to which they exercise control (extent) and the mechanisms of control used (formal and informal). Australian parent partners of IJVs generally are, partnering in countries close to Australia in the Asia‐Pacific, in activities similar to those they undertake in Australia, contributing a significant amount of resources, but overall have only limited IJV experience. Australian parent partners focus on a limited set of controls, often with tighter formalised control structures. Finally, overall they are satisfied with the performance of their IJVs, with higher satisfaction for organisational learning and product/customer dimensions than financial performance.
Accounting for SGARAs: Towards Comparability and Consistency
Authors: Williams Belinda , Wilmshurst Trevor
Published: May 2009

The objectives of this study were to examine whether consistency and comparability has been achieved through the introduction of AASB 1037 and the subsequent adoption of AASB 141. We find that consistency in measurement methods has not been achieved through the introduction of a prescribed accounting method under AASB 1037 and is not likely to be achieved through the application of AASB 141. Consistency was found however in the application of measurement methods over time and, in particular, in these SGARA types of native forests and plantation timber. The study contributes to an understanding of the issues faced by Australian firms surrounding the processes leading to the introduction of a new accounting standard.
Mandatory Adoption of IASB Standards: Value Relevance and Country‐Specific Factors
Authors: Morais Ana Isabel , Curto José Dias
Published: May 2009

The objective of this study is to investigate if the value relevance of European‐listed companies increased after the mandatory application of International Accounting Standards (IAS)/International Financial Reporting Standards (IFRS) and how the value relevance of accounting information prepared under IAS/IFRS is shaped by the specific factors of the country in which companies are domiciled. Results show that the value relevance of financial information during the period companies applied mandatory IAS/IFRS is higher than for the period during which they applied local accounting standards. We also found that countries where accounting and tax are clearly separated show more relevant accounting information. Finally, we found that companies from countries with more legal and public enforcement mechanisms disclose less relevant accounting information under IAS/IFRS.
New roles of calsequestrin and triadin in cardiac muscle
Authors: Knollmann Björn C.
Published: May 2009

Cardiac calsequestrin (Casq2) and triadin are proteins located in specialized areas of the sarcoplasmic reticulum (SR) where the SR forms junctions with the sarcolemma (junctional SR). Casq2, triadin and junctin form a protein complex that is associated with cardiac ryanodine receptor 2 (RyR2) SR Ca2+ release channels. This review highlights new insights of the roles of triadin and Casq2 derived from gene‐targeted knock‐out and knock‐in mouse models that have recently become available. Characterization of the mouse models suggests that Casq2's contribution to SR Ca2+ storage and release during excitation–contraction coupling is largely dispensable. Casq2's primary role appears to be in protecting the heart against premature Ca2+ release and triggered arrhythmias. Furthermore, both cardiac Casq2 and triadin are important for the structural organization of the SR, which had previously not been recognized. In particular, ablation of triadin causes a 50% reduction in the extent of the junctional SR, which results in impaired excitation–contraction coupling at the level of the myocyte. While catecholamines could normalize contractile function by increasing ICa and SR Ca2+ content, it comes at the price of an increased risk for spontaneous Ca2+ releases in triadin knock‐out myocytes and catecholamine‐induced ventricular arrhythmias in triadin knock‐out mice.
Placental efficiency and adaptation: endocrine regulation
Authors: Fowden A. L. , Sferruzzi‐Perri A. N. , Coan P. M. , Constancia M. , Burton G. J.
Published: May 2009

Size at birth is critical in determining life expectancy and is dependent primarily on the placental supply of nutrients. However, the fetus is not just a passive recipient of nutrients from the placenta. It exerts a significant acquisitive drive for nutrients, which acts through morphological and functional adaptations in the placenta, particularly when the genetically determined drive for fetal growth is compromised by adverse intrauterine conditions. These adaptations alter the efficiency with which the placenta supports fetal growth, which results in optimal growth for prevailing conditions in utero. This review examines placental efficiency as a means of altering fetal growth, the morphological and functional adaptations that influence placental efficiency and the endocrine regulation of these processes.
Trypanocidal Activity of 8-Methyl-5′-{[(
Z
)-4-Aminobut-2-enyl]-(Methylamino)}Adenosine (Genz-644131), an Adenosylmethionine Decarboxylase Inhibitor
Authors: Bacchi Cyrus J. , Barker Robert H. , Rodriguez Aixa , Hirth Bradford , Rattendi Donna , Yarlett Nigel , Hendrick Clifford L. , Sybertz Edmund
Published: May 2009

Genzyme 644131, 8-methyl-5′-{[(
Z
)-4-aminobut-2-enyl](methylamino)}adenosine, is an analog of the enzyme activated
S
-adenosylmethionine decarboxylase (AdoMetDC) inhibitor and the trypanocidal agent MDL-7381, 5-{[(
Z
)-4-aminobut-2-enyl](methylamino)}adenosine. The analog differs from the parent in having an 8-methyl group on the purine ring that bestows favorable pharmacokinetic, biochemical, and trypanocidal activities. The compound was curative in acute
Trypanosoma brucei brucei
and drug-resistant
Trypanosoma brucei rhodesiense
model infections, with single-dose activity in the 1- to 5-mg/kg/day daily dose range for 4 days against
T. brucei brucei
and 25- to 50-mg/kg twice-daily dosing against
T. brucei rhodesiense
infections. The compound was not curative in the TREU 667 central nervous system model infection but cleared blood parasitemia and extended time to recrudescence in several groups. This study shows that AdoMetDC remains an attractive chemotherapeutic target in African trypanosomes and that chemical changes in AdoMetDC inhibitors can produce more favorable drug characteristics than the lead compound.
Identifying Exposure Targets for Treatment of Staphylococcal Pneumonia with Ceftobiprole
Authors: Rodvold Keith A. , Nicolau David P. , Lodise Thomas P. , Khashab Mohammed , Noel Gary J. , Kahn James B. , Gotfried Mark , Murray Sara A. , Nicholson Susan , Laohavaleeson Somvadee , Tessier Pamela R. , Drusano G. L.
Published: May 2009

Ceftobiprole is a cephalosporin with potent activity against methicillin (meticillin)-resistant
Staphylococcus aureus
(MRSA). In order to treat patients with severe staphylococcal pneumonia, it is important to understand the drug exposure required to mediate the killing of multiple log
10
cells in a preclinical-infection model. We measured drug exposure in terms of the percentage of penetration of the drug into epithelial lining fluid (ELF) and in terms of the time for which the drug concentration was above the MIC (time>MIC) in plasma and ELF. In a murine model of staphylococcal pneumonia, we demonstrated that ceftobiprole penetrated into ELF from the plasma at a median level of nearly 69% (25th to 75th percentile range, 25 to 187%), as indexed to the ratio of values for the area under the concentration-time curve in ELF and plasma. The total-drug times>MIC in ELF that were required to kill 1 log
10
and 2 log
10
CFU/g of lung tissue were 15% and 25% of the dosing interval. We also examined the penetration of ELF by ceftobiprole in volunteers, demonstrating mean and median penetration percentages of 25.5% and 15.3%, respectively (25th to 75th percentile range, 8 to 30%). Attainment rates were calculated for kill targets of 1 log
10
and 2 log
10
CFU/g, taken from the murine model, but using the volunteer ceftobiprole ELF penetration data. The standard dose for ceftobiprole is 0.5 g every 8 h as a 2-h infusion. The attainment rates remained above 90% for 1-log
10
and 2-log
10
CFU/g kill targets at MICs of 1 and 0.5 mg/liter, respectively. Taking the expectation over the distribution of ceftobiprole MICs for 4,958 MRSA isolates showed an overall target attainment of 85.6% for a 1-log
10
CFU/g kill and 79.7% for a 2-log
10
CFU/g kill. It is important to derive exposure targets in preclinical-infection models of the infection site so that these targets can be explored in clinical trials in order to optimize the probability of a good clinical outcome.
In Vitro Interactions between Antifungals and Immunosuppressive Drugs against Zygomycetes
Authors: Dannaoui Eric , Schwarz Patrick , Lortholary Olivier
Published: May 2009

The in vitro interaction of antifungals with immunosuppressive drugs was evaluated against zygomycetes. The combination of amphotericin B with cyclosporine, rapamycin, or tacrolimus was synergistic for 90%, 70%, and 30% of the isolates, respectively. For posaconazole, itraconazole, and ravuconazole, synergy was more frequently observed with cyclosporine than with rapamycin or tacrolimus and antagonistic interactions were rarely noted. In summary, calcineurin inhibitors and rapamycin can be synergistic in vitro with amphotericin B and azoles against zygomycetes.
In Vitro and Murine Efficacy and Toxicity Studies of Nebulized SCC1, a Methylated Caffeine-Silver(I) Complex, for Treatment of Pulmonary Infections
Authors: Cannon Carolyn L. , Hogue Lisa A. , Vajravelu Ravy K. , Capps George H. , Ibricevic Aida , Hindi Khadijah M. , Kascatan-Nebioglu Aysegul , Walter Michael J. , Brody Steven L. , Youngs Wiley J.
Published: May 2009

The expanding clinical challenge of respiratory tract infections due to resistant bacteria necessitates the development of new forms of therapy. The development of a compound composed of silver coupled to a methylated caffeine carrier (silver carbene complex 1 [SCC1]) that demonstrated in vitro efficacy against bacteria, including drug-resistant organisms, isolated from patients with respiratory tract infections was described previously. The findings of current in vitro studies now suggest that bactericidal concentrations of SCC1 are not toxic to airway epithelial cells in primary culture. Thus, it was hypothesized that SCC1 could be administered by the aerosolized route to concentrate delivery to the lung while minimizing systemic toxicity. In vivo, aerosolized SCC1 delivered to mice resulted in mild aversion behavior, but it was otherwise well tolerated and did not cause lung inflammation following administration over a 5-day period. The therapeutic efficacy of SCC1 compared to that of water was shown in a 3-day prophylaxis protocol, in which mice infected with a clinical strain of
Pseudomonas aeruginosa
had increased survival, decreased amounts of bacteria in the lung, and a lower prevalence of bacteremia. Similarly, by using an airway infection model in which bacteria were impacted in the airways by agarose beads, the administration of SCC1 was significantly superior to water in decreasing the lung bacterial burden and the levels of bacteremia and markers of airway inflammation. These observations indicate that aerosolized SCC1, a novel antimicrobial agent, warrants further study as a potential therapy for bacterial respiratory tract infections.
Selection of Heterogeneous Vancomycin-Intermediate
Staphylococcus aureus
by Imipenem
Authors: Katayama Yuki , Murakami-Kuroda Hiroko , Cui Longzhu , Hiramatsu Keiichi
Published: May 2009

Vancomycin (VAN)-intermediate
Staphylococcus aureus
(VISA) and heterogeneous VISA (hVISA) isolates are considered to have emerged from VAN-susceptible
S. aureus
(VSSA) by spontaneous mutation during VAN exposure. We previously reported that laboratory mutant H14, obtained from VSSA strain ΔIP by exposure to imipenem (IPM), showed overexpression of the
vraSR
two-component system and a typical hVISA phenotype. In the present study, to elucidate the mechanism of VSSA conversion to hVISA, we further characterized strain H14 by determining its whole-genome sequence, morphology, cell wall synthetic activity, and gene expression. Genome sequencing revealed that H14 harbored a mutated
vraS
(designated
vraS
H14
) that caused an amino acid substitution (S
329
→L). This mutation is different from the VraS mutation (N
5
→I) identified in representative clinical hVISA strain Mu3. However, H14 exhibited a phenotype similar to that of Mu3, including heterogeneous resistance to VAN, enhanced cell wall synthetic activity, and
vraSR
overexpression. Replacement of the
vraS
gene of ΔIP with the mutated
vraS
H14
gene confirmed that the S
329
→L substitution was responsible for both the upregulation of
vraSR
and conversion to the hVISA phenotype. This conversion was also achieved by using the
vraS
gene of Mu3, which carries a mutation (N
5
→I), but not with the native
vraS
gene of strain N315. Finally, we carried out a study to analyze the appearance of hVISA from VSSA by exposure of ΔIP to selective concentrations of VAN and beta-lactam antibiotics. A total of 8 and 5 hVISA isolates were detected among 50 isolates selected with VAN and IPM, respectively. Among the 13 hVISA mutants, mutation in
vraSR
was detected only in mutant strain H14, suggesting that additional mutational mechanisms can be responsible for evolution to the hVISA phenotype. We conclude that exposure not only to VAN but also to beta-lactams may select for reduced glycopeptide susceptibility in
S. aureus
.
Pharmacokinetic and Pharmacodynamic Evaluation of Liposomal Amikacin for Inhalation in Cystic Fibrosis Patients with Chronic Pseudomonal Infection
Authors: Okusanya Ólanrewaju O. , Bhavnani Sujata M. , Hammel Jeffrey , Minic Predrag , Dupont Lieven J. , Forrest Alan , Mulder Geert-Jan , Mackinson Constance , Ambrose Paul G. , Gupta Renu
Published: May 2009

The pharmacokinetics and pharmacodynamics of a novel liposomal amikacin for inhalation were evaluated in cystic fibrosis patients with chronic pseudomonas infection. Twenty-four patients from two studies received 500 mg of liposomal amikacin by inhalation once daily for 14 days. Serum, sputum, and 24-h urine samples were collected on days 1 and 14 of therapy; pulmonary function tests (PFT) and sputum for quantitative microbiology were assessed at baseline and serially for 14 days. Relationships between amikacin exposure in serum and sputum and absolute change in PFT endpoints and log10CFU ofPseudomonas aeruginosafrom baseline on days 7 and 14 of therapy were assessed. On days 7 and 14, absolute change from baseline in forced expiratory volume in 1 s (FEV1), percent predicted forced expiratory volume in 1 s (FEV1% predicted), and forced expiratory flow between 25 and 75% of forced vital capacity (FEF25-75%) increased by 0.24 (P= 0.002) and 0.13 (P= 0.10) liters, 7.49 (P< 0.001) and 4.38 (P= 0.03), and 0.49 (P< 0.001) and 0.42 (P= 0.02) liters/s, respectively. In addition, relative change from baseline in FEV1% predicted was 10.8% (P< 0.001) and 5.62% (P= 0.073) on days 7 and 14, respectively. While significant relationships between absolute change in PFT endpoints and the ratio of serum or sputum area under the concentration-time curve to the MIC (AUC/MIC) were not observed, relationships between change in log10CFU and serum AUC/MIC ratio and change in log10CFU and absolute changes in all PFT endpoints were significant. Together, these findings likely represent drug effect and warrant the further development of liposomal amikacin for inhalation.
Imcroporin, a New Cationic Antimicrobial Peptide from the Venom of the Scorpion
Isometrus maculates
Authors: Zhao Zhenhuan , Ma Yibao , Dai Chao , Zhao Ruiming , Li SongRyong , Wu Yingliang , Cao Zhijian , Li Wenxin
Published: May 2009

The pace of resistance against antibiotics almost exceeds that of the development of new drugs. As many bacteria have become resistant to conventional antibiotics, new drugs or drug resources are badly needed to combat antibiotic-resistant pathogens, like methicillin-resistant
Staphylococcus aureus
(MRSA). Antimicrobial peptides, rich sources existing in nature, are able to effectively kill multidrug-resistant pathogens. Here, imcroporin, a new antimicrobial peptide, was screened and isolated from the cDNA library of the venomous gland of
Isometrus maculates
. The MIC of imcroporin against MRSA was 50 μg/ml, 8-fold lower than that of cefotaxime and 40-fold lower than that of penicillin. Imcroporin killed bacteria rapidly in vitro, inhibited bacterial growth, and cured infected mice. These results revealed that imcroporin could be considered a potential anti-infective drug or lead compound, especially for treating antibiotic-resistant pathogens.
Effects of Azithromycin in Combination with Vancomycin, Daptomycin, Fosfomycin, Tigecycline, and Ceftriaxone on
Staphylococcus epidermidis
Biofilms
Authors: Presterl Elisabeth , Hajdu Stefan , Lassnigg Andrea M. , Hirschl Alexander M. , Holinka Johannes , Graninger Wolfgang
Published: May 2009

Staphylococcal biofilms on surgical implants are the underlying cause of a lack of response to antimicrobial treatment. We investigated the effects of vancomycin (VAN), daptomycin (DAP), fosfomycin (FOS), tigecycline (TGC), and ceftriaxone (CRX), alone and in combination with azithromycin (AZI), on established biofilms of
Staphylococcus epidermidis
. Biofilms were studied using the static microtiter plate model with established
S. epidermidis
biofilms, with an initial inoculum of 10
6
/ml in 96-well polystyrene flat-bottom microtiter plates. Biofilms were inoculated with VAN, DAP, FOS, TGC, or CRX at two concentrations, alone or in combination with AZI (2, 512, or 1,024 mg/liter). To assess the reduction in biomass, the optical density ratio (ODr), calculated as (optical density [OD] of the treated biofilm)/(OD of the untreated biofilm, taken as 1), was used. For antibacterial efficacy, the viable bacterial count was used. Reductions in the biofilm ODr were observed for VAN (15 and 40 mg/liter) and FOS (200 mg/liter) only (ODr [mean ± standard deviation] for VAN at 15 and 40 mg/liter, 0.77 ± 0.32 and 0.8 ± 0.35, respectively; ODr for FOS at 200 mg/liter, 0.78 ± 0.26;
P
< 0.05), but not for DAP (2 and 5 mg/liter), TGC (0.2 and 2 mg/liter), or CRX (600 and 2,400 mg/liter). The addition of AZI had no further effect on the ODr, but a significant reduction of bacterial growth was achieved with high doses of AZI plus TGC or AZI plus CRX (a 3-log count reduction for AZI at 1,024 mg/liter plus CRX at 600 mg/liter and for AZI at 512 or 1,024 mg/liter plus CRX at 2,400 mg/liter; a 2-log count reduction for AZI at 512 or 1,024 mg/liter plus TGC at 2 mg/liter [
P
< 0.05]). No significant reduction in bacterial growth was observed for FOS (50 and 200 mg/liter), DAP (2 and 5 mg/liter), or TGC (0.2 mg/liter) in combination with AZI. None of the antibiotics at either concentration reduced the bacterial count of the biofilms when used alone. Thus, the use of a combination of AZI plus TGC, FOS, or CRX at high concentrations has little effect on biofilm density but significantly reduces bacterial growth.
Protease Inhibitor Resistance Analysis in the MONARK Trial Comparing First-Line Lopinavir-Ritonavir Monotherapy to Lopinavir-Ritonavir plus Zidovudine and Lamivudine Triple Therapy
Authors: Delaugerre Constance , Flandre Philippe , Chaix Marie Laure , Ghosn Jade , Raffi François , Dellamonica Pierre , Jaeger H. , Shürmann D. , Cohen-Codar Isabelle , Ngo Van Philippe , Norton Michael , Taburet Anne-Marie , Delfraissy Jean-François , Rouzioux Christine
Published: May 2009

The MONARK study was a pilot randomized trial comparing the safety and efficacy of lopinavir-ritonavir (LPV/r) monotherapy to those of LPV/r-zidovudine-lamivudine triple therapy for antiretroviral-naïve human immunodeficiency virus type 1 (HIV-1)-infected patients. Resistance testing was performed at the time of initial screening and at the time of virological failure (defined to include low-level viremia with >50 and <400 HIV-1 virus RNA copies/ml of plasma). Changes from the baseline sequences, including mutations noted on the 2008 International AIDS Society—USA list of resistance-associated protease mutations, were considered. Drug resistance testing was performed for 38 patients (5 of 53 on triple therapy and 33 of 83 on monotherapy). By week 96 (W96), virus samples from 18 of 33 patients in the monotherapy arm showed changes from baseline sequences, and 5 of these patients had viruses with major protease inhibitor (PI) resistance-associated mutations (M46I at W40, L76V at W48, M46I and L76V at W48, L10F and V82A at W72, and L76V at W84). Data on virus phenotypes detected at the time of initial screening and the time of virological failure were available for four patients in whom major PI resistance mutations developed, and these data revealed a mean increase of 2.2-fold (range, 0.75- to 4.6-fold) in the LPV 50% inhibitory concentration. All three patients in whom the L76V PI resistance mutation developed were infected with HIV-1 subtype CRF02_AG. In the triple-therapy group, no major PI resistance mutation was selected among the three patients with protease changes by W48. No association between the baseline CD4 cell count and the viral load, the W4 and final viral loads, or the final LPV trough concentration and the emergence of a major PI resistance mutation was found. Major PI resistance-associated mutations were detected in 5 (6%) of 83 patients treated with LPV/r monotherapy, suggesting that LPV/r monotherapy is an inappropriate first option. The mutation L76V may be considered in further studies of lopinavir resistance.
Pharmacokinetics-Pharmacodynamics of Pyrazinamide in a Novel In Vitro Model of Tuberculosis for Sterilizing Effect: a Paradigm for Faster Assessment of New Antituberculosis Drugs
Authors: Gumbo Tawanda , Siyambalapitiyage Dona Chandima S. W. , Meek Claudia , Leff Richard
Published: May 2009

There are currently renewed efforts to develop drugs that could shorten the duration of antituberculosis therapy. This is best achieved by optimizing the sterilizing effect. However, the current pathway for the development of new molecules with the potential to have a sterilizing effect is inefficient. We designed an in vitro pharmacokinetic-pharmacodynamic model in which
Mycobacterium tuberculosis
replicating slowly at pH 5.8 was exposed to pyrazinamide by use of the concentration-time profiles encountered in patients. The sterilizing effect rates and the time to the emergence of drug resistance were examined. Daily pyrazinamide dosing for 28 days accurately achieved (i) the pyrazinamide pharmacokinetic parameters, (ii) the lack of early bactericidal activity, (iii) a sterilizing effect rate of 0.10 log
10
CFU/ml per day starting on day 6 of therapy, and (iv) a time to the emergence of resistance of the from 2 to 3 weeks of monotherapy encountered in patients with tuberculosis. Next, dose-scheduling studies were performed. The sterilizing effect was linked to the pyrazinamide ratio of the area under the concentration-time curve from 0 to 24 h (AUC
0-24
) to the MIC (
r
2
= 0.80 to 0.90), with 90% of the maximal effect being achieved by an AUC
0-24
/MIC of 209.08. Resistance suppression was associated with the percentage of time that the concentration persisted above the MIC (
r
2
= 0.73 to 0.91). Monte Carlo simulations of 10,000 patients demonstrated that the currently recommended pyrazinamide doses (15 to 30 mg/kg of body weight/day) achieved the AUC
0-24
/MIC of 209.08 in the epithelial lining fluid of only 15.1 to 53.3% of patients. Doses of >60 mg/kg per day performed better. Our vitro model for the sterilizing effect, together with Monte Carlo simulations, can be used for the faster identification of the clinical doses that are needed to achieve a sterilizing effect and that can then be studied in clinical trials.
Daptomycin Rapidly Penetrates a
Staphylococcus epidermidis
Biofilm
Authors: Stewart Philip S. , Davison William M. , Steenbergen Judith N.
Published: May 2009

Fluorescently tagged daptomycin accessed the interior of
Staphylococcus epidermidis
biofilm cell clusters within minutes. The diffusion coefficient of daptomycin in the biofilm was 28% of its value in pure water. Daptomycin activity against staphylococci embedded in biofilms is unlikely to be limited by penetration of the antibiotic into the biofilm.
An Immunogenic, Surface-Exposed Domain of
Haemophilus ducreyi
Outer Membrane Protein HgbA Is Involved in Hemoglobin Binding
Authors: Nepluev Igor , Afonina Galyna , Fusco William G. , Leduc Isabelle , Olsen Bonnie , Temple Brenda , Elkins Christopher
Published: May 2009

HgbA is the sole TonB-dependent receptor for hemoglobin (Hb) acquisition of
Haemophilus ducreyi
. Binding of Hb to HgbA is the initial step in heme acquisition from Hb. To better understand this step, we mutagenized
hgbA
by deletion of each of the 11 putative surface-exposed loops and expressed each of the mutant proteins in
trans
in host strain
H
.
ducreyi
FX547
hgbA
. All mutant proteins were expressed, exported, and detected on the surface by anti-HgbA immunoglobulin G (IgG). Deletion of sequences in loops 5 and 7 of HgbA abolished Hb binding in two different formats. In contrast, HgbA proteins containing deletions in the other nine loops retained the ability to bind Hb. None of the clones expressing mutant proteins were able to grow on plates containing low concentrations of Hb. Previously we demonstrated in a swine model of chancroid infection that an HgbA vaccine conferred complete protection from a challenge infection. Using anti-HgbA IgG from this study and the above deletion mutants, we show that loops 4, 5, and 7 of HgbA were immunogenic and surface exposed and that IgG directed against loops 4 and 5 blocked Hb binding. Furthermore, loop 6 was cleaved by protease on intact
H
.
ducreyi
, suggesting surface exposure. These data implicate a central domain of HgbA (in respect to the primary amino acid sequence) as important in Hb binding and suggest that this region of the molecule might have potential as a subunit vaccine.
Surfactant Protein D Increases Phagocytosis of HypocapsularCryptococcus neoformansby Murine Macrophages and Enhances Fungal Survival
Authors: Geunes-Boyer Scarlett , Oliver Timothy N. , Janbon Guilhem , Lodge Jennifer K. , Heitman Joseph , Perfect John R. , Wright Jo Rae
Published: May 2009

Cryptococcus neoformansis a facultative intracellular opportunistic pathogen and the leading cause of fungal meningitis in humans. In the absence of a protective cellular immune response, the inhalation ofC. neoformanscells or spores results in pulmonary infection.C. neoformanscells produce a polysaccharide capsule composed predominantly of glucuronoxylomannan, which constitutes approximately 90% of the capsular material. In the lungs, surfactant protein A (SP-A) and SP-D contribute to immune defense by facilitating the aggregation, uptake, and killing of many microorganisms by phagocytic cells. We hypothesized that SP-D plays a role inC. neoformanspathogenesis by binding to and enhancing the phagocytosis of the yeast. Here, the abilities of SP-D to bind to and facilitate the phagocytosis and survival of the wild-type encapsulated strain H99 and thecap59Δ mutant hypocapsular strain are assessed. SP-D binding tocap59Δ mutant cells was approximately sixfold greater than binding to wild-type cells. SP-D enhanced the phagocytosis ofcap59Δ cells by approximately fourfold in vitro. To investigate SP-D binding in vivo, SP-D−/−mice were intranasally inoculated with Alexa Fluor 488-labeledcap59Δ or H99 cells. By confocal microscopy, a greater number of phagocytosedC. neoformanscells in wild-type mice than in SP-D−/−mice was observed, consistent with in vitro data. Interestingly, SP-D protectedC. neoformanscells against macrophage-mediated defense mechanisms in vitro, as demonstrated by an analysis of fungal viability using a CFU assay. These findings provide evidence thatC. neoformanssubverts host defense mechanisms involving surfactant, establishing a novel virulence paradigm that may be targeted for therapy.
Evidence for Capsule Switching between Carried and Disease-CausingNeisseria meningitidisStrains
Authors: Beddek Amanda J. , Li Ming-Shi , Kroll J. Simon , Jordan T. William , Martin Diana R.
Published: May 2009

Changing antigenic structure such as with capsule polysaccharide is a common strategy for bacterial pathogens to evade a host immune system. The recent emergence of an invasive W:2a:P1.7-2,4 sequence type 11 (ST-11) strain ofNeisseria meningitidisin New Zealand, an uncommon serogroup/serotype in New Zealand disease cases, was investigated for its genetic origins. Molecular typing of 107 meningococcal isolates with similar serotyping characteristics was undertaken to determine genetic relationships. Results indicated that the W:2a:P1.7-2,4 strain had emerged via capsule switching from a group C strain (C:2a:P1.7-2,4). Neither the upstream nor downstream sites of recombination could be elucidated, but sequence analysis demonstrated that at least 45 kb of DNA was involved in the recombination, including the entire capsule gene cluster. TheoatWYgene carried by the W:2a:P1.7-2,4 strain contained the insertion sequence element IS1301, one of five variants ofoatWYfound in group W135 strains belonging to the carriage-associated ST-22 clonal complex. This suggested that the origin of the capsule genes carried by the invasive W:2a:P1.7-2,4 strain is carriage associated. These results provide novel evidence for the long-standing dogma that disease-associated strains acquire antigenic structure from carriage-associated strains. Moreover, the capsule switch described here has arisen from the exchange of the entire capsule locus.
The Posttranslocation Chaperone PrsA2 Contributes to Multiple Facets ofListeria monocytogenesPathogenesis
Authors: Alonzo Francis , Port Gary C. , Cao Min , Freitag Nancy E.
Published: May 2009

Listeria monocytogenesis an intracellular bacterial pathogen whose virulence depends on the regulated expression of numerous secreted bacterial factors. As for other gram-positive bacteria, many proteins secreted byL. monocytogenesare translocated across the bacterial membrane in an unfolded state to the compartment existing between the membrane and the cell wall. This compartment presents a challenging environment for protein folding due to its high density of negative charge, high concentrations of cations, and low pH. We recently identified PrsA2 as a gene product required forL. monocytogenesvirulence. PrsA2 was identified based on its increased secretion by strains containing a mutationally activated form ofprfA, the key regulator ofL. monocytogenesvirulence gene expression. TheprsA2gene product is one of at least two predicted peptidyl-prolylcis/trans-isomerases encoded byL. monocytogenes; these proteins function as posttranslocation protein chaperones and/or foldases. In this study, we demonstrate that PrsA2 plays a unique and important role inL. monocytogenespathogenesis by promoting the activity and stability of at least two critical secreted virulence factors: listeriolysin O (LLO) and a broad-specificity phospholipase. Loss of PrsA2 activity severely attenuated virulence in mice and impaired bacterial cell-to-cell spread in host cells. In contrast, mutants lackingprsA1resembled wild-type bacteria with respect to intracellular growth and cell-to-cell spread as well as virulence in mice. PrsA2 is thus distinct from PrsA1 in its unique requirement for the stability and full activity ofL. monocytogenes-secreted factors that contribute to host infection.
Elucidating the Pathogenesis of Spores from the Human Fungal PathogenCryptococcus neoformans
Authors: Giles Steven S. , Dagenais Taylor R. T. , Botts Michael R. , Keller Nancy P. , Hull Christina M.
Published: May 2009

Cryptococcus neoformanswas first described as a human fungal pathogen more than a century ago. One aspect of theC. neoformansinfectious life cycle that has been the subject of earnest debate is whether the spores are pathogenic. Despite much speculation, no direct evidence has been presented to resolve this outstanding question. We present evidence thatC. neoformansspores are pathogenic in a mouse intranasal inhalation model of infection. In addition, we provide mechanistic insights into spore-host interactions. We found thatC. neoformansspores were phagocytosed by alveolar macrophages via interactions between fungal β-(1,3)-glucan and the host receptors Dectin-1 and CD11b. Moreover, we discovered an important link between spore survival and macrophage activation state: intracellular spores were susceptible to reactive oxygen-nitrogen species. We anticipate these results will serve as the basis for a model to further investigate the pathogenic implications of infections caused by fungal spores.
Pseudomonas aeruginosa
Inhibition of Flagellin-Activated NF-κB and Interleukin-8 by Human Airway Epithelial Cells
Authors: Pena Jose , Fu Zhu , Schwarzer Christian , Machen Terry E.
Published: May 2009

Pseudomonas aeruginosa
-induced activation of NF-κB and secretion of proinflammatory cytokines by airway epithelial cells require that the bacteria express flagellin. We tested whether
P. aeruginosa
and human airway epithelial cells secrete factors that modulated this response. Experiments were performed with both the Calu-3 cell line and primary cultures of tracheal epithelial cells.
P. aeruginosa
strain PAK Δ
fliC
(flagellin knockout) did not activate NF-κB or interleukin-8 (IL-8) but inhibited flagellin-activated NF-κB by 40 to 50% and IL-8 secretion by 20 to 25%. PAK Δ
fliC
also inhibited NF-κB induced by IL-1β and Toll-like receptor 2 agonist Pam3CSK4. Similar inhibitions were observed with strains PAK, PAO1, and PA14. The inhibitory factor was present in conditioned medium isolated from PAK Δ
fliC
or Calu-3 plus PAK Δ
fliC
, but it was not present in conditioned medium isolated from Calu-3 cells alone or from PAK Δ
fliC
that had been heat treated. Inhibition by PAK Δ
fliC
-conditioned medium was exerted from either the apical or the basolateral side of the epithelium, was enhanced in simple Ringer's solution over that in tissue culture medium, and did not result from altered pH or depletion of glucose. The inhibitory effect of conditioned medium was abolished by boiling and appeared from filtration studies to result from effects of a factor with a molecular mass of <3 kDa. These and further studies with isogenic mutants led to the conclusion that the NF-κB and IL-8 response of airway epithelial cells to
P. aeruginosa
results from a balance of proinflammatory effects of flagellin and antiinflammatory effects of a small (<3-kDa), heat-sensitive factor(s) that is not lipopolysaccharide, C12 homoserine lactone, alginate, CIF, or exotoxin A, S, T, U, or Y.
Diminished Hematopoietic Activity Associated with Alterations in Innate and Adaptive Immunity in a Mouse Model of Human Monocytic Ehrlichiosis
Authors: MacNamara Katherine C. , Racine Rachael , Chatterjee Madhumouli , Borjesson Dori , Winslow Gary M.
Published: May 2009

Human monocytic ehrlichiosis (HME) is a tick-borne disease caused by
Ehrlichia chaffeensis
. Patients exhibit diagnostically important hematological changes, including anemia and thrombocytopenia, although the basis of the abnormalities is unknown. To begin to understand these changes, we used a mouse model of ehrlichiosis to determine whether the observed hematological changes induced by infection are associated with altered hematopoietic activity. Infection with
Ehrlichia muris
, a pathogen closely related to
E. chaffeensis
, resulted in anemia, thrombocytopenia, and a marked reduction in bone marrow cellularity. CFU assays, conducted on days 10 and 15 postinfection, revealed a striking decrease in multipotential myeloid and erythroid progenitors. These changes were accompanied by an increase in the frequency of immature granulocytes in the bone marrow and a decrease in the frequency of B lymphocytes. Equally striking changes were observed in spleen cellularity and architecture, and infected mice exhibited extensive extramedullary hematopoiesis. Splenomegaly, a characteristic feature of
E. muris
infection, was associated with an expanded and disorganized marginal zone and a nearly 66-fold increase in the level of Ter119
+
erythroid cells, indicative of splenic erythropoiesis. We hypothesize that inflammation associated with ehrlichia infection suppresses bone marrow function, induces the emigration of B cells, and establishes hematopoietic activity in the spleen. We propose that these changes, which may be essential for providing the innate and acquired immune cells to fight infection, are also responsible in part for blood cytopenias and other clinical features of HME.
A time-series study of the health effects of water-soluble and total-extractable metal content of airborne particulate matter: Table 1
Authors: Heal M R , Elton R A , Hibbs L R , Agius R M , Beverland I J
Published: May 2009

Objectives:

To assess whether adverse acute cardiopulmonary health outcomes are associated with concentration of trace metals in airborne particulate matter.

Methods:

Daily PM10and PM2.5were collected for 1 year in Edinburgh, UK, and the water-soluble and total-extractable content of 11 trace metals determined in each sample. Time series were analysed using generalised additive Poisson regression models, including adjustment for minimum temperature and loess smoothing of trends. Methods were explored of extending the time series of metal concentration in daily PM10for the previous 7 years using multiple regression of the variation in metal content for the 1 year of measurements and the associated variation in air mass source region and other concurrently-measured potential predictor variables.

Results:

The 1 year of direct measurements showed no evidence of significant associations of particle-bound metal concentration with health outcomes beyond that expected by chance. Analysis of the extended time series showed significant positive associations with cardiovascular admissions both for total PM10and for a number of the metals (eg, Cu, Fe, Ni, V, Zn) but the metal effects were no longer significant after adjusting for PM10.

Conclusions:

Within the limitations of the study power, the epidemiological results have not provided evidence for associations between particle-bound metal concentrations and adverse health outcomes that are substantially greater than for total PM. The generally strong correlations between metal and total PM suggest that quantifying independent effects of PM metal exposure on health will be difficult, even using more powerful time series of direct measurements.
THE SPACE OF FINITELY GENERATED RINGS
Authors: CORNULIER YVES
Published: May 2009

The space of marked commutative rings on n given generators is a compact metrizable space. We compute the Cantor–Bendixson rank of any member of this space. For instance, the Cantor–Bendixson rank of the free commutative ring on n generators is ωn, where ω is the smallest infinite ordinal. More generally, we work in the space of finitely generated modules over a given commutative ring.
COMPUTING THE LAW OF A FAMILY OF SOLVABLE LIE ALGEBRAS
Authors: BENJUMEA JUAN C. , NÚÑEZ JUAN , TENORIO ÁNGEL F.
Published: May 2009

This paper shows an algorithm which computes the law of the Lie algebra associated with the complex Lie group of n × n upper-triangular matrices with exponential elements in their main diagonal. For its implementation two procedures are used, respectively, to define a basis of the Lie algebra and the nonzero brackets in its law with respect to that basis. These brackets constitute the final output of the algorithm, whose unique input is the matrix order n. Besides, its complexity is proved to be polynomial and some complementary computational data relative to its implementation are also shown.
COUNTING ELEMENTS IN THE SYMMETRIC GROUP
Authors: BEN-EZRA DAVID EL-CHAI
Published: May 2009

By using simple ideas from subgroup growth of pro-finite groups we deduce some combinatorial identities on generating functions counting various elements in symmetric groups.
PERIODIC CONFIGURATIONS OF SUBSHIFTS ON GROUPS
Authors: FIORENZI FRANCESCA
Published: May 2009

We study the density of periodic configurations for shift spaces defined on (the Cayley graph of) a finitely generated group. We prove that in the case of a full shift on a residually finite group and in that of a group shift space on an abelian group, the periodic configurations are dense. In the one-dimensional case we prove the density for irreducible sofic shifts. In connection with this we study the surjunctivity of cellular automata and local selfmappings. Some related decision problems for shift spaces of finite type are also investigated.
SUBALGEBRAS OF GOLOD–SHAFAREVICH ALGEBRAS
Authors: VODEN THOMAS
Published: May 2009

A graded associative algebra generated by m elements of degree one is called Golod–Shafarevich (GS) if it is presented with less than m2/4 relators of degree at least two. We explore conditions under which subalgebras of graded GS algebras are themselves GS. We prove that infinitely many Veronese powers of an algebra presented by m generators and r relators are GS if [Formula: see text]. For quadratic algebras, the bound is improved to [Formula: see text]. We also show that if A is a generic quadratic algebra presented by m generators and r relators, then all Veronese powers of A are GS if [Formula: see text], and all but finitely many Veronese powers of A are not GS if [Formula: see text].
NUCLEAR STRUCTURE ADDRESSED AT GSI/RISING
Authors:   and the RISING collaboration, GÓRSKA M. , GRAWE H. , CACERES L. , ALGORA A. , BÖHMER M. , BOUTACHKOV P. , EPPINGER K. , FAESTERMANN T. , FUJITA Y. , GADEA A. , GARNSWORTHY A. , GELLETLY W. , GERL J. , GERNHÄUSER R. , HINKE C. , JUNGCLAUS A. , KOJOUHAROV I. , KRÜCKEN R. , MAIER L. , MOLINA P. , PFÜTZNER M. , PIETRI S. , PODOLYÁK Z. , REGAN P. H. , RUBIO B. , RUDOLPH D. , WOLLERSHEIM H. J.
Published: May 2009

Nuclear structure spectroscopy studies at GSI recently gained increased momentum within a broad international community with the installation of the Rare Isotopes Spectroscopic INvestigation at GSI (RISING) project. A wide range of physical phenomena has been addressed by high-resolution in-beam γ-ray spectroscopy experiments with radioactive beams. Relativistic radioactive beams are implanted and their subsequent γ and β decay is investigated. Within this "stopped beam campaign" germanium detectors were arranged in a close geometry around the passive stopper or an array of DSSSD detectors. The exceptionally high γ-ray efficiency of that configuration made it possible to identify decays of excited or ground states of nuclei which have not been observed before. The results discussed here include the astrophysically relevant shell structure of N =82 isotones, N = Z nuclei around 54 Ni , and proton drip-line nuclei below 100 Sn . The experimental data are compared to the results of large scale shell-model calculations using various sets of realistic residual two-body interaction.
FISSION OF SUPER-HEAVY NUCLEI EXPLORED WITH SKYRME FORCES
Authors: SCHINDZIELORZ N. , ERLER J. , KLÜPFEL P. , REINHARD P.–G. , HAGER G.
Published: May 2009

We present a large scale survey of life-times for spontaneous fission in the regime of super-heavy elements (SHE), i.e. nuclei with Z =104-122. This is done on the basis of the Skyrme-Hartree-Fock model. The axially symmetric fission path is computed using a quadrupole constraint. Self-consistent cranking is used for the collective masses and associated quantum corrections. The actual tunneling probability is estimated by the WKB approximation. Three typical Skyrme forces are used to explore the sensitivity of the results. Benchmarks in the regime Z =104-108 show an acceptable agreement. The general systematics reflects nicely the islands of shell stabilization and the crossover from α-decay to fission for the decay chains from the region of Z / N =118/176.
FISSION FRAGMENT PROPERTIES FROM A MICROSCOPIC APPROACH WITH THE GOGNY FORCE
Authors: DUBRAY N.
Published: May 2009

Potential energy surfaces are calculated in the elongation-asymmetry plane, with nuclear shapes ranging from sphericity to very large deformations, using the Hartree-Fock-Bogoliubov method and the Gogny nucleon-nucleon effective interaction (parameterization D1S), for the 226 Th and 256,258,260 Fm fissioning systems. In order to discriminate between pre- and post-scission configurations, we define a criterion based on the nuclear density. Using this criterion, a big number of scission configurations are identified, and several fragment properties are extracted from them, namely fragment deformations, deformation energies, energy partitioning, neutron binding energies at scission, charge polarization, total fragment kinetic energies and neutron emission multiplicities.
FISSION PROPERTIES OF ODD-A NUCLEI IN A MEAN FIELD FRAMEWORK
Authors: PEREZ-MARTIN S. , ROBLEDO L. M.
Published: May 2009

Theoretical tools at the level of the mean field approximation are used to explore the spontaneous fission properties of odd-A nuclei. The tools rely on the equal (or uniform) filling approximation to deal with the unpaired nucleon in a time-reversal preserving manner. Realistic calculations have been carried out with the finite range Gogny force D1S, which was tailored to reasonably reproduce fission properties in the actinides. The preliminary results obtained for the nucleus 235 U are analyzed and the physical origin for the hindrance factor for the spontaneous fission half life is discussed.