bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum Nucleic Acids in an Experimental Bovine Transmissible Spongiform Encephalopathy Model
Authors: Beck Julia , Urnovitz Howard B. , Groschup Martin H. , Ziegler Ute , Brenig Bertram , Schütz Ekkehard 
Published: May 2009

SummaryRepetitive genomic nucleic acid sequences (RGNASs) have been detected in serum samples from both PrPres confirmed cows and cohorts and unexposed cattle. These RGNASs have polymorphisms that can be candidates for detecting subclinical disease processes. To confirm the presence of serum RGNAS polymorphisms in bovine spongiform encephalopathy (BSE), samples were obtained from an experimental study whereby cows were inoculated orally with BSE‐infectious or control brain material. Fleckvieh/Brown Swiss cattle were fed 100 g of either PrPres‐positive brain stem macerate or normal brain material (controls). Serum samples were taken 40 months post‐inoculation (15 infected, 6 control non‐infected and 5 randomly selected normal animals). Approximately, 6e5 sequences were analysed and the results showed that serum RGNAS polymorphisms could be detected in all of the infected animals but not in the control animals. In addition, polymorphisms in serum non‐RGNASs were detected in BSE‐infected animals that differed significantly from the controls (P < 0.01). These data reveal the complexity of serum nucleic acid sequences that can be detected in 200 μl of serum and further add to the guidelines for using serum nucleic acids in diagnostics. In conclusion, RGNAS polymorphism detection may have general applications for the study of other emerging zoonoses.
Rabies in the Face of the 21st Century
Authors: Koprowski H. 
Published: May 2009

SummaryReference to an ancient Hindu picture of a snarling dog may be a convincing enough proof to consider the fact that rabies has been known in the world for the past 50 centuries. Prior to the monumental observation about rabies of Fracastoro in the 16th century, facts and fantasies were intermingled in the study of rabies. In the realm of fantasy, consider the statement of Aristotle (otherwise a great philosopher) that only animals and not humans die of rabies. It took 19 centuries before Fracastoro finally established that infection with rabies is lethal for all warm‐blooded beings including humans. The new era of rabies dates from the time of Galtier who isolated the virus and Pasteur who was able to create a somewhat attenuated strain of virus fixe which became the tool of laboratory studies for many decades after Pasteur. During the last 50 years of the past century, our knowledge of rabies increased by leaps and bounds. First of all, using molecular biology as a tool, it was possible to ‘take the virus apart’, so to speak and describe and analyse all of its components. Establishment of multivariability among viruses as ‘de la rue’ permitted not only a construct of a genetic linkage among lyssa family but also solved some puzzles of pathogenesis of rabies which defied solution when all work concentrated on one laboratory strain of the virus. As an example, we know much more now about the genetic background regulating virulence of the virus. In addition, it is now possible to use rabies as a vector of biological materials such as vaccines or sera. There is no progress in the treatment of the uniformly lethal disease. Perhaps, optimistically speaking, the 21st century will bring us a glimmer of hope for the successful treatment of human rabies.
Changing Ideals in a Donor Organisation: ‘Participation’ in Sida
Authors: Cornwall Andrea 
Published: May 2009

SummaryDevelopment buzzwords shelter diverse and often divergent strands of meaning and practice, lending an air of credibility and currency to the policies of the agencies that espouse them. Tracing the trajectory of one of these buzzwords, ‘participation’, in Swedish development cooperation, this paper seeks to unpack some of those diverse meanings and lend form to some of those divergent practices. It weaves together institutional ethnography with oral history and textual analysis, fortified by insights from a unique action research initiative on participation. This innovative process brought together desk officers from across the institution in a participatory learning group that met for the best part of a year to explore the challenge of institutionalising participation in Sida.The paper tells the tale of efforts to promote and negotiate participation in a changing external and institutional environment. It begins in a time when the term had not yet gained currency but in which the practice of Swedish development cooperation resonated with many of the ideals that were associated with popular participation. It goes on to chart the rise of ‘popular participation’ (folkligt deltagende) and other variants, community participation, beneficiary participation, stakeholder participation and civil society participation, as Swedish development cooperation came to be influenced by the discourses and practices of bilateral and multilateral development institutions. Pursuing the trajectory of participation into an era in which other buzzwords – harmonisation, ownership and account‐ability – have taken precedence, it reflects on the paradoxes of efforts to institutionalise ideals within development bureaucracies as they grapple with the opportunities, challenges and contradictions of the Paris Agenda and the reconfiguration of the business of aid.
MurF Inhibitors with Antibacterial Activity: Effect on Muropeptide Levels
Authors: Baum Ellen Z. , Crespo-Carbone Steven M. , Foleno Barbara D. , Simon Lee D. , Guillemont Jerome , Macielag Mark , Bush Karen 
Published: May 2009

ABSTRACT

MurF catalyzes the last cytoplasmic step of bacterial cell wall synthesis and is essential for bacterial survival. Our previous studies used a pharmacophore model of a MurF inhibitor to identify additional inhibitors with improved properties. We now present the characterization of two such inhibitors, the diarylquinolines DQ1 and DQ2. DQ1 inhibited
Escherichia coli
MurF (50% inhibitory concentration, 24 μM) and had modest activity (MICs, 8 to 16 μg/ml) against lipopolysaccharide (LPS)-defective
E. coli
and wild-type
E. coli
rendered permeable with polymyxin B nonapeptide. DQ2 additionally displayed activity against gram-positive bacteria (MICs, 8 to 16 μg/ml), including methicillin (meticillin)-susceptible and -resistant
Staphylococcus aureus
isolates and vancomycin-susceptible and -resistant
Enterococcus faecalis
and
Enterococcus faecium
isolates. Treatment of LPS-defective
E. coli
cells with ≥2× MIC of DQ1 resulted in a 75-fold-greater accumulation of the MurF substrate compared to the control, a 70% decline in the amount of the MurF product, and eventual cell lysis, consistent with the inhibition of MurF within bacteria. DQ2 treatment of
S. aureus
resulted in similar effects on the MurF substrate and product quantities. At lower levels of DQ1 (≤1× MIC), the level of accumulation of the substrate was less pronounced (15-fold greater compared to the amount for the control). However, a 50% increase in the amount of the MurF product compared to the control was reproducibly observed, consistent with the possible upregulation of muropeptide biosynthesis upon partial inhibition of this pathway. The overexpression of cloned MurF appeared to partly alleviate the DQ1-mediated inhibition of muropeptide synthesis. The identification of MurF inhibitors such as DQ1 and DQ2 that disrupt cell wall biosynthesis suggests that MurF remains a viable target for an antibacterial agent.
Three-Dimensional Model of Lanosterol 14α-Demethylase from
Cryptococcus neoformans
: Active-Site Characterization and Insights into Azole Binding
Authors: Sheng Chunquan , Miao Zhenyuan , Ji Haitao , Yao Jianzhong , Wang Wenya , Che Xiaoying , Dong Guoqiang , Lü Jiaguo , Guo Wei , Zhang Wannian 
Published: May 2009

ABSTRACT

Cryptococcus neoformans
is one of the most important causes of life-threatening fungal infections in immunocompromised patients. Lanosterol 14α-demethylase (CYP51) is the target of azole antifungal agents. This study describes, for the first time, the 3-dimensional model of CYP51 from
Cryptococcus neoformans
(CnCYP51). The model was further refined by energy minimization and molecular-dynamics simulations. The active site of CnCYP51 was well characterized by multiple-copy simultaneous-search calculations, and four functional regions important for rational drug design were identified. The mode of binding of the natural substrate and azole antifungal agents with CnCYP51 was identified by flexible molecular docking. A G484S substitution mechanism for azole resistance in CnCYP51, which might be important for the conformation of the heme environment, is suggested.
UropathogenicEscherichia coli-Induced Inflammation Alters Mouse Urinary Bladder Contraction via an Interleukin-6-Activated Inducible Nitric Oxide Synthase-Related Pathway
Authors: Weng Te I. , Wu Hsiao Yi , Lin Pei Ying , Liu Shing Hwa 
Published: May 2009

ABSTRACTEscherichia coliis the most common cause of urinary tract infection. Elevated blood and urine interleukin-6 (IL-6) levels have been shown in inflammatory urinary tract diseases. The role of IL-6 in mediating the urodynamic dysfunction in response toE. coli-induced urinary tract infection has not yet been fully elucidated. In this study, we investigated the role of IL-6 in the nitric oxide (NO)-triggered alteration of contractile responses in the urinary bladder under anE. coli-induced inflammatory condition. The electrical field stimulation (EFS)-evoked contractions of the isolated detrusor strips, and immunoblotting for detecting protein expression in the bladders was measured short term (1 h) or long term (6 or 24 h) after intraperitoneal injection ofE. coliendotoxin (lipopolysaccharide [LPS]) or intravesical instillation of human pyelonephritogenicE. coli-J96 (O4:K6) strain or LPS into mice. IL-6 and NO productions were increased in the urinary bladders of mice 1 to 24 h after LPS orE. coli-J96 treatment. Inducible NO synthase (iNOS) expression and protein kinase C (PKC) activation and EFS-evoked detrusor contractions were increased in the bladders at 6 h after LPS orE. coli-J96 treatment, which could be reversed by anti-IL-6 antibody and iNOS inhibitor aminoguanidine. At 1 h after LPS administration, bladder NO generation, endothelial NOS expression, and EFS-evoked detrusor contractions were effectively increased, whereas anti-IL-6 antibody could not reverse these LPS-induced responses. These results indicate that IL-6 may play an important role in the iNOS/NO-triggered PKC-activated contractile response in urinary bladder duringE. colior LPS-induced inflammation.
Mycobacterium tuberculosisCpn60.2 and DnaK Are Located on the Bacterial Surface, Where Cpn60.2 Facilitates Efficient Bacterial Association with Macrophages
Authors: Hickey Tyler B. M. , Thorson Lisa M. , Speert David P. , Daffé Mamadou , Stokes Richard W. 
Published: May 2009

ABSTRACTMycobacterium tuberculosis, the causative agent of tuberculosis, initially contacts host cells with elements of its outer cell wall, or capsule. We have shown that capsular material from the surface ofM. tuberculosiscompetitively inhibits the nonopsonic binding of wholeM. tuberculosisbacilli to macrophages in a dose-dependent manner that is not acting through a global inhibition of macrophage binding. We have further demonstrated that isolatedM. tuberculosiscapsular proteins mediate a major part of this inhibition. Two-dimensional polyacrylamide gel electrophoresis analysis of the capsular proteins showed the presence of a wide variety of protein species, including proportionately high levels of the Cpn60.2 (Hsp65, GroEL2) and DnaK (Hsp70) molecular chaperones. Both of these proteins were subsequently detected on the bacterial surface. To determine whether these molecular chaperones play a role in bacterial binding, recombinant Cpn60.2 and DnaK were tested for their ability to inhibit the association ofM. tuberculosisbacilli with macrophages. We found that recombinant Cpn60.2 can inhibit ∼57% of bacterial association with macrophages, while DnaK was not inhibitory at comparable concentrations. Additionally, when polyclonal F(ab′)2fragments of anti-Cpn60.2 and anti-DnaK were used to mask the surface presentation of these molecular chaperones, a binding reduction of ∼34% was seen for anti-Cpn60.2 F(ab′)2, while anti-DnaK F(ab′)2did not significantly reduce bacterial association with macrophages. Thus, our findings suggest that whileM. tuberculosisdisplays both surface-associated Cpn60.2 and DnaK, only Cpn60.2 demonstrates adhesin functionality with regard to macrophage interaction.
Strain and Virulence Diversity in the Mouse Pathogen
Chlamydia muridarum
Authors: Ramsey Kyle H. , Sigar Ira M. , Schripsema Justin H. , Denman Cecele J. , Bowlin Anne K. , Myers Garry A. S. , Rank Roger G. 
Published: May 2009

ABSTRACT

The mouse chlamydial pathogen
Chlamydia muridarum
has been used as a model organism for the study of human
Chlamydia trachomatis
urogenital and respiratory tract infections. To date, two commonly used
C. muridarum
isolates have been used interchangeably and are essentially taken to be identical. Herein, we present data that indicate that this is not the case. The
C. muridarum
Weiss isolate and
C. muridarum
Nigg isolate varied significantly in their virulences in vivo and possessed different growth characteristics in vitro. Distinct differences were observed in intravaginal 50% infectious doses and in challenge infections, with the Weiss isolate displaying greater virulence. Respiratory infection by the intranasal route also indicated a greater virulence of the Weiss isolate. In vitro, morphometric analysis revealed that the Weiss isolate produced consistently smaller inclusions in human cervical adenocarcinoma cells (HeLa 229) and smaller plaques in monolayers of mouse fibroblasts (L929) than did the Nigg isolate. In addition, the Weiss isolate possessed significantly higher replicative yields in vitro than did the Nigg isolate. In plaque-purified isolates derived from our stocks of these two strains, total genomic sequencing identified several unique nonsynonymous single nucleotide polymorphisms and insertion/deletion mutations when our Weiss (
n
= 4) and Nigg (
n
= 5) isolates were compared with the published Nigg sequence. In addition, the two isolates shared 11 mutations compared to the published Nigg sequence. These results prove that there is genotypic and virulence diversity among
C. muridarum
isolates. These findings can be exploited to determine factors related to chlamydial virulence and immunity.
Establishment of an Adult Mouse Model for Direct Evaluation of the Efficacy of Vaccines against
Vibrio cholerae
Authors: Nygren E. , Li B.-L. , Holmgren J. , Attridge S. R. 
Published: May 2009

ABSTRACT

We describe here a new animal model that offers the prospect of using conventional adult mice for direct evaluation of the protective potential of new cholera vaccines. Pretreatment of adult mice with oral streptomycin allowed intestinal colonization by streptomycin-resistant
Vibrio cholerae
strains of either the O1 or the O139 serogroup. Bacteria were recovered in greatest numbers from the cecum and large intestine, but recoveries from all regions of the gut correlated significantly with bacterial excretion in fresh fecal pellets, which thus provides a convenient indicator of the extent and duration of gut colonization. Mice immunized mucosally or systemically with viable or inactivated
V. cholerae
were shown to be comparatively refractory to colonization after challenge with the immunizing strain. Several variables were examined to optimize the model, the most significant being the size of the challenge inoculum; surprisingly, a smaller challenge dose resulted in more consistent and sustained colonization. Studies with mutant strains unable to produce cholera toxin or toxin-coregulated pili revealed that neither factor contributed significantly to colonization potential. Protection against
V. cholerae
challenge was shown to be serogroup restricted, and significant inverse correlations were detected between serum and intestinal anti-lipopolysaccharide antibody responses and the levels of excretion of challenge organisms.
Activation of Rap1 Promotes Prostate Cancer Metastasis
Authors: Bailey Candice L. , Kelly Patrick , Casey Patrick J. 
Published: May 2009

Abstract
Elucidating the mechanisms of prostate cancer (CaP) survival and metastasis are critical to the discovery of novel therapeutic targets. The monomeric G protein Rap1 has been implicated in cancer tumorigenesis. Rap1 signals to pathways involved in cell adhesion, migration, and survival, suggesting Rap1 may promote several processes associated with cancer cell metastasis. Examination of CaP cell lines revealed cells with a high metastatic ability exhibited increased Rap1 activity and reduced expression of the negative regulator Rap1GAP. Rap1 can be further stimulated in these cells by stromal-derived factor (SDF-1), an agonist known to regulate tumor cell metastasis and tropism to bone. Activation of Rap1 increased CaP cell migration and invasion, and inhibition of Rap1A activity via RNAi-mediated knockdown or ectopic expression of Rap1GAP markedly impaired CaP cell migration and invasion. Additional studies implicate integrins α4, β3, and αvβ3 in the mechanism of Rap1-mediated CaP migration and invasion. Extending the effect of Rap1 activity in CaP metastasis in vivo, introduction of activated Rap1 into CaP cells dramatically enhanced the rate and incidence of CaP metastasis in a xenograft mouse model. These studies provide compelling evidence to support a role for aberrant Rap1 activation in CaP progression, and suggest that targeting Rap1 signaling could provide a means to control metastatic progression of this cancer. [Cancer Res 2009;69(12):4962–8]
Multi-center, Placebo-controlled, Double-blind, Randomized Study of Oral Toceranib Phosphate (SU11654), a Receptor Tyrosine Kinase Inhibitor, for the Treatment of Dogs with Recurrent (Either Local or Distant) Mast Cell Tumor Following Surgical Excision
Authors: London Cheryl A. , Malpas Phyllis B. , Wood-Follis Stacey L. , Boucher Joseph F. , Rusk Anthony W. , Rosenberg Mona P. , Henry Carolyn J. , Mitchener Kathy L. , Klein Mary K. , Hintermeister John G. , Bergman Philip J. , Couto Guillermo C. , Mauldin Guy N. , Michels Gina M. 
Published: May 2009

Abstract
Purpose: The purpose of this study was to determine the objective response rate (ORR) following treatment of canine mast cell tumors (MCT) with toceranib phosphate (Palladia, SU11654), a kinase inhibitor with both antitumor and antiangiogenic activity through inhibition of KIT, vascular endothelial growth factor receptor 2, and PDGFRβ. Secondary objectives were to determine biological response rate, time to tumor progression, duration of objective response, health-related quality of life, and safety of Palladia.
Experimental Design: Dogs were randomized to receive oral Palladia 3.25 mg/kg or placebo every other day for 6 weeks in the blinded phase. Thereafter, eligible dogs received open-label Palladia.
Results: The blinded phase ORR in Palladia-treated dogs (n = 86) was 37.2% (7 complete response, 25 partial response) versus 7.9% (5 partial response) in placebo-treated dogs (n = 63; P = 0.0004). Of 58 dogs that received Palladia following placebo-escape, 41.4% (8 complete response, 16 partial response) experienced objective response. The ORR for all 145 dogs receiving Palladia was 42.8% (21 complete response, 41 partial response); among the 62 responders, the median duration of objective response and time to tumor progression was 12.0 weeks and 18.1 weeks, respectively. Palladia-treated responders scored higher on health-related quality of life versus Palladia-treated nonresponders (P = 0.030). There was no significant difference in the number of dogs with grade 3/4 (of 4) adverse events; adverse events were generally manageable with dose modification and/or supportive care.
Conclusions: Palladia has biological activity against canine MCTs and can be administered on a continuous schedule without need for routine planned treatment breaks. This clinical trial further shows that spontaneous tumors in dogs are good models to evaluate therapeutic index of targeted therapeutics in a clinical setting.
“Antimyeloangiogenic” Therapy for Cancer by Inhibiting PlGF
Authors: Loges Sonja , Schmidt Thomas , Carmeliet Peter 
Published: May 2009

Abstract
Inhibition of tumor angiogenesis emerged as valuable strategy to treat cancer and has revolutionized the face of clinical oncology by prolonging the life of numerous cancer patients. However, the duration of this response is rather short and tumors rapidly evade treatment, leaving antiangiogenic treatment thus far unable to cure cancer. Hence, novel targets are needed to diversify antiangiogenic treatments and to overcome resistance. Recent data support the concept that tumor infiltration by bone marrow-derived myeloid cells confers resistance to current antiangiogenic drugs targeting primarily vascular endothelial growth factor (VEGF). In this review, we will summarize (pre)clinical data on the role of PlGF and its receptor VEGFR-1 in promoting angiogenesis and inflammation, and the “antimyeloangiogenic” activity of an antibody against PlGF (αPlGF), which may help to overcome resistance against VEGF(R)Is. Because of these promising results, a humanized αPlGF antibody (TB403) is currently evaluated in different phase I clinical trials in cancer patients.
Therapeutic Targeting of ATP7B in Ovarian Carcinoma
Authors: Mangala Lingegowda S. , Zuzel Vesna , Schmandt Rosemarie , Leshane Erik S. , Halder Jyotsna B. , Armaiz-Pena Guillermo N. , Spannuth Whitney A. , Tanaka Takemi , Shahzad Mian M.K. , Lin Yvonne G. , Nick Alpa M. , Danes Christopher G. , Lee Jeong-Won , Jennings Nicholas B. , Vivas-Mejia Pablo E. , Wolf Judith K. , Coleman Robert L. , Siddik Zahid H. , Lopez-Berestein Gabriel , Lutsenko Svetlana , Sood Anil K. 
Published: May 2009

Abstract
Purpose: Resistance to platinum chemotherapy remains a significant problem in ovarian carcinoma. Here, we examined the biological mechanisms and therapeutic potential of targeting a critical platinum resistance gene, ATP7B, using both in vitro and in vivo models.
Experimental Design: Expression of ATP7A and ATP7B was examined in ovarian cancer cell lines by real-time reverse transcription-PCR and Western blot analysis. ATP7A and ATP7B gene silencing was achieved with targeted small interfering RNA (siRNA) and its effects on cell viability and DNA adduct formation were examined. For in vivo therapy experiments, siRNA was incorporated into the neutral nanoliposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC).
Results: ATP7A and ATP7B genes were expressed at higher levels in platinum-resistant cells compared with sensitive cells; however, only differences in ATP7B reached statistical significance. ATP7A gene silencing had no significant effect on the sensitivity of resistant cells to cisplatin, but ATP7B silencing resulted in 2.5-fold reduction of cisplatin IC50 levels and increased DNA adduct formation in cisplatin-resistant cells (A2780-CP20 and RMG2). Cisplatin was found to bind to the NH2-terminal copper-binding domain of ATP7B, which might be a contributing factor to cisplatin resistance. For in vivo therapy experiments, ATP7B siRNA was incorporated into DOPC and was highly effective in reducing tumor growth in combination with cisplatin (70-88% reduction in both models compared with controls). This reduction in tumor growth was accompanied by reduced proliferation, increased tumor cell apoptosis, and reduced angiogenesis.
Conclusion: These data provide a new understanding of cisplatin resistance in cancer cells and may have implications for therapeutic reversal of drug resistance.