bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic Evaluation of Polyamine Analogue Drug Candidates against
Enterocytozoon bieneusi
in a SCID Mouse Model
Authors: Feng Xiaochuan , Reddy Venudhar K. , Mayanja-Kizza Harriet , Weiss Louis M. , Marton Laurence J. , Tzipori Saul
Published: March 2009

Enterocytozoon bieneusi
is the most common cause of chronic diarrhea in individuals with human immunodeficiency virus infection or AIDS, and there is no effective therapy. The inhibitory activities of polyamine analogues (PG-11157, PG-11158, and PG-11302) against
E. bieneusi
infection were evaluated in SCID mice preconditioned with anti-gamma interferon monoclonal antibody intraperitoneally (i.p.). Mice were challenged orally with 10
4
E. bieneusi
spores, and groups of mice were treated orally or i.p. 14 days later for 7 days. The inhibitory activities of the drugs against infection were determined by enumerating the
E. bieneusi
spores in feces three times a week by an immunofluorescence assay. Immunohistochemistry staining confirmed the infection within enterocytes. Oral administration of the analogues PG-11157 (at 150 or 75 mg/kg of body weight/day) and PG-11302 (at 250 mg/kg/day) had significant inhibitory activity (96.2 to 99.6%) that was slightly better than that of fumagillin (1 mg/kg/day; 93.7%). The inhibitory activity with i.p. injection was significant only with PG-11302 at 20 mg/kg/day. While the treatments considerably reduced the levels of spore excretion, neither polyamine analogues nor fumagillin was able to completely eliminate
E. bieneusi
, as excretion reappeared within 7 days after the end of treatment. Drug toxicity was apparent during treatment, but it disappeared at the end of treatment. These results warrant further examination of the analogues PG-11157 and PG-11302.
Regulation of
mprF
in Daptomycin-Nonsusceptible
Staphylococcus aureus
Strains
Authors: Yang Soo-Jin , Xiong Yan Q. , Dunman Paul M. , Schrenzel Jacques , François Patrice , Peschel Andreas , Bayer Arnold S.
Published: March 2009

We used a well-characterized isogenic set of clinical bloodstream
Staphylococcus aureus
strains to study (i) regulation of
mprF
-mediated phosphatidylglycerol lysinylation in the contexts of in vitro daptomycin (DAP) nonsuceptibility and (ii) the role of
mprF
mutation in endovascular virulence. We observed a correlation between increased expression of a mutant
mprF
gene and reduced in vitro DAP susceptibility. There were no detectable fitness differences between strains in experimental infective endocarditis.
In Vitro Activity of Terbinafine Combined with Caspofungin and Azoles against
Pythium insidiosum
Authors: Cavalheiro Ayrton S. , Maboni Grazieli , de Azevedo Maria I. , Argenta Juliana S. , Pereira Daniela I. B. , Spader Tatiana B. , Alves Sydney H. , Santurio Janio M.
Published: March 2009

In this text we evaluated the in vitro antifungal activities of terbinafine combined with caspofungin, miconazole, ketoconazole, and fluconazole against 17
Pythium insidiosum
strains by using the microdilution checkerboard method. Synergistic interactions were observed with terbinafine combined with caspofungin (41.2% of the strains), fluconazole (41.2%), ketoconazole (29.4%), and miconazole (11.8%). No antagonistic effects were observed. The combination of terbinafine plus caspofungin or terbinafine plus fluconazole may have significant therapeutic potential for treatment of pythiosis.
The Octadecyloxyethyl Ester of (
S
)-9-[3-Hydroxy-2-(Phosphonomethoxy) Propyl]Adenine Is a Potent and Selective Inhibitor of Hepatitis C Virus Replication in Genotype 1A, 1B, and 2A Replicons
Authors: Wyles David L. , Kaihara Kelly A. , Korba Brent E. , Schooley Robert T. , Beadle James R. , Hostetler Karl Y.
Published: March 2009

The octadecyloxyethyl (ODE) and hexadecyloxypropyl (HDP) esters of (
S
)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine (HPMPA) are potent inhibitors of orthopoxvirus, herpesvirus, human immunodeficiency virus type 1, and hepatitis B virus replication in vitro. HDP and ODE esters of (
S
)-HPMPA and (
R
)-HPMPA were evaluated for their activity in hepatitis C virus (HCV) replicon assays using luciferase (1B and 2A replicons) or RNA (1B) quantification. The ODE ester of (
S
)-HPMPA [ODE-(
S
)-HPMPA] was the most active compound, with 50% effective concentrations (EC
50
s) in the 0.69 to 1.31 μM range. HDP and ODE esters of (
R
)-HPMPA were severalfold less active, while (
S
)-HPMPA and (
R
)-HPMPA were inactive. In genotype 1A and 1B replicons analyzed by HCV RNA analysis, ODE-(
S
)-HPMPA was the most active compound, with EC
50
s of 1.8 and 2.1 μM, respectively.
Antiviral Activity of MK-4965, a Novel Nonnucleoside Reverse Transcriptase Inhibitor
Authors: Lai Ming-Tain , Munshi Vandna , Touch Sinoeun , Tynebor Robert M. , Tucker Thomas J. , McKenna Philip M. , Williams Theresa M. , DiStefano Daniel J. , Hazuda Daria J. , Miller Michael D.
Published: March 2009

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are the mainstays of therapy for the treatment of human immunodeficiency virus type 1 (HIV-1) infections. However, the effectiveness of NNRTIs can be hampered by the development of resistance mutations which confer cross-resistance to drugs in the same class. Extensive efforts have been made to identify new NNRTIs that can suppress the replication of the prevalent NNRTI-resistant viruses. MK-4965 is a novel NNRTI that possesses both diaryl ether and indazole moieties. The compound displays potency at subnanomolar concentrations against wild-type (WT), K103N, and Y181C reverse transcriptase (RT) in biochemical assays. MK-4965 is also highly potent against the WT virus and two most prevalent NNRTI-resistant viruses (viruses that harbor the K103N or the Y181C mutation), against which it had 95% effective concentrations (EC95s) of <30 nM in the presence of 10% fetal bovine serum. The antiviral EC95of MK-4965 was reduced approximately four- to sixfold when it was tested in 50% human serum. Moreover, MK-4965 was evaluated with a panel of 15 viruses with NNRTI resistance-associated mutations and showed a superior mutant profile to that of efavirenz but not to that of etravirine. MK-4965 was similarly effective against various HIV-1 subtypes and viruses containing nucleoside reverse transcriptase inhibitor or protease inhibitor resistance-conferring mutations. A two-drug combination study showed that the antiviral activity of MK-4965 was nonantagonistic with each of the 18 FDA-licensed drugs tested vice versa in the present study. Taken together, these in vitro data show that MK-4965 possesses the desired properties for further development as a new NNRTI for the treatment of HIV-1 infection.
NovelS-Adenosylmethionine Decarboxylase Inhibitors for the Treatment of Human African Trypanosomiasis
Authors: Barker Robert H. , Liu Hanlan , Hirth Bradford , Celatka Cassandra A. , Fitzpatrick Richard , Xiang Yibin , Willert Erin K. , Phillips Margaret A. , Kaiser Marcel , Bacchi Cyrus J. , Rodriguez Aixa , Yarlett Nigel , Klinger Jeffrey D. , Sybertz Edmund
Published: March 2009

Trypanosomiasis remains a significant disease across the sub-Saharan African continent, with 50,000 to 70,000 individuals infected. The utility of current therapies is limited by issues of toxicity and the need to administer compounds intravenously. We have begun a program to pursue lead optimization around MDL 73811, an irreversible inhibitor ofS-adenosylmethionine decarboxylase (AdoMetDC). This compound is potent but in previous studies cleared rapidly from the blood of rats (T. L. Byers, T. L. Bush, P. P. McCann, and A. J. Bitonti, Biochem. J. 274:527-533). One of the analogs synthesized (Genz-644131) was shown to be highly active againstTrypanosoma brucei rhodesiensein vitro (50% inhibitory concentration, 400 pg/ml). Enzyme kinetic studies showed Genz-644131 to be approximately fivefold more potent than MDL 73811 against theT. brucei bruceiAdoMetDC-prozyme complex. This compound was stable in vitro in rat and human liver microsomal and hepatocyte assays, was stable in rat whole-blood assays, did not significantly inhibit human cytochrome P450 enzymes, had no measurable efflux in CaCo-2 cells, and was only 41% bound by serum proteins. Pharmacokinetic studies of mice following intraperitoneal dosing showed that the half-life of Genz-644131 was threefold greater than that of MDL 73811 (7.4 h versus 2.5 h). Furthermore, brain penetration of Genz-644131 was 4.3-fold higher than that of MDL 73811. Finally, in vivo efficacy studies ofT. b. bruceistrain STIB 795-infected mice showed that Genz-644131 significantly extended survival (from 6.75 days for controls to >30 days for treated animals) and cured animals infected withT. b. bruceistrain LAB 110 EATRO. Taken together, the data strengthen validation of AdoMetDC as an important parasite target, and these studies have shown that analogs of MDL 73811 can be synthesized with improved potency and brain penetration.
Yersinia pestisCan Reside in Autophagosomes and Avoid Xenophagy in Murine Macrophages by Preventing Vacuole Acidification
Authors: Pujol Céline , Klein Kathryn A. , Romanov Galina A. , Palmer Lance E. , Cirota Carol , Zhao Zijiang , Bliska James B.
Published: March 2009

Yersinia pestissurvives and replicates in phagosomes of murine macrophages. Previous studies demonstrated thatY. pestis-containing vacuoles (YCVs) acquire markers of late endosomes or lysosomes in naïve macrophages and that this bacterium can survive in macrophages activated with the cytokine gamma interferon. An autophagic process known as xenophagy, which destroys pathogens in acidic autophagolysosomes, can occur in naïve macrophages and is upregulated in activated macrophages. Studies were undertaken here to investigate the mechanism ofY. pestissurvival in phagosomes of naïve and activated macrophages and to determine if the pathogen avoids or co-opts autophagy. Colocalization of the YCV with markers of autophagosomes or acidic lysosomes and the pH of the YCV were determined by microscopic imaging of infected macrophages. Some YCVs contained double membranes characteristic of autophagosomes, as determined by electron microscopy. Fluorescence microscopy showed that ∼40% of YCVs colocalized with green fluorescent protein (GFP)-LC3, a marker of autophagic membranes, and that YCVs failed to acidify below pH 7 in naïve macrophages. Replication ofY. pestisin naïve macrophages caused accumulation of LC3-II, as determined by immunoblotting. While activation of infected macrophages increased LC3-II accumulation, it decreased the percentage of GFP-LC3-positive YCVs (∼30%). A viable count assay showed thatY. pestissurvived equally well in macrophages proficient for autophagy and macrophages rendered deficient for this process by Cre-mediated deletion ofATG5, revealing that this pathogen does not require autophagy for intracellular replication. We conclude that although YCVs can acquire an autophagic membrane and accumulate LC3-II, the pathogen avoids xenophagy by preventing vacuole acidification.
Genetically Modified L3,7 and L2 Lipooligosaccharides from
Neisseria meningitidis
Serogroup B Confer a Broad Cross-Bactericidal Response
Authors: Weynants V. , Denoël P. , Devos N. , Janssens D. , Feron C. , Goraj K. , Momin P. , Monnom D. , Tans C. , Vandercammen A. , Wauters F. , Poolman Jan T.
Published: March 2009

Currently available
Neisseria meningitidis
serogroup B (MenB) vaccines are based on outer membrane vesicles (OMVs) that are obtained from wild-type strains. They are purified with the aim of decreasing the lipooligosaccharide (LOS) content and hence reduce the reactogenicity of the vaccine even though LOS is a potential protective antigen. In <2-year-old children, these MenB vaccines confer protection only against strains expressing homologous PorA, a major and variable outer membrane protein. Our objective was to develop a safe LOS-based vaccine against MenB. To this end, we used modified
porA
knockout strains expressing genetically detoxified (
msbB
gene-deleted) L2 and L3,7 LOSs, allowing the production of LOS-enriched OMVs. The vaccine-induced antibodies were found to be bactericidal against nearly all invasive strains, irrespective of capsular serogroup. In addition, we have also demonstrated that LOS lacking the terminal galactose (with a
lgtB
mutation; truncated L3 LOS), but not LOS produced without the
galE
gene, induced a bactericidal antibody response in mice similar to that seen for LOS containing the full lacto-
N
-neotetraose (L3,7 LOS). In conclusion, a bivalent detoxified LOS OMV-based vaccine demonstrated the potential to afford a broad cross-protection against meningococcal disease.
Lex2B, a Phase-Variable Glycosyltransferase, Adds either a Glucose or a Galactose to
Haemophilus influenzae
Lipopolysaccharide
Authors: Deadman M. E. , Hermant P. , Engskog M. , Makepeace K. , Moxon E. R. , Schweda E. K. H. , Hood D. W.
Published: March 2009

Nontypeable
Haemophilus influenzae
is a commensal that frequently causes otitis media and respiratory tract infections. The
lex2
locus encodes a glycosyltransferase that is phase variably expressed and contributes to the significant intrastrain heterogeneity of lipopolysaccharide (LPS) composition in
H. influenzae
. In serotype b strains, Lex2B adds the second β-glucose in the oligosaccharide extension from the proximal heptose of the triheptose inner core backbone; this extension includes a digalactoside that plays a role in resistance of the bacteria to the killing effect of serum. As part of our studies of the structure and genetics of LPS in nontypeable
H. influenzae
, we show here that there are allelic polymorphisms in the
lex2B
sequence that correlate with addition of either a glucose or a galactose to the same position in the LPS molecule across strains. Through exchange of
lex2
alleles between strains we show that alteration of a single amino acid at position 157 in Lex2B appears to be sufficient to direct the alternative glucosyl- or galactosyltransferase activities. Allelic exchange strains express LPS with altered structure and biological properties compared to the wild-type LPS. Thus, Lex2B contributes to both inter- and intrastrain LPS heterogeneity through its polymorphic sequences and phase-variable expression.
Virus et prophages dans les écosystèmes aquatiques
Authors: Sime-Ngando Télesphore , Colombet Jonathan
Published: March 2009

In this review, available data on the structure (diversity, abundance, biomass) and functional imprints (bacteriolysis, lysogeny, gene transfers, regulation of prokaryotic diversity) of natural viruses in the context of food webs in aquatic microbial ecology, and the related biogeochemical cycles, are summarized. Viruses are the most abundant, and probably the most diverse, biological entities in aquatic ecosystems and in the biosphere (i.e., viriosphere). Aquatic viruses typically exceed 107particles/mL in mesotrophic conditions, the majority being represented by phages without tails and by tailed-phages such as members of the family Siphoviridae. Both types of phages have a small capsid and a small genome size, which is considered an evolutionary adaptation to planktonic life. Their contribution to microbial mortality is significant. There is strong evidence that phages exert a significant pressure on the community structure and diversity and on the diversification of potential hosts, mainly through two major pathways: biogeochemical catalysis from lysis products and horizontal gene transfers. In turn, phages are sensitive to environmental factors, both in terms of integrity and of infectivity. Some phages contain typical viral genes that code for biological functions of interest, such as photosynthesis. In general, development in viral ecology is a source of new knowledge for the scientific community in the domain of environmental sciences, but also in the context of evolutionary biology of living cellular organisms, the obligatory hosts for viruses. For example, the recent discovery of a giant virus that becomes ill through infection by another virus (i.e., a viriophage) is fuelling debate about whether viruses are alive. Finally, future research directions are identified in the context of general aquatic ecology, including ecological researches on cyanophages and other phytoplanktonic phages as a priority, primarily in freshwater lakes.
Morphological and biochemical changes inPseudomonas fluorescensbiofilms induced by sub-inhibitory exposure to antimicrobial agents
Authors: Dynes James J. , Lawrence John R. , Korber Darren R. , Swerhone George D.W. , Leppard Gary G. , Hitchcock Adam P.
Published: March 2009

Confocal laser scanning microscopy (CLSM) and scanning transmission X-ray microscopy (STXM) were used to examine the morphological and biochemical changes in Pseudomonas fluorescens biofilms grown in the presence of subinhibitory concentrations of 4 antimicrobial agents: triclosan, benzalkonium chloride, chlorhexidine dihydrochloride, and trisodium phosphate. CLSM analyses using the stains SYTO9 and propidium iodide indicated that the antimicrobial agents affected cell membrane integrity and cellular density to differing degrees. However, fluorescein diacetate assays and plate counts demonstrated that the cells remained metabolically active. Fluorescent lectin binding assays showed that changes in the arrangement and composition of the exopolymer matrix of the biofilms also occurred and that these changes depended on the antimicrobial agent. Detailed single cell analyses using STXM provided evidence that the cell morphology, and the spatial distribution and relative amounts of protein, lipids and polysaccharides in the biofilms and within the cells were different for each antimicrobial. The distribution of chlorhexidine in the biofilm, determined from its distinct spectral signature, was localized mainly inside the bacterial cells. Each antimicrobial agent elicited a unique response; P. fluorescens cells and biofilms changed their morphology and architecture, as well as the distribution and abundance of biomacromolecules, in particular the exopolymer matrix. Pseudomonas fluorescens also exhibited adaptation to benzalkonium chloride at 10 µg/mL. Our observations point to the importance of changes in the quantity and chemistry of the exopolymeric matrix in the response to antimicrobial agents and suggest their importance as targets for control.
Extracellular superoxide anion production contributes to the virulence ofXanthomonas oryzaepv.oryzae
Authors: Li Xin , Pang Xinyue , Zhi Dejuan , Wang Jinsheng , Li Minquan , Li Hongyu
Published: March 2009

Endogenous superoxide anion production was determined by electron spin resonance in wild-type strains and avrXa7 mutants of Xanthomonas oryzae pv. oryzae . The localization of superoxide anion was carried out in the intra- and extra-cellular fractions. Results showed the presence of superoxide anion in multi-locations of X. oryzae pv. oryzae cells. The extracellular fraction was the major location of superoxide anion production. Furthermore, a positive relationship was shown between the levels of endogenous superoxide anion and the virulence of strains. These indubitable results suggested that the superoxide anion contributes to the virulence of X. oryzae pv. oryzae.
Reduced in vivo phosphodiesterase-4 response to acute noradrenaline challenge in diet-induced obese rats
Authors: Greene Michael , Thackeray James T. , Kenk Miran , Thorn Stephanie L. , Bevilacqua Lisa , Harper Mary-Ellen , Beanlands Rob S. , DaSilva Jean N.
Published: March 2009

Altered sympathetic nervous activity has been linked to the development and persistence of obesity, partly relating to overfeeding. Binding of the selective, positron-emitting phosphodiesterase-4 (PDE4) inhibitor (R)-[11C]rolipram provides a direct index of the cAMP-hydrolyzing enzyme PDE4. This study examines progressive alterations in PDE4 in a high-fat-fed obese animal model. (R)-[11C]Rolipram was injected into diet-induced obese (DIO) and diet-resistant (DR) rats; the animals were killed after 45 min, tissues were extracted, and radioactivity was quantified. Responsiveness of PDE4 to acute noradrenaline (NA) stimulation was determined by 3 h pretreatment with the NA reuptake inhibitor desipramine. There was minimal variance in caloric intake, weight gain, fasting glucose, insulin, and energy expenditure (indirect calorimetry) measures. Basal (R)-[11C]rolipram binding was comparable between DIO and DR rats at 2 or 8 weeks of feeding. The normal increase of PDE4 levels in response to elevated NA by desipramine pretreatment was ablated in PDE4-rich tissues, including brain, heart, and skeletal muscle, of DIO animals after 8 weeks of high-fat diet. Lean DR rats maintained PDE4 responsiveness indicative of a normal NA signal transduction.
Role of protein kinase C β2activation in TNF-α-induced human vascular endothelial cell apoptosis
Authors: Wang Fang , Liu Hui-min , Irwin Michael G. , Xia Zhong-yuan , Huang Zhiyong , Ouyang Jingping , Xia Zhengyuan
Published: March 2009

The circulatory inflammatory cytokine tumor necrosis factor alpha (TNF-α) is increased in pathologic conditions that initiate or exacerbate vascular endothelial injury, such as diabetes. Protein kinase C (PKC) has been shown to play a critical role in TNF-α-induced human endothelial cell apoptosis. However, the relative roles played by specific isoforms of PKC in TNF-α-induced human endothelial cell apoptosis have not been addressed. We investigated the effects of a selective PKCβ2inhibitor (CGP53353) on TNF-α-induced apoptosis in human vascular endothelial cells (cell line ECV304) and on the production of reactive oxygen species and nitric oxide, and compared its effects with rottlerin, a reagent that has been shown to reduce PKCδ protein levels. Cultured human vascular endothelial cells (ECV304) were treated for 24 h with one of 4 regimes: 40 ng/mL TNF-α alone (TNF-α), TNF-α with 10 µmol/L rottlerin (T+rottlerin), TNF-α with 1 µmol/L CGP53353 (T+CGP), or untreated (control). Cell viability was measured by MTT assay, and cell apoptosis was assessed by flow cytometry. TNF-α-induced endothelial cell apoptosis was associated with dramatic increases in production of intracellular hydrogen peroxide (approximately 20 times greater than control) and superoxide (approximately 16 times greater than control), as measured by dichlorofluorescein and dihydroethidium fluorescent staining, respectively. This increase was accompanied by reduced activity of superoxide dismutase and glutathione peroxidase and, subsequently, an increase in the lipid peroxidation product malondialdehyde. CGP53353, but not rottlerin, abolished or attenuated all these changes. We conclude that PKCβ2plays a major role in TNF-α-induced human vascular endothelial cell apoptosis.
NovelLPLmutations associated with lipoprotein lipase deficiency: two case reports and a literature review
Authors: Rahalkar Amit R. , Giffen Fiona , Har Bryan , Ho Josephine , Morrison Katherine M. , Hill John , Wang Jian , Hegele Robert A. , Joy Tisha
Published: March 2009

Lipoprotein lipase (LPL) is a key enzyme involved with hydrolysis and removal of triglycerides from plasma. LPL deficiency is a rare condition with an estimated prevalence of 1 in 106. It is characterized biochemically by elevated triglycerides and lowered HDL in the plasma and clinically by a constellation of signs and symptoms during childhood including failure to thrive, lipemia retinalis, eruptive xanthomas, hepatosplenomegaly, and acute pancreatitis. Nearly 100 mutations in the LPL gene have been associated with LPL deficiency. Here we report 2 unrelated pedigrees with LPL deficiency from 2 novel disease-causing LPL mutations: a Gly159Glu missense mutation in exon 5 and a 4-bp ACGG deletion at the 3′ boundary of exon 2. We present molecular findings of these 2 cases and review the biochemical, clinical, and genetic features of LPL deficiency.
Growth and ionoregulatory ontogeny of wild and hatchery-raised juvenile pink salmon (Oncorhynchus gorbuscha)
Authors: Grant A. , Gardner M. , Nendick L. , Sackville M. , Farrell A. P. , Brauner C. J.
Published: March 2009

Juvenile pink salmon ( Oncorhynchus gorbuscha (Walbaum, 1792)) enter seawater (SW) shortly following emergence. Little is known about growth and development during this life-history stage when sensitivity to sea louse exposure may be high, an issue that is of current concern in British Columbia. We tested the hypothesis that growth and ionoregulatory development were similar in hatchery-raised (Quinsam) and wild (Glendale and One’s Point) juvenile pink salmon (measured over 22 weeks) following SW entry. Fish body mass increased from 0.20 ± 0.01 to 6.47 ± 0.37 g, with mean specific growth rates of 2.74% to 3.05% body mass·day–1among the three groups. In all three groups, gill Na+–K+-ATPase (NKA) activity peaked at 12 µmol ADP·mg protein–1·h–1following 8 weeks post-transfer to SW. Whole body Na+and Cl–concentrations, which again did not differ among groups, were highest upon initial exposure to SW (~70 mmol·kg wet mass–1) and declined over time as gill NKA activity increased, indicating that the hypo-osmoregulatory capacity was not fully developed following emergence and initial entry into SW. Thus, consistent with our hypothesis, few differences were observed between hatchery-raised and wild juvenile pink salmon reared under laboratory conditions. These baseline data may be important for future studies in determining the effects of sea lice on wild juvenile pink salmon.
Ambient temperature and annual timing affect torpor bouts and euthermic phases of hibernating European ground squirrels (Spermophilus citellus)
Authors: Németh István , Nyitrai Viktor , Altbäcker Vilmos
Published: March 2009

The low body temperature state of hibernating mammals is interrupted regularly by short euthermic phases. The frequency of these euthermic phases changes according to the phase of hibernation. This typical pattern, common among ground squirrels (genus Spermophilus F. Cuvier, 1825), can be regulated by internal factors and affected by outside temperature. To evaluate the effects of internal annual timing and ambient temperature, we monitored nest temperatures of overwintering European ground squirrels ( Spermophilus citellus (L., 1766)) under three temperature conditions during late hibernation (9, 5, 0 °C). Our results showed that in spite of constant thermal conditions, an annual timing effect changed torpor-bout length (TBL) at 9 and 5 °C but not at 0 °C. Ambient temperature had an independent influence on TBL and euthermic phases. The loss in body mass was higher at higher ambient temperatures and was affected by TBL and euthermic phases. Thus, the hibernation pattern of European ground squirrels is regulated by both an annual timing pattern and the ambient temperature in the hibernacula.
Transportation of Pacific salmon carcasses from streams to riparian forests by bears
Authors: Quinn Thomas P. , Carlson Stephanie M. , Gende Scott M. , Rich, Jr. Harry B.
Published: March 2009

Predation on Pacific salmon by bears (genus Ursus L., 1758) can be an important ecosystem process because the spatial distribution of carcasses largely determines whether marine-derived nutrients cycle through aquatic or terrestrial pathways. Direct observations on three streams in southeastern Alaska indicated that 49% of the pink ( Oncorhynchus gorbuscha (Walbaum, 1792)) and chum ( Oncorhynchus keta (Walbaum in Artedi, 1792)) salmon killed by bears were carried into the forest. The tendency of bears to transport carcasses was independent of the sex and species of salmon, but unspawned fish were more often transported than fish that had completed spawning. Data on tagged sockeye salmon ( Oncorhynchus nerka (Walbaum in Artedi, 1792)) in one southwestern Alaska stream indicated that 42.6% of the killed salmon were transported, and that higher percentages were transported in years when salmon densities were greater. At six other streams, on average, 68.1% of the sockeye salmon killed were apparently transported away from the stream into the forest. Combining the data from all sites, the proportion of carcasses transported increased with water depth at the site. These results emphasize the role that bears play in mediating the interactions between nutrients from salmon and the terrestrial and aquatic ecosystems, and the variation in carcass distribution among streams and among years.
Molecular systematics of the genus Sigmodon: results from mitochondrial and nuclear gene sequences
Authors: Henson Dallas D. , Bradley Robert D.
Published: March 2009

Phylogenetic relationships within the genus Sigmodon Say and Ord, 1825 were examined using sequence data from multiple gene regions, including exon 1 of the nuclear-encoded interphotoreceptor retinoid binding protein, intron 7 of the nuclear beta-fibrinogen gene, and the mitochondrial cytochrome b gene from 27 individuals representing 11 species of Sigmodon. Nuclear genes were analyzed independently, combined with each other, and combined with the mitochondrial data. Topologies were constructed using parsimony and Bayesian methods, with nodal support provided by bootstrap and posterior probability values. All analyses recovered four independent clades (I–IV), each representing unique species groups: hispidus , fulviventer , peruanus , and alstoni . The analyses from the combined data also provided support for relationships previously proposed within those species groups.
THE INFLUENCE OF NET QUARKS ON YIELDS AND RAPIDITY SPECTRA OF IDENTIFIED HADRONS
Authors: SONG JUN , SHAO FENG-LAN , XIE QU-BING
Published: March 2009

Within a quark combination model, we study systematically the yields and rapidity spectra of various hadrons in central Au + Au collisions at [Formula: see text]. We find that considering the difference in rapidity between net quarks and newborn quarks, the data of multiplicities, rapidity distributions for π±, K±, [Formula: see text] and, in particular, the ratios of charged antihadron to hadron as a function of rapidity, can be well described. The effects of net quarks on various hadrons are analyzed, and the rapidity distributions for [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text] are predicted. We discuss the rapidity distribution of net baryons, and find that it reflects exactly the energy loss of colliding nuclei.
SUPERGRAVITY SOLUTIONS WITH CONSTANT SCALAR INVARIANTS
Authors: COLEY A. , FUSTER A. , HERVIK S.
Published: March 2009

We study a class of constant scalar invariant (CSI) space–times which belong to the higher-dimensional Kundt class and which are solutions of supergravity. We review the known CSI supergravity solutions in this class and we explicitly present a number of new exact CSI supergravity solutions, some of which are Einstein.
INTERACTION OF LASER BEAMS WITH A PLASMA
Authors: COLIN THIERRY , EBRARD GÉRALDINE , GALLICE GÉRARD
Published: March 2009

In this paper, we construct a model for the propagation of two laser beams in a plasma. The originality of our model lies in the fact that it is valid uniformly in terms of the angle between both beams while it is not the case for standard models. In a simplified case we show that the solution converges towards the solution of the classical ones for large angles.
CESÀRO–VOLTERRA PATH INTEGRAL FORMULA ON A SURFACE
Authors: CIARLET PHILIPPE G. , GRATIE LILIANA , SERPILLI MICHELE
Published: March 2009

If a symmetric matrix field e = (eij) of order three satisfies the Saint-Venant compatibility relations in a simply-connected open subset Ω of ℝ3, then e is the linearized strain tensor field of a displacement field v of Ω, i.e. [Formula: see text] in Ω. A classical result, due to Cesàro and Volterra, asserts that, if the field e is smooth, the unknown displacement field v(x) at any point x ∈ Ω can be explicitly written as a path integral inside Ω with endpoint x, and whose integrand is an explicit function of the functions eij and their derivatives.

Now let ω be a simply-connected open subset in ℝ2 and let θ : ω → ℝ3 be a smooth immersion. If two symmetric matrix fields (γαβ) and (ραβ) of order two satisfy appropriate compatibility relations in ω, then (γαβ) and (ραβ) are the linearized change of metric and change of curvature tensor field corresponding to a displacement vector field η of the surface θ(ω).

We show here that a "Cesàro–Volterra path integral formula on a surface" likewise holds when the fields (γαβ) and (ραβ) are smooth. This means that the displacement vector η(y) at any point θ(y), y ∈ ω, of the surface θ(ω) can be explicitly computed as a path integral inside ω with endpoint y, and whose integrand is an explicit function of the functions γαβ and ραβ and their covariant derivatives.

Such a formula has potential applications to the mathematical analysis and numerical simulation of linear "intrinsic" shell models.
CONTEXTUAL AND TACTICAL CHANGES IN STANDARDS WARS: WHAT CONSEQUENCES FOR "WINNERS"?
Authors: VARÉ ARNAUD X. , SEIFERT RALF W.
Published: March 2009

Over the last decades, battles for technological dominance between competing technologies have had a significant impact on many industries. In this paper, we investigate how the fast-moving technology environment influences the tactical choices of companies trying to establish their products as de facto standards. We analyze contextual changes in the evolution of standards wars using a literature survey supported by three integrated case studies. We develop the portfolio of tactics that competing companies should apply in the management of emerging standards wars, composed both of traditional and new deployment tactics. We demonstrate that contextual and tactical changes heighten the pressures on timing and the competition exposure in today's standards competitions. As a consequence, it becomes more difficult for an alleged "winner" to "take all" in the marketplace.
ASSESSING UNIVERSITY TECHNOLOGY TRANSFER: A MEASURE OF EFFICIENCY PATTERNS
Authors: KIM JISUN , ANDERSON TIMOTHY , DAIM TUGRUL
Published: March 2009

There have been very active and significant studies done in the area of university technologies transfer (UTT). One interested topic among them is to measure performance of the UTT. Data Envelopment Analysis (DEA) has been regarded as a proper approach to measure the university technology transfer efficiency (UTTE). However, current studies stay in identifying efficient and inefficient universities and related output or input variables which could contribute to improve their efficiencies. This study is intended to understand further how the universities recognized efficient are different and the changes of their performance over years. For this purpose, this study proposes a new approach, the efficiency pattern diagram, to identify changing patterns of the technology transfer of 17 efficient universities out of 51 US universities from 2001 to 2004. Five efficiency patterns are identified by this study: "newly emerging", "strengthening", "strong", "weakening", and "declining". The properties of each pattern and limitations of the approach are discussed with verification of the pattern by extending them to 2005.
Data structures and requirements for
hp
finite element software
Authors: Bangerth W. , Kayser-Herold O.
Published: March 2009

Finite element methods approximate solutions of partial differential equations by restricting the problem to a finite dimensional function space. In
hp
adaptive finite element methods, one defines these discrete spaces by choosing different polynomial degrees for the shape functions defined on a locally refined mesh.

Although this basic idea is quite simple, its implementation in algorithms and data structures is challenging. It has apparently not been documented in the literature in its most general form. Rather, most existing implementations appear to be for special combinations of finite elements, or for discontinuous Galerkin methods.

In this article, we discuss generic data structures and algorithms used in the implementation of
hp
methods for arbitrary elements, and the complications and pitfalls one encounters. As a consequence, we list the information a description of a finite element has to provide to the generic algorithms for it to be used in an
hp
context. We support our claim that our reference implementation is efficient using numerical examples in two dimensions and three dimensions, and demonstrate that the
hp
-specific parts of the program do not dominate the total computing time. This reference implementation is also made available as part of the Open Source deal.II finite element library.
Algorithm 892
Authors: Jonasson Kristjan
Published: March 2009

A standard Fortran 95 module for printing scalars, vectors, and matrices to external files is provided. The module can display variables of default kind of all intrinsic types (integer, real, complex, logical, and character), and add-on modules are provided for data of the nondefault kind. The main module is self-contained and incorporating it only requires that it be compiled and linked with a program containing a “use dispmodule” statement. A generic interface and optional parameters are used, so that the same subroutine name, DISP, is used to display items of different data type and rank, irrespective of display options. The subroutine is quite versatile, and hopefully can improve Fortran's competitiveness against other array programming languages. The module also contains a function TOSTRING to convert numerical scalars and vectors to strings.
Security in the Browser
Authors: Wadlow Thomas , Gorelik Vlad
Published: March 2009

Sealed in a depleted uranium sphere at the bottom of the ocean. That’s the often-mentioned description of what it takes to make a computer reasonably secure. Obviously, in the Internet age or any other, such a machine would be fairly useless.
Sulfur amino acid deficiency upregulates intestinal methionine cycle activity and suppresses epithelial growth in neonatal pigs
Authors: Bauchart-Thevret Caroline , Stoll Barbara , Chacko Shaji , Burrin Douglas G.
Published: March 2009

We recently showed that the developing gut is a significant site of methionine transmethylation to homocysteine and transsulfuration to cysteine. We hypothesized that sulfur amino acid (SAA) deficiency would preferentially reduce mucosal growth and antioxidant function in neonatal pigs. Neonatal pigs were enterally fed a control or an SAA-free diet for 7 days, and then whole body methionine and cysteine kinetics were measured using an intravenous infusion of [1-13C;methyl-2H3]methionine and [15N]cysteine. Body weight gain and plasma methionine, cysteine, homocysteine, and taurine and total erythrocyte glutathione concentrations were markedly decreased (−46% to −85%) in SAA-free compared with control pigs. Whole body methionine and cysteine fluxes were reduced, yet methionine utilization for protein synthesis and methionine remethylation were relatively preserved at the expense of methionine transsulfuration, in response to SAA deficiency. Intestinal tissue concentrations of methionine and cysteine were markedly reduced and hepatic levels were maintained in SAA-free compared with control pigs. SAA deficiency increased the activity of methionine metabolic enzymes, i.e., methionine adenosyltransferase, methionine synthase, and cystathionine β-synthase, and S-adenosylmethionine concentration in the jejunum, whereas methionine synthase activity increased and S-adenosylmethionine level decreased in the liver. Small intestine weight and protein and DNA mass were lower, whereas liver weight and DNA mass were unchanged, in SAA-free compared with control pigs. Dietary SAA deficiency induced small intestinal villus atrophy, lower goblet cell numbers, and Ki-67-positive proliferative crypt cells in association with lower tissue glutathione, especially in the jejunum. We conclude that SAA deficiency upregulates intestinal methionine cycle activity and suppresses epithelial growth in neonatal pigs.
Decreased ADP‐Ribosyl Cyclase Activity in Peripheral Blood Mononuclear Cells from Diabetic Patients with Nephropathy
Authors: Ohtsuji Michio , Yagi Kunimasa , Shintaku-Kubota Miyuki , Kojima-Koba Yukiko , Ito Naoko , Sugihara Masako , Yamaaki Naoto , Chujo Daisuke , Nohara Atsushi , Takeda Yoshiyu , Kobayashi Junji , Yamagishi Masakazu , Higashida Haruhiro
Published: March 2009

Aims/hypothesis. ADP‐ribosyl‐cyclase activity (ADPRCA) of CD38 and other ectoenzymes mainly generate cyclic adenosine 5′diphosphate‐(ADP‐) ribose (cADPR) as a second messenger in various mammalian cells, including pancreatic beta cells and peripheral blood mononuclear cells (PBMCs). Since PBMCs contribute to the pathogenesis of diabetic nephropathy, ADPRCA of PBMCs could serve as a clinical prognostic marker for diabetic nephropathy. This study aimed to investigate the connection between ADPRCA in PBMCs and diabetic complications.
Methods. PBMCs from 60 diabetic patients (10 for type 1 and 50 for type 2) and 15 nondiabetic controls were fluorometrically measured for ADPRCA based on the conversion of nicotinamide guanine dinucleotide (NGD+) into cyclic GDP‐ribose.
Results. ADPRCA negatively correlated with the level of HbA1c (P = .040, R2 = .073), although ADPRCA showed no significant correlation with gender, age, BMI, blood pressure, level of fasting plasma glucose and lipid levels, as well as type, duration, or medication of diabetes. Interestingly, patients with nephropathy, but not other complications, presented significantly lower ADPRCA than those without nephropathy
(P = .0198) and diabetes (P = .0332). ANCOVA analysis adjusted for HbA1c showed no significant correlation between ADPRCA and nephropathy. However, logistic regression analyses revealed that determinants for nephropathy were systolic blood pressure and ADPRCA, not HbA1c.
Conclusion/interpretation. Decreased ADPRCA significantly correlated with diabetic nephropathy. ADPRCA in PBMCs would be an important marker associated with diabetic nephropathy.
Systems-Based Improvement in Door-to-Balloon Times at a Large Urban Teaching Hospital
Authors: Parikh Shailja V. , Treichler D. Brent , DePaola Sheila , Sharpe Jennifer , Valdes Marisa , Addo Tayo , Das Sandeep R. , McGuire Darren K. , de Lemos James A. , Keeley Ellen C. , Warner John J. , Holper Elizabeth M.
Published: March 2009

Background—

Timely reperfusion in ST-segment elevation myocardial infarction (STEMI) patients improves clinical outcomes. Implementing strategies to target institutional-specific delays are crucial for improved patient care.

Methods and Results—

Using a novel strategy to analyze specific components of door-to-balloon time (DBT) at our institution, we previously identified several specific interval delays in our prior STEMI protocol. We then implemented 4 strategies to reduce DBT: (1) emergency department physician activation of the STEMI protocol; (2) “single call” broadcast paging of the STEMI team by the page operator; (3) immediate feedback to the emergency and cardiology departments with joint monthly quality improvement meetings; and (4) transfer of the off-hours STEMI patient directly to the laboratory on activation by an in-hospital team. After implementation of the new protocol, we examined each component time interval from the first 59 consecutive STEMI patients treated with the new protocol between March 2007 and June 2008 and compared time intervals with the previous 184 STEMI patients. Compared with the previous 184 STEMI patients, the median DBT of the subsequent 59 STEMI patients significantly improved from 125 to 86 minutes (
P
<0.0001). This improvement was largely driven by a decrease in the interval from the initial 12-lead ECG to activation of the on-call catheterization team (from 40 to 11 minutes,
P
<0.0001).

Conclusions—

After examining specific component delays in our institution’s DBT, we were able to successfully use quality improvement strategies to focus on specific sources of delay in our institution. This dramatically improved our median DBT toward the goal of achieving a guideline-recommended <90 minutes for all patients.
A Statewide Collaborative Initiative to Improve the Quality of Care for Patients With Acute Myocardial Infarction and Heart Failure
Authors: Brush John E. , Rensing Edna , Song Frank , Cook Sallie , Lynch Janet , Thacker Leroy , Gurram Sarat , Bonow Robert O. , Brough Joani , Valentine C. Michael
Published: March 2009

Background—

To enhance quality improvement, we created a unique statewide collaboration among 3 organizations: the Virginia Health Quality Center (Virginia’s Medicare Quality Improvement Organization), the American College of Cardiology, and the American Heart Association. The goal was to improve discharge measures for acute myocardial infarction and heart failure.

Methods and Results—

In 2004, 29 hospitals participated in the collaborative initiative. Using Medicare data submitted from 2004 through the second quarter of 2006, we analyzed adherence to individual discharge measures and all-or-none appropriate care measures for acute myocardial infarction, heart failure, and both. To control for differences in hospital characteristics, we were able to match 21 of the participating hospitals with 21 similar nonparticipating hospitals. In this paired analysis, the total appropriate care measure increased from 61% to 77% in participating hospitals compared with an increase from 51% to 60% in nonparticipating hospitals (
P
<0.0001). A generalized linear mixed model examining the full data set at the patient level failed to show a clear advantage among participating hospitals. Participating hospitals had higher baseline rates for most quality measures, suggesting a possible effect of a prior collaborative. Further analysis of only hospitals that participated in a prior collaborative showed that participants in the current collaborative initiative had higher rates of improvement for 7 of 10 quality measures and appropriate care measures for heart failure, acute myocardial infarction, or both (all
P
<0.05).

Conclusions—

We report a unique collaboration of a Medicare Quality Improvement Organization and 2 national organizations to address quality of care for acute myocardial infarction and heart failure. A composite measure of quality (the total appropriate care measure) improved more in the participating hospitals during the timeframe of the intervention, although the greater improvement in this and other measures in the participating hospitals appeared to be dependent on participation in a prior collaborative initiative.