WorldWideScience

Sample records for broad spectrum contracts

  1. Treatment of Organic-Contaminated Mixed Waste Utilizing the Oak Ridge Broad Spectrum Contracts

    Energy Technology Data Exchange (ETDEWEB)

    Estes, C. H.; Heacker, F. K.; Cunningham, J.; Westich, B.

    2003-02-25

    To meet the requirements of the State of Tennessee's Department of Environment and Conservation Commissioner's Order for treatment of mixed low level wastes, Oak Ridge has utilized commercial treatment companies to treat and dispose mixed waste. Over the past year, Oak Ridge has shipped organic-contaminated mixed waste for treatment to meet milestones under the Site Treatment Plan. Oak Ridge has established contracts with commercial treatment companies accessible by all DOE sites for treatment of a wide range of mixed wastes. The paper will describe and summarize the activities involved in treating and disposing of organic-contaminated mixed waste utilizing DOE complex-wide contracts and the treatment and disposal activities required. This paper will describe the case history of treatment of several organic-contaminated mixed wastes from the Oak Ridge Reservation requiring treatment prior to disposal. The paper will include waste category information, implementation activities, and contract access. The paper will discuss the specifics of the mixed waste treatment including waste characteristics, treatment process and equipment utilized, and treatment results. Additional information will be provided on task order development, waste profiling, treatment pricing, and the disposal process.

  2. Broad-Spectrum Drugs Against Viral Agents

    Directory of Open Access Journals (Sweden)

    Jonathan P. Wong

    2008-09-01

    Full Text Available Development of antivirals has focused primarily on vaccines and on treatments for specific viral agents. Although effective, these approaches may be limited in situations where the etiologic agent is unknown or when the target virus has undergone mutation, recombination or reassortment. Augmentation of the innate immune response may be an effective alternative for disease amelioration. Nonspecific, broad-spectrum immune responses can be induced by double-stranded (dsRNAs such as poly (ICLC, or oligonucleotides (ODNs containing unmethylated deocycytidyl-deoxyguanosinyl (CpG motifs. These may offer protection against various bacterial and viral pathogens regardless of their genetic makeup, zoonotic origin or drug resistance.

  3. Ceftaroline: a new broad-spectrum cephalosporin.

    Science.gov (United States)

    Lim, Lauren; Sutton, Elizabeth; Brown, Jack

    2011-03-15

    The pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of ceftaroline are reviewed. Ceftaroline, a new broad- spectrum antibiotic, is approved for the treatment of complicated skin and skin structure infections (cSSSIs) and community- acquired pneumonia (CAP). This β-lactam antibiotic has extended activity against gram-positive organisms and has activity against common gram-negative organisms. The drug's spectrum of activity includes both methicillin-resistant Staphylococcus aureus and multidrug-resistant Streptococcus pneumoniae. However, its activity against extended-spectrum β-lactamase-producing bacteria is limited. These bacteria, particularly those that express AmpC β-lactamase, greatly reduce the activity of ceftaroline. The prodrug of ceftaroline (ceftaroline fosamil) is rapidly converted to its active form (ceftaroline) in plasma. This dose-linear drug has been found to be pharmacodynamically best correlated with the percentage of time that free drug concentrations remain above the minimum inhibitory concentration. Ceftaroline's safety profile is similar to that of the other cephalosporins, with minimal adverse drug reactions, most of which are considered mild. Currently available pharmacokinetic, animal, and clinical studies have found that ceftaroline has reasonable efficacy and tolerability but have also revealed that dosing regimen modifications may be needed in patients with moderate-to-severe renal impairment. The recommended dosage of ceftaroline for the treatment of cSSSIs and CAP is 600 mg infused intravenously over 60 minutes every 12 hours. The recommended duration of therapy is 5-14 and 5-7 days for cSSSIs and CAP, respectively. Additional Phase III studies are currently underway. Ceftaroline is a new broad-spectrum cephalosporin indicated for the treatment of cSSSIs and CAP caused by susceptible gram-positive and gram-negative organisms.

  4. Development of a Broad-Spectrum Antiviral Agent with Activity ...

    African Journals Online (AJOL)

    Development of a Broad-Spectrum Antiviral Agent with Activity Against Herpesvirus Replication and Gene Expression. ... Tropical Journal of Pharmaceutical Research ... Purpose: To evaluate the broad-spectrum antiviral activity of peptide H9 (H9) in vitro in order to gain insight into its underlying molecular mechanisms.

  5. Broad Spectrum Sanitizing Wipes with Food Additives, Phase I

    Data.gov (United States)

    National Aeronautics and Space Administration — Microcide proposes to develop novel multipurpose non-toxic sanitizing wipes that are aqueous based, have shelf life of 3-5 years, have broad spectrum microbicidal...

  6. Broad spectrum antiangiogenic treatment for ocular neovascular diseases.

    Directory of Open Access Journals (Sweden)

    Ofra Benny

    2010-09-01

    Full Text Available Pathological neovascularization is a hallmark of late stage neovascular (wet age-related macular degeneration (AMD and the leading cause of blindness in people over the age of 50 in the western world. The treatments focus on suppression of choroidal neovascularization (CNV, while current approved therapies are limited to inhibiting vascular endothelial growth factor (VEGF exclusively. However, this treatment does not address the underlying cause of AMD, and the loss of VEGF's neuroprotective can be a potential side effect. Therapy which targets the key processes in AMD, the pathological neovascularization, vessel leakage and inflammation could bring a major shift in the approach to disease treatment and prevention. In this study we have demonstrated the efficacy of such broad spectrum antiangiogenic therapy on mouse model of AMD.Lodamin, a polymeric formulation of TNP-470, is a potent broad-spectrum antiangiogenic drug. Lodamin significantly reduced key processes involved in AMD progression as demonstrated in mice and rats. Its suppressive effects on angiogenesis, vascular leakage and inflammation were studied in a wide array of assays including; a Matrigel, delayed-type hypersensitivity (DTH, Miles assay, laser-induced CNV and corneal micropocket assay. Lodamin significantly suppressed the secretion of various pro-inflammatory cytokines in the CNV lesion including monocyte chemotactic protein-1 (MCP-1/Ccl2. Importantly, Lodamin was found to regress established CNV lesions, unlike soluble fms-like tyrosine kinase-1 (sFlk-1. The drug was found to be safe in mice and have little toxicity as demonstrated by electroretinography (ERG assessing retinal and by histology.Lodamin, a polymer formulation of TNP-470, was identified as a first in its class, broad-spectrum antiangiogenic drug that can be administered orally or locally to treat corneal and retinal neovascularization. Several unique properties make Lodamin especially beneficial for ophthalmic

  7. Arbidol as a broad-spectrum antiviral: an update.

    Science.gov (United States)

    Blaising, Julie; Polyak, Stephen J; Pécheur, Eve-Isabelle

    2014-07-01

    Arbidol (ARB) is a Russian-made small indole-derivative molecule, licensed in Russia and China for prophylaxis and treatment of influenza and other respiratory viral infections. It also demonstrates inhibitory activity against other viruses, enveloped or not, responsible for emerging or globally prevalent infectious diseases such as hepatitis B and C, gastroenteritis, hemorrhagic fevers or encephalitis. In this review, we will explore the possibility and pertinence of ARB as a broad-spectrum antiviral, after a careful examination of its physico-chemical properties, pharmacokinetics, toxicity, and molecular mechanisms of action. Recent studies suggest that ARB's dual interactions with membranes and aromatic amino acids in proteins may be central to its broad-spectrum antiviral activity. This could impact on the virus itself, and/or on cellular functions or critical steps in virus-cell interactions, thereby positioning ARB as both a direct-acting antiviral (DAA) and a host-targeting agent (HTA). In the context of recent studies in animals and humans, we will discuss the prospective clinical use of ARB in various viral infections. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Genetically Engineered Broad-Spectrum Disease Resistance in Tomato

    Science.gov (United States)

    Oldroyd, Giles E. D.; Staskawicz, Brian J.

    1998-08-01

    Resistance in tomato to the bacterial pathogen Pseudomonas syringae pathovar tomato requires Pto and Prf. Mutations that eliminate Prf show a loss of both Pto resistance and sensitivity to the organophosphate insecticide fenthion, suggesting that Prf controls both phenotypes. Herein, we report that the overexpression of Prf leads to enhanced resistance to a number of normally virulent bacterial and viral pathogens and leads to increased sensitivity to fenthion. These plants express levels of salicylic acid comparable to plants induced for systemic acquired resistance (SAR) and constitutively express pathogenesis related genes. These results suggest that the overexpression of Prf activates the Pto and Fen pathways in a pathogen-independent manner and leads to the activation of SAR. Transgene-induced SAR has implications for the generation of broad spectrum disease resistance in agricultural crop plants.

  9. Broad spectrum microarray for fingerprint-based bacterial species identification

    Directory of Open Access Journals (Sweden)

    Frey Jürg E

    2010-02-01

    Full Text Available Abstract Background Microarrays are powerful tools for DNA-based molecular diagnostics and identification of pathogens. Most target a limited range of organisms and are based on only one or a very few genes for specific identification. Such microarrays are limited to organisms for which specific probes are available, and often have difficulty discriminating closely related taxa. We have developed an alternative broad-spectrum microarray that employs hybridisation fingerprints generated by high-density anonymous markers distributed over the entire genome for identification based on comparison to a reference database. Results A high-density microarray carrying 95,000 unique 13-mer probes was designed. Optimized methods were developed to deliver reproducible hybridisation patterns that enabled confident discrimination of bacteria at the species, subspecies, and strain levels. High correlation coefficients were achieved between replicates. A sub-selection of 12,071 probes, determined by ANOVA and class prediction analysis, enabled the discrimination of all samples in our panel. Mismatch probe hybridisation was observed but was found to have no effect on the discriminatory capacity of our system. Conclusions These results indicate the potential of our genome chip for reliable identification of a wide range of bacterial taxa at the subspecies level without laborious prior sequencing and probe design. With its high resolution capacity, our proof-of-principle chip demonstrates great potential as a tool for molecular diagnostics of broad taxonomic groups.

  10. Ceftaroline fosamil: a new broad-spectrum cephalosporin.

    Science.gov (United States)

    Laudano, Joseph B

    2011-04-01

    Ceftaroline fosamil, the prodrug of the active metabolite, ceftaroline, is a new, broad-spectrum cephalosporin recently approved in the USA for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia (CABP). Ceftaroline has potent in vitro activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae, as well as common Gram-negative organisms. The high affinity of ceftaroline for penicillin-binding proteins is responsible for the potent activity observed against clinically relevant pathogens. With respect to the treatment of CABP, the activity of ceftaroline against pathogens such as S. pneumoniae, S. aureus, Haemophilus influenzae and Moraxella catarrhalis demonstrates coverage across a broad range of pathogens typically encountered in clinical practice. Ceftaroline is also very active against common pathogens seen in ABSSSIs such as S. aureus (methicillin-susceptible S. aureus and methicillin-resistant S. aureus) and Streptococcus pyogenes. Ceftaroline exhibits a dose-proportional pharmacokinetic profile, similar to other renally excreted cephalosporins, and has a well-tolerated safety profile consistent with the cephalosporin class. Ceftaroline fosamil is compatible via Y-site administration with many other commonly administered parenteral drugs.

  11. A Broad-Spectrum Inhibitor of CRISPR-Cas9.

    Science.gov (United States)

    Harrington, Lucas B; Doxzen, Kevin W; Ma, Enbo; Liu, Jun-Jie; Knott, Gavin J; Edraki, Alireza; Garcia, Bianca; Amrani, Nadia; Chen, Janice S; Cofsky, Joshua C; Kranzusch, Philip J; Sontheimer, Erik J; Davidson, Alan R; Maxwell, Karen L; Doudna, Jennifer A

    2017-09-07

    CRISPR-Cas9 proteins function within bacterial immune systems to target and destroy invasive DNA and have been harnessed as a robust technology for genome editing. Small bacteriophage-encoded anti-CRISPR proteins (Acrs) can inactivate Cas9, providing an efficient off switch for Cas9-based applications. Here, we show that two Acrs, AcrIIC1 and AcrIIC3, inhibit Cas9 by distinct strategies. AcrIIC1 is a broad-spectrum Cas9 inhibitor that prevents DNA cutting by multiple divergent Cas9 orthologs through direct binding to the conserved HNH catalytic domain of Cas9. A crystal structure of an AcrIIC1-Cas9 HNH domain complex shows how AcrIIC1 traps Cas9 in a DNA-bound but catalytically inactive state. By contrast, AcrIIC3 blocks activity of a single Cas9 ortholog and induces Cas9 dimerization while preventing binding to the target DNA. These two orthogonal mechanisms allow for separate control of Cas9 target binding and cleavage and suggest applications to allow DNA binding while preventing DNA cutting by Cas9. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Evaluation of Novel Antimicrobial Peptides as Topical Anti-Infectives with Broad-Spectrum Activity against Combat-Related Bacterial and Fungal Wound Infections

    Science.gov (United States)

    2017-10-01

    succeeded in developing resistance to a variety of AMPs. 2. Keywords Antimicrobial, peptides, anti-fungal, wounds, burns, bacterial resistance ...against Combat- Related Bacterial and Fungal Wound Infections PRINCIPAL INVESTIGATOR: Louis Edward Clemens Ph.D. CONTRACTING ORGANIZATION: Riptide...Anti-Infectives with Broad- Spectrum Activity against Combat-Related Bacterial and Fungal Wound Infections 5a. CONTRACT NUMBER 5b. GRANT NUMBER

  13. Risk Factors for Emergence of Resistance to Broad-Spectrum Cephalosporins among Enterobacter spp.

    Science.gov (United States)

    Kaye, Keith S.; Cosgrove, Sara; Harris, Anthony; Eliopoulos, George M.; Carmeli, Yehuda

    2001-01-01

    Among 477 patients with susceptible Enterobacter spp., 49 subsequently harbored third-generation cephalosporin-resistant Enterobacter spp. Broad-spectrum cephalosporins were independent risk factors for resistance (relative risk [OR] = 2.3, P = 0.01); quinolone therapy was protective (OR = 0.4, P = 0.03). There were trends toward decreased risk for resistance among patients receiving broad-spectrum cephalosporins and either aminoglycosides or imipenem. Of the patients receiving broad-spectrum cephalosporins, 19% developed resistance. PMID:11502540

  14. Detection of broad ultraviolet Fe II lines in the spectrum of NGC 1068

    International Nuclear Information System (INIS)

    Snijders, M.A.J.; Netzer, Hagai; Boksenberg, A.

    1986-01-01

    Ultraviolet observations of the nucleus of NGC 1068, obtained by the IUE over a period of 5 yr, are combined to give a high signal-to-noise spectrum of this source. The ultraviolet stellar continuum, obtained by comparison with ground-based data, is subtracted to show the nuclear non-stellar component. The resulting spectrum shows clearly the presence of strong broad FeII emission bands similar to those observed in many broad-line objects. Broad profiles are also seen in other strong emission lines. These observations confirm the recent discovery of an optical Seyfert type 1 spectrum in NGC 1068. (author)

  15. Ceftaroline fosamil: a novel broad-spectrum cephalosporin.

    Science.gov (United States)

    Bazan, J A; Martin, S I

    2010-10-01

    Ceftaroline fosamil is a new extended-spectrum cephalosporin with activity against drug-resistant Grampositive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae. At the same time, its Gramnegative spectrum of coverage includes common respiratory pathogens such as Haemophilus influenzae and Moraxella catarrhalis, as well as wild-type Enterobacteriaceae. In vivo efficacy for the treatment of experimental endocarditis, pneumonia, myositis and osteomyelitis has been demonstrated in animal models, while efficacy in the treatment of complicated skin and soft tissue infections and community-acquired pneumonia has been demonstrated in phase II and III clinical trials in humans. The drug is well tolerated and has a low rate of reported adverse events. The dose of ceftaroline fosamil used is 600 mg i.v. every 12 h for patients with normal renal function or mild renal dysfunction. In patients with moderate renal dysfunction, it has been suggested that ceftaroline fosamil be dosed at 400 mg i.v. over 60 min every 12 h. Ceftaroline fosamil is still under review by the U.S. FDA, and when approved, will be one of the first commercially available β-lactams with the ability to treat infections due to MRSA and other drug-resistant Gram-positive pathogens. Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

  16. Enhanced methanol production in plants provides broad spectrum insect resistance.

    Directory of Open Access Journals (Sweden)

    Sameer Dixit

    Full Text Available Plants naturally emit methanol as volatile organic compound. Methanol is toxic to insect pests; but the quantity produced by most of the plants is not enough to protect them against invading insect pests. In the present study, we demonstrated that the over-expression of pectin methylesterase, derived from Arabidopsis thaliana and Aspergillus niger, in transgenic tobacco plants enhances methanol production and resistance to polyphagous insect pests. Methanol content in the leaves of transgenic plants was measured using proton nuclear spectroscopy (1H NMR and spectra showed up to 16 fold higher methanol as compared to control wild type (WT plants. A maximum of 100 and 85% mortality in chewing insects Helicoverpa armigera and Spodoptera litura larvae was observed, respectively when fed on transgenic plants leaves. The surviving larvae showed less feeding, severe growth retardation and could not develop into pupae. In-planta bioassay on transgenic lines showed up to 99 and 75% reduction in the population multiplication of plant sap sucking pests Myzus persicae (aphid and Bemisia tabaci (whitefly, respectively. Most of the phenotypic characters of transgenic plants were similar to WT plants. Confocal microscopy showed no deformities in cellular integrity, structure and density of stomata and trichomes of transgenic plants compared to WT. Pollen germination and tube formation was also not affected in transgenic plants. Cell wall enzyme transcript levels were comparable with WT. This study demonstrated for the first time that methanol emission can be utilized for imparting broad range insect resistance in plants.

  17. Enhanced methanol production in plants provides broad spectrum insect resistance.

    Science.gov (United States)

    Dixit, Sameer; Upadhyay, Santosh Kumar; Singh, Harpal; Sidhu, Om Prakash; Verma, Praveen Chandra; K, Chandrashekar

    2013-01-01

    Plants naturally emit methanol as volatile organic compound. Methanol is toxic to insect pests; but the quantity produced by most of the plants is not enough to protect them against invading insect pests. In the present study, we demonstrated that the over-expression of pectin methylesterase, derived from Arabidopsis thaliana and Aspergillus niger, in transgenic tobacco plants enhances methanol production and resistance to polyphagous insect pests. Methanol content in the leaves of transgenic plants was measured using proton nuclear spectroscopy (1H NMR) and spectra showed up to 16 fold higher methanol as compared to control wild type (WT) plants. A maximum of 100 and 85% mortality in chewing insects Helicoverpa armigera and Spodoptera litura larvae was observed, respectively when fed on transgenic plants leaves. The surviving larvae showed less feeding, severe growth retardation and could not develop into pupae. In-planta bioassay on transgenic lines showed up to 99 and 75% reduction in the population multiplication of plant sap sucking pests Myzus persicae (aphid) and Bemisia tabaci (whitefly), respectively. Most of the phenotypic characters of transgenic plants were similar to WT plants. Confocal microscopy showed no deformities in cellular integrity, structure and density of stomata and trichomes of transgenic plants compared to WT. Pollen germination and tube formation was also not affected in transgenic plants. Cell wall enzyme transcript levels were comparable with WT. This study demonstrated for the first time that methanol emission can be utilized for imparting broad range insect resistance in plants.

  18. Enhanced Methanol Production in Plants Provides Broad Spectrum Insect Resistance

    Science.gov (United States)

    Dixit, Sameer; Upadhyay, Santosh Kumar; Singh, Harpal; Sidhu, Om Prakash; Verma, Praveen Chandra; K, Chandrashekar

    2013-01-01

    Plants naturally emit methanol as volatile organic compound. Methanol is toxic to insect pests; but the quantity produced by most of the plants is not enough to protect them against invading insect pests. In the present study, we demonstrated that the over-expression of pectin methylesterase, derived from Arabidopsis thaliana and Aspergillus niger, in transgenic tobacco plants enhances methanol production and resistance to polyphagous insect pests. Methanol content in the leaves of transgenic plants was measured using proton nuclear spectroscopy (1H NMR) and spectra showed up to 16 fold higher methanol as compared to control wild type (WT) plants. A maximum of 100 and 85% mortality in chewing insects Helicoverpa armigera and Spodoptera litura larvae was observed, respectively when fed on transgenic plants leaves. The surviving larvae showed less feeding, severe growth retardation and could not develop into pupae. In-planta bioassay on transgenic lines showed up to 99 and 75% reduction in the population multiplication of plant sap sucking pests Myzus persicae (aphid) and Bemisia tabaci (whitefly), respectively. Most of the phenotypic characters of transgenic plants were similar to WT plants. Confocal microscopy showed no deformities in cellular integrity, structure and density of stomata and trichomes of transgenic plants compared to WT. Pollen germination and tube formation was also not affected in transgenic plants. Cell wall enzyme transcript levels were comparable with WT. This study demonstrated for the first time that methanol emission can be utilized for imparting broad range insect resistance in plants. PMID:24223989

  19. Improved PCR Amplification of Broad Spectrum GC DNA Templates.

    Science.gov (United States)

    Guido, Nicholas; Starostina, Elena; Leake, Devin; Saaem, Ishtiaq

    2016-01-01

    Many applications in molecular biology can benefit from improved PCR amplification of DNA segments containing a wide range of GC content. Conventional PCR amplification of DNA sequences with regions of GC less than 30%, or higher than 70%, is complex due to secondary structures that block the DNA polymerase as well as mispriming and mis-annealing of the DNA. This complexity will often generate incomplete or nonspecific products that hamper downstream applications. In this study, we address multiplexed PCR amplification of DNA segments containing a wide range of GC content. In order to mitigate amplification complications due to high or low GC regions, we tested a combination of different PCR cycling conditions and chemical additives. To assess the fate of specific oligonucleotide (oligo) species with varying GC content in a multiplexed PCR, we developed a novel method of sequence analysis. Here we show that subcycling during the amplification process significantly improved amplification of short template pools (~200 bp), particularly when the template contained a low percent of GC. Furthermore, the combination of subcycling and 7-deaza-dGTP achieved efficient amplification of short templates ranging from 10-90% GC composition. Moreover, we found that 7-deaza-dGTP improved the amplification of longer products (~1000 bp). These methods provide an updated approach for PCR amplification of DNA segments containing a broad range of GC content.

  20. Observing broad-absorption line quasars with Spectrum-Rontgen-Gamma

    DEFF Research Database (Denmark)

    Singh, K.P.; Schnopper, H.W.; Westergaard, Niels Jørgen Stenfeldt

    1998-01-01

    Broad-absorption line quasars are found to have extremely weak soft X-ray emission when compared with other optically selected quasars. In the only example of PHL 5200 for which a detailed X-ray spectrum has been obtained with ASCA, strong absorption in the source appears to be responsible...... for the lack of soft Xray emission. Broad-band X-ray observations of a sample of BAL QSOs are proposed with a high throughput mission SPECTRUM-RONTGEN-GAMMA (SRG), to find out whether these sources are intrinsically weak over the entire bandwidth of X-rays or only in the soft X-rays due to absorption resulting...

  1. Novel water-based antiseptic lotion demonstrates rapid, broad-spectrum kill compared with alcohol antiseptic.

    Science.gov (United States)

    Czerwinski, Steven E; Cozean, Jesse; Cozean, Colette

    2014-01-01

    A novel alcohol-based antiseptic and a novel water-based antiseptic lotion, both with a synergistic combination of antimicrobial ingredients containing 0.2% benzethonium chloride, were evaluated using the standard time-kill method against 25 FDA-specified challenge microorganisms. The purpose of the testing was to determine whether a non-alcohol product could have equivalent rapid and broad-spectrum kill to a traditional alcohol sanitizer. Both the alcohol- and water-based products showed rapid and broad-spectrum antimicrobial activity. The average 15-s kill was 99.999% of the challenge organism for the alcohol-based antiseptic and 99.971% for the water-based antiseptic. The alcohol-based product demonstrated 100% of peak efficacy (60s) within the first 15s, whereas the water-based product showed 99.97%. The novel alcohol-based antiseptic reduced concentrations of 100% of organisms by 99.999%, whereas the water-based antiseptic lotion showed the same reduction for 96% of organisms. A novel water-based antiseptic product demonstrated equivalent rapid, broad-spectrum antimicrobial activity to an alcohol-based sanitizer and provided additional benefits of reduced irritation, persistent effect, and greater efficacy against common viruses. The combination of rapid, broad-spectrum immediate kill and persistent efficacy against pathogens may have significant clinical benefit in limiting the spread of disease. Copyright © 2014 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.

  2. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

    DEFF Research Database (Denmark)

    Taylor, Jenny C; Martin, Hilary C; Lise, Stefano

    2015-01-01

    To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the numb...

  3. Broad- versus Narrow-Spectrum Oral Antibiotic Transition and Outcomes in Health Care-associated Pneumonia.

    Science.gov (United States)

    Buckel, Whitney R; Stenehjem, Edward; Sorensen, Jeff; Dean, Nathan; Webb, Brandon

    2017-02-01

    Guidelines recommend a switch from intravenous to oral antibiotics once patients who are hospitalized with pneumonia achieve clinical stability. However, little evidence guides the selection of an oral antibiotic for patients with health care-associated pneumonia, especially where no microbiological diagnosis is made. To compare outcomes between patients who were transitioned to broad- versus narrow-spectrum oral antibiotics after initially receiving broad-spectrum intravenous antibiotic coverage. We performed a secondary analysis of an existing database of adults with community-onset pneumonia admitted to seven Utah hospitals. We identified 220 inpatients with microbiology-negative health care-associated pneumonia from 2010 to 2012. After excluding inpatient deaths and treatment failures, 173 patients remained in which broad-spectrum intravenous antibiotics were transitioned to an oral regimen. We classified oral regimens as broad-spectrum (fluoroquinolone) versus narrow-spectrum (usually a β-lactam). We compared demographic and clinical characteristics between groups. Using a multivariable regression model, we adjusted outcomes by severity (electronically calculated CURB-65), comorbidity (Charlson Index), time to clinical stability, and length of intravenous therapy. Age, severity, comorbidity, length of intravenous therapy, and clinical response were similar between the two groups. Observed 30-day readmission (11.9 vs. 21.4%; P = 0.26) and 30-day all-cause mortality (2.3 vs. 5.3%; P = 0.68) were also similar between the narrow and broad oral antibiotic groups. In multivariable analysis, we found no statistically significant differences for adjusted odds of 30-day readmission (adjusted odds ratio, 0.56; 95% confidence interval, 0.06-5.2; P = 0.61) or 30-day all-cause mortality (adjusted odds ratio, 0.55; 95% confidence interval, 0.19-1.6; P = 0.26) between narrow and broad oral antibiotic groups. On the basis of analysis of a limited number of patients

  4. Broad-Spectrum Antibiotic Treatment and Subsequent Childhood Type 1 Diabetes

    DEFF Research Database (Denmark)

    Clausen, Tine D; Bergholt, Thomas; Bouaziz, Olivier

    2016-01-01

    BACKGROUND: Studies link antibiotic treatment and delivery by cesarean section with increased risk of chronic diseases through changes of the gut-microbiota. We aimed to evaluate the association of broad-spectrum antibiotic treatment during the first two years of life with subsequent onset...... of childhood type 1 diabetes and the potential effect-modification by mode of delivery. MATERIALS AND METHODS: A Danish nationwide cohort study including all singletons born during 1997-2010. End of follow-up by December 2012. Four national registers provided information on antibiotic redemptions, outcome...... and confounders. Redemptions of antibiotic prescriptions during the first two years of life was classified into narrow-spectrum or broad-spectrum antibiotics. Children were followed from age two to fourteen, both inclusive. The risk of type 1 diabetes with onset before the age of 15 years was assessed by Cox...

  5. Antibiotic combination therapy can select for broad-spectrum multidrug resistance in Pseudomonas aeruginosa.

    Science.gov (United States)

    Vestergaard, Martin; Paulander, Wilhelm; Marvig, Rasmus L; Clasen, Julie; Jochumsen, Nicholas; Molin, Søren; Jelsbak, Lars; Ingmer, Hanne; Folkesson, Anders

    2016-01-01

    Combination therapy with several antibiotics is one strategy that has been applied in order to limit the spread of antimicrobial resistance. We compared the de novo evolution of resistance during combination therapy with the β-lactam ceftazidime and the fluoroquinolone ciprofloxacin with the resistance evolved after single-drug exposure. Combination therapy selected for mutants that displayed broad-spectrum resistance, and a major resistance mechanism was mutational inactivation of the repressor gene mexR that regulates the multidrug efflux operon mexAB-oprM. Deregulation of this operon led to a broad-spectrum resistance phenotype that decreased susceptibility to the combination of drugs applied during selection as well as to unrelated antibiotic classes. Mutants isolated after single-drug exposure displayed narrow-spectrum resistance and carried mutations in the MexCD-OprJ efflux pump regulator gene nfxB conferring ciprofloxacin resistance, or in the gene encoding the non-essential penicillin-binding protein DacB conferring ceftazidime resistance. Reconstruction of resistance mutations by allelic replacement and in vitro fitness assays revealed that in contrast to single antibiotic use, combination therapy consistently selected for mutants with enhanced fitness expressing broad-spectrum resistance mechanisms. Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

  6. Acquisition of Broad-Spectrum Cephalosporin Resistance Leading to Colistin Resistance in Klebsiella pneumoniae.

    Science.gov (United States)

    Jayol, Aurélie; Nordmann, Patrice; Desroches, Marine; Decousser, Jean-Winoc; Poirel, Laurent

    2016-05-01

    An extended-spectrum β-lactamase (ESBL)-producing and colistin-resistant Klebsiella pneumoniae clinical isolate was recovered from a patient who was treated with cefotaxime. This isolate harbored a blaCTX-M-15 ESBL gene that was associated with an ISEcp1 insertion sequence. Transposition of that tandem occurred within the chromosomal mgrB gene, leading to inactivation of the mgrB gene and consequently to acquired resistance to colistin. We showed here a coselection of colistin resistance as a result of a broad-spectrum cephalosporin selective pressure. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  7. Investigating AAK1-and GAK-Regulated Virus-Host Interactions Uncovers Broad-Spectrum Antivirals

    Science.gov (United States)

    2017-02-16

    vaccines or 46 therapies. Targeting host pathways exploited by multiple viruses could offer broad-spectrum 47 solutions. We previously reported that...known as severe dengue, particularly 71 upon a secondary infection with a heterologous DENV strain. Consequently, development of a 72 dengue vaccine ...disease severity (3-5). While an Ebola vaccine has shown promise 76 recently (6), it is not yet approved. Moreover, there is no effective antiviral

  8. Broad-Spectrum Antimicrobial Epiphytic and Endophytic Fungi from Marine Organisms: Isolation, Bioassay and Taxonomy

    Directory of Open Access Journals (Sweden)

    Yan-Hua Zhu

    2009-04-01

    Full Text Available In the search for new marine derived antibiotics, 43 epi- and endophytic fungal strains were isolated from the surface or the inner tissue of different marine plants and invertebrates. Through preliminary and secondary screening, 10 of them were found to be able to produce broad-spectrum antimicrobial metabolites. By morphological and molecular biological methods, three active strains were characterized to be Penicillium glabrum, Fusarium oxysporum, and Alternaria alternata.

  9. Broad-Spectrum Antimicrobial Epiphytic and Endophytic Fungi from Marine Organisms: Isolation, Bioassay and Taxonomy

    Science.gov (United States)

    Zhang, Yi; Mu, Jun; Feng, Yan; Kang, Yue; Zhang, Jia; Gu, Peng-Juan; Wang, Yu; Ma, Li-Fang; Zhu, Yan-Hua

    2009-01-01

    In the search for new marine derived antibiotics, 43 epi- and endophytic fungal strains were isolated from the surface or the inner tissue of different marine plants and invertebrates. Through preliminary and secondary screening, 10 of them were found to be able to produce broad-spectrum antimicrobial metabolites. By morphological and molecular biological methods, three active strains were characterized to be Penicillium glabrum, Fusarium oxysporum, and Alternaria alternata. PMID:19597575

  10. FGI-104: a broad-spectrum small molecule inhibitor of viral infection.

    Science.gov (United States)

    Kinch, Michael S; Yunus, Abdul S; Lear, Calli; Mao, Hanwen; Chen, Hanson; Fesseha, Zena; Luo, Guangxiang; Nelson, Eric A; Li, Limin; Huang, Zhuhui; Murray, Michael; Ellis, William Y; Hensley, Lisa; Christopher-Hennings, Jane; Olinger, Gene G; Goldblatt, Michael

    2009-01-05

    The treatment of viral diseases remains an intractable problem facing the medical community. Conventional antivirals focus upon selective targeting of virus-encoded targets. However, the plasticity of viral nucleic acid mutation, coupled with the large number of progeny that can emerge from a single infected cells, often conspire to render conventional antivirals ineffective as resistant variants emerge. Compounding this, new viral pathogens are increasingly recognized and it is highly improbable that conventional approaches could address emerging pathogens in a timely manner. Our laboratories have adopted an orthogonal approach to combat viral disease: Target the host to deny the pathogen the ability to cause disease. The advantages of this novel approach are many-fold, including the potential to identify host pathways that are applicable to a broad-spectrum of pathogens. The acquisition of drug resistance might also be minimized since selective pressure is not directly placed upon the viral pathogen. Herein, we utilized this strategy of host-oriented therapeutics to screen small molecules for their abilities to block infection by multiple, unrelated virus types and identified FGI-104. FGI-104 demonstrates broad-spectrum inhibition of multiple blood-borne pathogens (HCV, HBV, HIV) as well as emerging biothreats (Ebola, VEE, Cowpox, PRRSV infection). We also demonstrate that FGI-104 displays an ability to prevent lethality from Ebola in vivo. Altogether, these findings reinforce the concept of host-oriented therapeutics and present a much-needed opportunity to identify antiviral drugs that are broad-spectrum and durable in their application.

  11. Targeting an Essential GTPase Obg for the Development of Broad-Spectrum Antibiotics.

    Directory of Open Access Journals (Sweden)

    Josephine A Bonventre

    Full Text Available A promising new drug target for the development of novel broad-spectrum antibiotics is the highly conserved small GTPase Obg (YhbZ, CgtA, a protein essential for the survival of all bacteria including Neisseria gonorrhoeae (GC. GC is the agent of gonorrhea, a prevalent sexually transmitted disease resulting in serious consequences on reproductive and neonatal health. A preventive anti-gonorrhea vaccine does not exist, and options for effective antibiotic treatments are increasingly limited. To address the dire need for alternative antimicrobial strategies, we have designed and optimized a 384-well GTPase assay to identify inhibitors of Obg using as a model Obg protein from GC, ObgGC. The assay was validated with a pilot screen of 40,000 compounds and achieved an average Z' value of 0.58 ± 0.02, which suggests a robust assay amenable to high-throughput screening. We developed secondary assessments for identified lead compounds that utilize the interaction between ObgGC and fluorescent guanine nucleotide analogs, mant-GTP and mant-GDP, and an ObgGC variant with multiple alterations in the G-domains that prevent nucleotide binding. To evaluate the broad-spectrum potential of ObgGC inhibitors, Obg proteins of Klebsiella pneumoniae and methicillin-resistant Staphylococcus aureus were assessed using the colorimetric and fluorescence-based activity assays. These approaches can be useful in identifying broad-spectrum Obg inhibitors and advancing the therapeutic battle against multidrug resistant bacteria.

  12. Relationship between the Broad Autism Phenotype, Social Relationships and Mental Health for Mothers of Children with Autism Spectrum Disorder

    Science.gov (United States)

    Pruitt, Megan M.; Rhoden, Madeline; Ekas, Naomi V.

    2018-01-01

    This study aimed to examine the mechanisms responsible for the association between the broad autism phenotype and depressive symptoms in mothers of a child with autism spectrum disorder. A total of 98 mothers who had a child with autism spectrum disorder between the ages of 2 and 16 years completed assessments of maternal broad autism phenotype,…

  13. Particle acceleration model for the broad-band baseline spectrum of the Crab nebula

    Science.gov (United States)

    Fraschetti, F.; Pohl, M.

    2017-11-01

    We develop a simple one-zone model of the steady-state Crab nebula spectrum encompassing both the radio/soft X-ray and the GeV/multi-TeV observations. By solving the transport equation for GeV-TeV electrons injected at the wind termination shock as a log-parabola momentum distribution and evolved via energy losses, we determine analytically the resulting differential energy spectrum of photons. We find an impressive agreement with the observed spectrum of synchrotron emission, and the synchrotron self-Compton component reproduces the previously unexplained broad 200-GeV peak that matches the Fermi/Large Area Telescope (LAT) data beyond 1 GeV with the Major Atmospheric Gamma Imaging Cherenkov (MAGIC) data. We determine the parameters of the single log-parabola electron injection distribution, in contrast with multiple broken power-law electron spectra proposed in the literature. The resulting photon differential spectrum provides a natural interpretation of the deviation from power law customarily fitted with empirical multiple broken power laws. Our model can be applied to the radio-to-multi-TeV spectrum of a variety of astrophysical outflows, including pulsar wind nebulae and supernova remnants, as well as to interplanetary shocks.

  14. Ceftobiprole: A novel, broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus.

    Science.gov (United States)

    Dauner, Daniel G; Nelson, Robert E; Taketa, Donna C

    2010-06-15

    The pharmacology, antimicrobial activity, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, and place in therapy of ceftobiprole are reviewed. Ceftobiprole, a novel, broad-spectrum, parenteral cephalosporin, inhibits the cell-wall synthesis of penicillin-binding proteins (PBPs) PBP2a and PBP2x, responsible for the resistance in staphylococci and pneumococci, respectively. Ceftobiprole has good activity against gram-positive aerobes and anaerobes, and its activity against gram-negative aerobes and anaerobes is species dependent. Ceftobiprole is relatively inactive against Acinetobacter species. Its ability to bind relevant PBPs of resistant gram-positive and gram-negative bacteria indicates its potential use in the treatment of hospital-acquired pneumonia and complicated skin and skin-structure infections (cSSSIs). Ceftobiprole is primarily excreted unchanged by the kidneys and exhibits linear pharmacokinetics. The half-life of the drug is approximately 3-4 hours. It exhibits minimal plasma protein binding (16%). Ceftobiprole does not inhibit the cytochrome P-450 isoenzyme system, so the possibility of drug-drug interactions is low. The drug has not been approved for use in the United States but has been approved in Canada and elsewhere. Ceftobiprole is currently undergoing Phase III clinical trials and has demonstrated activity against methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, and Pseudomonas aeruginosa. Completed Phase III trials used i.v. dosages of 500 mg every 8-12 hours. The most commonly observed adverse effects of ceftobiprole included headache and gastrointestinal upset. Ceftobiprole is a novel, broad-spectrum, parenteral cephalosporin undergoing Phase III clinical trials. Its broad spectrum of activity makes it a candidate for monotherapy of cSSSIs and pneumonias that have required combination therapy in the past.

  15. Broad spectrum moderators and advanced reflector filters using 208Pb

    DEFF Research Database (Denmark)

    Schönfeldt, Troels; Batkov, K.; Klinkby, Esben Bryndt

    2015-01-01

    thermalizing property of 208Pb to design a broad spectrum moderator, i.e. a moderator which emits thermal and cold neutrons from the same position. Using 208Pb as a reflector filter material is shown to be slightly less efficient than a conventional beryllium reflector filter. However, when surrounding...... the reflector filter by a cold moderator it is possible to regain the neutrons with wavelengths below the Bragg edge, which are suppressed in the beryllium reflector filter. In both the beryllium and lead case surrounding the reflector filter with a cold moderator increases the cold brightness significantly...

  16. Mimotope ELISA for detection of broad spectrum antibody against avian H5N1 influenza virus.

    Directory of Open Access Journals (Sweden)

    Yingwei Chen

    Full Text Available BACKGROUND: We have raised a panel of broad spectrum neutralizing monoclonal antibodies against the highly pathogenic H5N1 avian influenza virus, which neutralize the infectivity of, and afford protection against infection by, most of the major genetic groups of the virus evolved since 1997. Peptide mimics reactive with one of these broad spectrum H5N1 neutralizing antibodies, 8H5, were identified from random phage display libraries. METHOD: The amino acid residues of the most reactive 12mer peptide, p125 (DTPLTTAALRLV, were randomly substituted to improve its mimicry of the natural 8H5 epitope. RESULT: 133 reactive peptides with unique amino acid sequences were identified from 5 sub-libraries of p125. Four residues (2,4,5.9 of the parental peptide were preserved among all the derived peptides and probably essential for 8H5 binding. These are interspersed among four other residues (1,3,8,10, which exhibit restricted substitution and probably could contribute to binding, and another four (6,7,11,12 which could be randomly substituted and probably are not essential for binding. One peptide, V-1b, derived by substituting 5 of the latter residues is the most reactive and has a binding constant of 3.16×10(-9 M, which is 38 fold higher than the affinity of the parental p125. Immunoassay produced with this peptide is specifically reactive with 8H5 but not also the other related broad spectrum H5N1 avian influenza virus neutralizing antibodies. Serum samples from 29 chickens infected with H5N1 avian influenza virus gave a positive result by this assay and those from 12 uninfected animals gave a negative test result. CONCLUSION: The immunoassay produced with the 12 mer peptide,V1-b, is specific for the natural 8H5 epitope and can be used for detection of antibody against the broad spectrum neutralization site of H5N1 avian influenza virus.

  17. Broad-spectrum biosensor capable of detecting and identifying diverse bacterial and Candida species in blood.

    Science.gov (United States)

    Metzgar, David; Frinder, Mark; Lovari, Robert; Toleno, Donna; Massire, Christian; Blyn, Lawrence B; Ranken, Raymond; Carolan, Heather E; Hall, Thomas A; Moore, David; Hansen, Christian J; Sampath, Rangarajan; Ecker, David J

    2013-08-01

    We describe an assay which uses broad-spectrum, conserved-site PCR paired with mass spectrometry analysis of amplicons (PCR/electrospray ionization-mass spectrometry [ESI-MS]) to detect and identify diverse bacterial and Candida species in uncultured specimens. The performance of the assay was characterized using whole-blood samples spiked with low titers of 64 bacterial species and 6 Candida species representing the breadth of coverage of the assay. The assay had an average limit of detection of 100 CFU of bacteria or Candida per milliliter of blood, and all species tested yielded limits of detection between 20 and 500 CFU per milliliter. Over 99% of all detections yielded correct identifications, whether they were obtained at concentrations well above the limit of detection or at the lowest detectable concentrations. This study demonstrates the ability of broad-spectrum PCR/ESI-MS assays to detect and identify diverse organisms in complex natural matrices that contain high levels of background DNA.

  18. Broad spectrum antiviral activity for paramyxoviruses is modulated by biophysical properties of fusion inhibitory peptides.

    Science.gov (United States)

    Mathieu, Cyrille; Augusto, Marcelo T; Niewiesk, Stefan; Horvat, Branka; Palermo, Laura M; Sanna, Giuseppina; Madeddu, Silvia; Huey, Devra; Castanho, Miguel A R B; Porotto, Matteo; Santos, Nuno C; Moscona, Anne

    2017-03-08

    Human paramyxoviruses include global causes of lower respiratory disease like the parainfluenza viruses, as well as agents of lethal encephalitis like Nipah virus. Infection is initiated by viral glycoprotein-mediated fusion between viral and host cell membranes. Paramyxovirus viral fusion proteins (F) insert into the target cell membrane, and form a transient intermediate that pulls the viral and cell membranes together as two heptad-repeat regions refold to form a six-helix bundle structure that can be specifically targeted by fusion-inhibitory peptides. Antiviral potency can be improved by sequence modification and lipid conjugation, and by adding linkers between the protein and lipid components. We exploit the uniquely broad spectrum antiviral activity of a parainfluenza F-derived peptide sequence that inhibits both parainfluenza and Nipah viruses, to investigate the influence of peptide orientation and intervening linker length on the peptides' interaction with transitional states of F, solubility, membrane insertion kinetics, and protease sensitivity. We assessed the impact of these features on biodistribution and antiviral efficacy in vitro and in vivo. The engineering approach based on biophysical parameters resulted in a peptide that is a highly effective inhibitor of both paramyxoviruses and a set of criteria to be used for engineering broad spectrum antivirals for emerging paramyxoviruses.

  19. Shape and size engineered cellulosic nanomaterials as broad spectrum anti-microbial compounds.

    Science.gov (United States)

    Sharma, Priyanka R; Kamble, Sunil; Sarkar, Dhiman; Anand, Amitesh; Varma, Anjani J

    2016-06-01

    Oxidized celluloses have been used for decades as antimicrobial wound gauzes and surgical cotton. We now report the successful synthesis of a next generation narrow size range (25-35nm) spherical shaped nanoparticles of 2,3,6-tricarboxycellulose based on cellulose I structural features, for applications as new antimicrobial materials. This study adds to our previous study of 6-carboxycellulose. A wide range of bacteria such as Escherichia coli, Staphloccocus aureus, Bacillus subtilis and Mycobacterium tuberculosis (non-pathogenic as well as pathogenic strains) were affected by these polymers in in vitro studies. Activity against Mycobacteria were noted at high concentrations (MIC99 values 250-1000μg/ml, as compared to anti-TB drug Isoniazid 0.3μg/ml). However, the broad spectrum activity of oxidized celluloses and their nanoparticles against a wide range of bacteria, including Mycobacteria, show that these materials are promising new biocompatible and biodegradable drug delivery vehicles wherein they can play the dual role of being a drug encapsulant as well as a broad spectrum anti-microbial and anti-TB drug. Copyright © 2016. Published by Elsevier B.V.

  20. Novel Bacterial Topoisomerase Inhibitors with Potent Broad-Spectrum Activity against Drug-Resistant Bacteria.

    Science.gov (United States)

    Charrier, Cédric; Salisbury, Anne-Marie; Savage, Victoria J; Duffy, Thomas; Moyo, Emmanuel; Chaffer-Malam, Nathan; Ooi, Nicola; Newman, Rebecca; Cheung, Jonathan; Metzger, Richard; McGarry, David; Pichowicz, Mark; Sigerson, Ralph; Cooper, Ian R; Nelson, Gary; Butler, Hayley S; Craighead, Mark; Ratcliffe, Andrew J; Best, Stuart A; Stokes, Neil R

    2017-05-01

    The novel bacterial topoisomerase inhibitor class is an investigational type of antibacterial inhibitor of DNA gyrase and topoisomerase IV that does not have cross-resistance with the quinolones. Here, we report the evaluation of the in vitro properties of a new series of this type of small molecule. Exemplar compounds selectively and potently inhibited the catalytic activities of Escherichia coli DNA gyrase and topoisomerase IV but did not block the DNA breakage-reunion step. Compounds showed broad-spectrum inhibitory activity against a wide range of Gram-positive and Gram-negative pathogens, including biodefence microorganisms and Mycobacterium tuberculosis No cross-resistance with fluoroquinolone-resistant Staphylococcus aureus and E. coli isolates was observed. Measured MIC 90 values were 4 and 8 μg/ml against a panel of contemporary multidrug-resistant isolates of Acinetobacter baumannii and E. coli , respectively. In addition, representative compounds exhibited greater antibacterial potency than the quinolones against obligate anaerobic species. Spontaneous mutation rates were low, with frequencies of resistance typically 100 μM). In summary, the compounds' distinct mechanism of action relative to the fluoroquinolones, whole-cell potency, low potential for resistance development, and favorable in vitro safety profile warrant their continued investigation as potential broad-spectrum antibacterial agents. Copyright © 2017 American Society for Microbiology.

  1. Nanomedicine for Infectious Disease Applications: Innovation towards Broad-Spectrum Treatment of Viral Infections.

    Science.gov (United States)

    Jackman, Joshua A; Lee, Jaywon; Cho, Nam-Joon

    2016-03-02

    Nanomedicine enables unique diagnostic and therapeutic capabilities to tackle problems in clinical medicine. As multifunctional agents with programmable properties, nanomedicines are poised to revolutionize treatment strategies. This promise is especially evident for infectious disease applications, for which the continual emergence, re-emergence, and evolution of pathogens has proven difficult to counter by conventional approaches. Herein, a conceptual framework is presented that envisions possible routes for the development of nanomedicines as superior broad-spectrum antiviral agents against enveloped viruses. With lipid membranes playing a critical role in the life cycle of medically important enveloped viruses including HIV, influenza, and Ebola, cellular and viral membrane interfaces are ideal elements to incorporate into broad-spectrum antiviral strategies. Examples are presented that demonstrate how nanomedicine strategies inspired by lipid membranes enable a wide range of targeting opportunities to gain control of critical stages in the virus life cycle through either direct or indirect approaches involving membrane interfaces. The capabilities can be realized by enabling new inhibitory functions or improving the function of existing drugs through nanotechnology-enabled solutions. With these exciting opportunities, due attention is also given to the clinical translation of nanomedicines for infectious disease applications, especially as pharmaceutical drug-discovery pipelines demand new routes of innovation. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Identification and Structural Characterization of Naturally-Occurring Broad-Spectrum Cyclic Antibiotics Isolated from Paenibacillus

    Science.gov (United States)

    Knolhoff, Ann M.; Zheng, Jie; McFarland, Melinda A.; Luo, Yan; Callahan, John H.; Brown, Eric W.; Croley, Timothy R.

    2015-08-01

    The rise of antimicrobial resistance necessitates the discovery and/or production of novel antibiotics. Isolated strains of Paenibacillus alvei were previously shown to exhibit antimicrobial activity against a number of pathogens, such as E. coli, Salmonella, and methicillin-resistant Staphylococcus aureus (MRSA). The responsible antimicrobial compounds were isolated from these Paenibacillus strains and a combination of low and high resolution mass spectrometry with multiple-stage tandem mass spectrometry was used for identification. A group of closely related cyclic lipopeptides was identified, differing primarily by fatty acid chain length and one of two possible amino acid substitutions. Variation in the fatty acid length resulted in mass differences of 14 Da and yielded groups of related MSn spectra. Despite the inherent complexity of MS/MS spectra of cyclic compounds, straightforward analysis of these spectra was accomplished by determining differences in complementary product ion series between compounds that differ in molecular weight by 14 Da. The primary peptide sequence assignment was confirmed through genome mining; the combination of these analytical tools represents a workflow that can be used for the identification of complex antibiotics. The compounds also share amino acid sequence similarity to a previously identified broad-spectrum antibiotic isolated from Paenibacillus. The presence of such a wide distribution of related compounds produced by the same organism represents a novel class of broad-spectrum antibiotic compounds.

  3. Treatment of Emphysematous Pyelonephritis with Broad-spectrum Antibacterials and Percutaneous Renal Drainage: An Analysis of 10 Patients

    Directory of Open Access Journals (Sweden)

    Pei-Hui Chan

    2005-01-01

    Conclusion: Combined broad-spectrum antibacterial therapy and percutaneous renal drainage is a safe and effective treatment for EPN, especially in high-risk patients for whom nephrectomy under general anesthesia is not feasible.

  4. Engineering of Paraoxonases for Pre- and Post-treatment of Intoxication by a Broad Spectrum of Nerve Agents and Pesticides

    Science.gov (United States)

    2013-05-01

    0047 TITLE: Engineering of Paraoxonases for Pre- and Post-treatment of Intoxication by a Broad Spectrum of Nerve Agents and Pesticides ...SUBTITLE Engineering of Paraoxonases for Pre- and Post-treatment of Intoxication by a Broad Spectrum of Nerve Agents and Pesticides 5a... mutations . Specifically, we targeted residues 72, 189, 192, 193, 196 and 292, which our docking model of VX with PON1 implicated in substrate binding

  5. Claramines : A new class of broad-spectrum antimicrobial agents with bimodal activity.

    Science.gov (United States)

    Blanchet, Marine; Borselli, Diane; Rodallec, Anne; Peiretti, Franck; Vidal, Nicolas; Bolla, Jean Michel; Digiorgio, Carole; Morrison, Kelly; Wuest, William; Brunel, Jean Michel

    2018-02-21

    The emergence of multidrug resistant bacteria/pathogens has highlighted the need for the development of new antibiotics. In this manuscript, we report herein our results dealing with the broad spectrum of antibacterial activity against both sensitive and resistant Gram-negative and Gram-positive bacterial strains of an easily prepared water soluble polyaminosterol compound namely claramine A1. We will also demonstrate its peculiar mechanism of action (different from all the well-known classes of antibiotics) towards Gram-negative and Gram-positive bacteria. Finally, due to its low cytotoxicity, this class of molecules could constitute one of the most appropriate response against the questionable emergence of multidrug resistant bacteria and the associated consequence in the name of nosocomial diseases. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. 5-Carboxy-8-hydroxyquinoline is a Broad Spectrum 2-Oxoglutarate Oxygenase Inhibitor which Causes Iron Translocation.

    Science.gov (United States)

    Hopkinson, Richard J; Tumber, Anthony; Yapp, Clarence; Chowdhury, Rasheduzzaman; Aik, WeiShen; Che, Ka Hing; Li, Xuan Shirley; Kristensen, Jan B L; King, Oliver N F; Chan, Mun Chiang; Yeoh, Kar Kheng; Choi, Hwanho; Walport, Louise J; Thinnes, Cyrille C; Bush, Jacob T; Lejeune, Clarisse; Rydzik, Anna M; Rose, Nathan R; Bagg, Eleanor A; McDonough, Michael A; Krojer, Tobias; Yue, Wyatt W; Ng, Stanley S; Olsen, Lars; Brennan, Paul E; Oppermann, Udo; Muller-Knapp, Susanne; Klose, Robert J; Ratcliffe, Peter J; Schofield, Christopher J; Kawamura, Akane

    2013-08-01

    2-Oxoglutarate and iron dependent oxygenases are therapeutic targets for human diseases. Using a representative 2OG oxygenase panel, we compare the inhibitory activities of 5-carboxy-8-hydroxyquinoline (IOX1) and 4-carboxy-8-hydroxyquinoline (4C8HQ) with that of two other commonly used 2OG oxygenase inhibitors, N -oxalylglycine (NOG) and 2,4-pyridinedicarboxylic acid (2,4-PDCA). The results reveal that IOX1 has a broad spectrum of activity, as demonstrated by the inhibition of transcription factor hydroxylases, representatives of all 2OG dependent histone demethylase subfamilies, nucleic acid demethylases and γ-butyrobetaine hydroxylase. Cellular assays show that, unlike NOG and 2,4-PDCA, IOX1 is active against both cytosolic and nuclear 2OG oxygenases without ester derivatisation. Unexpectedly, crystallographic studies on these oxygenases demonstrate that IOX1, but not 4C8HQ, can cause translocation of the active site metal, revealing a rare example of protein ligand-induced metal movement.

  7. Synergistic effect of broad-spectrum Sunscreens and antihistamines in the control of idiopathic solar urticaria

    DEFF Research Database (Denmark)

    Faurschou, A.; Wulf, Hans Chr.

    2008-01-01

    . Observations: Three patients with idiopathic solar urticaria underwent phototesting with UV-B and UV-A radiation. The minimal urticarial dose (MUD) was determined 15 minutes after irradiation. The patients were subsequently tested with 5 times the MUD, and the reaction was graded every minute for 15 minutes....... The patients were then treated with a high-protection, broad-spectrum sunscreen and a nonsedative antihistamine alone and in combination and underwent similar phototesting. The use of sunscreen allowed the patients to tolerate much higher doses of UV radiation (32-38 times the MUD on untreated skin......). Antihistamine use did not increase the patients' MUD but did suppress wheal formation and itch, and only immediate erythema sharply located in the irradiated areas occurred. The combination of sunscreen and antihistamine acted synergistically and increased the tolerance to UV radiation markedly (80-267 times...

  8. Varo-achro-phobia: the fear of broad spectrum zoom optics

    Science.gov (United States)

    Vogel, Steven; Pollica, Naomi

    2015-05-01

    Today's battlefield is evolving at light speed. Our war fighters are being tasked with highly complex missions requiring the very best technology our industry can offer. The demand for advanced ISR platforms is challenging designers and engineers in the optics industry to push the envelope and develop wider band solutions to support multiple and broadband sensor platforms. Recently, significant attention has been directed towards the development of optical systems that enable simultaneous operation in the visible and shortwave infrared spectral wavebands. This paper will present a review of the evolution of StingRay Optics' GhostSight™ continuous zoom optics that offer broad chromatic imaging capabilities from the visible through the shortwave infrared spectrum.

  9. Development of a broad-spectrum antiviral with activity against Ebola virus.

    Science.gov (United States)

    Aman, M Javad; Kinch, Michael S; Warfield, Kelly; Warren, Travis; Yunus, Abdul; Enterlein, Sven; Stavale, Eric; Wang, Peifang; Chang, Shaojing; Tang, Qingsong; Porter, Kevin; Goldblatt, Michael; Bavari, Sina

    2009-09-01

    We report herein the identification of a small molecule therapeutic, FGI-106, which displays potent and broad-spectrum inhibition of lethal viral hemorrhagic fevers pathogens, including Ebola, Rift Valley and Dengue Fever viruses, in cell-based assays. Using mouse models of Ebola virus, we further demonstrate that FGI-106 can protect animals from an otherwise lethal infection when used either in a prophylactic or therapeutic setting. A single treatment, administered 1 day after infection, is sufficient to protect animals from lethal Ebola virus challenge. Cell-based assays also identified inhibitory activity against divergent virus families, which supports a hypothesis that FGI-106 interferes with a common pathway utilized by different viruses. These findings suggest FGI-106 may provide an opportunity for targeting viral diseases.

  10. Synergistic effect of broad-spectrum Sunscreens and antihistamines in the control of idiopathic solar urticaria

    DEFF Research Database (Denmark)

    Faurschou, A.; Wulf, Hans Chr.

    2008-01-01

    Background: It can be difficult to provide patients with idiopathic solar urticaria adequate protection from sunlight. In a nonrandomized controlled trial, we used a standardized phototest procedure to determine the effects of using sunscreen and antihistamine to control idiopathic solar urticaria....... The patients were then treated with a high-protection, broad-spectrum sunscreen and a nonsedative antihistamine alone and in combination and underwent similar phototesting. The use of sunscreen allowed the patients to tolerate much higher doses of UV radiation (32-38 times the MUD on untreated skin......). Antihistamine use did not increase the patients' MUD but did suppress wheal formation and itch, and only immediate erythema sharply located in the irradiated areas occurred. The combination of sunscreen and antihistamine acted synergistically and increased the tolerance to UV radiation markedly (80-267 times...

  11. Immune Responses to Broad-Spectrum Antibiotic Treatment and Fecal Microbiota Transplantation in Mice.

    Science.gov (United States)

    Ekmekciu, Ira; von Klitzing, Eliane; Fiebiger, Ulrike; Escher, Ulrike; Neumann, Christian; Bacher, Petra; Scheffold, Alexander; Kühl, Anja A; Bereswill, Stefan; Heimesaat, Markus M

    2017-01-01

    Compelling evidence demonstrates the pivotal role of the commensal intestinal microbiota in host physiology and the detrimental effects of its perturbations following antibiotic treatment. Aim of this study was to investigate the impact of antibiotics induced depletion and subsequent restoration of the intestinal microbiota composition on the murine mucosal and systemic immunity. To address this, conventional C57BL/6j mice were subjected to broad-spectrum antibiotic treatment for 8 weeks. Restoration of the intestinal microbiota by peroral fecal microbiota transplantation (FMT) led to reestablishment of small intestinal CD4 + , CD8 + , and B220 + as well as of colonic CD4 + cell numbers as early as 7 days post-FMT. However, at d28 following FMT, colonic CD4 + and B220 + cell numbers were comparable to those in secondary abiotic (ABx) mice. Remarkably, CD8 + cell numbers were reduced in the colon upon antibiotic treatment, and FMT was not sufficient to restore this immune cell subset. Furthermore, absence of gut microbial stimuli resulted in decreased percentages of memory/effector T cells, regulatory T cells, and activated dendritic cells in the small intestine, colon, mesenteric lymph nodes (MLN), and spleen. Concurrent antibiotic treatment caused decreased cytokine production (IFN-γ, IL-17, IL-22, and IL-10) of CD4 + cells in respective compartments. These effects were, however, completely restored upon FMT. In summary, broad-spectrum antibiotic treatment resulted in profound local (i.e., small and large intestinal), peripheral (i.e., MLN), and systemic (i.e., splenic) changes in the immune cell repertoire that could, at least in part, be restored upon FMT. Further studies need to unravel the distinct molecular mechanisms underlying microbiota-driven changes in immune homeostasis subsequently providing novel therapeutic or even preventive approaches in human immunopathologies.

  12. Ceftaroline fosamil: a novel broad-spectrum cephalosporin with expanded anti-Gram-positive activity.

    Science.gov (United States)

    Biek, Donald; Critchley, Ian A; Riccobene, Todd A; Thye, Dirk A

    2010-11-01

    Ceftaroline fosamil is a novel cephalosporin with broad-spectrum activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae, and common Gram-negative organisms. The activity of ceftaroline against MRSA is attributed to its ability to bind to penicillin-binding protein (PBP) 2a with high affinity and inhibit the biochemical activity of PBP 2a more efficiently than other presently available β-lactams. The activity of ceftaroline against MRSA and the β-haemolytic streptococci makes it an attractive monotherapy agent for the treatment of complicated skin and skin structure infections (cSSSIs). Recent profiling and surveillance studies have shown that ceftaroline is active against contemporary skin pathogens collected from US and European medical centres in 2008. The mean free drug %T  >  MIC (percentage of time the drug concentration remains above the MIC) needed for stasis ranged from 26% for S. aureus to 39% for S. pneumoniae in the murine thigh infection model. Pharmacokinetic and pharmacodynamic target attainment predictions for 600 mg of ceftaroline fosamil every 12 h showed that the mean %T  >  MICs for which plasma free-drug concentrations exceeded an MIC of 1 and 2 mg/L were 71% and 51% of the dosing interval, respectively. For a 40% T  >  MIC target, the predicted attainments for infections due to pathogens for which ceftaroline MICs were 1 or 2 mg/L were 100% and 90%, respectively. Clinical and microbiological successes of ceftaroline fosamil in treating cSSSIs were demonstrated in two Phase III clinical studies, in which 96.8% of all baseline cSSSI isolates from the microbiologically evaluable population were inhibited by ceftaroline at ≤ 2 mg/L. Ceftaroline fosamil is a promising broad-spectrum agent for the treatment of cSSSIs.

  13. Surveillance of broad-spectrum antibiotic prescription in Singaporean hospitals: a 5-year longitudinal study.

    Directory of Open Access Journals (Sweden)

    Yi-Xin Liew

    Full Text Available BACKGROUND: Inappropriate prescription of antibiotics may contribute towards higher levels antimicrobial resistance. A key intervention for improving appropriate antibiotic prescription is surveillance of prescription. This paper presents the results of a longitudinal surveillance of broad-spectrum antibiotic prescription in 5 public-sector hospitals in Singapore from 2006 to 2010. METHODOLOGY/PRINCIPAL FINDINGS: Quarterly antibiotic prescription data were obtained and converted to defined daily doses (DDDs per 1,000 inpatient-days. The presence of significant trends in antibiotic prescription over time for both individual and combined hospitals was tested by regression analysis and corrected for autocorrelation between time-points. Excluding fluoroquinolones, there was a significant increase in prescription of all monitored antibiotics from an average of 233.12 defined daily doses (DDD/1,000 inpatient-days in 2006 to 254.38 DDD/1,000 inpatient-days in 2010 (Coefficient = 1.13, 95%CI: 0.16-2.09, p = 0.025. Increasing utilization of carbapenems, piperacillin/tazobactam, and Gram-positive agents were seen in the majority of the hospitals, while cephalosporins were less prescribed over time. The combined expenditure for 5 hospitals increased from USD9.9 million in 2006 to USD16.7 million in 2010. CONCLUSIONS/SIGNIFICANCE: The rate of prescription of broad-spectrum antibiotics in Singaporean hospitals is much higher compared to those of European hospitals. This may be due to high rates of antimicrobial resistance. The increase in expenditure on monitored antibiotics over the past 5 years outstripped the actual increase in DDD/1,000 inpatient-days of antibiotics prescribed. Longitudinal surveillance of antibiotic prescription on a hospital and countrywide level is important for detecting trends for formulating interventions or policies. Further research is needed to understand the causes for the various prescription trends and to act on these where

  14. Broad spectrum antibiotic enrofloxacin modulates contact sensitivity through gut microbiota in a murine model.

    Science.gov (United States)

    Strzępa, Anna; Majewska-Szczepanik, Monika; Lobo, Francis M; Wen, Li; Szczepanik, Marian

    2017-07-01

    Medical advances in the field of infection therapy have led to an increasing use of antibiotics, which, apart from eliminating pathogens, also partially eliminate naturally existing commensal bacteria. It has become increasingly clear that less exposure to microbiota early in life may contribute to the observed rise in "immune-mediated" diseases, including autoimmunity and allergy. We sought to test whether the change of gut microbiota with the broad spectrum antibiotic enrofloxacin will modulate contact sensitivity (CS) in mice. Natural gut microbiota were modified by oral treatment with enrofloxacin prior to sensitization with trinitrophenyl chloride followed by CS testing. Finally, adoptive cell transfers were performed to characterize the regulatory cells that are induced by microbiota modification. Oral treatment with enrofloxacin suppresses CS and production of anti-trinitrophenyl chloride IgG1 antibodies. Adoptive transfer experiments show that antibiotic administration favors induction of regulatory cells that suppress CS. Flow cytometry and adoptive transfer of purified cells show that antibiotic-induced suppression of CS is mediated by TCR αβ + CD4 + CD25 + FoxP3 + Treg, CD19 + B220 + CD5 + IL-10 + , IL-10 + Tr1, and IL-10 + TCR γδ + cells. Treatment with the antibiotic induces dysbiosis characterized by increased proportion of Clostridium coccoides (cluster XIVa), C coccoides-Eubacterium rectale (cluster XIVab), Bacteroidetes, and Bifidobacterium spp, but decreased segmented filamentous bacteria. Transfer of antibiotic-modified gut microbiota inhibits CS, but this response can be restored through oral transfer of control gut bacteria to antibiotic-treated animals. Oral treatment with a broad spectrum antibiotic modifies gut microbiota composition and promotes anti-inflammatory response, suggesting that manipulation of gut microbiota can be a powerful tool to modulate the course of CS. Copyright © 2017 American Academy of Allergy, Asthma & Immunology

  15. Development of broad-spectrum human monoclonal antibodies for rabies post-exposure prophylaxis

    International Nuclear Information System (INIS)

    Benedictis, P. de; Minola, A.; Rota, E.; Aiello, R.; Zecchin, B.; Salomoni, A.; Foglierini, M.; Agatic, G.; Vanzetta, F.; Lavenir, R.; Lepelletier, A.; Bentley, E.; Weiss, R.; Cattoli, G.

    2016-01-01

    Full text: Currently available rabies post-exposure prophylaxis (PEP) for use in humans includes equine or human rabies immunoglobulins (RIG). The replacement of RIG with an equally or more potent and safer product is strongly encouraged due to the high costs and limited availability of existing RIG. In this study, we identified two broadly neutralizing human monoclonal antibodies that represent a valid and affordable alternative to RIG in rabies PEP. Memory B cells from four selected vaccinated donors were immortalized and monoclonal antibodies were tested for neutralizing activity and epitope specificity. Two antibodies, identified as RVC20 and RVC58 (binding to antigenic site I and III, respectively), were selected for their potency and broad-spectrum reactivity. In vitro, RVC20 and RVC58 were able to neutralize all 35 rabies virus (RABV) and 25 non-RABV lyssaviruses. They showed higher potency and breath compared to antibodies under clinical development (namely CR57, CR4098, and RAB1) and commercially available human RIG. In vivo, the RVC20–RVC58 cocktail protected Syrian hamsters from a lethal RABV challenge and did not affect the endogenous hamster post-vaccination antibody response. (author)

  16. Parametric instability producing broad symmetrical structure in the spectrum of ionospheric heating-induced radiation

    International Nuclear Information System (INIS)

    Kuo, S.P.

    1997-01-01

    A four-wave interaction process in which an O-mode electromagnetic pump decays parametrically into a lower hybrid decay mode and two-electron Bernstein sidebands is analyzed. It is shown that the instability can be excited in a spatial region near the electron Bernstein/upper hybrid double resonance and in a narrow pump frequency range slightly below the third harmonic electron cyclotron resonance. The two electron Bernstein sidebands have about the same intensity and thus, produce Broad Symmetrical Structure (BSS) in the emission spectrum after being converted into electromagnetic radiation by scattering off background field-aligned density irregularities. The results also show that the size of the instability zone becomes very small as the pump frequency operates near a cyclotron harmonic higher than the third. Thus, the converted emission will be too weak to be detected. This explains why the BSS feature in the spectrum of stimulated electromagnetic emissions (SEEs) has only been observed in the third harmonic case. copyright 1997 American Institute of Physics

  17. Trends in broad-spectrum antibiotic prescribing for children with acute otitis media in the United States, 1998–2004

    Directory of Open Access Journals (Sweden)

    Gambler Angela S

    2009-06-01

    Full Text Available Abstract Background Overuse of broad-spectrum antibiotics is associated with antibiotic resistance. Acute otitis media (AOM is responsible for a large proportion of antibiotics prescribed for US children. Rates of broad-spectrum antibiotic prescribing for AOM are unknown. Methods Analysis of the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, 1998 to 2004 (N = 6,878. Setting is office-based physicians, hospital outpatient departments, and emergency departments. Patients are children aged 12 years and younger prescribed antibiotics for acute otitis media. Main outcome measure is percentage of broad-spectrum antibiotics, defined as amoxicillin/clavulanate, macrolides, cephalosporins and quinolones. Results Broad-spectrum prescribing for acute otitis media increased from 34% of visits in 1998 to 45% of visits in 2004 (P Conclusion Prescribing of broad-spectrum antibiotics for acute otitis media has steadily increased from 1998 to 2004. Associations with non-clinical factors suggest potential for improvement in prescribing practice.

  18. A Broad-Spectrum Integrative Design for Cancer Prevention and Therapy

    Science.gov (United States)

    Block, Keith I.; Gyllenhaal, Charlotte; Lowe, Leroy; Amedei, Amedeo; Amin, A.R.M. Ruhul; Amin, Amr; Aquilano, Katia; Arbiser, Jack; Arreola, Alexandra; Arzumanyan, Alla; Ashraf, S. Salman; Azmi, Asfar S.; Benencia, Fabian; Bhakta, Dipita; Bilsland, Alan; Bishayee, Anupam; Blain, Stacy W.; Block, Penny B.; Boosani, Chandra S.; Carey, Thomas E.; Carnero, Amancio; Carotenuto, Marianeve; Casey, Stephanie C.; Chakrabarti, Mrinmay; Chaturvedi, Rupesh; Chen, Georgia Zhuo; Chen, Helen; Chen, Sophie; Chen, Yi Charlie; Choi, Beom K.; Ciriolo, Maria Rosa; Coley, Helen M.; Collins, Andrew R.; Connell, Marisa; Crawford, Sarah; Curran, Colleen S.; Dabrosin, Charlotta; Damia, Giovanna; Dasgupta, Santanu; DeBerardinis, Ralph J.; Decker, William K.; Dhawan, Punita; Diehl, Anna Mae E.; Dong, Jin-Tang; Dou, Q. Ping; Drew, Janice E.; Elkord, Eyad; El-Rayes, Bassel; Feitelson, Mark A.; Felsher, Dean W.; Ferguson, Lynnette R; Fimognari, Carmela; Firestone, Gary L.; Frezza, Christian; Fujii, Hiromasa; Fuster, Mark M.; Generali, Daniele; Georgakilas, Alexandros G.; Gieseler, Frank; Gilbertson, Michael; Green, Michelle F.; Grue, Brendan; Guha, Gunjan; Halicka, Dorota; Helferich, William G.; Heneberg, Petr; Hentosh, Patricia; Hirschey, Matthew D.; Hofseth, Lorne J.; Holcombe, Randall F.; Honoki, Kanya; Hsu, Hsue-Yin; Huang, Gloria S.; Jensen, Lasse D.; Jiang, Wen G.; Jones, Lee W.; Karpowicz, Phillip A.; Keith, W Nicol; Kerkar, Sid P.; Khan, Gazala N.; Khatami, Mahin; Ko, Young H.; Kucuk, Omer; Kulathinal, Rob J.; Kumar, Nagi B.; Kumara, H.M.C. Shantha; Kwon, Byoung S.; Le, Anne; Lea, Michael A.; Lee, Ho-Young; Lichtor, Terry; Lin, Liang-Tzung; Locasale, Jason W.; Lokeshwar, Bal L.; Longo, Valter D.; Lyssiotis, Costas A.; MacKenzie, Karen L.; Malhotra, Meenakshi; Marino, Maria; Martinez-Chantar, Maria L.; Matheu, Ander; Maxwell, Christopher; McDonnell, Eoin; Meeker, Alan K.; Mehrmohamadi, Mahya; Mehta, Kapil; Michelotti, Gregory A.; Mohammad, Ramzi M.; Mohammed, Sulma I.; Morre, D. James; Muqbil, Irfana; Muralidhar, Vinayak; Murphy, Michael P.; Nagaraju, Ganji Purnachandra; Nahta, Rita; Niccolai, Elena; Nowsheen, Somaira; Panis, Carolina; Pantano, Francesco; Parslow, Virginia R.; Pawelec, Graham; Pedersen, Peter L.; Poore, Brad; Poudyal, Deepak; Prakash, Satya; Prince, Mark; Raffaghello, Lizzia; Rathmell, Jeffrey C.; Rathmell, W. Kimryn; Ray, Swapan K.; Reichrath, Jörg; Rezazadeh, Sarallah; Ribatti, Domenico; Ricciardiello, Luigi; Robey, R. Brooks; Rodier, Francis; Rupasinghe, H.P. Vasantha; Russo, Gian Luigi; Ryan, Elizabeth P.; Samadi, Abbas K.; Sanchez-Garcia, Isidro; Sanders, Andrew J.; Santini, Daniele; Sarkar, Malancha; Sasada, Tetsuro; Saxena, Neeraj K.; Shackelford, Rodney E; Sharma, Dipali; Shin, Dong M.; Sidransky, David; Siegelin, Markus David; Signori, Emanuela; Singh, Neetu; Sivanand, Sharanya; Sliva, Daniel; Smythe, Carl; Spagnuolo, Carmela; Stafforini, Diana M.; Stagg, John; Subbarayan, Pochi R.; Sundin, Tabetha; Talib, Wamidh H.; Thompson, Sarah K.; Tran, Phuoc T.; Ungefroren, Hendrik; Vander Heiden, Matthew G.; Venkateswaran, Vasundara; Vinay, Dass S.; Vlachostergios, Panagiotis J.; Wang, Zongwei; Wellen, Kathryn E.; Whelan, Richard L.; Yang, Eddy S.; Yang, Huanjie; Yang, Xujuan; Yaswen, Paul; Yedjou, Clement; Yin, Xin; Zhu, Jiyue; Zollo, Massimo

    2016-01-01

    Targeted therapies and the consequent adoption of “personalized” oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity “broad-spectrum” therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested; many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to help us address disease relapse, which is a

  19. Broad-spectrum enhanced absorption of graphene-molybdenum disulfide photovoltaic cells in metal-mirror microcavity

    Science.gov (United States)

    Jiang-Tao, Liu; Yun-Kai, Cao; Hong, Tong; Dai-Qiang, Wang; Zhen-Hua, Wu

    2018-04-01

    The optical absorption of graphene-molybdenum disulfide photovoltaic cells (GM-PVc) in wedge-shaped metal-mirror microcavities (w-MMCs) combined with a spectrum-splitting structure was studied. Results showed that the combination of spectrum-splitting structure and w-MMC can enable the light absorption of GM-PVcs to reach about 65% in the broad spectrum. The influence of processing errors on the absorption of GM-PVcs in w-MMCs was 3-14 times lower than that of GM-PVcs in wedge photonic crystal microcavities. The light absorption of GM-PVcs reached 60% in the broad spectrum, even with the processing errors. The proposed structure is easy to implement and may have potentially important applications in the development of ultra-thin and high-efficiency solar cells and optoelectronic devices.

  20. Broad-spectrum sun-protective action of Porphyra-334 derived from Porphyra vietnamensis

    Science.gov (United States)

    Bhatia, Saurabh; Sharma, K.; Namdeo, Ajay G.; Chaugule, B. B.; Kavale, M.; Nanda, S.

    2010-01-01

    There are enormous UV-protective compounds present in the current world market, out of which 98% give protection against UV-B range and the remaining 2% are potent against far UV-A range only. Furthermore, these synthetic compounds have various problems related to photo-stability and cross-stability. There is a vital need of sunscreen agents that will remain stable for prolonged periods and provide broad-spectrum protection against harmful UV range. The Indian Ocean contains large amounts of macro-algae which synthesize varied amount of mycosporine amino acids, “sun-protective compounds” by shikmic acid pathway. In the present study, we have evaluated the sunscreen protection provided by Porphyra-334, a mycosporine amino acid isolated from Indian sp. of Porphyra. Furthermore, the isolated compound was detected by high performance thin layer chromatography (HPTLC) fingerprinting, high performance liquid chromatography (HPLC) and ultraviolet (UV), whereas nuclear magnetic resonance (NMR) spectroscopy and infrared spectrometry were used for its structural characterization. Stability studies were performed under different storage and pH conditions. Ultimately a sunscreen formulation was developed and its potential against marketed Aloe vera gel was evaluated by in vitro sunscreen protection method. It was observed that sunscreen potential of Porphyra-334 was 5.11-fold greater than that of the marketed Aloe vera gel preparation. PMID:21808539

  1. Oxabicyclooctane-Linked Novel Bacterial Topoisomerase Inhibitors as Broad Spectrum Antibacterial Agents

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Sheo B.; Kaelin, David E.; Wu, Jin; Miesel, Lynn; Tan, Christopher M.; Meinke, Peter T.; Olsen, David; Lagrutta, Armando; Bradley, Prudence; Lu, Jun; Patel, Sangita; Rickert, Keith W.; Smith, Robert F.; Soisson, Stephen; Wei, Changqing; Fukuda, Hideyuki; Kishii, Ryuta; Takei, Masaya; Fukuda, Yasumichi (Merck); (WuXi App Tec); (Kyorin)

    2014-05-08

    Bacterial resistance is eroding the clinical utility of existing antibiotics necessitating the discovery of new agents. Bacterial type II topoisomerase is a clinically validated, highly effective, and proven drug target. This target is amenable to inhibition by diverse classes of inhibitors with alternative and distinct binding sites to quinolone antibiotics, thus enabling the development of agents that lack cross-resistance to quinolones. Described here are novel bacterial topoisomerase inhibitors (NBTIs), which are a new class of gyrase and topo IV inhibitors and consist of three distinct structural moieties. The substitution of the linker moiety led to discovery of potent broad-spectrum NBTIs with reduced off-target activity (hERG IC50 > 18 μM) and improved physical properties. AM8191 is bactericidal and selectively inhibits DNA synthesis and Staphylococcus aureus gyrase (IC50 = 1.02 μM) and topo IV (IC50 = 10.4 μM). AM8191 showed parenteral and oral efficacy (ED50) at less than 2.5 mg/kg doses in a S. aureus murine infection model. A cocrystal structure of AM8191 bound to S. aureus DNA-gyrase showed binding interactions similar to that reported for GSK299423, displaying a key contact of Asp83 with the basic amine at position-7 of the linker.

  2. Ceftiofur sodium, a broad-spectrum cephalosporin: evaluation in vitro and in vivo in mice.

    Science.gov (United States)

    Yancey, R J; Kinney, M L; Roberts, B J; Goodenough, K R; Hamel, J C; Ford, C W

    1987-07-01

    Ceftiofur sodium, a broad-spectrum beta-lactamase-resistant cephalosporin, was evaluated in vitro and in vivo in mice. Ceftiofur is the sodium salt of (6R, 7R)-7[( 2-amino-4-thiazolyl)-Z- (methoxyimino)acetyl]amino)-3-[( (2-furanylcarbonyl)thio]methyl)-8-oxo-5- thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylate. Minimal inhibitory concentration values were obtained with 264 strains representing 9 genera and 17 species of bacterial pathogens from cattle, swine, sheep, horses, poultry, dogs, cats, and human beings. Ceftiofur was more active than was ampicillin against all strains tested including beta-lactamase-producing organisms. In mice with systemic infections, ceftiofur was more active than or equivalent to ampicillin, cephalothin, cefamandole, cloxacillin, cefoperazone, or pirlimycin. These protection tests included infections with Escherichia coli, Haemophilus pleuropneumoniae, H somnus, Pasteurella haemolytica, P multocida, Salmonella typhimurium, or Staphylococcus aureus. In infant mice with E coli-induced lethal diarrhea and in mice with S aureus and E coli-induced mastitis, ceftiofur was comparable or more active than was ampicillin.

  3. Development and characterization of novel chimeric monoclonal antibodies for broad spectrum neutralization of rabies virus.

    Directory of Open Access Journals (Sweden)

    Pan Kyeom Kim

    Full Text Available Current post-exposure prophylaxis for rabies virus infection has several limitations in terms of supply, cost, safety, and efficacy. Attempts to replace human or equine rabies immune globulins (HRIG or ERIG have been made by several companies and institutes. We developed potent monoclonal antibodies to neutralize a broad spectrum of rabies viruses by screening hybridomas received from the U.S. Centers for Disease Control and Prevention (CDC. Two kinds of chimeric human antibodies (chimeric #7 and #17 were constructed by cloning the variable regions from selected hybridomas and the constant region of a human antibody. Two antibodies were bound to antigenic site III and I/IV, respectively, and were able to neutralize 51 field isolates of rabies virus that were isolated at different times and places such as Asia, Africa, North America, South America, and Australia. These two antibodies neutralize rabies viruses with high efficacy in an in vivo test using Syrian hamster and mouse models and show low risk for adverse immunogenicity.

  4. [Ceftaroline, a new broad-spectrum cephalosporin in the era of multiresistance].

    Science.gov (United States)

    Horcajada, Juan Pablo; Cantón, Rafael

    2014-03-01

    Antimicrobial resistance has increased during the last few years, representing a public health concern. Among Gram-positive organisms, methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae are paradigms of resistance and of the dispersion of multiresistant clones. Ceftaroline, a broad-spectrum cephalosporin that includes MRSA and penicillin-resistant S. pneumoniae, is the first β-lactam antibiotic useful in infections due to MRSA. Phase-III clinical trials have demonstrated its efficacy in the treatment of community-acquired pneumonia and in skin and soft tissue infections, which are the current indications for ceftaroline. Due to its microbiological and pharmacological (PK/PD) profiles, these indications could be expanded to include bacteremia, endocarditis, and even osteoarticular infections. Another notable feature is the activity of this drug against Gram-negative bacilli susceptible to third generation cephalosporins, indicating that ceftaroline could be useful when these organisms are suspected or demonstrated in polymicrobial infections. Clinical follow-up of ceftaroline use will more clearly define future ceftaroline indications. Copyright © 2014 Elsevier España, S.L. All rights reserved.

  5. Characterization and partial purification of a broad spectrum antibiotic AS-48 produced by Streptococcus faecalis.

    Science.gov (United States)

    Gálvez, A; Maqueda, M; Valdivia, E; Quesada, A; Montoya, E

    1986-10-01

    Streptococcus faecalis S-48 produces a broad spectrum antibiotic, active against Gram-positive and Gram-negative bacteria. This substance is produced in solid and liquid media and also in a defined basal medium. It is sensitive to protease, pronase, or trypsin, heating at 70 degrees C, and alkaline pH, but resistant to treatment with lipase, lysozyme, alkaline phosphatase, DNAase, RNAase, acidic or neutral pHs, and also lower temperatures (60 degrees C). Several organic solvents cause precipitation, but not inactivation. This antibiotic has been partially purified by gel filtration and further ion-exchange chromatography. Its molecular weight has been estimated close to 2000. The biological activity of this antagonistic substance against the selected indicator strains, Streptococcus faecalis S-47 and Escherichia coli U-9, is bactericidal. The characterization of this substance, initially classified as a bacteriocin, indicates that it is an antibiotic of peptidic nature. The significance of antibiotic occurrence in group D of the genus Streptococcus is also discussed.

  6. Systematic study of non-natural short cationic lipopeptides as novel broad-spectrum antimicrobial agents.

    Science.gov (United States)

    Lohan, Sandeep; Cameotra, Swaranjit S; Bisht, Gopal S

    2013-11-01

    We describe the design and synthesis of a new series of non-natural short cationic lipopeptides (MW = 700) as antimicrobial agents. All of the synthesized lipopeptides were tested against a range of microbes such as Gram-positive, Gram-negative bacteria, fungi including methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE). By systematic study of design template, we found that three ornithine residues conjugated with myristic acid are minimum requirement for a compound to be an antimicrobial agent. The most potent lipopeptide LP16 possesses broad-spectrum antimicrobial activity and has MICs in the range of 1.5-6.25 μg/mL against Escherichia coli, S. aureus, Pseudomonas aeruginosa, Bacillus subtilis, and MRSE. All lipopeptides showed high selectivity toward microbial strains as compared to human red blood cells (HC50 > 250 μg/mL). Moreover, most potent lipopeptides (LP16 and LP23) did not induce drug resistance in S. aureus even after 15 rounds of passaging. In addition, a representative lipopeptide (LP16) showed tryptic stability for 24 h. These results suggest the potential of short cationic lipopeptides to boost the discovery of future antimicrobial therapeutics. © 2013 John Wiley & Sons A/S.

  7. Broad-spectrum light versus blue light for phototherapy in neonatal hyperbilirubinemia: a randomized controlled trial.

    Science.gov (United States)

    Pratesi, Simone; Di Fabio, Sandra; Bresci, Cecilia; Di Natale, Cecilia; Bar, Shahar; Dani, Carlo

    2015-07-01

    Phototherapy is standard care for treatment of neonatal hyperbilirubinemia. Our aim was to compare the effectiveness of broad-spectrum light (BSL) to that of blue light emitting diodes (LED) phototherapy for the treatment of jaundiced late preterm and term infants. Infants with gestational age from 35(+0) to 41(+6) weeks of gestation and nonhemolytic hyperbilirubinemia were randomized to treatment with BSL phototherapy or blue LED phototherapy. A total of 20 infants were included in the blue LED phototherapy group and 20 in the BSL phototherapy group. The duration of phototherapy was lower in the BSL than in the blue LED phototherapy group (15.8 ± 4.9 vs. 20.6 ± 6.0 hours; p = 0.009), and infants in the former group had a lower probability (p = 0.015) of remaining in phototherapy than infants in the latter. We concluded that BSL phototherapy is more effective than blue LED phototherapy for the treatment of hyperbilirubinemia in late preterm and term infants. Our data suggest that these results are not due to the different irradiance of the two phototherapy systems, but probably depend on their different peak light emissions. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  8. Broad spectrum pro-quorum-sensing molecules as inhibitors of virulence in vibrios.

    Directory of Open Access Journals (Sweden)

    Wai-Leung Ng

    Full Text Available Quorum sensing (QS is a bacterial cell-cell communication process that relies on the production and detection of extracellular signal molecules called autoinducers. QS allows bacteria to perform collective activities. Vibrio cholerae, a pathogen that causes an acute disease, uses QS to repress virulence factor production and biofilm formation. Thus, molecules that activate QS in V. cholerae have the potential to control pathogenicity in this globally important bacterium. Using a whole-cell high-throughput screen, we identified eleven molecules that activate V. cholerae QS: eight molecules are receptor agonists and three molecules are antagonists of LuxO, the central NtrC-type response regulator that controls the global V. cholerae QS cascade. The LuxO inhibitors act by an uncompetitive mechanism by binding to the pre-formed LuxO-ATP complex to inhibit ATP hydrolysis. Genetic analyses suggest that the inhibitors bind in close proximity to the Walker B motif. The inhibitors display broad-spectrum capability in activation of QS in Vibrio species that employ LuxO. To the best of our knowledge, these are the first molecules identified that inhibit the ATPase activity of a NtrC-type response regulator. Our discovery supports the idea that exploiting pro-QS molecules is a promising strategy for the development of novel anti-infectives.

  9. Development and characterization of novel chimeric monoclonal antibodies for broad spectrum neutralization of rabies virus.

    Science.gov (United States)

    Kim, Pan Kyeom; Keum, Sun Ju; Osinubi, Modupe O V; Franka, Richard; Shin, Ji Young; Park, Sang Tae; Kim, Man Su; Park, Mi Jung; Lee, Soo Young; Carson, William; Greenberg, Lauren; Yu, Pengcheng; Tao, Xiaoyan; Lihua, Wang; Tang, Qing; Liang, Guodong; Shampur, Madhusdana; Rupprecht, Charles E; Chang, Shin Jae

    2017-01-01

    Current post-exposure prophylaxis for rabies virus infection has several limitations in terms of supply, cost, safety, and efficacy. Attempts to replace human or equine rabies immune globulins (HRIG or ERIG) have been made by several companies and institutes. We developed potent monoclonal antibodies to neutralize a broad spectrum of rabies viruses by screening hybridomas received from the U.S. Centers for Disease Control and Prevention (CDC). Two kinds of chimeric human antibodies (chimeric #7 and #17) were constructed by cloning the variable regions from selected hybridomas and the constant region of a human antibody. Two antibodies were bound to antigenic site III and I/IV, respectively, and were able to neutralize 51 field isolates of rabies virus that were isolated at different times and places such as Asia, Africa, North America, South America, and Australia. These two antibodies neutralize rabies viruses with high efficacy in an in vivo test using Syrian hamster and mouse models and show low risk for adverse immunogenicity.

  10. Development of Broad-Spectrum Halomethyl Ketone Inhibitors Against Coronavirus Main Protease 3CL(pro)

    Energy Technology Data Exchange (ETDEWEB)

    Bacha,U.; Barilla, J.; Gabelli, S.; Kiso, Y.; Amzel, L.; Freire, E.

    2008-01-01

    Coronaviruses comprise a large group of RNA viruses with diverse host specificity. The emergence of highly pathogenic strains like the SARS coronavirus (SARS-CoV), and the discovery of two new coronaviruses, NL-63 and HKU1, corroborates the high rate of mutation and recombination that have enabled them to cross species barriers and infect novel hosts. For that reason, the development of broad-spectrum antivirals that are effective against several members of this family is highly desirable. This goal can be accomplished by designing inhibitors against a target, such as the main protease 3CLpro (Mpro), which is highly conserved among all coronaviruses. Here 3CLpro derived from the SARS-CoV was used as the primary target to identify a new class of inhibitors containing a halomethyl ketone warhead. The compounds are highly potent against SARS 3CLpro with Ki's as low as 300 nm. The crystal structure of the complex of one of the compounds with 3CLpro indicates that this inhibitor forms a thioether linkage between the halomethyl carbon of the warhead and the catalytic Cys 145. Furthermore, Structure Activity Relationship (SAR) studies of these compounds have led to the identification of a pharmacophore that accurately defines the essential molecular features required for the high affinity.

  11. Broad-spectrum non-toxic antiviral nanoparticles with a virucidal inhibition mechanism

    Science.gov (United States)

    Cagno, Valeria; Andreozzi, Patrizia; D'Alicarnasso, Marco; Jacob Silva, Paulo; Mueller, Marie; Galloux, Marie; Le Goffic, Ronan; Jones, Samuel T.; Vallino, Marta; Hodek, Jan; Weber, Jan; Sen, Soumyo; Janeček, Emma-Rose; Bekdemir, Ahmet; Sanavio, Barbara; Martinelli, Chiara; Donalisio, Manuela; Rameix Welti, Marie-Anne; Eleouet, Jean-Francois; Han, Yanxiao; Kaiser, Laurent; Vukovic, Lela; Tapparel, Caroline; Král, Petr; Krol, Silke; Lembo, David; Stellacci, Francesco

    2018-02-01

    Viral infections kill millions yearly. Available antiviral drugs are virus-specific and active against a limited panel of human pathogens. There are broad-spectrum substances that prevent the first step of virus-cell interaction by mimicking heparan sulfate proteoglycans (HSPG), the highly conserved target of viral attachment ligands (VALs). The reversible binding mechanism prevents their use as a drug, because, upon dilution, the inhibition is lost. Known VALs are made of closely packed repeating units, but the aforementioned substances are able to bind only a few of them. We designed antiviral nanoparticles with long and flexible linkers mimicking HSPG, allowing for effective viral association with a binding that we simulate to be strong and multivalent to the VAL repeating units, generating forces (~190 pN) that eventually lead to irreversible viral deformation. Virucidal assays, electron microscopy images, and molecular dynamics simulations support the proposed mechanism. These particles show no cytotoxicity, and in vitro nanomolar irreversible activity against herpes simplex virus (HSV), human papilloma virus, respiratory syncytial virus (RSV), dengue and lenti virus. They are active ex vivo in human cervicovaginal histocultures infected by HSV-2 and in vivo in mice infected with RSV.

  12. Dissecting disease entities out of the broad spectrum of bipolar-disorders.

    Science.gov (United States)

    Levine, Joseph; Toker, Lilach; Agam, Galila

    2018-01-01

    The etiopathology of bipolar disorders is yet unraveled and new avenues should be pursued. One such avenue may be based on the assumption that the bipolar broad spectrum includes, among others, an array of rare medical disease entities. Towards this aim we propose a dissecting approach based on a search for rare medical diseases with known etiopathology which also exhibit bipolar disorders symptomatology. We further suggest that the etiopathologic mechanisms underlying such rare medical diseases may also underlie a rare variant of bipolar disorder. Such an assumption may be further reinforced if both the rare medical disease and its bipolar clinical phenotype demonstrate a] a similar mode of inheritance (i.e, autosomal dominant); b] brain involvement; and c] data implicating that the etiopathological mechanisms underlying the rare diseases affect biological processes reported to be associated with bipolar disorders and their treatment. We exemplify our suggested approach by a rare case of autosomal dominant leucodystrophy, a disease entity exhibiting nuclear lamin B1 pathology also presenting bipolar symptomatology. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Bismuth antimicrobial drugs serve as broad-spectrum metallo-β-lactamase inhibitors.

    Science.gov (United States)

    Wang, Runming; Lai, Tsz-Pui; Gao, Peng; Zhang, Hongmin; Ho, Pak-Leung; Woo, Patrick Chiu-Yat; Ma, Guixing; Kao, Richard Yi-Tsun; Li, Hongyan; Sun, Hongzhe

    2018-01-30

    Drug-resistant superbugs pose a huge threat to human health. Infections by Enterobacteriaceae producing metallo-β-lactamases (MBLs), e.g., New Delhi metallo-β-lactamase 1 (NDM-1) are very difficult to treat. Development of effective MBL inhibitors to revive the efficacy of existing antibiotics is highly desirable. However, such inhibitors are not clinically available till now. Here we show that an anti-Helicobacter pylori drug, colloidal bismuth subcitrate (CBS), and related Bi(III) compounds irreversibly inhibit different types of MBLs via the mechanism, with one Bi(III) displacing two Zn(II) ions as revealed by X-ray crystallography, leading to the release of Zn(II) cofactors. CBS restores meropenem (MER) efficacy against MBL-positive bacteria in vitro, and in mice infection model, importantly, also slows down the development of higher-level resistance in NDM-1-positive bacteria. This study demonstrates a high potential of Bi(III) compounds as the first broad-spectrum B1 MBL inhibitors to treat MBL-positive bacterial infection in conjunction with existing carbapenems.

  14. The effects of exogenous catalase on broad-spectrum near-UV (300-400nm) treated Escherichia coli cells

    International Nuclear Information System (INIS)

    Sammartano, L.J.; Tuveson, R.W.

    1984-01-01

    Catalase incorporated into plating medium protects against inactivation and mutagenesis by broad-spectrum near-ultraviolet wavelength (300-400nm) (NUV) radiation in strains of Escherichia coli. Plating medium containing catalase does not provide protection against inactivation by wavelengths in the FUV region. Catalase added to the cell suspension during or added immediately after NUV exposure also protects against inactivation. The protection provided by catalase suggests a possible role for hydrogen peroxide in the processes of inactivation and mutagenesis by broad-spectrum NUV. (author)

  15. Successful five-item triage for the broad spectrum of mental disorders in pregnancy - A validation study

    NARCIS (Netherlands)

    C. Quispel (Chantal); T.A.J. Schneider (Tom); W.J.G. Hoogendijk (Witte); G.J. Bonsel (Gouke); M.P. Lambregtse-van den Berg (Mijke)

    2015-01-01

    textabstractBackground: Mental disorders are prevalent during pregnancy, affecting 10% of women worldwide. To improve triage of a broad spectrum of mental disorders, we investigated the decision impact validity of: 1) a short set of currently used psychiatric triage items, 2) this set with the

  16. Expression of mouse beta defensin 2 in Escherichia coli and its broad-spectrum antimicrobial activity

    Directory of Open Access Journals (Sweden)

    Tianxiang Gong

    2011-09-01

    Full Text Available Mature mouse beta defensin 2 (mBD2 is a small cationic peptide with antimicrobial activity. Here we established a prokaryotic expression vector containing the cDNA of mature mBD2 fused with thioredoxin (TrxA, pET32a-mBD2. The vector was transformed into Escherichia Coli (E. coli Rosseta-gami (2 for expression fusion protein. Under the optimization of fermentation parameters: induce with 0.6 mM isopropylthiogalactoside (IPTG at 34ºC in 2×YT medium and harvest at 6 h postinduction, fusion protein TrxA-mBD2 was high expressed in the soluble fraction (>95%. After cleaved fusion protein by enterokinase, soluble mature mBD2 was achieved 6 mg/L with a volumetric productivity. Purified recombinant mBD2 demonstrated clear broad-spectrum antimicrobial activity for fungi, bacteria and virus. The MIC of antibacterial activity of against Staphylococcus aureus was 50 µg/ml. The MIC of against Candida albicans (C. albicans and Cryptococcus neoformans (C. neoformans was 12.5µg/ml and 25µg/ml, respectively. Also, the antimicrobial activity of mBD2 was effected by NaCl concentration. Additionally, mBD2 showed antiviral activity against influenza A virus (IAV, the protective rate for Madin-Darby canine kidney cells (MDCK was 93.86% at the mBD2 concentration of 100 µg/ml. These works might provide a foundation for the following research on the mBD2 as therapeutic agent for medical microbes.

  17. Depletion of Cultivatable Gut Microbiota by Broad-Spectrum Antibiotic Pretreatment Worsens Outcome After Murine Stroke

    Science.gov (United States)

    Winek, Katarzyna; Engel, Odilo; Koduah, Priscilla; Heimesaat, Markus M.; Fischer, André; Bereswill, Stefan; Dames, Claudia; Kershaw, Olivia; Gruber, Achim D.; Curato, Caterina; Oyama, Naoki; Meisel, Christian; Meisel, Andreas

    2016-01-01

    Background and Purpose— Antibiotics disturbing microbiota are often used in treatment of poststroke infections. A bidirectional brain–gut microbiota axis was recently suggested as a modulator of nervous system diseases. We hypothesized that gut microbiota may be an important player in the course of stroke. Methods— We investigated the outcome of focal cerebral ischemia in C57BL/6J mice after an 8-week decontamination with quintuple broad-spectrum antibiotic cocktail. These microbiota-depleted animals were subjected to 60 minutes middle cerebral artery occlusion or sham operation. Infarct volume was measured using magnetic resonance imaging, and mice were monitored clinically throughout the whole experiment. At the end point, tissues were preserved for further analysis, comprising histology and immunologic investigations using flow cytometry. Results— We found significantly decreased survival in the middle cerebral artery occlusion microbiota-depleted mice when the antibiotic cocktail was stopped 3 days before surgery (compared with middle cerebral artery occlusion specific pathogen-free and sham-operated microbiota-depleted mice). Moreover, all microbiota-depleted animals in which antibiotic treatment was terminated developed severe acute colitis. This phenotype was rescued by continuous antibiotic treatment or colonization with specific pathogen-free microbiota before surgery. Further, infarct volumes on day one did not differ between any of the experimental groups. Conclusions— Conventional microbiota ensures intestinal protection in the mouse model of experimental stroke and prevents development of acute and severe colitis in microbiota-depleted mice not given antibiotic protection after cerebral ischemia. Our experiments raise the clinically important question as to whether microbial colonization or specific microbiota are crucial for stroke outcome. PMID:27056982

  18. Characteristics of a broad lytic spectrum endolysin from phage BtCS33 of Bacillus thuringiensis.

    Science.gov (United States)

    Yuan, Yihui; Peng, Qin; Gao, Meiying

    2012-12-19

    Endolysins produced by bacteriophages lyse bacteria, and are thus considered a novel type of antimicrobial agent. Several endolysins from Bacillus phages or prophages have previously been characterized and used to target Bacillus strains that cause disease in animals and humans. B. thuringiensis phage BtCS33 is a Siphoviridae family phage and its genome has been sequenced and analyzed. In the BtCS33 genome, orf18 was found to encode an endolysin protein (PlyBt33). Bioinformatic analyses showed that endolysin PlyBt33 was composed of two functional domains, the N-terminal catalytic domain and the C-terminal cell wall binding domain. In this study, the entire endolysin PlyBt33, and both the N- and C-termini,were expressed in Escherichia coli and then purified. The lytic activities of PlyBt33 and its N-terminus were tested on bacteria. Both regions exhibited lytic activity, although PlyBt33 showed a higher lytic activity than the N-terminus. PlyBt33 exhibited activity against all Bacillus strains tested from five different species, but was not active against Gram-negative bacteria. Optimal conditions for PlyBt33 reactivity were pH 9.0 and 50 °C. PlyBt33 showed high thermostability, with 40% of initial activity remaining following 1 h of treatment at 60 °C. The C-terminus of PlyBt33 bound to B. thuringiensis strain HD-73 and Bacillus subtilis strain 168. This cell wall binding domain might be novel, as its amino acid sequence showed little similarity to previously reported endolysins. PlyBt33 showed potential as a novel antimicrobial agent at a relatively high temperature and had a broad lytic spectrum within the Bacillus genus. The C-terminus of PlyBt33 might be a novel kind of cell wall binding domain.

  19. Mur-LH, the Broad-Spectrum Endolysin of Lactobacillus helveticus Temperate Bacteriophage φ-0303

    Science.gov (United States)

    Deutsch, Stéphanie-Marie; Guezenec, Stéphane; Piot, Michel; Foster, Simon; Lortal, Sylvie

    2004-01-01

    φ-0303 is a temperate bacteriophage isolated from Lactobacillus helveticus CNRZ 303 strain after mitomycin C induction. In this work, the gene coding for a lytic protein of this bacteriophage was cloned using a library of φ-0303 in Escherichia coli DH5α. The lytic activity was detected by its expression, using whole cells of the sensitive strain L. helveticus CNRZ 892 as the substrate. The lysin gene was within a 4.1-kb DNA fragment of φ-0303 containing six open reading frames (ORFs) and two truncated ORFs. No sequence homology with holin genes was found within the cloned fragment. An integrase-encoding gene was also present in the fragment, but it was transcribed in a direction opposite that of the lysin gene. The lysin-encoding lys gene was verified by PCR amplification from the total phage DNA and subcloned. The lys gene is a 1,122-bp sequence encoding a protein of 373 amino acids (Mur-LH), whose product had a deduced molecular mass of 40,207 Da. Comparisons with sequences in sequence databases showed homology with numerous endolysins of other bacteriophages. Mur-LH was expressed in E. coli BL21, and by renaturing sodium dodecyl sulfate-polyacrylamide gel electrophoresis with L. helveticus CNRZ 892 as the substrate, the recombinant protein showed an apparent molecular mass of 40 kDa. The N-terminal sequence of the protein confirmed the start codon. Hydrolysis of cell walls of L. helveticus CNRZ 303 by the endolysin and biochemical analysis of the residues produced demonstrated that Mur-LH has N-acetylmuramidase activity. Last, the endolysin exhibited a broad spectrum of lytic activity, as it was active on different species, mainly thermophilic lactobacilli but also lactococci, pediococci, Bacillus subtilis, Brevibacterium linens, and Enterococcus faecium. PMID:14711630

  20. Characteristics of a broad lytic spectrum endolysin from phage BtCS33 of Bacillus thuringiensis

    Directory of Open Access Journals (Sweden)

    Yuan Yihui

    2012-12-01

    Full Text Available Abstract Background Endolysins produced by bacteriophages lyse bacteria, and are thus considered a novel type of antimicrobial agent. Several endolysins from Bacillus phages or prophages have previously been characterized and used to target Bacillus strains that cause disease in animals and humans. B. thuringiensis phage BtCS33 is a Siphoviridae family phage and its genome has been sequenced and analyzed. In the BtCS33 genome, orf18 was found to encode an endolysin protein (PlyBt33. Results Bioinformatic analyses showed that endolysin PlyBt33 was composed of two functional domains, the N-terminal catalytic domain and the C-terminal cell wall binding domain. In this study, the entire endolysin PlyBt33, and both the N- and C-termini,were expressed in Escherichia coli and then purified. The lytic activities of PlyBt33 and its N-terminus were tested on bacteria. Both regions exhibited lytic activity, although PlyBt33 showed a higher lytic activity than the N-terminus. PlyBt33 exhibited activity against all Bacillus strains tested from five different species, but was not active against Gram-negative bacteria. Optimal conditions for PlyBt33 reactivity were pH 9.0 and 50°C. PlyBt33 showed high thermostability, with 40% of initial activity remaining following 1 h of treatment at 60°C. The C-terminus of PlyBt33 bound to B. thuringiensis strain HD-73 and Bacillus subtilis strain 168. This cell wall binding domain might be novel, as its amino acid sequence showed little similarity to previously reported endolysins. Conclusions PlyBt33 showed potential as a novel antimicrobial agent at a relatively high temperature and had a broad lytic spectrum within the Bacillus genus. The C-terminus of PlyBt33 might be a novel kind of cell wall binding domain.

  1. Overexpression of NPR1 in Brassica juncea Confers Broad Spectrum Resistance to Fungal Pathogens

    Directory of Open Access Journals (Sweden)

    Sajad Ali

    2017-10-01

    Full Text Available Brassica juncea (Indian mustard is a commercially important oil seed crop, which is highly affected by many biotic stresses. Among them, Alternaria leaf blight and powdery mildew are the most devastating diseases leading to huge yield losses in B. juncea around the world. In this regard, genetic engineering is a promising tool that may possibly allow us to enhance the B. juncea disease resistance against these pathogens. NPR1 (non-expressor of pathogen-related gene 1 is a bonafide receptor of salicylic acid (SA which modulates multiple immune responses in plants especially activation of induced and systemic acquired resistance (SAR. Here, we report the isolation and characterization of new NPR1 homolog (BjNPR1 from B. juncea. The phylogenetic tree constructed based on the deduced sequence of BjNPR1 with homologs from other species revealed that BjNPR1 grouped together with other known NPR1 proteins of Cruciferae family, and was nearest to B. napus. Furthermore, expression analysis showed that BjNPR1 was upregulated after SA treatment and fungal infection but not by jasmonic acid or abscisic acid. To understand the defensive role of this gene, we generated B. juncea transgenic lines overexpressing BjNPR1, and further confirmed by PCR and Southern blotting. The transgenic lines showed no phenotypic abnormalities, and constitutive expression of BjNPR1 activates defense signaling pathways by priming the expression of antifungal PR genes. Moreover, BjNPR1 transgenic lines showed enhanced resistance to Alternaria brassicae and Erysiphe cruciferarum as there was delay in symptoms and reduced disease severity than non-transgenic plants. In addition, the rate of disease spreading to uninfected or distal parts was also delayed in transgenic plants thus suggesting the activation of SAR. Altogether, the present study suggests that BjNPR1 is involved in broad spectrum of disease resistance against fungal pathogens.

  2. Isolation and Characterization of a Broad Spectrum Bacteriocin from Bacillus amyloliquefaciens RX7

    Directory of Open Access Journals (Sweden)

    Kong Boon Lim

    2016-01-01

    Full Text Available We isolated a Bacillus strain, RX7, with inhibitory activity against Listeria monocytogenes from soil and identified it as Bacillus amyloliquefaciens based on 16S rRNA gene sequencing. The inhibitory activity was stable over a wide range of pH and was fully retained after 30 min at 80°C, after which it decreased gradually at higher temperatures. The activity was sensitive to the proteolytic action of α-chymotrypsin, proteinase-K, and trypsin, indicating its proteinaceous nature. This bacteriocin was active against a broad spectrum of bacteria and the fungus Candida albicans. Direct detection of antimicrobial activity on a sodium dodecyl sulfate-polyacrylamide gel suggested an apparent molecular mass of approximately 5 kDa. Ammonium sulfate precipitation and anion-exchange and gel permeation chromatography integrated with reverse phase-high-performance liquid chromatography were used for bacteriocin purification. Automated N-terminal Edman degradation of the purified RX7 bacteriocin recognized the first 15 amino acids as NH2-X-Ala-Trp-Tyr-Asp-Ile-Arg-Lys-Leu-Gly-Asn-Lys-Gly-Ala, where the letter X in the sequence indicates an unknown or nonstandard amino acid. Based on BLAST similarity search and multiple alignment analysis, the obtained partial sequence showed high homology with the two-peptide lantibiotic haloduracin (HalA1 from Bacillus halodurans, although at least two amino acids differed between the sequences. A time-kill study demonstrated a bactericidal mode of action of RX7 bacteriocin.

  3. Ceftaroline fosamil: a novel broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus.

    Science.gov (United States)

    Jorgenson, Margaret R; DePestel, Daryl D; Carver, Peggy L

    2011-11-01

    To review the pharmacology, microbiology, chemistry, in vitro activity, pharmacokinetics, clinical efficacy, safety, dosage, and administration of ceftaroline fosamil (Teflaro, Forest Laboratories, Inc.), a novel parenteral broad-spectrum cephalosporin approved by the Food and Drug Administration (FDA) on October 29, 2010, for the treatment of adults with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). A search of MEDLINE (1966-July 2011) using the search terms ceftaroline fosamil, ceftaroline, TAK-599, PPI-0903, PPI-0903M, and T-91825 was performed. Supplementary sources included program abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society of Microbiology, European Congress on Clinical Microbiology and Infectious Diseases, and the Infectious Diseases Society of America from 2005 to 2010, as well as information available from the manufacturer's Web site. All English-language articles identified from the data sources were evaluated. In vitro, preclinical, and Phase 1, 2, and 3 clinical trials were included. Clinical trials have been conducted evaluating use of ceftaroline for treatment of ABSSSI and CABP. Safety data from Phase 1, 2, and 3 clinical trials suggest that it is well tolerated and has a safety and tolerability profile common to the cephalosporin class. Ceftaroline has excellent in vitro activity against gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), which makes it an attractive monotherapy for the treatment of ABSSSI. However, it lacks activity against problem gram-negative bacteria (eg, Pseudomonas spp.), which will likely limit its use for serious health care-associated infections. While its role in treating CABP is supported by excellent in vitro activity against Streptococcus pneumoniae and clinical efficacy data, currently available comparators may offer some advantages over ceftaroline. Finally

  4. Integrated DNA walking system to characterize a broad spectrum of GMOs in food/feed matrices.

    Science.gov (United States)

    Fraiture, Marie-Alice; Herman, Philippe; Lefèvre, Loic; Taverniers, Isabel; De Loose, Marc; Deforce, Dieter; Roosens, Nancy H

    2015-08-14

    In order to provide a system fully integrated with qPCR screening, usually used in GMO routine analysis, as well as being able to detect, characterize and identify a broad spectrum of GMOs in food/feed matrices, two bidirectional DNA walking methods targeting p35S or tNOS, the most common transgenic elements found in GM crops, were developed. These newly developed DNA walking methods are completing the previously implemented DNA walking method targeting the t35S pCAMBIA element. Food/feed matrices containing transgenic crops (Bt rice or MON863 maize) were analysed using the integrated DNA walking system. First, the newly developed DNA walking methods, anchored on the sequences used for the p35S or tNOS qPCR screening, were tested on Bt rice that contains these two transgenic elements. Second, the methods were assessed on a maize sample containing a low amount of the GM MON863 event, representing a more complex matrix in terms of genome size and sensitivity. Finally, to illustrate its applicability in GMO routine analysis by enforcement laboratories, the entire workflow of the integrated strategy, including qPCR screening to detect the potential presence of GMOs and the subsequent DNA walking methods to characterize and identify the detected GMOs, was applied on a GeMMA Scheme Proficiency Test matrix. Via the characterization of the transgene flanking region between the transgenic cassette and the plant genome as well as of a part of the transgenic cassette, the presence of GMOs was properly confirmed or infirmed in all tested samples. Due to their simple procedure and their short time-frame to get results, the developed DNA walking methods proposed here can be easily implemented in GMO routine analysis by the enforcement laboratories. In providing crucial information about the transgene flanking regions and/or the transgenic cassettes, this DNA walking strategy is a key molecular tool to prove the presence of GMOs in any given food/feed matrix.

  5. Reverse engineering truncations of an antimicrobial peptide dimer to identify the origins of potency and broad spectrum of action.

    Science.gov (United States)

    Anantharaman, Aparna; Sahal, Dinkar

    2010-08-26

    Antimicrobial peptides hold promise against antibiotic resistant pathogens. Here, to find the physicochemical origins of potency and broad spectrum antimicrobial action, we report the structure-activity relationships of synthetic intermediates (peptides A-D) of a potent lysine branched dimeric antibacterial peptide DeltaFd. Our studies show that a tetracationic character in a weak helical fold (peptide C) elicits potent but narrow spectrum antimicrobial activity [Minimum inhibitory concentrations (MICs) E. coli 10 microM, S. aureus>100 microM]. In contrast, a hexacationic character in a strong, amphipathic helix (DeltaFd) confers potent and broad spectrum action [MICs E. coli 2.5 microM, S. aureus 5 microM]. While DeltaFd caused rapid and potent permeabilization of the E. coli membranes, the less helical intermediates (peptides A-D) showed slow and weak to no responses. Two seminal findings that may aid future drug design are (a) at identical helicity, increasing charge enhanced outer membrane permeabilization, and (b) at identical charge, increasing helicity stimulated rate of outer membrane permeabilization and kill kinetics besides enhancing potency leading to broad spectrum action.

  6. Pharmacy sales data versus ward stock accounting for the surveillance of broad-spectrum antibiotic use in hospitals.

    Science.gov (United States)

    Haug, Jon B; Myhr, Randi; Reikvam, Asmund

    2011-12-13

    Antibiotic consumption in hospitals is commonly measured using the accumulated amount of drugs delivered from the pharmacy to ward held stocks. The reliability of this method, particularly the impact of the length of the registration periods, has not been evaluated and such evaluation was aim of the study. During 26 weeks, we performed a weekly ward stock count of use of broad-spectrum antibiotics--that is second- and third-generation cephalosporins, carbapenems, and quinolones--in five hospital wards and compared the data with corresponding pharmacy sales figures during the same period. Defined daily doses (DDDs) for antibiotics were used as measurement units (WHO ATC/DDD classification). Consumption figures obtained with the two methods for different registration intervals were compared by use of intraclass correlation analysis and Bland-Altman statistics. Broad-spectrum antibiotics accounted for a quarter to one-fifth of all systemic antibiotics (ATC group J01) used in the hospital and varied between wards, from 12.8 DDDs per 100 bed days in a urological ward to 24.5 DDDs in a pulmonary diseases ward. For the entire study period of 26 weeks, the pharmacy and ward defined daily doses figures for all broad-spectrum antibiotics differed only by 0.2%; however, for single wards deviations varied from -4.3% to 6.9%. The intraclass correlation coefficient, pharmacy versus ward data, increased from 0.78 to 0.94 for parenteral broad-spectrum antibiotics with increasing registration periods (1-4 weeks), whereas the corresponding figures for oral broad-spectrum antibiotics (ciprofloxacin) were from 0.46 to 0.74. For all broad-spectrum antibiotics and for parenteral antibiotics, limits of agreement between the two methods showed, according to Bland-Altman statistics, a deviation of ± 5% or less from average mean DDDs at 3- and 4-weeks registration intervals. Corresponding deviation for oral antibiotics was ± 21% at a 4-weeks interval. There is a need for caution in

  7. Treatment of Emphysematous Pyelonephritis with Broad-spectrum Antibacterials and Percutaneous Renal Drainage: An Analysis of 10 Patients

    OpenAIRE

    Chan, Pei-Hui; Kho, Victor Ka-Siong; Lai, Siu-Kei; Yang, Ching-Hwa; Chang, Hsiao-Chun; Chiu, Bin; Tseng, Shei-Chain

    2005-01-01

    This retrospective study was designed to determine the efficacy of broad-spectrum antibacterials combined with percutaneous renal drainage in the treatment of emphysematous pyelonephritis (EPN). Methods: From July 1992 to September 2002, 10 patients (nine females and one male) with EPN were managed at our institution. All patients had diabetes and presented with fever and chills, flank pain or tenderness, vomiting, and altered consciousness. The diagnosis of EPN was confirmed by the presen...

  8. Overexpression of BSR1 confers broad-spectrum resistance against two bacterial diseases and two major fungal diseases in rice.

    Science.gov (United States)

    Maeda, Satoru; Hayashi, Nagao; Sasaya, Takahide; Mori, Masaki

    2016-06-01

    Broad-spectrum disease resistance against two or more types of pathogen species is desirable for crop improvement. In rice, Xanthomonas oryzae pv. oryzae (Xoo), the causal bacteria of rice leaf blight, and Magnaporthe oryzae, the fungal pathogen causing rice blast, are two of the most devastating pathogens. We identified the rice BROAD-SPECTRUM RESISTANCE 1 (BSR1) gene for a BIK1-like receptor-like cytoplasmic kinase using the FOX hunting system, and demonstrated that BSR1-overexpressing (OX) rice showed strong resistance to the bacterial pathogen, Xoo and the fungal pathogen, M. oryzae. Here, we report that BSR1-OX rice showed extended resistance against two other different races of Xoo, and to at least one other race of M. oryzae. In addition, the rice showed resistance to another bacterial species, Burkholderia glumae, which causes bacterial seedling rot and bacterial grain rot, and to Cochliobolus miyabeanus, another fungal species causing brown spot. Furthermore, BSR1-OX rice showed slight resistance to rice stripe disease, a major viral disease caused by rice stripe virus. Thus, we demonstrated that BSR1-OX rice shows remarkable broad-spectrum resistance to at least two major bacterial species and two major fungal species, and slight resistance to one viral pathogen.

  9. Impact of computerized pre-authorization of broad spectrum antibiotics in Pseudomonas aeruginosa at a children's hospital in Japan.

    Science.gov (United States)

    Horikoshi, Yuho; Higuchi, Hiroshi; Suwa, Junichi; Isogai, Mihoko; Shoji, Takayo; Ito, Kenta

    2016-08-01

    The spread of antimicrobial-resistant organisms is a global concern. To stem this tide, an antimicrobial stewardship program at hospitals is essential to optimize the prescription of broad spectrum antibiotics. In this study we examined the impact of computerized pre-authorization for broad spectrum antibiotics for Pseudomonas aeruginosa at a children's hospital. An antimicrobial stewardship program at Tokyo Metropolitan Children's Medical Center was assessed between March 2010 and March 2015. A paper-based post-prescription audit was switched to computerized pre-authorization for broad antipseudomonal agents in October 2011. The prescriber was required to obtain approval from physicians in the pediatric infectious diseases division before prescribing restricted antimicrobial agents. Approved prescriptions were processed and logged electronically. We evaluated days of therapy per 1000 patient-days, the cost of antibiotics, and the susceptibility of P. aeruginosa to piperacillin, ceftazidime, cefepime, piperacillin/tazobactam, carbapenems, and ciprofloxacin. Also, the average length of admission and infection-related mortality at 30 days were compared pre- and post-intervention. Administration of carbapenems, piperacillin/tazobactam, and ceftazidime decreased significantly after the introduction of computerized pre-authorization. Antibiotic costs were reduced by JPY2.86 million (USD 26,000) annually. None of the antipseudomonal agents showed decreased sensitivity. The average length of admission was shorter in post-intervention. Infection-related mortality at 30 days showed no difference between the pre- and post-intervention periods. An antimicrobial stewardship program using computerized pre-authorization decreased the use and cost of broad spectrum antibiotics without significant difference in infection-related mortality at 30 days, although our study did not improve susceptibilities of P. aeruginosa. Copyright © 2016 Japanese Society of Chemotherapy and The

  10. Molecular detection of TEM broad spectrum β-lactamase in clinical ...

    African Journals Online (AJOL)

    Resistance to β-lactam antibiotics, along with clinical isolates, frequently results to production of β- lactamase enzymes. In recent years, the production of extended spectrum β-lactamases (ESBLs) among clinical isolates, especially Escherichia coli has greatly increased. On the other hand, β lactamase genes have several ...

  11. Designing a polytope for use in a broad-spectrum dengue virus vaccine

    Directory of Open Access Journals (Sweden)

    Karimatul Himmah, M.Si

    2018-04-01

    virus. The results of this study suggest that this polytope warrants further development for use in a broad-spectrum vaccine against dengue virus. الكلمات المفتاحية: حمى الضنك, أجسام مضادة محايدة على نطاق واسع, بوليتوب, نمط غير متجانس, بقايا, Keywords: bnAbs, Dengue, Heterotype, Polytope, Residue

  12. A Broad Iron Line in the Chandra/HETG Spectrum of 4U 1705-44

    NARCIS (Netherlands)

    di Salvo, T.; Iaria, R.; Méndez, R.M.; Burderi, L.; Robba, N.R.; Stella, L.; van der Klis, M.; Tovmassian, G.; Sion, E.

    2004-01-01

    We present preliminary results from a Chandra 30 ks observation of the atoll source 4U 1705-44. In particular we concentrate on the study of the iron K alpha line, using the HEG spectrometer. The iron K alpha line at ~ 6.6 keV is found to be intrinsically broad ( FWHM ~ 1.7 keV); its width can be

  13. Association of Broad- vs Narrow-Spectrum Antibiotics With Treatment Failure, Adverse Events, and Quality of Life in Children With Acute Respiratory Tract Infections.

    Science.gov (United States)

    Gerber, Jeffrey S; Ross, Rachael K; Bryan, Matthew; Localio, A Russell; Szymczak, Julia E; Wasserman, Richard; Barkman, Darlene; Odeniyi, Folasade; Conaboy, Kathryn; Bell, Louis; Zaoutis, Theoklis E; Fiks, Alexander G

    2017-12-19

    Acute respiratory tract infections account for the majority of antibiotic exposure in children, and broad-spectrum antibiotic prescribing for acute respiratory tract infections is increasing. It is not clear whether broad-spectrum treatment is associated with improved outcomes compared with narrow-spectrum treatment. To compare the effectiveness of broad-spectrum and narrow-spectrum antibiotic treatment for acute respiratory tract infections in children. A retrospective cohort study assessing clinical outcomes and a prospective cohort study assessing patient-centered outcomes of children between the ages of 6 months and 12 years diagnosed with an acute respiratory tract infection and prescribed an oral antibiotic between January 2015 and April 2016 in a network of 31 pediatric primary care practices in Pennsylvania and New Jersey. Stratified and propensity score-matched analyses to account for confounding by clinician and by patient-level characteristics, respectively, were implemented for both cohorts. Broad-spectrum antibiotics vs narrow-spectrum antibiotics. In the retrospective cohort, the primary outcomes were treatment failure and adverse events 14 days after diagnosis. In the prospective cohort, the primary outcomes were quality of life, other patient-centered outcomes, and patient-reported adverse events. Of 30 159 children in the retrospective cohort (19 179 with acute otitis media; 6746, group A streptococcal pharyngitis; and 4234, acute sinusitis), 4307 (14%) were prescribed broad-spectrum antibiotics including amoxicillin-clavulanate, cephalosporins, and macrolides. Broad-spectrum treatment was not associated with a lower rate of treatment failure (3.4% for broad-spectrum antibiotics vs 3.1% for narrow-spectrum antibiotics; risk difference for full matched analysis, 0.3% [95% CI, -0.4% to 0.9%]). Of 2472 children enrolled in the prospective cohort (1100 with acute otitis media; 705, group A streptococcal pharyngitis; and 667, acute sinusitis), 868

  14. Epilithic biofilms in Saint Callixtus Catacombs (Rome) harbour a broad spectrum of Acidobacteria.

    Science.gov (United States)

    Zimmermann, Johannes; Gonzalez, Juan M; Saiz-Jimenez, Cesareo

    2006-01-01

    The phylum Acidobacteria is broadly represented in a variety of environments as reported during microbial molecular surveys. This study represents the first attempt to analyze the diversity of Acidobacteria in Roman Catacombs (Rome, Italy). Both 16S and 23S rRNA gene sequences were used to confirm the affiliation within different acidobacterial subgroups. The results showed Acidobacteria belonging to subgroups 3, 4, 6, 9, and 10 in the analyzed samples. The presence of acidobacterial sequences in biodeteriorating biofilms in Roman Catacombs suggest they could participate in this negative process, most likely in cooperation with other microbial groups.

  15. Genome-Wide Association Studies of a Broad Spectrum of Antisocial Behavior.

    Science.gov (United States)

    Tielbeek, Jorim J; Johansson, Ada; Polderman, Tinca J C; Rautiainen, Marja-Riitta; Jansen, Philip; Taylor, Michelle; Tong, Xiaoran; Lu, Qing; Burt, Alexandra S; Tiemeier, Henning; Viding, Essi; Plomin, Robert; Martin, Nicholas G; Heath, Andrew C; Madden, Pamela A F; Montgomery, Grant; Beaver, Kevin M; Waldman, Irwin; Gelernter, Joel; Kranzler, Henry R; Farrer, Lindsay A; Perry, John R B; Munafò, Marcus; LoParo, Devon; Paunio, Tiina; Tiihonen, Jari; Mous, Sabine E; Pappa, Irene; de Leeuw, Christiaan; Watanabe, Kyoko; Hammerschlag, Anke R; Salvatore, Jessica E; Aliev, Fazil; Bigdeli, Tim B; Dick, Danielle; Faraone, Stephen V; Popma, Arne; Medland, Sarah E; Posthuma, Danielle

    2017-12-01

    Antisocial behavior (ASB) places a large burden on perpetrators, survivors, and society. Twin studies indicate that half of the variation in this trait is genetic. Specific causal genetic variants have, however, not been identified. To estimate the single-nucleotide polymorphism-based heritability of ASB; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to reevaluate the candidate gene era data through the Broad Antisocial Behavior Consortium. Genome-wide association data from 5 large population-based cohorts and 3 target samples with genome-wide genotype and ASB data were used for meta-analysis from March 1, 2014, to May 1, 2016. All data sets used quantitative phenotypes, except for the Finnish Crime Study, which applied a case-control design (370 patients and 5850 control individuals). This study adopted relatively broad inclusion criteria to achieve a quantitative measure of ASB derived from multiple measures, maximizing the sample size over different age ranges. The discovery samples comprised 16 400 individuals, whereas the target samples consisted of 9381 individuals (all individuals were of European descent), including child and adult samples (mean age range, 6.7-56.1 years). Three promising loci with sex-discordant associations were found (8535 female individuals, chromosome 1: rs2764450, chromosome 11: rs11215217; 7772 male individuals, chromosome X, rs41456347). Polygenic risk score analyses showed prognostication of antisocial phenotypes in an independent Finnish Crime Study (2536 male individuals and 3684 female individuals) and shared genetic origin with conduct problems in a population-based sample (394 male individuals and 431 female individuals) but not with conduct disorder in a substance-dependent sample (950 male individuals and 1386 female individuals) (R2 = 0.0017 in the most optimal model, P = 0.03). Significant inverse genetic correlation

  16. Aerosol Absorption Retrievals from the PACE Broad Spectrum Ocean Color Instrument (OCI)

    Science.gov (United States)

    Mattoo, Shana; Remer, Lorraine A.; Levy, Robert C.; Gupta, Pawan; Ahmad, Ziauddin; Martins, J. Vanderlei; Lima, Adriana Rocha; Torres, Omar

    2016-01-01

    The PACE (Pre-­Aerosol, Clouds and ocean Ecosystem) mission, anticipated for launch in the early 2020s, is designed to characterize oceanic and atmospheric properties. The primary instrument on-­-board will be a moderate resolution (approximately 1 km nadir) radiometer, called the Ocean Color Instrument (OCI). OCI will provide high spectral resolution (5 nm) from the UV to NIR (350 - 800 nm), with additional spectral bands in the NIR and SWIR. The OCI itself is an excellent instrument for atmospheric objectives, providing measurements across a broad spectral range that in essence combines the capabilities of MODIS and OMI, but with the UV channels from OMI to be available at moderate resolution. (Image credit: PACE Science Definition Team Report). Objective: Can we make use of the UV-­SWIR measurements to derive information about aerosol absorption when aerosol loading is high?

  17. Leapfrog diagnostics: Demonstration of a broad spectrum pathogen identification platform in a resource-limited setting

    Directory of Open Access Journals (Sweden)

    Leski Tomasz A

    2012-07-01

    Full Text Available Abstract Background Resource-limited tropical countries are home to numerous infectious pathogens of both human and zoonotic origin. A capability for early detection to allow rapid outbreak containment and prevent spread to non-endemic regions is severely impaired by inadequate diagnostic laboratory capacity, the absence of a “cold chain” and the lack of highly trained personnel. Building up detection capacity in these countries by direct replication of the systems existing in developed countries is not a feasible approach and instead requires “leapfrogging” to the deployment of the newest diagnostic systems that do not have the infrastructure requirements of systems used in developed countries. Methods A laboratory for molecular diagnostics of infectious agents was established in Bo, Sierra Leone with a hybrid solar/diesel/battery system to ensure stable power supply and a satellite modem to enable efficient communication. An array of room temperature stabilization and refrigeration technologies for reliable transport and storage of reagents and biological samples were also tested to ensure sustainable laboratory supplies for diagnostic assays. Results The laboratory demonstrated its operational proficiency by conducting an investigation of a suspected avian influenza outbreak at a commercial poultry farm at Bo using broad range resequencing microarrays and real time RT-PCR. The results of the investigation excluded influenza viruses as a possible cause of the outbreak and indicated a link between the outbreak and the presence of Klebsiella pneumoniae. Conclusions This study demonstrated that by application of a carefully selected set of technologies and sufficient personnel training, it is feasible to deploy and effectively use a broad-range infectious pathogen detection technology in a severely resource-limited setting.

  18. Snake Venom PLA2, a Promising Target for Broad-Spectrum Antivenom Drug Development

    Directory of Open Access Journals (Sweden)

    Huixiang Xiao

    2017-01-01

    Full Text Available Snakebite envenomation is a neglected global health problem, causing substantial mortality, disability, and psychological morbidity, especially in rural tropical and subtropical zones. Antivenin is currently the only specific medicine for envenomation. However, it is restricted by cold storage, snakebite diagnosis, and high price. Snake venom phospholipase A2s (svPLA2s are found in all kinds of venomous snake families (e.g., Viperidae, Elapidae, and Colubridae. Along with their catalytic activity, svPLA2s elicit a wide variety of pharmacological effects that play a pivotal role in envenomation damage. Hence, neutralization of the svPLA2s could weaken or inhibit toxic damage. Here we overviewed the latest knowledge on the distribution, pathophysiological effects, and inhibitors of svPLA2s to elucidate the potential for a novel, wide spectrum antivenom drug targeting svPLA2s.

  19. Broad spectrum of neuropsychiatric phenotypes associated with white matter disease in PTEN hamartoma tumor syndrome.

    Science.gov (United States)

    Balci, Tugce B; Davila, Jorge; Lewis, Denice; Boafo, Addo; Sell, Erick; Richer, Julie; Nikkel, Sarah M; Armour, Christine M; Tomiak, Eva; Lines, Matthew A; Sawyer, Sarah L

    2018-01-01

    White matter lesions have been described in patients with PTEN hamartoma tumor syndrome (PHTS). How these lesions correlate with the neurocognitive features associated with PTEN mutations, such as autism spectrum disorder (ASD) or developmental delay, has not been well established. We report nine patients with PTEN mutations and white matter changes on brain magnetic resonance imaging (MRI), eight of whom were referred for reasons other than developmental delay or ASD. Their clinical presentations ranged from asymptomatic macrocephaly with normal development/intellect, to obsessive compulsive disorder, and debilitating neurological disease. To our knowledge, this report constitutes the first detailed description of PTEN-related white matter changes in adult patients and in children with normal development and intelligence. We present a detailed assessment of the neuropsychological phenotype of our patients and discuss the relationship between the wide array of neuropsychiatric features and observed white matter findings in the context of these individuals. © 2017 Wiley Periodicals, Inc.

  20. Isolation and characterization of broad spectrum bacteriophages lytic to Vibrio harveyi from shrimp farms of Kerala, India.

    Science.gov (United States)

    Surekhamol, I S; Deepa, G D; Somnath Pai, S; Sreelakshmi, B; Varghese, S; Bright Singh, I S

    2014-03-01

    Of 33 phages isolated from various shrimp farms in Kerala, India, six were segregated to have broad spectrum lytic efficiency towards 87 isolates of Vibrio harveyi with cross-infecting potential to a few other important aquaculture pathogens. They were further tested on beneficial aquaculture micro-organisms such as probiotics and nitrifying bacterial consortia and proved to be noninfective. Morphological characterization by transmission electron microscopy (TEM) and molecular characterization by RAPD and SDS-PAGE proved them distinct and positioned under Caudovirales belonging to Myoviridae and Siphoviridae. In sustainable aquaculture, application of antibiotics is prohibited to manage vibriosis, including the one caused by Vibrio harveyi. In lieu of antibiotics, an eco-friendly alternative method, phage therapy, is recommended here. To facilitate the same, a set of six broad spectrum V. harveyi phages, as cocktail, has been constituted and characterized based on morphological traits and by employing molecular tools. These phages were also found to infect other aquaculture pathogens belonging to Vibrio and Aeromonas. Subsequent to in vivo trials, they can find application in shrimp hatcheries as prophylactics and therapeutics. © 2013 The Society for Applied Microbiology.

  1. Novel engineered cationic antimicrobial peptides display broad-spectrum activity against Francisella tularensis, Yersinia pestis and Burkholderia pseudomallei.

    Science.gov (United States)

    Abdelbaqi, Suha; Deslouches, Berthony; Steckbeck, Jonathan; Montelaro, Ronald; Reed, Douglas S

    2016-02-01

    Broad-spectrum antimicrobials are needed to effectively treat patients infected in the event of a pandemic or intentional release of a pathogen prior to confirmation of the pathogen's identity. Engineered cationic antimicrobial peptides (eCAPs) display activity against a number of bacterial pathogens including multi-drug-resistant strains. Two lead eCAPs, WLBU2 and WR12, were compared with human cathelicidin (LL-37) against three highly pathogenic bacteria: Francisella tularensis, Yersinia pestis and Burkholderia pseudomallei. Both WLBU2 and WR12 demonstrated bactericidal activity greater than that of LL-37, particularly against F. tularensis and Y. pestis. Only WLBU2 had bactericidal activity against B. pseudomallei. WLBU2, WR12 and LL-37 were all able to inhibit the growth of the three bacteria in vitro. Because these bacteria can be facultative intracellular pathogens, preferentially infecting macrophages and dendritic cells, we evaluated the activity of WLBU2 against F. tularensis in an ex vivo infection model with J774 cells, a mouse macrophage cell line. In that model WLBU2 was able to achieve greater than 50% killing of F. tularensis at a concentration of 12.5 μM. These data show the therapeutic potential of eCAPs, particularly WLBU2, as a broad-spectrum antimicrobial for treating highly pathogenic bacterial infections.

  2. Photobiological interactions of blue light and photosynthetic photon flux: effects of monochromatic and broad-spectrum light sources.

    Science.gov (United States)

    Cope, Kevin R; Snowden, M Chase; Bugbee, Bruce

    2014-01-01

    Photosynthesis (Pn) and photomorphogenesis (Pm) are affected by light quality, light intensity and photoperiod. Although blue light (BL) is necessary for normal development, it is less efficient in driving Pn than other wavelengths of photosynthetically active radiation. The effects of BL on Pm are highly species dependent. Here we report the interacting effects of BL and photosynthetic photon flux (PPF) on growth and development of lettuce, radish and pepper. We used light-emitting diode (LED) arrays to provide BL fractions from 11% to 28% under broad-spectrum white LEDs, and from 0.3% to 92% under monochromatic LEDs. All treatments were replicated three times at each of two PPFs (200 and 500 μmol m(-2) s(-1)). Other than light quality, environmental conditions were uniformly maintained across chambers. Regardless of PPF, BL was necessary to prevent shade-avoidance responses in radish and lettuce. For lettuce and radish, increasing BL reduced stem length, and for both species, there were significant interactions of BL with PPF for leaf expansion. Increasing BL reduced petiole length in radish and flower number in pepper. BL minimally affected pepper growth and other developmental parameters. Pepper seedlings were more photobiologically sensitive than older plants. Surprisingly, there were few interactions between monochromatic and broad-spectrum light sources. © 2013 The American Society of Photobiology.

  3. Changes in Cell Viability of Wounded Fibroblasts following Laser Irradiation in Broad-Spectrum or Infrared Light

    International Nuclear Information System (INIS)

    Hawkins, D.; Abrahamse, H.

    2007-01-01

    Objective. This study aimed to establish if broad-spectrum or infrared (IR) light in combination with laser therapy can assist phototherapy to improve the cell function of wounded cells. Background. The effect of laser light may be partly or completely reduced by broad-spectrum light. Methods. Wounded human skin fibroblasts were irradiated with 5 J/cm2 using a helium-neon laser, a diode laser, or an Nd:YAG laser in the dark, in the light, or in IR. Changes in cell viability were evaluated by cell morphology, ATP cell viability, LDH membrane integrity, and caspase 3/7 as an early marker of apoptosis. Results. Wounded cells exposed to 5 J/cm2 using 632.8 nm in the dark or 830 nm in the light or 1064 nm in the dark showed an increase in ATP viability, an increase in cytokine expression, and a decrease in LDH cytotoxicity indicating that the metabolic activity of the wounded cells was stimulated. Conclusion. Wounded cells irradiated in IR light showed an undesirable thermal effect that was proportional to the duration of exposure.

  4. The broad-spectrum caspase inhibitor Boc-Asp-CMK induces cell death in human leukaemia cells.

    Science.gov (United States)

    Frydrych, Ivo; Mlejnek, Petr; Dolezel, Petr; Zoumpourlis, Vassilis; Krumpochova, Petra

    2008-08-01

    Synthetic caspase inhibitors and particularly broad-spectrum caspase inhibitors can prevent cells from death or at least slow down cell death process and abrogate some apoptotic hallmarks [Kitanaka, C., Kuchino, Y., 1999. Caspase-independent programmed cell death with necrotic morphology. Cell Death and Differentiation 6, 508-515]. However, not all synthetic caspase inhibitors diminish cell death. We have found that the broad-spectrum caspase inhibitor Boc-Asp-CMK induced cell death at micromolar concentrations in human leukaemia cells. Interestingly, low concentrations of Boc-Asp-CMK induced cell death with apoptotic hallmarks. Increasing concentrations of Boc-Asp-CMK led to necrotic cell death. The switch between apoptosis and necrosis seemed to depend upon the degree of inhibition of executioner caspases, including caspase-3/7 with Boc-Asp-CMK. Interestingly, caspase-3 processing was not inhibited even for the highest concentration of Boc-Asp-CMK used. We assume, that toxic properties of Boc-Asp-CMK can be attributed to the chloromethylketone residuum in its molecule, as its analogue Boc-Asp-FMK with fluoromethylketone residuum was more than 13 times less toxic. Our results further indicated that toxicity of Boc-Asp-CMK might arise from its interference with mitochondrial metabolism.

  5. Broad spectrum pesticide application alters natural enemy communities and may facilitate secondary pest outbreaks

    Directory of Open Access Journals (Sweden)

    Matthew P. Hill

    2017-12-01

    Full Text Available Background Pesticide application is the dominant control method for arthropod pests in broad-acre arable systems. In Australia, organophosphate pesticides are often applied either prophylactically, or reactively, including at higher concentrations, to control crop establishment pests such as false wireworms and earth mite species. Organophosphates are reported to be disruptive to beneficial species, such as natural enemies, but this has not been widely assessed in Australian systems. Neither has the risk that secondary outbreaks may occur if the natural enemy community composition or function is altered. Methods We examine the abundance of ground-dwelling invertebrate communities in an arable field over successive seasons under rotation; barley, two years of wheat, then canola. Two organophosphates (chlorpyrifos and methidathion were initially applied at recommended rates. After no discernible impact on target pest species, the rate for chlorpyrifos was doubled to elicit a definitive response to a level used at establishment when seedling damage is observed. Invertebrates were sampled using pitfalls and refuge traps throughout the experiments. We applied measures of community diversity, principal response curves and multiple generalised linear modelling techniques to understand the changes in pest and natural enemy communities. Results There was large variability due to seasonality and crop type. Nevertheless, both pest (e.g., mites and aphids and natural enemy (e.g., predatory beetles invertebrate communities were significantly affected by application of organophosphates. When the rate of chlorpyrifos was increased there was a reduction in the number of beetles that predate on slug populations. Slugs displayed opposite trends to many of the other target pests, and actually increased in numbers under the higher rates of chlorpyrifos in comparison to the other treatments. Slug numbers in the final rotation of canola resulted in significant yield

  6. Community fecal carriage of broad-spectrum cephalosporin-resistant Escherichia coli in Tunisian children.

    Science.gov (United States)

    Ferjani, Sana; Saidani, Mabrouka; Hamzaoui, Zeineb; Alonso, Carla Andrea; Torres, Carmen; Maamar, Elaa; Slim, Amine Faouzi; Boutiba, Ben Boubaker Ilhem

    2017-02-01

    The spread of extended spectrum β-lactamases (ESBL) and plasmid mediated AmpC β-lactamases (pAmpC) was evaluated in Escherichia coli strains collected from the intestinal microbiota of healthy children in Tunisia. The carriage rate of CTX R E. coli was 6.6% (7 of 105 samples) and one strain/sample was further characterized (7 isolates). These isolates harbored bla CTX-M-1 (n = 4), bla CTX-M-15 (n = 2), and bla CMY-2 gene (n = 1), which were usually located on FIB replicon type and carried class 1 integrons. The acc(6')-Ib-cr variant was identified in one isolate that harbored bla CTX-M-15 . CTX R E. coli isolates were genetically unrelated and belonged to B1 (n = 3/ST155/ST398/ST58), D (n = 2/ST117/ST493), B2 (n = 1/ST127), and A (n = 1/ST746) phylogroups. Strain virulence scores varied from 3 to 12, and frequently harbored the pathogenicity island PAI IV 536 . The intestinal tract of healthy children constitute an important reservoir of ESBL producing E. coli. Thus, improvement of hygiene measures mainly in the school environment and rational use of antibiotics would be of great help in preventing selection and diffusion of resistant strains from intestinal microbiota. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Novel gramicidin formulations in cationic lipid as broad-spectrum microbicidal agents

    Directory of Open Access Journals (Sweden)

    Ragioto DA

    2014-06-01

    Full Text Available Danielle AMT Ragioto, Letícia DM Carrasco, Ana M Carmona-Ribeiro Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil Abstract: Dioctadecyldimethylammonium bromide (DODAB is an antimicrobial lipid that can be dispersed as large closed bilayers (LV or bilayer disks (BF. Gramicidin (Gr is an antimicrobial peptide assembling as channels in membranes and increasing their permeability towards cations. In mammalian cells, DODAB and Gr have the drawbacks of Gram-positive resistance and high toxicity, respectively. In this study, DODAB bilayers incorporating Gr showed good antimicrobial activity and low toxicity. Techniques employed were spectroscopy, photon correlation spectroscopy for sizing and evaluation of the surface potential at the shear plane, turbidimetric detection of dissipation of osmotic gradients in LV/Gr, determination of bacterial cell lysis, and counting of colony-forming units. There was quantitative incorporation of Gr and development of functional channels in LV. Gr increased the bilayer charge density in LV but did not affect the BF charge density, with localization of Gr at the BF borders. DODAB/Gr formulations substantially reduce Gr toxicity against eukaryotic cells and advantageously broaden the antimicrobial activity spectrum, effectively killing Escherichia coli and Staphylococcus aureus bacteria with occurrence of cell lysis. Keywords: antimicrobial peptides, cationic bilayers, bilayer fragments, dioctadecyldimethylammonium bromide, gramicidin A, self-assembly

  8. Broad Spectrum Microbicidal Activity of Photocatalysis by TiO2

    Directory of Open Access Journals (Sweden)

    Yoshinobu Kubota

    2013-03-01

    Full Text Available Photocatalytically active titanium dioxide (TiO2 is widely used as a self-cleaning and self-disinfecting material in many applications to keep environments biologically clean. Several studies on the inactivation of bacteria and viruses by photocatalytic reactions have also been reported; however, only few studies evaluated the spectrum of the microbicidal activity with photocatalysis for various species. There is a need to confirm the expected effectiveness of disinfection by photocatalysis against multidrug-resistant bacteria and viruses. In this study, microbicidal activity of photocatalysis was evaluated by comparing the inactivation of various species of bacteria and viruses when their suspensions were dropped on the surface of TiO2-coated glass. Gram-positive bacteria, e.g., methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis, and penicillin-resistant Streptococcus pneumoniae, were easily inactivated by photocatalysis, whereas some gram-negative bacteria, e.g., Escherichia coli and multidrug-resistant Pseudomonas aeruginosa, were gradually inactivated by photocatalysis. Influenza virus, an enveloped virus, was significantly inactivated by photocatalysis compared with feline calicivirus, a non-enveloped virus. The effectiveness of microbicidal activity by photocatalysis may depend on the surface structure. However, they are effectively inactivated by photocatalysis on the surface of TiO2-coated glass. Our data emphasize that effective cleaning and disinfection by photocatalysis in nosocomial settings prevents pathogen transmission.

  9. Broad spectrum of mimiviridae virophage allows its isolation using a mimivirus reporter.

    Directory of Open Access Journals (Sweden)

    Morgan Gaia

    Full Text Available The giant virus Mimiviridae family includes 3 groups of viruses: group A (includes Acanthamoeba polyphaga Mimivirus, group B (includes Moumouvirus and group C (includes Megavirus chilensis. Virophages have been isolated with both group A Mimiviridae (the Mamavirus strain and the related Cafeteria roenbergensis virus, and they have also been described by bioinformatic analysis of the Phycodnavirus. Here, we found that the first two strains of virophages isolated with group A Mimiviridae can multiply easily in groups B and C and play a role in gene transfer among these virus subgroups. To isolate new virophages and their Mimiviridae host in the environment, we used PCR to identify a sample with a virophage and a group C Mimiviridae that failed to grow on amoeba. Moreover, we showed that virophages reduce the pathogenic effect of Mimivirus (plaque formation, establishing its parasitic role on Mimivirus. We therefore developed a co-culture procedure using Acanthamoeba polyphaga and Mimivirus to recover the detected virophage and then sequenced the virophage's genome. We present this technique as a novel approach to isolating virophages. We demonstrated that the newly identified virophages replicate in the viral factories of all three groups of Mimiviridae, suggesting that the spectrum of virophages is not limited to their initial host.

  10. Recognition of emotional facial expressions and broad autism phenotype in parents of children diagnosed with autistic spectrum disorder.

    Science.gov (United States)

    Kadak, Muhammed Tayyib; Demirel, Omer Faruk; Yavuz, Mesut; Demir, Türkay

    2014-07-01

    Research findings debate about features of broad autism phenotype. In this study, we tested whether parents of children with autism have problems recognizing emotional facial expression and the contribution of such an impairment to the broad phenotype of autism. Seventy-two parents of children with autistic spectrum disorder and 38 parents of control group participated in the study. Broad autism features was measured with Autism Quotient (AQ). Recognition of Emotional Face Expression Test was assessed with the Emotion Recognition Test, consisting a set of photographs from Ekman & Friesen's. In a two-tailed analysis of variance of AQ, there was a significant difference for social skills (F(1, 106)=6.095; p<.05). Analyses of variance revealed significant difference in the recognition of happy, surprised and neutral expressions (F(1, 106)=4.068, p=.046; F(1, 106)=4.068, p=.046; F(1, 106)=6.064, p=.016). According to our findings, social impairment could be considered a characteristic feature of BAP. ASD parents had difficulty recognizing neutral expressions, suggesting that ASD parents may have impaired recognition of ambiguous expressions as do autistic children. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Evaluation of Carbohydrate-Derived Fulvic Acid (CHD-FA) as a Topical Broad-Spectrum Antimicrobial for Drug-Resistant Wound Infections

    Science.gov (United States)

    2016-10-01

    of Carbohydrate-Derived Fulvic Acid (CHD-FA) as a Topical Broad- Spectrum Antimicrobial for Drug- Resistant Wound Infections 5b. GRANT NUMBER 5c...demonstrated the antimicrobial properties of Carbohydrate-Derived Fulvic Acid (CHD-FA) against a broad collection of multi-drug resistant bacterial and...spectrum antimicrobial for drug- resistant wound infections) at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2014

  12. Host-directed antimicrobial drugs with broad-spectrum efficacy against intracellular bacterial pathogens.

    Science.gov (United States)

    Czyż, Daniel M; Potluri, Lakshmi-Prasad; Jain-Gupta, Neeta; Riley, Sean P; Martinez, Juan J; Steck, Theodore L; Crosson, Sean; Shuman, Howard A; Gabay, Joëlle E

    2014-07-29

    We sought a new approach to treating infections by intracellular bacteria, namely, by altering host cell functions that support their growth. We screened a library of 640 Food and Drug Administration (FDA)-approved compounds for agents that render THP-1 cells resistant to infection by four intracellular pathogens. We identified numerous drugs that are not antibiotics but were highly effective in inhibiting intracellular bacterial growth with limited toxicity to host cells. These compounds are likely to target three kinds of host functions: (i) G protein-coupled receptors, (ii) intracellular calcium signals, and (iii) membrane cholesterol distribution. The compounds that targeted G protein receptor signaling and calcium fluxes broadly inhibited Coxiella burnetii, Legionella pneumophila, Brucella abortus, and Rickettsia conorii, while those directed against cholesterol traffic strongly attenuated the intracellular growth of C. burnetii and L. pneumophila. These pathways probably support intracellular pathogen growth so that drugs that perturb them may be therapeutic candidates. Combining host- and pathogen-directed treatments is a strategy to decrease the emergence of drug-resistant intracellular bacterial pathogens. Importance: Although antibiotic treatment is often successful, it is becoming clear that alternatives to conventional pathogen-directed therapy must be developed in the face of increasing antibiotic resistance. Moreover, the costs and timing associated with the development of novel antimicrobials make repurposed FDA-approved drugs attractive host-targeted therapeutics. This paper describes a novel approach of identifying such host-targeted therapeutics against intracellular bacterial pathogens. We identified several FDA-approved drugs that inhibit the growth of intracellular bacteria, thereby implicating host intracellular pathways presumably utilized by bacteria during infection. Copyright © 2014 Czyż et al.

  13. Oncogenic Determination of a Broad Spectrum of Phenotypes of Hepatocyte-Derived Mouse Liver Tumors.

    Science.gov (United States)

    Yamamoto, Masahiro; Xin, Bing; Watanabe, Kenji; Ooshio, Takako; Fujii, Kiyonaga; Chen, Xi; Okada, Yoko; Abe, Hiroaki; Taguchi, Yoshimitsu; Miyokawa, Naoyuki; Furukawa, Hiroyuki; Nishikawa, Yuji

    2017-12-01

    Activation of the phosphoinositide 3-kinase-AKT, Yes-associated protein (YAP), and MYC pathways is involved in human liver cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). However, the nature of the interactions among these pathways has remained poorly understood. Herein, we demonstrate the coordination of these pathways during the formation of mouse liver tumors induced by hepatocyte-specific somatic integration of myristoylated AKT, mutant YAP, Myc, or their combinations. Although the introduction of YAP or Myc alone was inefficient in inducing tumors, these proteins accelerated tumorigenesis induced by AKT. The generated tumors demonstrated various histological features: low-grade HCC by AKT/Myc, CC by AKT/YAP, and high-grade HCC by AKT/Myc/YAP. CC induced by AKT/YAP was associated with activation of the Notch pathway. Interestingly, the combination of Myc and YAP generated tumors composed of hepatoblast/stem-like cells expressing mRNA for Afp, Dlk1, Nanog, and Sox2 and occasionally forming immature ducts. Finally, immunohistochemical analysis revealed that human HCC and CC were predominantly associated with phosphorylation of S6 and glycogen synthase kinase-3β, respectively, and >60% of CC cases were positive for both phosphorylated glycogen synthase kinase--3β and YAP. Our study suggests that hepatocyte-derived tumors demonstrate a wide spectrum of tumor phenotypes, including HCC, CC, and hepatoblastoma-like, through the combinatory effects of the oncogenic pathways and that the state of the phosphoinositide 3-kinase-AKT pathway is a key determinant of differentiation. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  14. Highly toxic and broad-spectrum insecticidal local Bacillus strains engineered using protoplast fusion.

    Science.gov (United States)

    El-Kawokgy, Tahany M A; Hussein, Hashem A; Aly, Nariman A H; Mohamed, Shereen A H

    2015-01-01

    Protoplast fusion was performed between a local Bacillus thuringiensis UV-resistant mutant 66/1a (Bt) and Bacillus sphaericus GHAI (Bs) to produce new Bacillus strains with a wider spectrum of action against different insects. Bt is characterized as sensitive to polymyxin and streptomycin and resistant to rifampicin and has shown 87% mortality against Spodoptera littoralis larvae at concentration of 1.5 × 10(7) cells/mL after 7 days of feeding; Bs is characterized as resistant to polymyxin and streptomycin and sensitive to rifampicin and has been shown to have 100% mortality against Culex pipiens after 1 day of feeding at the same concentration as that of Bt. Among a total of 64 Bt::Bs fusants produced on the selective medium containing polymyxin, streptomycin, and rifampicin, 17 fusants were selected because of their high mortality percentages against S. littoralis (Lepidoptera) and C. pipiens (Diptera). While Bt harboured 3 plasmids (600, 350, and 173 bp) and Bs had 2 plasmids (544 and 291 bp), all the selected fusants acquired plasmids from both parental strains. SDS-PAGE protein analysis of the 17 selected fusants and their parental strains confirmed that all fusant strains acquired and expressed many specific protein bands from the 2 parental strains, especially the larvicidal proteins to both lepidopteran and dipteran species with molecular masses of 65, 70, 80, 88, 100, and 135 kDa. Four protein bands with high molecular masses of 281, 263, 220, and 190 kDa, which existed in the Bt parental strain and did not exist in the Bs parental strain, and 2 other protein bands with high molecular masses of 185 and 180 kDa, which existed in the Bs parental strain and did not exist in the Bt parental strain, were expressed in most fusants. The results indicated the expression of some cry genes encoded for insecticidal crystal proteins from Bt and the binary toxin genes from Bs in all fusant strains. The recombinant fusants have more efficient and potential values for

  15. Applications of a broad-spectrum tool for conservation and fisheries analysis: aquatic gap analysis

    Science.gov (United States)

    McKenna, James E.; Steen, Paul J.; Lyons, John; Stewart, Jana S.

    2009-01-01

    . Aquatic gap analysis naturally focuses on aquatic habitats. The analytical tools are largely based on specification of the species-habitat relations for the system and organism group of interest (Morrison et al. 2003; McKenna et al. 2006; Steen et al. 2006; Sowa et al. 2007). The Great Lakes Regional Aquatic Gap Analysis (GLGap) project focuses primarily on lotic habitat of the U.S. Great Lakes drainage basin and associated states and has been developed to address fish and fisheries issues. These tools are unique because they allow us to address problems at a range of scales from the region to the stream segment and include the ability to predict species specific occurrence or abundance for most of the fish species in the study area. The results and types of questions that can be addressed provide better global understanding of the ecological context within which specific natural resources fit (e.g., neighboring environments and resources, and large and small scale processes). The geographic analysis platform consists of broad and flexible geospatial tools (and associated data) with many potential applications. The objectives of this article are to provide a brief overview of GLGap methods and analysis tools, and demonstrate conservation and planning applications of those data and tools. Although there are many potential applications, we will highlight just three: (1) support for the Eastern Brook Trout Joint Venture (EBTJV), (2) Aquatic Life classification in Wisconsin, and (3) an educational tool that makes use of Google Earth (use of trade or product names does not imply endorsement by the U.S. Government) and Internet accessibility.

  16. Toxicity modulation, resistance enzyme evasion, and A-site X-ray structure of broad-spectrum antibacterial neomycin analogs.

    Science.gov (United States)

    Maianti, Juan Pablo; Kanazawa, Hiroki; Dozzo, Paola; Matias, Rowena D; Feeney, Lee Ann; Armstrong, Eliana S; Hildebrandt, Darin J; Kane, Timothy R; Gliedt, Micah J; Goldblum, Adam A; Linsell, Martin S; Aggen, James B; Kondo, Jiro; Hanessian, Stephen

    2014-09-19

    Aminoglycoside antibiotics are pseudosaccharides decorated with ammonium groups that are critical for their potent broad-spectrum antibacterial activity. Despite over three decades of speculation whether or not modulation of pKa is a viable strategy to curtail aminoglycoside kidney toxicity, there is a lack of methods to systematically probe amine-RNA interactions and resultant cytotoxicity trends. This study reports the first series of potent aminoglycoside antibiotics harboring fluorinated N1-hydroxyaminobutyryl acyl (HABA) appendages for which fluorine-RNA contacts are revealed through an X-ray cocrystal structure within the RNA A-site. Cytotoxicity in kidney-derived cells was significantly reduced for the derivative featuring our novel β,β-difluoro-HABA group, which masks one net charge by lowering the pKa without compromising antibacterial potency. This novel side-chain assists in evasion of aminoglycoside-modifying enzymes, and it can be easily transferred to impart these properties onto any number of novel analogs.

  17. An "All-In-One" Pharmacophoric Architecture for the Discovery of Potential Broad-Spectrum Anti-Flavivirus Drugs.

    Science.gov (United States)

    Ncube, Nomagugu B; Ramharack, Pritika; Soliman, Mahmoud E S

    2018-01-18

    A precipitous increase in the number of flaviviral infections has been noted over the last 5 years. Despite these outbreaks, treatment protocols for infected individuals remain ambiguous. Numerous studies have identified NITD008 as a potent flavivirus inhibitor; however, clinical testing was dismissed due to undesirable toxic effects. The binding landscape of NITD008 in complex with five detrimental flaviviruses at the RNA-dependent RNA polymerase active sites was explored. An "all-in-one" pharmacophore model was created for the design of small molecules that may inhibit a broad spectrum of flaviviruses. This pharmacophore model approach serves as a robust cornerstone, thus assisting medicinal experts in the composition of multifunctional inhibitors that will eliminate cross-resistance and toxicity and enhance patient adherence.

  18. Mechanisms of Broad-Spectrum Antiemetic Efficacy of Cannabinoids against Chemotherapy-Induced Acute and Delayed Vomiting

    Directory of Open Access Journals (Sweden)

    Nissar A. Darmani

    2010-09-01

    Full Text Available Chemotherapy-induced nausea and vomiting (CINV is a complex pathophysiological condition and consists of two phases. The conventional CINV neurotransmitter hypothesis suggests that the immediate phase is mainly due to release of serotonin (5-HT from the enterochromaffin cells in the gastrointestinal tract (GIT, while the delayed phase is a consequence of release of substance P (SP in the brainstem. However, more recent findings argue against this simplistic neurotransmitter and anatomical view of CINV. Revision of the hypothesis advocates a more complex, differential and overlapping involvement of several emetic neurotransmitters/modulators (e.g. dopamine, serotonin, substance P, prostaglandins and related arachidonic acid derived metabolites in both phases of emesis occurring concomitantly in the brainstem and in the GIT enteric nervous system (ENS [1]. No single antiemetic is currently available to completely prevent both phases of CINV. The standard antiemetic regimens include a 5-HT3 antagonist plus dexamethasone for the prevention of acute emetic phase, combined with an NK1 receptor antagonist (e.g. aprepitant for the delayed phase. Although NK1 antagonists behave in animals as broad-spectrum antiemetics against different emetogens including cisplatin-induced acute and delayed vomiting, by themselves they are not very effective against CINV in cancer patients. Cannabinoids such as D9-THC also behave as broad-spectrum antiemetics against diverse emetic stimuli as well as being effective against both phases of CINV in animals and patients. Potential side effects may limit the clinical utility of direct-acting cannabinoid agonists which could be avoided by the use of corresponding indirect-acting agonists. Cannabinoids (both phyto-derived and synthetic behave as agonist antiemetics via the activation of cannabinoid CB1 receptors in both the brainstem and the ENS emetic loci. An endocannabinoid antiemetic tone may exist since inverse CB1

  19. Weak turbulence and broad-spectrum excitation in a nonmagnetized electron beam via second-harmonic generation

    International Nuclear Information System (INIS)

    Bogdanov, A.T.

    1990-01-01

    The nonlinear evolution of an initially monoenergetic [ν-bar(t = 0) = (0,0,u)] electron beam propagating in a nonmagnetized dielectric medium of permittivity ε > 1, with initial velocity u ≥ c/√ε (where c is the vacuum speed of light) is investigated. The specific instability of the beam under such conditions is the cause of the generation of a broad spectrum of transverse electromagnetic waves coupled to the simultaneous excitation of the second harmonic of the beam's oscillations, both at the expense of the beam's initial kinetic energy. The system of self-consistent nonlinear equations, describing the particle-field dynamics, is treated in the spirit of the weak-turbulence approach. The integrals of the resulting nonlinear system of equations for the amplitudes of the fields of the electron density are used to evaluate the spectral distribution of the amplitudes in the saturation phase, and hence the efficiency of the transformation of the beam's energy into electromagnetic radiation as a function of the width of the spectrum of the initially present electromagnetic fluctuations. A substantial increase in this efficiency is observed in comparison with the single-mode case. (author)

  20. An A-D-A'-D-A type small molecule acceptor with a broad absorption spectrum for organic solar cells.

    Science.gov (United States)

    Miao, Junhui; Meng, Bin; Liu, Jun; Wang, Lixiang

    2018-01-02

    Organic molecules with wide absorption spectra exhibit great sunlight harvesting capability and are critically important for solar cell applications. In this manuscript, we develop an A-D-A'-D-A type small molecule acceptor (IID-IC) using isoindigo (IID) as the electron-deficient core unit (A'), thiophene as the electron-rich bridging units (D) and 2-(3-oxo-2,3-dihydroinden-1-ylidene)malononitrile (IC) as the electron-deficient endcapping groups (A). IID-IC shows a wide absorption spectrum with the full width at half maximum (FWHM) of 190 nm, which is almost twice that of a typical A-D-A type molecule acceptor. The wide absorption spectrum of IID-IC is possibly due to the partially suppressed intramolecular charge transfer effect with the additional electron-deficient core unit. An organic solar cell (OSC) device based on IID-IC exhibits the power conversion efficiency of 2.82% with broad photoresponse from 320 nm to 780 nm.

  1. New insights into broad spectrum communities of the Early Holocene Near East: The birds of Hallan Çemi

    Science.gov (United States)

    Zeder, Melinda A.; Spitzer, Megan D.

    2016-11-01

    The Early Holocene in Near East was a pivotal transitional period that witnessed dramatic changes in climate and environment, human settlement, major changes in subsistence strategies focusing on a broad range of different plant and animal resources, and a radical restructuring of social relations. The remarkable corpus of avifauna from the Early Holocene site of Hallan Çemi in southeastern Turkey sheds new light on key issues about this dynamic period that has been termed the ;Broad Spectrum Revolution;. The avifauna from this important site demonstrate how Hallan Çemi occupants took advantage of the site's strategic location at the junction of multiple environmental zones by extracting a diverse range of seasonally available resources from both near-by and more distant eco-zones to cobble together a stable subsistence economy capable of supporting this small community throughout the year. They give testimony to the impacts of resource utilization over time, especially on species unable to rebound from sustained human hunting. At the same time, they show how Hallan Çemi residents mitigated these impacts by replacing depleted resources with alternative, more resilient ones that could be more sustainably harvested. They open a window onto the growing investment in feasting and ritual activity that helped bind this community together. In so doing they provide a means of empirically evaluating the efficacy of contrasting explanatory frameworks for the Broad Spectrum Revolution that gave rise to the subsequent domestication of plant and animals in the Near East. Contrary to frameworks that cast these developments as responses to resource depression, lessons learned from the Hallan Çemi avifauna lend support to frameworks that emphasize the human capacity to strategically target, capitalize, and improve upon circumscribed resource rich environments in a way that permits more permanent occupation of these niches. And they underscore the degree to which social and

  2. A comparison of broad-spectrum and narrow-spectrum dry cow therapy used alone and in combination with a teat sealant.

    Science.gov (United States)

    Bradley, A J; Breen, J E; Payne, B; Green, M J

    2011-02-01

    The dry period is a critical time in the lactation cycle, offering the optimum time for cure of existing intramammary infection (IMI), while also encompassing the periods of highest susceptibility to new intramammary infection. Until recent years, intramammary infection in the dry period has been controlled with the use of antibiotic dry cow therapy. The aim of this study was to investigate 3 different dry cow therapy regimens, in low-somatic cell count (SCC; bulk milk SCCcows was recruited to the study and randomly allocated to receive either the broad-spectrum antibiotic cefquinome, a combination treatment comprising the narrow-spectrum antibiotic cloxacillin and an internal teat sealant, or the narrow-spectrum antibiotic cloxacillin alone. All quarters were sampled for bacteriology at drying off and again in the week immediately postcalving; 2 quarters were also sampled 2 wk before the estimated calving date to allow an assessment of infection dynamics during the dry period. Quarters were subsequently monitored for clinical mastitis for the first 100 d of lactation. Conventional multilevel (random effects) models were constructed to assess the efficacy of products in preventing IMI. Survival analysis was used to examine factors that influenced the risk of clinical mastitis using conventional Cox proportional hazards models. No differences were identified between the treatment groups in terms of cure of IMI caused by the major pathogens. Quarters in both the combination and cefquinome-treated groups were more likely to be free of a major pathogen or enterobacterial pathogen postcalving. With respect to clinical mastitis, the cefquinome-treated group was less likely to develop clinical mastitis than was the cloxacillin treated group. Copyright © 2011 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  3. White LEDs as broad spectrum light sources for spectrophotometry: demonstration in the visible spectrum range in a diode-array spectrophotometric detector.

    Science.gov (United States)

    Piasecki, Tomasz; Breadmore, Michael C; Macka, Mirek

    2010-11-01

    Although traditional lamps, such as deuterium lamps, are suitable for bench-top instrumentation, their compatibility with the requirements of modern miniaturized instrumentation is limited. This study investigates the option of utilizing solid-state light source technology, namely white LEDs, as a broad band spectrum source for spectrophotometry. Several white light LEDs of both RGB and white phosphorus have been characterized in terms of their emission spectra and energy output and a white phosphorus Luxeon LED was then chosen for demonstration as a light source for visible-spectrum spectrophotometry conducted in CE. The Luxeon LED was fixed onto the base of a dismounted deuterium (D(2) ) lamp so that the light-emitting spot was geometrically positioned exactly where the light-emitting spot of the original D(2) lamp is placed. In this manner, the detector of a commercial CE instrument equipped with a DAD was not modified in any way. As the detector hardware and electronics remained the same, the change of the deuterium lamp for the Luxeon white LED allowed a direct comparison of their performances. Several anionic dyes as model analytes with absorption maxima between 450 and 600 nm were separated by CE in an electrolyte of 0.01 mol/L sodium tetraborate. The absorbance baseline noise as the key parameter was 5 × lower for the white LED lamp, showing clearly superior performance to the deuterium lamp in the available, i.e. visible part of the spectrum. Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Eggplant Resistance to the Ralstonia solanacearum Species Complex Involves Both Broad-Spectrum and Strain-Specific Quantitative Trait Loci

    Directory of Open Access Journals (Sweden)

    Sylvia Salgon

    2017-05-01

    Full Text Available Bacterial wilt (BW is a major disease of solanaceous crops caused by the Ralstonia solanacearum species complex (RSSC. Strains are grouped into five phylotypes (I, IIA, IIB, III, and IV. Varietal resistance is the most sustainable strategy for managing BW. Nevertheless, breeding to improve cultivar resistance has been limited by the pathogen’s extensive genetic diversity. Identifying the genetic bases of specific and non-specific resistance is a prerequisite to breed improvement. A major gene (ERs1 was previously mapped in eggplant (Solanum melongena L. using an intraspecific population of recombinant inbred lines derived from the cross of susceptible MM738 (S × resistant AG91-25 (R. ERs1 was originally found to control three strains from phylotype I, while being totally ineffective against a virulent strain from the same phylotype. We tested this population against four additional RSSC strains, representing phylotypes I, IIA, IIB, and III in order to clarify the action spectrum of ERs1. We recorded wilting symptoms and bacterial stem colonization under controlled artificial inoculation. We constructed a high-density genetic map of the population using single nucleotide polymorphisms (SNPs developed from genotyping-by-sequencing and added 168 molecular markers [amplified fragment length polymorphisms (AFLPs, simple sequence repeats (SSRs, and sequence-related amplified polymorphisms (SRAPs] developed previously. The new linkage map based on a total of 1,035 markers was anchored on eggplant, tomato, and potato genomes. Quantitative trait locus (QTL mapping for resistance against a total of eight RSSC strains resulted in the detection of one major phylotype-specific QTL and two broad-spectrum QTLs. The major QTL, which specifically controls three phylotype I strains, was located at the bottom of chromosome 9 and corresponded to the previously identified major gene ERs1. Five candidate R-genes were underlying this QTL, with different alleles

  5. GLD-2/RNP-8 cytoplasmic poly(A) polymerase is a broad-spectrum regulator of the oogenesis program

    Science.gov (United States)

    Wilson, Tracy L.; Kimble, Judith

    2010-01-01

    Regulated polyadenylation is a broadly conserved mechanism that controls key events during oogenesis. Pivotal to that mechanism is GLD-2, a catalytic subunit of cytoplasmic poly(A) polymerase (PAP). Caenorhabditis elegans GLD-2 forms an active PAP with multiple RNA-binding partners to regulate diverse aspects of germline and early embryonic development. One GLD-2 partner, RNP-8, was previously shown to influence oocyte fate specification. Here we use a genomic approach to identify transcripts selectively associated with both GLD-2 and RNP-8. Among the 335 GLD-2/RNP-8 potential targets, most were annotated as germline mRNAs and many as maternal mRNAs. These targets include gld-2 and rnp-8 themselves, suggesting autoregulation. Removal of either GLD-2 or RNP-8 resulted in shortened poly(A) tails and lowered abundance of four target mRNAs (oma-2, egg-1, pup-2, and tra-2); GLD-2 depletion also lowered the abundance of most GLD-2/RNP-8 putative target mRNAs when assayed on microarrays. Therefore, GLD-2/RNP-8 appears to polyadenylate and stabilize its target mRNAs. We also provide evidence that rnp-8 influences oocyte development; rnp-8 null mutants have more germ cell corpses and fewer oocytes than normal. Furthermore, RNP-8 appears to work synergistically with another GLD-2–binding partner, GLD-3, to ensure normal oogenesis. We propose that the GLD-2/RNP-8 enzyme is a broad-spectrum regulator of the oogenesis program that acts within an RNA regulatory network to specify and produce fully functional oocytes. PMID:20855596

  6. Identification and growth optimization of a Marine Bacillus DK1-SA11 having potential of producing broad spectrum antimicrobial compounds.

    Science.gov (United States)

    Khan, Muhammad Naseem; Lin, Hong; Li, Meng; Wang, Jingxue; Mirani, Zulfiqar Ali; Khan, Seema Ismat; Buzdar, Muhammad Aslam; Ali, Imran; Jamil, Khalid

    2017-05-01

    Control of harmful bacteria in food, aquaculture, pharmaceuticals, agriculture, hospitals and recreation water pools are of great global concern. Marine bacteria are an enormous source of bio-controlling agents. The aim of this study was to identify and optimize the growth conditions including effect of different biotic and abiotic factors on antimicrobial activity of strain DK1-SA11 isolated from Qingdao Bay of China Yellow Sea. Microscopic characterization, API® 20E and 50 CHB kit base carbohydrates utilization, 16S rDNA and DNA gyrB gene sequencing studies identified the bacterium as Bacillus subtilis subsp. spizizenii DK1-SA11. Antimicrobial spectrum of cell free supernatant (CFS) has shown antimicrobial activities against all test strains including methicillin-resistant Staphylococcus aureus, E. coli O157:H7, Candida albicans, Klebsiella pneumoniae, Listeria monocytogenes, Vibrio parahaemolyticus, E. coli, Pseudomonas fluorescens, Salmonella typhimurium and Vibrio cholerae. Among all the media tested, Marine Broth 2216 was found to be the best medium for bacterial growth and production of antibacterial compounds. The other optimum conditions for growth were pH:7 and incubation temperature: 25°C with < 180 rpm for 60-72 h. Out of 49 different carbohydrates tested, D-mannose increases the antibacterial activity by 33.3% while D-arabitol decreases it by 44.4%. Crude CFS showed activity even after three months of storage below -20°C and boiling for 10 min, whereas it loses 100% of its antimicrobial activity after enzymatic treatments of lipase, trypsin and papain. The production of antimicrobial compounds and broad spectrum of antimicrobial activity against all tested pathogens suggested that the strain DK1-SA11 can be used as a source for probiotics, synbiotics and antibiotics.

  7. Environmental Enteric Dysfunction Includes a Broad Spectrum of Inflammatory Responses and Epithelial Repair ProcessesSummary

    Directory of Open Access Journals (Sweden)

    Jinsheng Yu

    2016-03-01

    Full Text Available Background & Aims: Environmental enteric dysfunction (EED, a chronic diffuse inflammation of the small intestine, is associated with stunting in children in the developing world. The pathobiology of EED is poorly understood because of the lack of a method to elucidate the host response. This study tested a novel microarray method to overcome limitation of RNA sequencing to interrogate the host transcriptome in feces in Malawian children with EED. Methods: In 259 children, EED was measured by lactulose permeability (%L. After isolating low copy numbers of host messenger RNA, the transcriptome was reliably and reproducibly profiled, validated by polymerase chain reaction. Messenger RNA copy number then was correlated with %L and differential expression in EED. The transcripts identified were mapped to biological pathways and processes. The children studied had a range of %L values, consistent with a spectrum of EED from none to severe. Results: We identified 12 transcripts associated with the severity of EED, including chemokines that stimulate T-cell proliferation, Fc fragments of multiple immunoglobulin families, interferon-induced proteins, activators of neutrophils and B cells, and mediators that dampen cellular responses to hormones. EED-associated transcripts mapped to pathways related to cell adhesion, and responses to a broad spectrum of viral, bacterial, and parasitic microbes. Several mucins, regulatory factors, and protein kinases associated with the maintenance of the mucous layer were expressed less in children with EED than in normal children. Conclusions: EED represents the activation of diverse elements of the immune system and is associated with widespread intestinal barrier disruption. Differentially expressed transcripts, appropriately enumerated, should be explored as potential biomarkers. Keywords: Environmental Enteropathy, Fecal Transcriptome, Stunting, Intestinal Inflammation

  8. Broad-spectrum health improvements with one year of soccer training in inactive mildly hypertensive middle-aged women.

    Science.gov (United States)

    Krustrup, P; Skoradal, M-B; Randers, M B; Weihe, P; Uth, J; Mortensen, J; Mohr, M

    2017-12-01

    The study tested the hypothesis that long-term soccer training has positive impact on cardiovascular profile, body composition, bone health, and physical capacity in inactive, pre-menopausal women with mild hypertension. The study applied a randomized controlled design in which physically inactive middle-aged women were separated into a soccer training group (n=19; SOC) and a control group (n=12; CON). SOC performed 128±29 (±SD) one-h small-sided soccer training sessions over one year. Blood pressure, body composition, blood lipid profile, and fitness level were determined pre- and post-intervention. Over one year, mean arterial pressure decreased more in SOC than in CON (-5±7 vs +4±5 mmHg; Psoccer training resulted in broad-spectrum improvements in the health profile of untrained, pre-menopausal women with mild hypertension, including cardiovascular, metabolic, and musculo-skeletal benefits. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Interacting Transcriptomes Revealing Molecular Mechanisms Underlying Xa39 Mediated Broad Spectrum Resistance of Rice to Bacterial Blight

    Directory of Open Access Journals (Sweden)

    Fan Zhang

    2015-11-01

    Full Text Available Interaction between rice ( L. and its bacterial blight (BB pathogen pv. ( is the model system between monocot plants and their bacterial pathogens. To understand the genome-wide interactions between and rice resulting from a broad-spectrum hypersensitive reaction (BSHR mediated by a new rice resistance ( gene, , comparative dynamic transcriptomic profiles in the incompatible and compatible interactions were investigated using three related rice lines and a highly virulent isolate, PXO99. Large numbers of rice and differentially expressed genes (DEGs were identified in comparisons between the incompatible interactions and compatible ones, suggesting the gene network consisted of 27 genes in four groups of distinct functions involving leading to BSHR of rice in the sequential events from the × interaction → signal recognition and transduction → protein modification → programmed cell death. Correspondingly, several groups of genes expressed or upregulated specifically in the incompatible interaction were those for type III secretion system (T3SS and type III secretion effectors (T3SEs. Combined evidence suggests LOC_Os11g37759, one of a two-member CC-NBS-LRR gene family on rice chromosome 11, as the most likely candidate for in rice and two genes, and involved in T3SS of , as the most likely candidate genes for the corresponding in . Our transcriptome data and identified rice and DEGs provided a valuable source of information for future investigations on the –rice interactions.

  10. The Tortoise and the Hare. Small-Game Use, the Broad-Spectrum Revolution, and Paleolithic Demography.

    Science.gov (United States)

    Stiner; Munro; Surovell

    2000-02-01

    This study illustrates the potential of small-game data for identifying and dating Paleolithic demographic pulses such as those associated with modern human origins and the later evolution of food-producing economies. Archaeofaunal series from Israel and Italy serve as our examples. Three important implications of this study are that (1) early Middle Paleolithic populations were exceptionally small and highly dispersed, (2) the first major population growth pulse in the eastern Mediterranean probably occurred before the end of the Middle Paleolithic, and (3) subsequent demographic pulses in the Upper and Epi-Paleolithic greatly reshaped the conditions of selection that operated on human subsistence ecology, technology, and society. The findings of this study are consistent with the main premise of Flannery's broad-spectrum-revolution hypothesis. However, ranking small prey in terms of work of capture (in the absence of special harvesting tools) proved far more effective in this investigation of human diet breadth than have the taxonomic-diversity analyses published previously.

  11. Choline and Geranate Deep Eutectic Solvent as a Broad-Spectrum Antiseptic Agent for Preventive and Therapeutic Applications.

    Science.gov (United States)

    Zakrewsky, Michael; Banerjee, Amrita; Apte, Sanjana; Kern, Theresa L; Jones, Mattie R; Sesto, Rico E Del; Koppisch, Andrew T; Fox, David T; Mitragotri, Samir

    2016-06-01

    Antiseptic agents are the primary arsenal to disinfect skin and prevent pathogens spreading within the host as well as into the surroundings; however the Food and Drug Administration published a report in 2015 requiring additional validation of nearly all current antiseptic agents before their continued use can be allowed. This vulnerable position calls for urgent identification of novel antiseptic agents. Recently, the ability of a deep eutectic, Choline And Geranate (CAGE), to treat biofilms of Pseudomonas aeruginosa and Salmonella enterica was demonstrated. Here it is reported that CAGE exhibits broad-spectrum antimicrobial activity against a number of drug-resistant bacteria, fungi, and viruses including clinical isolates of Mycobacterium tuberculosis, Staphylococcus aureus, and Candida albicans as well as laboratory strains of Herpes Simplex Virus. Studies in human keratinocytes and mice show that CAGE affords negligible local or systemic toxicity, and an ≈180-14 000-fold improved efficacy/toxicity ratio over currently used antiseptic agents. Further, CAGE penetrates deep into the dermis and treats pathogens located in deep skin layers as confirmed by the ability of CAGE in vivo to treat Propionibacterium acnes infection. In combination, the results clearly demonstrate CAGE holds promise as a transformative platform antiseptic agent for preventive as well as therapeutic applications. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Efficient full-spectrum utilization, reception and conversion of solar energy by broad-band nanospiral antenna.

    Science.gov (United States)

    Zhao, Huaqiao; Gao, Huotao; Cao, Ting; Li, Boya

    2018-01-22

    In this work, the collection of solar energy by a broad-band nanospiral antenna is investigated in order to solve the low efficiency of the solar rectenna based on conventional nanoantennas. The antenna impedance, radiation, polarization and effective area are all considered in the efficiency calculation using the finite integral technique. The wavelength range investigated is 300-3000 nm, which corresponds to more than 98% of the solar radiation energy. It's found that the nanospiral has stronger field enhancement in the gap than a nanodipole counterpart. And a maximum harvesting efficiency about 80% is possible in principle for the nanospiral coupled to a rectifier resistance of 200 Ω, while about 10% for the nanodipole under the same conditions. Moreover, the nanospiral could be coupled to a rectifier diode of high resistance more easily than the nanodipole. These results indicate that the efficient full-spectrum utilization, reception and conversion of solar energy can be achieved by the nanospiral antenna, which is expected to promote the solar rectenna to be a promising technology in the clean, renewable energy application.

  13. Marker-assisted introgression of broad-spectrum blast resistance genes into the cultivated MR219 rice variety.

    Science.gov (United States)

    Miah, Gous; Rafii, Mohd Y; Ismail, Mohd R; Puteh, Adam B; Rahim, Harun A; Latif, Mohammad A

    2017-07-01

    The rice cultivar MR219 is famous for its better yield and long and fine grain quality; however, it is susceptible to blast disease. The main objective of this study was to introgress blast resistance genes into MR219 through marker-assisted selection (MAS). The rice cultivar MR219 was used as the recurrent parent, and Pongsu Seribu 1 was used as the donor. Marker-assisted foreground selection was performed using RM6836 and RM8225 to identify plants possessing blast resistance genes. Seventy microsatellite markers were used to estimate recurrent parent genome (RPG) recovery. Our analysis led to the development of 13 improved blast resistant lines with Piz, Pi2 and Pi9 broad-spectrum blast resistance genes and an MR219 genetic background. The RPG recovery of the selected improved lines was up to 97.70% with an average value of 95.98%. Selected improved lines showed a resistance response against the most virulent blast pathogen pathotype, P7.2. The selected improved lines did not express any negative effect on agronomic traits in comparison with MR219. The research findings of this study will be a conducive approach for the application of different molecular techniques that may result in accelerating the development of new disease-resistant rice varieties, which in turn will match rising demand and food security worldwide. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

  14. Multifocal outbreaks of metallo-beta-lactamase-producing Pseudomonas aeruginosa resistant to broad-spectrum beta-lactams, including carbapenems.

    Science.gov (United States)

    Senda, K; Arakawa, Y; Nakashima, K; Ito, H; Ichiyama, S; Shimokata, K; Kato, N; Ohta, M

    1996-02-01

    A total of 3,700 Pseudomonas aeruginosa isolates were collected from 17 general hospitals in Japan from 1992 to 1994. Of these isolates, 132 carbapenem-resistant strains were subjected to DNA hybridization analysis with the metallo-beta-lactamase gene (blaIMP)-specific probe. Fifteen strains carrying the metallo-beta-lactamase gene were identified in five hospitals in different geographical areas. Three strains of P. aeruginosa demonstrated high-level imipenem resistance (MIC, > or = 128 micrograms/ml), two strains exhibited low-level imipenem resistance (MIC, carbapenems. In several strains, the metallo-beta-lactamase gene was carried by large plasmids, and carbapenem resistance was transferred from P. aeruginosa to Escherichia coli by electroporation in association with the acquisition of the large plasmid. Southern hybridization analysis and genomic DNA fingerprinting profiles revealed different genetic backgrounds for these 15 isolates, although considerable similarity was observed for the strains isolated from the same hospital. These findings suggest that the metallo-beta-lactamase-producing P. aeruginosa strains are not confined to a unique clonal lineage but proliferated multifocally by plasmid-mediated dissemination of the metallo-beta-lactamase gene in strains of different genetic backgrounds. Thus, further proliferation of metallo-beta-lactamase-producing strains with resistance to various beta-lactams may well be inevitable in the future, which emphasizes the need for early recognition of metallo-beta-lactamase-producing strains, rigorous infection control, and restricted clinical use of broad-spectrum beta-lactams including carbapenems.

  15. UVA-activated synthesis of metalloproteinases 1, 3 and 9 is prevented by a broad-spectrum sunscreen.

    Science.gov (United States)

    Jean, Christine; Bogdanowicz, Patrick; Haure, Marie-José; Castex-Rizzi, Nathalie; Fournié, Jean-Jacques; Laurent, Guy

    2011-12-01

    Specific sunscreens against ultraviolet (UV) A and B radiations are essential to prevent matrix degradation and the activation of intracellular signaling pathways involved in photoaging and photocarcinogenesis. Matrix degradation results from UVA-induced production of matrix metalloproteinases (MMP) and activation of intracellular pathways in fibroblasts and keratinocytes. In particular, in keratinocytes, UVA radiation induces β-catenin nuclear translocation and stimulates MMP gene transcription. Our study was aimed at assessing the efficacy of a specific broad-spectrum sunscreen in preventing β-catenin translocation and MMPs enhanced expression in cultured keratinocytes after UVA irradiation. Sunscreen or the vehicle was spread on quartz sheet. Irradiation of HaCaT cells with 6 J/cm(2) UVA was performed through the sheet, and cells were collected for β-catenin immunostaining then visualization by confocal microscopy, and quantitative real-time polymerase chain reaction analysis of MMP-1, -3 and -9 gene expression. As shown by immunostaining and confocal microscopy, the sunscreen abrogated UVA-induced beta-catenin translocation to the nucleus, in comparison with control groups. MMP-1, -3 and -9 mRNA expression was enhanced by 7, 7 and 4 folds (P cells compared to the non-irradiated control. Sunscreen protection of the cells significantly reduced UVA-induced expression of MMP-1, -3 and -9 by 83% (P protect HaCaT keratinocytes from UVA-induced β-catenin translocation to the nucleus and MMPs expression. © 2011 John Wiley & Sons A/S.

  16. Characterisation of two novel bacteriocin-like substances produced by Bacillus amyloliquefaciens ELI149 with broad-spectrum antimicrobial activity.

    Science.gov (United States)

    Salazar, Francisco; Ortiz, Aurelio; Sansinenea, Estibaliz

    2017-12-01

    The aim of this study was to isolate and characterise antifungal and bactericidal compounds from Bacillus amyloliquefaciens strain ELI149. An absorbent resin (Amberlite ® XAD-16) and silica gel column chromatography were used for isolation and purification purposes, respectively. Antibacterial and antifungal assays were performed by the well diffusion method to demonstrate the biological activity of each compound. Cell damage of the tested fungi was evaluated for fengycin under phase-contrast microscopy. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and mass spectroscopy techniques were performed to estimate the approximate molecular mass of each compound. Two bacteriocin-like substances (BLSs) with different physical properties and inhibitory activities were isolated along with two known antifungal compounds. The two BLSs were heat stable and were not sensitive to acid or alkaline conditions (pH 2-10), with broad-spectrum antimicrobial activity. The antifungal compounds were identified as surfactin and fengycin. Only fengycin showed marked antifungal properties against several phytopathogens. The two isolated BLSs were partially characterised and their bactericidal properties were analysed. The antifungals compounds were identified as surfactin and fengycin, this latter being mainly responsible for the antifungal activity. Copyright © 2017 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.

  17. A cost analysis of a broad-spectrum antibiotic therapy in the empirical treatment of health care-associated infections in cirrhotic patients

    Directory of Open Access Journals (Sweden)

    Lucidi C

    2017-06-01

    Full Text Available Cristina Lucidi,1 Vincenza Di Gregorio,1 Giancarlo Ceccarelli,2 Mario Venditti,2 Oliviero Riggio,1 Manuela Merli1 1Gastroenterology, Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy; 2Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy Background: Early diagnosis and appropriate treatment of infections in cirrhosis are crucial. As new guidelines in this context, particularly for health care-associated (HCA infections, would be needed, we performed a trial documenting whether an empirical broad-spectrum antibiotic therapy is more effective than the standard one for these infections. Because of the higher daily cost of broad-spectrum than standard antibiotics, we performed a cost analysis to compare: 1 total drug costs, 2 profitability of hospital admissions. Methods: This retrospective observational analysis was performed on patients enrolled in the trial NCT01820026, in which consecutive cirrhotic patients with HCA infections were randomly assigned to a standard vs a broad-spectrum treatment. Antibiotic daily doses, days of treatment, length of hospital stay, and DRG (diagnosis-related group were recorded from the clinical trial medical records. The profitability of hospitalizations was calculated considering DRG tariffs divided by length of hospital stay.Results: We considered 84 patients (42 for each group. The standard therapy allowed to obtain a first-line treatment cost lower than in the broad-spectrum therapy. Anyway, the latter, being related to a lower failure rate (19% vs 57.1%, resulted in cost saving in terms of cumulative antibiotic costs (first- and second-line treatments. The mean cost saving per patient for the broad-spectrum arm was €44.18 (–37.6%, with a total cost saving of about €2,000. Compared to standard group, we observed a statistically significant reduction in hospital stay from 17.8 to 11.8 days (p<0.002 for patients treated with broad-spectrum

  18. An examination of the clinical outcomes of adolescents and young adults with broad autism spectrum traits and autism spectrum disorder and anorexia nervosa: A multi centre study.

    Science.gov (United States)

    Nazar, Bruno Palazzo; Peynenburg, Vanessa; Rhind, Charlotte; Hibbs, Rebecca; Schmidt, Ulrike; Gowers, Simon; Macdonald, Pamela; Goddard, Elizabeth; Todd, Gillian; Micali, Nadia; Treasure, Janet

    2018-02-01

    To compare the clinical outcomes of adolescents and young adults with anorexia nervosa (AN) comorbid with broad autism spectrum disorder (ASD) or ASD traits. The developmental and well-being assessment and social aptitude scale were used to categorize adolescents and young adults with AN (N = 149) into those with ASD traits (N = 23), and those who also fulfilled diagnostic criteria for a possible/probable ASD (N = 6). We compared both eating disorders specific measures and broader outcome measures at intake and 12 months follow-up. Those with ASD traits had significantly more inpatient/day-patient service use (p = .015), as well as medication use (p eating disorder symptoms at 12 months was similar between groups with or without ASD traits. Treatment completion rates between AN only and ASD traits were similar (80.1 vs. 86.5%). Adolescents with AN and ASD traits show similar reductions in their eating disorder symptoms. Nevertheless, their social difficulties remain high suggesting that these are life-long difficulties rather than starvation effects. © 2018 Wiley Periodicals, Inc.

  19. Draft Genome Sequence of Streptomyces sp. Strain Wb2n-11, a Desert Isolate with Broad-Spectrum Antagonism against Soilborne Phytopathogens

    Energy Technology Data Exchange (ETDEWEB)

    Köberl, Martina; White, Richard A.; Erschen, Sabine; El-Arabi, Tarek F.; Jansson, Janet K.; Berg, Gabriele

    2015-08-06

    Streptomyces sp. strain Wb2n-11, isolated from native desert soil, exhibited broad-spectrum antagonism against plant pathogenic fungi, bacteria and nematodes. The 8.2 Mb draft genome reveals genes putatively responsible for its promising biocontrol activity and genes which enable the soil bacterium to directly interact beneficially with plants.

  20. Comparison of nitroethane, 2-nitro-1-propanol, lauric acid, Lauricidin and the Hawaiian marine algae, Chaetoceros, for potential broad-spectrum control of anaerobically grown lactic acid bacteria

    Science.gov (United States)

    The gastrointestinal tract of bovines often contains bacteria that contribute to disorders of the rumen and may also contain foodborne or opportunistic human pathogens as well as bacteria capable of causing mastitis in cows. Thus, there is a need to develop broad-spectrum therapies that are effecti...

  1. Durable broad-spectrum powdery mildew resistance in pea er1 plants is conferred by natural loss-of-function mutations in PsMLO1

    NARCIS (Netherlands)

    Humphry, M.; Reinstädler, A.; Ivanov, S.; Bisseling, T.; Panstruga, R.

    2011-01-01

    Loss-of-function alleles of plant-specific MLO (Mildew Resistance Locus O) genes confer broad-spectrum powdery mildew resistance in monocot (barley) and dicot (Arabidopsis thaliana, tomato) plants. Recessively inherited powdery mildew resistance in pea (Pisum sativum) er1 plants is, in many aspects,

  2. Complete Genome Sequence of Bacillus velezensis YJ11-1-4, a Strain with Broad-Spectrum Antimicrobial Activity, Isolated from Traditional Korean Fermented Soybean Paste.

    Science.gov (United States)

    Lee, Hyo Jung; Chun, Byung-Hee; Jeon, Hye Hee; Kim, Yeon Bee; Lee, Se Hee

    2017-11-30

    Bacillus velezensis YJ11-1-4 is a strain that exhibits broad-spectrum antimicrobial activity against various pathogens. It was isolated from doenjang, a traditional Korean fermented soybean paste. The genome comprises a single circular chromosome of 4,006,637 bp with 46.42% G+C content without plasmids. Copyright © 2017 Lee et al.

  3. Broad-spectrum sunscreens prevent the secretion of proinflammatory cytokines in human keratinocytes exposed to ultraviolet A and phototoxic lomefloxacin

    International Nuclear Information System (INIS)

    Reinhardt, P.; Cybulski, M.; Miller, S.M.; Ferrarotto, C.; Wilkins, R.; Deslauriers, Y.

    2006-01-01

    The combination of phototoxic drugs and ultraviolet (UV) radiation can trigger the release of proinflammatory cytokines. The present study measured the ability of sunscreens to prevent cytokine secretion in human keratinocytes following cotreatment of these cells with a known photoreactive drug and UVA. Keratinocytes were treated for 1 h with increasing concentrations of lomefloxacin (LOM) or norfloxacin (NOR), exposed to 15 J/cm 2 UVA, and incubated for 24 h. NOR, owing to the absence of a fluorine atom in position 8, was non-phototoxic and used as a negative control. Cell viability and the release of 3 cytokines were assessed, namely interleukin-1α (IL-1α), interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α). The measurement of these cytokines may be a useful tool for detecting photoreactive compounds. To measure their ability to prevent cytokine secretion, various sunscreens were inserted between the UVA source and the cells. Treatment with NOR, NOR plus UVA, or LOM had no effect on the cells. LOM plus UVA, however, had an effect on cell viability and on cytokine secretion. IL-1α levels increased with LOM concentration. The release of TNF-α and IL-6 followed the same pattern at lower concentrations of LOM but peaked at 15 μmol/L and decreased at higher concentrations. Sunscreens protected the cells from the effects of LOM plus UVA, as cell viability and levels of cytokines remained the same as in the control cells. In conclusion, the application of broad-spectrum sunscreen by individuals exposed to UVA radiation may prevent phototoxic reactions initiated by drugs such as LOM. (author)

  4. Allelic variation for broad-spectrum resistance and susceptibility to bacterial pathogens identified in a rice MAGIC population.

    Science.gov (United States)

    Bossa-Castro, Ana M; Tekete, Cheick; Raghavan, Chitra; Delorean, Emily E; Dereeper, Alexis; Dagno, Karim; Koita, Ousmane; Mosquera, Gloria; Leung, Hei; Verdier, Valérie; Leach, Jan E

    2018-02-06

    Quantitative trait loci (QTL) that confer broad-spectrum resistance (BSR), or resistance that is effective against multiple and diverse plant pathogens, have been elusive targets of crop breeding programmes. Multiparent advanced generation intercross (MAGIC) populations, with their diverse genetic composition and high levels of recombination, are potential resources for the identification of QTL for BSR. In this study, a rice MAGIC population was used to map QTL conferring BSR to two major rice diseases, bacterial leaf streak (BLS) and bacterial blight (BB), caused by Xanthomonas oryzae pathovars (pv.) oryzicola (Xoc) and oryzae (Xoo), respectively. Controlling these diseases is particularly important in sub-Saharan Africa, where no sources of BSR are currently available in deployed varieties. The MAGIC founders and lines were genotyped by sequencing and phenotyped in the greenhouse and field by inoculation with multiple strains of Xoc and Xoo. A combination of genomewide association studies (GWAS) and interval mapping analyses revealed 11 BSR QTL, effective against both diseases, and three pathovar-specific QTL. The most promising BSR QTL (qXO-2-1, qXO-4-1 and qXO-11-2) conferred resistance to more than nine Xoc and Xoo strains. GWAS detected 369 significant SNP markers with distinguishable phenotypic effects, allowing the identification of alleles conferring disease resistance and susceptibility. The BSR and susceptibility QTL will improve our understanding of the mechanisms of both resistance and susceptibility in the long term and will be immediately useful resources for rice breeding programmes. © 2018 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

  5. Competition between Phytophthora infestans effectors leads to increased aggressiveness on plants containing broad-spectrum late blight resistance.

    Directory of Open Access Journals (Sweden)

    Dennis A Halterman

    Full Text Available BACKGROUND: The destructive plant disease potato late blight is caused by the oomycete pathogen Phytophthora infestans (Mont. de Bary. This disease has remained particularly problematic despite intensive breeding efforts to integrate resistance into cultivated potato, largely because of the pathogen's ability to quickly evolve to overcome major resistance genes. The RB gene, identified in the wild potato species S. bulbocastanum, encodes a protein that confers broad-spectrum resistance to most P. infestans isolates through its recognition of highly conserved members of the corresponding pathogen effector family IPI-O. IpiO is a multigene family of effectors and while the majority of IPI-O proteins are recognized by RB to elicit host resistance, some variants exist that are able to elude detection (e.g. IPI-O4. METHODS AND FINDINGS: In the present study, analysis of ipiO variants among 40 different P. infestans isolates collected from Guatemala, Thailand, and the United States revealed a high degree of complexity within this gene family. Isolate aggressiveness was correlated with increased ipiO diversity and especially the presence of the ipiO4 variant. Furthermore, isolates expressing IPI-O4 overcame RB-mediated resistance in transgenic potato plants even when the resistance-eliciting IPI-O1 variant was present. In support of this finding, we observed that expression of IPI-O4 via Agrobacterium blocked recognition of IPI-O1, leading to inactivation of RB-mediated programmed cell death in Nicotiana benthamiana. CONCLUSIONS: In this study we definitively demonstrate and provide the first evidence that P. infestans can defeat an R protein through inhibition of recognition of the corresponding effector protein.

  6. Controlled delivery of a new broad spectrum antibacterial agent against colitis: In vitro and in vivo performance.

    Science.gov (United States)

    Nieto-Bobadilla, M S; Siepmann, F; Djouina, M; Dubuquoy, L; Tesse, N; Willart, J-F; Dubreuil, L; Siepmann, J; Neut, C

    2015-10-01

    Coated pellets and mini-tablets were prepared containing a new broad spectrum antibacterial agent: CIN-102, a well-defined, synergistic blend of trans-cinnamaldehyde, trans-2-methoxycinnamaldehyde, cinnamyl acetate, linalool, β-caryophyllene, cineol and benzyl benzoate. The aim was to provide a new treatment method for colitis, especially for Inflammatory Bowel Disease (IBD) patients. Since the simple oral gavage of CIN-102 was not able to reduce the pathogenic bacteria involved in colitis (rat model), the drug was incorporated into multiparticulates. The idea was to minimize undesired drug release in the upper gastrointestinal tract and to control CIN-102 release in the colon, in order to optimize the resulting antibiotic concentration at the site of action. A particular challenge was the fact that CIN-102 is a volatile hydrophobic liquid. Pellet cores were prepared by extrusion-spheronization and coated with polymer blends, which are sensitive to colonic bacterial enzymes. Mini-tablets were prepared by direct compression. The release of the main compound of CIN-102 (cinnamaldehyde, 86.7% w/w) was monitored in vitro. Optimized coated pellets and mini-tablets were also tested in vivo: in seven-week-old, male mice suffering from dextran sodium sulfate induced colitis. Importantly, both types of multiparticulates were able: (i) to significantly reduce the number of luminal and mucosal enterobacteria in the mice (the levels of which are increased in the disease state), and (ii) to improve the clinical course of the intestinal inflammation (decrease in the percentages of mice with bloody stools and diarrhea). Thus, the proposed coated pellets and matrix mini-tablets allowing for controlled CIN-102 release show a promising potential for new treatment methods of colitis. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. X-Ray Emitting GHz-Peaked Spectrum Galaxies: Testing a Dynamical-Radiative Model with Broad-Band Spectra

    Energy Technology Data Exchange (ETDEWEB)

    Ostorero, L.; /Turin U. /INFN, Turin; Moderski, R.; /Warsaw, Copernicus Astron. Ctr. /KIPAC, Menlo Park; Stawarz, L.; /KIPAC, Menlo Park /Jagiellonian U., Astron. Observ.; Diaferio, A.; /Turin U. /INFN, Turin; Kowalska, I.; /Warsaw U. Observ.; Cheung, C.C.; /NASA, Goddard /Naval Research Lab, Wash., D.C.; Kataoka, J.; /Waseda U., RISE; Begelman, M.C.; /JILA, Boulder; Wagner, S.J.; /Heidelberg Observ.

    2010-06-07

    In a dynamical-radiative model we recently developed to describe the physics of compact, GHz-Peaked-Spectrum (GPS) sources, the relativistic jets propagate across the inner, kpc-sized region of the host galaxy, while the electron population of the expanding lobes evolves and emits synchrotron and inverse-Compton (IC) radiation. Interstellar-medium gas clouds engulfed by the expanding lobes, and photoionized by the active nucleus, are responsible for the radio spectral turnover through free-free absorption (FFA) of the synchrotron photons. The model provides a description of the evolution of the GPS spectral energy distribution (SED) with the source expansion, predicting significant and complex high-energy emission, from the X-ray to the {gamma}-ray frequency domain. Here, we test this model with the broad-band SEDs of a sample of eleven X-ray emitting GPS galaxies with Compact-Symmetric-Object (CSO) morphology, and show that: (i) the shape of the radio continuum at frequencies lower than the spectral turnover is indeed well accounted for by the FFA mechanism; (ii) the observed X-ray spectra can be interpreted as non-thermal radiation produced via IC scattering of the local radiation fields off the lobe particles, providing a viable alternative to the thermal, accretion-disk dominated scenario. We also show that the relation between the hydrogen column densities derived from the X-ray (N{sub H}) and radio (N{sub HI}) data of the sources is suggestive of a positive correlation, which, if confirmed by future observations, would provide further support to our scenario of high-energy emitting lobes.

  8. Hexadecylphosphocholine (miltefosine) has broad-spectrum fungicidal activity and is efficacious in a mouse model of cryptococcosis.

    Science.gov (United States)

    Widmer, Fred; Wright, Lesley C; Obando, Daniel; Handke, Rosemary; Ganendren, Ranjini; Ellis, David H; Sorrell, Tania C

    2006-02-01

    The alkyl phosphocholine drug miltefosine is structurally similar to natural substrates of the fungal virulence determinant phospholipase B1 (PLB1), which is a potential drug target. We determined the MICs of miltefosine against key fungal pathogens, correlated antifungal activity with inhibition of the PLB1 activities (PLB, lysophospholipase [LPL], and lysophospholipase-transacylase [LPTA]), and investigated its efficacy in a mouse model of disseminated cryptococcosis. Miltefosine inhibited secreted cryptococcal LPTA activity by 35% at the subhemolytic concentration of 25 microM (10.2 microg/ml) and was inactive against mammalian pancreatic phospholipase A2 (PLA2). At 250 microM, cytosolic PLB, LPL, and LPTA activities were inhibited by 25%, 51%, and 77%, respectively. The MICs at which 90% of isolates were inhibited (MIC90s) against Candida albicans, Candida glabrata, Candida krusei, Cryptococcus neoformans, Cryptococcus gattii, Aspergillus fumigatus, Fusarium solani, Scedosporium prolificans, and Scedosporium apiospermum were 2 to 4 microg/ml. The MICs of miltefosine against Candida tropicalis (n = 8) were 2 to 4 microg/ml, those against Aspergillus terreus and Candida parapsilosis were 8 microg/ml (MIC90), and those against Aspergillus flavus (n = 8) were 2 to 16 microg/ml. Miltefosine was fungicidal for C. neoformans, with rates of killing of 2 log units within 4 h at 7.0 microM (2.8 microg/ml). Miltefosine given orally to mice on days 1 to 5 after intravenous infection with C. neoformans delayed the development of illness and mortality and significantly reduced the brain cryptococcal burden. We conclude that miltefosine has broad-spectrum antifungal activity and is active in vivo in a mouse model of disseminated cryptococcosis. The relatively small inhibitory effect on PLB1 enzyme activities at concentrations exceeding the MIC by 2 to 20 times suggests that PLB1 inhibition is not the only mechanism of the antifungal effect.

  9. Exoproteome and secretome derived broad spectrum novel drug and vaccine candidates in Vibrio cholerae targeted by Piper betel derived compounds.

    Directory of Open Access Journals (Sweden)

    Debmalya Barh

    Full Text Available Vibrio cholerae is the causal organism of the cholera epidemic, which is mostly prevalent in developing and underdeveloped countries. However, incidences of cholera in developed countries are also alarming. Because of the emergence of new drug-resistant strains, even though several generic drugs and vaccines have been developed over time, Vibrio infections remain a global health problem that appeals for the development of novel drugs and vaccines against the pathogen. Here, applying comparative proteomic and reverse vaccinology approaches to the exoproteome and secretome of the pathogen, we have identified three candidate targets (ompU, uppP and yajC for most of the pathogenic Vibrio strains. Two targets (uppP and yajC are novel to Vibrio, and two targets (uppP and ompU can be used to develop both drugs and vaccines (dual targets against broad spectrum Vibrio serotypes. Using our novel computational approach, we have identified three peptide vaccine candidates that have high potential to induce both B- and T-cell-mediated immune responses from our identified two dual targets. These two targets were modeled and subjected to virtual screening against natural compounds derived from Piper betel. Seven compounds were identified first time from Piper betel to be highly effective to render the function of these targets to identify them as emerging potential drugs against Vibrio. Our preliminary validation suggests that these identified peptide vaccines and betel compounds are highly effective against Vibrio cholerae. Currently we are exhaustively validating these targets, candidate peptide vaccines, and betel derived lead compounds against a number of Vibrio species.

  10. Comparison of broad-spectrum cephalosporin-resistant Escherichia coli isolated from dogs and humans in Hokkaido, Japan.

    Science.gov (United States)

    Okubo, Torahiko; Sato, Toyotaka; Yokota, Shin-ichi; Usui, Masaru; Tamura, Yutaka

    2014-04-01

    Resistance to broad-spectrum cephalosporins (BSCs) in Enterobacteriaceae in companion animals has become a great concern for public health. To estimate the dissemination of BSC-resistant bacteria between dog and human, we examined the BSC-resistance determinants of and genetic similarities between 69 BSC-resistant Escherichia coli isolates derived from canine rectal swabs (n = 28) and human clinical samples (n = 41). Some E. coli isolates possessed blaTEM-1b (14 canine and 16 human isolates), blaCTx-M-2 (6 human isolates), blaCTx-M-14 (3 canine and 14 human isolates), blaCTx-M-27 (1 canine and 15 human isolates), and blaCMY-2 (11 canine and 3 human isolates). The possession of CTX-M-type β-lactamases was significantly more frequent in human isolates, whereas CMY-2 was more common in canine isolates. Bacterial typing methods (phylogenetic typing, O-antigen serotyping, and pulsed-field gel electrophoresis) showed little clonal relationship between canine isolates and human isolates. Plasmid analysis and Southern blotting indicated that the plasmids encoding CMY-2 were similar among canine and human isolates. Based on the differences in the major β-lactamase and the divergence of bacterial types between canine and human isolates, it seems that clonal dissemination of BSC-resistant E. coli between canines and humans is limited. The similarity of the CMY-2-encoding plasmid suggests that plasmid-mediated β-lactamase gene transmission plays a role in interspecies diffusion of BSC-resistant E. coli between dog and human. Copyright © 2013 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  11. Photomorphogenesis and photoassimilation in soybean and sorghum grown under broad spectrum or blue-deficient light sources

    Science.gov (United States)

    Britz, S. J.; Sager, J. C.; Knott, W. M. (Principal Investigator)

    1990-01-01

    The role of blue light in plant growth and development was investigated in soybean (Glycine max [L.] Merr. cv Williams) and sorghum (Sorghum bicolor [L.] Moench. cv Rio) grown under equal photosynthetic photon fluxes (approximately 500 micromoles per square meter per second) from broad spectrum daylight fluorescent or blue-deficient, narrow-band (589 nanometers) low pressure sodium (LPS) lamps. Between 14 and 18 days after sowing, it was possible to relate adaptations in photosynthesis and leaf growth to dry matter accumulation. Soybean development under LPS light was similar in several respects to that of shaded plants, consistent with an important role for blue light photoreceptors in regulation of growth response to irradiance. Thus, soybeans from LPS conditions partitioned relatively more growth to leaves and maintained higher average leaf area ratios (mean LAR) that compensated lower net assimilation rates (mean NAR). Relative growth rates were therefore comparable to plants from daylight fluorescent lamps. Reductions in mean NAR were matched by lower rates of net photosynthesis (A) on an area basis in the major photosynthetic source (first trifoliolate) leaf. Lower A in soybean resulted from reduced leaf dry matter per unit leaf area, but lower A under LPS conditions in sorghum correlated with leaf chlorosis and reduced total nitrogen (not observed in soybean). In spite of a lower A, mean NAR was larger in sorghum from LPS conditions, resulting in significantly greater relative growth rates (mean LAR was approximately equal for both light conditions). Leaf starch accumulation rate was higher for both species and starch content at the end of the dark period was elevated two- and three-fold for sorghum and soybean, respectively, under LPS conditions. Possible relations between starch accumulation, leaf export, and plant growth in response to spectral quality were considered.

  12. Inhibition of an aquatic rhabdovirus demonstrates promise of a broad-spectrum antiviral for use in aquaculture

    Science.gov (United States)

    Balmer, Bethany F.; Powers, Rachel L.; Zhang, Ting-Hu; Lee, Jihye; Vigant, Frederic; Lee, Benhur; Jung, Michael E.; Purcell, Maureen K.; Snekvik, Kevin; Aguilar, Hector C.

    2017-01-01

    Many enveloped viruses cause devastating disease in aquaculture, resulting in significant economic impact. LJ001 is a broad-spectrum antiviral compound that inhibits enveloped virus infections by specifically targeting phospholipids in the lipid bilayer via the production of singlet oxygen (1O2). This stabilizes positive curvature and decreases membrane fluidity, which inhibits virus-cell membrane fusion during viral entry. Based on data from previous mammalian studies and the requirement of light for the activation of LJ001, we hypothesized that LJ001 may be useful as a preventative and/or therapeutic agent for infections by enveloped viruses in aquaculture. Here, we report that LJ001 was more stable with a prolonged inhibitory half-life at relevant aquaculture temperatures (15°C), than in mammalian studies at 37°C. When LJ001 was preincubated with our model virus, infectious hematopoietic necrosis virus (IHNV), infectivity was significantly inhibited in vitro (using the epithelioma papulosum cyprini [EPC] fish cell line) and in vivo (using rainbow trout fry) in a dose-dependent and time-dependent manner. While horizontal transmission of IHNV in a static cohabitation challenge model was reduced by LJ001, transmission was not completely blocked at established antiviral doses. Therefore, LJ001 may be best suited as a therapeutic for aquaculture settings that include viral infections with lower virus-shedding rates than IHNV or where higher viral titers are required to initiate infection of naive fish. Importantly, our data also suggest that LJ001-inactivated IHNV elicited an innate immune response in the rainbow trout host, making LJ001 potentially useful for future vaccination approaches.

  13. Baulamycins A and B, broad-spectrum antibiotics identified as inhibitors of siderophore biosynthesis in Staphylococcus aureus and Bacillus anthracis.

    Science.gov (United States)

    Tripathi, Ashootosh; Schofield, Michael M; Chlipala, George E; Schultz, Pamela J; Yim, Isaiah; Newmister, Sean A; Nusca, Tyler D; Scaglione, Jamie B; Hanna, Philip C; Tamayo-Castillo, Giselle; Sherman, David H

    2014-01-29

    Siderophores are high-affinity iron chelators produced by microorganisms and frequently contribute to the virulence of human pathogens. Targeted inhibition of the biosynthesis of siderophores staphyloferrin B of Staphylococcus aureus and petrobactin of Bacillus anthracis hold considerable potential as a single or combined treatment for methicillin-resistant S. aureus (MRSA) and anthrax infection, respectively. The biosynthetic pathways for both siderophores involve a nonribosomal peptide synthetase independent siderophore (NIS) synthetase, including SbnE in staphyloferrin B and AsbA in petrobactin. In this study, we developed a biochemical assay specific for NIS synthetases to screen for inhibitors of SbnE and AsbA against a library of marine microbial-derived natural product extracts (NPEs). Analysis of the NPE derived from Streptomyces tempisquensis led to the isolation of the novel antibiotics baulamycins A (BmcA, 6) and B (BmcB, 7). BmcA and BmcB displayed in vitro activity with IC50 values of 4.8 μM and 19 μM against SbnE and 180 μM and 200 μM against AsbA, respectively. Kinetic analysis showed that the compounds function as reversible competitive enzyme inhibitors. Liquid culture studies with S. aureus , B. anthracis , E. coli , and several other bacterial pathogens demonstrated the capacity of these natural products to penetrate bacterial barriers and inhibit growth of both Gram-positive and Gram-negative species. These studies provide proof-of-concept that natural product inhibitors targeting siderophore virulence factors can provide access to novel broad-spectrum antibiotics, which may serve as important leads for the development of potent anti-infective agents.

  14. Characterization of a broad host-spectrum virulent Salmonella bacteriophage fmb-p1 and its application on duck meat.

    Science.gov (United States)

    Wang, Changbao; Chen, Qiming; Zhang, Chong; Yang, Jie; Lu, Zhaoxin; Lu, Fengxia; Bie, Xiaomei

    2017-05-15

    The aim of this study was to find a virulent bacteriophage for the biocontrol of Salmonella in duck meat. A broad host-spectrum virulent phage, fmb-p1, was isolated and purified from an duck farm, and its host range was determined to include S. Typhimurium, S. Enteritidis, S. Saintpaul, S. Agona, S. Miami, S. Anatum, S. Heidelberg and S. Paratyphi-C. Electron microscopy and genome sequencing showed that fmb-p1 belongs to the family Siphoviridae. The genome of fmb-p1 is composed of a 43,327-bp double-stranded DNA molecule with 60 open reading frames and a total G+C content of 46.09%. There are no deleterious sequences or genes encoding known harmful products in the phage fmb-p1 genome. Phage fmb-p1 was stable under different temperature (40-75°C), pH (4-10) and NaCl solutions (1-11%). The phage treatment (9.9×10 9 PFU/cm 2 ) caused a peak reduction in S. Typhimurium of 4.52 log CFU/cm 2 in ready-to-eat (RTE) duck meat, whereas potassium sorbate treatment (PS, 2mg/cm 2 ) resulted in a 0.05-0.12 log reduction. Compared to PS treatment, there was significant difference in the S. Typhimurium reduction (P˂0.05) by phage treatment at both 4°C and 25°C. The results suggested that phage could be applied to reduce Salmonella, on commercial poultry products. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. X-ray Emitting GHz-Peaked Spectrum Galaxies: Testing a Dynamical-Radiative Model with Broad-Band Spectra

    International Nuclear Information System (INIS)

    Ostorero, L.; Moderski, R.; Stawarz, L.; Diaferio, A.; Kowalska, I.; Cheung, C.C.; Kataoka, J.; Begelman, M.C.; Wagner, S.J.

    2010-01-01

    In a dynamical-radiative model we recently developed to describe the physics of compact, GHz-Peaked-Spectrum (GPS) sources, the relativistic jets propagate across the inner, kpc-sized region of the host galaxy, while the electron population of the expanding lobes evolves and emits synchrotron and inverse-Compton (IC) radiation. Interstellar-medium gas clouds engulfed by the expanding lobes, and photoionized by the active nucleus, are responsible for the radio spectral turnover through free-free absorption (FFA) of the synchrotron photons. The model provides a description of the evolution of the GPS spectral energy distribution (SED) with the source expansion, predicting significant and complex high-energy emission, from the X-ray to the γ-ray frequency domain. Here, we test this model with the broad-band SEDs of a sample of eleven X-ray emitting GPS galaxies with Compact-Symmetric-Object (CSO) morphology, and show that: (i) the shape of the radio continuum at frequencies lower than the spectral turnover is indeed well accounted for by the FFA mechanism; (ii) the observed X-ray spectra can be interpreted as non-thermal radiation produced via IC scattering of the local radiation fields off the lobe particles, providing a viable alternative to the thermal, accretion-disk dominated scenario. We also show that the relation between the hydrogen column densities derived from the X-ray (N H ) and radio (N HI ) data of the sources is suggestive of a positive correlation, which, if confirmed by future observations, would provide further support to our scenario of high-energy emitting lobes.

  16. A Novel, Broad-Spectrum Inhibitor of Enterovirus Replication That Targets Host Cell Factor Phosphatidylinositol 4-Kinase IIIβ

    Science.gov (United States)

    van der Schaar, Hilde M.; Leyssen, Pieter; Thibaut, Hendrik J.; de Palma, Armando; van der Linden, Lonneke; Lanke, Kjerstin H. W.; Lacroix, Céline; Verbeken, Erik; Conrath, Katja; MacLeod, Angus M.; Mitchell, Dale R.; Palmer, Nicholas J.; van de Poël, Hervé; Andrews, Martin

    2013-01-01

    Despite their high clinical and socioeconomic impacts, there is currently no approved antiviral therapy for the prophylaxis or treatment of enterovirus infections. Here we report on a novel inhibitor of enterovirus replication, compound 1, 2-fluoro-4-(2-methyl-8-(3-(methylsulfonyl)benzylamino)imidazo[1,2-a]pyrazin-3-yl)phenol. This compound exhibited a broad spectrum of antiviral activity, as it inhibited all tested species of enteroviruses and rhinoviruses, with 50% effective concentrations ranging between 4 and 71 nM. After a lengthy resistance selection process, coxsackievirus mutants resistant to compound 1 were isolated that carried substitutions in their 3A protein. Remarkably, the same substitutions were recently shown to provide resistance to inhibitors of phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ), a lipid kinase that is essential for enterovirus replication, suggesting that compound 1 may also target this host factor. Accordingly, compound 1 directly inhibited PI4KIIIβ in an in vitro kinase activity assay. Furthermore, the compound strongly reduced the PI 4-phosphate levels of the Golgi complex in cells. Rescue of coxsackievirus replication in the presence of compound 1 by a mutant PI4KIIIβ carrying a substitution in its ATP-binding pocket revealed that the compound directly binds the kinase at this site. Finally, we determined that an analogue of compound 1, 3-(3-fluoro-4-methoxyphenyl)-2-methyl-N-(pyridin-4-ylmethyl)imidazo[1,2-a]pyrazin-8-amine, is well tolerated in mice and has a dose-dependent protective activity in a coxsackievirus serotype B4-induced pancreatitis model. PMID:23896472

  17. Contracting

    Science.gov (United States)

    EPA buys many supplies and services to support the agency's mission. Here you'll find out about contracting with the EPA, including: our policies; what we're looking to buy right now; what we've bought recently, and what we're looking to buy in the future.

  18. Targeting N-glycan cryptic sugar moieties for broad-spectrum virus neutralization: progress in identifying conserved molecular targets in viruses of distinct phylogenetic origins.

    Science.gov (United States)

    Wang, Denong; Tang, Jin; Tang, Jiulai; Wang, Lai-Xi

    2015-03-12

    Identifying molecular targets for eliciting broadly virus-neutralizing antibodies is one of the key steps toward development of vaccines against emerging viral pathogens. Owing to genomic and somatic diversities among viral species, identifying protein targets for broad-spectrum virus neutralization is highly challenging even for the same virus, such as HIV-1. However, viruses rely on host glycosylation machineries to synthesize and express glycans and, thereby, may display common carbohydrate moieties. Thus, exploring glycan-binding profiles of broad-spectrum virus-neutralizing agents may provide key information to uncover the carbohydrate-based virus-neutralizing epitopes. In this study, we characterized two broadly HIV-neutralizing agents, human monoclonal antibody 2G12 and Galanthus nivalis lectin (GNA), for their viral targeting activities. Although these agents were known to be specific for oligomannosyl antigens, they differ strikingly in virus-binding activities. The former is HIV-1 specific; the latter is broadly reactive and is able to neutralize viruses of distinct phylogenetic origins, such as HIV-1, severe acute respiratory syndrome coronavirus (SARS-CoV), and human cytomegalovirus (HCMV). In carbohydrate microarray analyses, we explored the molecular basis underlying the striking differences in the spectrum of anti-virus activities of the two probes. Unlike 2G12, which is strictly specific for the high-density Man9GlcNAc2Asn (Man9)-clusters, GNA recognizes a number of N-glycan cryptic sugar moieties. These include not only the known oligomannosyl antigens but also previously unrecognized tri-antennary or multi-valent GlcNAc-terminating N-glycan epitopes (Tri/m-Gn). These findings highlight the potential of N-glycan cryptic sugar moieties as conserved targets for broad-spectrum virus neutralization and suggest the GNA-model of glycan-binding warrants focused investigation.

  19. Targeting N-Glycan Cryptic Sugar Moieties for Broad-Spectrum Virus Neutralization: Progress in Identifying Conserved Molecular Targets in Viruses of Distinct Phylogenetic Origins

    Directory of Open Access Journals (Sweden)

    Denong Wang

    2015-03-01

    Full Text Available Identifying molecular targets for eliciting broadly virus-neutralizing antibodies is one of the key steps toward development of vaccines against emerging viral pathogens. Owing to genomic and somatic diversities among viral species, identifying protein targets for broad-spectrum virus neutralization is highly challenging even for the same virus, such as HIV-1. However, viruses rely on host glycosylation machineries to synthesize and express glycans and, thereby, may display common carbohydrate moieties. Thus, exploring glycan-binding profiles of broad-spectrum virus-neutralizing agents may provide key information to uncover the carbohydrate-based virus-neutralizing epitopes. In this study, we characterized two broadly HIV-neutralizing agents, human monoclonal antibody 2G12 and Galanthus nivalis lectin (GNA, for their viral targeting activities. Although these agents were known to be specific for oligomannosyl antigens, they differ strikingly in virus-binding activities. The former is HIV-1 specific; the latter is broadly reactive and is able to neutralize viruses of distinct phylogenetic origins, such as HIV-1, severe acute respiratory syndrome coronavirus (SARS-CoV, and human cytomegalovirus (HCMV. In carbohydrate microarray analyses, we explored the molecular basis underlying the striking differences in the spectrum of anti-virus activities of the two probes. Unlike 2G12, which is strictly specific for the high-density Man9GlcNAc2Asn (Man9-clusters, GNA recognizes a number of N-glycan cryptic sugar moieties. These include not only the known oligomannosyl antigens but also previously unrecognized tri-antennary or multi-valent GlcNAc-terminating N-glycan epitopes (Tri/m-Gn. These findings highlight the potential of N-glycan cryptic sugar moieties as conserved targets for broad-spectrum virus neutralization and suggest the GNA-model of glycan-binding warrants focused investigation.

  20. Broad Energy Range Neutron Spectroscopy using a Liquid Scintillator and a Proportional Counter: Application to a Neutron Spectrum Similar to that from an Improvised Nuclear Device.

    Science.gov (United States)

    Xu, Yanping; Randers-Pehrson, Gerhard; Marino, Stephen A; Garty, Guy; Harken, Andrew; Brenner, David J

    2015-09-11

    A novel neutron irradiation facility at the Radiological Research Accelerator Facility (RARAF) has been developed to mimic the neutron radiation from an Improvised Nuclear Device (IND) at relevant distances (e.g. 1.5 km) from the epicenter. The neutron spectrum of this IND-like neutron irradiator was designed according to estimations of the Hiroshima neutron spectrum at 1.5 km. It is significantly different from a standard reactor fission spectrum, because the spectrum changes as the neutrons are transported through air, and it is dominated by neutron energies from 100 keV up to 9 MeV. To verify such wide energy range neutron spectrum, detailed here is the development of a combined spectroscopy system. Both a liquid scintillator detector and a gas proportional counter were used for the recoil spectra measurements, with the individual response functions estimated from a series of Monte Carlo simulations. These normalized individual response functions were formed into a single response matrix for the unfolding process. Several accelerator-based quasi-monoenergetic neutron source spectra were measured and unfolded to test this spectroscopy system. These reference neutrons were produced from two reactions: T(p,n) 3 He and D(d,n) 3 He, generating neutron energies in the range between 0.2 and 8 MeV. The unfolded quasi-monoenergetic neutron spectra indicated that the detection system can provide good neutron spectroscopy results in this energy range. A broad-energy neutron spectrum from the 9 Be(d,n) reaction using a 5 MeV deuteron beam, measured at 60 degrees to the incident beam was measured and unfolded with the evaluated response matrix. The unfolded broad neutron spectrum is comparable with published time-of-flight results. Finally, the pair of detectors were used to measure the neutron spectrum generated at the RARAF IND-like neutron facility and a comparison is made to the neutron spectrum of Hiroshima.

  1. Insight into the mechanism of action of temporin-SHa, a new broad-spectrum antiparasitic and antibacterial agent.

    Directory of Open Access Journals (Sweden)

    Zahid Raja

    Full Text Available Antimicrobial peptides (AMPs are promising drugs to kill resistant pathogens. In contrast to bacteria, protozoan parasites, such as Leishmania, were little studied. Therefore, the antiparasitic mechanism of AMPs is still unclear. In this study, we sought to get further insight into this mechanism by focusing our attention on temporin-SHa (SHa, a small broad-spectrum AMP previously shown to be active against Leishmania infantum. To improve activity, we designed analogs of SHa and compared the antibacterial and antiparasitic mechanisms. [K3]SHa emerged as a highly potent compound active against a wide range of bacteria, yeasts/fungi, and trypanosomatids (Leishmania and Trypanosoma, with leishmanicidal intramacrophagic activity and efficiency toward antibiotic-resistant strains of S. aureus and antimony-resistant L. infantum. Multipassage resistance selection demonstrated that temporins-SH, particularly [K3]SHa, are not prone to induce resistance in Escherichia coli. Analysis of the mode of action revealed that bacterial and parasite killing occur through a similar membranolytic mechanism involving rapid membrane permeabilization and depolarization. This was confirmed by high-resolution imaging (atomic force microscopy and field emission gun-scanning electron microscopy. Multiple combined techniques (nuclear magnetic resonance, surface plasmon resonance, differential scanning calorimetry allowed us to detail peptide-membrane interactions. [K3]SHa was shown to interact selectively with anionic model membranes with a 4-fold higher affinity (KD = 3 x 10-8 M than SHa. The amphipathic α-helical peptide inserts in-plane in the hydrophobic lipid bilayer and disrupts the acyl chain packing via a detergent-like effect. Interestingly, cellular events, such as mitochondrial membrane depolarization or DNA fragmentation, were observed in L. infantum promastigotes after exposure to SHa and [K3]SHa at concentrations above IC50. Our results indicate that these

  2. Generation of a scale-invariant spectrum of adiabatic fluctuations in cosmological models with a contracting phase

    International Nuclear Information System (INIS)

    Finelli, Fabio; Brandenberger, Robert

    2002-01-01

    In pre-big-bang and in ekpyrotic cosmology, perturbations on cosmological scales today are generated from quantum vacuum fluctuations during a phase when the Universe is contracting (viewed in the Einstein frame). The backgrounds studied to date do not yield a scale-invariant spectrum of adiabatic fluctuations. Here, we present a new contracting background model (neither of pre-big-bang nor of the ekpyrotic form) involving a single scalar field coupled to gravity in which a scale-invariant spectrum of curvature fluctuations and gravitational waves results. The equation of state of this scalar field corresponds to cold matter. We demonstrate that if this contracting phase can be matched via a nonsingular bounce to an expanding Friedmann cosmology, the scale-invariance of the curvature fluctuations is maintained. We also find new background solutions for pre-big-bang and for ekpyrotic cosmology, which involve two scalar fields with exponential potentials with background values which are evolving in time. We comment on the difficulty of obtaining a scale-invariant spectrum of adiabatic fluctuations with background solutions which have been studied in the past

  3. The historical roots of the "bipolar spectrum": did Aristotle anticipate Kraepelin's broad concept of manic-depression?

    Science.gov (United States)

    Pies, Ronald

    2007-06-01

    The construct of bipolar disorder, or bipolar spectrum disorders, has been a source of controversy in recent years. Some have argued that subtle variants within the putative bipolar spectrum are merely the creation of overzealous clinicians, perhaps encouraged by various special interest groups. In reality, the concept of a bipolar spectrum may be inferred from numerous classical sources, dating back to the 19th century and even into antiquity. The Greek philosopher Aristotle, usually considered the author of a work called Problemata, appears to have recognized some form of the bipolar spectrum, more than two millennia ago. This recognition continues throughout the 19th century, and into our own time. Such transcultural findings across many centuries have implications for the "objective" nature of psychiatric disease.

  4. A broad-spectrum sunscreen prevents cumulative damage from repeated exposure to sub-erythemal solar ultraviolet radiation representative of temperate latitudes.

    Science.gov (United States)

    Seité, S; Christiaens, F; Bredoux, C; Compan, D; Zucchi, H; Lombard, D; Fourtanier, A; Young, A R

    2010-02-01

    We have previously shown the detrimental effects of 19 sub-erythemal exposures to daily ultraviolet radiation (DUVR, which mimics non-extreme exposure conditions), delivered over 4 weeks to volunteers. This source had UVA (320-400 nm) to UVB (290-320 nm) irradiance ratio of 25, instead of that close to 10 that is typically the case with solar-simulated radiation (SSR) that represents summer global sunlight with a clear sky and quasi-zenith solar irradiance. Here, we report on an extension of this previous study, in which we evaluated the photoprotection afforded by a broad-spectrum daily-care product with a low-sun protection factor (SPF 8, UVA-PF 7 and 3* rated UVA protection). We assessed cellular and molecular markers of photodamage that are relevant to skin cancer and photoageing. This study shows that biological effects of repeated exposure to DUVR can be prevented by a broad-spectrum daily-care product and that the level of protection afforded varies with the studied endpoint. Efficient daily UVR protection, as provided by a broad-spectrum daily-care product, is necessary to prevent the 'silent' sub-erythemal cumulative effects of UVR from inadvertent sun exposure.

  5. Effect of healthcare associated infections and broad spectrum antibiotic use in newborn period on development of asthma, allergic rhinitis and atopic dermatitis in early childhood

    Directory of Open Access Journals (Sweden)

    Hacer Yapicioglu Yildizdas

    2017-03-01

    Full Text Available Purpose: The iam of this study was to investigate the effect of healthcare associated infections (HAIs and broad spectrum antibiotic use in newborn period on asthma, allergic rhinitis and atopic dermatitis. Material and Methods: Seventy three children treated for HAIs in newborn period in Neonatal Intesive Care Unitin a 6 years period, and their 41 siblings who were healthy in newborn period were included in the study. Parents answered a detailed questionnaire, children were examined and complete blood count, serum total Ig E and specific Ig E levels were studied. Results: Ventilator associated pneumonia was observed in 32 (45.2%, blood stream infection in 28 (38.4% and clinic sepsis in 12 (16.4% of 73 children with HAIs. Asthma was significantly higher in HAIs group compared to sibling group (32.9% vs. 4.9, whereas there was no significant difference in allergic rhinitis (4.1% vs.2.4% and atopic dermatitis (6.8% vs. 0% among groups. When non-allergic 85 subjects and allergic 29 children compared, children who had been hospitalised and treated with broad-spectrum antibiotics in newborn period were almost 11.5 times as likely to have an allergic disease. Conclusion: Asthma was significantly higher in HAI group, and allergic disease risk seems to increase in children treated with broad-spectrum antibiotics for HAIs in newborn period. [Cukurova Med J 2017; 42(1.000: 132-139

  6. Broad-spectrum sunscreens provide better protection from solar ultraviolet-simulated radiation and natural sunlight-induced immunosuppression in human beings.

    Science.gov (United States)

    Moyal, Dominique D; Fourtanier, Anny M

    2008-05-01

    It is well established that ultraviolet (UV) radiation induces immunomodulatory effects that may be involved in skin cancer. Recent studies have shown that UVA (320-400 nm) and UVB (290-320 nm) radiation are immunosuppressive. As a result, sunscreens, which mainly absorb UVB, may be less effective in preventing UV radiation-induced immunosuppression than broad-spectrum products. We sought to study the effects of UVA exposure on human delayed-type hypersensitivity (DTH) response and compare the efficacy of sunscreens having different levels of sun-protection factor (SPF) and UVA protection against both solar-simulated radiation and outdoor real-life sunlight exposure conditions. DTH was assessed using a kit which includes 7 recall antigens that most of the participants encountered during childhood immunization. Evaluation of DTH test response was made 48 hours after test application before and after UV exposure with or without sunscreens. In unprotected participants, the response to DTH tests was significantly reduced irrespective of UV types of exposure (full-spectrum UVA, long UVA, solar-simulated radiation). A UVB sunscreen failed to protect from solar-simulated radiation-induced immunosuppression. In contrast, a broad-spectrum sunscreen with the same SPF but providing a high protection in the UVA range significantly reduced local UV-induced immunosuppression and prevented the distant effects. In the outdoor study, as compared with DTH responses obtained before sun exposure, no alteration of immune response was detected when the skin was protected by a broad-spectrum sunscreen having a high protection level in the UVA (SPF 25, UVA protection factor 14). Conversely a broad-spectrum sunscreen with lower protection against UVA (SPF 25, UVA protection factor 6) failed to prevent UV-impaired response. These results have been obtained after repeated exposure. Additional experiments obtained under acute exposure are in progress. These findings clearly demonstrated the

  7. An Intrinsic Baldwin Effect in the H Beta Broad Emission Line in the Spectrum of NGC 5548

    Science.gov (United States)

    Gilbert, Karoline M.; Peterson, Bradley M.

    2003-01-01

    We investigate the possibility of an intrinsic Baldwin effect (i.e., nonlinear emission-line response to continuum variations) in the broad HP emission line of the active galaxy NGC 5548 using crosscorrelation techniques to remove light-travel time effects from the data. We find a nonlinear relationship between the HP emission line and continuum fluxes that is in good agreement with theoretical predictions. We suggest that similar analysis of multiple lines might provide a useful diagnostic of physical conditions in the broad-line region.

  8. Tricyclic GyrB/ParE (TriBE inhibitors: a new class of broad-spectrum dual-targeting antibacterial agents.

    Directory of Open Access Journals (Sweden)

    Leslie W Tari

    Full Text Available Increasing resistance to every major class of antibiotics and a dearth of novel classes of antibacterial agents in development pipelines has created a dwindling reservoir of treatment options for serious bacterial infections. The bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV, are validated antibacterial drug targets with multiple prospective drug binding sites, including the catalytic site targeted by the fluoroquinolone antibiotics. However, growing resistance to fluoroquinolones, frequently mediated by mutations in the drug-binding site, is increasingly limiting the utility of this antibiotic class, prompting the search for other inhibitor classes that target different sites on the topoisomerase complexes. The highly conserved ATP-binding subunits of DNA gyrase (GyrB and topoisomerase IV (ParE have long been recognized as excellent candidates for the development of dual-targeting antibacterial agents with broad-spectrum potential. However, to date, no natural product or small molecule inhibitors targeting these sites have succeeded in the clinic, and no inhibitors of these enzymes have yet been reported with broad-spectrum antibacterial activity encompassing the majority of Gram-negative pathogens. Using structure-based drug design (SBDD, we have created a novel dual-targeting pyrimidoindole inhibitor series with exquisite potency against GyrB and ParE enzymes from a broad range of clinically important pathogens. Inhibitors from this series demonstrate potent, broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens of clinical importance, including fluoroquinolone resistant and multidrug resistant strains. Lead compounds have been discovered with clinical potential; they are well tolerated in animals, and efficacious in Gram-negative infection models.

  9. Tricyclic GyrB/ParE (TriBE) inhibitors: a new class of broad-spectrum dual-targeting antibacterial agents.

    Science.gov (United States)

    Tari, Leslie W; Li, Xiaoming; Trzoss, Michael; Bensen, Daniel C; Chen, Zhiyong; Lam, Thanh; Zhang, Junhu; Lee, Suk Joong; Hough, Grayson; Phillipson, Doug; Akers-Rodriguez, Suzanne; Cunningham, Mark L; Kwan, Bryan P; Nelson, Kirk J; Castellano, Amanda; Locke, Jeff B; Brown-Driver, Vickie; Murphy, Timothy M; Ong, Voon S; Pillar, Chris M; Shinabarger, Dean L; Nix, Jay; Lightstone, Felice C; Wong, Sergio E; Nguyen, Toan B; Shaw, Karen J; Finn, John

    2013-01-01

    Increasing resistance to every major class of antibiotics and a dearth of novel classes of antibacterial agents in development pipelines has created a dwindling reservoir of treatment options for serious bacterial infections. The bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV, are validated antibacterial drug targets with multiple prospective drug binding sites, including the catalytic site targeted by the fluoroquinolone antibiotics. However, growing resistance to fluoroquinolones, frequently mediated by mutations in the drug-binding site, is increasingly limiting the utility of this antibiotic class, prompting the search for other inhibitor classes that target different sites on the topoisomerase complexes. The highly conserved ATP-binding subunits of DNA gyrase (GyrB) and topoisomerase IV (ParE) have long been recognized as excellent candidates for the development of dual-targeting antibacterial agents with broad-spectrum potential. However, to date, no natural product or small molecule inhibitors targeting these sites have succeeded in the clinic, and no inhibitors of these enzymes have yet been reported with broad-spectrum antibacterial activity encompassing the majority of Gram-negative pathogens. Using structure-based drug design (SBDD), we have created a novel dual-targeting pyrimidoindole inhibitor series with exquisite potency against GyrB and ParE enzymes from a broad range of clinically important pathogens. Inhibitors from this series demonstrate potent, broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens of clinical importance, including fluoroquinolone resistant and multidrug resistant strains. Lead compounds have been discovered with clinical potential; they are well tolerated in animals, and efficacious in Gram-negative infection models.

  10. Forming of space charge wave with broad frequency spectrum in helical relativistic two-stream electron beams

    DEFF Research Database (Denmark)

    Lysenko, Alexander V.; Volk, Iurii I.; Serozhko, A.

    2017-01-01

    expands with the increase of the beam entrance angle. Moreover, we obtain that utilizing helical electron beams in multiharmonic two-stream superheterodyne free-electron lasers leads to the improvement of their amplification characteristics, the frequency spectrum broadening in multiharmonic signal...

  11. A Broad Iron Line in the Chandra High Energy Transmission Grating Spectrum of 4U 1705-44

    NARCIS (Netherlands)

    di Salvo, T.; Iaria, R.; Méndez, R.M.; Burderi, L.; Lavagetto, G.; Robba, N.R.; Stella, L.; van der Klis, M.

    2005-01-01

    We present the results of a Chandra 30 ks observation of the low-mass X-ray binary and atoll source 4U 1705-44. Here we concentrate on the study of discrete features in the energy spectrum at energies below ~3 keV, as well as on the iron Kalpha line, using the High Energy Transmission Grating

  12. Broad-spectrum inhibition of HIV-1 by a monoclonal antibody directed against a gp120-induced epitope of CD4.

    Directory of Open Access Journals (Sweden)

    Samuele E Burastero

    Full Text Available To penetrate susceptible cells, HIV-1 sequentially interacts with two highly conserved cellular receptors, CD4 and a chemokine receptor like CCR5 or CXCR4. Monoclonal antibodies (MAbs directed against such receptors are currently under clinical investigation as potential preventive or therapeutic agents. We immunized Balb/c mice with molecular complexes of the native, trimeric HIV-1 envelope (Env bound to a soluble form of the human CD4 receptor. Sera from immunized mice were found to contain gp120-CD4 complex-enhanced antibodies and showed broad-spectrum HIV-1-inhibitory activity. A proportion of MAbs derived from these mice preferentially recognized complex-enhanced epitopes. In particular, a CD4-specific MAb designated DB81 (IgG1Κ was found to preferentially bind to a complex-enhanced epitope on the D2 domain of human CD4. MAb DB81 also recognized chimpanzee CD4, but not baboon or macaque CD4, which exhibit sequence divergence in the D2 domain. Functionally, MAb DB81 displayed broad HIV-1-inhibitory activity, but it did not exert suppressive effects on T-cell activation in vitro. The variable regions of the heavy and light chains of MAb DB81 were sequenced. Due to its broad-spectrum anti-HIV-1 activity and lack of immunosuppressive effects, a humanized derivative of MAb DB81 could provide a useful complement to current preventive or therapeutic strategies against HIV-1.

  13. Prescriptions of broad-spectrum antibiotics to outpatients do not match increased prevalence and antibiotic resistance of respiratory pathogens in Bavaria.

    Science.gov (United States)

    Borgmann, Stefan; Jakobiak, Thomas; Gruber, Heribert; Schröder, Helmut; Sagel, Ulrich

    2009-01-01

    In this study we present an analysis of prescription numbers of various antibiotic classes to Bavarian (Southern Germany) outpatients between 2000 and 2006 compared to fluctuating resistance patterns in representative respiratory pathogens. Prescriptions of "narrow-spectrum" antibiotics (e.g. penicillins, macrolides) decreased by 39% while prescriptions of "broad-spectrum" antibiotics increased by 38%. The most prominent increase was for quinolones and cephalosporines class II. Prescriptions of these antibiotics exhibited prominent seasonal alterations suggesting that these drugs had been used for treatment of respiratory infections. In contrast, the numbers of S. pneumoniae and H. influenzae detected in respiratory specimen decreased. Almost constant resistance rates of S. pneumoniae for first line antibiotics do not justify an increased use of cephalosporins class II and quinolones. Compared to Europe and Germany in general, consumption of antibiotics is low in Bavaria. Even at this low level we propose an education of physicians treating outpatients in a way to avoid an excessive use of antimicrobials.

  14. An action spectrum for lethal photosensitization of Candida albicans by 8-MOP after low-dose broad-band UV-A irradiation; an action spectrum for 8-MOP 4',5'-monoadducts

    International Nuclear Information System (INIS)

    Baydoun, S.A.; Young, A.R.

    1987-01-01

    An action spectrum was obtained for lethal photosensitization of Candida albicans that had been pre-irradiated with a sub-lethal low dose of broad-band UV-A after incubation with 8-methoxypsoralen and then washed to remove any non-photobound 8-methoxypsoralen. The resultant spectrum with a peak in the 320-335 nm region was similar to that obtained by a conventional method (single irradiation only) and also to the absorption spectrum of the 4',5'-monoadduct. These data support the hypothesis that the chromophore for lethal photosensitization by 8-methoxypsoralen is the 8-methoxypsoralen/DNA 4',5'-monoadduct rather than 8-methoxypsoralen itself. (author)

  15. The broad-band X-ray spectrum of IC 4329A from a joint NuSTAR/Suzaku observation

    DEFF Research Database (Denmark)

    Brenneman, L. W.; Madejski, G.; Fuerst, F.

    2014-01-01

    We have obtained a deep, simultaneous observation of the bright, nearby Seyfert galaxy IC 4329A with Suzaku andNuSTAR. Through a detailed spectral analysis, we are able to robustly separate the continuum, absorption, and distant reflection components in the spectrum. The absorbing column is found...... also updated our previously reported measurement of the high-energy cutoff of the hard X-ray emission using both observatories rather than justNuSTAR alone: Ecut = 186±14 keV. This high-energy cutoff acts as a proxy for the temperature of the coronal electron plasma, enabling us to further separate...

  16. Influence of two-stream relativistic electron beam parameters on the space-charge wave with broad frequency spectrum formation

    Science.gov (United States)

    Alexander, LYSENKO; Iurii, VOLK

    2018-03-01

    We developed a cubic non-linear theory describing the dynamics of the multiharmonic space-charge wave (SCW), with harmonics frequencies smaller than the two-stream instability critical frequency, with different relativistic electron beam (REB) parameters. The self-consistent differential equation system for multiharmonic SCW harmonic amplitudes was elaborated in a cubic non-linear approximation. This system considers plural three-wave parametric resonant interactions between wave harmonics and the two-stream instability effect. Different REB parameters such as the input angle with respect to focusing magnetic field, the average relativistic factor value, difference of partial relativistic factors, and plasma frequency of partial beams were investigated regarding their influence on the frequency spectrum width and multiharmonic SCW saturation levels. We suggested ways in which the multiharmonic SCW frequency spectrum widths could be increased in order to use them in multiharmonic two-stream superheterodyne free-electron lasers, with the main purpose of forming a powerful multiharmonic electromagnetic wave.

  17. Identification of a novel endophytic Bacillus sp. from Capsicum annuum with highly efficient and broad spectrum plant probiotic effect.

    Science.gov (United States)

    Jasim, B; Mathew, J; Radhakrishnan, E K

    2016-10-01

    The study mainly aimed the isolation and characterization of plant probiotic endophytic bacteria from Capsicum annuum to explore its multipotent agricultural applications. Endophytic bacteria were isolated from the surface sterilized fruit tissue. The isolates were then subjected to PCR-based screening for the presence of potential biosynthetic gene clusters. The PCR positive isolate was then analysed for its inhibitory effect towards fungal and bacterial pathogens. The compounds responsible for the antimicrobial activity was purified from large scale culture and subjected to identification by LC-MS/MS. The ability of the selected isolate in plant growth enhancement was also done using Vigna radiata seedlings. In this study, an endophytic bacterium isolated from C. annuum was found to have the phenotypic and genetic basis for broad antimicrobial property. PCR-based sequence analysis has resulted in the identification of nonribosomal peptide synthases, PKS Type I, Iturin, surfactin, DAPG and gacA genes in the selected isolate CaB 5. The bioactivity-guided fractionation using column and HPLC purification of active fraction followed by LC-MS/MS analysis has proved the presence of surfactin derivatives (M+H(+) - 1008 & 1036) and iturin (M+H(+) - 1058) as the basis of antimicrobial activity of CaB 5. The isolate was identified as a novel Bacillus sp. because of its low (76%) identity to the reported sequences. Endophytes are considered to have the genetic basis for a diverse array of bioactive metabolites which can have significant applications in both pharmaceutical industry and agriculture. The identification of CaB 5 with broad bioactivity and excellent plant growth enhancement on taxonomically distinct plant species as explained in current study and our previous reports highlights its plant probiotic applicability. This proves the potential of the isolate obtained in the study to be an excellent plant probiotic. © 2016 The Society for Applied Microbiology.

  18. Whole-genome sequencing of Bacillus velezensis LS69, a strain with a broad inhibitory spectrum against pathogenic bacteria.

    Science.gov (United States)

    Liu, Guoqiang; Kong, Yingying; Fan, Yajing; Geng, Ce; Peng, Donghai; Sun, Ming

    2017-05-10

    Bacillus velezensis LS69 was found to exhibit antagonistic activity against a diverse spectrum of pathogenic bacteria. It has one circular chromosome of 3,917,761bp with 3,643 open reading frames. Genome analysis identified ten gene clusters involved in nonribosomal synthesis of polyketides (macrolactin, bacillaene and difficidin), lipopeptides (surfactin, fengycin, bacilysin and iturin A) and bacteriocins (amylolysin and amylocyclicin). In addition, B. velezensis LS69 was found to contain a series of genes involved in enhancing plant growth and triggering plant immunity. Whole genome sequencing of Bacillus velezensis LS69 will provide a basis for elucidation of its biocontrol mechanisms and facilitate its applications in the future. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Biogenic synthesis of Zinc oxide nanostructures from Nigella sativa seed: Prospective role as food packaging material inhibiting broad-spectrum quorum sensing and biofilm

    Science.gov (United States)

    Al-Shabib, Nasser A.; Husain, Fohad Mabood; Ahmed, Faheem; Khan, Rais Ahmad; Ahmad, Iqbal; Alsharaeh, Edreese; Khan, Mohd Shahnawaz; Hussain, Afzal; Rehman, Md Tabish; Yusuf, Mohammad; Hassan, Iftekhar; Khan, Javed Masood; Ashraf, Ghulam Md; Alsalme, Ali Mohammed; Al-Ajmi, Mohamed F.; Tarasov, Vadim V.; Aliev, Gjumrakch

    2016-01-01

    Bacterial spoilage of food products is regulated by density dependent communication system called quorum sensing (QS). QS control biofilm formation in numerous food pathogens and Biofilms formed on food surfaces act as carriers of bacterial contamination leading to spoilage of food and health hazards. Agents inhibiting or interfering with bacterial QS and biofilm are gaining importance as a novel class of next-generation food preservatives/packaging material. In the present study, Zinc nanostructures were synthesised using Nigella sativa seed extract (NS-ZnNPs). Synthesized nanostructures were characterized hexagonal wurtzite structure of size ~24 nm by UV-visible, XRD, FTIR and TEM. NS-ZnNPs demonstrated broad-spectrum QS inhibition in C. violaceum and P. aeruginosa biosensor strains. Synthesized nanostructures inhibited QS regulated functions of C. violaceum CVO26 (violacein) and elastase, protease, pyocyanin and alginate production in PAO1 significantly. NS-ZnNPs at sub-inhibitory concentrations inhibited the biofilm formation of four-food pathogens viz. C. violaceum 12472, PAO1, L. monocytogenes, E. coli. Moreover, NS-ZnNPs was found effective in inhibiting pre-formed mature biofilms of the four pathogens. Therefore, the broad-spectrum inhibition of QS and biofilm by biogenic Zinc oxide nanoparticles and it is envisaged that these nontoxic bioactive nanostructures can be used as food packaging material and/or as food preservative. PMID:27917856

  20. Protease-sensitive conformers in broad spectrum of distinct PrPSc structures in sporadic Creutzfeldt-Jakob disease are indicator of progression rate.

    Directory of Open Access Journals (Sweden)

    Chae Kim

    2011-09-01

    Full Text Available The origin, range, and structure of prions causing the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD, are largely unknown. To investigate the molecular mechanism responsible for the broad phenotypic variability of sCJD, we analyzed the conformational characteristics of protease-sensitive and protease-resistant fractions of the pathogenic prion protein (PrP(Sc using novel conformational methods derived from a conformation-dependent immunoassay (CDI. In 46 brains of patients homozygous for polymorphisms in the PRNP gene and exhibiting either Type 1 or Type 2 western blot pattern of the PrP(Sc, we identified an extensive array of PrP(Sc structures that differ in protease sensitivity, display of critical domains, and conformational stability. Surprisingly, in sCJD cases homozygous for methionine or valine at codon 129 of the PRNP gene, the concentration and stability of protease-sensitive conformers of PrP(Sc correlated with progression rate of the disease. These data indicate that sCJD brains exhibit a wide spectrum of PrP(Sc structural states, and accordingly argue for a broad spectrum of prion strains coding for different phenotypes. The link between disease duration, levels, and stability of protease-sensitive conformers of PrP(Sc suggests that these conformers play an important role in the pathogenesis of sCJD.

  1. Sucrose-mediated priming of plant defense responses and broad-spectrum disease resistance by overexpression of the maize pathogenesis-related PRms protein in rice plants.

    Science.gov (United States)

    Gómez-Ariza, Jorge; Campo, Sonia; Rufat, Mar; Estopà, Montserrat; Messeguer, Joaquima; San Segundo, Blanca; Coca, María

    2007-07-01

    Expression of pathogenesis-related (PR) genes is part of the plant's natural defense response against pathogen attack. The PRms gene encodes a fungal-inducible PR protein from maize. Here, we demonstrate that expression of PRms in transgenic rice confers broad-spectrum protection against pathogens, including fungal (Magnaporthe oryzae, Fusarium verticillioides, and Helminthosporium oryzae) and bacterial (Erwinia chrysanthemi) pathogens. The PRms-mediated disease resistance in rice plants is associated with an enhanced capacity to express and activate the natural plant defense mechanisms. Thus, PRms rice plants display a basal level of expression of endogenous defense genes in the absence of the pathogen. PRms plants also exhibit stronger and quicker defense responses during pathogen infection. We also have found that sucrose accumulates at higher levels in leaves of PRms plants. Sucrose responsiveness of rice defense genes correlates with the pathogen-responsive priming of their expression in PRms rice plants. Moreover, pretreatment of rice plants with sucrose enhances resistance to M. oryzae infection. Together, these results support a sucrose-mediated priming of defense responses in PRms rice plants which results in broad-spectrum disease resistance.

  2. Nucleic acid polymers: Broad spectrum antiviral activity, antiviral mechanisms and optimization for the treatment of hepatitis B and hepatitis D infection.

    Science.gov (United States)

    Vaillant, Andrew

    2016-09-01

    Antiviral polymers are a well-studied class of broad spectrum viral attachment/entry inhibitors whose activity increases with polymer length and with increased amphipathic (hydrophobic) character. The newest members of this class of compounds are nucleic acid polymers whose activity is derived from the sequence independent properties of phosphorothioated oligonucleotides as amphipathic polymers. Although the antiviral mechanisms and broad spectrum antiviral activity of nucleic acid polymers mirror the functionality of other members of this class, they exert in addition a unique post entry activity in hepatitis B infection which inhibits the release of HBsAg from infected hepatocytes. This review provides a general overview of the antiviral polymer class with a focus on nucleic acid polymers and their development as therapeutic agents for the treatment of hepatitis B/hepatitis D. This article forms part of a symposium in Antiviral Research on ''An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B.''. Copyright © 2016 The Author. Published by Elsevier B.V. All rights reserved.

  3. Broad phenotypic spectrum in familial adenomatous polyposis; from early onset and severe phenotypes to late onset of attenuated polyposis with the first manifestation at age 72

    Directory of Open Access Journals (Sweden)

    Johannsson Oskar

    2008-11-01

    Full Text Available Abstract Background Familial adenomatous polyposis (FAP is typically characterized by multiple colonic polyps and frequent extracolonic features. Whereas the number of colonic polyps has been linked to the APC gene mutation, possible genotype-phenotype correlations largely remain to be defined for the extracolonic manifestations. Methods Full genomic sequencing combined with multiplex ligation-dependent probe amplification was used to identify APC gene mutations, which were correlated to the clinical presentations. Results 10 novel APC gene mutations were identified in 11 families. A broad spectrum of extracolonic manifestations was identified in most of these individuals. Two sisters with an insertion in codon 528 (c.1582_1583insGC both showed severe phenotypes with classical polyposis, upper gastrointestinal polyps and thyroid cancer. A woman with a 3'APC mutation (c.5030_5031insAA developed colon cancer at age 72 as the first manifestation of attenuated FAP. Conclusion With an increasing number of FAP families diagnosed, a broad and variable tumor spectrum and a high frequency of extracolonic manifestations are gradually recognized. We report novel APC mutations and present two FAP cases that suggest familial aggregation of thyroid cancer and demonstrate the need to consider attenuated FAP also among elderly patients with colon cancer.

  4. Protease-sensitive conformers in broad spectrum of distinct PrPSc structures in sporadic Creutzfeldt-Jakob disease are indicator of progression rate.

    Science.gov (United States)

    Kim, Chae; Haldiman, Tracy; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Sy, Man-Sun; Cohen, Mark; Safar, Jiri G

    2011-09-01

    The origin, range, and structure of prions causing the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD), are largely unknown. To investigate the molecular mechanism responsible for the broad phenotypic variability of sCJD, we analyzed the conformational characteristics of protease-sensitive and protease-resistant fractions of the pathogenic prion protein (PrP(Sc)) using novel conformational methods derived from a conformation-dependent immunoassay (CDI). In 46 brains of patients homozygous for polymorphisms in the PRNP gene and exhibiting either Type 1 or Type 2 western blot pattern of the PrP(Sc), we identified an extensive array of PrP(Sc) structures that differ in protease sensitivity, display of critical domains, and conformational stability. Surprisingly, in sCJD cases homozygous for methionine or valine at codon 129 of the PRNP gene, the concentration and stability of protease-sensitive conformers of PrP(Sc) correlated with progression rate of the disease. These data indicate that sCJD brains exhibit a wide spectrum of PrP(Sc) structural states, and accordingly argue for a broad spectrum of prion strains coding for different phenotypes. The link between disease duration, levels, and stability of protease-sensitive conformers of PrP(Sc) suggests that these conformers play an important role in the pathogenesis of sCJD.

  5. The antimicrobial efficacy of a silver alginate dressing against a broad spectrum of clinically relevant wound isolates.

    Science.gov (United States)

    Percival, Steven L; Slone, Will; Linton, Sara; Okel, Tyler; Corum, Linda; Thomas, John G

    2011-06-01

    Wound dressings impregnated with silver have a role to play in aiding to reduce both the dressing and wound microbial bioburden. It is therefore imperative that antimicrobial wound dressings have efficacy on a broad range of clinical significant microorganisms. Accordingly, this study aimed to determine the antimicrobial efficacy of a silver alginate dressing against 115 wound isolates that had been isolated routinely from patients at West Virginia University Hospital. Standardised corrected zones of inhibition (CZOIs) were performed on all clinical isolates. It was found that the silver alginate dressing was able to inhibit the growth of all microorganisms tested. In particular, the silver alginate dressing inhibited the growth of Candida albicans and yeasts with CZOI of 3-11·5 mm. All meticillin-resistant Staphylococcus aureus (MRSA) strains were found to be sensitive to the silver alginate dressing with a CZOI range calculated at 3-7·8 mm. Sensitivity to the silver alginate dressing was also evident for S. aureus and vancomycin-resistant Enterococci. CZOIs of 4·25 mm were calculated for Enterococcus faecium and 9·8 mm for viridans streptococcus. The bacteria which demonstrated the highest tolerance to ionic silver included Enterobacter cloacae and Acinetobacter baumannii. Contrary to this the most responsive microorganisms to ionic silver included strains of staphylococci, viridans streptococcus and Candida albicans. No antibiotic-resistant isolates, as identified by Kirby Bauer Clinical Laboratory Standards Institute classification system, were found to be resistant to ionic silver. When a selected number of microorganisms were grown in the biofilm phenotypic state enhanced tolerance to silver was observed, compared to their non biofilm counterparts. Overall, this study has demonstrated the broad antimicrobial activity of a silver alginate dressing on wound isolates grown in the non biofilm and biofilm state. This finding is clinically relevant as both the

  6. The Freshwater Sponge Ephydatia fluviatilis Harbours Diverse Pseudomonas Species (Gammaproteobacteria, Pseudomonadales) with Broad-Spectrum Antimicrobial Activity

    Science.gov (United States)

    Keller-Costa, Tina; Jousset, Alexandre; van Overbeek, Leo; van Elsas, Jan Dirk; Costa, Rodrigo

    2014-01-01

    Bacteria are believed to play an important role in the fitness and biochemistry of sponges (Porifera). Pseudomonas species (Gammaproteobacteria, Pseudomonadales) are capable of colonizing a broad range of eukaryotic hosts, but knowledge of their diversity and function in freshwater invertebrates is rudimentary. We assessed the diversity, structure and antimicrobial activities of Pseudomonas spp. in the freshwater sponge Ephydatia fluviatilis. Polymerase Chain Reaction – Denaturing Gradient Gel Electrophoresis (PCR-DGGE) fingerprints of the global regulator gene gacA revealed distinct structures between sponge-associated and free-living Pseudomonas communities, unveiling previously unsuspected diversity of these assemblages in freshwater. Community structures varied across E. fluviatilis specimens, yet specific gacA phylotypes could be detected by PCR-DGGE in almost all sponge individuals sampled over two consecutive years. By means of whole-genome fingerprinting, 39 distinct genotypes were found within 90 fluorescent Pseudomonas isolates retrieved from E. fluviatilis. High frequency of in vitro antibacterial (49%), antiprotozoan (35%) and anti-oomycetal (32%) activities was found among these isolates, contrasting less-pronounced basidiomycetal (17%) and ascomycetal (8%) antagonism. Culture extracts of highly predation-resistant isolates rapidly caused complete immobility or lysis of cells of the protozoan Colpoda steinii. Isolates tentatively identified as P. jessenii, P. protegens and P. oryzihabitans showed conspicuous inhibitory traits and correspondence with dominant sponge-associated phylotypes registered by cultivation-independent analysis. Our findings suggest that E. fluviatilis hosts both transient and persistent Pseudomonas symbionts displaying antimicrobial activities of potential ecological and biotechnological value. PMID:24533086

  7. Characterization of a topologically unique oxygenase from Sphingobium sp. PNB capable of catalyzing a broad spectrum of aromatics.

    Science.gov (United States)

    Khara, Pratick; Roy, Madhumita; Chakraborty, Joydeep; Dutta, Arindam; Dutta, Tapan K

    2018-04-01

    A Rieske non-heme iron ring-hydroxylating oxygenase (RHO) from Sphingobium sp. PNB involved in the initial oxidation of a wide range of low and high molecular weight polycyclic aromatic hydrocarbons (PAHs) was investigated. The RHO was shown to comprise of the gene products of distantly located ahdA1f-ahdA2f, ahdA3 and ahdA4 genes, which encoded the oxygenase α- and β-subunits, ferredoxin and reductase, respectively. In silico structural analysis of AhdA1f revealed a very large substrate-binding pocket, satisfying the spatial requirements to accommodate high molecular weight substrates. In addition, an atypical substrate access channel was noticed from the topology analysis of the oxygenase. Guided by molecular docking studies, dioxygenation of several PAHs as well as alkyl- and aryl benzenes was examined with the recombinant AhdA1fA2f expressed in Escherichia coli. Chromatographic and mass spectrometric analyses confirmed that AhdA1fA2f displays broad substrate specificity towards a wide range of aromatic hydrocarbons including potential xenobiotics, demonstrating metabolic robustness of strain PNB. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Dissemination and genetic support of broad-spectrum beta-lactam-resistant Escherichia coli strain isolated from two Tunisian hospitals during 2004-2012.

    Science.gov (United States)

    Ayari, Khaoula; Bourouis, Amel; Chihi, Hela; Mahrouki, Sihem; Naas, Thierry; Belhadj, Omrane

    2017-06-01

    The dissemination of extended-spectrum β-lactamase (ESBL)-producing bacteria presented a great concern worldwide. Gram-negative organisms such as Escherichia coli and Klebsiella pneumoniae are the most frequently isolated pathogens responsible for nosocomial infections. The aim of this study was to investigate and to follow the emergence of resistance and the characterization of Extended-Spectrum Beta-Lactamases (ESBL) among broad-spectrum beta-lactam- Escherichia coli clinical isolates recovered from the military hospital and Habib Thameur hospital in Tunisia. A total of 113 E.coli isolates obtained during the period 2004 through 2012 showed a significant degree of multi-resistance. Among these strains, the double-disk synergy test confirmed the ESBL phenotype in 46 isolates. These included 32(70%) strains from Hospital A and 14(30%) from Hospital B. The ESBL was identified as CTX-M-15. The ESBL resistance was transferred by a 60 kb plasmid CTXM-15-producing isolates were unrelated according to the PFGE analysis and characterization of the regions surrounding the blaCTX-M-15 showed the ISEcp1 elements located in the upstream region of the bla gene and 20 of them truncated by IS26. ESBL producing E. coli strains are a serious threat in the community in Tunisia and we should take into consideration any possible spread of such epidemiological resistance.

  9. Discovery and development of kibdelomycin, a new class of broad-spectrum antibiotics targeting the clinically proven bacterial type II topoisomerase.

    Science.gov (United States)

    Singh, Sheo B

    2016-12-15

    Kibdelomycin is a complex novel antibiotic, discovered by applying a highly sophisticated chemical-genetic Staphylococcus aureus Fitness Test (SaFT) approach, that inhibits the clinically established bacterial targets, gyrase and topoisomerase IV. It exhibits broad-spectrum antibacterial activity against aerobic bacteria including MRSA and Acinetobacter baumannii. It is slowly bactericidal and has a low frequency of resistance. In an anaerobic environment, it exhibits narrow-spectrum activity and inhibits the growth of gut bacteria Clostridium difficile (MIC 0.125μg/mL) without affecting the growth of commensal Gram-negative organisms particularly, Bacteroides sp. It is highly efficacious in the hamster model of C. difficile infection providing 100% protection at >6mg/kg and 80% protection at 1.56mg/kg by oral dosing without systemic exposure. X-ray co-crystal structures of kibdelomycin bound to GyrB and ParE showed a unique dual arm 'U shaped' multisite binding never encountered with any other gyrase inhibitors. Kibdelomycin is poised for preclinical development for C. difficile treatment, and most importantly, the co-crystal structures of kibdelomycin provide unique insight for structure-guided structure modification, which could lead to better broader-spectrum systemic antibiotic potentially covering many ESKAPE pathogens. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. "The Math You Need" When Faculty Need It: Enhancing Quantitative Skills at a Broad Spectrum of Higher Education Institutions

    Science.gov (United States)

    Baer, E. M.; Wenner, J. M.

    2014-12-01

    Implementation of "The Math You Need, When You Need It" (TMYN) modules at a wide variety of institutions suggests a broad need for faculty support in helping students develop quantitative skills necessary in introductory geoscience courses. Designed to support students in applying geoscience relevant quantitative skills, TMYN modules are web-based, self-paced and commonly assigned outside of class. They include topics such as calculating slope, rearranging equations, and unit conversions and provide several applications of the mathematical technique to geoscience problems. Each instructor chooses modules that are applicable to the content in his/her individual course and students typically work through the module immediately before the module topic is applied in lab or class. Instructors assigned TMYN modules in their courses at more than 40 diverse institutions, including four-year colleges and universities (4YCs) that vary from non-selective to highly selective and open-door two-year colleges (2YCs). Analysis of module topics assigned, frequency of module use, and institutional characteristics reveals similarities and differences among faculty perception of required quantitative skills and incoming student ability at variably selective institutions. Results indicate that institutional type and selectivity are not correlated with module topic; that is, faculty apply similar quantitative skills in all introductory geoscience courses. For example, nearly every instructor assigned the unit conversions module, whereas very few required the trigonometry module. However, differences in number of assigned modules and faculty expectations are observed between 2YCs and 4YCs (no matter the selectivity). Two-year college faculty typically assign a higher number of modules per course and faculty at 4YCs more often combine portions of multiple modules or cover multiple mathematical concepts in a single assignment. These observations suggest that quantitative skills required

  11. Sequence-Specific Modifications Enhance the Broad-Spectrum Antiviral Response Activated by RIG-I Agonists

    Science.gov (United States)

    Chiang, Cindy; Beljanski, Vladimir; Yin, Kevin; Olagnier, David; Ben Yebdri, Fethia; Steel, Courtney; Goulet, Marie-Line; DeFilippis, Victor R.; Streblow, Daniel N.; Haddad, Elias K.; Trautmann, Lydie; Ross, Ted; Lin, Rongtuan

    2015-01-01

    properties against influenza, dengue, and chikungunya viruses. A novel, sequence-dependent, uridine-rich RIG-I agonist generated a protective antiviral response in vitro and in vivo and was effective at concentrations 100-fold lower than prototype sequences or other RNA agonists, highlighting the robust activity and potential clinical use of the 5′pppRNA against RNA virus infection. Altogether, the results identify a novel, sequence-specific RIG-I agonist as an attractive therapeutic candidate for the treatment of a broad range of RNA viruses, a pressing issue in which a need for new and more effective options persists. PMID:26018150

  12. Spectrum

    DEFF Research Database (Denmark)

    Høgfeldt Hansen, Leif

    2016-01-01

    The publication functions as a proces description of the development and construction of an urban furniture SPECTRUM in the city of Gwangju, Republic of Korea. It is used as the cataloque for the exhibition of Spectrum.......The publication functions as a proces description of the development and construction of an urban furniture SPECTRUM in the city of Gwangju, Republic of Korea. It is used as the cataloque for the exhibition of Spectrum....

  13. Report of the 5th meeting on influenza vaccines that induce broad spectrum and long-lasting immune responses, World Health Organization, Geneva, 16-17 November 2011.

    Science.gov (United States)

    Hughes, Bethan; Hayden, Frederick; Perikov, Yuri; Hombach, Joachim; Tam, John S

    2012-10-19

    On 16-17 November 2011, the Initiative for Vaccine Research of the World Health Organization convened jointly with the Wellcome Trust the fifth meeting on 'Influenza vaccines that induce broad spectrum and long-lasting immune responses'. The goals of the meeting were to examine new influenza vaccine research developments related to increased duration and breadth of protection, including immune responses against novel strains that may present zoonotic and pandemic threats; improved delivery and administration; and safety issues related to novel vaccine approaches. A number of investigational vaccines based on unique antigens, adjuvants, and/or modes of delivery were presented. The challenges for feasible regulatory pathways to approval of such vaccines were discussed. Copyright © 2012. Published by Elsevier Ltd.. All rights reserved.

  14. Facile synthesis of Fe3O4 nanoparticles decorated on 3D graphene aerogels as broad-spectrum sorbents for water treatment

    Science.gov (United States)

    Li, Yong; Zhang, Ruofang; Tian, Xike; Yang, Chao; Zhou, Zhaoxin

    2016-04-01

    In order to develop efficient and environment benign sorbents for water purification, the macroscopic multifunctional magnetite-reduced graphene oxides aerogels (M-RGOs) with strong interconnected networks were prepared via a one pot solvothermal method of graphene oxide sheets adsorbing iron ions and in situ simultaneous deposition of Fe3O4 nanoparticles in ethylene glycol or triethylene glycol solvents. Such M-RGOs exhibited excellent sorption capacity to different contaminants, including oils, organic solvents, arsenite ions, as well as dyes. In addition, it was demonstrated that the M-RGOs could be used as column packing materials to manufacture column for water purification by filtration. The method proposed was proved to be versatile to induce synergistic assembly of RGO sheets with other functional metal oxides nanoparticles and as a kind of broad-spectrum sorbents for removing different types of contaminants in water purification, simultaneously.

  15. Bio-Inspired Wide-Angle Broad-Spectrum Cylindrical Lens Based on Reflections from Micro-Mirror Array on a Cylindrical Elastomeric Membrane

    Directory of Open Access Journals (Sweden)

    Chi-Chieh Huang

    2014-06-01

    Full Text Available We present a wide-angle, broad-spectrum cylindrical lens based on reflections from an array of three-dimensional, high-aspect-ratio micro-mirrors fabricated on a cylindrical elastomeric substrate, functionally inspired by natural reflecting superposition compound eyes. Our device can perform one-dimensional focusing and beam-shaping comparable to conventional refraction-based cylindrical lenses, while avoiding chromatic aberration. The focal length of our cylindrical lens is 1.035 mm, suitable for micro-optical systems. Moreover, it demonstrates a wide field of view of 152° without distortion, as well as modest spherical aberrations. Our work could be applied to diverse applications including laser diode collimation, barcode scanning, holography, digital projection display, microlens arrays, and optical microscopy.

  16. Multiple copies of eukaryotic translation initiation factors in Brassica rapa facilitate redundancy, enabling diversification through variation in splicing and broad-spectrum virus resistance.

    Science.gov (United States)

    Nellist, Charlotte F; Qian, Wei; Jenner, Carol E; Moore, Jonathan D; Zhang, Shujiang; Wang, Xiaowu; Briggs, William H; Barker, Guy C; Sun, Rifei; Walsh, John A

    2014-01-01

    Recessive strain-specific resistance to a number of plant viruses in the Potyvirus genus has been found to be based on mutations in the eukaryotic translation initiation factor 4E (eIF4E) and its isoform, eIF(iso)4E. We identified three copies of eIF(iso)4E in a number of Brassica rapa lines. Here we report broad-spectrum resistance to the potyvirus Turnip mosaic virus (TuMV) due to a natural mechanism based on the mis-splicing of the eIF(iso)4E allele in some TuMV-resistant B. rapa var. pekinensis lines. Of the splice variants, the most common results in a stop codon in intron 1 and a much truncated, non-functional protein. The existence of multiple copies has enabled redundancy in the host plant's translational machinery, resulting in diversification and emergence of the resistance. Deployment of the resistance is complicated by the presence of multiple copies of the gene. Our data suggest that in the B. rapa subspecies trilocularis, TuMV appears to be able to use copies of eIF(iso)4E at two loci. Transformation of different copies of eIF(iso)4E from a resistant B. rapa line into an eIF(iso)4E knockout line of Arabidopsis thaliana proved misleading because it showed that, when expressed ectopically, TuMV could use multiple copies which was not the case in the resistant B. rapa line. The inability of TuMV to access multiple copies of eIF(iso)4E in B. rapa and the broad spectrum of the resistance suggest it may be durable. © 2013 The Authors The Plant Journal © 2013 John Wiley & Sons Ltd.

  17. Ectopic expression of MgSM1, a Cerato-platanin family protein from Magnaporthe grisea, confers broad-spectrum disease resistance in Arabidopsis.

    Science.gov (United States)

    Yang, Yayun; Zhang, Huijuan; Li, Guojun; Li, Wei; Wang, Xiao'e; Song, Fengming

    2009-10-01

    Proteins belonging to the newly identified Cerato-platanin (CP) family have been shown to have elicitor activity in inducing disease resistance responses in various plants. In this study, we characterized a gene, MgSM1, from Magnaporthe grisea, encoding a putative small protein belonging to the CP family. MgSM1 was constitutively expressed not only in different fungal growth stages but also during its infection process in rice plants. Agrobacterium-mediated transient expression of MgSM1 in Arabidopsis resulted in hypersensitive response in the infiltrated local leaves and enhanced disease resistance against Botrytis cinerea and Pseudomonas syringae pv. tomato (Pst) DC3000 in upper leaves of plants, accompanyed by up-regulated expression of defense genes (PR-1, PR-5 and PDF1.2). Transgenic Arabidopsis plants expressing MgSM1 under control of a dexamethasone (DEX)-inducible promoter were generated. Expression of MgSM1 in transgenic plants was induced by exogenous application of DEX. MgSM1-expressing plants showed normal growth with application of resistance against B. cinerea, Alternaria brassicicola and Psto DC3000 as well as up-regulated expression of some of defense genes. Moreover, accumulation of reactive oxygen species was observed in MgSM1-expressing plants. These results collectively suggest that ectopic expression of MgSM1 in transgenic plants confers broad-spectrum resistance against different types of pathogens. Our study also provides a novel strategy to generate environment-friendly crops with enhanced broad-spectrum resistance through ectopic expression of microbe-derived disease resistance-inducing proteins.

  18. Use of artificial intelligence in the design of small peptide antibiotics effective against a broad spectrum of highly antibiotic-resistant superbugs.

    Science.gov (United States)

    Cherkasov, Artem; Hilpert, Kai; Jenssen, Håvard; Fjell, Christopher D; Waldbrook, Matt; Mullaly, Sarah C; Volkmer, Rudolf; Hancock, Robert E W

    2009-01-16

    Increased multiple antibiotic resistance in the face of declining antibiotic discovery is one of society's most pressing health issues. Antimicrobial peptides represent a promising new class of antibiotics. Here we ask whether it is possible to make small broad spectrum peptides employing minimal assumptions, by capitalizing on accumulating chemical biology information. Using peptide array technology, two large random 9-amino-acid peptide libraries were iteratively created using the amino acid composition of the most active peptides. The resultant data was used together with Artificial Neural Networks, a powerful machine learning technique, to create quantitative in silico models of antibiotic activity. On the basis of random testing, these models proved remarkably effective in predicting the activity of 100,000 virtual peptides. The best peptides, representing the top quartile of predicted activities, were effective against a broad array of multidrug-resistant "Superbugs" with activities that were equal to or better than four highly used conventional antibiotics, more effective than the most advanced clinical candidate antimicrobial peptide, and protective against Staphylococcus aureus infections in animal models.

  19. The sun protection factor (SPF) inadequately defines broad spectrum photoprotection: demonstration using skin reconstructed in vitro exposed to UVA, UVBor UV-solar simulated radiation.

    Science.gov (United States)

    Bernerd, Françoise; Vioux, Corinne; Lejeune, François; Asselineau, Daniel

    2003-01-01

    Wavelength specific biological damage has been previously identified in human skin reconstructed in vitro. Sunburn cell and pyrimidine dimers were found after UVB exposure, and alterations of dermal fibroblasts after UVA exposure. These damages permitted us to discriminate UVB and UVA single absorbers. The present study shows that these biological effects can be obtained simultaneously by a combined UVB + UVA exposure using ultraviolet solar simulated light (UV-SSR), which represents a relevant UV source. In addition, the protection afforded by two broad spectrum sunscreen complex formulations was assessed after topical application. These two formulations displayed the same sun protection factor but different UVA protection factors determined by the persistent pigment darkening (PPD) method. Dose response experiments of UVA or UV-SSR showed that the preparation with the highest PF-UVA provided a better protection with regard to dermal damage compared to the other formulation. Using an original UVB source to obtain the UVB portion of SSR spectrum, the preparations provided the same protection. This study strikingly illustrates the fact that the photoprotection afforded by two sunscreen formulations having similar SPF values is not equal with regard to dermal damage related to photoaging.

  20. Broad spectrum β-lactam resistance in faecal Escherichia coli isolated from severely malnourished and nourished children attending Mbagathi district hospital, Nairobi: A case-control study

    Directory of Open Access Journals (Sweden)

    Samuel Mwangi Njoroge

    2014-01-01

    Full Text Available Context: Severely malnourished children have increased risk of being put on antibiotics due to co-morbidities. Aim: The study′s objective was to characterize the Escherichia coli β-lactamase mediated resistance to the broad spectrum β-lactam antimicrobials among this population and compare them with nourished children as controls. Settings and Design: In this case-control, hospital-based setup, 109 E. coli isolates were obtained from each group, one isolate per subject. Materials and Methods: Stool or anal swabs were collected, enriched in buffered peptone water and cultured on MacConkey and eosin methylene blue agars. Biochemical test were used to identify E. coli. antibiograms to determine phenotypic resistance were determined using a panel of 14 drugs. Only the isolates showing synergy between ampicillin-calvulanic acid and one or more third generation cephalosporins were picked as extended spectrum β-lactamase (ESBL producers. Statistical Analysis: Differences in ESBL rates and susceptibility percentages between cases and controls were evaluated for significance using 2-tailed Fisher′s exact test. Results: Prevalence of ESBL phenotype was higher in severely malnourished children (39% as compared to the controls (7%. The plasmid-encoded AmpC′s (pAmpC-like phenotype was observed in 11% isolates. Conclusions: Isolation of ESBL-E. coli among severely malnourished children is high. Surveillance of ESBL producers, both in the community and hospital settings needs to be stepped up in Kenya.

  1. Preclinical optimization of a broad-spectrum anti-bladder cancer tri-drug regimen via the Feedback System Control (FSC) platform

    Science.gov (United States)

    Liu, Qi; Zhang, Cheng; Ding, Xianting; Deng, Hui; Zhang, Daming; Cui, Wei; Xu, Hongwei; Wang, Yingwei; Xu, Wanhai; Lv, Lei; Zhang, Hongyu; He, Yinghua; Wu, Qiong; Szyf, Moshe; Ho, Chih-Ming; Zhu, Jingde

    2015-06-01

    Therapeutic outcomes of combination chemotherapy have not significantly advanced during the past decades. This has been attributed to the formidable challenges of optimizing drug combinations. Testing a matrix of all possible combinations of doses and agents in a single cell line is unfeasible due to the virtually infinite number of possibilities. We utilized the Feedback System Control (FSC) platform, a phenotype oriented approach to test 100 options among 15,625 possible combinations in four rounds of assaying to identify an optimal tri-drug combination in eight distinct chemoresistant bladder cancer cell lines. This combination killed between 82.86% and 99.52% of BCa cells, but only 47.47% of the immortalized benign bladder epithelial cells. Preclinical in vivo verification revealed its markedly enhanced anti-tumor efficacy as compared to its bi- or mono-drug components in cell line-derived tumor xenografts. The collective response of these pathways to component drugs was both cell type- and drug type specific. However, the entire spectrum of pathways triggered by the tri-drug regimen was similar in all four cancer cell lines, explaining its broad spectrum killing of BCa lines, which did not occur with its component drugs. Our findings here suggest that the FSC platform holdspromise for optimization of anti-cancer combination chemotherapy.

  2. INVESTIGATING THE COMPLEX X-RAY SPECTRUM OF A BROAD-LINE 2MASS RED QUASAR: XMM-NEWTON OBSERVATION OF FTM 0830+3759

    International Nuclear Information System (INIS)

    Piconcelli, Enrico; Nicastro, Fabrizio; Fiore, Fabrizio; Vignali, Cristian; Bianchi, Stefano; Miniutti, Giovanni

    2010-01-01

    We report results from a 50 ks XMM-Newton observation of the dust-reddened broad-line quasar FTM 0830+3759 (z = 0.413) selected from the Faint Images of the Radio Sky at Twenty cm/Two Micron All Sky Survey red quasar survey. For this active galactic nucleus (AGN), a very short 9 ks Chandra exposure had suggested a feature-rich X-ray spectrum and Hubble Space Telescope images revealed a very disturbed host galaxy morphology. Contrary to classical, optically selected quasars, the X-ray properties of red (i.e., with J - K s > 1.7 and R - K s > 4.0) broad-line quasars are still quite unexplored, although there is a growing consensus that, due to moderate obscuration, these objects can offer a unique view of spectral components typically swamped by the AGN light in normal, blue quasars. The XMM-Newton observation discussed here has definitely confirmed the complexity of the X-ray spectrum revealing the presence of a cold (or mildly ionized) absorber with N H ∼ 10 22 cm -2 along the line of sight to the nucleus and a Compton reflection component accompanied by an intense Fe Kα emission line in this quasar with a L 2-10 k eV ∼ 5 x 10 44 erg s -1 . A soft-excess component is also required by the data. The match between the column density derived by our spectral analysis and that expected on the basis of reddening due to the dust suggests the possibility that both absorptions occur in the same medium. FTM 0830+3759 is characterized by an extinction/absorption-corrected X-ray-to-optical flux ratio α ox = -2.3, which is steeper than expected on the basis of its UV luminosity. These findings indicate that the X-ray properties of FTM 0830+3759 differ from those typically observed for optically selected broad-line quasars with comparable hard X-ray luminosity.

  3. A natural component from Euphorbia humifusa Willd displays novel, broad-spectrum anti-influenza activity by blocking nuclear export of viral ribonucleoprotein

    Energy Technology Data Exchange (ETDEWEB)

    Chang, So Young; Park, Ji Hoon [Respiratory Viruses Research Laboratory, Discovery Biology Department, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400 (Korea, Republic of); Kim, Young Ho; Kang, Jong Seong [College of Pharmacy, Chungnam National University, Daejeon, 305-764 (Korea, Republic of); Min, Ji-Young, E-mail: jiyoung.min@ip-korea.org [Respiratory Viruses Research Laboratory, Discovery Biology Department, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400 (Korea, Republic of)

    2016-03-04

    The need to develop anti-influenza drugs with novel antiviral mechanisms is urgent because of the rapid rate of antigenic mutation and the emergence of drug-resistant viruses. We identified a novel anti-influenza molecule by screening 861 plant-derived natural components using a high-throughput image-based assay that measures inhibition of the influenza virus infection. 1,3,4,6-tetra-O-galloyl-β-D-glucopyranoside (TGBG) from Euphorbia humifusa Willd showed broad-spectrum anti-influenza activity against two seasonal influenza A strains, A/California/07/2009 (H1N1) and A/Perth/16/2009 (H3N2), and seasonal influenza B strain B/Florida/04/2006. We investigated the mode of action of TGBG using neuraminidase activity inhibition and time-of-addition assays, which evaluate the viral release and entry steps, respectively. We found that TGBG exhibits a novel antiviral mechanism that differs from the FDA-approved anti-influenza drugs oseltamivir which inhibits viral release, and amantadine which inhibits viral entry. Immunofluorescence assay demonstrated that TGBG significantly inhibits nuclear export of influenza nucleoproteins (NP) during the early stages of infection causing NP to accumulate in the nucleus. In addition, influenza-induced activation of the Akt signaling pathway was suppressed by TGBG in a dose-dependent manner. These data suggest that a putative mode of action of TGBG involves inhibition of viral ribonucleoprotein (vRNP) export from the nucleus to the cytoplasm consequently disrupting the assembly of progeny virions. In summary, TGBG has potential as novel anti-influenza therapeutic with a novel mechanism of action. - Highlights: • The plant-derived natural product TGBG has broad-spectrum antiviral activity against seasonal influenza A and B viruses. • TGBG has a novel anti-viral mechanism of action that from differs from the currently available anti-influenza drugs. • TGBG hinders nuclear export of the influenza virus ribonucleoprotein (v

  4. Fungal Root Microbiome from Healthy and Brittle Leaf Diseased Date Palm Trees (Phoenix dactylifera L.) Reveals a Hidden Untapped Arsenal of Antibacterial and Broad Spectrum Antifungal Secondary Metabolites

    Science.gov (United States)

    Mefteh, Fedia B.; Daoud, Amal; Chenari Bouket, Ali; Alenezi, Faizah N.; Luptakova, Lenka; Rateb, Mostafa E.; Kadri, Adel; Gharsallah, Neji; Belbahri, Lassaad

    2017-01-01

    In this study, we aimed to explore and compare the composition, metabolic diversity and antimicrobial potential of endophytic fungi colonizing internal tissues of healthy and brittle leaf diseased (BLD) date palm trees (Phoenix dactylifera L.) widely cultivated in arid zones of Tunisia. A total of 52 endophytic fungi were isolated from healthy and BLD roots of date palm trees, identified based on internal transcribed spacer-rDNA sequence analysis and shown to represent 13 species belonging to five genera. About 36.8% of isolates were shared between healthy and diseased root fungal microbiomes, whereas 18.4 and 44.7% of isolates were specific to healthy and BLD root fungal microbiomes, respectively. All isolates were able to produce at least two of the screened enzymes including amylase, cellulase, chitinase, pectinase, protease, laccase and lipase. A preliminary screening of the isolates using disk diffusion method for antibacterial activity against four Gram-positive and three Gram-negative bacteria and antifungal activities against three phytopathogenic fungi indicated that healthy and BLD root fungal microbiomes displayed interesting bioactivities against examined bacteria and broad spectrum bioactivity against fungal pathogens. Some of these endophytic fungi (17 isolates) were fermented and their extracts were evaluated for antimicrobial potential against bacterial and fungal isolates. Results revealed that fungal extracts exhibited antibacterial activities and were responsible for approximately half of antifungal activities against living fungi. These results suggest a strong link between fungal bioactivities and their secondary metabolite arsenal. EtOAc extracts of Geotrichum candidum and Thielaviopsis punctulata originating from BLD microbiome gave best results against Micrococcus luteus and Bacillus subtilis with minimum inhibitory concentration (MIC, 0.78 mg/mL) and minimum bactericidal concentration (6.25 mg/mL). G. candidum gave the best result against

  5. Efficacy of Oral E1210, a New Broad-Spectrum Antifungal with a Novel Mechanism of Action, in Murine Models of Candidiasis, Aspergillosis, and Fusariosis▿

    Science.gov (United States)

    Hata, Katsura; Horii, Takaaki; Miyazaki, Mamiko; Watanabe, Nao-aki; Okubo, Miyuki; Sonoda, Jiro; Nakamoto, Kazutaka; Tanaka, Keigo; Shirotori, Syuji; Murai, Norio; Inoue, Satoshi; Matsukura, Masayuki; Abe, Shinya; Yoshimatsu, Kentaro; Asada, Makoto

    2011-01-01

    E1210 is a first-in-class, broad-spectrum antifungal with a novel mechanism of action—inhibition of fungal glycosylphosphatidylinositol biosynthesis. In this study, the efficacies of E1210 and reference antifungals were evaluated in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. Oral E1210 demonstrated dose-dependent efficacy in infections caused by Candida species, Aspergillus spp., and Fusarium solani. In the treatment of oropharyngeal candidiasis, E1210 and fluconazole each caused a significantly greater reduction in the number of oral CFU than the control treatment (P candidiasis model, mice treated with E1210, fluconazole, caspofungin, or liposomal amphotericin B showed significantly higher survival rates than the control mice (P candidiasis caused by azole-resistant Candida albicans or Candida tropicalis. A 24-h delay in treatment onset minimally affected the efficacy outcome of E1210 in the treatment of disseminated candidiasis. In the Aspergillus flavus pulmonary aspergillosis model, mice treated with E1210, voriconazole, or caspofungin showed significantly higher survival rates than the control mice (P candidiasis, pulmonary aspergillosis, and disseminated fusariosis. These data suggest that further studies to determine E1210's potential for the treatment of disseminated fungal infections are indicated. PMID:21788462

  6. Efficacy of oral E1210, a new broad-spectrum antifungal with a novel mechanism of action, in murine models of candidiasis, aspergillosis, and fusariosis.

    Science.gov (United States)

    Hata, Katsura; Horii, Takaaki; Miyazaki, Mamiko; Watanabe, Nao-Aki; Okubo, Miyuki; Sonoda, Jiro; Nakamoto, Kazutaka; Tanaka, Keigo; Shirotori, Syuji; Murai, Norio; Inoue, Satoshi; Matsukura, Masayuki; Abe, Shinya; Yoshimatsu, Kentaro; Asada, Makoto

    2011-10-01

    E1210 is a first-in-class, broad-spectrum antifungal with a novel mechanism of action-inhibition of fungal glycosylphosphatidylinositol biosynthesis. In this study, the efficacies of E1210 and reference antifungals were evaluated in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. Oral E1210 demonstrated dose-dependent efficacy in infections caused by Candida species, Aspergillus spp., and Fusarium solani. In the treatment of oropharyngeal candidiasis, E1210 and fluconazole each caused a significantly greater reduction in the number of oral CFU than the control treatment (P candidiasis model, mice treated with E1210, fluconazole, caspofungin, or liposomal amphotericin B showed significantly higher survival rates than the control mice (P candidiasis caused by azole-resistant Candida albicans or Candida tropicalis. A 24-h delay in treatment onset minimally affected the efficacy outcome of E1210 in the treatment of disseminated candidiasis. In the Aspergillus flavus pulmonary aspergillosis model, mice treated with E1210, voriconazole, or caspofungin showed significantly higher survival rates than the control mice (P candidiasis, pulmonary aspergillosis, and disseminated fusariosis. These data suggest that further studies to determine E1210's potential for the treatment of disseminated fungal infections are indicated.

  7. Oldest human occupation of Wallacea at Laili Cave, Timor-Leste, shows broad-spectrum foraging responses to late Pleistocene environments

    Science.gov (United States)

    Hawkins, Stuart; O'Connor, Sue; Maloney, Tim Ryan; Litster, Mirani; Kealy, Shimona; Fenner, Jack N.; Aplin, Ken; Boulanger, Clara; Brockwell, Sally; Willan, Richard; Piotto, Elena; Louys, Julien

    2017-09-01

    The Wallacea Archipelago provides an extraordinary laboratory for the study of human colonisation and adaptation, yet few detailed archaeological studies have been conducted in the region that span the earliest phase of human settlement. Laili Cave, in northern Timor-Leste, preserves the oldest human occupation in this insular region with a cultural sequence spanning 11,200 to 44,600 cal BP. Small-bodied vertebrates and invertebrates were recovered to the lowest excavated levels, associated with highly concentrated stone artefacts. We report on human behavioural adaptations within the context of Pleistocene environments and changing landscapes using zooarchaeological, stone artefact, bathymetric, and experimental isotopic analyses. Results indicate that Pleistocene humans used the abundant local chert liberally and engaged in mobile broad-spectrum exploitation of invertebrates and fishes from marine, estuarine, and freshwater environments within close proximity of Laili Cave. The faunal assemblage indicates heterogeneous but relatively stable environments during the late Pleistocene. Variability in subsistence strategies over time appears to be a response to changing landscapes and concomitant local resources. This record contrasts with marine specialisations evident from other sites in Timor-Leste and within the broader Wallacean region.

  8. Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model.

    Science.gov (United States)

    Julander, Justin G; Siddharthan, Venkatraman; Evans, Joe; Taylor, Ray; Tolbert, Kelsey; Apuli, Chad; Stewart, Jason; Collins, Preston; Gebre, Makda; Neilson, Skot; Van Wettere, Arnaud; Lee, Young-Min; Sheridan, William P; Morrey, John D; Babu, Y S

    2017-01-01

    Zika virus (ZIKV) is currently undergoing pandemic emergence. While disease is typically subclinical, severe neurologic manifestations in fetuses and newborns after congenital infection underscore an urgent need for antiviral interventions. The adenosine analog BCX4430 has broad-spectrum activity against a wide range of RNA viruses, including potent in vivo activity against yellow fever, Marburg and Ebola viruses. We tested this compound against African and Asian lineage ZIKV in cytopathic effect inhibition and virus yield reduction assays in various cell lines. To further evaluate the efficacy in a relevant animal model, we developed a mouse model of severe ZIKV infection, which recapitulates various human disease manifestations including peripheral virus replication, conjunctivitis, encephalitis and myelitis. Time-course quantification of viral RNA accumulation demonstrated robust viral replication in several relevant tissues, including high and persistent viral loads observed in the brain and testis. The presence of viral RNA in various tissues was confirmed by an infectious culture assay as well as immunohistochemical staining of tissue sections. Treatment of ZIKV-infected mice with BCX4430 significantly improved outcome even when treatment was initiated during the peak of viremia. The demonstration of potent activity of BCX4430 against ZIKV in a lethal mouse model warrant its continued clinical development. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Varespladib (LY315920 Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation

    Directory of Open Access Journals (Sweden)

    Matthew Lewin

    2016-08-01

    Full Text Available Snakebite remains a neglected medical problem of the developing world with up to 125,000 deaths each year despite more than a century of calls to improve snakebite prevention and care. An estimated 75% of fatalities from snakebite occur outside the hospital setting. Because phospholipase A2 (PLA2 activity is an important component of venom toxicity, we sought candidate PLA2 inhibitors by directly testing drugs. Surprisingly, varespladib and its orally bioavailable prodrug, methyl-varespladib showed high-level secretory PLA2 (sPLA2 inhibition at nanomolar and picomolar concentrations against 28 medically important snake venoms from six continents. In vivo proof-of-concept studies with varespladib had striking survival benefit against lethal doses of Micrurus fulvius and Vipera berus venom, and suppressed venom-induced sPLA2 activity in rats challenged with 100% lethal doses of M. fulvius venom. Rapid development and deployment of a broad-spectrum PLA2 inhibitor alone or in combination with other small molecule inhibitors of snake toxins (e.g., metalloproteases could fill the critical therapeutic gap spanning pre-referral and hospital setting. Lower barriers for clinical testing of safety tested, repurposed small molecule therapeutics are a potentially economical and effective path forward to fill the pre-referral gap in the setting of snakebite.

  10. 9-Deazapurines as Broad-Spectrum Inhibitors of the ABC Transport Proteins P-Glycoprotein, Multidrug Resistance-Associated Protein 1, and Breast Cancer Resistance Protein.

    Science.gov (United States)

    Stefan, Katja; Schmitt, Sven Marcel; Wiese, Michael

    2017-11-09

    P-Glycoprotein (P-gp, ABCB1), multidrug resistance-associated protein 1 (MRP1, ABCC1), and breast cancer resistance protein (BCRP, ABCG2) are the three major ABC transport proteins conferring resistance to many structurally diverse anticancer agents, leading to the phenomenon called multidrug resistance (MDR). Much effort has been put into the development of clinically useful compounds to reverse MDR. Broad-spectrum inhibitors of ABC transport proteins can be of great use in cancers that simultaneously coexpress two or three transporters. In this work, we continued our effort to generate new, potent, nontoxic, and multiply effective inhibitors of the three major ABC transporters. The best compound was active in a very low micromolar concentration range against all three transporters and restored sensitivity toward daunorubicin (P-gp and MRP1) and SN-38 (BCRP) in A2780/ADR (P-gp), H69AR (MRP1), and MDCK II BCRP (BCRP) cells. Additionally, the compound is a noncompetitive inhibitor of daunorubicin (MRP1), calcein AM (P-gp), and pheophorbide A (BCRP) transport.

  11. Phosphatase Inhibitors Function as Novel, Broad Spectrum Botulinum Neurotoxin Antagonists in Mouse and Human Embryonic Stem Cell-Derived Motor Neuron-Based Assays.

    Science.gov (United States)

    Kiris, Erkan; Nuss, Jonathan E; Stanford, Stephanie M; Wanner, Laura M; Cazares, Lisa; Maestre, Michael F; Du, Hao T; Gomba, Glenn Y; Burnett, James C; Gussio, Rick; Bottini, Nunzio; Panchal, Rekha G; Kane, Christopher D; Tessarollo, Lino; Bavari, Sina

    2015-01-01

    There is an urgent need to develop novel treatments to counter Botulinum neurotoxin (BoNT) poisoning. Currently, the majority of BoNT drug development efforts focus on directly inhibiting the proteolytic components of BoNT, i.e. light chains (LC). Although this is a rational approach, previous research has shown that LCs are extremely difficult drug targets and that inhibiting multi-serotype BoNTs with a single LC inhibitor may not be feasible. An alternative approach would target neuronal pathways involved in intoxication/recovery, rather than the LC itself. Phosphorylation-related mechanisms have been implicated in the intoxication pathway(s) of BoNTs. However, the effects of phosphatase inhibitors upon BoNT activity in the physiological target of BoNTs, i.e. motor neurons, have not been investigated. In this study, a small library of phosphatase inhibitors was screened for BoNT antagonism in the context of mouse embryonic stem cell-derived motor neurons (ES-MNs). Four inhibitors were found to function as BoNT/A antagonists. Subsequently, we confirmed that these inhibitors protect against BoNT/A in a dose-dependent manner in human ES-MNs. Additionally, these compounds provide protection when administered in post-intoxication scenario. Importantly, the inhibitors were also effective against BoNT serotypes B and E. To the best of our knowledge, this is the first study showing phosphatase inhibitors as broad-spectrum BoNT antagonists.

  12. A PKS/NRPS/FAS hybrid gene cluster from Serratia plymuthica RVH1 encoding the biosynthesis of three broad spectrum, zeamine-related antibiotics.

    Science.gov (United States)

    Masschelein, Joleen; Mattheus, Wesley; Gao, Ling-Jie; Moons, Pieter; Van Houdt, Rob; Uytterhoeven, Birgit; Lamberigts, Chris; Lescrinier, Eveline; Rozenski, Jef; Herdewijn, Piet; Aertsen, Abram; Michiels, Chris; Lavigne, Rob

    2013-01-01

    Serratia plymuthica strain RVH1, initially isolated from an industrial food processing environment, displays potent antimicrobial activity towards a broad spectrum of Gram-positive and Gram-negative bacterial pathogens. Isolation and subsequent structure determination of bioactive molecules led to the identification of two polyamino antibiotics with the same molecular structure as zeamine and zeamine II as well as a third, closely related analogue, designated zeamine I. The gene cluster encoding the biosynthesis of the zeamine antibiotics was cloned and sequenced and shown to encode FAS, PKS as well as NRPS related enzymes in addition to putative tailoring and export enzymes. Interestingly, several genes show strong homology to the pfa cluster of genes involved in the biosynthesis of long chain polyunsaturated fatty acids in marine bacteria. We postulate that a mixed FAS/PKS and a hybrid NRPS/PKS assembly line each synthesize parts of the backbone that are linked together post-assembly in the case of zeamine and zeamine I. This interaction reflects a unique interplay between secondary lipid and secondary metabolite biosynthesis. Most likely, the zeamine antibiotics are produced as prodrugs that undergo activation in which a nonribosomal peptide sequence is cleaved off.

  13. A PKS/NRPS/FAS hybrid gene cluster from Serratia plymuthica RVH1 encoding the biosynthesis of three broad spectrum, zeamine-related antibiotics.

    Directory of Open Access Journals (Sweden)

    Joleen Masschelein

    Full Text Available Serratia plymuthica strain RVH1, initially isolated from an industrial food processing environment, displays potent antimicrobial activity towards a broad spectrum of Gram-positive and Gram-negative bacterial pathogens. Isolation and subsequent structure determination of bioactive molecules led to the identification of two polyamino antibiotics with the same molecular structure as zeamine and zeamine II as well as a third, closely related analogue, designated zeamine I. The gene cluster encoding the biosynthesis of the zeamine antibiotics was cloned and sequenced and shown to encode FAS, PKS as well as NRPS related enzymes in addition to putative tailoring and export enzymes. Interestingly, several genes show strong homology to the pfa cluster of genes involved in the biosynthesis of long chain polyunsaturated fatty acids in marine bacteria. We postulate that a mixed FAS/PKS and a hybrid NRPS/PKS assembly line each synthesize parts of the backbone that are linked together post-assembly in the case of zeamine and zeamine I. This interaction reflects a unique interplay between secondary lipid and secondary metabolite biosynthesis. Most likely, the zeamine antibiotics are produced as prodrugs that undergo activation in which a nonribosomal peptide sequence is cleaved off.

  14. Broad-range TRP channel inhibitors (2-APB, flufenamic acid, SKF-96365) affect differently contraction of resistance and conduit femoral arteries of rat

    Czech Academy of Sciences Publication Activity Database

    Bencze, Michal; Behuliak, Michal; Vavřínová, Anna; Zicha, Josef

    2015-01-01

    Roč. 765, Oct 15 (2015), s. 533-540 ISSN 0014-2999 R&D Projects: GA ČR(CZ) GAP304/12/0259 Institutional support: RVO:67985823 Keywords : femoral artery * TRP channel * 2-APB * flufenamic acid * SKF-96365 * vascular contraction Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 2.730, year: 2015

  15. Efficacy of broad-spectrum sunscreens against the suppression of elicitation of delayed-type hypersensitivity responses in humans depends on the level of ultraviolet A protection.

    Science.gov (United States)

    Moyal, D D; Fourtanier, A M

    2003-04-01

    Sunscreens have been designed to protect against sunburn and their efficacy has, therefore, been labeled by the so-called sun protection factor (SPF). Although this value is well determined using a standardized protocol and it affords a good evaluation of the protection against erythema it may be inadequate to provide a relevant measurement of efficacy against other biologic damages. This is particularly true when action spectra and threshold dose are different from those of erythema. In the case of ultraviolet (UV)-induced immune suppression, the action spectrum is not known, so it cannot be asserted that SPF may accurately predict the level of protection against this endpoint. We addressed this issue by measuring in human volunteers the ability of two broad-spectrum SPF 15 sunscreens with different ultraviolet A (UVA) protection levels, to prevent the alteration of the efferent phase of the local delayed-type hypersensitivity (DTH) response to recall antigens (Multitest Pasteur/Mérieux, Lyon, France) after acute solar-simulated UV exposure. We first determined the ultraviolet radiation (UVR) dose needed to induce a significant DTH inhibition in several groups of 15 volunteers. Two minimal erythemal doses (2 MED) were found to be the minimal immunosuppressive dose (MISD). As a result, the immune DTH response is reduced in average by 36%. The lower doses tested (0.5 and 1 MED) were ineffective. Sunscreen-treated groups were exposed to either 1 or 2 MED x SPF doses. As expected, no alteration in DTH response was observed in the groups exposed to 1 MED x SPF whatever the sunscreen applied. In contrast, after exposure to 2 MED x SPF, the DTH response remained unaltered in the group pretreated with the sunscreen product with the higher protection in the UVA range but was significantly suppressed by 55.7% in the group pretreated with sunscreen with a much lower protection in the UVA range. These data suggest that SPF may not be sufficient to predict the ability of

  16. Accelerated molecular breeding of a novel P/TGMS line with broad-spectrum resistance to rice blast and bacterial blight in two-line hybrid rice.

    Science.gov (United States)

    Mi, Jiaming; Yang, Dabing; Chen, Yi; Jiang, Jiefeng; Mou, Haipeng; Huang, Junbin; Ouyang, Yidan; Mou, Tongmin

    2018-02-17

    Breeding two-line hybrid rice with disease resistance is an effective approach to stabilize rice yield in commercial rice production of China. We improved the blast and bacterial blight resistance of Guangzhan63-4S, an elite photoperiod- and thermo-sensitive male sterile (P/TGMS) line widely used in two-line hybrid rice, by introducing the R genes Pi2 and Xa7 conferring resistance to rice blast and bacterial blight, respectively. Through the backcrossing and gene pyramiding breeding coupled with molecular marker-assisted selection, a new P/TGMS line Hua1228S carrying Pi2, Xa7, and tms5 was developed. Based on 200,000 SNP markers by next-generation sequencing, Hua1228S covered 87.6% of the recurrent genome, as well as 4.5% of the donor genome from VE6219 and 7.9% from YR7029-39. When infected with seven tested Xanthomonas oryzae pv. oryzae strains, Hua1228S conferred high resistance (0 level) to six bacterial blight strains. Moreover, Hua1228S showed broad-spectrum resistance to rice blast isolates with a high resistance frequency of 90.91%. High levels of resistance to leaf blast and neck blast were observed under heavy disease pressure in natural field. Importantly, Hua1228S showed identical fertility-sterility alteration pattern to Guangzhan63-4S. Thus, two hybrid combinations Hua Liangyou 2821 and Hua Liangyou 284 derived from Hua1228S exhibited enhanced resistance and higher yield compared with the control variety Feng Liangyou 4. These results indicate that Hua1228S has tremendous potentiality to increase and stabilize the rice yield, through the introgression of two R genes by marker-assisted selection strategy.

  17. Microbiota Disruption Induced by Early Use of Broad-Spectrum Antibiotics Is an Independent Risk Factor of Outcome after Allogeneic Stem Cell Transplantation.

    Science.gov (United States)

    Weber, Daniela; Jenq, Robert R; Peled, Jonathan U; Taur, Ying; Hiergeist, Andreas; Koestler, Josef; Dettmer, Katja; Weber, Markus; Wolff, Daniel; Hahn, Joachim; Pamer, Eric G; Herr, Wolfgang; Gessner, André; Oefner, Peter J; van den Brink, Marcel R M; Holler, Ernst

    2017-05-01

    In allogeneic stem cell transplantation (ASCT), systemic broad-spectrum antibiotics are frequently used for treatment of infectious complications, but their effect on microbiota composition is still poorly understood. This retrospective analysis of 621 patients who underwent ASCT at the University Medical Center of Regensburg and Memorial Sloan Kettering Cancer Center in New York assessed the impact of timing of peritransplant antibiotic treatment on intestinal microbiota composition as well as transplant-related mortality (TRM) and overall survival. Early exposure to antibiotics was associated with lower urinary 3-indoxyl sulfate levels (P antibiotic treatment, which was particularly significant (P = .005) for Clostridium cluster XIVa in the Regensburg group. Earlier antibiotic treatment before ASCT was further associated with a higher TRM (34%, 79/236) compared with post-ASCT (21%, 62/297, P = .001) or no antibiotics (7%, 6/88, P antibiotic treatment was the dominant independent risk factor for TRM (HR, 2.0; P ≤ .001) in multivariate analysis besides increase age (HR, 2.15; P = .004), reduced Karnofsky performance status (HR, 1.47; P = .03), and female donor-male recipient sex combination (HR, 1.56; P = .02) A competing risk analysis revealed the independent effect of early initiation of antibiotics on graft-versus-host disease-related TRM (P = .004) in contrast to infection-related TRM and relapse (not significant). The poor outcome associated with early administration of antibiotic therapy that is active against commensal organisms, and specifically the possibly protective Clostridiales, calls for the use of Clostridiales-sparing antibiotics and rapid restoration of microbiota diversity after cessation of antibiotic treatment. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  18. Decreased Resistance to Broad-Spectrum Cephalosporin in Escherichia coli from Healthy Broilers at Farms in Japan After Voluntary Withdrawal of Ceftiofur.

    Science.gov (United States)

    Hiki, Mototaka; Kawanishi, Michiko; Abo, Hitoshi; Kojima, Akemi; Koike, Ryoji; Hamamoto, Shuichi; Asai, Tetsuo

    2015-07-01

    The high prevalence of broad-spectrum cephalosporin (BSC) resistance in Escherichia coli isolates from healthy broilers at farms is a source of grave concern in Japan. In an effort to solve this problem, the off-label use of ceftiofur (CTF) at hatcheries was voluntarily withdrawn around March 2012. The objective of this study was to assess the effect of the voluntary withdrawal on the prevalence of BSC resistance in E. coli from healthy broilers at farms. A total of 693 E. coli isolates collected from 362 fecal samples of healthy broilers at farms between 2010 and 2013 were examined to determine their antimicrobial resistance profiles and β-lactamase genes. β-Lactamase genes were characterized by polymerase chain reaction and sequencing. BSC resistance was detected in 84 of the 693 E. coli isolates (12.1%) from healthy broilers between 2010 and 2013. The percentage of BSC-resistant E. coli isolates was significantly decreased: from 16.4% (32/195) in 2010 and 16.8% (27/161) in 2011 to 9.2% (19/206) in 2012 and 4.6% (6/131) in 2013 (2010 versus 2012: p=0.024, 2010 versus 2013: p=0.001, 2011 versus 2012: p=0.038, and 2011 versus 2013: p=0.001). Regarding ß-lactamase genes, 58 of the 84 BSC-resistant E. coli isolates (69.0%) harbored blaCMY-2. The prevalence of BSC resistance in E. coli isolated from healthy broilers at farms was markedly decreased within a year after the voluntary withdrawal from CTF use at hatcheries. This indicates that BSC resistance in E. coli isolates from broilers could be controlled by restricting the use of CTF at the hatchery level.

  19. Phosphatase Inhibitors Function as Novel, Broad Spectrum Botulinum Neurotoxin Antagonists in Mouse and Human Embryonic Stem Cell-Derived Motor Neuron-Based Assays.

    Directory of Open Access Journals (Sweden)

    Erkan Kiris

    Full Text Available There is an urgent need to develop novel treatments to counter Botulinum neurotoxin (BoNT poisoning. Currently, the majority of BoNT drug development efforts focus on directly inhibiting the proteolytic components of BoNT, i.e. light chains (LC. Although this is a rational approach, previous research has shown that LCs are extremely difficult drug targets and that inhibiting multi-serotype BoNTs with a single LC inhibitor may not be feasible. An alternative approach would target neuronal pathways involved in intoxication/recovery, rather than the LC itself. Phosphorylation-related mechanisms have been implicated in the intoxication pathway(s of BoNTs. However, the effects of phosphatase inhibitors upon BoNT activity in the physiological target of BoNTs, i.e. motor neurons, have not been investigated. In this study, a small library of phosphatase inhibitors was screened for BoNT antagonism in the context of mouse embryonic stem cell-derived motor neurons (ES-MNs. Four inhibitors were found to function as BoNT/A antagonists. Subsequently, we confirmed that these inhibitors protect against BoNT/A in a dose-dependent manner in human ES-MNs. Additionally, these compounds provide protection when administered in post-intoxication scenario. Importantly, the inhibitors were also effective against BoNT serotypes B and E. To the best of our knowledge, this is the first study showing phosphatase inhibitors as broad-spectrum BoNT antagonists.

  20. Wheezing and asthma may be enhanced by broad spectrum antibiotics used in early childhood. Concept and results of a pharmacoepidemiology study.

    Science.gov (United States)

    Jedrychowski, W; Perera, F; Maugeri, U; Mroz, E; Flak, E; Perzanowski, M; Majewska, R

    2011-04-01

    One of the mechanisms supposed to explain the increasing prevalence of asthma, among children in particular, is the use of antibiotics because they may modify natural microbial exposure and development of the immune system in early childhood. The aim of this study is to investigate the association between the use of various classes of antibiotics (penicillin, cephalosporin and macrolide derivatives) in early childhood and the medical diagnosis of asthma or wheezing reported by mothers over the follow-up after adjustment for potential confounders and respiratory infections. In a population-based sample of 5-year-olds, a part of the ongoing birth cohort study, the standardized interviews on health outcomes, potential confounders (child's gender, maternal atopy, parity, prenatal and postnatal environmental tobacco smoke) and the use of antibiotics were gathered from mothers of 310 children. While the overall use of antibiotics during the early childhood was insignificantly associated with asthma (adjusted OR = 1.65, 95%CI: 0.93 - 2.93), the risk estimates were significant both for macrolide antibiotics (adjusted OR=2.14, 95%CI: 1.16-3.95) and cephalosporins (OR=1.98, 95%CI: 1.14-3.37). The significant excess in IRR (incident risk ratio) of wheezing episodes was related only to the use of macrolide antibiotics (adjusted IRR=1.91, 95%CI: 1.12-3.27). The use of other classes of antibiotics was found not to be associated with the medical diagnosis of asthma or wheezing episodes recorded in the study period. as early childhood use of broad spectrum antibiotics is associated with an increased risk of developing asthma in 5-year-olds, it may be hypothesized that the antibiotic- related suppression of allergic inflammatory responses in the course of treatment may later lead to greater than before atopic immune response in Th2 children or an impairment of Th1 immune responses in early childhood.

  1. Pentocin MQ1: A Novel, Broad-Spectrum, Pore-Forming Bacteriocin From Lactobacillus pentosus CS2 With Quorum Sensing Regulatory Mechanism and Biopreservative Potential

    Directory of Open Access Journals (Sweden)

    Samson B. Wayah

    2018-03-01

    Full Text Available Micrococcus luteus, Listeria monocytogenes, and Bacillus cereus are major food-borne pathogenic and spoilage bacteria. Emergence of antibiotic resistance and consumer demand for foods containing less of chemical preservatives led to a search for natural antimicrobials. A study aimed at characterizing, investigating the mechanism of action and regulation of biosynthesis and evaluating the biopreservative potential of pentocin from Lactobacillus pentosus CS2 was conducted. Pentocin MQ1 is a novel bacteriocin isolated from L. pentosus CS2 of coconut shake origin. The purification strategy involved adsorption-desorption of bacteriocin followed by RP-HPLC. It has a molecular weight of 2110.672 Da as determined by MALDI-TOF mass spectrometry and a molar extinction value of 298.82 M−1 cm−1. Pentocin MQ1 is not plasmid-borne and its biosynthesis is regulated by a quorum sensing mechanism. It has a broad spectrum of antibacterial activity, exhibited high chemical, thermal and pH stability but proved sensitive to proteolytic enzymes. It is potent against M. luteus, B. cereus, and L. monocytogenes at micromolar concentrations. It is quick-acting and exhibited a bactericidal mode of action against its targets. Target killing was mediated by pore formation. We report for the first time membrane permeabilization as a mechanism of action of the pentocin from the study against Gram-positive bacteria. Pentocin MQ1 is a cell wall-associated bacteriocin. Application of pentocin MQ1 improved the microbiological quality and extended the shelf life of fresh banana. This is the first report on the biopreservation of banana using bacteriocin. These findings place pentocin MQ1 as a potential biopreservative for further evaluation in food and medical applications.

  2. Synthesis, Characterization, and In Vitro and In Vivo Evaluations of 4-(N-Docosahexaenoyl 2′, 2′-Difluorodeoxycytidine with Potent and Broad-Spectrum Antitumor Activity

    Directory of Open Access Journals (Sweden)

    Youssef W. Naguib

    2016-01-01

    Full Text Available In this study, a new compound, 4-(N-docosahexaenoyl 2′, 2′-difluorodeoxycytidine (DHA-dFdC, was synthesized and characterized. Its antitumor activity was evaluated in cell culture and in mouse models of pancreatic cancer. DHA-dFdC is a poorly soluble, pale yellow waxy solid, with a molecular mass of 573.3 Da and a melting point of about 96°C. The activation energy for the degradation of DHA-dFdC in an aqueous Tween 80–based solution is 12.86 kcal/mol, whereas its stability is significantly higher in the presence of vitamin E. NCI-60 DTP Human Tumor Cell Line Screening revealed that DHA-dFdC has potent and broad-spectrum antitumor activity, especially in leukemia, renal, and central nervous system cancer cell lines. In human and murine pancreatic cancer cell lines, the IC50 value of DHA-dFdC was up to 105-fold lower than that of dFdC. The elimination of DHA-dFdC in mouse plasma appeared to follow a biexponential model, with a terminal phase t1/2 of about 58 minutes. DHA-dFdC significantly extended the survival of genetically engineered mice that spontaneously develop pancreatic ductal adenocarcinoma. In nude mice with subcutaneously implanted human Panc-1 pancreatic tumors, the antitumor activity of DHA-dFdC was significantly stronger than the molar equivalent of dFdC alone, DHA alone, or the physical mixture of them (1:1, molar ratio. DHA-dFdC also significantly inhibited the growth of Panc-1 tumors orthotopically implanted in the pancreas of nude mice, whereas the molar equivalent dose of dFdC alone did not show any significant activity. DHA-dFdC is a promising compound for the potential treatment of cancers in organs such as the pancreas.

  3. Discovery and cellular stress pathway analysis of 1,4-naphthoquinone derivatives with novel, highly potent broad-spectrum anticancer activity.

    Science.gov (United States)

    Ghosh, Sajal K; Ganta, Abhishek; Spanjaard, Remco A

    2018-02-08

    Chemotherapy and targeted therapies have made important strides in cancer treatment yet they often fail and new therapies are still needed. Here, we employed a phenotypic screen to identify and analyze the mechanism of action of novel small molecules that interfere with critical pathways involved in tumor cell growth, using chemoresistant A375 melanoma cells as a model. Cell culture studies were performed in ATCC-recommended media. Compounds, and compound libraries were obtained from Boston University or purchased commercially. Effects on A375 cell viability, proliferation and morphology were determined by Celigo Image Cytometer and viability staining. Anticancer activity of the lead compound was tested in a xenograft nude mouse model. Signaling and cell death pathways were analyzed by SDS-PAGE and immunoblotting, and/or fluorescence microscopy. After evaluating 4477 compounds, one hit compound CB533 was identified that caused significant reduction of A375 cell growth. CB533 is an unexplored 1,4-naphthoquinone (NQ) derivative which unlike 1,4-NQ, induced rapid cell death without generating reactive oxygen species (ROS). Structure-activity relationship analysis showed that a pyrrolidine in the 1,4-NQ nucleus in lead compound Pyr-1 yielded optimal activity. CB533 and Pyr-1 had growth-suppressing effects on a large variety of chemotherapy-resistant cancer cell lines in the nano to picomolar range. Pyr-1 also significantly reduced growth of MDA-MB-231 breast cancer cells in nude mice. Pyr-1 rapidly induced activation of major stress pathways and autophagy, which was efficiently blocked by ERK, and somewhat by PI3K inhibitors. CB533 and lead Pyr-1 represent novel broad-spectrum, anticancer compounds that are up to 1000-fold more potent than plumbagin, a natural 1,4-NQ with known anticancer activity. Since the growth suppression activities of CB533 and Pyr-1 are unaffected by the chemotherapy resistance of cancer cells, these compounds have promising therapeutic

  4. Diversity of plasmid replicons encoding the bla(CMY-2) gene in broad-spectrum cephalosporin-resistant Escherichia coli from livestock animals in Japan.

    Science.gov (United States)

    Hiki, Mototaka; Usui, Masaru; Kojima, Akemi; Ozawa, Manao; Ishii, Yoshikazu; Asai, Tetsuo

    2013-03-01

    Broad-spectrum cephalosporin (BSC) resistance has increased in Escherichia coli isolates from broiler chickens in Japan since 2004. The purpose of this study was to understand the epidemiology of BSC-resistant E. coli in livestock animals. Among 3274 E. coli isolates from 1767 feces of apparently healthy animals on 1767 farms between 2004 and 2009, 118 ceftiofur (CTF)-resistant isolates (CTF MIC ≥4 μg/mL) were identified on 74 farms. After elimination of apparently clonal isolates from a single animal, 75 selected CTF-resistant isolates (62 isolates from 61 broiler chickens, 10 isolates from 10 layer chickens, two isolates from two cows, and one isolate from a pig) were characterized. The bla(CMY-2) gene was most frequently detected in 50 isolates, followed by bla(CTX-M) (CTX-M-2: six isolates; CTX-M-14: four isolates; CTX-M-25: two isolates; CTX-M-1: one isolate) and bla(SHV) (SHV-12: seven isolates; SHV-2, SHV-2a, SHV-5: one isolate each). In particular, 42 of 62 broiler chicken isolates harbored bla(CMY-2). Pulsed-field gel electrophoresis analyses using XbaI revealed divergent profiles among the BSC-resistant isolates. The incompatibility groups of bla(CMY-2) plasmids from 34 of the 42 broiler chicken isolates belonged to IncIγ (10 isolates), IncA/C (nine isolates), IncB/O (seven isolates) and IncI1 (six isolates), or were nontypeable (two isolates). Co-transmission of resistance to non-β-lactam antibiotics was observed in transconjugants with IncA/C plasmids, but not with IncI1, IncIγ, and IncB/O plasmids except for one isolate with IncB/O. Our findings suggest that the bla(CMY-2) gene is a key player in BSC-resistant E. coli isolates and that coselection is unlikely to be associated with the abundance of bla(CMY-2) plasmids, except for IncA/C plasmids.

  5. Resolution 679/013 Resolution 679/013 ANCAP is authorized to direct contracting with the firm Spectrum Geo Inc. for the performance of a contract for the implementation, marketing and revenue sharing program for the acquisition and processing of 2D seismic data in the offshore Uruguay between ANCAP and Spectrum, nonexclusive multi client

    International Nuclear Information System (INIS)

    2013-01-01

    The National Administration Portland Alchool and Fuels from Uruguay in the hydrocarbon researching signed a direct contracting with the firm Spectrum GEO Inc. with the aim to provide regional 2D seismic data in shallow, deep and ultra deep offshore waters of Uruguay, in order to delineate more leads and illuminating detail the prospects that lie in footage from the early Cretaceous (3 to 8 seconds TWT) to tertiary (1-4 sec)

  6. Comparison of a Broad-Based Screen versus Disorder-Specific Screen in Detecting Young Children with an Autism Spectrum Disorder

    Science.gov (United States)

    Wiggins, Lisa D; Piazza, Vivian; Robins, Diana L

    2014-01-01

    The goals of our study were to (a) compare agreement between autism spectrum disorder diagnosis and outcome of the Modified Checklist for Autism in Toddlers and Parents Evaluation of Developmental Status in a sample of toddlers and (b) examine specific concerns noted for toddlers who screened negative on the Modified Checklist for Autism in…

  7. On the use of continuous spectrum and discrete-mode differential models to predict contraction-flow pressure drops for Boger fluids

    Science.gov (United States)

    López-Aguilar, J. E.; Webster, M. F.; Tamaddon-Jahromi, H. R.; Manero, O.; Binding, D. M.; Walters, K.

    2017-12-01

    Over recent years, there has been slow but steady progress towards the qualitative numerical prediction of observed behaviour when highly elastic Boger fluids flow in contraction geometries. This has led to an obvious desire to seek quantitative agreement between prediction and experiment, a subject which is addressed in the current paper. We conclude that constitutive models of non-trivial complexity are required to make headway in this regard. However, we suggest that the desire to move from qualitative to quantitative agreement between theory and experiment is making real progress. In the present case with differential models, this has involved the introduction of a generalized continuous spectrum model. This is based on direct data input from material functions and rheometrical measurements. The class of such models assumes functional separability across shear and extensional deformation, through two master functions, governing independently material-time and viscous-response. The consequences of such a continuous spectrum representation are compared and contrasted against discrete-mode alternatives, via an averaged single-mode approximation and a multi-modal approximation. The effectiveness of each chosen form is gauged by the quality of match to complex flow response and experimental measurement. Here, this is interpreted in circular contraction-type flows with Boger fluids, where large experimental pressure-drop data are available and wide disparity between different fluid responses has been recorded in the past. Findings are then back-correlated to base-material response from ideal viscometric flow.

  8. Evaluation of Carbohydrate-Derived Fulvic Acid (CHD-FA) as a Topical Broad-Spectrum Antimicrobial for Drug-Resistant Wound Infections

    Science.gov (United States)

    2015-10-01

    resistant organisms, and prevents the use of more specific but more limited spectrum antibiotics . The overall goal of this preclinical program is to...CHD-FA treated, 6 in vehicle (batch #2367) controls, and 6 in antibiotic ( Colistin 20 ug/ml) treatment controls (batch #SLBG4834V) at day 1, day 3...on days 3- 6. The antibiotic control group ( Colistin 20 µg/ml) had improved wound closure early in the infection with >15% closure relative to the

  9. Broad-spectrum antiemetic potential of the L-type calcium channel antagonist nifedipine and evidence for its additive antiemetic interaction with the 5-HT(3) receptor antagonist palonosetron in the least shrew (Cryptotis parva).

    Science.gov (United States)

    Darmani, Nissar A; Zhong, Weixia; Chebolu, Seetha; Vaezi, Mariam; Alkam, Tursun

    2014-01-05

    Cisplatin-like chemotherapeutics cause vomiting via release of multiple neurotransmitters (dopamine, serotonin (5-HT), or substance P (SP)) from the gastrointestinal enterochromaffin cells and/or the brainstem via a calcium dependent process. Diverse channels in the plasma membrane allow extracellular Ca(2+) entry into cells for the transmitter release process. Agonists of 5-HT3 receptors increase calcium influx through both 5-HT3 receptors and L-type Ca(2+) channels. We envisaged that L-type calcium agonists such as FPL 64176 should cause vomiting and corresponding antagonists such as nifedipine would behave as broad-spectrum antiemetics. Administration of FPL 64176 did cause vomiting in the least shrew in a dose-dependent fashion. Nifedipine and the 5-HT3 receptor antagonist palonosetron, potently suppressed FPL 64176-induced vomiting, while a combination of ineffective doses of these antagonists was more efficacious. Subsequently, we investigated the broad-spectrum antiemetic potential of nifedipine against diverse emetogens including agonists of serotonergic 5-HT3- (e.g. 5-HT or 2-Me-5-HT), SP tachykinin NK1- (GR73632), dopamine D2- (apomorphine or quinpirole), and cholinergic M1- (McN-A-343) receptors, as well as the non-specific emetogen, cisplatin. Nifedipine by itself suppressed vomiting in a potent and dose-dependent manner caused by the above emetogens except cisplatin. Moreover, low doses of nifedipine potentiated the antiemetic efficacy of non-effective or semi-effective doses of palonosetron against vomiting caused by either 2-Me-5-HT or cisplatin. Thus, our findings demonstrate that activation of L-type calcium channels causes vomiting, whereas blockade of these ion channels by nifedipine-like antagonists not only provides broad-spectrum antiemetic activity but can also potentiate the antiemetic efficacy of well-established antiemetics such as palonosetron. L-type calcium channel antagonists should also provide antiemetic activity against drug

  10. Chromosomal and plasmid-mediated fluoroquinolone resistance mechanisms among broad-spectrum-cephalosporin-resistant Escherichia coli isolates recovered from companion animals in the USA.

    Science.gov (United States)

    Shaheen, Bashar W; Nayak, Rajesh; Foley, Steven L; Boothe, Dawn M

    2013-05-01

    To determine the prevalence of plasmid-mediated quinolone resistance (PMQR) determinants and investigate mutations in gyrase and topoisomerase genes that may contribute to increased fluoroquinolone resistance in canine and feline Escherichia coli isolates in the USA that displayed reduced susceptibility to extended-spectrum cephalosporins. This study was undertaken because previous epidemiological studies identified a potential correlation between extended-spectrum cephalosporins and fluoroquinolone resistance. Isolates (n = 54) with reduced susceptibility to ceftazidime or cefotaxime were screened by PCR for the presence of PMQR determinants and gyrase and topoisomerase genes were sequenced. Isolates were further characterized by conjugation and phylogenetic analyses. PMQR determinants aac(6')-Ib-cr, qnrS and qepA were identified in 30, 23 and 5 isolates, respectively. Multiple mutations were identified in the quinolone resistance-determining region, including the novel substitutions of Glu-84 → Ala and Leu-88 → Gln in ParC and Arg-432 → Ser and Glu-460 → Val in ParE. The isolate that exhibited the highest level of enrofloxacin resistance (MIC > 256 mg/L) had a double mutation in gyrA (Ser-83 → Leu and Asp-87 → Asn) and a triple mutation in parC (Ser-80 → Ile, Glu-84 → Gly and a novel mutation, Leu-88 → Gln). The presence of PMQR genes increased the ciprofloxacin MIC values 4-fold to 8-fold in transconjugants relative to the recipient strain. Approximately 39% of the isolates belonged to phylogenetic group D and 30% to group B2, which typically contain an increased number of virulence determinants compared with other groups. Novel mutations in topoisomerase genes and PMQR determinants aac(6')-Ib-cr, qnrS and qepA genes were detected among extended-spectrum β-lactamase-producing E. coli in the USA.

  11. Quest for a universal density functional: the accuracy of density functionals across a broad spectrum of databases in chemistry and physics.

    Science.gov (United States)

    Peverati, Roberto; Truhlar, Donald G

    2014-03-13

    Kohn-Sham density functional theory is in principle an exact formulation of quantum mechanical electronic structure theory, but in practice we have to rely on approximate exchange-correlation (xc) functionals. The objective of our work has been to design an xc functional with broad accuracy across as wide an expanse of chemistry and physics as possible, leading--as a long-range goal--to a functional with good accuracy for all problems, i.e. a universal functional. To guide our path towards that goal and to measure our progress, we have developed-building on earlier work of our group-a set of databases of reference data for a variety of energetic and structural properties in chemistry and physics. These databases include energies of molecular processes, such as atomization, complexation, proton addition and ionization; they also include molecular geometries and solid-state lattice constants, chemical reaction barrier heights, and cohesive energies and band gaps of solids. For this paper, we gather many of these databases into four comprehensive databases, two with 384 energetic data for chemistry and solid-state physics and another two with 68 structural data for chemistry and solid-state physics, and we test two wave function methods and 77 density functionals (12 Minnesota meta functionals and 65 others) in a consistent way across this same broad set of data. We especially highlight the Minnesota density functionals, but the results have broader implications in that one may see the successes and failures of many kinds of density functionals when they are all applied to the same data. Therefore, the results provide a status report on the quest for a universal functional.

  12. Antimicrobial peptides effectively kill a broad spectrum of Listeria monocytogenes and Staphylococcus aureus strains independently of origin, sub-type, or virulence factor expression

    DEFF Research Database (Denmark)

    Gottlieb, Caroline Trebbien; Thomsen, L.E.; Ingmer, H.

    2008-01-01

    Background Host defense peptides (HDPs), or antimicrobial peptides (AMPs), are important components of the innate immune system that bacterial pathogens must overcome to establish an infection and HDPs have been suggested as novel antimicrobial therapeutics in treatment of infectious diseases......-type, and phenotypic behavior. Strains within each species were equally sensitive to HDPs and oxidative stress representing important components of the innate immune defense system. Four non-human peptides (protamine, plectasin, novicidin, and novispirin G10) were similar in activity profile (MIC value spectrum...... Caenorhabditis elegans. For L. monocytogenes, proliferation in whole blood was paralleled by high invasion in Caco-2 cells and fast killing of C. elegans, however, no such pattern in phenotypic behavior was observed for S. aureus and none of the phenotypic differences were correlated to sensitivity to HDPs...

  13. A Sequential Statistical Approach towards an Optimized Production of a Broad Spectrum Bacteriocin Substance from a Soil Bacterium Bacillus sp. YAS 1 Strain

    Directory of Open Access Journals (Sweden)

    Amira M. Embaby

    2014-01-01

    Full Text Available Bacteriocins, ribosomally synthesized antimicrobial peptides, display potential applications in agriculture, medicine, and industry. The present study highlights integral statistical optimization and partial characterization of a bacteriocin substance from a soil bacterium taxonomically affiliated as Bacillus sp. YAS 1 after biochemical and molecular identifications. A sequential statistical approach (Plackett-Burman and Box-Behnken was employed to optimize bacteriocin (BAC YAS 1 production. Using optimal levels of three key determinants (yeast extract (0.48% (w/v, incubation time (62 hrs, and agitation speed (207 rpm in peptone yeast beef based production medium resulted in 1.6-fold enhancement in BAC YAS 1 level (470 AU/mL arbitrary units against Erwinia amylovora. BAC YAS 1 showed activity over a wide range of pH (1–13 and temperature (45–80°C. A wide spectrum antimicrobial activity of BAC YAS 1 against the human pathogens (Clostridium perfringens, Staphylococcus epidermidis, Campylobacter jejuni, Enterobacter aerogenes, Enterococcus sp., Proteus sp., Klebsiella sp., and Salmonella typhimurium, the plant pathogen (E. amylovora, and the food spoiler (Listeria innocua was demonstrated. On top and above, BAC YAS 1 showed no antimicrobial activity towards lactic acid bacteria (Lactobacillus bulgaricus, L. casei, L. lactis, and L. reuteri. Promising characteristics of BAC YAS 1 prompt its commercialization for efficient utilization in several industries.

  14. From dizziness to severe ataxia and dysarthria: New cases of anti-Ca/ARHGAP26 autoantibody-associated cerebellar ataxia suggest a broad clinical spectrum.

    Science.gov (United States)

    Wallwitz, Ulrike; Brock, Sebastian; Schunck, Antje; Wildemann, Brigitte; Jarius, Sven; Hoffmann, Frank

    2017-08-15

    In 2010, a novel anti-neuronal autoantibody, termed anti-Ca, was described in a patient with subacute cerebellar ataxia, and Rho GTPase-activating protein 26 (ARHGAP26) was identified as the target antigen. Recently, three additional cases of anti-Ca-positive cerebellar ataxia have been published. In addition to ataxia, cognitive decline and depression have been observed in some patients. Here, we report two new cases of anti-Ca-associated autoimmune cerebellar ataxia. Patient 1 presented with dizziness and acute yet mild limb and gait ataxia. Symptoms stabilized with long-term oral corticosteroid therapy but transiently worsened when steroids were tapered. Interestingly, both initial occurrence and worsening of the patient's neurological symptoms after steroid withdrawal were accompanied by spontaneous cutaneous hematomas. Patient 2 initially presented with an increased startle response and myoclonic jerks, and subsequently developed severe limb and gait ataxia, dysarthria, oculomotor disturbances, head and voice tremor, dysphagia, cognitive symptoms and depression. Steroid treatment was started five years after disease onset. The symptoms then responded only poorly to corticosteroids. At most recent follow-up, 19 years after disease onset, the patient was wheelchair-bound. These cases extend the clinical spectrum associated with anti-ARHGAP26 autoimmunity and suggest that early treatment may be important in patients with this rare syndrome. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. A new amino acid substitution (Ala-205-Phe) in acetolactate synthase (ALS) confers broad spectrum resistance to ALS-inhibiting herbicides.

    Science.gov (United States)

    Brosnan, James T; Vargas, Jose J; Breeden, Gregory K; Grier, Logan; Aponte, Raphael A; Tresch, Stefan; Laforest, Martin

    2016-01-01

    This is a first report of an Ala-205-Phe substitution in acetolactate synthase conferring resistance to imidazolinone, sulfonylurea, triazolopyrimidines, sulfonylamino-carbonyl-triazolinones, and pyrimidinyl (thio) benzoate herbicides. Resistance to acetolactate synthase (ALS) and photosystem II inhibiting herbicides was confirmed in a population of allotetraploid annual bluegrass (Poa annua L.; POAAN-R3) selected from golf course turf in Tennessee. Genetic sequencing revealed that seven of eight POAAN-R3 plants had a point mutation in the psbA gene resulting in a known Ser-264-Gly substitution on the D1 protein. Whole plant testing confirmed that this substitution conferred resistance to simazine in POAAN-R3. Two homeologous forms of the ALS gene (ALSa and ALSb) were detected and expressed in all POAAN-R3 plants sequenced. The seven plants possessing the Ser-264-Gly mutation conferring resistance to simazine also had a homozygous Ala-205-Phe substitution on ALSb, caused by two nucleic acid substitutions in one codon. In vitro ALS activity assays with recombinant protein and whole plant testing confirmed that this Ala-205-Phe substitution conferred resistance to imidazolinone, sulfonylurea, triazolopyrimidines, sulfonylamino-carbonyl- triazolinones, and pyrimidinyl (thio) benzoate herbicides. This is the first report of Ala-205-Phe mutation conferring wide spectrum resistance to ALS inhibiting herbicides.

  16. Genes optimized by evolution for accurate and fast translation encode in Archaea and Bacteria a broad and characteristic spectrum of protein functions

    Directory of Open Access Journals (Sweden)

    Merkl Rainer

    2010-11-01

    Full Text Available Abstract Background In many microbial genomes, a strong preference for a small number of codons can be observed in genes whose products are needed by the cell in large quantities. This codon usage bias (CUB improves translational accuracy and speed and is one of several factors optimizing cell growth. Whereas CUB and the overrepresentation of individual proteins have been studied in detail, it is still unclear which high-level metabolic categories are subject to translational optimization in different habitats. Results In a systematic study of 388 microbial species, we have identified for each genome a specific subset of genes characterized by a marked CUB, which we named the effectome. As expected, gene products related to protein synthesis are abundant in both archaeal and bacterial effectomes. In addition, enzymes contributing to energy production and gene products involved in protein folding and stabilization are overrepresented. The comparison of genomes from eleven habitats shows that the environment has only a minor effect on the composition of the effectomes. As a paradigmatic example, we detailed the effectome content of 37 bacterial genomes that are most likely exposed to strongest selective pressure towards translational optimization. These effectomes accommodate a broad range of protein functions like enzymes related to glycolysis/gluconeogenesis and the TCA cycle, ATP synthases, aminoacyl-tRNA synthetases, chaperones, proteases that degrade misfolded proteins, protectants against oxidative damage, as well as cold shock and outer membrane proteins. Conclusions We made clear that effectomes consist of specific subsets of the proteome being involved in several cellular functions. As expected, some functions are related to cell growth and affect speed and quality of protein synthesis. Additionally, the effectomes contain enzymes of central metabolic pathways and cellular functions sustaining microbial life under stress situations. These

  17. HLA-A2–Restricted Cytotoxic T Lymphocyte Epitopes from Human Heparanase as Novel Targets for Broad-Spectrum Tumor Immunotherapy

    Directory of Open Access Journals (Sweden)

    Ting Chen

    2008-09-01

    Full Text Available Peptide vaccination for cancer immunotherapy requires identification of peptide epitopes derived from antigenic proteins associated with tumors. Heparanase (Hpa is broadly expressed in various advanced tumors and seems to be an attractive new tumor-associated antigen. The present study was designed to predict and identify HLA-A2– restricted cytotoxic T lymphocyte (CTL epitopes in the protein of human Hpa. For this purpose, HLA-A2–restricted CTL epitopes were identified using the following four-step procedure: 1 a computer-based epitope prediction from the amino acid sequence of human Hpa, 2 a peptide-binding assay to determine the affinity of the predicted protein with the HLA-A2 molecule, 3 stimulation of the primary T-cell response against the predicted peptides in vitro, and 4 testing of the induced CTLs toward different kinds of carcinoma cells expressing Hpa antigens and/or HLA-A2. The results demonstrated that, of the tested peptides, effectors induced by peptides of human Hpa containing residues 525-533 (PAFSYSFFV, Hpa525, 277-285 (KMLKSFLKA, Hpa277, and 405-413 (WLSLLFKKL, Hpa405 could effectively lyse various tumor cell lines that were Hpa-positive and HLA-A2-matched. We also found that these peptide-specific CTLs could not lyse autologous lymphocytes with low Hpa activity. Further study revealed that Hpa525, Hpa277, and Hpa405 peptides increased the frequency of IFN-γ–producing T cells compared to a negative peptide. Our results suggest that Hpa525, Hpa277, and Hpa405 peptides are new HLA-A2–restricted CTL epitopes capable of inducing Hpa-specific CTLs in vitro. Because Hpa is expressed in most advanced malignant tumors, Hpa525, Hpa277, and Hpa405 peptide–based vaccines may be useful for the immunotherapy for patients with advanced tumors.

  18. Identification of a broad-spectrum antiviral small molecule against severe acute respiratory syndrome coronavirus and Ebola, Hendra, and Nipah viruses by using a novel high-throughput screening assay.

    Science.gov (United States)

    Elshabrawy, Hatem A; Fan, Jilao; Haddad, Christine S; Ratia, Kiira; Broder, Christopher C; Caffrey, Michael; Prabhakar, Bellur S

    2014-04-01

    Severe acute respiratory syndrome coronavirus (SARS-CoV) and Ebola, Hendra, and Nipah viruses are members of different viral families and are known causative agents of fatal viral diseases. These viruses depend on cathepsin L for entry into their target cells. The viral glycoproteins need to be primed by protease cleavage, rendering them active for fusion with the host cell membrane. In this study, we developed a novel high-throughput screening assay based on peptides, derived from the glycoproteins of the aforementioned viruses, which contain the cathepsin L cleavage site. We screened a library of 5,000 small molecules and discovered a small molecule that can inhibit the cathepsin L cleavage of all viral peptides with minimal inhibition of cleavage of a host protein-derived peptide (pro-neuropeptide Y). The small molecule inhibited the entry of all pseudotyped viruses in vitro and the cleavage of SARS-CoV spike glycoprotein in an in vitro cleavage assay. In addition, the Hendra and Nipah virus fusion glycoproteins were not cleaved in the presence of the small molecule in a cell-based cleavage assay. Furthermore, we demonstrate that the small molecule is a mixed inhibitor of cathepsin L. Our broad-spectrum antiviral small molecule appears to be an ideal candidate for future optimization and development into a potent antiviral against SARS-CoV and Ebola, Hendra, and Nipah viruses. We developed a novel high-throughput screening assay to identify small molecules that can prevent cathepsin L cleavage of viral glycoproteins derived from SARS-CoV and Ebola, Hendra, and Nipah viruses that are required for their entry into the host cell. We identified a novel broad-spectrum small molecule that could block cathepsin L-mediated cleavage and thus inhibit the entry of pseudotypes bearing the glycoprotein derived from SARS-CoV or Ebola, Hendra, or Nipah virus. The small molecule can be further optimized and developed into a potent broad-spectrum antiviral drug.

  19. Crystal Structure of the New Investigational Drug Candidate VT-1598 in Complex with Aspergillus fumigatus Sterol 14α-Demethylase Provides Insights into Its Broad-Spectrum Antifungal Activity

    Energy Technology Data Exchange (ETDEWEB)

    Hargrove, Tatiana Y.; Garvey, Edward P.; Hoekstra, William J.; Yates, Christopher M.; Wawrzak, Zdzislaw; Rachakonda, Girish; Villalta, Fernando; Lepesheva, Galina I.

    2017-05-01

    ABSTRACT

    Within the past few decades, the incidence and complexity of human fungal infections have increased, and therefore, the need for safer and more efficient, broad-spectrum antifungal agents is high. In the study described here, we characterized the new tetrazole-based drug candidate VT-1598 as an inhibitor of sterol 14α-demethylase (CYP51B) from the filamentous fungusAspergillus fumigatus. VT-1598 displayed a high affinity of binding to the enzyme in solution (dissociation constant, 13 ± 1 nM) and in the reconstituted enzymatic reaction was revealed to have an inhibitory potency stronger than the potencies of all other simultaneously tested antifungal drugs, including fluconazole, voriconazole, ketoconazole, and posaconazole. The X-ray structure of the VT-1598/A. fumigatusCYP51 complex was determined and depicts the distinctive binding mode of the inhibitor in the enzyme active site, suggesting the molecular basis of the improved drug potency and broad-spectrum antifungal activity. These data show the formation of an optimized hydrogen bond between the phenoxymethyl oxygen of VT-1598 and the imidazole ring nitrogen of His374, the CYP51 residue that is highly conserved across fungal pathogens and fungus specific. Comparative structural analysis ofA. fumigatusCYP51/voriconazole andCandida albicansCYP51/VT-1161 complexes supports the role of H bonding in fungal CYP51/inhibitor complexes and emphasizes the importance of an optimal distance between this interaction and the inhibitor-heme iron interaction. Cellular experiments using twoA. fumigatusstrains (strains 32820 and 1022) displayed a direct

  20. Growing Escherichia coli mutants deficient in riboflavin biosynthesis with non-limiting riboflavin results in sensitization to inactivation by broad-spectrum near-ultraviolet light (320-400 nm)

    International Nuclear Information System (INIS)

    Lloyd, R.E.; Rinkenberger, J.L.; Hug, B.A.; Tuveson, R.W.

    1990-01-01

    Two mutants of Escherichia coli unable to synthesize riboflavin were grown with limiting (2 μg ml -1 ) and non-limiting (10 μg ml -1 ) concentrations of riboflavin. These riboflavin auxotrophs when grown to exponential phase with non-limiting riboflavin are more sensitive to broad spectrum near-ultraviolet light (NUV, 320-400 nm) inactivation than when they are grown with limiting riboflavin. Exponential phase cells of the riboflavin auxotrophs grown with limiting riboflavin are sensitized when irradiated in saline supplemented with riboflavin. This suggests that extracellular riboflavin is important as a NUV sensitizer when intracellular levels of riboflavin are reduced. The concentration of riboflavin in crude extracts from exponentially growing cells correlates well with the sensitivity of these mutants to NUV inactivation. The level of riboflavin supplementation has little effect on the NUV sensitivity of the parental strain. (author)

  1. Short Communication: The Broad-Spectrum Histone Deacetylase Inhibitors Vorinostat and Panobinostat Activate Latent HIV in CD4(+) T Cells In Part Through Phosphorylation of the T-Loop of the CDK9 Subunit of P-TEFb.

    Science.gov (United States)

    Jamaluddin, Md Saha; Hu, Pei-Wen; Jan, Yih; Siwak, Edward B; Rice, Andrew P

    2016-02-01

    Cessation of highly active antiretroviral therapy (HAART) in HIV-infected individual leads to a rebound of viral replication due to reactivation of a viral reservoir composed largely of latently infected memory CD4(+) T cells. Efforts to deplete this reservoir have focused on reactivation of transcriptionally silent latent proviruses. HIV provirus transcription depends critically on the positive transcription elongation factor b (P-TEFb), whose core components are cyclin-dependent kinase 9 (CDK9) and cyclin T1. In resting CD4(+) cells, the functional levels of P-TEFb are extremely low. Cellular activation upregulates cyclin T1 protein levels and CDK9 T-loop (T186) phosphorylation. The broad-spectrum histone deacetylase inhibitors (HDACis) vorinostat and panobinostat have been shown to reactivate latent virus in vivo in HAART-treated individuals. In this study, we have found that vorinostat and panobinostat activate P-TEFb in resting primary CD4(+) T cells through induction of CDK9 T-loop phosphorylation. In contrast, tacedinaline and romidepsin, HDAC 1 and 2 inhibitors, were unable to activate CDK9 T-loop phosphorylation. We used a CCL19 primary CD4(+) T-cell model HIV latency to assess the correlation between induction of CDK9 T-loop phosphorylation and reactivation of latent HIV virus by HDACis. Vorinostat and panobinostat treatment of cells harboring latent HIV increased CDK9 T-loop phosphorylation and reactivation of latent virus, whereas tacedinaline and romidepsin failed to induce T-loop phosphorylation or reactivate latent virus. We conclude that the ability of vorinostat and panobinostat to induce latent HIV is, in part, likely due to the ability of the broad-spectrum HDACis to upregulate P-TEFb through increased CDK9 T-loop phosphorylation.

  2. Rapid detection of amoxicillin-susceptible Escherichia coli in fresh uncultured urine: a new tool to limit the use of broad-spectrum empirical therapy of community-acquired pyelonephritis.

    Science.gov (United States)

    Chapelet, Guillaume; Corvec, Stéphane; Montassier, Emmanuel; Herbreteau, Guillaume; Berrut, Gilles; Batard, Eric; de Decker, Laure

    2016-06-01

    Because of the high prevalence of amoxicillin resistance among uropathogens, amoxicillin is not recommended as an empirical treatment of urinary tract infections (UTIs). Quick detection of an amoxicillin-susceptible Escherichia coli (ASEC) would allow prescribing amoxicillin without preliminary broad-spectrum empirical treatment in uncomplicated pyelonephritis. To quickly diagnose UTIs due to ASEC, we developed a real-time PCR that detects in fresh uncultured urine the E. coli-specific gene yccT as well as the blaTEM and blaCTX-M genes. The ASEC rapid test was considered positive if the PCR was positive for the yccT gene but negative for blaTEM and blaCTX-M. The test was compared with culture and susceptibility testing. Among 200 patients with a suspected community-acquired UTI, 61 (30.5%) had a monobacterial UTI due to ASEC. The ASEC rapid test result was obtained in 3 h 13 [95% confidence interval (CI) 3 h 12-3 h 15] and was positive for 43 patients (21.5%). Specificity and sensitivity were 97.8% (95% CI 95.8-99.8%) and 65.6% (95% CI 59.0-72.1%), respectively. Positive and negative predictive values were 93.0% (95% CI 89.5-96.5%) and 86.6% (95% CI 81.9-91.3%), respectively. Owing to its high specificity and positive predictive value, the ASEC rapid test allows the diagnosis of UTI due to ASEC only 3 h after urine sampling. A positive ASEC rapid test may be used to treat uncomplicated pyelonephritis with amoxicillin from the start, without preliminary broad-spectrum empirical treatment. The ASEC rapid test is a promising tool to spare fluoroquinolones and third-generation cephalosporins in UTIs. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  3. Marker-Assisted Development and Evaluation of Near-Isogenic Lines for Broad-Spectrum Powdery Mildew Resistance Gene Pm2b Introgressed into Different Genetic Backgrounds of Wheat

    Directory of Open Access Journals (Sweden)

    Hongxing Xu

    2017-07-01

    Full Text Available At present, most of released wheat cultivars or breeding lines in China are susceptible to powdery mildew (Pm (caused by Blumeria graminis f. sp. tritici, Bgt, so there is an urgent need to rapidly transfer effective and broad-spectrum Pm resistance genes into elite cultivars/lines. Near-isogenic lines (NILs with short target gene region are very important in molecular breeding and map-based cloning and can be developed by combining marker-assisted selection and conventional phenotypic identification. However, no Pm gene NILs were reported by using this method in the previous studies. A new broad-spectrum dominant resistance gene Pm2b, derived from the Chinese wheat breeding line KM2939, conferred high resistance to Pm at both the seedling and adult stages. In this study, with the aid of forward and background selection (FS and BS using molecular markers, the Pm2b gene was introgressed into three elite susceptible commercial cultivars Shimai 15, Shixin 828, and Kenong 199 through the back-crossing procedure. With the appropriate backcrossing generations, selected population sizes and marker number for BS, the homozygous resistant BC3F2:3 NILs of Pm2b gene in the three genetic backgrounds with the highest recipient genome composition of about 99%, confirmed by simple sequence repeat markers and 660K single nucleotide polymorphic array, were developed and evaluated for the powdery mildew resistance and agronomic traits. The different resistance and similar or improved agronomic performance between Pm2b NILs and their corresponding recurrent parents indicated their potential value in the marker-assisted breeding of the Pm2b gene. Moreover, the development of four flanked diagnostic markers (CFD81, BWM25, BWM20, and BWM21 of the Pm2 gene can effectively assist the forward selection and accelerate the transfer and use of this resistance gene.

  4. Genotypic analysis of plasmid-mediated beta-lactamases amongst Enterobacteriaceae other than Escherichia spp. and Klebsiella spp. that are non-susceptible to a broad-spectrum cephalosporin.

    Science.gov (United States)

    Kiratisin, Pattarachai; Henprasert, Arunocha

    2010-10-01

    Enterobacteriaceae other than Escherichia spp. and Klebsiella spp. are recognisable for their increasing resistance. Plasmid-mediated beta-lactamases, including extended-spectrum beta-lactamases (ESBLs), plasmid-mediated AmpC beta-lactamases (pAmpCs) and the newly emerged KPC, play an important role in beta-lactam resistance. In this study, we investigated the genetic characteristics of plasmid-mediated beta-lactamases amongst non-Escherichia, non-Klebsiella Enterobacteriaceae that were non-susceptible to at least a broad-spectrum cephalosporin. A total of 143 (23.9%) of 598 isolates during the 6-month study period met the screening criteria, amongst which 142 (99.3%) and 99 (69.2%) isolates carried ESBL and pAmpC genes, respectively. Resistance genotypes were described. bla(KPC) was not detected in isolates with reduced susceptibility to carbapenems. This study provides an insight into plasmid-mediated resistance determinants amongst cephalosporin-non-susceptible Enterobacteriaceae other than Escherichia spp. and Klebsiella spp. Copyright 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

  5. Broad-spectrum pollination of Plectranthus neochilus

    Directory of Open Access Journals (Sweden)

    C. H. Stirton

    1977-11-01

    Full Text Available The pollination ecology of Plectranthus neochilus Schltr. is discussed and compared with that of another garden plant,  Plectranthus barbatus Andr.. Pollinators and flower visitors of P. neochilus include members of  the Megachilidae, Anthophoridae, Syrphidae, Bombyliidae, Sphingidae, Apidae.

  6. Broad-spectrum antiviral properties of andrographolide.

    Science.gov (United States)

    Gupta, Swati; Mishra, K P; Ganju, Lilly

    2017-03-01

    Andrographolide, a diterpenoid, is known for its anti-inflammatory effects. It can be isolated from various plants of the genus Andrographis, commonly known as 'creat'. This purified compound has been tested for its anti-inflammatory effects in various stressful conditions, such as ischemia, pyrogenesis, arthritis, hepatic or neural toxicity, carcinoma, and oxidative stress, Apart from its anti-inflammatory effects, andrographolide also exhibits immunomodulatory effects by effectively enhancing cytotoxic T cells, natural killer (NK) cells, phagocytosis, and antibody-dependent cell-mediated cytotoxicity (ADCC). All these properties of andrographolide form the foundation for the use of this miraculous compound to restrain virus replication and virus-induced pathogenesis. The present article covers antiviral properties of andrographolide in variety of viral infections, with the hope of developing of a new highly potent antiviral drug with multiple effects.

  7. Third generation cephalosporin resistant Enterobacteriaceae and multidrug resistant gram-negative bacteria causing bacteremia in febrile neutropenia adult cancer patients in Lebanon, broad spectrum antibiotics use as a major risk factor, and correlation with poor prognosis

    Directory of Open Access Journals (Sweden)

    Rima eMoghnieh

    2015-02-01

    Full Text Available Bacteremia remains a major cause of life-threatening complications in patients receiving anticancer chemotherapy. The spectrum and susceptibility profiles of causative microorganisms differ with time and place. Data from Lebanon are scarce. We aim at evaluating the epidemiology of bacteremia in cancer patients in a university hospital in Lebanon, emphasizing antibiotic resistance and risk factors of multi-drug resistant organism (MDRO-associated bacteremia.This is a retrospective study of 75 episodes of bacteremia occurring in febrile neutropenic patients admitted to the hematology-oncology unit at Makassed General Hospital, Lebanon, from October 2009-January 2012.It corresponds to epidemiological data on bacteremia episodes in febrile neutropenic cancer patients including antimicrobial resistance and identification of risk factors associated with third generation cephalosporin resistance (3GCR and MDRO-associated bacteremia. Out of 75 bacteremias, 42.7% were gram-positive (GP, and 57.3% were gram-negative (GN. GP bacteremias were mostly due to methicillin-resistant coagulase negative staphylococci (28% of total bacteremias and 66% of GP bacteremias. Among the GN bacteremias, Escherichia coli (22.7% of total, 39.5% of GN organisms and Klebsiellapneumoniae(13.3% of total, 23.3% of GN organisms were the most important causative agents. GN bacteremia due to 3GC sensitive (3GCS bacteria represented 28% of total bacteremias, while 29% were due to 3GCR bacteria and 9% were due to carbapenem-resistant organisms. There was a significant correlation between bacteremia with MDRO and subsequent intubation, sepsis and mortality. Among potential risk factors, only broad spectrum antibiotic intake >4 days before bacteremia was found to be statistically significant for acquisition of 3GCR bacteria. Using carbapenems or piperacillin/ tazobactam>4 days before bacteremia was significantly associated with the emergence of MDRO (p value<0.05.

  8. Comparison of nitroethane, 2-nitro-1-propanol, lauric acid, Lauricidin® and the Hawaiian marine algae, Chaetoceros, for potential broad-spectrum control of anaerobically grown lactic acid bacteria.

    Science.gov (United States)

    Božic, Aleksandar K; Anderson, Robin C; Ricke, Steven C; Crandall, Philip G; O'Bryan, Corliss A

    2012-01-01

    The gastrointestinal tract of bovines often contains bacteria that contribute to disorders of the rumen, and may also contain foodborne or opportunistic human pathogens as well as bacteria capable of causing mastitis in cows. Thus there is a need to develop broad-spectrum therapies that are effective while not leading to unacceptably long antibiotic withdrawal times. The effects of the CH(4)-inhibitors nitroethane (2 mg/mL), 2-nitro-1-propanol (2 mg/mL), lauric acid (5 mg/mL), the commercial product Lauricidin® (5 mg/mL), and a finely ground product of the Hawaiian marine algae, Chaetoceros (10 mg/mL), were compared in pure cultures of Streptococcus agalactia, Enterococcus faecium, Streptococcus bovis, and in a mixed lactic acid rumen bacterial culture. Lauricidin® and lauric acid exhibited the most bactericidal acidity against all bacteria. These results suggest potential animal health benefits from supplementing cattle diets with lauric acid or Lauricidin® to improve the health of the rumen and help prevent shedding of human pathogens.

  9. Report of the fourth meeting on 'Influenza vaccines that induce broad spectrum and long-lasting immune responses', World Health Organization and Wellcome Trust, London, United Kingdom, 9-10 November 2009.

    Science.gov (United States)

    Stephenson, Iain; Hayden, Frederick; Osterhaus, Albert; Howard, Wendy; Pervikov, Yuri; Palkonyay, Laszlo; Kieny, Marie-Paule

    2010-05-21

    Current influenza vaccines are limited by the need for annual immunisation, frequent antigenic updating to match the evolution of circulating influenza virus strains, and reduced efficacy in elderly persons. On 9-10 November 2009, the Initiative for Vaccine Research of the World Health Organization convened jointly with the Wellcome Trust in London, United Kingdom, the fourth meeting on 'Influenza vaccines that induce broad spectrum and long-lasting immune responses'. Presentations were made by representatives from industry, academia, governmental and non-governmental organisations. The objectives of the meeting were to update the progress of research in the field of influenza vaccine strategies able to generate cross protection against divergent influenza virus strains. Improvements in existing strategies including live attenuated influenza vaccines and adjuvantation of inactivated vaccines were summarised. Developments in novel antigen production methods, new routes of vaccine delivery and administration, and vaccine approaches based on conserved virus antigens were explored. In addition, correlates of immune protection and regulatory issues for the evaluation and approval of future novel vaccine strategies were discussed. Copyright 2010. Published by Elsevier Ltd.. All rights reserved.

  10. Characterization by deep sequencing of divergent plum bark necrosis stem pitting-associated virus (PBNSPaV) isolates and development of a broad-spectrum PBNSPaV detection assay.

    Science.gov (United States)

    Marais, Armelle; Faure, Chantal; Couture, Carole; Bergey, Bernard; Gentit, Pascal; Candresse, Thierry

    2014-06-01

    Plum bark necrosis stem pitting-associated virus (PBNSPaV), the causal agent of plum bark necrosis stem pitting disease, belongs to the genus Ampelovirus in the family Closteroviridae. The complete genome sequence of PBNSPaV isolates from four Prunus sources was determined by pyrosequencing. All isolates showed the same genomic organization as the PBNSPaV reference isolate. The least divergent isolate, found in a peach tree from China, showed an overall 91.8% of nucleotide identity with the type isolate. Two closely related isolates, defining a second cluster of diversity, were found in two Japanese plum lines from France and showed only 82.8% identity with the type isolate. On the other hand, they were highly homologous with two recently described PBNSPaV divergent isolates from China. The fourth and most divergent isolate, from a Chinese peach, showed only 71.2% identity to other PBNSPaV isolates and was not detected by currently available PBNSPaV reverse-transcription polymerase chain reaction detection assays. Complete sequencing of the divergent isolates allowed the development of a more broad-spectrum detection test targeting a conserved region in the P61 gene. Taken together, these results indicate a much broader diversity of PBNSPaV than previously thought and provide for a more robust detection of this still poorly characterized pathogen.

  11. Broad-spectrum immunoaffinity cleanup for the determination of aflatoxins B1, B2, G1, G2, M1, M2in Ophiocordyceps sinensis and its pharmaceutical preparations by ultra performance liquid chromatography tandem mass spectrometry.

    Science.gov (United States)

    Sun, Shujuan; Xie, Jie; Peng, Tao; Shao, Bing; Zhu, Kui; Sun, Yuanze; Yao, Kai; Gu, Qiang; Zhang, Jing; Fan, Chunlin; Chen, Ying; Jiang, Haiyang

    2017-11-15

    An ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the simultaneous determination of aflatoxins B 1 , B 2 , G 1 , G 2 , M 1 and M 2 (AFB 1 , AFB 2 , AFG 1 , AFG 2 , AFM 1 and AFM 2 ) in Ophiocordyceps sinensis and its pharmaceutical preparations. A rapid and reliable immunoaffinity column containing a broad-spectrum monoclonal antibody for six aflatoxins was used for sample cleanup. Under the optimized conditions, the home-made immunoaffinity column capacity were about 315, 319, 292, 102, 444 and 369ng/mL gel for AFB 1 , AFB 2 , AFG 1 , AFG 2 , AFM 1 and AFM 2 , respectively. Recoveries for all tested aflatoxins ranged from 79.28% to 103.42% with relative standard deviation less than 8%. The limits of quantitation were in the range of 0.008-0.045μg/kg. Among 31 real samples analyzed, one sample was contaminated with AFB 1 , AFB 2 and AFM 1 at levels of 0.483, 0.068 and 0.104μg/kg, respectively. The established method is simple, accurate, and can be effectively used to determine the aflatoxins in Ophiocordyceps sinensis and its pharmaceutical preparations. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. A Randomized Double-Blind, Placebo Controlled, Four-Arm Parallel Study Investigating the Effect of a Broad-Spectrum Wellness Beverage on Mood State in Healthy, Moderately Stressed Adults.

    Science.gov (United States)

    Evans, Malkanthi; Antony, Joseph; Guthrie, Najla; Landes, Bernie; Aruoma, Okezie I

    2018-01-01

    The objective of this study was to investigate the effect of a broad-spectrum wellness beverage (Zeal Wellness [ZW]) on standardized measures of mood states, including overall feelings of vitality, in healthy, moderately stressed adults. A randomized, double-blind, placebo-controlled clinical trial was conducted among 99 eligible participants prescreened for moderate stress. Participants were randomized to one of four groups and received ZW once daily (1-dose-ZW; 14 g), ZW twice daily (2-dose-ZW; 28 g), placebo once daily (1-dose-placebo), or placebo twice daily (2-dose-placebo) for 4 weeks. A stress/vitality questionnaire assessed stress and the Profile of Moods (POMS) Questionnaire assessed vigor via mental/physical energy and global mood state. Safety was assessed by clinical chemistry, liver, kidney function, and anthropometric measures and adverse event reporting. Participants receiving 2-dose-ZW reported a 6.6% decrease in scores on POMS-Total Mood Disturbance (TMD; p state (p state and shifted the POMS iceberg profile to a healthy profile compared to the combined placebo, reflecting the functional benefit of rice-bran-fruit-vegetable extracts based beverage on health.

  13. Third generation cephalosporin resistant Enterobacteriaceae and multidrug resistant gram-negative bacteria causing bacteremia in febrile neutropenia adult cancer patients in Lebanon, broad spectrum antibiotics use as a major risk factor, and correlation with poor prognosis.

    Science.gov (United States)

    Moghnieh, Rima; Estaitieh, Nour; Mugharbil, Anas; Jisr, Tamima; Abdallah, Dania I; Ziade, Fouad; Sinno, Loubna; Ibrahim, Ahmad

    2015-01-01

    Bacteremia remains a major cause of life-threatening complications in patients receiving anticancer chemotherapy. The spectrum and susceptibility profiles of causative microorganisms differ with time and place. Data from Lebanon are scarce. We aim at evaluating the epidemiology of bacteremia in cancer patients in a university hospital in Lebanon, emphasizing antibiotic resistance and risk factors of multi-drug resistant organism (MDRO)-associated bacteremia. This is a retrospective study of 75 episodes of bacteremia occurring in febrile neutropenic patients admitted to the hematology-oncology unit at Makassed General Hospital, Lebanon, from October 2009-January 2012. It corresponds to epidemiological data on bacteremia episodes in febrile neutropenic cancer patients including antimicrobial resistance and identification of risk factors associated with third generation cephalosporin resistance (3GCR) and MDRO-associated bacteremia. Out of 75 bacteremias, 42.7% were gram-positive (GP), and 57.3% were gram-negative (GN). GP bacteremias were mostly due to methicillin-resistant coagulase negative staphylococci (28% of total bacteremias and 66% of GP bacteremias). Among the GN bacteremias, Escherichia coli (22.7% of total, 39.5% of GN organisms) and Klebsiella pneumoniae(13.3% of total, 23.3% of GN organisms) were the most important causative agents. GN bacteremia due to 3GC sensitive (3GCS) bacteria represented 28% of total bacteremias, while 29% were due to 3GCR bacteria and 9% were due to carbapenem-resistant organisms. There was a significant correlation between bacteremia with MDRO and subsequent intubation, sepsis and mortality. Among potential risk factors, only broad spectrum antibiotic intake >4 days before bacteremia was found to be statistically significant for acquisition of 3GCR bacteria. Using carbapenems or piperacillin/tazobactam>4 days before bacteremia was significantly associated with the emergence of MDRO (p < 0.05). Our findings have major

  14. Targeted simplification versus antipseudomonal broad-spectrum beta-lactams in patients with bloodstream infections due toEnterobacteriaceae(SIMPLIFY): a study protocol for a multicentre, open-label, phase III randomised, controlled, non-inferiority clinical trial.

    Science.gov (United States)

    López-Cortés, Luis Eduardo; Rosso-Fernández, Clara; Núñez-Núñez, María; Lavín-Alconero, Lucía; Bravo-Ferrer, José; Barriga, Ángel; Delgado, Mercedes; Lupión, Carmen; Retamar, Pilar; Rodríguez-Baño, Jesús

    2017-06-09

    Within the context of antimicrobial stewardship programmes, de-escalation of antimicrobial therapy is one of the proposed strategies for reducing the unnecessary use of broad-spectrum antibiotics (BSA). The empirical treatment of nosocomial and some healthcare-associated bloodstream infections (BSI) frequently includes a beta-lactam with antipseudomonal activity as monotherapy or in combination with other drugs, so there is a great opportunity to optimise the empirical therapy based on microbiological data. De-escalation is assumed as standard of care for experts in infectious diseases. However, it is less frequent than it would desirable. The SIMPLIFY trial is a multicentre, open-label, non-inferiority phase III randomised controlled clinical trial, designed as a pragmatic 'real-practice' trial. The aim of this trial is to demonstrate the non-inferiority of de-escalation from an empirical beta-lactam with antipseudomonal activity to a targeted narrow-spectrum antimicrobial in patients with BSI due to Enterobacteriaceae . The primary outcome is clinical cure, which will be assessed at the test of cure visit. It will be conducted at 19 Spanish public and university hospitals. Each participating centre has obtained the approval of the ethics review committee, the agreement of the directors of the institutions and authorisation from the Spanish Regulatory Agency (Agencia Española del Medicamento y Productos Sanitarios). Data will be presented at international conferences and published in peer-reviewed journals. Strategies to reduce the use of BSA should be a priority. Most of the studies that support de-escalation are observational, retrospective and heterogeneous. A recent Cochrane review stated that well-designed clinical trials should be conducted to assess the safety and efficacy of de-escalation. The European Union Clinical Trials Register: EudraCT number 2015-004219-19. Clinical trials.gov: NCT02795949. Protocol version: V.2.0, dated 16 May 2016. All items from

  15. Novel Clostridium difficile Anti-Toxin (TcdA and TcdB Humanized Monoclonal Antibodies Demonstrate In Vitro Neutralization across a Broad Spectrum of Clinical Strains and In Vivo Potency in a Hamster Spore Challenge Model.

    Directory of Open Access Journals (Sweden)

    Hongyu Qiu

    Full Text Available Clostridium difficile (C. difficile infection (CDI is the main cause of nosocomial antibiotic-associated colitis and increased incidence of community-associated diarrhea in industrialized countries. At present, the primary treatment of CDI is antibiotic administration, which is effective but often associated with recurrence, especially in the elderly. Pathogenic strains produce enterotoxin, toxin A (TcdA, and cytotoxin, toxin B (TcdB, which are necessary for C. difficile induced diarrhea and gut pathological changes. Administration of anti-toxin antibodies provides an alternative approach to treat CDI, and has shown promising results in preclinical and clinical studies. In the current study, several humanized anti-TcdA and anti-TcdB monoclonal antibodies were generated and their protective potency was characterized in a hamster infection model. The humanized anti-TcdA (CANmAbA4 and anti-TcdB (CANmAbB4 and CANmAbB1 antibodies showed broad spectrum in vitro neutralization of toxins from clinical strains and neutralization in a mouse toxin challenge model. Moreover, co-administration of humanized antibodies (CANmAbA4 and CANmAbB4 cocktail provided a high level of protection in a dose dependent manner (85% versus 57% survival at day 22 for 50 mg/kg and 20 mg/kg doses, respectively in a hamster gastrointestinal infection (GI model. This study describes the protective effects conferred by novel neutralizing anti-toxin monoclonal antibodies against C. difficile toxins and their potential as therapeutic agents in treating CDI.

  16. Banking contracts

    OpenAIRE

    Sochorová, Silvie

    2012-01-01

    Resumé - Bank Contracts Bank Contracts are an integral part of our everyday lives. Citizen and bussines entities used bank contracts very often. Despite this fact we can't find legal definition in the Czech law. Banking contracts understand contracts that are signed by banks in their business activities and obligations under these contracts arise. While the banking contracts have been widely used, in Czech law there is not too much literature and judgements abou this issue. Lack of legislatio...

  17. THE PSYCHOLOGICAL CONTRACT

    Directory of Open Access Journals (Sweden)

    Blanca Giorgiana GRAMA

    2015-04-01

    Full Text Available The psychological contract became known as a research paradigm within corporate research, providing a broad framework which explains the employee-company relations. Despite all this, there are still many debates on the concept and a series of criticism were expressed that led to the necessity of some more rigorous theoretical and empirical analysis. The psychological contract refers to the unwritten, implicit expectations that employees have from the company and vice versa; it is that which defines the things the employee expects from the employer. Consequently, each of the parties involved in the contract may have different perceptions on these commitments and obligations. Thus the psychological contract may be regarded as an exchange relation between the employer and the employee. Breaking the psychological contract affects the performance, the morale, and the motivation of the staff in a negative manner. The information presented in this paper is intended to contribute to the theoretical and methodological development of the concept.

  18. Contract archaeology and news archaeological contracts

    Directory of Open Access Journals (Sweden)

    Wilhelm Londoño

    2016-09-01

    Full Text Available This paper addresses two topics related to the current situation of archaeology in Latin America and Colombia. The first section of the paper deals with the impact of contract archaeology in Colombia. The fact that programs of contract or preventive archaeology have rocketed in recent years is well known. Less known, however, are the broad tendencies and dimensions of this phenomenon. The second issue discussed here is the relationship between global tourism politics and processes of local recovery and enhancement of heritage assets, which will be explored through the analysis of two archaeological sites. The recovery and touristification of an archaeological site is used as starting point to reflect about the differences between a new tendency in archaeological contract opposed to the dominant tendency in the field.

  19. The 2010 Broad Prize

    Science.gov (United States)

    Education Digest: Essential Readings Condensed for Quick Review, 2011

    2011-01-01

    A new data analysis, based on data collected as part of The Broad Prize process, provides insights into which large urban school districts in the United States are doing the best job of educating traditionally disadvantaged groups: African-American, Hispanics, and low-income students. Since 2002, The Eli and Edythe Broad Foundation has awarded The…

  20. Administrative contracts

    Directory of Open Access Journals (Sweden)

    Vukićević-Petković Milica

    2015-01-01

    Full Text Available Administrative contracts are a special type of contract where usually one of the contracting parties is a public law body and which is concluded for the performance of public service and the realization of a public interest. They go a long way since its inception to its eventual final acceptance of all the legal systems. One of the enduring characteristics of this type of contract is their disquised or unnoticed existence. This is why only monitoring their development may lead to a complete understanding of the importance and essence of this institution as well as the need for its complete legal regulation.

  1. Electrical contracting

    CERN Document Server

    Neidle, Michael

    2013-01-01

    Electrical Contracting, Second Edition is a nine-chapter text guide for the greater efficiency in planning and completing installations for the design, installation and control of electrical contracts. This book starts with a general overview of the efficient cabling and techniques that must be employed for safe wiring design, as well as the cost estimation of the complete electrical contract. The subsequent chapters are devoted to other electrical contracting requirements, including electronic motor control, lighting, and electricity tariffs. A chapter focuses on the IEE Wiring Regulations an

  2. Administrative contracts

    OpenAIRE

    Vukićević-Petković Milica

    2015-01-01

    Administrative contracts are a special type of contract where usually one of the contracting parties is a public law body and which is concluded for the performance of public service and the realization of a public interest. They go a long way since its inception to its eventual final acceptance of all the legal systems. One of the enduring characteristics of this type of contract is their disquised or unnoticed existence. This is why only monitoring their development may lead to a complete u...

  3. Three-dimensional Ag2O/Bi5O7I p-n heterojunction photocatalyst harnessing UV-vis-NIR broad spectrum for photodegradation of organic pollutants.

    Science.gov (United States)

    Chen, Yannan; Zhu, Gangqiang; Hojamberdiev, Mirabbos; Gao, Jianzhi; Zhu, Runliang; Wang, Chenghui; Wei, Xiumei; Liu, Peng

    2018-02-15

    Ag 2 O nanoparticles-loaded Bi 5 O 7 I microspheres forming a three dimensional Ag 2 O/Bi 5 O 7 I p-n heterojunction photocatalyst with wide-spectrum response were synthesized in this study. The results of transmission electron microscopy observations revealed that the Ag 2 O nanoparticles with the diameter of ca. 10-20nm were distributed on the surfaces of Bi 5 O 7 I nanosheets. The as-synthesized Ag 2 O/Bi 5 O 7 I exhibited an excellent wide-spectrum response to wavelengths ranging from ultraviolet (UV) to near-infrared (NIR), indicating its potential for effective utilization of solar energy. Compared with pure Bi 5 O 7 I, the Ag 2 O/Bi 5 O 7 I composite also demonstrated excellent photocatalytic activity for the degradation of Bisphenol A and phenol in aqueous solution under visible LED light irradiation. Among samples, the 20% Ag 2 O/Bi 5 O 7 I composite photocatalyst showed the highest photocatalytic activity for the degradation of Bisphenol A and phenol in aqueous solution. In addition, the 20% Ag 2 O/Bi 5 O 7 I composite also exhibited a photocatalytic activity for the degradation of Bisphenol A under NIR light irradiation. The improved photocatalytic activity is attributed to the formation of a p-n heterojunction between Ag 2 O and Bi 5 O 7 I, allowing the efficient utilization of solar energy (from UV to NIR) and high separation efficiency of photogenerated electron-hole pairs. The present work is desirable to explore a possible avenue for the full utilization of solar energy. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Feleucin-BO1: a novel antimicrobial non-apeptide amide from the skin secretion of the toad, Bombina orientalis, and design of a potent broad-spectrum synthetic analogue, feleucin-K3.

    Science.gov (United States)

    Hou, Xiaojuan; Du, Qiang; Li, Renjie; Zhou, Mei; Wang, Hui; Wang, Lei; Guo, Can; Chen, Tianbao; Shaw, Chris

    2015-03-01

    Feleucins-BV1 and -BV2 are recently described prototypes of a novel antimicrobial non-apeptide (AMP) family identified in the skin secretion of the bombinid toad, Bombina variegata. They are encoded on different precursors that also encode a novel bombinin. Here we describe the identification of feleucin-BO1 (FLGLLGSLLamide) which is co-encoded with a different novel bombinin, named feleucin precursor-associated bombinin (FPA-bombinin-BO), from the skin secretion of Bombina orientalis. Synthetic feleucin-BO1 displayed activity against a reference Gram-positive bacterium. Staphylococcus aureus (MIC 34 μm) but was inactive (> 250 μm) against the Gram-negative bacterium, Escherichia coli, and the yeast, Candida albicans. This pattern of activity was similar to that of the prototypes. Design and synthesis of a cationicity-enhanced analogue, feleucin-K3 (F-K3), in which the amino acid residues at positions 3 (G), 6 (G) and 7 (S) of feleucin-BO1 were substituted with Lys (K) residues, resulted in a peptide with significantly enhanced potency and spectrum of activity. The MICs of F-K3 against the reference micro-organisms were 7 μm (S. aureus), 14 μm (E. coli) and 7 μm (C. albicans). These data indicate that the skin secretions of amphibians can continue to provide novel peptide templates for the rational design of analogues with possible therapeutic utility. © 2014 John Wiley & Sons A/S.

  5. The BpeAB-OprB efflux pump of Burkholderia pseudomallei 1026b does not play a role in quorum sensing, virulence factor production, or extrusion of aminoglycosides but is a broad-spectrum drug efflux system.

    Science.gov (United States)

    Mima, Takehiko; Schweizer, Herbert P

    2010-08-01

    Most Burkholderia pseudomallei strains are intrinsically aminoglycoside resistant, mainly due to AmrAB-OprA-mediated efflux. Rare naturally occurring or genetically engineered mutants lacking this pump are aminoglycoside susceptible despite the fact that they also encode and express BpeAB-OprB, which was reported to mediate efflux of aminoglycosides in the Singapore strain KHW. To reassess the role of BpeAB-OprB in B. pseudomallei aminoglycoside resistance, we used mutants overexpressing or lacking this pump in either AmrAB-OprA-proficient or -deficient strain 1026b backgrounds. Our data show that BpeAB-OprB does not mediate efflux of aminoglycosides but is a multidrug efflux system which extrudes macrolides, fluoroquinolones, tetracyclines, acriflavine, and, to a lesser extent, chloramphenicol. Phylogenetically, BpeAB-OprB is closely related to Pseudomonas aeruginosa MexAB-OprM, which has a similar substrate spectrum. AmrAB-OprA is most closely related to MexXY, the only P. aeruginosa efflux pump known to extrude aminoglycosides. Since BpeAB-OprB in strain KHW was also implicated in playing a major role in export of acylated homoserine lactone (AHL) quorum-sensing molecules and in expression of diverse virulence factors, we explored whether this was also true in the strain 1026b background. The results showed that BpeAB-OprB was not required for AHL export, and mutants lacking this efflux system exhibited normal swimming motility and siderophore production, which were severely impaired in KHW bpeAB-oprB mutants. Biofilm formation was impaired in 1026b Delta(amrRAB-oprA) and Delta(amrRAB-oprA) Delta(bpeAB-oprB) mutants. At present, we do not know why our BpeAB-OprB susceptibility and virulence factor expression results with 1026b and its derivatives are different from those previously published for Singapore strain KHW.

  6. The North Sea contracting industry

    International Nuclear Information System (INIS)

    Wright, P.J.C.

    1996-09-01

    The North Sea Contracting Industry provides in-depth profiles of major contracting organisations including manpower, facilities, expertise, future directions and financial details. It addresses key issues such as: how will the role of operators and contractors change toward 2000 and beyond?; how will the contractor-operator relationship develop?; will the contractors take a more speculative role in projects such as leasing and contract to produce?; does the future belong to broad skilled providers or small specialised niche players, or both?; and how will rapid technological improvements affect the industry? (author)

  7. Contract Renewal Information - all Contracts

    Data.gov (United States)

    Department of Housing and Urban Development — Multifamily Portfolio datasets (section 8 contracts) - The information has been compiled from multiple data sources within FHA or its contractors. HUD oversees more...

  8. Contract theory and EU Contract Law

    OpenAIRE

    Hesselink, M.W.; Twigg-Flesner, C.

    2016-01-01

    This paper explores the relationship between contract theory and European contract law. In particular, it confronts the leading contract law theories with the main characteristics of EU contract law. The conclusion is that the two do not match well. In particular, monist normative contract theories are largely irreconcilable with the contract law of the EU. The paper further addresses the main implications of this mismatch, both for contract theory and for EU contract law. It suggests that in...

  9. Agile Contracts

    DEFF Research Database (Denmark)

    Pries-Heje, Jan; Pries-Heje, Lene

    2014-01-01

    When you have stable and non-ambiguous requirements then a classic contract for IS between a supplier and a public sector institution based on a requirements specification may be well suited. However, if you have to accept many changes or have ambiguous requirements then you may end up...... with “endless” re-negotiation of the requirements; you need a more flexible way to develop IS. A new way of coping with many changes is to use an agile development approach and a fixed budget and resources contract. This paper presents an example case. We analyse the case and design a guideline for how...... to implement a fixed budget and resources contract in the public sector. The guideline includes elements to cope with challenges in a tender process such as transparency, criteria for supplier selection, and live assessment of resource skills and capabilities, as well as achieving the flexibility for change...

  10. Turnkey contracts

    International Nuclear Information System (INIS)

    Langetepe, G.

    1977-01-01

    To make energy available economically and in sufficient quantity is a main point for the future of an industrial and more for a developing country. The investment costs and the availability of a power plant and in particular for a nuclear power plant are the most significant factors in the economic operation of the plant. In the phase before signing the contract the essential decisions are made with high influence in the economic operation and the availability of the plant. A turn-key contract offers good possibilities to minimize the risks referring a) the plant quality and functionality, b) the plant investment cost, c) the plant completion date, d) the handling of the licensing procedures, e) the availability of the operation. The lecture mentions the points which are of high influence for a successful erection and operation period and which must be clarified before signing the contract between the buyer and supplier of the plant. (orig./HP) [de

  11. Evaluation of the immunogenicity and safety of different doses and formulations of a broad spectrum influenza vaccine (FLU-v) developed by SEEK: study protocol for a single-center, randomized, double-blind and placebo-controlled clinical phase IIb trial.

    Science.gov (United States)

    van Doorn, Eva; Pleguezuelos, Olga; Liu, Heng; Fernandez, Ana; Bannister, Robin; Stoloff, Gregory; Oftung, Fredrik; Norley, Stephen; Huckriede, Anke; Frijlink, Henderik W; Hak, Eelko

    2017-04-04

    Current influenza vaccines, based on antibodies against surface antigens, are unable to provide protection against newly emerging virus strains which differ from the vaccine strains. Therefore the population has to be re-vaccinated annually. It is thus important to develop vaccines which induce protective immunity to a broad spectrum of influenza viruses. This trial is designed to evaluate the immunogenicity and safety of FLU-v, a vaccine composed of four synthetic peptides with conserved epitopes from influenza A and B strains expected to elicit both cell mediated immunity (CMI) and humoral immunity providing protection against a broad spectrum of influenza viruses. In a single-center, randomized, double-blind and placebo-controlled phase IIb trial, 222 healthy volunteers aged 18-60 years will be randomized (2:2:1:1) to receive two injections of a suspension of 500 μg FLU-v in saline (arm 1), one dose of emulsified 500 μg FLU-v in Montanide ISA-51 and water for injection (WFI) followed by one saline dose (arm 2), two saline doses (arm 3), or one dose of Montanide ISA-51 and WFI emulsion followed by one saline dose (arm 4). All injections will be given subcutaneously. Primary endpoints are safety and FLU-v induced CMI, evaluated by cytokine production by antigen specific T cell populations (flow-cytometry and ELISA). Secondary outcomes are measurements of antibody responses (ELISA and multiplex), whereas exploratory outcomes include clinical efficacy and additional CMI assays (ELISpot) to show cross-reactivity. Broadly protective influenza vaccines able to provide protection against multiple strains of influenza are urgently needed. FLU-v is a promising vaccine which has shown to trigger the cell-mediated immune response. The dosages and formulations tested in this current trial are also estimated to induce antibody response. Therefore, both cellular and humoral immune responses will be evaluated. EudraCT number 2015-001932-38 ; retrospectively registered

  12. Broad spectrum probiotic (Sakhabactisubtil recovered from Yakutia permafrost soil

    Directory of Open Access Journals (Sweden)

    Mikhail Petrovich Neustroev

    2011-10-01

    Full Text Available Probiotic “Sakhabactisubtil” has been developed, it has unique biological properties: frank antagonistic effect against pathogen and opportunistic microorganisms (bacteria, fungi and viruses, interferon-evoke activity, immune system enhancing effect, producing a range of ferments, beneficial microflora formation's stimulation, resistance to a number of antibiotics. [Vet. World 2011; 4(5.000: 222-224

  13. Development of a Broad-Spectrum Antiviral Agent with Activity ...

    African Journals Online (AJOL)

    72 h; 6 = ACV, 72 h; 7.5 ng/mL H9, 72 h;8.10 ng/mL. H9, 72 h). Anti-HCMV activity. H9 inhibited the production of pp65 in HCMV- infected Helf cell culture supernatant in a dose-dependent manner. EC50 of H9 (0.46 ng/ml) was greater than that of the standard ganciclovir. (GCV) group (0.68 ng/ml). As shown in Fig 3A,.

  14. Silver nanoparticles are broad-spectrum bactericidal and virucidal compounds

    Directory of Open Access Journals (Sweden)

    Ixtepan-Turrent Liliana

    2011-08-01

    Full Text Available Abstract The advance in nanotechnology has enabled us to utilize particles in the size of the nanoscale. This has created new therapeutic horizons, and in the case of silver, the currently available data only reveals the surface of the potential benefits and the wide range of applications. Interactions between viral biomolecules and silver nanoparticles suggest that the use of nanosystems may contribute importantly for the enhancement of current prevention of infection and antiviral therapies. Recently, it has been suggested that silver nanoparticles (AgNPs bind with external membrane of lipid enveloped virus to prevent the infection. Nevertheless, the interaction of AgNPs with viruses is a largely unexplored field. AgNPs has been studied particularly on HIV where it was demonstrated the mechanism of antiviral action of the nanoparticles as well as the inhibition the transmission of HIV-1 infection in human cervix organ culture. This review discusses recent advances in the understanding of the biocidal mechanisms of action of silver Nanoparticles.

  15. Antipneumococcal activity of ceftobiprole, a novel broad-spectrum cephalosporin.

    Science.gov (United States)

    Kosowska, Klaudia; Hoellman, Dianne B; Lin, Gengrong; Clark, Catherine; Credito, Kim; McGhee, Pamela; Dewasse, Bonifacio; Bozdogan, Bülent; Shapiro, Stuart; Appelbaum, Peter C

    2005-05-01

    Ceftobiprole (previously known as BAL9141), an anti-methicillin-resistant Staphylococcus aureus cephalosporin, was very highly active against a panel of 299 drug-susceptible and -resistant pneumococci, with MIC(50) and MIC(90) values (microg/ml) of 0.016 and 0.016 (penicillin susceptible), 0.06 and 0.5 (penicillin intermediate), and 0.5 and 1.0 (penicillin resistant). Ceftobiprole, imipenem, and ertapenem had lower MICs against all pneumococcal strains than amoxicillin, cefepime, ceftriaxone, cefotaxime, cefuroxime, or cefdinir. Macrolide and penicillin G MICs generally varied in parallel, whereas fluoroquinolone MICs did not correlate with penicillin or macrolide susceptibility or resistance. All strains were susceptible to linezolid, quinupristin-dalfopristin, daptomycin, vancomycin, and teicoplanin. Time-kill analyses showed that at 1x and 2x the MIC, ceftobiprole was bactericidal against 10/12 and 11/12 strains, respectively. Levofloxacin, moxifloxacin, vancomycin, and teicoplanin were each bactericidal against 10 to 12 strains at 2x the MIC. Azithromycin and clarithromycin were slowly bactericidal, and telithromycin was bactericidal against only 5/12 strains at 2x the MIC. Linezolid was mainly bacteriostatic, whereas quinupristin-dalfopristin and daptomycin showed marked killing at early time periods. Prolonged serial passage in the presence of subinhibitory concentrations of ceftobiprole failed to yield mutants with high MICs towards this cephalosporin, and single-passage selection showed very low frequencies of spontaneous mutants with breakthrough MICs towards ceftobiprole.

  16. Pc1 with a broad frequency spectrum - "Goose pulsations"

    Czech Academy of Sciences Publication Activity Database

    Feygin, F. Z.; Prikner, Karel; Kangas, J.

    2009-01-01

    Roč. 53, č. 4 (2009), s. 519-536 ISSN 0039-3169 Institutional research plan: CEZ:AV0Z30120515 Keywords : geomagnetic pulsations * nonlinear particle-wave interaction * Pc1 wave packets * ionospheric Alfvén resonator (IAR) Subject RIV: DE - Earth Magnetism, Geodesy, Geography Impact factor: 1.000, year: 2009

  17. Focused versus Broad-Spectrum Behavior Therapy for Problem Drinkers.

    Science.gov (United States)

    Miller, William R.; And Others

    1980-01-01

    Results of this comparison of treatment methods indicated that all groups improved significantly on drinking measures. Breath testing was found to be unhelpful as an assessment procedure. The degree to which therapists showed accurate empathy proved to be a good predictor of client outcome. (Author)

  18. Broad-spectrum physical fitness benefits of recreational football

    DEFF Research Database (Denmark)

    Milanović, Zoran; Pantelić, Saša; Čović, Nedim

    2018-01-01

    , narrative reviews have demonstrated beneficial effects of recreational football on physical fitness and health status. OBJECTIVE: The purpose of this systematic review and meta-analysis was to evaluate the magnitude of effects of recreational football on blood pressure, body composition, lipid profile...... to a recreational football group or any other type of exercises or passive control group were included. Training programmes had to last at least 2 weeks to meet the inclusion criteria. The primary outcome measures were blood pressure, resting heart rate, body composition, muscular fitness, and blood lipids....... Possibly beneficial decreases were found in low-density lipoprotein levels (ES=0.21 mmol/L; 95% CI 0.06 to 0.36). Possibly largely beneficial effect was observed for DBP in comparison with continuous running training. Small harmful and unclear results were noted for SBP, fat and lean body mass, body mass...

  19. Predictive compound accumulation rules yield a broad-spectrum antibiotic

    Science.gov (United States)

    Richter, Michelle F.; Drown, Bryon S.; Riley, Andrew P.; Garcia, Alfredo; Shirai, Tomohiro; Svec, Riley L.; Hergenrother, Paul J.

    2017-05-01

    Most small molecules are unable to rapidly traverse the outer membrane of Gram-negative bacteria and accumulate inside these cells, making the discovery of much-needed drugs against these pathogens challenging. Current understanding of the physicochemical properties that dictate small-molecule accumulation in Gram-negative bacteria is largely based on retrospective analyses of antibacterial agents, which suggest that polarity and molecular weight are key factors. Here we assess the ability of over 180 diverse compounds to accumulate in Escherichia coli. Computational analysis of the results reveals major differences from the retrospective studies, namely that the small molecules that are most likely to accumulate contain an amine, are amphiphilic and rigid, and have low globularity. These guidelines were then applied to convert deoxynybomycin, a natural product that is active only against Gram-positive organisms, into an antibiotic with activity against a diverse panel of multi-drug-resistant Gram-negative pathogens. We anticipate that these findings will aid in the discovery and development of antibiotics against Gram-negative bacteria.

  20. Studies on broad spectrum corrosion resistant oxide coatings

    Indian Academy of Sciences (India)

    Unknown

    Abstract. The corrosion resistant oxide coatings, developed and applied by the conventional vitreous enamelling techniques, showed superior resistance to a range of mineral acids at various strengths and temperatures, alkaline solutions, boiling water and chrome plating solutions. These coatings possess considerable ...

  1. Studies on broad spectrum corrosion resistant oxide coatings

    Indian Academy of Sciences (India)

    Unknown

    900°C. Subsequently, the coatings were heat-treated at 698°C for 1 h. The coating materials were analysed by differential thermal analysis (DTA) and thermogravimetric analysis. (TGA) techniques (Netzsch STA 409C model instrument).

  2. Molecular detection of TEM broad spectrum β- lactamase in clinical ...

    African Journals Online (AJOL)

    Jane

    2011-08-22

    Aug 22, 2011 ... the recommendations of the Clinical and Laboratory. Standards Institute (CLSI), isolates that show reduced susceptibility to β-lactam antibiotics, especially third generation antibiotics, such as cephalosporins, are potential ESBL-expressing strains and can be confirmed in phenotypic tests using clavulanate ...

  3. Broad Spectrum Photoelectrochemical Diodes for Solar Hydrogen Generation

    Energy Technology Data Exchange (ETDEWEB)

    Grimes, Craig A.

    2014-11-26

    Under program auspices we have investigated material chemistries suitable for the solar generation of hydrogen by water photoelectrolysis. We have built upon, and extended, our knowledge base on the synthesis and application of TiO2 nanotube arrays, a material architecture that appears ideal for water photoelectrolysis. To date we have optimized, refined, and greatly extended synthesis techniques suitable for achieving highly ordered TiO2 nanotube arrays of given length, wall thickness, pore diameter, and tube-to-tube spacing for use in water photoelectrolysis. We have built upon this knowledge based to achieve visible light responsive, photocorrosion stable n-type and p-type ternary oxide nanotube arrays for use in photoelectrochemical diodes.

  4. Volatile aldehydes are promising broad-spectrum postharvest insecticides.

    Science.gov (United States)

    Hammond, D G; Rangel, S; Kubo, I

    2000-09-01

    A variety of naturally occurring aldehydes common in plants have been evaluated for their insecticidal activity and for phytotoxicity to postharvest fruits, vegetables, and grains. Twenty-nine compounds were initially screened for their activity against aphids on fava bean leaf disks. Application under reduced pressure (partial vacuum) for the first quarter of fumigation increased insecticidal activity severalfold. The 11 best aldehydes were assayed against aphids placed under the third leaf of whole heads of iceberg lettuce using the same two-tier reduced-pressure regime, which caused no additional detriment to the commodity over fumigation at atmospheric pressure. Phytotoxicity to naked and wrapped iceburg lettuce, green and red table grapes, lemon, grapefruit, orange, broccoli, avocado, cabbage, pinto bean, and rice at doses that killed 100% of aphids was recorded for three promising fumigants: propanal, (E)-2-pentenal, and 2-methyl-(E)-2-butenal. These three compounds have excellent potential as affordable postharvest insect control agents, killing 100% of the aphids with little or no detectable harm to a majority of the commodities tested. Preliminary assays indicate that similar doses are also effective against mealybugs, thrips, and whitefly.

  5. Studies on broad spectrum corrosion resistant oxide coatings

    Indian Academy of Sciences (India)

    The corrosion resistant oxide coatings, developed and applied by the conventional vitreous enamelling techniques, showed superior resistance to a range of mineral acids at various strengths and temperatures, alkaline solutions, boiling water and chrome plating solutions. These coatings possess considerable abrasion ...

  6. Contract theory and EU Contract Law

    NARCIS (Netherlands)

    Hesselink, M.W.; Twigg-Flesner, C.

    2016-01-01

    This paper explores the relationship between contract theory and European contract law. In particular, it confronts the leading contract law theories with the main characteristics of EU contract law. The conclusion is that the two do not match well. In particular, monist normative contract theories

  7. Broad resonances and beta-decay

    DEFF Research Database (Denmark)

    Riisager, K.; Fynbo, H. O. U.; Hyldegaard, S.

    2015-01-01

    Beta-decay into broad resonances gives a distorted lineshape in the observed energy spectrum. Part of the distortion arises from the phase space factor, but we show that the beta-decay matrix element may also contribute. Based on a schematic model for p-wave continuum neutron states it is argued...... that beta-decay directly to the continuum should be considered as a possible contributing mechanism in many decays close to the driplines. The signatures in R-matrix fits for such decays directly to continuum states are discussed and illustrated through an analysis of the beta-decay of $^8$B into $2...

  8. Broad band exciplex dye lasers

    International Nuclear Information System (INIS)

    Dienes, A.; Shank, C.V.; Trozzolo, A.M.

    1975-01-01

    The disclosure is concerned with exciplex dye lasers, i.e., lasers in which the emitting species is a complex formed only from a constituent in an electronically excited state. Noting that an exciplex laser, favorable from the standpoint of broad tunability, results from a broad shift in the peak emission wavelength for the exciplex relative to the unreacted species, a desirable class resulting in such broad shift is described. Preferred classes of laser media utilizing specified resonant molecules are set forth. (auth)

  9. European contract law and the capabilities approach: on distributive responsibility for contract law

    NARCIS (Netherlands)

    Tjon Soei Len, L.; Weidtmann, N.; Hölzchen, Y.M.; Hawa, B.

    2012-01-01

    This paper argues that the normative requirements of Nussbaum’s capabilities approach extend to contract law (and private law more broadly). Contract law is part of a society’s basic structure, i.e. the responsibility bearing structure that is to secure and enhance individuals’ basic capabilities.

  10. Integrating Hot and Cool Intelligences: Thinking Broadly about Broad Abilities

    Directory of Open Access Journals (Sweden)

    W. Joel Schneider

    2016-01-01

    Full Text Available Although results from factor-analytic studies of the broad, second-stratum abilities of human intelligence have been fairly consistent for decades, the list of broad abilities is far from complete, much less understood. We propose criteria by which the list of broad abilities could be amended and envision alternatives for how our understanding of the hot intelligences (abilities involving emotionally-salient information and cool intelligences (abilities involving perceptual processing and logical reasoning might be integrated into a coherent theoretical framework.

  11. Types of contracts and contracting procedures

    International Nuclear Information System (INIS)

    Zijl, N.A. van

    1977-01-01

    Contracting for a nuclear power plant can be carried out in many different ways, from a bilateral agreement between two countries to an international open bidding competition. Also the kind of contracts (turnkey, split-package or multi-contract type) are discussed with their pros and cons as well as the contracting procedures which can be followed to come to the conclusion of a contract. (orig.) [de

  12. Method Determining the Contents of the Contract

    Directory of Open Access Journals (Sweden)

    Agus Yudha Hernoko

    2017-03-01

    Full Text Available The contents of the contract are primarily determined by what the real mutually agreed upon by the parties. By interpreting some certain statements, in this case to determine its meaning, to be clear based on what the parties committed themselves. Why is the interpretation required? In facts, on the many cases provided a valuable lesson, how many commercial disputes arise when the performance of the contract. The dispute begins when the parties have a different understanding of the statement that they use in the contract. Indeed, businesses are very familiar with the business processes that they do, but at the time of the business process are set forth in the contract language and designed by those who do not understand the legal aspects of the contract, the contract can be ascertained open possibility for disputes. The power of contract binding (the contents of the agreement toward to the characteristic and the wide spectrum of the rights and obligations contractually, basically a contract represents the power of performance among others in order implementing the rights and obligations of the parties. As an instrument to understand the contract, the method of determining the content of the contract (e.g., through interpretation, autonomous and heteronomous factors, further can be used to assess the reciprocation of rights and obligations in a meaningful and proportional contractual relationship.

  13. 48 CFR 1335.016-70 - DOC procedures for the use of broad agency announcements.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false DOC procedures for the use of broad agency announcements. 1335.016-70 Section 1335.016-70 Federal Acquisition Regulations System DEPARTMENT OF COMMERCE SPECIAL CATEGORIES OF CONTRACTING RESEARCH AND DEVELOPMENT CONTRACTING 1335.016-70 DOC...

  14. Spectrophotometry of six broad absorption line QSOs

    Science.gov (United States)

    Junkkarinen, Vesa T.; Burbidge, E. Margaret; Smith, Harding E.

    1987-01-01

    Spectrophotometric observations of six broad absorption-line QSOs (BALQSOs) are presented. The continua and emission lines are compared with those in the spectra of QSOs without BALs. A statistically significant difference is found in the emission-line intensity ratio for (N V 1240-A)/(C IV 1549-A). The median value of (N V)/(C IV) for the BALQSOs is two to three times the median for QSOs without BALs. The absorption features of the BALQSOs are described, and the column densities and limits on the ionization structure of the BAL region are discussed. If the dominant ionization mechanism is photoionization, then it is likely that either the ionizing spectrum is steep or the abundances are considerably different from solar. Collisional ionization may be a significant factor, but it cannot totally dominate the ionization rate.

  15. AMP-activated protein kinase in contraction regulation of skeletal muscle metabolism: necessary and/or sufficient?

    DEFF Research Database (Denmark)

    Jensen, Thomas Elbenhardt; Wojtaszewski, Jørgen; Richter, Erik

    2009-01-01

    in mitochondrial biogenesis and other aspects of promoting an oxidative muscle phenotype. Here, the current knowledge on the expression of AMPK subunits in human quadriceps muscle and evidence from rodent studies suggesting distinct AMPK subunit expression pattern in different muscle types is reviewed. Then......, the intensity and time dependence of AMPK activation in human quadriceps and rodent muscle are evaluated. Subsequently, a major part of this review critically examines the evidence supporting a necessary and/or sufficient role of AMPK in a broad spectrum of skeletal muscle contraction-relevant processes...

  16. EFFECTS OF COMMERCIAL CONTRACT

    OpenAIRE

    Ana-Maria Florea; Constantin Giurca

    2014-01-01

    The contract is a legal instrument used to organize economic and social life. International trade agreement has certain features in order to ensure the international exchange of goods and services between the Contracting Parties. In terms of commercial contract, there is a foreign origin element, that gives the parties the right to determine the law to govern the contract. A fundamental aspect of commercial contract, in addition to that of determining the law applicable to judicial report est...

  17. A prism based magnifying hyperlens with broad-band imaging

    DEFF Research Database (Denmark)

    Habib, Md. Samiul; Stefani, Alessio; Atakaramians, Shaghik

    2017-01-01

    Magnification in metamaterial hyperlenses has been demonstrated using curved geometries or tapered devices, at frequencies ranging from the microwave to the ultraviolet spectrum. One of the main issues of such hyperlenses is the difficulty in manufacturing. In this letter, we numerically and expe......Magnification in metamaterial hyperlenses has been demonstrated using curved geometries or tapered devices, at frequencies ranging from the microwave to the ultraviolet spectrum. One of the main issues of such hyperlenses is the difficulty in manufacturing. In this letter, we numerically...... frequency dependent artefacts, a priori limiting the use of the device for broad-band imaging. We identify the main source of image aberration as the reflections supported by the wire medium and also show that even the weaker reflections severely affect the imaging quality. In order to correct...... for the reflections, we devise a filtering technique equivalent to spatially variable time gating so that ultra-broad band imaging is achieved....

  18. Reviving Ulysses contracts.

    Science.gov (United States)

    Spellecy, Ryan

    2003-12-01

    Ulysses contracts have faced paternalism objections since they first were proposed. Since the contracts are designed to override a present request from a legally competent patient in favor of a past request made by that patient, enforcement of these contracts was argued to be unjustifiable strong paternalism. Recent legal developments and new theories of practical reasoning suggest that the discussion of Ulysses contracts should be revived. This paper argues that with a proper understanding of the future-directed planning embodied in Ulysses contracts, the charge of strong paternalism can be answered, and the enforcement of some Ulysses contracts may be justified under the rubric of weak paternalism.

  19. ADMINISTRATIVE CONTRACTS. DELIMITATIONS

    Directory of Open Access Journals (Sweden)

    Liana Teodora PASCARIU

    2016-12-01

    Full Text Available Article examines whether all contracts of public persons are administrative contracts; in other words, if the administration may conclude contracts that, according to their legal nature, are not administrative. If we start from the definition of administrative contracts as it appears in Law no. 554/2004, these include contracts by public authorities which concern the enhancement of public property execution of works of public interest, public services, public procurement and other administrative contracts provided by special laws and subject to the jurisdiction of the administrative courts.

  20. Contractibility of curves

    Directory of Open Access Journals (Sweden)

    Janusz Charatonik

    1991-11-01

    Full Text Available Results concerning contractibility of curves (equivalently: of dendroids are collected and discussed in the paper. Interrelations tetween various conditions which are either sufficient or necessary for a curve to be contractible are studied.

  1. International sales contract

    OpenAIRE

    Lauermannová, Irena

    2013-01-01

    75 International Sales Contract Abstract The objective of this thesis is to describe the ways of avoidance of the contract available under the United Nations Convention on Contracts for the International Sale of Goods (hereinafter the "Convention") and to make an analysis of its key term "fundamental breach of contract" as it is defined in its article 25. The thesis is composed of the introduction, three main chapters and the conclusion. The first chapter introduces the Convention itself. It ...

  2. Broad-Band Activatable White-Opsin.

    Directory of Open Access Journals (Sweden)

    Subrata Batabyal

    Full Text Available Currently, the use of optogenetic sensitization of retinal cells combined with activation/inhibition has the potential to be an alternative to retinal implants that would require electrodes inside every single neuron for high visual resolution. However, clinical translation of optogenetic activation for restoration of vision suffers from the drawback that the narrow spectral sensitivity of an opsin requires active stimulation by a blue laser or a light emitting diode with much higher intensities than ambient light. In order to allow an ambient light-based stimulation paradigm, we report the development of a 'white-opsin' that has broad spectral excitability in the visible spectrum. The cells sensitized with white-opsin showed excitability at an order of magnitude higher with white light compared to using only narrow-band light components. Further, cells sensitized with white-opsin produced a photocurrent that was five times higher than Channelrhodopsin-2 under similar photo-excitation conditions. The use of fast white-opsin may allow opsin-sensitized neurons in a degenerated retina to exhibit a higher sensitivity to ambient white light. This property, therefore, significantly lowers the activation threshold in contrast to conventional approaches that use intense narrow-band opsins and light to activate cellular stimulation.

  3. Broad-Application Test Reactor

    International Nuclear Information System (INIS)

    Motloch, C.G.

    1992-05-01

    This report is about a new, safe, and operationally efficient DOE reactor of nuclear research and testing proposed for the early to mid- 21st Century. Dubbed the Broad-Application Test Reactor (BATR), the proposed facility incorporates a multiple-application, multiple-mission design to support DOE programs such as naval reactors and space power and propulsion, as well as research in medical, science, isotope, and electronics arenas. DOE research reactors are aging, and implementing major replacement projects requires long lead times. Primary design drivers include safety, low risk, minimum operation cost, mission flexibility, waste minimization, and long life. Scientists and engineers at the Idaho National Engineering Laboratory are evaluating possible fuel forms, structural materials, reactor geometries, coolants, and moderators

  4. The Joy of Contracts.

    Science.gov (United States)

    Hegarty, Kevin

    This paper is a practical guide that explains and illustrates contracts between libraries and vendors for computerized circulation systems. It describes the elements of a typical contract to include the equipment and services that should be specified in the contract and establishes scheduling and acceptance testing needs. Included in a contract…

  5. Contracting for nuclear fuels

    International Nuclear Information System (INIS)

    Schuessler, C.M.

    1981-10-01

    This paper deals with uranium sales contracts, i.e. with contractual arrangements in the first steps of the fuel cycle, which cover uranium production and conversion. The various types of contract are described and, where appropriate, their underlying business philosophy and their main terms and conditions. Finally, the specific common features of such contracts are reviewed. (NEA) [fr

  6. Teaching about Contracts.

    Science.gov (United States)

    Froman, Michael; Kosnoff, Kathy

    1978-01-01

    Presents teaching strategies for introducing high school students to contract law. Offers as a case study a contract agreement between pro football players and team owners. Stresses basic elements of contracts (offer, acceptance, consideration, and understanding the bargaining process). Journal available from the American Bar Association, 1155…

  7. Other enrichment related contracts

    International Nuclear Information System (INIS)

    Hall, J.C.

    1978-01-01

    In addition to long-term enrichment contracts, DOE has other types of contracts: (1) short-term, fixed-commitment enrichment contract; (2) emergency sales agreement for enriched uranium; (3) feed material lease agreement; (4) enriched uranium storage agreement; and (5) feed material usage agreement

  8. Broad-band beam buncher

    International Nuclear Information System (INIS)

    Goldberg, D.A.; Flood, W.S.; Arthur, A.A.; Voelker, F.

    1986-01-01

    This patent describes a broad-band beam buncher. This beam buncher consists of: a housing adapted to be eacuated, an electron gun in the housing for producing a beam of electrons, buncher means in the housing forming a buncher cavity which has an entrance opening for receiving the electron beam and an exit opening through which the electron beam passes out of the buncher cavity, a drift tube electrode in the buncher cavity and disposed between the entrance opening and the exit opening with first and second gaps between the drift tube electrode and the entrance and exit openings, the drift tube electrode which has a first drift space through which the electron beam passes in traveling between the entrance and exit openings, modulating means for supplying an ultrahigh frequeny modulating signal to the drift tube electrode for producing velocity modulation of the electrons in the electron beam as the electrons pass through the buncher cavity and the drift tube electrode between the entrance opening and the exit opening, drift space means in the housing forming a second drift space for receiving the velocity modulated electron beam from the exit opening, the velocity modulated electron beam being bunched as it passes along the second drift space, the drift space means has a discharge opening through which the electron beam is discharged from the second drift space after being bunched therein, the modulating means containing a signal source for producing an ultrahigh frequency signal, a transmission line connected between the signal source and the drift tube electrode, and terminating means connected to the drift tube electrode for terminating the transmission line in approximately its characteristic impedance to afford a broad response band with minimum 6 variations therein

  9. Contracting for Public Services

    DEFF Research Database (Denmark)

    Greve, Carsten

    Insightful and comprehensive and covering new subjects like globalization and IT, this text, international in its approach, provides a thorough introduction to the key phases of the contracting process and the skills required by managers in its implementation. These include: policy for contracting...... theoretical ‘contract management model' and a ‘mature contract model', and explores the mechanisms, formal rules and informal norms that influence the way governments contract for public services. This book is essential reading for all students of public management and all public service managers....

  10. Partnering and contracting

    DEFF Research Database (Denmark)

    Bohnstedt, Kristian Ditlev

    2014-01-01

    contradicts the incomplete contracting theory. Secondly, in complete contract setting partnering can be motivated when seen as a willingness to renegotiate complete contracts i.e. partnering lowers transaction costs for renegotiation. Partnering can make it rational for one party to accept disadvantageous...... outcomes with the conception of being repaid later in accordance to reciprocity. Value - Seeing partnering as the willingness to renegotiate complete contracts can reduce the risk for the contractor and lead to lower prices for a given service. Keywords Partnering, Contracting, Pareto efficiency...

  11. Negotiating Efficient PPP Contracts

    DEFF Research Database (Denmark)

    Tvarnø, Christina D.

    This paper concerns Public Private Partnership (PPP) contracts in concern to the coming new 2014/24IEU public procurement directive. The new EU public procurement directive gives the public authority the opportunity to negotiate PPPs much more when they are implemented in national law....... An opportunity the member states should consider using when procuring a PPP. This paper looks at the negotiation and contracting of a PPP in an economic theoretical and EU public procurement perspective and discusses how to establish an efficient PPP contract under a strong public law doctrine. Governments...... procurement law. Furthermore, the paper seeks to establish a connection between public law, private law and the efficient PPP contract by drawing upon economic theory and empirical contract data from UK, US and Danish partnering contracts from the construction industry and the aim of contracting joint utility...

  12. Extreme Variability in a Broad Absorption Line Quasar

    Energy Technology Data Exchange (ETDEWEB)

    Stern, Daniel; Jun, Hyunsung D. [Jet Propulsion Laboratory, California Institute of Technology, 4800 Oak Grove Drive, Mail Stop 169-221, Pasadena, CA 91109 (United States); Graham, Matthew J.; Djorgovski, S. G.; Donalek, Ciro; Drake, Andrew J.; Mahabal, Ashish A.; Steidel, Charles C. [California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125 (United States); Arav, Nahum; Chamberlain, Carter [Department of Physics, Virginia Tech, Blacksburg, VA 24061 (United States); Barth, Aaron J. [Department of Physics and Astronomy, 4129 Frederick Reines Hall, University of California, Irvine, CA 92697 (United States); Glikman, Eilat, E-mail: daniel.k.stern@jpl.nasa.gov [Department of Physics, Middlebury College, Middlebury, VT 05753 (United States)

    2017-04-20

    CRTS J084133.15+200525.8 is an optically bright quasar at z = 2.345 that has shown extreme spectral variability over the past decade. Photometrically, the source had a visual magnitude of V ∼ 17.3 between 2002 and 2008. Then, over the following five years, the source slowly brightened by approximately one magnitude, to V ∼ 16.2. Only ∼1 in 10,000 quasars show such extreme variability, as quantified by the extreme parameters derived for this quasar assuming a damped random walk model. A combination of archival and newly acquired spectra reveal the source to be an iron low-ionization broad absorption line quasar with extreme changes in its absorption spectrum. Some absorption features completely disappear over the 9 years of optical spectra, while other features remain essentially unchanged. We report the first definitive redshift for this source, based on the detection of broad H α in a Keck/MOSFIRE spectrum. Absorption systems separated by several 1000 km s{sup −1} in velocity show coordinated weakening in the depths of their troughs as the continuum flux increases. We interpret the broad absorption line variability to be due to changes in photoionization, rather than due to motion of material along our line of sight. This source highlights one sort of rare transition object that astronomy will now be finding through dedicated time-domain surveys.

  13. Contracting out local services

    DEFF Research Database (Denmark)

    Petersen, Ole Helby; Houlberg, Kurt; Ring Christensen, Lasse

    2015-01-01

    Governments face a fundamental choice between in-house production and contracting out for the delivery of services to citizens. This article examines the importance of ideology, fiscal pressure, and size for contracting out in technical and social services. The analysis builds on a panel data set...... covering municipal spending on services in all 98 Danish municipalities. The authors find that contracting out is shaped by ideology in social services but not in technical services, which indicates that social services are the contemporary ideological battlefield of privatization. The analysis further...... reveals that economically prosperous municipalities are more likely to contract out social services, whereas contracting out of technical services is not influenced by economic affluence. Finally, larger municipalities contract out more in technical services but less in social services, demonstrating...

  14. New staff contract policy

    CERN Multimedia

    HR Department

    2006-01-01

    Following discussion at TREF and on the recommendation of the Finance Committee, Council approved a new staff contract policy, which became effective on 1 January 2006. Its application is covered by a new Administrative Circular No. 2 (Rev. 3) 'Recruitment, appointment and possible developments regarding the contractual position of staff members'. The revised circular replaces the previous Circulars No. 9 (Rev. 3) 'Staff contracts' and No. 2 (Rev. 2) 'Guidelines and procedures concerning recruitment and probation period for staff members'. The main features of the new contract policy are as follows: The new policy provides chances for long-term employment for all staff recruits staying for four years without distinguishing between those assigned to long-term or short-term activities when joining CERN. In addition, it presents a number of simplifications for the award of ICs. There are henceforth only 2 types of contract: Limited Duration (LD) contracts for all recruitment and Indefinite Contracts (IC) for...

  15. BOT Outsourcing Contracts

    DEFF Research Database (Denmark)

    Ørberg Jensen, Peter D.; Petersen, Bent

    2012-01-01

    Build-operate-transfer (BOT) contracting has been widely usen in the engineering and construction industry, but has only recently been introduced in services industry domains. Notably, service provider firms from emerging markets have recently started offering BOT outsourcing contracts....... In this paper we investigate under which circumstances a BOT outsourcing contract (i.e. a contract where the client firm exercises its call option) is beneficial, or the opposite, to the emerging market vendor firm. We draw on various theoretical literatures (transaction cost economics, real options, inter......-firm linkages) and develop three scenarios for the implications for vendor firms. We find that BOT contracts, under certain circumstances, may imply benefits of process and knowledge upgrading for the emerging market vendor firm. However, given different sets of circumstances, engaging in a BOT contract carries...

  16. BOT Outsourcing Contracts

    DEFF Research Database (Denmark)

    Ørberg Jensen, Peter D.; Petersen, Bent

    2012-01-01

    Build-operate-transfer (BOT) contracting has been widely usen in the engineering and construction industry, but has only recently been introduced in services industry domains. Notably, service provider firms from emerging markets have recently started offering BOT outsourcing contracts. In this p......Build-operate-transfer (BOT) contracting has been widely usen in the engineering and construction industry, but has only recently been introduced in services industry domains. Notably, service provider firms from emerging markets have recently started offering BOT outsourcing contracts....... In this paper we investigate under which circumstances a BOT outsourcing contract (i.e. a contract where the client firm exercises its call option) is beneficial, or the opposite, to the emerging market vendor firm. We draw on various theoretical literatures (transaction cost economics, real options, inter...

  17. Discovery of (10 R )-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro- 2H -8,4-(metheno)pyrazolo[4,3- h ][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant Mutations

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, Ted W.; Richardson, Paul F.; Bailey, Simon; Brooun, Alexei; Burke, Benjamin J.; Collins, Michael R.; Cui, J.Jean; Deal, Judith G.; Deng, Ya-Li; Dinh, Dac; Engstrom, Lars D.; He, Mingying; Hoffman, Jacqui; Hoffman, Robert L.; Huang, Qinhua; Kania, Robert S.; Kath, John C.; Lam, Hieu; Lam, Justine L.; Le, Phuong T.; Lingardo, Laura; Liu, Wei; McTigue, Michele; Palmer, Cynthia L.; Sach, Neal W.; Smeal, Tod; Smith, Graham L.; Stewart, Albert E.; Timofeevski, Sergei; Zhu, Huichun; Zhu, Jinjiang; Zou, Helen Y.; Edwards, Martin P. (Pfizer)

    2014-06-12

    Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.

  18. Copyright Preemption of Contracts

    OpenAIRE

    Bohannan, Christina

    2008-01-01

    This Article argues that both courts and scholars are wrong in their categorical approaches to preemption of contracts under the Copyright Act, and proposes an intermediate approach that recognizes the importance of both contract rights and federal policy in preemption analysis. First, it argues that both courts and scholars have misapplied preemption law to breach of contract claims. Although the two sides tend to favor opposite results, they take equally categorical approaches. Categori...

  19. Contracting for Public Services

    DEFF Research Database (Denmark)

    Greve, Carsten

    strategic purchasing understanding markets communicating the contracting decision designing and drafting the contract the role of the consumer the regulation of service provision Illustrated throughout with practitioner case-studies from a range of OECD countries, this book presents an important new......Insightful and comprehensive and covering new subjects like globalization and IT, this text, international in its approach, provides a thorough introduction to the key phases of the contracting process and the skills required by managers in its implementation. These include: policy for contracting...

  20. Gas contracts in transition

    Energy Technology Data Exchange (ETDEWEB)

    Wright, A.J. [Delhi Gas Pipeline Corp., Dallas, TX (United States)

    1992-12-31

    The transition of gas marketing by producers from a regulated and structured market to an open competitive and commodity market has created new challenges for attorneys drafting gas sales contracts. This article examines the following related topics: Interruptible contracts; pricing provisions; transport imbalances.

  1. Contract JAVYS - CEZ

    International Nuclear Information System (INIS)

    Anon

    2009-01-01

    The Nuclear Decommissioning Company (JAVYS) and Czech energy firm CEZ signed a contract on setting up of a joint venture to build a new nuclear facility at Jaslovske Bohunice (Trnava region). The value of the investment is estimated at 4-6 billion Eur. The contract was approved by the Slovak Government; the state will own a majority stake in the company via JAVYS.

  2. Negotiating Efficient PPP Contracts

    DEFF Research Database (Denmark)

    Tvarnø, Christina D.

    This paper concerns Public Private Partnership (PPP) contracts in concern to the coming new 2014/24IEU public procurement directive. The new EU public procurement directive gives the public authority the opportunity to negotiate PPPs much more when they are implemented in national law. An opportu......This paper concerns Public Private Partnership (PPP) contracts in concern to the coming new 2014/24IEU public procurement directive. The new EU public procurement directive gives the public authority the opportunity to negotiate PPPs much more when they are implemented in national law....... An opportunity the member states should consider using when procuring a PPP. This paper looks at the negotiation and contracting of a PPP in an economic theoretical and EU public procurement perspective and discusses how to establish an efficient PPP contract under a strong public law doctrine. Governments...... procurement law. Furthermore, the paper seeks to establish a connection between public law, private law and the efficient PPP contract by drawing upon economic theory and empirical contract data from UK, US and Danish partnering contracts from the construction industry and the aim of contracting joint utility...

  3. Contract Teachers in India

    Science.gov (United States)

    Goyal, Sangeeta; Pandey, Priyanka

    2013-01-01

    In this paper, we use non-experimental data from government schools in Uttar Pradesh and Madhya Pradesh, two of the largest Indian states, to present average school outcomes by contract status of teachers. We find that contract teachers are associated with higher effort than civil service teachers with permanent tenures, before as well as after…

  4. Democratic contract law

    NARCIS (Netherlands)

    Hesselink, M.W.

    2015-01-01

    This article discusses the normative relationship between contract law and democracy. In particular, it argues that in order to be legitimate contract law needs to have a democratic basis. Private law is not different in this respect from public law. Thus, the first claim made in this article will

  5. Do contracts help?

    DEFF Research Database (Denmark)

    Tumennasan, Norovsambuu

    Economists perceive moral hazard as an undesirable problem because it undermines efficiency. Carefully designed contracts can mitigate the moral hazard problem, but this assumes that a team is already formed. This paper demonstrates that these contracts are sometimes the reason why teams do...

  6. Comparing contracting performance

    DEFF Research Database (Denmark)

    Lindholst, Andrej Christian

    One key question for the last three decades of public management reforms is whether country differences between radical and modest reform approaches make a difference for performance in a reformed public sector. This paper compares differences in the implementation and performance of contracting....... Hypotheses are suggested for the role of culture, competition, contracts, capabilities and collaboration for contracting performance between and across the countries. Arguments are tested against data from on four comparable national surveys of private delivery of park and road maintenance services in local...... governments. Contracting performance is found to be higher in the United Kingdom due to a stronger overall combination of institutional features while performance differences across the countries in ranked order are found to be collaboration, contracts, capabilities and competition. Overall, the study support...

  7. Drilling contracts and incentives

    International Nuclear Information System (INIS)

    Osmundsen, Petter; Sorenes, Terje; Toft, Anders

    2008-01-01

    Shortages of rigs and personnel have encouraged discussion of designing incentive contracts in the drilling sector. However, for the drilling contracts, there are not a large variety of contract types in use. This article describes and analyses incentives for drilling contractors. These are directly represented by the compensation formats utilised in the present and in the consecutive drilling contracts. Indirectly, incentives are also provided by the evaluation criteria that oil companies use for awarding drilling assignments. Changes in contract format pose a number of relevant questions relating to resource management, and the article takes an in-depth look at some of these. Do evaluation criteria for awarding drilling assignments encourage the development of new technology and solutions? How will a stronger focus on drilling efficiency influence reservoir utilisation?

  8. Drilling contract issues

    International Nuclear Information System (INIS)

    Davison, G.B.; Worden, D.R.; Borbridge, G.K.D.

    1997-01-01

    Some selected issues which are facing both operators and contractors in drilling for oil and gas, such as the allocation of risk by contract and by statute and the implementation of new technologies, were discussed. There are three varieties of written drilling contracts used in Canada: (1) day work and meterage contracts, (2) master drilling agreements, and (3) contracts that are used in construction projects that do not specifically relate to drilling. Issues relevant to the contractual allocation of risk, to implementing new drilling technologies, to reconciling contract and statute liability, and the formation of strategic alliances for mutual benefit, and the factors contributing to the success of such alliances were explored. 12 refs

  9. Beyond the Spectrum: Rethinking Autism

    Directory of Open Access Journals (Sweden)

    Heather Thomas

    2017-03-01

    Full Text Available The "spectrum" has become the dominant metaphor for conceptualizing autism, with fundamental consequences for notions of disability, diversity, and normality. In this article, we draw on ethnographic research with autistic communities to explore how the notion of the autism spectrum has become a focus of explicit identification, reflection, and contestation. To further this inquiry, we place these debates into conversation with earlier debates regarding another spectrum—the Kinsey Scale, a "spectrum" for conceptualizing sexual orientation that first appeared in 1948 but has been critiqued since the 1970s. How might responses to the Kinsey Scale (like the Klein Grid contribute to rethinking the autism spectrum? This is a question about the cultural and political implications of metaphors and conceptual models. It is of broad importance because the spectrum metaphor is being extended to a range of conditions beyond autism itself. Our goal is thus to build on insights from sexuality studies as well as the insights of autistic persons, advocates, and researchers who wish to forestall the naturalization of "the spectrum." In doing so, we seek to contribute to a discussion of what alternative frameworks might bring to questions of social justice, ability, and human flourishing.

  10. On Deep e-Contracting

    NARCIS (Netherlands)

    Grefen, P.W.P.J.; Angelov, S.A.

    The use of electronic contracts is emerging as a way to improve the effi-ciency of contracting processes. Electronic contracts are, however, often used as a direct replacement for traditional paper contracts - which we call shallow e-contracting. Consequently, business processes in general and

  11. Contract Award Decisions Resulting in Contract Termination for Default

    National Research Council Canada - National Science Library

    1996-01-01

    .... Specifically, the audit focused on contracts terminated either for default or convenience and determined whether the contract terminations could have been averted based on information available before contract award...

  12. Incentive drilling contracts

    International Nuclear Information System (INIS)

    Moomjian, C.A. Jr.

    1992-01-01

    Incentive drilling contracts historically have been based on the footage and turnkey concepts. Because these concepts have not been used widely in the international and offshore arenas, this paper discusses other innovative approaches to incentive contracts. Case studies of recently completed or current international and offshore contracts are presented to describe incentive projects based on a performance bonus (Case 1), lump sum per well (Case 2), target time and cap for a specified hole section (Case 3), and per-well target time (Case 4). This paper concludes with a review and comparison of the case studies and a general discussion of factors that produce successful innovative incentive programs that enhance drilling efficiency

  13. Industrial Services Contracts

    CERN Document Server

    2006-01-01

    This document gives an overview of Industrial Services contracts at CERN, including the probable expenditure in 2006 and the estimated expenditure for 2007. The Finance Committee is invited: - to take note of the revised amount in 2006 for Industrial Services contracts referred to in this document of 138.02 MCHF at 2006 prices compared to the previously anticipated amount of 122.67 MCHF at 2005 prices; - to take note that the estimated amount in 2007 for the contracts referred to in this document will be 112.54 MCHF at 2006 prices; - for the reasons set out in this document, the Finance Committee is also invited to approve the requests for the contracts presented and highlighted in the Annexes.

  14. Premature Ventricular Contractions (PVCs)

    Science.gov (United States)

    ... Premature ventricular contractions (PVCs) Symptoms & causes Diagnosis & treatment Advertisement Mayo Clinic does not endorse companies or products. ... a Job Site Map About This Site Twitter Facebook Google YouTube Pinterest Mayo Clinic is a not- ...

  15. Superfund Contract Laboratory Program

    Science.gov (United States)

    The Contract Laboratory Program (CLP) is a national network of EPA personnel, commercial laboratories, and support contractors whose primary mission is to provide data of known and documented quality to the Superfund program.

  16. Establishing contract periods

    International Nuclear Information System (INIS)

    Huffman, F.C.

    1978-01-01

    The lead time for executing the Adjustable Fixed-Commitment (AFC) contract and exceptions which may be considered are discussed. The initial delivery period is also discussed. Delays, deferrals, and schedule adjustment charges are finally considered

  17. Contracting the Facebook API

    Directory of Open Access Journals (Sweden)

    Ben Rubinger

    2010-09-01

    Full Text Available In recent years, there has been an explosive growth in the popularity of online social networks such as Facebook. In a new twist, third party developers are now able to create their own web applications which plug into Facebook and work with Facebook's "social" data, enabling the entire Facebook user base of more than 400 million active users to use such applications. These client applications can contain subtle errors that can be hard to debug if they misuse the Facebook API. In this paper we present an experience report on applying Microsoft's new code contract system for the .NET framework to the Facebook API.We wrote contracts for several classes in the Facebook API wrapper which allows Microsoft .NET developers to implement Facebook applications. We evaluated the usefulness of these contracts during implementation of a new Facebook application. Our experience indicates that having code contracts provides a better and quicker software development experience.

  18. Distributed System Contract Monitoring

    Directory of Open Access Journals (Sweden)

    Adrian Francalanza Ph.D

    2011-09-01

    Full Text Available The use of behavioural contracts, to specify, regulate and verify systems, is particularly relevant to runtime monitoring of distributed systems. System distribution poses major challenges to contract monitoring, from monitoring-induced information leaks to computation load balancing, communication overheads and fault-tolerance. We present mDPi, a location-aware process calculus, for reasoning about monitoring of distributed systems. We define a family of Labelled Transition Systems for this calculus, which allow formal reasoning about different monitoring strategies at different levels of abstractions. We also illustrate the expressivity of the calculus by showing how contracts in a simple contract language can be synthesised into different mDPi monitors.

  19. Broad Prize: Do the Successes Spread?

    Science.gov (United States)

    Samuels, Christina A.

    2011-01-01

    When the Broad Prize for Urban Education was created in 2002, billionaire philanthropist Eli Broad said he hoped the awards, in addition to rewarding high-performing school districts, would foster healthy competition; boost the prestige of urban education, long viewed as dysfunctional; and showcase best practices. Over the 10 years the prize has…

  20. Broad Academy's Growing Reach Draws Scrutiny

    Science.gov (United States)

    Samuels, Christina A.

    2011-01-01

    Billionaire businessman Eli Broad, one of the country's most active philanthropists, founded the Broad Superintendents Academy in 2002 with an extraordinarily optimistic goal: Find leaders from both inside and outside education, train them, and have them occupying the superintendencies in a third of the 75 largest school districts--in just two…

  1. The anomalous tides near Broad Sound

    Science.gov (United States)

    Middleton, Jason H.; Buchwald, V. T.; Huthnance, John M.

    Observations of tidal current and height, in conjunction with theoretical mathematical models are used to investigate the propagation of the tide near Broad Sound, a narrowing estuary situated on a wide section of continental shelf toward the southern end of the Great Barrier Reef. The observations indicate that the dense offshore reefs severely inhibit tidal flow, with the result that tides flood toward Broad Sound from the north and from the south, along the main lagoon. There is a local magnification of the semi-diurnal tides within Broad Sound itself. Models of flow across reefs confirm the effectiveness of dense, shallow, and broad reefs in acting as a barrier to the tide. The diffraction of tides through large gaps in the reef is modelled using conformal mapping techniques and with the inclusion of energy leakage, the diffraction model predicts magnification of the semi-diurnal tidal heights by a factor of about 4 and a phase lag of 3 h on the shelf near Broad Sound, these values being consistent with observation. The observed convergence of the tide close to, and within Broad Sound itself is consistent with the proximity of the semi-diurnal tidal period to the natural period for flow in Broad Sound, considered as a narrowing estuary. This results in further amplification, by an additional factor of about 1.5, so that the tides in Broad Sound are increased by a factor of between 5 and 6, altogether, compared with those elsewhere on the east Australian coast.

  2. Statutes and contracts

    DEFF Research Database (Denmark)

    Trosborg, Anna

    1995-01-01

    This paper is concerned with the language used in legal speech acts in legislative texts and contracts in the field of English Contract Law. The central objects of study are regulative functions with a particular view to establishing realization patterns of the rhetorical functions of directive...... institutions, as well as in terms of the face redress required by the socio-pragmatic situation. Udgivelsesdato: JAN...

  3. Corrupt Relational Contracting

    OpenAIRE

    Johann Graf Lambsdorff; Sitki Utku Teksoz

    2002-01-01

    Because corruption must be hidden from the public and is not enforced by courts it entails transaction costs, which are larger than those from legal exchange. This suggests that corrupt contracts are primarily relational contracts where legal exchange serves as a basis for sealing and enforcing corrupt agreements. Legal exchange not only provides for corrupt opportunities, but for the necessary enforcement mechanisms. Examples of such legal exchange are long-term business exchange, belonging ...

  4. An unsatisfactory contract policy

    CERN Multimedia

    Staff Association

    2012-01-01

    For the last 15 years contract policy has been one of the top priorities of CERN staff, as expressed in successive surveys initiated by the Staff Association. In one’s professional life, having some forward vision of one’s career prospects is the key to loyalty and motivation. On the contrary, instability about the future is always at the root of anxiety, conflicts, or even health problems. A good employer must therefore balance the needs of the Company and those of its employees. CERN’s current contract policy, as described in the Administrative Circular No 2, states that staff members should first obtain a limited duration (LD) contract of up to five years. Then, if they want to stay in the Organization, staff members must apply, usually once a year, and before the end of their LD contract, for an indefinite contract (IC) post. All candidates for an IC post are considered by the Review Board for the award of indefinite contracts (Review Board) which will choose the most suita...

  5. Maternal Brain-Reactive Antibodies and Autism Spectrum Disorder

    Science.gov (United States)

    2015-10-01

    AWARD NUMBER: W81XWH-14-1-0369 TITLE: Maternal Brain-Reactive Antibodies and Autism Spectrum Disorder PRINCIPAL INVESTIGATOR: Betty Diamond...Sep 2015 4. TITLE AND SUBTITLE Maternal Brain-Reactive Antibodies and Autism Spectrum 5a. CONTRACT NUMBER Disorder 5b. GRANT NUMBER W81XWH-14-1...to approximately 5% of cases of ASD. 15. SUBJECT TERMS Fetal brain; Autism spectrum disorder ; antibody; B cells; Caspr2 16. SECURITY CLASSIFICATION

  6. Media contracts formalization using a standardized contract expression language

    OpenAIRE

    Rodríguez Luna, Eva; Delgado Mercè, Jaime; Boch, Laurent; Rodríguez-Doncel, Víctor

    2014-01-01

    Contract Expression Languages allow representing business contracts in a digital and structured form. Some examples are the Content Reference Forum format, the OASIS eContracts standard or a proposed extension for MPEG-21 Part 5. These formats have influenced the design of the MPEG-21 Contract Expression Language (CEL), which has been recently specified by modelling the most relevant clauses in audiovisual contracts. The MPEG-21 CEL, described in this paper, defines a language for representin...

  7. Energetics of contraction.

    Science.gov (United States)

    Barclay, C J

    2015-04-01

    Muscles convert energy from ATP into useful work, which can be used to move limbs and to transport ions across membranes. The energy not converted into work appears as heat. At the start of contraction heat is also produced when Ca(2+) binds to troponin-C and to parvalbumin. Muscles use ATP throughout an isometric contraction at a rate that depends on duration of stimulation, muscle type, temperature and muscle length. Between 30% and 40% of the ATP used during isometric contraction fuels the pumping Ca(2+) and Na(+) out of the myoplasm. When shortening, muscles produce less force than in an isometric contraction but use ATP at a higher rate and when lengthening force output is higher than the isometric force but rate of ATP splitting is lower. Efficiency quantifies the fraction of the energy provided by ATP that is converted into external work. Each ATP molecule provides 100 zJ of energy that can potentially be converted into work. The mechanics of the myosin cross-bridge are such that at most 50 zJ of work can be done in one ATP consuming cycle; that is, the maximum efficiency of a cross-bridge is ∼50%. Cross-bridges in tortoise muscle approach this limit, producing over 90% of the possible work per cycle. Other muscles are less efficient but contract more rapidly and produce more power. © 2015 American Physiological Society.

  8. INDEFINITE CONTRACT REVIEW 2000

    CERN Multimedia

    Division des ressources humaines

    2000-01-01

    The Director-General has decided to review staff members in professional categories 2 to 5 satisfying the criteria for consideration for the award of an indefinite contract, in accordance with Article R II 1.20 of the Staff Regulations. Staff members holding a fixed-term contract which it has been decided not to renew will not be considered. The following stages are foreseen:1.\tCandidates qualifying for review in accordance with Article R II 1.20 of the Staff Regulations and the Administrative Circular N° 9 will be contacted by Human Resources Division. 2.\tThe criteria as to when staff members qualify for review are described in Administrative Circular N° 9. These include the following:staff members who are in their fourth year of service on a fixed-term contract;in addition, for staff members having three years or more of previous relevant service in the Organization on a contract of limited duration (or term-contract) and upon proposal by the division leader concerned, consid...

  9. INDEFINITE CONTRACT REVIEW 2001

    CERN Multimedia

    Human Resources Division

    2001-01-01

    The Director-General has decided to review staff members in professional categories 2 to 5 satisfying the criteria for consideration for the award of an indefinite contract, in accordance with Article R II 1.20 of the Staff Regulations. Staff members holding a fixed-term contract which it has been decided not to renew will not be considered. The following stages are foreseen: 1. Candidates qualifying for review in accordance with Article R II 1.20 of the Staff Regulations and the Administrative Circular N° 9 will be contacted by Human Resources Division. 2. The criteria as to when staff members qualify for review are described in Administrative Circular N° 9. These include the following: staff members who are in their fourth year of service on a fixed-term contract; in addition, for staff members having three years or more of previous relevant service in the Organization on a contract of limited duration (or term-contract) and upon proposal by the division leader concerned, consideration fo...

  10. Networks and informal contract law

    NARCIS (Netherlands)

    Tjong Tjin Tai, Eric; Brownsword, Roger; van Gestel, Rob A.J.; Micklitz, Hans-W.

    2017-01-01

    It is often argued that formal contract law cannot treat networks correctly. An analysis of networks in an informal contract law system shows that informal contract law is no panacea. Remaining problems require a different approach to legal regulation and contract practice.

  11. Moral Contract Theory and Social Cognition : An Empirical Perspective

    NARCIS (Netherlands)

    Timmerman, Peter

    2014-01-01

    This interdisciplinary work draws on research from psychology and behavioral economics to evaluate the plausibility of moral contract theory. In a compelling manner with implications for moral theory more broadly, the author’s novel approach resolves a number of key contingencies in contractarianism

  12. Issues in contracting with small minority businesses

    Energy Technology Data Exchange (ETDEWEB)

    Wood, M.T.; Radford, M.L.; Saari, L.M.; Wright, J.

    1986-04-01

    The focus of this investigation was to identify issues central to increasing the involvement of small minority businesses (MBs) in federal or prime contracts with the Department of Energy (DOE), as a foundation for designing a program to assist buyers of contracted goods and services. The approach to determining issues involved interviewing the owners of 15 MBs, representing a range of businesses, and buyers and purchasing officers from three large DOE prime contractors. The interviewees identified issues related to positive working relationships and rated a predetermined set of 27 potential MB-DOE problems regarding their existence and criticalness. The issues identified by MBs were of two broad types. The predominant issues and barriers were associated with their being small businesses. Secondary issues reflected the disadvantaged status of the business (woman and/or minority-owned).

  13. PROCUREMENT AND CONTRACT MANAGEMENT

    CERN Multimedia

    Training & Development Group; Linda Orr-Easo; Tel. 72460; Nathalie Dumeaux; Tel. 78144

    2001-01-01

    We are pleased to announce the launch of a new training on: Procurement and Contract Management (This seminar will be run by CERN experts in French or in English) Level 1 The aim is to raise awareness of the key issues involved. Date : 8 June 2001 This level is open to everyone. Participants should register via our Web page as soon as possible. Level 2 To develop the skills needed to effectively manage contracts, from the Technical, Commercial and Legal aspects. Dates : Three days, Autumn 2001 This Level is open to those who are/will be more directly responsible for procurement and contract management. Participants should have followed Level 1. For a description of the seminar, please consult:   Level 1: http://training.web.cern.ch/Training/MANCO/P9798/9-cm_e.htm Level 2: http://training.web.cern.ch/Training/MANCO/P9798/9-cm2_e.htm

  14. Panel discussion : contract design

    Energy Technology Data Exchange (ETDEWEB)

    Vallas, A. [Sempra Energy Trading, Toronto, ON (Canada); Vegh, G. [MacLeod Dixon, Toronto, ON (Canada); McGee, M. [Energy Profiles Ltd., Etobicoke, ON (Canada); Zaremba, T. [Direct Energy Marketing, Calgary, AB (Canada); Seshan, A. [Larson and Toubro Information Technology, Toronto, ON (Canada); Harricks, P. [Gowlings, Toronto, ON (Canada); Bertoldi, L. [Borden Ladner Gervais, Toronto, ON (Canada); Taylor, R. [Hydro One Networks Inc., Markham, ON (Canada)

    2003-05-01

    This session presented highlights of the comments of 8 panelists who discussed the issue of contract design. The new electricity market in Ontario has introduced the energy trader, who enters into a contract with the consumer, based on the spot price set by the Independent Electricity Market Operator. Every contract has a fixed price payer as well as floating-price payers. If the floating price for a given amount of energy is higher than the fixed price, then the consumer gets the difference. Confusion, however, arises with the purchase of retail physical power in the market, particularly in deciding a fixed rate that the consumer will be paying. Different billing options were also discussed with emphasis on mid to large retail customers that have portfolios in the tens of MW and up to 100 MW or more. figs.

  15. Amending Contracts for Choreographies

    Directory of Open Access Journals (Sweden)

    Laura Bocchi

    2011-07-01

    Full Text Available Distributed interactions can be suitably designed in terms of choreographies. Such abstractions can be thought of as global descriptions of the coordination of several distributed parties. Global assertions define contracts for choreographies by annotating multiparty session types with logical formulae to validate the content of the exchanged messages. The introduction of such constraints is a critical design issue as it may be hard to specify contracts that allow each party to be able to progress without violating the contract. In this paper, we propose three methods that automatically correct inconsistent global assertions. The methods are compared by discussing their applicability and the relationships between the amended global assertions and the original (inconsistent ones.

  16. Bunker purchasing with contracts

    DEFF Research Database (Denmark)

    Plum, Christian Edinger Munk; Neergaard Jensen, Peter; Pisinger, David

    2014-01-01

    The cost for bunker fuel represents a major part of the daily running costs of liner shipping vessels. The vessels, sailing on a fixed roundtrip of ports, can lift bunker at these ports, having differing and fluctuating prices. The stock of bunker on a vessel is subject to a number of operational...... constraints such as capacity limits, reserve requirements and sulphur content. Contracts are often used for bunker purchasing, ensuring supply and often giving a discounted price. A contract can supply any vessel in a period and port, and is thus a shared resource between vessels, which must be distributed...... optimally to reduce overall costs. The Bunker Purchasing with Contracts Problem has been formulated as a mixed integer programme, which has been Dantzig-Wolfe decomposed. To solve it, a novel column generation algorithm has been developed. The algorithm has been run on a series of real-world instances...

  17. Panel discussion : contract design

    International Nuclear Information System (INIS)

    Vallas, A.; Vegh, G.; McGee, M.; Zaremba, T.; Seshan, A.; Harricks, P.; Bertoldi, L.; Taylor, R.

    2003-01-01

    This session presented highlights of the comments of 8 panelists who discussed the issue of contract design. The new electricity market in Ontario has introduced the energy trader, who enters into a contract with the consumer, based on the spot price set by the Independent Electricity Market Operator. Every contract has a fixed price payer as well as floating-price payers. If the floating price for a given amount of energy is higher than the fixed price, then the consumer gets the difference. Confusion, however, arises with the purchase of retail physical power in the market, particularly in deciding a fixed rate that the consumer will be paying. Different billing options were also discussed with emphasis on mid to large retail customers that have portfolios in the tens of MW and up to 100 MW or more. figs

  18. International contracts within the business of MSMEs

    Directory of Open Access Journals (Sweden)

    Martha Cecilia López Fonseca

    2012-07-01

    Full Text Available The purpose is to explain, in general terms, some of the possibilities for micro, small and medium enterprises (MSMEs to internationalize, taking into consideration, among other aspects, the elaboration of the contract, preferably written. The meaning of international trade comes from the mercantilist, classical and neoclassical currents and from contemporary postulates, such as the theory of competitive advantage, which demonstrate the importance of the exchange of goods and services for economies. International trade relations of any company are based on requirements of importing or exporting raw materials, machinery, final and intermediate goods or services procurement. However, in practice, relations can cover a wider spectrum than the abovementioned operations. This essay mentions some elements that should be considered by the parties when making the negotiation and which will be reflected in the body of the contract.

  19. Atividade antimicrobiana in vitro da cefpiroma em comparação com outros beta-lactâmicos de amplo espectro contra 804 amostras clínicas de nove hospitais brasileiros Antimicrobial activity of Cefpirome compared to other broad-spectrum Beta-Lactam drugs against 804 clinical isolates from 9 Brazilian hospitals

    Directory of Open Access Journals (Sweden)

    H.S. Sader

    1998-12-01

    imipenem apresentou atividade um pouco superior. CONCLUSÃO: Os resultados desse estudo sugerem que, no Brasil, a cefpiroma apresenta espectro de ação superior ao das CTGs contra bactérias gram-negativas (Enterobacteriaceae e não-fermentadares e gram-positivas e semelhante ao do imipenem contra algumas espécies de enterobactérias e contra P. aeruginosa.OBJECTIVE: To evaluate the in vitro activity of the fourth-generation cephalosporin cefpirome in comparison to that of ceftazidime, ceftriaxone, cefotaxime and imipenem in a multicenter study involving nine hospitals from six cities (four States. MATERIAL AND METHOD: A total of 804 isolates from patients hospitalized in either intensive care units or Oncology/Hematology units was evaluated. The isolates were collected between June and November of 1995, i.e. before cefpirome became commercially available in Brazil, and susceptibility tested by broth microdilution following the NCCLS procedures. All isolates resistant to cefpirome were retested by E-test. RESULTS: Against Enterobacteriaceae (n=344, cefpirome demonstrated an activity 2 to 32-fold higher than that of the third-generation cephalosporins (TGCs and similar to that of imipenem. The percentages of Enterobacteriaceae susceptible were: 88%, 69% and 96% for cefpirome, TGCs and imipenem, respectively. The cefpirome spectrum was greater or equal than that of imipenem against Citrobacter freundii, Enterobacter aerogenes, Morganella morganii and Serratia marcescens. Against Acinetobacter sp. (n=77, cefpirome was slightly more active than ceftazidime; however, the percentages of isolates resistant to these compounds were high (84% and 88%, respectively. The activities of cefpirome, ceftazidime and imipenem were very similar against P. aeruginosa isolates (n=128, with MIC50(mg/ml/percent susceptible of 8/59%, 8/62% and 4/62% respectively. Against aerobic gram-positive bacteria, the cefpirome activity was 4 to 16-fold higher than that of TGCs but 2 to 8-fold lower than

  20. Culture and Contract Laws

    DEFF Research Database (Denmark)

    Lando, Ole

    2007-01-01

    In the article it is argued that the wish to preserve the cultural values of national law should not prevent the EU from preparing a Code or an Optional Instrument. The no-code countries on the British Isles and in Scandinavia are the most ardent opponents to the idea of unifying European Contract...... Law by way of a code on Contracts. In both these regions however the absence of a code causes problems. In England a prominent writer has found that the major weakness of the judge-made law is its immense diffusion and the consequent difficulty of access to it and the Nordic countries face the same...

  1. Spectral properties of a broad-area diode laser with off-axis external-cavity feedback

    DEFF Research Database (Denmark)

    Chi, Mingjun; Petersen, Paul Michael

    2013-01-01

    . The intensity noise spectrum of the diode laser shows that the intensity noise is increased strongly by the external-cavity feedback. External-cavity modes are excited in the external cavity even in the off-axis configuration. The peak spacing of the intensity noise spectrum shows that single roundtrip external......Spectral properties, both the optical spectrum and the intensity noise spectrum, of a broad-area diode laser with off-axis external-cavity feedback are presented. We show that the optical spectrum of the diode laser system is shifted to longer wavelengths due to the external-cavity feedback......-cavity modes are excited. We believe that the four-wave mixing process in the broad-area diode laser is responsible for the establishment of the external-cavity mode....

  2. DELIMITATION OF ADMINISTRATIVE CONTRACTS FOR OTHER TYPES OF CONTRACTS

    Directory of Open Access Journals (Sweden)

    Liana Teodora PASCARIU

    2016-12-01

    Full Text Available Article examines whether all contracts of public persons are administrative contracts; in other words, if the administration may conclude contracts that, according to their legal nature, are not administrative. to qualify a contract as an administrative contract, besides the determination of the law, we must pay attention to the case-law, the administrative contract concluded by a public or on behalf of a public person and that either contains within it derogation clause from the common law or is as object the execution of a public service.

  3. Cross-spectrum symbol synchronization

    Science.gov (United States)

    Mccallister, R. D.; Simon, M. K.

    1981-01-01

    A popular method of symbol synchronization exploits one aspect of generalized harmonic analysis, normally referred to as the cross-spectrum. Utilizing nonlinear techniques, the input symbol energy is effectively concentrated onto multiples of the symbol clock frequency, facilitating application of conventional phase lock synchronization techniques. A general treatment of the cross-spectrum technique is developed and shown to be applicable across a broad class of symbol modulation formats. An important specific symbol synchronization application is then treated, focusing the general development to provide both insight and quantitative measure of the performance impact associated with variation in these key synchronization parameters: symbol modulation format, symbol transition probability, symbol energy to noise density ratio, and symbol rate to filter bandwidth ratio.

  4. Paradental Training Contract.

    Science.gov (United States)

    Lane Community Coll., Eugene, OR.

    This report describes institutional, faculty, and student activities and problems resulting from Lane Community College's acceptance of a federal contract to develop a paradental training program designed specifically to provide training/retraining required to quality military-trained dental corpsmen for examination by the Oregon State Board of…

  5. Validating Timed Component Contracts

    DEFF Research Database (Denmark)

    Le Guilly, Thibaut; Liu, Shaoying; Olsen, Petur

    2015-01-01

    This paper presents a technique for testing software components with contracts that specify functional behavior, synchronization, as well as timing behavior. The approach combines elements from unit testing with model-based testing techniques for timed automata. The technique is implemented...... in an online testing tool, and we demonstrate its use on a concrete use case....

  6. Culture and Contract Laws

    DEFF Research Database (Denmark)

    Lando, Ole

    2007-01-01

    In the article it is argued that the wish to preserve the cultural values of national law should not prevent the EU from preparing a Code or an Optional Instrument. The no-code countries on the British Isles and in Scandinavia are the most ardent opponents to the idea of unifying European Contract...

  7. The Danish Contracting System

    DEFF Research Database (Denmark)

    Bonke, Sten; Levring, Peter

    The paper is mainly concerned with the institutional framework of the Danish construction industry, describing structures, rules and actors' roles within a perspective of nationally defined procedural guidelines on construction projects. These aspects are treated under the concept of a "contracting...

  8. CONTRACTING AND ERUPTING COMPONENTS OF SIGMOIDAL ACTIVE REGIONS

    International Nuclear Information System (INIS)

    Liu Rui; Wang Yuming; Liu Chang; Wang Haimin; Török, Tibor

    2012-01-01

    It has recently been noted that solar eruptions can be associated with the contraction of coronal loops that are not involved in magnetic reconnection processes. In this paper, we investigate five coronal eruptions originating from four sigmoidal active regions, using high-cadence, high-resolution narrowband EUV images obtained by the Solar Dynamic Observatory (SDO). The magnitudes of the flares associated with the eruptions range from GOES class B to class X. Owing to the high-sensitivity and broad temperature coverage of the Atmospheric Imaging Assembly (AIA) on board SDO, we are able to identify both the contracting and erupting components of the eruptions: the former is observed in cold AIA channels as the contracting coronal loops overlying the elbows of the sigmoid, and the latter is preferentially observed in warm/hot AIA channels as an expanding bubble originating from the center of the sigmoid. The initiation of eruption always precedes the contraction, and in the energetically mild events (B- and C-flares), it also precedes the increase in GOES soft X-ray fluxes. In the more energetic events, the eruption is simultaneous with the impulsive phase of the nonthermal hard X-ray emission. These observations confirm that loop contraction is an integrated process in eruptions with partially opened arcades. The consequence of contraction is a new equilibrium with reduced magnetic energy, as the contracting loops never regain their original positions. The contracting process is a direct consequence of flare energy release, as evidenced by the strong correlation of the maximal contracting speed, and strong anti-correlation of the time delay of contraction relative to expansion, with the peak soft X-ray flux. This is also implied by the relationship between contraction and expansion, i.e., their timing and speed.

  9. Spectrum of pediatric neuromyelitis optica.

    Science.gov (United States)

    Lotze, Timothy E; Northrop, Jennifer L; Hutton, George J; Ross, Benjamin; Schiffman, Jade S; Hunter, Jill V

    2008-11-01

    Our goal was to describe the spectrum of clinical phenotypes, laboratory and imaging features, and treatment in pediatric patients with neuromyelitis optica. The study consisted of a retrospective chart review of patients followed in a pediatric multiple sclerosis center with a diagnosis of neuromyelitis optica spectrum disorder. Nine patients with neuromyelitis optica spectrum disorders were included, all of whom were female. There were 4 black children, 2 Latin American children, 2 white children, and 1 child of mixed Latin American/white heritage. Median age at initial attack was 14 years (range: 1.9-16 years). Median disease duration was 4 years (range: 0.6-9 years). Tests for neuromyelitis optica immunoglobulin G were positive for 7 patients. Eight patients had transverse myelitis and optic neuritis, and 1 patient had longitudinally extensive transverse myelitis without optic neuritis but had a positive neuromyelitis optica immunoglobulin G antibody titer. Cerebral involvement on MRI was found in all subjects, 5 of whom were symptomatic with encephalopathy, seizures, hemiparesis, aphasia, vomiting, or hiccups. Immunosuppressive therapy reduced attack frequency and progression of disability. Pediatric neuromyelitis optica has a diverse clinical presentation and may be difficult to distinguish from multiple sclerosis in the early stages of the disease. The recognition of the broad spectrum of this disease to include signs and symptoms of brain involvement is aided by the availability of a serum biomarker: neuromyelitis optica immunoglobulin G. Early diagnosis and immunosuppresive treatment may help to slow the accumulation of severe disability.

  10. Employee contract issues for dermatologists.

    Science.gov (United States)

    Brown, Christopher E; Indest, George F

    2013-12-01

    Employees and employers routinely face negotiating and preparing physician employment contracts. It is important for both sides to know and understand the basic information on what a comprehensive employment contract for a dermatologist should contain. There are various employment contract provisions from both the employee's perspective and the employer's perspective that must be considered when preparing physician employment contracts. This article provides basic advice and recommendations on requirements that should be included in such contracts. It suggests legal pitfalls that can be avoided through various contract clauses.

  11. Practical concepts in Contract Law

    OpenAIRE

    Ehsan, zarrokh

    2008-01-01

    A contract is a legally binding exchange of promises or agreement between parties that the law will enforce. Contract law is based on the Latin phrase pacta sunt servanda (literally, promises must be kept) [1]. Breach of a contract is recognised by the law and remedies can be provided. Almost everyone makes contracts everyday. Sometimes written contracts are required, e.g., when buying a house [2]. However the vast majority of contracts can be and are made orally, like buying a law text book,...

  12. Belene nuclear power plant contracting approach

    International Nuclear Information System (INIS)

    Tankosic, D.; Mignone, O.

    2004-01-01

    Historically, three main types of project execution and contractual approaches have been applied to energy and industrial projects, including nuclear projects. These approaches are grouped into three broad categories: 1) Turnkey Approach; 2) Split Package (Island) Approach; and 3)Multiple Package Approach. Based on a preliminary screening done by an ongoing feasibility study work for NPP Belene (NEK contract to Parsons E and C), the recommended approach is going to follow that general trend i.e., with some variation between the Split Package and the Turnkey approach. Before deciding on an execution approach or at least before issuing bid specifications for the nuclear power plant, it is prudent, even for a country with existing nuclear power program (like Bulgaria), to re-check/verify capabilities of the interested bidders to handle contracts of this size and nature. During the last decades, nuclear energy went through a substantial restructuring and most of the capabilities (human and financial) that existed before are not any more available. This re-checking should mainly cover the experience of the bidders as regards the design, construction and operation of the stations where they were involved, but also include items such as local experience, capability to bring favorable financing, liability coverage, general background, potential and organizational structures. The advantages and disadvantages for the Owner of the three contracting approaches can be briefly summarized as follows: Turnkey Approach - main advantages: all responsibilities rest in a Contractor or Consortium. Main disadvantages - limited project control by Owner and restricted local participation. For Split Package Contract Approach main advantage are more favorable financing conditions and increased local participation. Main disadvantage is the increased interface problems. For Multiple package Contract Approach main advantages are the opportunity to tailor the plant and maximum increase of local

  13. Reconciling Contracts and Relational Governance through Strategic Contracting

    DEFF Research Database (Denmark)

    Petersen, Bent; Østergaard, Kim

    2018-01-01

    on contract types, such as strategic versus conventional, may reconcile the enduring research controversy between the substitution and complements perspectives. Practical implications: Today, formal contracts with foreign distributors tend to resemble “prenuptial agreements”. The opportunity for relational...

  14. Lutetium-177 - Broad Production Capabilities are Expected to Stimulate Clinical Applications of this Important Therapeutic Radioisotope

    International Nuclear Information System (INIS)

    Knapp, F.F. Jr.

    2009-01-01

    Lutetium-177 (Lu-177) is of broad interest for therapeutic applications where the deposition of localized radiation can benefit from the limited soft tissue penetration of the 0.497 MeV beta particle (max. = 2.76 mm). Examples of Lu-177 therapeutic strategies include treatment of small SS2/SS5-expressing tumors with targeted peptides and radiosynovectomy. Emission of a 208 keV gamma photon (11 %) allows imaging for evaluation of localization and biokinetics, and for targeting applications, correlation of uptake with therapeutic response. A broad spectrum of research reactors with even modest thermal neutron flux (e.g. > 1 x 10 14 ) can produce carrier-added Lu-177 with sufficient specific activity (SA) > 10 Ci/mg Lu by the 'direct' approach by irradiation of Lu-176. For low SA applications, thermal flux of > 10 13 in low-medium flux reactors provides sufficient SA (> 0.5 mCi Lu-177/mg) for preparation of Lu-EDTMP for synovectomy. Although relative Lu-177m/Lu-177 activity levels from 'direct' production can be very low (> 10 -5 ), the Lu-177m impurity levels can present an issue with radioactive waste storage requirements at some institutions. The alternative 'indirect' approach using decay of reactor produced ytterbium-177 available from by neutron irradiation of enriched Yb-176 targets provides no-carrier-added (nca) Lu-177 (theoretical SA = 109 Ci/mg Lu). Purification of the microscopic levels of nca Lu-177 from macroscopic Yb levels at the high multi Curie production level is a more challenging approach, since production yields are relatively low even at high thermal flux (e.g. 2 x 10 15 neutrons/cm 2 /sec). In addition, high mass Lu/Yb separation is especially time consuming, can generate significant waste, and the relatively expensive Yb-176 target material (> 97%, ∼ $ 20/mg) must be recovered, re-purified and used for subsequent target preparation. However, a number of effective methods for the Lu/Yb separation and Yb recovery have been reported, and even

  15. Broad-line Type Ic supernova SN 2014ad

    Science.gov (United States)

    Sahu, D. K.; Anupama, G. C.; Chakradhari, N. K.; Srivastav, S.; Tanaka, Masaomi; Maeda, Keiichi; Nomoto, Ken'ichi

    2018-04-01

    We present optical and ultraviolet photometry and low-resolution optical spectroscopy of the broad-line Type Ic supernova SN 2014ad in the galaxy PGC 37625 (Mrk 1309), covering the evolution of the supernova during -5 to +87 d with respect to the date of maximum in the B band. A late-phase spectrum obtained at +340 d is also presented. With an absolute V-band magnitude at peak of MV = -18.86 ± 0.23 mag, SN 2014ad is fainter than supernovae associated with gamma ray bursts (GRBs), and brighter than most of the normal and broad-line Type Ic supernovae without an associated GRB. The spectral evolution indicates that the expansion velocity of the ejecta, as measured using the Si II line, is as high as ˜33 500 km s-1 around maximum, while during the post-maximum phase it settles at ˜15 000 km s-1. The expansion velocity of SN 2014ad is higher than that of all other well-observed broad-line Type Ic supernovae except for the GRB-associated SN 2010bh. The explosion parameters, determined by applying Arnett's analytical light-curve model to the observed bolometric light-curve, indicate that it was an energetic explosion with a kinetic energy of ˜(1 ± 0.3) × 1052 erg and a total ejected mass of ˜(3.3 ± 0.8) M⊙, and that ˜0.24 M⊙ of 56Ni was synthesized in the explosion. The metallicity of the host galaxy near the supernova region is estimated to be ˜0.5 Z⊙.

  16. Fetal Alcohol Spectrum Disorders.

    Science.gov (United States)

    Williams, Janet F; Smith, Vincent C

    2015-11-01

    Prenatal exposure to alcohol can damage the developing fetus and is the leading preventable cause of birth defects and intellectual and neurodevelopmental disabilities. In 1973, fetal alcohol syndrome was first described as a specific cluster of birth defects resulting from alcohol exposure in utero. Subsequently, research unequivocally revealed that prenatal alcohol exposure causes a broad range of adverse developmental effects. Fetal alcohol spectrum disorder (FASD) is the general term that encompasses the range of adverse effects associated with prenatal alcohol exposure. The diagnostic criteria for fetal alcohol syndrome are specific, and comprehensive efforts are ongoing to establish definitive criteria for diagnosing the other FASDs. A large and growing body of research has led to evidence-based FASD education of professionals and the public, broader prevention initiatives, and recommended treatment approaches based on the following premises:▪ Alcohol-related birth defects and developmental disabilities are completely preventable when pregnant women abstain from alcohol use.▪ Neurocognitive and behavioral problems resulting from prenatal alcohol exposure are lifelong.▪ Early recognition, diagnosis, and therapy for any condition along the FASD continuum can result in improved outcomes.▪ During pregnancy:◦no amount of alcohol intake should be considered safe;◦there is no safe trimester to drink alcohol;◦all forms of alcohol, such as beer, wine, and liquor, pose similar risk; and◦binge drinking poses dose-related risk to the developing fetus. Copyright © 2015 by the American Academy of Pediatrics.

  17. Water and Muscle Contraction

    Directory of Open Access Journals (Sweden)

    Enrico Grazi

    2008-08-01

    Full Text Available The interaction between water and the protein of the contractile machinery as well as the tendency of these proteins to form geometrically ordered structures provide a link between water and muscle contraction. Protein osmotic pressure is strictly related to the chemical potential of the contractile proteins, to the stiffness of muscle structures and to the viscosity of the sliding of the thin over the thick filaments. Muscle power output and the steady rate of contraction are linked by modulating a single parameter, a viscosity coefficient. Muscle operation is characterized by working strokes of much shorter length and much quicker than in the classical model. As a consequence the force delivered and the stiffness attained by attached cross-bridges is much larger than usually believed.

  18. Energy contracting in Switzerland

    International Nuclear Information System (INIS)

    Muggli, C.

    2000-01-01

    The article discusses the status of energy contracting in Switzerland and compares it with the situation in USA, Germany and France, where it has been standard practice for many years. The fact that this financing and operating instrument is not widely used in Switzerland in spite of its benefits for users and suppliers is discussed, as are the obstacles placed in its way. The results of a study made by the Federal Office of Energy are presented, whereby some 220 existing contracting arrangements with a total investment volume of around CHF 200 million were noted and a further potential of around CHF 1.1 billion estimated. The author notes that in order to utilise this potential, great efforts must be made by all parties involved

  19. Expansionary fiscal contractions

    DEFF Research Database (Denmark)

    Bergman, Ulf Michael; Hutchison, Michael

    2010-01-01

    The Expansionary Fiscal Contraction (EFC) hypothesis predicts that a major fiscal consolidation leads to an economic expansion under certain circumstances. We test this hypothesis, and the implied non-linear responses of the economy to large and small changes in fiscal policy, using data from...... and tax changes) have the expected Keynesian effects on output and consumption. However, we find no evidence that the large fiscal consolidation in Denmark slowed the economy after controlling for a host of exogenous shocks and business cycle effects. Rather, we find some support for the hypothesis...... that the exogenous fiscal contraction in Denmark was a credible regime shift and, together with other reforms undertaken at the time, increased both private consumption and aggregate output....

  20. Effect of 3-substituted 1,4-benzodiazepin-2-ones on maximal normalized rate of bradykinin-induced smooth muscle contraction in the presence of calcium channel blockers

    Directory of Open Access Journals (Sweden)

    P. A. Virych

    2017-05-01

    Full Text Available The development of modern organic chemistry and molecular modeling technologies simplify the search for potential inhibitors of various receptor systems and biological processes. The one of the directions is the development of analgesics of broad spectrum and low toxicity. It is important to search for inhibitors of the kinin-kallikrein system that regulates many functions: inflammation, pain, carcinogenesis, vascular tone, smooth muscle contraction and other. Derivatives of 3-substituted 1,4-benzodiazepine-2-ones have a unique spatial conformation that allows one to simulate β-structures of bioactive peptides. The functional activity of compounds is determined by properties of their peripheral chemical radicals. We analyzed the effect of 3-substituted 1,4-benzodiazepin-2-ones derivatives on the normalized maximal rate of bradykinin-induced smooth muscle contraction and relaxation of the stomach in the presence of calcium channel blockers: verapamil (1 μM, gadolinium (300 μM and 2-aminoethyl diphenylborinate (0.1 μM. The levels of bradykinin and 3-arylamino-1,2-dihydro-3H-1,4-benzodiazepine-2-ones in incubation solution were 10–6 M. Data processing on dynamics of contraction was performed according to the method of Burdyha and Kosterin. Compounds MX-1775 and MX-1925 reduced maximal normalized rate (Vn of bradykinin-induced smooth muscle contraction in the presence of Gd3+ by 21.2% and 31.0% respectively. Compound MX-1925 increased Vn of relaxation by 11.6%. A similar effect is typical for MX-2011, where there is an increase by 34.6%. In the presence of verapamil this compound additionally decreased Vn contraction by 20.5%. Substances MX-1775, MX-2004 and MX-1925 restored maximal normalized rate of relaxation to original values of bradykinin-induced contraction. In the presence of 2-aminoethyldiphenylborinate MX-1775 additionally reduced Vn of contractions by 7.5%. 3-substituted 1,4-benzo­diazepine-2-ones did not change the maximal

  1. Between Status and Contract?

    Directory of Open Access Journals (Sweden)

    Thorsten Keiser

    2013-01-01

    Full Text Available This contribution deals with unfree labour in Germany from the early modern age until the beginning of the 20th century. It presents the main conclusions of a book published in 2013 on this subject in German. Unfree labour is not identified in the first place with slavery or any other labour relationship based on status. Instead, this study aims at an analysis of freedom and coercion in contractual labour relationships. It will be argued that in Germany contractual labour relationships before 1800 were embedded in a legal system that strongly restricted contractual autonomy and aimed at the suppression of free labour markets. The scope of this legislation was to guarantee efficient labour performance, which was not only perceived as being in the personal interest of an employer, but as a fundamental element of the common good. After 1800 the system changed to more incentive-based legislation that established freedom of contract for labour relations. Nevertheless, coercion in order to perform the contractual duties of a work contract remained important for many groups of workers, especially farmhands and industrial workers. The last criminal sanctions for breaches of labour contracts were only abolished in the revolution of 1919. This development shows the difficulties German law had in extending the principles of private law to workers. When a system of free labour was fully established, the issue of unemployment and economic problems, especially in the Weimar Republic, required a new system of protective rules. The history of free market based labour contracts in Germany was therefore very short, with state intervention shi ing from control and coercion to social assistance.

  2. Contract types - turnkey

    International Nuclear Information System (INIS)

    Loeffler, G.

    1975-01-01

    Turnkey or the turnkey type of contract refers to a system of management according to which one organization accepts total responsibility for completing all parts and all phases of a project. In the case of a power project the turnkey contractor undertakes to design the plant, supply or procure and erect the equipment, build the station and put it into operation. (orig./FW) [de

  3. Giant Broad Line Regions in Dwarf Seyferts

    Indian Academy of Sciences (India)

    2016-01-27

    Jan 27, 2016 ... High angular resolution spectroscopy obtained with the Hubble Space Telescope (HST) has revealed a remarkable population of galaxies hosting dwarf Seyfert nuclei with an unusually large broad-line region (BLR). These objects are remarkable for two reasons. Firstly, the size of the BLR can, in some ...

  4. Education and Broad Concepts of Agency

    Science.gov (United States)

    Winch, Christopher

    2014-01-01

    Drawing on recent debates about the relationship between propositional and practical knowledge, this article is concerned with broad concepts of agency. Specifically, it is concerned with agency that involves the forming and putting into effect of intentions over relatively extended periods, particularly in work contexts (called, for want of a…

  5. Giant Broad Line Regions in Dwarf Seyferts

    Indian Academy of Sciences (India)

    one can determine the inner and outer radii of the BLRs by modeling the ... The physics behind the production of broad emission lines in active galactic nuclei ... shapes. The inner radius of the volume defines the full velocity width at zero intensity of the model emission line, and the outer radius of the volume defines the ...

  6. Utility Energy Services Contracts Guide

    Energy Technology Data Exchange (ETDEWEB)

    None

    2013-09-01

    The UESC Guide is a compilation of samples and templates developed as a resource to help contracting officers implement task orders for UESCs under existing U.S. General Services Administration areawide contracts.

  7. Forestry contracting in South Africa

    CSIR Research Space (South Africa)

    Khosa, M

    2000-01-01

    Full Text Available ........................................................................................... 4 Duration of contractor firm in the market.................................................................................. 5 STATUS AND CLASSIFICATION OF THE ENTERPRISE... ................................................................................. 10 Duration of the contract........................................................................................................ 11 Duration of contract by classification...

  8. CONTRACT FOLLOW UP TRAINING

    CERN Multimedia

    Technical Training; Tel. 74460

    2001-01-01

    SPL is organizing Training Sessions on the Contract Follow Up application. CFU is a Web based tool, developped and supported by the Administrative Information Services. It allows the creation of Divisional Requests and the follow up of their processing, from the Market Survey to the Invitation to Tender or Price Enquiry, approval by the Finance Committee, up to the actual signature of a Contract, acccording to the CERN Purchasing procedures. It includes a document management component. It also provides link with other AIS applications such as BHT and EDH. The course is primarily intended for DPOs, Contract Technical responsibles in the division and their assistants, but is beneficial to anybody involved in the follow up of such Purchasing Procedures. This course is free of charge, but application is necessary. The details of the course may be found at http://training.web.cern.ch/Training/ENSTEC/P2001/Bureautique/cfu4_f.htm General information of CFU may be found at http://ais.cern.ch/apps/cfu/ The dates of t...

  9. Exit from contract

    Directory of Open Access Journals (Sweden)

    Oren Bar-Gill

    2016-01-01

    Full Text Available Objective to study the procedure of exiting the contract its costs and benefits. Methods statistical method comparative analysis. Results free exit from contract is one of the most powerful tools for the consumer rights protection. The procedure frees consumers from bad deals and keeps businesses honest. Yet consumers often choose transactions with lockin provisions trading off exit rights for other perks. This article examines the costs and benefits of free exit as compared to the lockin alternative. According to the authors the present regulation of exit penalties in the USA is poorly tailored to address concerns about lockin particularly in light of increasingly ubiquitous marketbased solutions. The article also calls regulatory attention to loyalty rewards which are shown to be as powerful as exit penalties and equally detrimental. Scientific novelty the article reveals a paradoxical state of the law exit regulations in the USA are used most where they are needed least. Termination penalties present an obvishyous target for regulatory intervention while loyalty programs seem benign not warranting any regulatory attention. Practical significance the article is of interest for the Russian juridical science and lawmaking authorities as in Russia the issue of exiting the contract is as topical as in the USA and requires solution which would impair neither the rights of consumers nor the rights of the sellers ofnbspproducts and services. nbsp

  10. Non-turnkey contract

    International Nuclear Information System (INIS)

    Shimoyama, Shunji

    1975-01-01

    A turnkey contract is recommended to such a country which is in the initial stage of nuclear power development with respect to a few plants being constructed earlier. The prime contractor may not necessarily be a reactor supplier. In some cases an architect engineering company may be a contractor. If this arrangement is not possible and the contract had to be a non-turnkey type, there might be some advantage to such a developing country capable of undertaking some major portions of the project works. Even if she might face with troubles and difficulties during construction of the first nuclear power station, she might have chance of aquiring technical kowledge and experience which would later enable her to make the plant of her own manufacture. In such a case it is advisable to limit the number of main contracts as small as possible and to utilize an organization to assist the owner in project management or to assume this function in his behalf. (orig./FW) [de

  11. 48 CFR 937.7040 - Contract clauses.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Contract clauses. 937.7040... CONTRACTING SERVICE CONTRACTING Protective Services Contracting 937.7040 Contract clauses. The contracting... services” in all protective services solicitations and contracts involving DOE-owned facilities requiring...

  12. 48 CFR 1516.505 - Contract clauses.

    Science.gov (United States)

    2010-10-01

    ... METHODS AND CONTRACT TYPES TYPES OF CONTRACTS Indefinite-Delivery Contracts 1516.505 Contract clauses. (a) The Contracting Officer shall insert the clause in 1552.216-72, Ordering—By Designated Ordering Officers, in indefinite delivery/indefinite quantity type solicitations and contracts. (b) The Contracting...

  13. The interpretation of administrative contracts

    Directory of Open Access Journals (Sweden)

    Cătălin-Silviu SĂRARU

    2014-06-01

    Full Text Available The article analyzes the principles of interpretation for administrative contracts, in French law and in Romanian law. In the article are highlighted derogations from the rules of contract interpretation in common law. Are examined the exceptions to the principle of good faith, the principle of common intention (willingness of the parties, the principle of good administration, the principle of extensive interpretation of the administrative contract. The article highlights the importance and role of the interpretation in administrative contracts.

  14. Measurement of the $^{8}B$ neutrino spectrum

    CERN Document Server

    Winter, W; Jiang, C L; Ahmad, I; Freedman, S J; Greene, J; Heinz, A; Henderson, D; Janssens, R V F; Moore, E F; Mukherjee, G; Pardo, R C; Paul, M; Pennington, T; Savard, G; Schiffer, J P; Seweryniak, D; Zinkann, G P; 10.1016/S0375-9474(03)01122-9

    2003-01-01

    The neutrino spectrum from the decay of /sup 8/B is a crucial ingredient in interpreting recent data from solar neutrino detectors. The beta /sup +/ decay of /sup 8/B proceeds to a broad state in /sup 8/Be, and the shape of the neutrino spectrum may be obtained from a measurement of the alpha spectrum following the beta /sup +/ decay. A new technique has been used at the ATLAS accelerator to measure this spectrum by implanting /sup 8/B particles into the midplane of a 91 mu m thick Si detector. The advantage of this method is that both alpha particles are detected and systematic effects due to energy loss in catcher foils and dead layers of the detector are eliminated. To calibrate the detector, alpha 's from the decay of /sup 20/Na ions produced and implanted with the same technique were used. (5 refs).

  15. Why radiologists lose their hospital contracts: is your contract secure?

    Science.gov (United States)

    Muroff, Lawrence R

    2010-03-01

    Previously, a hospital contract meant tenure for the incumbent group of radiologists; however, those days are long gone. Exclusive contracts have morphed into exclusive contracts with carve-outs. Turf erosion has become a fact of life for radiology practices. Now radiologists are losing their hospital contracts in record numbers. Group size, though helpful for a variety of reasons, does not ensure that a practice will be secure in its hospital setting. The reasons that groups lose their hospital contracts are varied, and in this paper, the author discusses the most common ones. Suggestions to help practices avoid this unfortunate fate are presented.

  16. Licensing open spectrum systems

    OpenAIRE

    Vázquez, Miguel Angel; Pérez Neira, Ana Isabel; Lagunas Hernandez, Miguel A.

    2012-01-01

    This paper studies how the spectrum regulation could change in the future open spectrum communication systems. Due to their huge success in short-range communication systems (WiFi, Zigbee, ...), broader area telecommunication providers might mimic the open spectrum philosophy to their systems. Nevertheless, current wireless open spectrum systems are not designed for wide areas and they do not provide QoS to their users. This work proposes an alternative to the nowadays open spectrum systems i...

  17. Transnational Law of Public Contracts

    NARCIS (Netherlands)

    Audit, M.; Schill, S.W.

    2016-01-01

    Public contracts were traditionally conceived as instruments of domestic public law and used within markets confined to the territory of the state party to the contract. Globalization, however, subjects public contracting to an increasing number of processes that take place at a transnational level

  18. Static Verification for Code Contracts

    Science.gov (United States)

    Fähndrich, Manuel

    The Code Contracts project [3] at Microsoft Research enables programmers on the .NET platform to author specifications in existing languages such as C# and VisualBasic. To take advantage of these specifications, we provide tools for documentation generation, runtime contract checking, and static contract verification.

  19. Practical guide on contract of technology

    International Nuclear Information System (INIS)

    Choi, Chiho

    1991-12-01

    This book gives descriptions of practical guide on contract of technology, which deals with basic of contract like meaning, function term, singing and sealing, contract and stamp tax, common things on contract of research like keeping secret and prevention and treat of dispute, compensation for damages, notice, expiration date of contract and measurement at end of contract, contract of joint research such as meaning and necessity, note at contract, check list at contract, and return of the research product.

  20. Broad line regions in Seyfert-1 galaxies

    International Nuclear Information System (INIS)

    Groningen, E. van.

    1984-01-01

    To reproduce observed emission profiles of Seyfert galaxies, rotation in an accretion disk has been proposed. In this thesis, the profiles emitted by such an accretion disk are investigated. Detailed comparison with the observed profiles yields that a considerable fraction can be fitted with a power-law function, as predicted by the model. The author analyzes a series of high quality spectra of Seyfert galaxies, obtained with the 2.5m telescope at Las Campanas. He presents detailed analyses of two objects: Mkn335 and Akn120. In both cases, strong evidence is presented for the presence of two separate broad line zones. These zones are identified with an accretion disk and an outflowing wind. The disk contains gas with very high densities and emits predominantly the lower ionization lines. He reports on the discovery of very broad wings beneath the strong forbidden line 5007. (Auth.)

  1. Fourier evaluation of broad Moessbauer spectra

    International Nuclear Information System (INIS)

    Vincze, I.

    1981-01-01

    It is shown by the Fourier analysis of broad Moessbauer spectra that the even part of the distribution of the dominant hyperfine interaction (hyperfine field or quadrupole splitting) can be obtained directly without using least-square fitting procedures. Also the odd part of this distribution correlated with other hyperfine parameters (e.g. isomer shift) can be directly determined. Examples for amorphous magnetic and paramagnetic iron-based alloys are presented. (author)

  2. Analysis of foreign petroleum contracts

    International Nuclear Information System (INIS)

    Moran, S.S.

    1991-01-01

    Most foreign exploration and production contracts are of two basic types: Production-Sharing contracts in which a portion of oil revenues, 'cost oil,' is available to the contractor for recoupment of exploration and production costs with the remainder, 'profit oil,' being shared according to an agreed-upon formula, and the familiar Tax-Royalty contract in which a share of petroleum revenues goes to the host country 'off the top' as royalties, and operating profits are taxed at the going rate. Bottom line splits of profits between host governments and contractors, which are approximately 50-50 in the United States, are typically in the 60-40 to 85-15 range elsewhere, with lower profit shares being offset by the higher volume potential and lower costs that may be associated with less mature exploration areas. Foreign contract qualities can be grossly compared by walking typical field models through the contracts to arrive at the bottom line profit splits. Variations within the contract forms include government participation, sliding scale contract elements, special taxes related to rates of return, etc. Often, contract terms are subject to negotiation and the tradeoffs between contract elements must be understood. Contract life, amortization schedules, fund repatriation, currency exchange rates, and the interaction of foreign and United States tax regimens are among the other factors that must be considered. Final decisions on foreign ventures must combine consideration of contracts, economic projections, hydrocarbon volumes, exploration cost estimates, and the estimated probability of success into an overall project assessment

  3. The Lanthanide Contraction Revisited

    Energy Technology Data Exchange (ETDEWEB)

    Seitz, Michael; Oliver, Allen G.; Raymond, Kenneth N.

    2007-04-19

    A complete, isostructural series of lanthanide complexes (except Pm) with the ligand TREN-1,2-HOIQO has been synthesized and structurally characterized by means of single-crystal X-ray analysis. All complexes are 1D-polymeric species in the solid state, with the lanthanide being in an eight-coordinate, distorted trigonal-dodecahedral environment with a donor set of eight unique oxygen atoms. This series constitutes the first complete set of isostructural lanthanide complexes with a ligand of denticity greater than two. The geometric arrangement of the chelating moieties slightly deviates across the lanthanide series, as analyzed by a shape parameter metric based on the comparison of the dihedral angles along all edges of the coordination polyhedron. The apparent lanthanide contraction in the individual Ln-O bond lengths deviates considerably from the expected quadratic decrease that was found previously in a number of complexes with ligands of low denticity. The sum of all bond lengths around the trivalent metal cation, however, is more regular, showing an almost ideal quadratic behavior across the entire series. The quadratic nature of the lanthanide contraction is derived theoretically from Slater's model for the calculation of ionic radii. In addition, the sum of all distances along the edges of the coordination polyhedron show exactly the same quadratic dependency as the Ln-X bond lengths. The universal validity of this coordination sphere contraction, concomitant with the quadratic decrease in Ln-X bond lengths, was confirmed by reexamination of four other, previously published, almost complete series of lanthanide complexes. Due to the importance of multidentate ligands for the chelation of rare-earth metals, this result provides a significant advance for the prediction and rationalization of the geometric features of the corresponding lanthanide complexes, with great potential impact for all aspects of lanthanide coordination.

  4. Broad spectrum antidermatophytic drug for the control of tinea infection in human beings.

    Science.gov (United States)

    Bhadauria, Seema; Kumar, Padma

    2012-07-01

    During antifungal evaluation of various plant extracts, free and bound flavonoids of Piper betle were found to be most effective as an antidermatophytic against human pathogenic dermatophytes Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum gypseum and Candida albicans. Dermatophytic fungi cause both superficial and internal mycoses. These mycoses, although normally not lethal, are unpleasant and difficult to cure and cause considerable financial losses. Earlier workers prove that allopathic drugs are still found effective against dermatomycoses, but these drugs could not be accepted as a routine treatment for every case, because they are expensive and require long treatment. It is almost unaffordable by middle and lower class people. In view of such prospects and constraints, our aim was to explore more new compounds of plant origin for controlling dermatophytic infections. Author explored water, methanolic and flavonoid extracts for screening as antidermatophytic agent. Plant extracts that showed good results in vitro were selected for clinical studies. The study may give cheaper treatment for medium and lower class patients suffering with tinea and may provide them much relief. Well-established paper disc method was used for the screening of different extracts of their antidermatophytic activity. Moreover, it did not exhibit any adverse side effect on mammalian skin. Flavonoids in the form of ointment Pi be I and Pi be II were subjected to topical testing on patients attending out patients department of S.M.S. Hospital, Jaipur, India. Patients were diagnosed as tinea corporis, tinea capitis, tinea manum or tinea pedis. All patients showed positive potassium hydroxide (KOH) results at the beginning of trial. Patients between the ages of 3 months to 58 years were enrolled. At the end of treatment, while 64% of patients cured completely, 24% showed significant improvement and 12% showed little improvement from the disease. Allopathic treatment took 4-8 weeks when compared with only 1-5 weeks taken by Pi be I and Pi be II ointments. The ointment, thus not only showed maximum affectivity but was also found to be a better and cost effective alternative to allopathic drug for tinea infections. The acceptability of alternative medicines, particularly herbal medicines, has now become a critical need of the times. © 2011 Blackwell Verlag GmbH.

  5. Novel Naja atra cardiotoxin 1 (CTX-1 derived antimicrobial peptides with broad spectrum activity.

    Directory of Open Access Journals (Sweden)

    Andrea Sala

    Full Text Available Naja atra subsp. atra cardiotoxin 1 (CTX-1, produced by Chinese cobra snakes, belonging to Elapidae family, is included in the three-finger toxin family and exerts high cytotoxicity and antimicrobial activity too. Using as template mainly the tip and the subsequent β-strand of the first "finger" of this toxin, different sequences of 20 amino acids linear peptides have been designed in order to avoid toxic effects but to maintain or even strengthen the partial antimicrobial activity already seen for the complete toxin. As a result, the sequence NCP-0 (Naja Cardiotoxin Peptide-0 was designed as ancestor and subsequently 4 other variant sequences of NCP-0 were developed. These synthesized variant sequences have shown microbicidal activity towards a panel of reference and field strains of Gram-positive and Gram-negative bacteria. The sequence named NCP-3, and its variants NCP-3a and NCP-3b, have shown the best antimicrobial activity, together with low cytotoxicity against eukaryotic cells and low hemolytic activity. Bactericidal activity has been demonstrated by minimum bactericidal concentration (MBC assay at values below 10 μg/ml for most of the tested bacterial strains. This potent antimicrobial activity was confirmed even for unicellular fungi Candida albicans, Candida glabrata and Malassezia pachydermatis (MBC 50-6.3 μg/ml, and against the fast-growing mycobacteria Mycobacterium smegmatis and Mycobacterium fortuitum. Moreover, NCP-3 has shown virucidal activity on Bovine Herpesvirus 1 (BoHV1 belonging to Herpesviridae family. The bactericidal activity is maintained even in a high salt concentration medium (125 and 250 mM NaCl and phosphate buffer with 20% Mueller Hinton (MH medium against E. coli, methicillin resistant Staphylococcus aureus (MRSA and Pseudomonas aeruginosa reference strains. Considering these in vitro obtained data, the search for active sequences within proteins presenting an intrinsic microbicidal activity could provide a new way for discovering a large number of novel and promising antimicrobial peptides families.

  6. Kidney failure related to broad-spectrum antibiotics in critically ill patients

    DEFF Research Database (Denmark)

    Jensen, Jens-Ulrik Stæhr; Hein, Lars; Lundgren, Bettina

    2012-01-01

    To explore whether a strategy of more intensive antibiotic therapy leads to emergence or prolongation of renal failure in intensive care patients.......To explore whether a strategy of more intensive antibiotic therapy leads to emergence or prolongation of renal failure in intensive care patients....

  7. The effect of broad-spectrum antibiotics on warfarin excretion and metabolism in the rat

    International Nuclear Information System (INIS)

    Remmel, R.P.; Elmer, G.W.

    1981-01-01

    The excretion and metabolism of 14 C-warfarin in rats was examined in a crossover experiment, the first phase consisting of treatment with normal saline, the second phase using the same animals given neomycin, bacitracin, and tetracycline orally. Urine and feces were collected every 24 hours for 72 hours and examined for warfarin and its metabolites, both unconjugated and conjugated. Significantly more radioactivity was eliminated in th feces of antibiotic-treated rats. The feces of antibiotic-treated rats contained only trace amounts of beta-glucuronidase activity. Urine contained a similar ratio of unconjugated to conjugated radioactivity in both treatment groups, but the antibiotic-treated animals had significantly larger amount of conjugates in their feces. Examination of metabolic profiles of conjugated and unconjugated fractions revealed significantly fewer hydroxylated metabolites in antibiotic-treated rats, especially in the feces. The lower amount of hydroxylative metabolism in attributed to a reduction in gut flora-medicated interohepatic recycling caused by the antibiotics

  8. Dissemination and genetic support of broad-spectrum beta-lactam ...

    African Journals Online (AJOL)

    (100 μg/ml). Transformation experiments were carried out by using E. coli DH5α as the recipient as previously described31,36. Transformants were selected on Luria-Bertani medium agar plates supplemented with ampicillin (100 mg/ml). Transformants were subjected to DDST to confirm the presence of ESBL genes and ...

  9. Lipophosphonoxins II: Design, Synthesis, and Properties of Novel Broad Spectrum Antibacterial Agents

    Czech Academy of Sciences Publication Activity Database

    Seydlová, G.; Pohl, Radek; Zborníková, Eva; Ehn, Marcel; Šimák, Ondřej; Panova, Natalya; Kolář, M.; Bogdanová, K.; Večeřová, R.; Fišer, R.; Šanderová, Hana; Vítovská, Dragana; Sudzinová, Petra; Pospíšil, Jiří; Benada, Oldřich; Křížek, T.; Sedlák, David; Bartůněk, Petr; Krásný, Libor; Rejman, Dominik

    2017-01-01

    Roč. 60, č. 14 (2017), s. 6098-6118 ISSN 0022-2623 R&D Projects: GA MŠk LO1220; GA MŠk LM2015063; GA ČR(CZ) GBP305/12/G034; GA MŠk(CZ) LM2015055; GA MZd(CZ) NV17-29680A Institutional support: RVO:61388963 ; RVO:61388971 ; RVO:68378050 Keywords : resistant Staphylococcus aureus * cationic steroid antibiotics * antimicrobial peptides Subject RIV: EE - Microbiology, Virology; EE - Microbiology, Virology (MBU-M) OBOR OECD: Microbiology; Microbiology (MBU-M) Impact factor: 6.259, year: 2016

  10. A mutagenesis-derived broad-spectrum disease resistance locus in wheat.

    Science.gov (United States)

    Campbell, Jackie; Zhang, Hongtao; Giroux, Michael J; Feiz, Leila; Jin, Yue; Wang, Meinan; Chen, Xianming; Huang, Li

    2012-07-01

    Wheat leaf rust, stem rust, stripe rust, and powdery mildew caused by the fungal pathogens Puccinia triticina, P. graminis f. sp. tritici, P. striiformis f. sp. tritici, and Blumeria graminis f. sp. tritici, respectively, are destructive diseases of wheat worldwide. Breeding durable disease resistance cultivars rely largely on continually introgressing new resistance genes, especially the genes with different defense mechanisms, into adapted varieties. Here, we describe a new resistance gene obtained by mutagenesis. The mutant, MNR220 (mutagenesis-derived new resistance), enhances resistance to three rusts and powdery mildew, with the characteristics of delayed disease development at the seedling stage and completed resistance at the adult plant stage. Genetic analysis demonstrated that the resistance in MNR220 is conferred by a single semidominant gene mapped on the short arm of chromosome 2B. Gene expression profiling of several pathogenesis-related genes indicated that MNR220 has an elevated and rapid pathogen-induced response. In addition to its potential use in breeding for resistance to multiple diseases, high-resolution mapping and cloning of the disease resistance locus in MNR220 may lead to a better understanding of the regulation of defense responses in wheat.

  11. Broad-spectrum antibacterial properties of metal-ion doped borate bioactive glasses for clinical applications

    Science.gov (United States)

    Ottomeyer, Megan

    Bioactive glasses with antimicrobial properties can be implemented as coatings on medical devices and implants, as well as a treatment for tissue repair and prevention of common hospital-acquired infections such as MRSA. A borate-containing glass, B3, is also undergoing clinical trials to assess wound-healing properties. The sensitivities of various bacteria to B3, B3-Ag, B3-Ga, and B3-I bioactive glasses were tested. In addition, the mechanism of action for the glasses was studied by spectroscopic enzyme kinetics experiments, Live-Dead staining fluorescence microscopy, and luminescence assays using two gene fusion strains of Escherichia coli. It was found that gram-positive bacteria were more sensitive to all four glasses than gram negative bacteria, and that a single mechanism of action for the glasses is unlikely, as the rates of catalysis for metabolic enzymes as well as membrane permeability were altered after glass exposure.

  12. Aryl hydantoin Ro 13-3978, a broad-spectrum antischistosomal.

    Science.gov (United States)

    Keiser, Jennifer; Panic, Gordana; Vargas, Mireille; Wang, Chunkai; Dong, Yuxiang; Gautam, Nagsen; Vennerstrom, Jonathan L

    2015-01-01

    Praziquantel is the only drug available for the treatment of schistosomiasis and the state of the exhausted drug discovery pipeline is alarming. We restarted investigations on the abandoned antischistosomal Ro 13-3978, an aryl hydantoin discovered in the early 1980s by Hoffmann La-Roche. Newly transformed schistosomula and adult Schistosoma mansoni were studied in the presence of Ro 13-3978 in vitro. The metabolic stability of Ro 13-3978 was determined in vitro using human and mouse liver S9 fractions. Dose-response relationship, stage specificity, hepatic shift and scanning electron microscopy studies were carried out in S. mansoni-infected mice. In addition, efficacy experiments were conducted in rodents infected with Echinostoma caproni and Fasciola hepatica as well as in S. mansoni-infected immunocompromised nude (Foxn1(nu)) mice. Ro 13-3978 showed minor in vitro activity and no damage to the tegument was found. No cytotoxicity was detected for Ro 13-3978. Ro 13-3978 was metabolically stable. ED50 values of 138.9 and 14.6 mg/kg were calculated for the treatment of juvenile and adult S. mansoni infections, respectively, with a single oral dose of Ro 13-3978. SEM studies revealed severe damage to the worms 48 h post-treatment of infected mice. A single oral dose of Ro 13-3978 (100 mg/kg) administered to S. mansoni-infected (Foxn1(nu)) mice reduced the worm burden by 88%. Ro 13-3978 was not active against E. caproni and F. hepatica in vivo. Ro 13-3978 has excellent antischistosomal properties in vivo. Structure-activity relationship studies with the aryl hydantoins have been launched in order to elucidate active pharmacophores, further investigate the mechanism of action and to identify a derivative with minimal antiandrogenic effects. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  13. Self-esteem in a broad-spectrum approach for mental health promotion

    NARCIS (Netherlands)

    Mann, M.; Hosman, C.M.H.; Schaalma, H.P.; Vries, N.K. de

    2004-01-01

    Self-evaluation is crucial to mental and social well-being. It influences aspirations, personal goals and interaction with others. This paper stresses the importance of self-esteem as a protective factor and a non-specific risk factor in physical and mental health. Evidence is presented illustrating

  14. Association between colistin resistance and broad-spectrum recipient deficiency in Klebsiella pneumoniae.

    OpenAIRE

    Lamousin-White, M; O'Callaghan, R J

    1986-01-01

    A colistin-resistant mutant of Klebsiella pneumoniae served well as a donor but not as a recipient in conjugation. A nearly 1,000-fold difference between colistin-susceptible and colistin-resistant forms of this strain was observed by using donors of plasmids of four incompatibility groups. Recipient efficiency was not restored by filter matings.

  15. Dyskeratosis congenita: a combined immunodeficiency with broad clinical spectrum--a single-center pediatric experience.

    Science.gov (United States)

    Jyonouchi, S; Forbes, L; Ruchelli, E; Sullivan, K E

    2011-05-01

    Dyskeratosis Congenita (DKC) is a syndrome characterized by immunodeficiency, bone marrow failure, somatic abnormalities, and cancer predisposition resulting from defective telomere maintenance. The immunologic features of DKC remain under diagnosed and under treated despite the fact that immunodeficiency is a major cause of premature mortality in DKC. This study undertook a retrospective review of 7 DKC patients diagnosed at the Children's Hospital of Philadelphia. In parallel, we reviewed previously reported immunologic findings in DKC patients. Immunologic abnormalities (lymphopenia, low B-cell numbers, hypogammaglobulinemia, and decreased T-cell function) were the most frequent laboratory findings at initial presentation, preceding the development of significant anemia or thrombocytopenia. Recurrent sinopulmonary or opportunistic infections were present in 6/7 patients. Infant-onset patients had more severe immunologic and somatic features (particularly severe enteropathy). In DKC, development of immunologic abnormalities can precede bone marrow failure, highlighting the importance of proper immunodeficiency management to minimize morbidity and premature mortality in this disease. © 2011 John Wiley & Sons A/S.

  16. Arbidol (Umifenovir): A broad-spectrum antiviral drug that inhibits medically important arthropod-borne flaviviruses

    Czech Academy of Sciences Publication Activity Database

    Haviernik, J.; Štefánik, M.; Fojtíková, M.; Kali, S.; Tordo, N.; Rudolf, Ivo; Hubálek, Zdeněk; Eyer, Luděk; Růžek, Daniel

    2018-01-01

    Roč. 10, č. 4 (2018), č. článku 184. ISSN 1999-4915 R&D Projects: GA ČR(CZ) GA16-20054S Institutional support: RVO:68081766 ; RVO:60077344 Keywords : Antiviral activity * Arbidol * Cell-type dependent antiviral effect * Cytotoxicity * Flavivirus * Umifenovir Subject RIV: EE - Microbiology, Virology OBOR OECD: Virology Impact factor: 3.465, year: 2016

  17. Lipophosphonoxins II: Design, Synthesis, and Properties of Novel Broad Spectrum Antibacterial Agents.

    Science.gov (United States)

    Seydlová, Gabriela; Pohl, Radek; Zborníková, Eva; Ehn, Marcel; Šimák, Ondřej; Panova, Natalya; Kolář, Milan; Bogdanová, Kateřina; Večeřová, Renata; Fišer, Radovan; Šanderová, Hana; Vítovská, Dragana; Sudzinová, Petra; Pospíšil, Jiří; Benada, Oldřich; Křížek, Tomáš; Sedlák, David; Bartůněk, Petr; Krásný, Libor; Rejman, Dominik

    2017-07-27

    The increase in the number of bacterial strains resistant to known antibiotics is alarming. In this study we report the synthesis of novel compounds termed Lipophosphonoxins II (LPPO II). We show that LPPO II display excellent activities against Gram-positive and -negative bacteria, including pathogens and multiresistant strains. We describe their mechanism of action-plasmatic membrane pore-forming activity selective for bacteria. Importantly, LPPO II neither damage nor cross the eukaryotic plasmatic membrane at their bactericidal concentrations. Further, we demonstrate LPPO II have low propensity for resistance development, likely due to their rapid membrane-targeting mode of action. Finally, we reveal that LPPO II are not toxic to either eukaryotic cells or model animals when administered orally or topically. Collectively, these results suggest that LPPO II are highly promising compounds for development into pharmaceuticals.

  18. Discovery of sarolaner: A novel, orally administered, broad-spectrum, isoxazoline ectoparasiticide for dogs.

    Science.gov (United States)

    McTier, Tom L; Chubb, Nathan; Curtis, Michael P; Hedges, Laura; Inskeep, Gregory A; Knauer, Christopher S; Menon, Sanjay; Mills, Brian; Pullins, Aleah; Zinser, Erich; Woods, Debra J; Meeus, Patrick

    2016-05-30

    The novel isoxazoline ectoparasiticide, sarolaner, was identified during a lead optimization program for an orally-active compound with efficacy against fleas and ticks on dogs. The aim of the discovery program was to identify a novel isoxazoline specifically for use in companion animals, beginning with de novo synthesis in the Zoetis research laboratories. The sarolaner molecule has unique structural features important for its potency and pharmacokinetic (PK) properties, including spiroazetidine and sulfone moieties. The flea and tick activity resides in the chirally pure S-enantiomer, which was purified to alleviate potential off-target effects from the inactive enantiomer. The mechanism of action was established in electrophysiology assays using CHO-K1 cell lines stably expressing cat flea (Ctenocephalides felis) RDL (resistance-to-dieldrin) genes for assessment of GABA-gated chloride channel (GABACls) pharmacology. As expected, sarolaner inhibited GABA-elicited currents at both susceptible (CfRDL-A285) and resistant (CfRDL-S285) flea GABACls with similar potency. Initial whole organism screening was conducted in vitro using a blood feeding assay against C. felis. Compounds which demonstrated robust activity in the flea feed assay were subsequently tested in an in vitro ingestion assay against the soft tick, Ornithodoros turicata. Efficacious compounds which were confirmed safe in rodents at doses up to 30mg/kg were progressed to safety, PK and efficacy studies in dogs. In vitro sarolaner demonstrated an LC80 of 0.3μg/mL against C. felis and an LC100 of 0.003μg/mL against O. turicata. In a head-to-head comparative in vitro assay with both afoxolaner and fluralaner, sarolaner demonstrated superior flea and tick potency. In exploratory safety studies in dogs, sarolaner demonstrated safety in dogs≥8 weeks of age upon repeated monthly dosing at up to 20mg/kg. Sarolaner was rapidly and well absorbed following oral dosing. Time to maximum plasma concentration occurred within the first day post-dose. Bioavailability for sarolaner was calculated at >85% and the compound was highly protein bound (>99.9%). The half-life for sarolaner was calculated at 11-12 days. Sarolaner plasma concentrations indicated dose proportionality over the range 1.25-5mg/kg, and these same doses provided robust efficacy (>99%) for ≥35days against both fleas (C. felis) and multiple species of ticks (Rhipicephalus sanguineus, Ixodes ricinus and Dermacentor reticulatus) after oral administration to dogs. As a result of these exploratory investigations, sarolaner was progressed for development as an oral monthly dose for treatment and control of fleas and ticks on dogs. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  19. Engineering of gadofluoroprobes: Broad-spectrum applications from cancer diagnosis to therapy

    Energy Technology Data Exchange (ETDEWEB)

    Dutta, Ranu A., E-mail: ranu.dutta16@gmail.com [Nanotechnology Application Centre, University of Allahabad, Allahabad 211002 (India); NanoeRA medicare Private Limited, Uttar Pradesh (India); Sharma, Prashant K. [Nanotechnology Application Centre, University of Allahabad, Allahabad 211002 (India); Indian School of Mines, Dhanbad (India); Tiwari, Vandana [Department of Pathology, KGMU, Lucknow (India); Tiwari, Vivek; Patel, Anant B. [Centre for Cellular and Molecular Biology, Hyderabad (India); Pandey, Ravindra [Department of Physics, Michigan Technological University, Michigan 49931-1295 (United States); Pandey, Avinash C. [Nanotechnology Application Centre, University of Allahabad, Allahabad 211002 (India); NanoeRA medicare Private Limited, Uttar Pradesh (India); Bundelkhand University, Jhansi (India)

    2014-01-13

    The engineering of the Gadolinium based nanostructures have been demonstrated in this paper. Nanostructures of α-Gd{sub 2}S{sub 3} exhibit a unique transition between ferromagnetic state and paramagnetic state of the system. It was demonstrated that their properties could be tuned for a wide range of applications ranging from hyperthermia to Magnetic Resonance Imaging, owing to their magnetic moments and large relaxivities. Metallic Gd nanoparticles obtained by reduction method were employed for cancer imaging in mice. The Gd nanoparticles were coated with Curcumin and their biomedical implications in the field of simultaneous diagnosis and therapy of cancer and related diseases has been discussed.

  20. Chitosanase purified from bacterial isolate Bacillus licheniformis of ruined vegetables displays broad spectrum biofilm inhibition.

    Science.gov (United States)

    Muslim, Sahira Nsayef; Al-Kadmy, Israa M S; Hussein, Nadheema Hammood; Mohammed Ali, Alaa Naseer; Taha, Buthainah Mohammed; Aziz, Sarah Naji; Kheraif, Abdulaziz Abdullah Al; Divakar, Darshan Devang; Ramakrishnaiah, Ravikumar

    2016-11-01

    A number of bacterial species produces chitosanases which has variety of applications because of its high biodegradability, non-toxicity and antimicrobial assets. In the present study chitosanase is purified from new bacterial species Bacillus licheniformis from spoiled vegetable. This novel strain of Bacillus licheniformis isolated from spoilt cucumber and pepper samples has the ability to produce the chitosanase enzyme when grown on chitosan substrate. Study also examined its antibiofilm properties against diverse bacterial species with biofilm forming ability. The purified chitosanase inhibited the biofilm formation ability for all Gram-negative and Gram-positive biofilm-forming bacteria [biofilm producers] tested in this study in congo red agar and microtiter plate's methods. Highly antibiofilm activity of chitosanase was recorded against Pseudomonas aeruginosa followed by Klebsiella pneumoniae with reduction of biofilm formation upto 22 and 29%, respectively compared with [100] % of control. Biofilm formation has multiple role including ability to enhance resistance and self-protection from external stress. This chitosanase has promising benefit as antibiofilm agent against biofilm forming pathogenic bacteria and has promising application as alternative antibiofilm agents to combat the growing number of multidrug resistant pathogen-associated infections, especially in situation where biofilms are involved. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Fungal Glucosylceramide-Specific Camelid Single Domain Antibodies Are Characterized by Broad Spectrum Antifungal Activity

    Directory of Open Access Journals (Sweden)

    Barbara De Coninck

    2017-06-01

    Full Text Available Chemical crop protection is widely used to control plant diseases. However, the adverse effects of pesticide use on human health and environment, resistance development and the impact of regulatory requirements on the crop protection market urges the agrochemical industry to explore innovative and alternative approaches. In that context, we demonstrate here the potential of camelid single domain antibodies (VHHs generated against fungal glucosylceramides (fGlcCer, important pathogenicity factors. To this end, llamas were immunized with purified fGlcCer and a mixture of mycelium and spores of the fungus Botrytis cinerea, one of the most important plant pathogenic fungi. The llama immune repertoire was subsequently cloned in a phage display vector to generate a library with a diversity of at least 108 different clones. This library was incubated with fGlcCer to identify phages that bind to fGlcCer, and VHHs that specifically bound fGlcCer but not mammalian or plant-derived GlcCer were selected. They were shown to inhibit the growth of B. cinerea in vitro, with VHH 41D01 having the highest antifungal activity. Moreover, VHH 41D01 could reduce disease symptoms induced by B. cinerea when sprayed on tomato leaves. Based on all these data, anti-fGlcCer VHHs show the potential to be used as an alternative approach to combat fungal plant diseases.

  2. [Effect of a computer application on appropriate use and control of broad spectrum antibiotics].

    Science.gov (United States)

    Raveh-Brawer, David; Wiener-Well, Yonit; Lachish, Tamar; Ben-Chetrit, Eli; Megged, Orly; Bar-Meir, Maskit; Dahan, Maymone; Shraber, Tzipora; Bukatman, Estelle; Yinnon, Amos M

    2015-03-01

    Antibiotics are among the greatest contributions of modern medicine. However, since the onset of the antibiotic age, resistance has emerged, threatening the future usability of these drugs. The complexity of antibiotic prescribing and associated expense has led to the development of infectious disease (ID) expert stewardship programs. To describe an in-house created computer application, in use since 2005 with which all restricted antimicrobials are ordered and approved by ID physicians before being supplied by the pharmacy. In the nine years since the application was adopted by the entire hospital, 173,436 prescriptions for restricted antibiotics have been ordered through the application, of which 52% were for male patients, 8% for children ≤ 20 years, 31% for adults 21-70 years old and 61% for patients > 70. All prescriptions were reviewed by ID physicians; their response included approval (mean 87%, range 82-92%), rejection (7%, 3-12%), or change (6%, 4-18%). The latter two decisions always involved written and/or oral interaction with the prescribing physicians. The result analysis showed that: by clinical diagnoses, the approval rate ranged from 82% (for central line associated infection) to 94% (for tuberculosis); by class of antimicrobial, the approval rate ranged from 71% (IV ciprofloxacin) to 95% (IV amoxicillin-calvulanate). Overall hospital expenditure on antimicrobials, corrected by 100 admissions and 100 admission days, did not change significantly. During the nine years of its use, the described computer program has significantly contributed to physician awareness of appropriate antibiotic use, provided tools to assist physicians in their choice of antimicrobial treatment, allowed ID supervision with unprecedented scope and depth and has significantly contributed to cost control.

  3. Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency

    NARCIS (Netherlands)

    Walter, Jolan E.; Rosen, Lindsey B.; Csomos, Krisztian; Rosenberg, Jacob M.; Mathew, Divij; Keszei, Marton; Ujhazi, Boglarka; Chen, Karin; Lee, Yu Nee; Tirosh, Irit; Dobbs, Kerry; Al-Herz, Waleed; Cowan, Morton J.; Puck, Jennifer; Bleesing, Jack J.; Grimley, Michael S.; Malech, Harry; de Ravin, Suk See; Gennery, Andrew R.; Abraham, Roshini S.; Joshi, Avni Y.; Boyce, Thomas G.; Butte, Manish J.; Nadeau, Kari C.; Balboni, Imelda; Sullivan, Kathleen E.; Akhter, Javeed; Adeli, Mehdi; El-Feky, Reem A.; El-Ghoneimy, Dalia H.; Dbaibo, Ghassan; Wakim, Rima; Azzari, Chiara; Palma, Paolo; Cancrini, Caterina; Capuder, Kelly; Condino-Neto, Antonio; Costa-Carvalho, Beatriz T.; Oliveira, Joao Bosco; Roifman, Chaim; Buchbinder, David; Kumanovics, Attila; Franco, Jose Luis; Niehues, Tim; Schuetz, Catharina; Kuijpers, Taco; Yee, Christina; Chou, Janet; Masaad, Michel J.; Geha, Raif; Uzel, Gulbu; Gelman, Rebecca; Holland, Steven M.; Recher, Mike; Utz, Paul J.; Browne, Sarah K.; Notarangelo, Luigi D.

    2015-01-01

    Patients with mutations of the recombination-activating genes (RAG) present with diverse clinical phenotypes, including severe combined immune deficiency (SCID), autoimmunity, and inflammation. However, the incidence and extent of immune dysregulation in RAG-dependent immunodeficiency have not been

  4. Using existing drugs as leads for broad spectrum anthelmintics targeting protein kinases.

    Directory of Open Access Journals (Sweden)

    Christina M Taylor

    2013-02-01

    Full Text Available As one of the largest protein families, protein kinases (PKs regulate nearly all processes within the cell and are considered important drug targets. Much research has been conducted on inhibitors for PKs, leading to a wealth of compounds that target PKs that have potential to be lead anthelmintic drugs. Identifying compounds that have already been developed to treat neglected tropical diseases is an attractive way to obtain lead compounds inexpensively that can be developed into much needed drugs, especially for use in developing countries. In this study, PKs from nematodes, hosts, and DrugBank were identified and classified into kinase families and subfamilies. Nematode proteins were placed into orthologous groups that span the phylum Nematoda. A minimal kinome for the phylum Nematoda was identified, and properties of the minimal kinome were explored. Orthologous groups from the minimal kinome were prioritized for experimental testing based on RNAi phenotype of the Caenorhabditis elegans ortholog, transcript expression over the life-cycle and anatomic expression patterns. Compounds linked to targets in DrugBank belonging to the same kinase families and subfamilies in the minimal nematode kinome were extracted. Thirty-five compounds were tested in the non-parasitic C. elegans and active compounds progressed to testing against nematode species with different modes of parasitism, the blood-feeding Haemonchus contortus and the filarial Brugia malayi. Eighteen compounds showed efficacy in C. elegans, and six compounds also showed efficacy in at least one of the parasitic species. Hypotheses regarding the pathway the compounds may target and their molecular mechanism for activity are discussed.

  5. Sarcomas associated with hereditary nonpolyposis colorectal cancer: broad anatomical and morphological spectrum

    DEFF Research Database (Denmark)

    Nilbert, Mef; Therkildsen, Christina; Nissen, Anja

    2009-01-01

    were represented with recurrent diagnoses of liposarcoma, leiomyosarcoma, and carcinosarcoma. Tumor tissue from eight cases was available for analysis of mismatch-repair (MMR) status using immunohistochemical staining and analysis of microsatellite instability, which revealed MMR defects in six...

  6. Isolation and characterization of broad-spectrum disease-resistant Arabidopsis mutants.

    Science.gov (United States)

    Maleck, Klaus; Neuenschwander, Urs; Cade, Rebecca M; Dietrich, Robert A; Dangl, Jeffery L; Ryals, John A

    2002-04-01

    To identify Arabidopsis mutants that constitutively express systemic acquired resistance (SAR), we constructed reporter lines expressing the firefly luciferase gene under the control of the SAR-inducible PR-1 promoter (PR-1/luc). After EMS mutagenesis of a well-characterized transgenic line, we screened 250,000 M(2) plants for constitutive expression of the reporter gene in vivo. From a mutant collection containing several hundred putative mutants, we concentrated on 16 mutants lacking spontaneous hypersensitive response (HR) cell death. We mapped 4 of these constitutive immunity (cim) mutants to chromosome arms. Constitutive expression of disease resistance was established by analyzing responses to virulent Peronospora parasitica and Pseudomonas syringae strains, by RNA blot analysis for endogenous marker genes, and by determination of salicylic acid levels in the mutants. The variety of the cim phenotypes allowed us to define distinct steps in both the canonical SAR signaling pathway and a separate pathway for resistance to Erysiphe cichoracearum, active in only a subset of the mutants.

  7. A mutagenesis-derived broad-spectrum disease resistance locus in wheat

    Science.gov (United States)

    Wheat leaf rust, stem rust, stripe rust, and powdery mildew caused by the fungal pathogens Puccinia triticina, P. graminis f. sp. tritici, P. striiformis f. sp. tritici, and Blumeria graminis f. sp. tritici, respectively, are destructive diseases of wheat worldwide. The most effective and widely uti...

  8. Surface structures for enhancement of quantum yield in broad spectrum emission nanocrystals

    Science.gov (United States)

    Schreuder, Michael A.; McBride, James R.; Rosenthal, Sandra J.

    2014-07-22

    Disclosed are inorganic nanoparticles comprising a body comprising cadmium and/or zinc crystallized with selenium, sulfur, and/or tellurium; a multiplicity of phosphonic acid ligands comprising at least about 20% of the total surface ligand coverage; wherein the nanocrystal is capable of absorbing energy from a first electromagnetic region and capable of emitting light in a second electromagnetic region, wherein the maximum absorbance wavelength of the first electromagnetic region is different from the maximum emission wavelength of the second electromagnetic region, thereby providing a Stokes shift of at least about 20 nm, wherein the second electromagnetic region comprises an at least about 100 nm wide band of wavelengths, and wherein the nanoparticle exhibits has a quantum yield of at least about 10%. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  9. Rapid In-situ hybridization for dematiaceous fungi using a broad-spectrum oligonucleotide DNA probe.

    Science.gov (United States)

    Montone, Kathleen T; Livolsi, Virginia A; Lanza, Donald C; Feldman, Michael D; Kennedy, David W; Palmer, James; Chiu, Alexander G; Nachamkin, Irving

    2011-09-01

    Dematiaceous fungi are a diverse group of "darkly" pigmented fungi, which contain melanin in their cell walls and are commonly found in soil worldwide. Although morphology and histochemical stains may aid identification in tissue sections, these means for species identification are not specific. In-situ hybridization (ISH) for abundant fungal rRNA sequences may provide a means for detecting dematiaceous fungi. In this study, a 24-base synthetic biotin-labeled oligonucleotide probe targeting rRNA sequences of a variety of dematiaceous fungi was developed. This probe was tested on a cohort of 29 patients with culture-proven cases of dematiaceous fungal-associated rhinosinusitis (26 allergic fungal sinusitis, 2 fungal ball, and 1 acute invasive fungal sinusitis). Fungal cultures were positive for Alternaria species (10), Bipolaris species (5), Curvularia species (10), Cladosporium species (1), Scedosporium prolificans (1), Scopulariopsis species (1), and dematiaceous species, not otherwise specific (1). ISH showed positivity in fungal organisms in 24 of 29 specimens. ISH was negative in culture-proven examples of Rhizopus species, Aspergillus species, Fusarium species, Paecilomyces species, Histoplasmosis capsulatum, Candida species, and Blastomyces dermatitidis. ISH with a dematiaceous-specific fungal probe may be useful for differentiating dematiaceous fungi from other filamentous fungi in tissues, particularly those responsible for fungal rhinosinusitis.

  10. Pediatric antibiotic stewardship: successful interventions to reduce broad-spectrum antibiotic use on general pediatric wards.

    Science.gov (United States)

    Kreitmeyr, Katharina; von Both, Ulrich; Pecar, Alenka; Borde, Johannes P; Mikolajczyk, Rafael; Huebner, Johannes

    2017-08-01

    Antibiotic stewardship programs (ASP) optimize antibiotic usage and combat antibiotic resistance of bacteria. The objective of this study was to assess the impact of specific ASP interventions on antibiotic consumption in general pediatric wards. We conducted a prospective study to compare a pre-intervention (Sept.-Dec. 2014) and post-intervention (Sept.-Dec. 2015) period. An ASP bundle was established including (1) infectious diseases (ID) ward rounds (prospective-audit-with-feedback), (2) ID consultation service, (3) internal guidelines on empiric antibiotic therapy. Medical records on four general pediatric wards were reviewed daily to analyze: (1) antibiotic consumption, (2) antibiotic dosage ranges according to local guidelines, and (3) guideline adherence for community-acquired pneumonia (CAP). Antibiotic prescribing for 273 patients (pre-intervention) was compared to 263 patients (post-intervention). Antibiotic prescription rate did not change (30.6 vs. 30.5%). However, overall days-of-therapy and length-of-therapy decreased by 10.5 and 7.7%, respectively. Use of cephalosporins and fluoroquinolones decreased by 35.5 and 59.9%, whereas the use of penicillins increased by 15.0%. An increase in dosage accuracy was noted (78.8 vs. 97.6%) and guideline adherence for CAP improved from 39.5 to 93.5%. Between the two study periods, no adverse effects regarding length of hospital stay and in-hospital mortality were observed. Our data demonstrate that implementation of an ASP was associated with a profound improvement of rational antibiotic use and, therefore, patient safety. Considering the relatively short observation period, the long-term effects of our ASP bundle need to be further investigated.

  11. A Novel Surfactant Nanoemulsion with Broad Spectrum Sporicidal Activity against Bacillus Species

    Science.gov (United States)

    1999-12-01

    B . cereus ( ATCC 14579 ), B . circulans ( ATCC 4513), B . megaterium ( ATCC 14581), and B . subtilis ( ATCC 11774) were grown for 1 week at 377C...Other members of the Bacillus genus are also reported to be etiologic agents for many human diseases. B . cereus is a com- mon pathogen. It is involved in...BCTP 401 against 2 Bacillus species. BCTP showed significant sporicidal activity after 4 h of treatment against Bacillus cereus , B .

  12. Dissemination and genetic support of broad-spectrum beta-lactam ...

    African Journals Online (AJOL)

    ther spread and in the light of the current and fabulous medical breakthroughs, that we are now witnessing on a daily basis of, has to be a wake-up call for us to further enhance our efforts and better our practical measures. Conflict of interest. There is no conflict of interest. Refrences. 1. Bradford PA, Cherubin CE, Idemyor V, ...

  13. Broad Spectrum Chemotherapy: A Novel Approach Using Beta-Galactosidase Activated Pro-Drugs

    National Research Council Canada - National Science Library

    Ma, Zenyi

    2005-01-01

    .... Gene therapy has been successfully exploited in several clinical trials. beta-galactosidase(beta-gal) as a reporter gene, has historically been the most popular gene for molecular biology work...

  14. Synthesis and antibacterial evaluation of novel cationic chalcone derivatives possessing broad spectrum antibacterial activity.

    Science.gov (United States)

    Chu, Wen-Chao; Bai, Peng-Yan; Yang, Zhao-Qing; Cui, De-Yun; Hua, Yong-Gang; Yang, Yi; Yang, Qian-Qian; Zhang, En; Qin, Shangshang

    2018-01-01

    There is an urgent need to identify new antibiotics with novel mechanisms that combat antibiotic resistant bacteria. Herein, a series of chalcone derivatives that mimic the essential properties of cationic antimicrobial peptides were designed and synthesized. Antibacterial activities against drug-sensitive bacteria, including Staphylococcus aureus, Enterococcus faecalis, Escherichia coli and Salmonella enterica, as well as clinical multiple drug resistant isolates of methicillin-resistant S. aureus (MRSA), KPC-2-producing and NDM-1-producing Carbapenem-resistant Enterobacteriaceae were evaluated. Representative compounds 5a (MIC: 1 μg/mL against S. aureus, 0.5 μg/mL against MRSA) and 5g (MIC: 0.5 μg/mL against S. aureus, 0.25 μg/mL against MRSA) showed good bactericidal activity against both Gram-positive and Gram-negative bacteria, including the drug-resistant species MRSA, KPC and NDM. These membrane-active antibacterial compounds were demonstrated to reduce the viable cell counts in bacterial biofilms effectively and do not induce the development of resistance in bacteria. Additionally, these representative molecules exhibited negligible toxicity toward mammalian cells at a suitable concentration. The combined results indicate that this series of cationic chalcone derivatives have potential therapeutic effects against bacterial infections. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  15. New broad-spectrum resistance to septoria tritici blotch derived from synthetic hexaploid wheat

    NARCIS (Netherlands)

    Tabib Ghaffary, M.S.; Faris, J.D.; Friesen, T.L.; Visser, R.G.F.; Lee, van der T.A.J.; Robert, O.; Kema, G.H.J.

    2012-01-01

    Septoria tritici blotch (STB), caused by the ascomycete Mycosphaerella graminicola, is one of the most devastating foliar diseases of wheat. We screened five synthetic hexaploid wheats (SHs), 13 wheat varieties that represent the differential set of cultivars and two susceptible checks with a global

  16. Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency.

    OpenAIRE

    Walter Jolan E; Rosen Lindsey B; Csomos Krisztian; Rosenberg Jacob M; Mathew Divij; Keszei Marton; Ujhazi Boglarka; Chen Karin; Lee Yu Nee; Tirosh Irit; Dobbs Kerry; Al-Herz Waleed; Cowan Morton J; Puck Jennifer; Bleesing Jack J

    2015-01-01

    Patients with mutations of the recombination-activating genes (RAG) present with diverse clinical phenotypes, including severe combined immune deficiency (SCID), autoimmunity, and inflammation. However, the incidence and extent of immune dysregulation in RAG-dependent immunodeficiency have not been studied in detail. Here, we have demonstrated that patients with hypomorphic RAG mutations, especially those with delayed-onset combined immune deficiency and granulomatous/autoimmune manifestation...

  17. Broad spectrum anti-microbial compounds producing bacteria from coast of Qingdao bays.

    Science.gov (United States)

    Khan, Muhammad Naseem; Li, Meng; Mirani, Zulfiqar Ali; Wang, Jingxue; Lin, Hong; Buzdar, Muhammad Aslam

    2015-03-01

    Anti-microbial resistance burden and hazard associated with chemical treatment of infections demanded for new anti-microbial natural products. Marine associated microorganisms are the enormous source of bioactive compounds. In this study we have isolated 272 marine bacteria among them 136 (50%) were antagonistic to at least one of the four pathogenic strains Listeria monocytogenes, Vibrio cholerae, E. coli and S. aureus. Only two strains exhibited antibacterial activity against all four test strains, which were identified by 16S rDNA sequencing as Bacillus sp. DK1-SA11 and Vibrio sp. DK6-SH8. Marine isolate DK1-SA11 has potential to resist boiling temperature and pH 2-12. Furthermore cell free extract (CFE) inhibited all test organisms including superbug MRSA and pathogenic yeast Candida albicans. Marine isolate Bacillus sp. DK1-SA11 could be a potential combatant for the battle of drugs and bugs.

  18. Legionella shows a diverse secondary metabolism dependent on a broad spectrum Sfp-type phosphopantetheinyl transferase

    Directory of Open Access Journals (Sweden)

    Nicholas J. Tobias

    2016-11-01

    Full Text Available Several members of the genus Legionella cause Legionnaires’ disease, a potentially debilitating form of pneumonia. Studies frequently focus on the abundant number of virulence factors present in this genus. However, what is often overlooked is the role of secondary metabolites from Legionella. Following whole genome sequencing, we assembled and annotated the Legionella parisiensis DSM 19216 genome. Together with 14 other members of the Legionella, we performed comparative genomics and analysed the secondary metabolite potential of each strain. We found that Legionella contains a huge variety of biosynthetic gene clusters (BGCs that are potentially making a significant number of novel natural products with undefined function. Surprisingly, only a single Sfp-like phosphopantetheinyl transferase is found in all Legionella strains analyzed that might be responsible for the activation of all carrier proteins in primary (fatty acid biosynthesis and secondary metabolism (polyketide and non-ribosomal peptide synthesis. Using conserved active site motifs, we predict some novel compounds that are probably involved in cell-cell communication, differing to known communication systems. We identify several gene clusters, which may represent novel signaling mechanisms and demonstrate the natural product potential of Legionella.

  19. Colostrum of Healthy Mothers Contains Broad Spectrum of Secretory IgA Autoantibodies

    Czech Academy of Sciences Publication Activity Database

    Přibylová, Jaroslava; Krausová, Klára; Kocourková, I.; Rossmann, Pavel; Klimešová, Klára; Kverka, Miloslav; Tlaskalová-Hogenová, Helena

    2012-01-01

    Roč. 32, č. 6 (2012), s. 1372-1380 ISSN 0271-9142 R&D Projects: GA ČR(CZ) GAP304/11/1252 Institutional support: RVO:61388971 Keywords : Autoantibodies * mucosal immunity * immunoglobulins Subject RIV: EC - Immunology Impact factor: 3.382, year: 2012

  20. Identification of an antioxidant small-molecule with broad-spectrum antiviral activity.

    Science.gov (United States)

    Panchal, Rekha G; Reid, St Patrick; Tran, Julie P; Bergeron, Alison A; Wells, Jay; Kota, Krishna P; Aman, Javad; Bavari, Sina

    2012-01-01

    The highly lethal filoviruses, Ebola and Marburg cause severe hemorrhagic fever in humans and non-human primates. To date there are no licensed vaccines or therapeutics to counter these infections. Identifying novel pathways and host targets that play an essential role during infection will provide potential targets to develop therapeutics. Small molecule chemical screening for Ebola virus inhibitors resulted in identification of a compound NSC 62914. The compound was found to exhibit anti-filovirus activity in cell-based assays and in vivo protected mice following challenge with Ebola or Marburg viruses. Additionally, the compound was found to inhibit Rift Valley fever virus, Lassa virus and Venezuelan equine encephalitis virus in cell-based assays. Investigation of the mechanism of action of the compound revealed that it had antioxidant properties. Specifically, compound NSC 62914 was found to act as a scavenger of reactive oxygen species, and to up-regulate oxidative stress-induced genes. However, four known antioxidant compounds failed to inhibit filovirus infection, thus suggesting that the mechanistic basis of the antiviral function of the antioxidant NSC 62914 may involve modulation of multiple signaling pathways/targets. Published by Elsevier B.V.

  1. Rational design of berberine-based FtsZ inhibitors with broad-spectrum antibacterial activity.

    Directory of Open Access Journals (Sweden)

    Ning Sun

    Full Text Available Inhibition of the functional activity of Filamenting temperature-sensitive mutant Z (FtsZ protein, an essential and highly conserved bacterial cytokinesis protein, is a promising approach for the development of a new class of antibacterial agents. Berberine, a benzylisoquinoline alkaloid widely used in traditional Chinese and native American medicines for its antimicrobial properties, has been recently reported to inhibit FtsZ. Using a combination of in silico structure-based design and in vitro biological assays, 9-phenoxyalkyl berberine derivatives were identified as potent FtsZ inhibitors. Compared to the parent compound berberine, the derivatives showed a significant enhancement of antibacterial activity against clinically relevant bacteria, and an improved potency against the GTPase activity and polymerization of FtsZ. The most potent compound 2 strongly inhibited the proliferation of Gram-positive bacteria, including methicillin-resistant S. aureus and vancomycin-resistant E. faecium, with MIC values between 2 and 4 µg/mL, and was active against the Gram-negative E. coli and K. pneumoniae, with MIC values of 32 and 64 µg/mL respectively. The compound perturbed the formation of cytokinetic Z-ring in E. coli. Also, the compound interfered with in vitro polymerization of S. aureus FtsZ. Taken together, the chemical modification of berberine with 9-phenoxyalkyl substituent groups greatly improved the antibacterial activity via targeting FtsZ.

  2. A review on toxicological properties of thymoquinone a natural broad spectrum ingredient

    Directory of Open Access Journals (Sweden)

    2017-11-01

    Full Text Available Background and objectives: Nigella sativa is a delicate floral vegetable belonging to Ranunculaceae family. Thymoquinone (TQ is the dominant active component in Nigella sativa seed oil which has a variety of pharmacological properties such as antioxidant, anticancer, anti-inflammatory and analgesic activities. However, TQ is a quinone derivative, which may lead to the generation of reactive oxygen species and resulting intermediate toxicity with various adverse effects in vivo, including acute cytotoxicity, genotoxicity, immunotoxicity, and carcinogenesis. In this review we have mentioned several studies on the toxicity properties of thymoquinone and Nigella sativa. Methods: A literature search was conducted using the Web of Science, PubMed, MEDLINE and Scopus. The search included the following keywords: "thymoquinone", "hydroquinone"," quinone" and "Nigella sativa". Citations within articles were also reviewed to identify the relevant sources. We studied about 170 articles and put aside the articles that were performed on the effect of Nigella sativa and thymoquinone on cancer cell lines. Results:  Since TQ is a quinone derivative, we observed the generation of reactive oxygen species and the toxicity of this substance in some studies. LD50 of Thymoquinone was very higher than Nigella sativa and also LD50 of this substance in oral route was higher than intrapritoneal route of administration. Conclusion: The findings have provided approximate safety information for TQ, which will further help researchers.

  3. Marine toxins consist of a broad spectrum of bio- logically active ...

    African Journals Online (AJOL)

    spamer

    nodinium and Pyrodinium (Yasumoto and Murata. 1993). Although bivalve molluscs are the most common vectors of PSP, gastropods, crustaceans and pelagic fish have also been reported as vectors of the toxins. (Shumway 1995). Many affected countries have estab- lished regulations, including stipulated methods and.

  4. Engineering of gadofluoroprobes: Broad-spectrum applications from cancer diagnosis to therapy

    International Nuclear Information System (INIS)

    Dutta, Ranu A.; Sharma, Prashant K.; Tiwari, Vandana; Tiwari, Vivek; Patel, Anant B.; Pandey, Ravindra; Pandey, Avinash C.

    2014-01-01

    The engineering of the Gadolinium based nanostructures have been demonstrated in this paper. Nanostructures of α-Gd 2 S 3 exhibit a unique transition between ferromagnetic state and paramagnetic state of the system. It was demonstrated that their properties could be tuned for a wide range of applications ranging from hyperthermia to Magnetic Resonance Imaging, owing to their magnetic moments and large relaxivities. Metallic Gd nanoparticles obtained by reduction method were employed for cancer imaging in mice. The Gd nanoparticles were coated with Curcumin and their biomedical implications in the field of simultaneous diagnosis and therapy of cancer and related diseases has been discussed

  5. Novel Peptides from Skins of Amphibians Showed Broad-Spectrum Antimicrobial Activities.

    Science.gov (United States)

    Wang, Ying; Zhang, Yue; Lee, Wen-Hui; Yang, Xinwang; Zhang, Yun

    2016-03-01

    Peptide agents are often considered as potential biomaterials for developing new drugs that can overcome the rising resistance of pathogenic micro-organisms to classic antibiotic treatments. One key source of peptide agents is amphibian skin, as they provide a great deal of naturally occurring antimicrobial peptide (AMP) templates awaiting further exploitation and utilization. In this study, 12 novel AMPs from the skins of 3 ranid frogs, Rana limnocharis, R. exilispinosa, and Amolops afghanus, were identified using a 5' PCR primer. A total of 11 AMPs exhibited similarities with currently known AMP families, including brevinin-1, brevinin-2, esculentin-1, and nigrocin, besides, one AMP, named as Limnochariin, represented a novel AMP family. All 12 AMPs contain a C-terminus cyclic motif and most of them show obvious antimicrobial activities against 18 standard and clinically isolated strains of bacteria, including 4 Gram-positive bacteria, 11 Gram-negative bacteria, and 3 fungus. These findings provide helpful insight that will be useful in the design of anti-infective peptide agents. © 2015 John Wiley & Sons A/S.

  6. The leaf size-twig size spectrum in evergreen broad- leaved forest of ...

    African Journals Online (AJOL)

    STORAGESEVER

    2010-06-07

    Jun 7, 2010 ... White, 1983a, b; Brouat et al., 1998; Preston and Ackerly,. 2003; Westoby and Wright, 2003; ... species including both trees and shrubs were investigated, with exception of those having fewer than ..... freezing-induced xylem cavitation in evergreen and deciduous oaks with contrasting habitats. Plant Cell ...

  7. Legionella shows a diverse secondary metabolism dependent on a broad spectrum Sfp-type phosphopantetheinyl transferase.

    Science.gov (United States)

    Tobias, Nicholas J; Ahrendt, Tilman; Schell, Ursula; Miltenberger, Melissa; Hilbi, Hubert; Bode, Helge B

    2016-01-01

    Several members of the genus Legionella cause Legionnaires' disease, a potentially debilitating form of pneumonia. Studies frequently focus on the abundant number of virulence factors present in this genus. However, what is often overlooked is the role of secondary metabolites from Legionella . Following whole genome sequencing, we assembled and annotated the Legionella parisiensis DSM 19216 genome. Together with 14 other members of the Legionella , we performed comparative genomics and analysed the secondary metabolite potential of each strain. We found that Legionella contains a huge variety of biosynthetic gene clusters (BGCs) that are potentially making a significant number of novel natural products with undefined function. Surprisingly, only a single Sfp-like phosphopantetheinyl transferase is found in all Legionella strains analyzed that might be responsible for the activation of all carrier proteins in primary (fatty acid biosynthesis) and secondary metabolism (polyketide and non-ribosomal peptide synthesis). Using conserved active site motifs, we predict some novel compounds that are probably involved in cell-cell communication, differing to known communication systems. We identify several gene clusters, which may represent novel signaling mechanisms and demonstrate the natural product potential of Legionella .

  8. A smooth bouncing cosmology with scale invariant spectrum

    International Nuclear Information System (INIS)

    Creminelli, P.; Senatore, L.

    2007-01-01

    We present a bouncing cosmology which evolves from the contracting to the expanding phase in a smooth way, without developing instabilities or pathologies and remaining in the regime of validity of 4d effective field theory. A nearly scale invariant spectrum of perturbations is generated during the contracting phase by an isocurvature scalar with a negative exponential potential and then converted to adiabatic. The model predicts a slightly blue spectrum, n S > or approx. 1, no observable gravitational waves and a high (but model dependent) level of non-Gaussianities with local shape. The model represents an explicit and predictive alternative to inflation, although, at present, it is clearly less compelling. (author)

  9. Tendering specification and contracting

    International Nuclear Information System (INIS)

    Koch, E. von

    1975-01-01

    The lecture tendering, specification and contracting is prepared in two parts: This first part deals with technical aspects while part two features the commercial and legal situation in the partnership of two: the supplier of the fuel bundles and the utility. In this lecture a look is given on the way how a supplier can offer its fuel and some certain points are mentioned which are important to compare the bid of one competitor to the other. The major points are summarized which are or at least should be in an offer so as to find out which offer is the best. (orig./FW) [de

  10. Expansionary fiscal contractions

    DEFF Research Database (Denmark)

    Bergman, Ulf Michael; Hutchison, Michael

    2010-01-01

    and tax changes) have the expected Keynesian effects on output and consumption. However, we find no evidence that the large fiscal consolidation in Denmark slowed the economy after controlling for a host of exogenous shocks and business cycle effects. Rather, we find some support for the hypothesis......The Expansionary Fiscal Contraction (EFC) hypothesis predicts that a major fiscal consolidation leads to an economic expansion under certain circumstances. We test this hypothesis, and the implied non-linear responses of the economy to large and small changes in fiscal policy, using data from...

  11. Defining International Contracting Terms

    Science.gov (United States)

    1994-09-01

    procedures laid down in the International Traffic of Arms Regulations (ITARS) and the Foreign Corrupt Practices Act." ( FCPA )(56:50) 2. Main Theme Discussion...direct control of the ODTC. This helps the ODTC follow the rules and procedures outlined in the ITARS and FCPA . This list is also used in applying the...Don’t Know May Hurt You," Contract Management. 30: 18-19, 4 i-44, 50 (October 1990). 22. Ellenson, Leslie A. "A Primer on Export Control Compliance

  12. CLIMATE CONDITIONS AFFECTING THE WITHIN-PLANT SPREAD OF BROAD MITES ON AZALEA.

    Science.gov (United States)

    Mechant, E; Pauwels, E; Gobin, B

    2014-01-01

    The broad mite Polyphagotarsonemus latus (Banks) is considered a major pest in potted azalea, Flanders' flagship ornamental crop of Rhododendron simsii hybrids. In addition to severe economic damage, the broad mite is dreaded for its increasing resistance to acaricides. Due to restrictions in the use of broad spectrum acaricides, Belgian azalea growers are left with only three compounds, belonging to two mode of action groups and restricted in their number of applications, for broad mite control: abamectin, milbemectin and pyrethrin. Although P. latus can be controlled with predatory mites, the high cost of this system makes it (not yet) feasible for integration into standard azalea pest management systems. Hence, a maximum efficacy of treatments with available compounds is essential. Because abamectin, milbemectin and pyrethrin are contact acaricides with limited trans laminar flow, only broad mites located on shoot tips of azalea plants will be controlled after spraying. Consequently, the efficacy of chemical treatments is influenced by the location and spread of P. latus on the plant. Unfortunately, little is known on broad mites' within-plant spread or how it is affected by climatic conditions like temperature and relative humidity. Therefore, experiments were set up to verify whether climate conditions have an effect on the location and migration of broad mites on azalea. Broad mite infected azalea plants were placed in standard growth chambers under different temperature (T:2.5-25°C) and relative humidity (RH:55-80%) treatments. Within-plant spread was determined by counting mites on the shoot tips and inner leaves of azalea plants. Results indicate that temperature and relative humidity have no significant effect on the within-plant spread of P. latus. To formulate recommendations for optimal spray conditions to maximize the efficacy of broad mite control with acaricides, further experiments on the effect of light intensity and rain are scheduled.

  13. Characteristics of nuclear contracts. Pt. 1

    International Nuclear Information System (INIS)

    Blanchard, R.

    1976-01-01

    While the object of nuclear contracts is specific, these contracts are concluded according to proven techniques based on general regulations on contracts. Following a review of contract classification, they are differentiated according to the nature of the co-contracting parties, the purpose of the contract itself, the procedure for drawing up the contracts, and payment. The operations prior to the contract vary in that they may include a call for tenders, an option for delays or a letter of intent. (NEA) [fr

  14. Strategic Vision for Spectrum

    Science.gov (United States)

    2010-01-01

    that defines spectrum requirements consistent with emerging tech- proactive spectrum nologies, commercial trends , and increasing market demands...Integration, Capital Planning, Competency Management, Computing and Communications Infrastructure, Critical Infrastructure Protection, eBusiness

  15. Pulsar Emission Spectrum

    OpenAIRE

    Gruzinov, Andrei

    2013-01-01

    Emission spectrum is calculated for a weak axisymmetric pulsar. Also calculated are the observed spectrum, efficiency, and the observed efficiency. The underlying flow of electrons and positrons turns out to be curiously intricate.

  16. Centralized contracting an imperative for reducing health system costs.

    Science.gov (United States)

    Baskel, Christopher

    2014-03-01

    As a health system expands, there is a concomitant need for its leaders to take steps to ensure that redundancies in purchasing processes do not drive up costs to unsustainable levels. Spectrum Health in Grand Rapids, Mich., tackled this challenge by instituting a revenue-driven, patient-care-focused value analysis process that centralized contracting processes in several areas of nonsalary expense. Spectrum went on to uncover opportunities for cutting costs in its decentralized, non-purchase order expenses, saving 24 percent in the first of four arenas.

  17. 48 CFR 315.371 - Contract preparation and award.

    Science.gov (United States)

    2010-10-01

    ... CONTRACTING METHODS AND CONTRACT TYPES CONTRACTING BY NEGOTIATION Source Selection 315.371 Contract... the contract until the finance office certifies that the funds are available for obligation. ...

  18. 48 CFR 1316.406 - Contract clauses.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Contract clauses. 1316.406 Section 1316.406 Federal Acquisition Regulations System DEPARTMENT OF COMMERCE CONTRACTING METHODS AND CONTRACT TYPES TYPES OF CONTRACTS Incentive Contracts 1316.406 Contract clauses. Insert a clause...

  19. 48 CFR 716.406 - Contract clauses.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Contract clauses. 716.406 Section 716.406 Federal Acquisition Regulations System AGENCY FOR INTERNATIONAL DEVELOPMENT CONTRACTING METHODS AND CONTRACT TYPES TYPES OF CONTRACTS Cost Reimbursement Contracts 716.406 Contract clauses. The...

  20. 48 CFR 916.307 - Contract clauses.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Contract clauses. 916.307 Section 916.307 Federal Acquisition Regulations System DEPARTMENT OF ENERGY CONTRACTING METHODS AND CONTRACT TYPES TYPES OF CONTRACTS Cost-Reimbursement Contracts 916.307 Contract clauses. (g) Insert the...

  1. 48 CFR 732.111 - Contract clauses.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Contract clauses. 732.111... CONTRACTING REQUIREMENTS CONTRACT FINANCING General 732.111 Contract clauses. (a) [Reserved] (b) USAID may... Agency-specific indefinite quantity contracts that are a combination of contract types. Rather than using...

  2. 48 CFR 935.071 - Contract clause.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Contract clause. 935.071... CONTRACTING RESEARCH AND DEVELOPMENT CONTRACTING 935.071 Contract clause. The contracting officer must insert the clause at 952.235-71, Research Misconduct, in contracts, including management and operating...

  3. 48 CFR 217.7406 - Contract clauses.

    Science.gov (United States)

    2010-10-01

    ... OF DEFENSE CONTRACTING METHODS AND CONTRACT TYPES SPECIAL CONTRACTING METHODS Undefinitized Contract..., in— (1) All UCAs; (2) Solicitations associated with UCAs; (3) Basic ordering agreements; (4) Indefinite-delivery contracts; (5) Any other type of contract providing for the use of UCAs; and (6) Unpriced...

  4. The broad utility of Trizac diamond tile

    Science.gov (United States)

    Gagliardi, John I.; Romero, Vincent D.; Sventek, Bruce; Zu, Lijun

    2017-10-01

    Sample finishing data from a broad range of materials — glasses, sapphire, silicon carbide, silicon, zirconium oxide, lithium tantalate, and flooring materials — are shown effectively processed with Trizact™ Diamond Tile (TDT). This data should provide the reader with an understanding of what to expect when using TDT on hard to grind or brittle materials. Keys to maintaining effective TDT pad wear rates, and therefore cost effect and stable processes, are described as managing 1) the proper lubricant flow rate for glasses and silicon-type materials and 2) the conditioning particle concentration for harder-to-grind materials

  5. Free electron broad-band THz radiator

    CERN Document Server

    Doria, A; Giovenale, E

    2002-01-01

    In this paper, a comparison between the conventional Tera-Hertz (THz) sources and a THz radiator based on free electron devices is proposed. The basic idea of the exploitation of some of the features of the RF FELs will be presented together with some examples that could represent an appealing source to start with. A discussion about the link between the spectrum of the emitted radiation and the electron bunch length is presented. The necessity of generating very short bunch of electrons to be injected in the radiator is demonstrated.

  6. A Randomized Clinical Trial of Cognitive Enhancement Therapy for Adults with Autism Spectrum Disorders

    Science.gov (United States)

    2013-10-01

    Eack et al., in press). The emotion regulation fMRI task used in this study makes use of a negative emotion induction paradigm in which participants... Autism Spectrum Disorders PRINCIPAL INVESTIGATOR: Nancy J. Minshew, M.D. CONTRACTING ORGANIZATION: University of Pittsburgh...Enhancement Therapy for Adults with Autism Spectrum Disorders 5a. CONTRACT NUMBER W81XWH-11-1-0665 5b. GRANT NUMBER W81XWH-11-1-0665 5c. PROGRAM

  7. Contractions of group representations. - I

    International Nuclear Information System (INIS)

    Celeghini, E.; Tarlini, M.

    1981-01-01

    A new definition of contraction as a limit on the parameters defining the basis of the space of representations is given. From the representations of the original group, those of the contracted one are directly obtained. The contraction of inner automorphisms into outer automorphisms and the splitting of one representation into representations of the same or different group are discussed and illustrated by examples. The procedure is also a technique for the study of representations of non-semi-simple groups. (author)

  8. Corrective justice and contract law

    OpenAIRE

    Martín Hevia

    2010-01-01

    This article suggests that the central aspects of contract law in various jurisdictions can be explained within the idea of corrective justice. The article is divided into three parts. The first part distinguishes between corrective justice and distributive justice. The second part describes contract law. The third part focuses on actions for breach of contract and within that context reflects upon the idea of corrective justice.

  9. Surface defect assisted broad spectra emission from CdSe quantum dots for white LED application

    Science.gov (United States)

    Samuel, Boni; Mathew, S.; Anand, V. R.; Correya, Adrine Antony; Nampoori, V. P. N.; Mujeeb, A.

    2018-02-01

    This paper reports, broadband photoluminescence from CdSe quantum dots (QDs) under the excitation of 403 nm using fluorimeter and 403 nm CW laser excitation. The broad spectrum obtained from the colloidal quantum dots was ranges from 450 nm to 800 nm. The broadness of the spectra was attributed to the merging of band edge and defect driven emissions from the QDs. Six different sizes of particles were prepared via kinetic growth method by using CdO and elemental Se as sources of Cd and Se respectively. The particle sizes were measured from TEM images. The size dependent effect on broad emission was also studied and the defect state emission was found to be predominant in very small QDs. The defect driven emission was also observed to be redshifted, similar to the band edge emission, due to quantum confinement effect. The emission corresponding to different laser power was also studied and a linear relation was obtained. In order to study the colour characteristics of the emission, CIE chromaticity coordinate, CRI and CCT of the prepared samples were measured. It is observed that, these values were tunable by the addition of suitable intensity of blue light from the excitation source to yield white light of various colour temperatures. The broad photoluminescence spectrum of the QDs, were compared with that of a commercially available white LED. It was found that the prepared QDs are good alternatives for the phosphor in phosphor converted white LEDs, to provide good spectral tunability.

  10. Forthcoming indefinite contract review procedure

    CERN Multimedia

    Human Resources Department

    2011-01-01

    The vacancy notices for posts opened with a view to the award of an indefinite contract will be published in early April 2011. In the meantime, the list of posts to be opened this spring is available at the following address: Indefinite contract posts - spring 2011 A second exercise will take place in autumn 2011 and, as of 2012, the indefinite contract award procedure will only be held once a year, in autumn. For more information please consult: https://hr-recruit.web.cern.ch/hr-recruit/staff/IndefiniteContracts.asp  

  11. Work and minor work contracts

    CERN Document Server

    1999-01-01

    The Work and Minor Work contracts are all of the result-oriented type. The work is specified by CERN and the contractor is given full responsibility for its performance. The contracts are thus very similar to supply contracts. The re-tendering of the existing contracts is almost complete, except for some building maintenance contracts. A new cycle of re-tendering for some activities will be launched in the next twelve months. The total estimated expenditure in the year 2000 for the contracts referred to in this document is 27 750 000 Swiss francs at 1999 prices. The Finance Committee is invited: - to approve the proposed expenditure for the extension of contracts for which the estimated amount for the year 2000 exceeds 750 000 Swiss francs, namely those under references 1, 2, 3, 5, 7, 8, 9 and 23, highlighted in Table I; - to take note that all Work and Minor Work contracts have been tendered since 1 January 1994, except the small contracts shown under references 12 and 16 in Table I; - to take note that the ...

  12. URGENSI STUDI TENTANG PROCUREMENT CONTRACT

    Directory of Open Access Journals (Sweden)

    Yohanes Sogar Simamora

    2006-01-01

    Full Text Available Contractualization is kind of goverment activity in acquiring goods, services and infrastructure as well. Procurement contract has several important function especially in enhancing economic development in a state. In Indonesia, this kind of contract also has function in empowering micro economic scale. Since the aim of procurement study is to provide equal protection between public fund interest in one hand and privat sector in the other hand, general principle of contract law must be taken into consideration together with transparency as the most important principle in government contract.

  13. Dramatic Changes in the Infrared Spectrum of V838 Monocerotis

    Science.gov (United States)

    Venturini, C. C.; Lynch, D. K.; Rudy, R. J.; Russell, R. W.; Mazuk, S.; Dimpfl, W.; Sitko, M.; Puetter, R. C.; Bernstein, L. S.; Perry, R. B.

    2003-05-01

    Multiple spectrum of V838 Mon have been obtained from two different instruments providing data with combined wavelength coverage between 0.8 to 14 microns. The first measurements were taken in January 2002 followed by another set of measurements about a year later. Initially, the 3-14 micron spectrum showed a source with a smooth continuum consistent with a black body at about 2350 K and roughly 50 percent excess above the black body fit between the 8 to 10 micron region. Data between 0.8-2.5 microns exhibited a continuum that peaked near one micron (implying a temperature of roughly 3000 K) with a slightly elevated continuum near 1.6 microns suggestive of the H-opacity minimum. The continuum also showed significant broad structure between 0.8 and 1.2 microns. Emission lines present included HI Paschen and weak Bracket lines, many with strong P-Cygni profiles indicating an expansion velocity of around 500 km/sec. Also present were the Ca II IR triplet with strong absorption and weak emission, and deep CO first overtone band absorption near 2.3 microns. The second set of measurements, taken approximately a year later, revealed a spectrum that had changed dramatically. The hydrogen emission lines had disappeared and the continuum shape indicted that the source had cooled by roughly one-two thousand degrees. Between the two epochs, the K brightness increased by about a factor of three while the N brightness increased by roughly a factor a 20. The source now showed deep molecular absorption bands of H2O, CO, TiO, AlO, VO and probably OH. The AlO bands were particularly prominent: the A-X (4,0) doublet with peak absorptions at 1.225 and 1.244 microns, and the A-X (2,0) doublet at 1.650 and 1.687 microns. CrH and FeH may have been present but methane was not seen. In a years time, V838 Mon went from looking like late type star around 3000 K with weak hydrogen emission from a small expanding shell to an object that was cool enough to show no atomic lines but only a wide

  14. Issue Framing and Sector Character as Critical Parameters for Government Contracting-Out in the UK

    DEFF Research Database (Denmark)

    Bækkeskov, Erik

    2011-01-01

    , and its reform faced unions that stood to lose a great deal from movement of janitorial jobs to private firms. In contrast, the New Labour government framed contracting-out broadly, as a means to efficient social justice, and faced unions with low stakes in government janitors. As a consequence, UK......This article shows that variations in how two UK governments justified contracting-out (issue framing), combined with shifting sector-derived incentives for union activism (sector character), can help explain the extent of contracting-out. Janitorial service, an activity of the UK government...... that should have been ‘low hanging fruit' for its prolific reformers, proved difficult to contract-out for Thatcher's New Right Conservatives, but easier to contract-out for Blair's New Labour. The New Right government framed contracting-out narrowly, as merely an improvement in operational efficiency...

  15. Unfair contract terms in B2C contracts

    NARCIS (Netherlands)

    Hesselink, M.W.; Loos, M.B.M.

    2012-01-01

    Because of its textual similarity to the Unfair Terms Directive 1993, Chapter 8 of the proposed CESL, on ‘Unfair contract terms’, can benefit from two decades of interpretative experience which is likely to provide a comparably high degree of instant legal certainty to contracting parties.

  16. From Wigner Inoenue group contraction to contractions of algebraic structures

    International Nuclear Information System (INIS)

    Gromov, N.A.

    2004-01-01

    The development of the notion of group contraction first introduced by Inoenue and Wigner in 1953 is briefly reviewed. The fundamental role of the idea of degenerate transformations is stressed. The significance of contractions of algebraic structures for exactly solvable problems of mathematical physics is noticed. (author)

  17. Demographics of the Contracting Workforce within the Army Contracting Command

    Science.gov (United States)

    2009-09-25

    Empresas in Madrid. Dr. Reed retired from Active Military Service in 2008 after 21 years in the Air Force. Dr. Reed held various assignments in...Contracting Implications Portfolio Optimization via KVA + RO Private Military Sector Software Requirements for OA Spiral Development Strategy...for Defense Acquisition Research The Software , Hardware Asset Reuse Enterprise (SHARE) repository Contract Management Commodity Sourcing

  18. The Relationship between the Employment Contract and other Civil Contracts

    Directory of Open Access Journals (Sweden)

    Răzvan Radu Popescu

    2015-05-01

    Full Text Available The employment relationship is a contractual one and as such must have all the basic elements of an enforceable contract to make it legally binding. In strict contractual terms, the offer is made by the employer and formally accepted by the employee. Once the acceptance has taken place, there is a legally binding agreement and an action will lie against the party who breaches that agreement, even though it may only just have come into existence. An employment contract, however, is unlike most other contracts. Although the parties will have negotiated the main terms, we shall see that a large number of terms will be implied into the agreement from all sorts of different sources and will not have been individually negotiated by the parties at all. This is what makes an employment contract so different from other contracts. We think this article is an important step in the disclosure of the problem eraised by these two concepts.

  19. Department of Energy contract/business management initiatives

    International Nuclear Information System (INIS)

    Fisher, S.B.

    1992-01-01

    More than 40 years ago the Department of Energy (DOE) developed a unique contractual instrument called a management and operating contract, to be used for the operation of our weapons production plants and the national laboratories. The contracts are very broad in scope. There is no output objective set forth in the contract. There are no cost targets, nor any contractually motivated cost objectives. Performance is measured against criteria which is often subjective. The time has come to make changes in the structure of these contracts to reflect changes in the work being performed and to make the contractors more accountable. DOE's work now, at these sites, and for years to come, consists largely of major project-type work such as environmental restoration which lends itself to a more definitized structure. DOE is in the process of implementing a work order authorization control system (task order contracting) under its management and operating contracts. Target date for implementation for our for-profit contractors is FY 1992, and for the non-profit contractors is FY 1993. Under this system, requirements will be contracted for as entities of work and contractors will be held accountable for performance, schedules and costs. Billings, payments and award fee will be tied to the specific planning objectives set forth in the tasks, including costs and schedules. Incentives will be provided for outstanding performance, fee may be withheld if performance is unacceptable. These changes will necessitate more DOE oversight of contractor operations and sound business support systems, as well as effective management disciplines. US DOE will perform business management reviews to assure contractors' systems are adequate and to support this form of contracting. The Contractor Procurement Systems Review Program will be enhanced to assure good subcontractor procurement practices

  20. Rainbow Vectors for Broad-Range Bacterial Fluorescence Labeling.

    Directory of Open Access Journals (Sweden)

    Mariette Barbier

    Full Text Available Since their discovery, fluorescent proteins have been widely used to study protein function, localization or interaction, promoter activity and regulation, drug discovery or for non-invasive imaging. They have been extensively modified to improve brightness, stability, and oligomerization state. However, only a few studies have focused on understanding the dynamics of fluorescent proteins expression in bacteria. In this work, we developed a set plasmids encoding 12 fluorescent proteins for bacterial labeling to facilitate the study of pathogen-host interactions. These broad-spectrum plasmids can be used with a wide variety of Gram-negative microorganisms including Escherichia coli, Pseudomonas aeruginosa, Burkholderia cepacia, Bordetella bronchiseptica, Shigella flexneri or Klebsiella pneumoniae. For comparison, fluorescent protein expression and physical characteristics in Escherichia coli were analyzed using fluorescence microscopy, flow cytometry and in vivo imaging. Fluorescent proteins derived from the Aequorea Victoria family showed high photobleaching, while proteins form the Discosoma sp. and the Fungia coccina family were more photostable for microscopy applications. Only E2-Crimson, mCherry and mKeima were successfully detected for in vivo applications. Overall, E2-Crimson was the fastest maturing protein tested in E. coli with the best overall performance in the study parameters. This study provides a unified comparison and comprehensive characterization of fluorescent protein photostability, maturation and toxicity, and offers general recommendations on the optimal fluorescent proteins for in vitro and in vivo applications.

  1. Broad targeting of resistance to apoptosis in cancer

    Science.gov (United States)

    Mohammad, Ramzi M.; Muqbil, Irfana; Lowe, Leroy; Yedjou, Clement; Hsu, Hsue-Yin; Lin, Liang-Tzung; Siegelin, Markus David; Fimognari, Carmela; Kumar, Nagi B.; Dou, Q. Ping; Yang, Huanjie; Samadi, Abbas K.; Russo, Gian Luigi; Spagnuolo, Carmela; Ray, Swapan K.; Chakrabarti, Mrinmay; Morre, James D.; Coley, Helen M.; Honoki, Kanya; Fujii, Hiromasa; Georgakilas, Alexandros G.; Amedei, Amedeo; Niccolai, Elena; Amin, Amr; Ashraf, S. Salman; Helferich, William G.; Yang, Xujuan; Boosani, Chandra S.; Guha, Gunjan; Bhakta, Dipita; Ciriolo, Maria Rosa; Aquilano, Katia; Chen, Sophie; Mohammed, Sulma I.; Keith, W. Nicol; Bilsland, Alan; Halicka, Dorota; Nowsheen, Somaira; Azmi, Asfar S.

    2015-01-01

    Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer. PMID:25936818

  2. Broad-lined Supernova 2016coi with a Helium Envelope

    Energy Technology Data Exchange (ETDEWEB)

    Yamanaka, Masayuki [Department of Physics, Faculty of Science and Engineering, Konan University, Okamoto, Kobe, Hyogo 658-8501 (Japan); Nakaoka, Tatsuya; Kawabata, Miho [Department of Physical Science, Hiroshima University, Kagamiyama 1-3-1, Higashi-Hiroshima 739-8526 (Japan); Tanaka, Masaomi [National Astronomical Observatory of Japan, National Institutes of Natural Sciences, Osawa, Mitaka, Tokyo 181-8588 (Japan); Maeda, Keiichi [Department of Astronomy, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502 (Japan); Honda, Satoshi; Hosoya, Kensuke; Karita, Mayu; Morihana, Kumiko [Nishi-Harima Astronomical Observatory, Center for Astronomy, University of Hyogo, 407-2 Nishigaichi, Sayo-cho, Sayo, Hyogo 679-5313 (Japan); Hanayama, Hidekazu [Ishigakijima Astronomical Observatory, National Astronomical Observatory of Japan, National Institutes of Natural Sciences, 1024-1 Arakawa, Ishigaki, Okinawa 907-0024 (Japan); Morokuma, Tomoki [Institute of Astronomy, Graduate School of Science, The University of Tokyo, 2-21-1 Osawa, Mitaka, Tokyo 181-0015 (Japan); Imai, Masataka [Department of Cosmosciences, Graduate School of Science, Hokkaido University, Kita 10 Nishi8, Kita-ku, Sapporo 060-0810 (Japan); Kinugasa, Kenzo [Nobeyama Radio Observatory, National Astronomical Observatory of Japan, National Institutes of Natural Sciences, 462-2 Nobeyama, Minamimaki, Minamisaku, Nagano 384-1305 (Japan); Murata, Katsuhiro L. [Department of Astrophysics, Nagoya University, Chikusa-ku, Nagoya 464-8602 (Japan); Nishimori, Takefumi; Gima, Hirotaka; Ito, Ayano; Morikawa, Yuto; Murakami, Kotone [Graduate School of Science and Engineering, Kagoshima University, 1-21-35 Korimoto, Kagoshima 890-0065 (Japan); Hashimoto, Osamu, E-mail: yamanaka@center.konan-u.ac.jp [Gunma Astronomical Observatory, Takayama, Gunma 377-0702 (Japan); and others

    2017-03-01

    We present the early-phase spectra and the light curves of the broad-lined (BL) supernova (SN) 2016coi from t = 7 to 67 days after the estimated explosion date. This SN was initially reported as a BL Type SN Ic (SN Ic-BL). However, we found that spectra up to t = 12 days exhibited the He i λ 5876, λ 6678, and λ 7065 absorption lines. We show that the smoothed and blueshifted spectra of normal SNe Ib are remarkably similar to the observed spectrum of SN 2016coi. The line velocities of SN 2016coi were similar to those of SNe Ic-BL and significantly faster than those of SNe Ib. Analyses of the line velocity and light curve suggest that the kinetic energy and the total ejecta mass of SN 2016coi are similar to those of SNe Ic-BL. Together with BL SNe 2009bb and 2012ap, for which the detection of He i was also reported, these SNe could be transitional objects between SNe Ic-BL and SNe Ib, and be classified as BL Type “Ib” SNe (SNe “Ib”-BL). Our work demonstrates the diversity of the outermost layer in BL SNe, which should be related to the variety of the evolutionary paths.

  3. Study on broad beam heavy ion CT

    International Nuclear Information System (INIS)

    Ohno, Yumiko; Kohno, Toshiyuki; Sasaki, Hitomi; Nanbu, S.; Kanai, Tatsuaki

    2003-01-01

    To achieve the heavy ion radiotherapy more precisely, it is important to know the distribution of the electron density in a human body, which is highly related to the range of charged particles. From a heavy ion CT image, we can directly obtain the 2-D distribution of the electron density in a sample. For this purpose, we have developed a broad beam heavy ion CT system. The electron density was obtained using some kinds of solutions targets. Also the dependence of the spatial resolution on the target size and the kinds of beams was estimated in this work using cylinders targets of 40, 60 and 80 mm in diameter, each of them has a hole of 10 mm in diameter at the center of it. (author)

  4. Compositional specification of commercial contracts

    DEFF Research Database (Denmark)

    Andersen, Jesper; Elsborg, Ebbe; Henglein, Fritz

    2006-01-01

    -definable analysis of their state before, during and after execution. We provide several realistic examples of commercial contracts and their analyses. A variety of (real) contracts can be expressed in such a fashion as to support their integration, management and analysis in an operational environment...

  5. On CNC commuting contractive tuples

    Indian Academy of Sciences (India)

    The characteristic function has been an important tool for studying completely non-unitary contractions on Hilbert spaces. In this note, we consider completely non-coisometric contractive tuples of commuting operators on a Hilbert space H . We show that the characteristic function, which is now an operator-valued analytic ...

  6. Pressure drop in contraction flow

    DEFF Research Database (Denmark)

    Rasmussen, Henrik Koblitz

    This note is a supplement to Dynamic of Polymeric Liquids (DPL) page 178. DPL gives an equation for the pressure drop in a tapered (and circular) contraction, valid only at low angles. Here the general definition of contraction flow (the Bagley correction) and a more general method to find...

  7. CONTRACT ADMINISTRATIVE TRACKING SYSTEM (CATS)

    Science.gov (United States)

    The Contract Administrative Tracking System (CATS) was developed in response to an ORD NHEERL, Mid-Continent Ecology Division (MED)-recognized need for an automated tracking and retrieval system for Cost Reimbursable Level of Effort (CR/LOE) Contracts. CATS is an Oracle-based app...

  8. Opportunities for health in contracting.

    Science.gov (United States)

    Hargadon, J

    1995-01-01

    Contracts are about much more than the simple purchasing of services. In an NHS context, they are also about working in partnership with patients, and about good employment practices, writes Judy Hargadon. Here she outlines how contracts can be used to improve health care services, and the health of those involved in both receiving and providing that care.

  9. Contracting and Performance in Agencies

    DEFF Research Database (Denmark)

    Bjørnholt, Bente; Houlberg Salomonsen, Heidi; Rennison, Betina Wolfgang

    As part of New Public Management (NPM), contracting represents a supplement to the traditional hierarchical and rule-based managing of relations between actors in order to improve performance (Fortin and van Hassel 2000; Greve and Ejersbo 2002; Drewry et al. 2005; Verhoest 2005). To various degrees...... contracts combine some degree of managerial autonomy and influence on goal setting in return for a consistent and congruent system of control and monitoring. Internal contracts are often finalized within the ‘shadow of hierarchy’ between mutually dependent parties in a long-term, co......-operation-based relationship (Brownsword 1996: 19; Greve 2000:155), which create special conditions for contracting. Few studies have empirically investigated internal contracting processes within public organizations (e.g. Verhoest 2005; Greve and Ejersbo 2005; Greve 2000) but resent research shows that agencies attain...

  10. Choreography Synthesis as Contract Agreement

    Directory of Open Access Journals (Sweden)

    Julien Lange

    2013-10-01

    Full Text Available We propose a formal model for distributed systems, where each participant advertises its requirements and obligations as behavioural contracts, and where multiparty sessions are started when a set of contracts allows to synthesise a choreography. Our framework is based on the CO2 calculus for contract-oriented computing, and borrows concepts and results from the session type literature. It supports sessions where the number of participants is not determined beforehand, and keeps CO2's ability to rule out participants that are culpable if contracts are not fulfilled at runtime. We show that we have progress and session fidelity in CO2, as a result of the honesty of participants — i.e., their ability to always adhere to their contracts.

  11. Alternative staffing services. Contract transcription.

    Science.gov (United States)

    Tessier, C

    1992-03-01

    Contract medical transcription services can be of great assistance in meeting the demands for transcription, without jeopardizing patient, physician, or institutional confidentiality. You simply must require the contract service to provide at least the same degree of protection and preservation of confidentiality that you should require inhouse. To achieve this you must make these requirements explicit, comprehensive, comprehensible, believable, and enforceable. Discuss the requirements with prospective contractors. Review them at least annually with existing contractors and when contracts are due for renewal. Be sure to specify the consequence of breaching confidentiality, and if there are breaches, enforce the terms of the contract. Consult your institution's legal counsel both in developing the contract and in enforcing its provisions. Take into consideration your department's and institution's policies, AHIMA's statement on confidentiality, as well as local, state, and federal laws. Above all, never lose sight of the patient. Ultimately, it is not patient information that you are obligated to protect. It is the patient.

  12. [Ulysses contract in psychiatry].

    Science.gov (United States)

    Daverio, Andrea; Piazzi, Gioia; Saya, Anna

    2017-01-01

    Over the last twenty years we have witnessed a growing focus on the rights of the ill people. The debate on informed consent and a new redefinition of the therapeutic relationship is constantly evolving. With this article, we propose a critical literature review of the so-called "Ulysses contract" or "psychiatric advance directives". It refers to the will that a subject expresses in writing, or orally, about the treatments he or she wishes or does not wish to be subject to if the time comes when it may be impossible to express his/her consent. This can especially occur in those with psychiatric disorders with serious clinical involvement and remitting-relapse (typically bipolar disorder, but also chronic delusional disorders and schizophrenia). In this context, the question is whether during intercritical periods the patient may or may not leave instructions to their care-givers. This aspect opens up to a series of interdisciplinary problems. In this article, we want to show the complexity of this debate from a clinical, ethical, legal and psychodynamic point of view, emphasizing the strengths and the major criticisms of the psychiatric advance directives for each area.

  13. INFINITY construction contract signed

    Science.gov (United States)

    2010-01-01

    Key state and community leaders celebrated April 6 with the signing of a construction contract for the state-of-the-art INFINITY Science Center planned near John C. Stennis Space Center in south Mississippi. Gulfport Mayor George Schloegel (l to r), chair of non-profit INFINITY Science Center Inc., was joined for the signing ceremony at the Hancock Bank in Gulfport by Virginia Wagner, sister of late Hancock Bank President Leo Seal Jr.; and Roy Anderson III, president and CEO of Roy Anderson Corp. Seal was the first chair of INFINITY Science Center Inc., which has led in development of the project. Roy Anderson Corp. plans to begin construction on the 72,000-square-foot, $28 million science and education center in May. The Mississippi Department of Transportation (MDOT) also is set to begin construction of a $2 million access road to the new center. The April 6 ceremony was attended by numerous officials, including former Stennis Space Center Directors Jerry Hlass and Roy Estess; Mississippi Senate President Pro Tempore Billy Hewes, R-Gulfport; Mississippi Rep. Diane Peranich, D-Pass Christian; and MDOT Southern District Commissioner Wayne Brown.

  14. Recipient luminophoric mediums having narrow spectrum luminescent materials and related semiconductor light emitting devices and methods

    Science.gov (United States)

    LeToquin, Ronan P; Tong, Tao; Glass, Robert C

    2014-12-30

    Light emitting devices include a light emitting diode ("LED") and a recipient luminophoric medium that is configured to down-convert at least some of the light emitted by the LED. In some embodiments, the recipient luminophoric medium includes a first broad-spectrum luminescent material and a narrow-spectrum luminescent material. The broad-spectrum luminescent material may down-convert radiation emitted by the LED to radiation having a peak wavelength in the red color range. The narrow-spectrum luminescent material may also down-convert radiation emitted by the LED into the cyan, green or red color range.

  15. Evaluating and Enhancing Driving Ability among Teens with Autism Spectrum Disorder (ASD)

    Science.gov (United States)

    2013-10-01

    among Teens with Autism Spectrum Disorder (ASD) PRINCIPAL INVESTIGATOR: Timothy L Brown, Ph.D...September 2013 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Evaluating and Enhancing Driving Ability among Teens with Autism Spectrum Disorder...with Cognitive Impairments and Anxiety Disorders” and one of the topics will be on transportation issues related to Autism. CONCLUSION To date, we

  16. Nicotinic acetylcholine receptors containing the α7-like subunit mediate contractions of muscles responsible for space positioning of the snail, Helix pomatia L. tentacle.

    Directory of Open Access Journals (Sweden)

    Tibor Kiss

    Full Text Available Three recently discovered tentacle muscles are crucial to perform patterned movements of upper tentacles of the terrestrial snail, Helix pomatia. The muscles receive central and peripheral excitatory cholinergic innervation lacking inhibitory innervation. Here, we investigate the pharmacology of acetylcholine (ACh responses in muscles to determine the properties of the ACh receptor (AChR, the functional availability of which was assessed using isotonic contraction measurement. Using broad spectrum of nicotinic and muscarinic ligands, we provide the evidence that contractions in the muscles are attributable to the activation of nAChRs that contain the α7-like subunit. Contractions could be evoked by nicotine, carbachol, succinylchloride, TMA, the selective α7-nAChR agonist choline chloride, 3-Bromocytisine and PNU-282987, and blocked by nAChR selective antagonists such as mytolon, hexamethonium, succinylchloride, d-tubocurarine, hemicholinium, DMDA (decamethonium, methyllycaconitine, α-Bungarotoxin (αBgTx and α-Conotoxin IMI. The specific muscarinic agonist oxotremorine and arecoline failed to elicit contractions. Based on these pharmacological properties we conclude that the Na+ and Ca2+ permeable AChRs of the flexor muscle are nicotinic receptors that contain the α7-like subunit. Immunodetection experiments confirmed the presence of α7- or α7-like AChRs in muscle cells, and α4-AChRs in nerves innervating the muscle. These results support the conclusion that the slowly desensitizing αBgTx-sensitive responses obtained from flexor muscles are produced by activation of α7- like AChRs. This is the first demonstration of postsynaptic expression and an obligatory role for a functional α7-like nAChR in the molluscan periphery.

  17. Nicotinic acetylcholine receptors containing the α7-like subunit mediate contractions of muscles responsible for space positioning of the snail, Helix pomatia L. tentacle.

    Science.gov (United States)

    Kiss, Tibor; Krajcs, Nóra; Pirger, Zsolt; Hernádi, László

    2014-01-01

    Three recently discovered tentacle muscles are crucial to perform patterned movements of upper tentacles of the terrestrial snail, Helix pomatia. The muscles receive central and peripheral excitatory cholinergic innervation lacking inhibitory innervation. Here, we investigate the pharmacology of acetylcholine (ACh) responses in muscles to determine the properties of the ACh receptor (AChR), the functional availability of which was assessed using isotonic contraction measurement. Using broad spectrum of nicotinic and muscarinic ligands, we provide the evidence that contractions in the muscles are attributable to the activation of nAChRs that contain the α7-like subunit. Contractions could be evoked by nicotine, carbachol, succinylchloride, TMA, the selective α7-nAChR agonist choline chloride, 3-Bromocytisine and PNU-282987, and blocked by nAChR selective antagonists such as mytolon, hexamethonium, succinylchloride, d-tubocurarine, hemicholinium, DMDA (decamethonium), methyllycaconitine, α-Bungarotoxin (αBgTx) and α-Conotoxin IMI. The specific muscarinic agonist oxotremorine and arecoline failed to elicit contractions. Based on these pharmacological properties we conclude that the Na+ and Ca2+ permeable AChRs of the flexor muscle are nicotinic receptors that contain the α7-like subunit. Immunodetection experiments confirmed the presence of α7- or α7-like AChRs in muscle cells, and α4-AChRs in nerves innervating the muscle. These results support the conclusion that the slowly desensitizing αBgTx-sensitive responses obtained from flexor muscles are produced by activation of α7- like AChRs. This is the first demonstration of postsynaptic expression and an obligatory role for a functional α7-like nAChR in the molluscan periphery.

  18. 48 CFR 1242.7000 - Contract clauses.

    Science.gov (United States)

    2010-10-01

    ... MANAGEMENT CONTRACT ADMINISTRATION AND AUDIT SERVICES Contract Administration Clauses 1242.7000 Contract... Information—Educational Institutions, in lieu of the clause at (TAR) 48 CFR 1252.242-72, Dissemination of Contract Information, in DOT research contracts with educational institutions that require the release or...

  19. 48 CFR 2432.908 - Contract clauses.

    Science.gov (United States)

    2010-10-01

    ...-reimbursement type solicitations and contracts when vouchers are to be sent directly to the paying office. The... GENERAL CONTRACTING REQUIREMENTS CONTRACT FINANCING Prompt Payment 2432.908 Contract clauses. (c)(1) The Contracting Officer shall insert a clause substantially the same as provided at 2452.232-70, Payment Schedule...

  20. Ontologies for commitment-based smart contracts

    NARCIS (Netherlands)

    de Kruijff, Joost; Weigand, Hans; Panetto, H; Debruyne, C.; Gaaloul, W.; Papazoglou, M.; Paschke, A.; Ardagna, C.A.; Meersman, R.

    2017-01-01

    Smart contracts gain rapid exposure since the inception of blockchain technology. Yet there is no unified ontology for smart contracts. Being categorized as coded contracts or substitutes of conventional legal contracts, there is a need to reduce the conceptual ambiguity of smart contracts. We