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We report the measurement of the helicity asymmetry E for the pπ^{0} and nπ^{+} final states using, for the first time, an elliptically polarized photon beam in combination with a longitudinally polarized target at the Crystal Ball experiment at MAMI. The results agree very well with data that were taken with a circularly polarized photon beam, showing that it is possible to simultaneously measure polarization observables that require linearly (e.g., G) and circularly polarized photons (e.g., E) and a longitudinally polarized target. The new data cover a photon energy range 270-1400 MeV for the pπ^{0} final state (230-842 MeV for the nπ^{+} final state) and the full range of pion polar angles, θ, providing the most precise measurement of the observable E. A moment analysis gives a clear observation of the pη cusp in the pπ^{0} final state.
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The target asymmetry T, recoil asymmetry P, and beam-target double polarization observable H were determined in exclusive π0 and η photoproduction off quasi-free protons and, for the first time, off quasi-free neutrons. The experiment was performed at the electron stretcher accelerator ELSA in Bonn, Germany, with the Crystal Barrel/TAPS detector setup, using a linearly polarized photon beam and a transversely polarized deuterated butanol target. Effects from the Fermi motion of the nucleons within deuterium were removed by a full kinematic reconstruction of the final state invariant mass. A comparison of the data obtained on the proton and on the neutron provides new insight into the isospin structure of the electromagnetic excitation of the nucleon. Earlier measurements of polarization observables in the γpâπ0p and γpâηp reactions are confirmed. The data obtained on the neutron are of particular relevance for clarifying the origin of the narrow structure in the ηn system at W=1.68GeV. A comparison with recent partial wave analyses favors the interpretation of this structure as arising from interference of the S11(1535) and S11(1650) resonances within the S11-partial wave.
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A precise measurement of the differential cross sections dσ/dΩ and the linearly polarized photon beam asymmetry Σ_{3} for Compton scattering on the proton below pion threshold has been performed with a tagged photon beam and almost 4π detector at the Mainz Microtron. The incident photons were produced by the recently upgraded Glasgow-Mainz photon tagging facility and impinged on a cryogenic liquid hydrogen target, with the scattered photons detected in the Crystal Ball/TAPS setup. Using the highest statistics Compton scattering data ever measured on the proton along with two effective field theories (both covariant baryon and heavy-baryon) and one fixed-t dispersion relation model, constraining the fits with the Baldin sum rule, we have obtained the proton electric and magnetic polarizabilities with unprecedented precision: α_{E1}=10.99±0.16±0.47±0.17±0.34, ß_{M1}=3.14±0.21±0.24±0.20±0.35; in units of 10^{-4} fm^{3} where the errors are statistical, systematic, spin polarizability dependent, and model dependent.
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PURPOSE: To evaluate the rates of ghost and honorary authorship in ophthalmology and to determine risk factors associated with ghost and honorary authorship. DESIGN: Cross-sectional survey. METHODS: Corresponding authors of articles published in Ophthalmology, JAMA Ophthalmology, and the American Journal of Ophthalmology from June 2019 to December 2020 were emailed an electronic survey. The rates of ghost and honorary authorship, demographic characteristics of the corresponding authors with and without ghost and honorary authorship, and risk factors for ghost and honorary authorship were evaluated. RESULTS: Corresponding authors (n = 830) were emailed a survey and 278 total responses (34.1%) were received; 227 responses (27.9%) were complete and included for analysis. Most respondents (n = 206, 90.7%) believed that the International Committee of Medical Journal Editors (ICMJE) guidelines for authorship adequately address criteria for authorship. Twenty-seven corresponding authors (11.9%) reported characteristics of their articles that indicated the presence of both ghost and honorary authorship (95% CI, 7.7%-16.1%). One hundred fifteen (50.7%) reported honorary authorship (44.2%-57.2%), and 37 (16.3%) indicated ghost authorship (11.5%-21.1%). Being a resident or fellow corresponding author increased the risk of honorary authorship (OR 11.75; 1.91-231.57; P = .03). There were no factors that predicted articles having ghost authors. CONCLUSIONS: While many authors believe the ICMJE guidelines for authorship comprehensively delineate fair authorship practices, listing authors on scientific publications honorarily and excluding authors who qualify for authorship are relatively common practices in ophthalmological research. Further investigation into the drivers of honorary and ghost authorship practices in ophthalmology, and the effectiveness of preventive measures are needed to ensure fair authorship attributions.
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Autoria , Oftalmologia , Estudos Transversais , Humanos , Editoração , Inquéritos e QuestionáriosRESUMO
The quasifree γ â d â π 0 n ( p ) photon beam asymmetry, Σ , has been measured at photon energies, E γ , from 390 to 610 MeV, corresponding to center of mass energy from 1.271 to 1.424 GeV, for the first time. The data were collected in the A2 hall of the MAMI electron beam facility with the Crystal Ball and TAPS calorimeters covering pion center-of-mass angles from 49 ∘ to 148 ∘ . In this kinematic region, polarization observables are sensitive to contributions from the Δ ( 1232 ) and N(1440) resonances. The extracted values of Σ have been compared to predictions based on partial-wave analyses (PWAs) of the existing pion photoproduction database. Our comparison includes the SAID, MAID and Bonn-Gatchina analyses; while a revised SAID fit, including the new Σ measurements, has also been performed. In addition, isospin symmetry is examined as a way to predict π 0 n photoproduction observables, based on fits to published data in the channels π 0 p , π + n and π - p .
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Oxyuricassis ekstromi n. sp. is the third species of the genus described from the intestine of Lasiancistrus saetiger Armbruster in Brazil. This species can be easily differentiated from its congeners by the presence of a tooth-like sclerotized piece that occupies half of the stoma and absence of spine projections on the tail of both males and females. Also, males of the new species lack caudal alae present in Oxyuricassis coronatus and Oxyuricassis hexaspinatus. Additionally, we observed a different number and pattern of the distribution of cloacal papilla; males of O. coronatus and O. hexaspinatus have 1 pair of pre-cloacal and 2 pairs of post-cloacal papillae; while the new species has 1 pre-cloacal and 3 post-cloacal pairs of papillae.
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Peixes-Gato/parasitologia , Doenças dos Peixes/parasitologia , Enteropatias Parasitárias/veterinária , Oxiuríase/veterinária , Oxyuroidea/classificação , Animais , Brasil , Feminino , Enteropatias Parasitárias/parasitologia , Intestinos/parasitologia , Masculino , Microscopia Eletrônica de Varredura/veterinária , Oxiuríase/parasitologia , Oxyuroidea/anatomia & histologia , Oxyuroidea/ultraestrutura , RiosRESUMO
The double-polarization observable E and helicity-dependent cross sections σ_{1/2}, σ_{3/2} have been measured for the photoproduction of π^{0} pairs off quasifree protons and neutrons at the Mainz MAMI accelerator with the Crystal Ball/TAPS setup. A circularly polarized photon beam was produced by bremsstrahlung from longitudinally polarized electrons and impinged on a longitudinally polarized deuterated butanol target. The reaction products were detected with an almost 4π covering calorimeter. The results reveal for the first time the helicity- and isospin-dependent structure of the γNâNπ^{0}π^{0} reaction. They are compared to predictions from reaction models in view of nucleon resonance contributions and also to a refit of one model that predicted results for the proton and for the neutron target. The comparison of the prediction and the refit demonstrates the large impact of the new data.
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Antibody autoreactivity against bactericidal/permeability-increasing protein (BPI) is strongly associated with Pseudomonas aeruginosa infection in cystic fibrosis (CF), non-CF bronchiectasis (BE), and chronic obstructive pulmonary disease (COPD). We examined the pathogen-specific nature of this autoreactivity by examining antibodies to BPI in bacteremia patients. Antibodies to BPI and bacterial antigens were measured in sera by ELISA from five patient cohorts (n = 214). Antibody avidity was investigated. Bacteremic patient sera (n = 32) exhibited IgG antibody autoreactivity against BPI in 64.7% and 46.7% of patients with positive blood cultures for P. aeruginosa and Escherichia coli, respectively. Autoantibody titers correlated with IgG responses to bacterial extracts and lipopolysaccharide (LPS). A prospective cohort of bacteremic patient sera exhibited anti-BPI IgG responses in 23/154 (14.9%) patients with autoreactivity present at the time of positive blood cultures in patients with Gram-negative and Gram-positive bacteria, including 8/60 (13.3%) patients with Staphylococcus aureus Chronic tissue infection with S. aureus was associated with BPI antibody autoreactivity in 2/15 patients (13.3%). Previously, we demonstrated that BPI autoreactivity in CF patient sera exhibits high avidity. Here, a similar pattern was seen in BE patient sera. In contrast, sera from patients with bacteremia exhibited low avidity. These data indicate that low-avidity IgG responses to BPI can arise acutely in response to bacteremia and that this association is not limited to P. aeruginosa This is to be contrasted with chronic respiratory infection with P. aeruginosa, suggesting that either the chronicity or the site of infection selects for the generation of high-avidity responses, with biologic consequences for airway immunity.
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Peptídeos Catiônicos Antimicrobianos/imunologia , Autoanticorpos/imunologia , Bacteriemia/imunologia , Proteínas Sanguíneas/imunologia , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Positivas/imunologia , Imunoglobulina G/imunologia , Doença Aguda , Afinidade de Anticorpos , Antígenos de Bactérias/imunologia , Autoanticorpos/sangue , Bacteriemia/microbiologia , Doença Crônica , Escherichia coli/imunologia , Escherichia coli/isolamento & purificação , Infecções por Bactérias Gram-Negativas/microbiologia , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Imunoglobulina G/sangue , Cinética , Estudos Prospectivos , Pseudomonas aeruginosa/imunologia , Pseudomonas aeruginosa/isolamento & purificação , Staphylococcus aureus/imunologia , Staphylococcus aureus/isolamento & purificaçãoRESUMO
We report a measurement of the spin polarization of the recoiling neutron in deuterium photodisintegration, utilizing a new large acceptance polarimeter within the Crystal Ball at MAMI. The measured photon energy range of 300-700 MeV provides the first measurement of recoil neutron polarization at photon energies where the quark substructure of the deuteron plays a role, thereby providing important new constraints on photodisintegration mechanisms. A very high neutron polarization in a narrow structure centered around E_{γ}â¼570 MeV is observed, which is inconsistent with current theoretical predictions employing nucleon resonance degrees of freedom. A Legendre polynomial decomposition suggests this behavior could be related to the excitation of the d^{*}(2380) hexaquark.
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BACKGROUND: The UK Health and Safety Executive's Stress Management Competency Framework and associated questionnaire, the Stress Management Competency Indicator Tool (SMCIT), address line managers' behaviours across four competency areas. The application in policing remains unexplored. AIMS: This study profiled English police officers' perception of their line managers' competencies in the framework areas. The odds of experiencing poor mental wellbeing and work attitudes associated with having a line manager with a development need on each competency area were tested. METHODS: Two hundred and sixty-three police officers completed a survey comprising the SMCIT and measures of psychological distress, resilience and work engagement. Bivariate correlations were calculated to identify patterns of relationships between variables. Binary logistic regression analyses tested the odds of psychological distress caseness, low resilience and low work engagement being associated with officers' perception of their line manager having a development need on the SMCIT criteria. RESULTS: Approximately half the participants reported their line manager had a development need on the 'Managing and Communicating Existing and Future Work', 'Managing the Individual Within the Team' and 'Reasoning and Managing Difficult Situations' competencies, and one quarter on the 'Respectful and Responsible: Managing Emotions and Having Integrity' competency. Officers' rating of their line manager having a development need on the four competency areas was associated with up to four-fold elevated odds of each undesirable state. CONCLUSIONS: The framework competency areas are relevant to English policing and offer a basis for stress reduction interventions targeted at line managers' behaviours.
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Estresse Ocupacional/prevenção & controle , Polícia/organização & administração , Polícia/psicologia , Estresse Psicológico/prevenção & controle , Adulto , Inglaterra , Feminino , Humanos , Masculino , Saúde Mental/estatística & dados numéricos , Pessoa de Meia-Idade , Resiliência Psicológica , Inquéritos e Questionários , Engajamento no Trabalho , Local de Trabalho/psicologiaRESUMO
BACKGROUND: Pseudomonas aeruginosa accounts for ~80% of cystic fibrosis (CF) airway infection. It shows a remarkable correlation with presence of autoantibody to bactericidal/permeability-increasing protein (BPI), which is not understood. In this study, we sought to better understand the characteristics of systemic and mucosal autoimmunity and their relation to humoral immunity to P. aeruginosa. METHODS: Antibody titers and isotypes to BPI and P. aeruginosa were characterized in sera and bronchoalveolar lavage (BAL) of adult and pediatric CF patients (nâ¯=â¯131), by ELISA and/or immunoblot. RESULTS: Serum BPI autoantibodies were common (~43%) in adult while rare (âª5%) in pediatric (≤18â¯yrs) CF patients. Serum BPI IgG autoantibodies were of high avidity and strongly correlated with anti-P. aeruginosa IgG responses. A parallel relationship was observed with IgA, but not IgG, responses in adult and pediatric CF patient in the BAL. Thus, BAL IgA anti-BPI antibodies were independent of age and correlated with the presence of BPI cleavage in BAL. CONCLUSIONS: IgG and IgA autoreactivity to BPI in CF patients was demonstrated in serum and BAL, respectively, and correlated with the isotype of the antibody response to P. aeruginosa. The co-occurrence of anti-BPI and anti-P. aeruginosa IgA in the BAL, but not serum, of pediatric CF patients suggests that BPI tolerance is broken in the P. aeruginosa-infected airway and that serologic IgG autoantibodies are later induced, potentially through a separate pathway. The relationship between P. aeruginosa, BPI cleavage, and IgA autoantibodies in the BAL suggests a role for cryptic epitope generation in the breaking of tolerance.
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Peptídeos Catiônicos Antimicrobianos/imunologia , Proteínas Sanguíneas/imunologia , Fibrose Cística , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Infecções por Pseudomonas , Pseudomonas aeruginosa , Mucosa Respiratória , Autoimunidade/imunologia , Criança , Fibrose Cística/imunologia , Fibrose Cística/microbiologia , Fibrose Cística/fisiopatologia , Feminino , Humanos , Imunidade Humoral/imunologia , Masculino , Infecções por Pseudomonas/sangue , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/imunologia , Pseudomonas aeruginosa/isolamento & purificação , Mucosa Respiratória/imunologia , Mucosa Respiratória/microbiologia , Testes Sorológicos/métodosRESUMO
BACKGROUND: Homelessness is increasing globally. It results in poorer physical and mental health than age matched people living in permanent housing. Better information on the health needs of people experiencing homelessness is needed to inform effective resourcing, planning and service delivery by government and care organisations. The aim of this review was to identify assessment tools that are valid, reliable and appropriate to measure the health status of people who are homeless. METHODS: Data sources: A systematic literature search was conducted in PubMed (and Medline), PsychInfo, Scopus, CINAHL and ERIC from database inception until September 2018. Key words used were homeless, homelessness, homeless persons, vagrancy, health status, health, health issues, health assessment and health screening. The protocol was registered with PROSPERO. The National Health and Medical Research Council of Australia (NHMRC) hierarchy of evidence was applied; methodological quality of included articles was assessed using the McMaster critical appraisal tools and psychometric properties of the tools were appraised using the International Centre for Allied Health Evidence Ready Reckoner. RESULTS: Diverse tools and measures (N = 71) were administered within, and across the reviewed studies (N = 37), with the main focus being on general health, oral health and nutrition. Eleven assessment tools in 13 studies had evidence of appropriate psychometric testing for the target population in domains of quality of life and health status, injury, substance use, mental health, psychological and cognitive function. Methodological quality of articles and tools were assessed as moderate to good. No validated tools were identified to assess oral health, chronic conditions, anthropometry, demography, nutrition, continence, functional decline and frailty, or vision and hearing. However, assessments of physical constructs (such as oral health, anthropometry, vision and hearing) could be applied to homeless people on a presumption of validity, because the constructs would be measured with clinical indicators in the same manner as people living in permanent dwellings. CONCLUSIONS: This review highlighted the need to develop consistent and comprehensive health assessment tools validated with, and tailored for, adults experiencing homelessness.
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Programas de Triagem Diagnóstica , Pessoas Mal Alojadas/psicologia , Programas de Rastreamento/métodos , Adulto , Austrália , Feminino , Nível de Saúde , Indicadores Básicos de Saúde , Humanos , Masculino , Psicometria , Adulto JovemRESUMO
OBJECTIVES: Timely HIV diagnosis and presentation to medical care are important for treatment and prevention. Our objective was to measure late diagnosis, delayed presentation and late presentation among individuals in the Ontario HIV Treatment Network Cohort Study (OCS) who were newly diagnosed in Ontario. METHODS: The OCS is a multi-site clinical cohort study of people living with HIV in Ontario, Canada. We measured prevalence of late diagnosis [CD4 count < 350 cells/µL or an AIDS-defining condition (ADC) within 3 months of HIV diagnosis], delayed presentation (≥ 3 months from HIV diagnosis to presentation to care), and late presentation (CD4 count < 350 cells/µL or ADC within 3 months of presentation). We identified characteristics associated with these outcomes and explored their overlap. RESULTS: A total of 1819 OCS participants were newly diagnosed in Ontario from 1999 to 2013. Late diagnosis (53.0%) and presentation (54.0%) were common, and a quarter (23.1%) of participants were delayed presenters. In multivariable models, the participants of delayed presentation decreased over calendar time, but that of late diagnosis/presentation did not. Late diagnosis contributed to the majority (> 87%) of late presentation, and the prevalence of delayed presentation was similar among those diagnosed late versus early (13.4 versus 13.4%, respectively; P = 0.99). Characteristics associated with higher odds of late diagnosis/presentation in multivariable analyses included older age at diagnosis/presentation; African, Caribbean and Black race/ethnicity; Indigenous race/ethnicity; female sex; and being a male who did not report sex with men. There were lower odds of late diagnosis/presentation among participants who had ever injected drugs. In contrast, delayed presentation risk factors included younger age at diagnosis and having ever injected drugs. CONCLUSIONS: Late presentation is common in Ontario, as it is in other high-income countries. Our findings suggest that efforts to reduce late presentation should focus on facilitating earlier diagnosis for the populations identified in this analysis.
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Diagnóstico Tardio/estatística & dados numéricos , Infecções por HIV/diagnóstico , Tempo para o Tratamento/estatística & dados numéricos , Adulto , Contagem de Linfócito CD4 , Estudos de Coortes , Diagnóstico Precoce , Feminino , Infecções por HIV/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Ontário/epidemiologia , PrevalênciaRESUMO
The flea genus Neotyphloceras Rothschild (Siphonaptera: Ctenophthalmidae) includes five species and two subspecies distributed from Venezuela to southern Chile and Argentina. Only Neotyphloceras crassispina hemisus Jordan has been registered in Bolivia. The present study examines species of Neotyphloceras collected in Bolivian localities in the Departments of La Paz, Cochabamba and Tarija, and describes the morphology of the modified abdominal segments in males and females of Neotyphloceras rosenbergi Rothschild on the basis of type material and specimens collected from Tarija. A new species, Neotyphloceras boliviensis n. sp., is described and new host associations are reported for N. rosenbergi, Neotyphloceras crassispina crassispina and N. crassispina hemisus. Neotyphloceras c. crassispina and N. rosenbergi are reported for the first time in Bolivia. The distribution of N. rosenbergi is extended 1600 km to the south. Given the potential medical and veterinary significance of fleas as disease vectors, and considering that in the Departments of La Paz and Tarija several human cases of plague have been reported, and species of flea have been identified as main vectors of these diseases, the new records of fleas in Bolivia reported herein may be useful for epidemiological studies on flea-borne diseases.
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Infestações por Pulgas/veterinária , Gambás/parasitologia , Ratos/parasitologia , Doenças dos Roedores/parasitologia , Sigmodontinae/parasitologia , Sifonápteros/classificação , Animais , Bolívia/epidemiologia , Feminino , Infestações por Pulgas/epidemiologia , Infestações por Pulgas/parasitologia , Masculino , Doenças dos Roedores/epidemiologia , Sifonápteros/anatomia & histologiaRESUMO
The continued emergence and global spread of bacterial antibiotic resistance has fuelled the search for novel antimicrobial agents and resistance-modifying compounds. Manuka honey has both antimicrobial properties and the ability to increase the efficacy of FDA-approved antibiotic drugs. Compared to other types of honey, manuka honey contains elevated levels of methylglyoxal (MGO), a small molecule that contributes to its antibacterial activity. Manuka honey has shown particular promise for the treatment of antibiotic-resistant Gram-positive organisms such as methicillin-resistant Staphylococcus aureus. Linezolid is an oxazolidinone antibiotic used in the treatment of infections caused by a range of Gram-positive pathogens. Here, we demonstrate that manuka honey, as well as MGO in isolation, increases the sensitivity of S. aureus to linezolid in both agar diffusion and broth microdilution assays. This synergistic interaction is mediated in part by increased intracellular accumulation of linezolid in the presence of MGO. SIGNIFICANCE AND IMPACT OF THE STUDY: Manuka honey is widely recognized for its antimicrobial activity. Our study adds to the growing body of evidence that manuka honey and its active ingredient, methylglyoxal (MGO), can also function as antibiotic adjuvants. In this study, we provide the first report of synergy between MGO and linezolid against Staphylococcus aureus. Both manuka honey and purified MGO significantly increased the sensitivity of S. aureus to linezolid.
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Antibacterianos/farmacologia , Mel/análise , Linezolida/farmacologia , Aldeído Pirúvico/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Farmacorresistência Bacteriana , Sinergismo Farmacológico , Humanos , Testes de Sensibilidade Microbiana , Aldeído Pirúvico/análise , Infecções Estafilocócicas/tratamento farmacológicoRESUMO
Macrocyclic peptides containing N-alkylated amino acids have emerged as a promising therapeutic modality, capable of modulating protein-protein interactions and an intracellular delivery of hydrophilic payloads. While multichannel automated solid-phase peptide synthesis (SPPS) is a practical approach for peptide synthesis, the requirement for slow and inefficient chromatographic purification of the product peptides is a significant limitation to exploring these novel compounds. Herein, we invent a "catch-release" strategy for the nonchromatographic purification of macrocyclic peptides. A traceless catch process is enabled by the invention of a dual-functionalized N-terminal acetate analogue, which serves as a handle for capture onto a purification resin and as a leaving group for macrocyclization. Displacement by a C-terminal nucleophilic side chain thus releases the desired macrocycle from the purification resin. By design, this catch/release process is a logic test for the presence of the key components required for cyclization, thus removing impurities which lack the required functionality, such as common classes of peptide impurities, including hydrolysis fragments and truncated sequences. The method was shown to be highly effective with three libraries of macrocyclic peptides, containing macrocycles of 5-20 amino acids, with either thioether- or amine-based macrocyclic linkages; in this latter class, the reported method represents an enabling technology. In all cases, the catch-release protocol afforded significant enrichment of the target peptides purity, in many cases completely obviating the need for chromatography. Importantly, we have adapted this process for automation on a standard multichannel peptide synthesizer, achieving an efficient and completely integrated synthesis and purification platform for the preparation of these important molecules.
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GSK2878175 is a potent, pan-genotypic, non-nucleoside, nonstructural protein 5B palm polymerase inhibitor being developed for the treatment of chronic hepatitis C (CHC). A first-in-human, randomized, placebo-controlled, dose escalation study, evaluated the safety and pharmacokinetics of GSK2878175 administered as single and repeat oral doses (once daily for 14 days) to healthy volunteers. A separate proof-of-concept, placebo-controlled, repeat dose (once daily for 2 days) study evaluated the safety, pharmacokinetics and antiviral activity of GSK2878175 monotherapy in treatment-naïve, noncirrhotic, subjects with hepatitis C virus (HCV) genotype 1 [1a and 1b], 2, or 3. No deaths or SAEs were reported in either study, and treatment was well-tolerated. Across all the HCV genotypes, GSK2878175 monotherapy at doses of 10, 30 or 60 mg once daily for 2 days produced a statistically significant multilog reduction (P<.001) in plasma HCV RNA log10 IU/mL from Baseline to 24, 48 and 72 hours after the first dose of GSK2878175 compared to placebo. The reduction in HCV RNA was sustained for a prolonged period across all of the active treatment groups, consistent with the long apparent half-life of GSK2878175 that was observed (mean t1/2 range: 60-63 hours in the CHC subjects). In summary, GSK2878175, when administered to healthy subjects and subjects with CHC, did not reveal any safety concerns that would limit or preclude further clinical development. GSK2878175 monotherapy across a wide dose range produced substantial reduction in HCV RNA, irrespective of HCV genotype. The results from these studies support further evaluation of GSK2878175-based regimens.
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Antivirais/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Adulto , Antivirais/farmacocinética , Antivirais/farmacologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , RNA Viral/sangue , Resposta Viral Sustentada , Resultado do Tratamento , Carga Viral , Proteínas não Estruturais Virais/antagonistas & inibidoresRESUMO
The reactions γpâηp and γpâη^{'}p are measured from their thresholds up to the center-of-mass energy W=1.96 GeV with the tagged-photon facilities at the Mainz Microtron, MAMI. Differential cross sections are obtained with unprecedented statistical accuracy, providing fine energy binning and full production-angle coverage. A strong cusp is observed in the total cross section for η photoproduction at the energies in the vicinity of the η^{'} threshold, W=1896 MeV (E_{γ}=1447 MeV). Within the framework of a revised ηMAID isobar model, the cusp, in connection with a steep rise of the η^{'} total cross section from its threshold, can only be explained by a strong coupling of the poorly known N(1895)1/2^{-} state to both ηp and η^{'}p. Including the new high-accuracy results in the ηMAID fit to available η and η^{'} photoproduction data allows the determination of the N(1895)1/2^{-} properties.
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The Ras proteins are essential GTPases involved in the regulation of cell proliferation and survival. Mutated oncogenic forms of Ras alter effector binding and innate GTPase activity, leading to deregulation of downstream signal transduction. Mutated forms of Ras are involved in approximately 30% of human cancers. Despite decades of effort to develop direct Ras inhibitors, Ras has long been considered "undruggable" due to its high affinity for GTP and its lack of hydrophobic binding pockets. Herein, we report a total chemical synthesis of all-l- and all-d-amino acid biotinylated variants of oncogenic mutant KRas(G12V). The protein is synthesized using Fmoc-based solid-phase peptide synthesis and assembled using combined native chemical ligation and isonitrile-mediated activation strategies. We demonstrate that both KRas(G12V) enantiomers can successfully fold and bind nucleotide substrates and binding partners with observable enantiodiscrimination. By demonstrating the functional competency of a mirror-image form of KRas bound to its corresponding enantiomeric nucleotide triphosphate, this study sets the stage for further biochemical studies with this material. In particular, this protein will enable mirror-image yeast surface display experiments to identify all-d peptide ligands for oncogenic KRas, providing a useful tool in the search for new therapeutics against this challenging disease target.
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Proteínas Proto-Oncogênicas p21(ras)/síntese química , Sequência de Aminoácidos , Variação Genética , Humanos , Dobramento de Proteína , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
A unique adaptation of many internal parasites of mammals is their ability to stay in the intestine for extended periods of time and resist the normal peristaltic movements and forces that push and expel material. To better understand parasite adhesion behaviour and replicate their attachment method in medical devices, an experiment was designed and performed using the rat tapeworm, Hymenolepis diminuta. The experiment employed a tensile test machine and a digital scale and was designed to calculate the attachment strength of the scolex to the mucosa through the change of the value of the digital scale during the tensile test. The attachment force of H. diminuta is 0.021 ± 0.011 g. This method could be applied in studies of parasite biomechanics and the results may help medical device researchers to better mimic the unique functional morphology of this species of parasite.