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Preparation of a redox-frustrated high-energy-density energetic material is achieved by gentle protolysis of Mn[N(SiMe3)2]2 with the perchlorate salt of the tetrazolamide [H2NtBuMeTz]ClO4 (Tz = tetrazole), yielding the Mn6N6 hexagonal prismatic cluster, Mn6(µ3-NTztBuMe)6(ClO4)6. Quantum mechanics-based molecular dynamics simulations of the decomposition of this molecule predict that magnetic ordering of the d5 Mn2+ ions influences the pathway and rates of decomposition, suggesting that the initiation of decomposition of the bulk material might be significantly retarded by an applied magnetic field. We report here experimental tests of the prediction showing that the presence of a 0.5 T magnetic field modulates the ignition onset temperature by +10.4 ± 3.9 °C (from 414 ± 4 °C), demonstrating the first example of a magnetically modulated explosive.
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IMPORTANCE: Rotaviruses are important causes of severe gastroenteritis in young children. A characteristic feature of rotaviruses is that they copy ribonucleic acid (RNA) inside of the viral particle. In fact, the viral polymerase (VP1) only functions when it is connected to the viral inner core shell protein (VP2). Here, we employed a biochemical assay to identify which sites of VP2 are critical for regulating VP1 activity. Specifically, we engineered VP2 proteins to contain amino acid changes at structurally defined sites and assayed them for their capacity to support VP1 function in a test tube. Through this work, we were able to identify several VP2 residues that appeared to regulate the activity of the polymerase, positively and negatively. These results are important because they help explain how rotavirus synthesizes its RNA while inside of particles and they identify targets for the future rational design of drugs to prevent rotavirus disease.
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RNA Polimerases Dirigidas por DNA , Rotavirus , Proteínas do Core Viral , Proteínas do Capsídeo/metabolismo , RNA/metabolismo , Rotavirus/fisiologia , Proteínas do Core Viral/metabolismo , RNA Polimerases Dirigidas por DNA/metabolismoRESUMO
The properties of catenated nitrogen molecules, molecules containing internal chains of bonded nitrogen atoms, is of fundamental scientific interest in chemical structure and bonding, as nitrogen is uniquely situated in the periodic table to form kinetically stable compounds often with chemically stable N-N bonds but which are thermodynamically unstable in that the formation of stable multiply bonded N2 is usually thermodynamically preferable. This unique placement in the periodic table makes catenated nitrogen compounds of interest for development of high-energy-density materials, including explosives for defense and construction purposes, as well as propellants for missile propulsion and for space exploration. This review, designed for a chemical audience, describes foundational subjects, methods, and metrics relevant to the energetic materials community and provides an overview of important classes of catenated nitrogen compounds ranging from theoretical investigation of hypothetical molecules to the practical application of real-world energetic materials. The review is intended to provide detailed chemical insight into the synthesis and decomposition of such materials as well as foundational knowledge of energetic science new to most chemists.
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The rotavirus polymerase VP1 mediates all stages of viral RNA synthesis within the confines of subviral particles and while associated with the core shell protein VP2. Transcription (positive-strand RNA [+RNA] synthesis) by VP1 occurs within double-layered particles (DLPs), while genome replication (double-stranded RNA [dsRNA] synthesis) by VP1 occurs within assembly intermediates. VP2 is critical for VP1 enzymatic activity; yet, the mechanism by which the core shell protein triggers polymerase function remains poorly understood. Structural analyses of transcriptionally competent DLPs show that VP1 is located beneath the VP2 core shell and sits slightly off-center from each of the icosahedral 5-fold axes. In this position, the polymerase is contacted by the core shell at 5 distinct surface-exposed sites, comprising VP1 residues 264 to 267, 547 to 550, 614 to 620, 968 to 980, and 1022 to 1025. Here, we sought to test the functional significance of these VP2 contact sites on VP1 with regard to polymerase activity. We engineered 19 recombinant VP1 (rVP1) proteins that contained single- or multipoint alanine mutations within each individual contact site and assayed them for the capacity to synthesize dsRNA in vitro in the presence of rVP2. Three rVP1 mutants (E265A/L267A, R614A, and D971A/S978A/I980A) exhibited diminished in vitro dsRNA synthesis. Despite their loss-of-function phenotypes, the mutants did not show major structural changes in silico, and they maintained their overall capacity to bind rVP2 in vitro via their nonmutated contact sites. These results move us toward a mechanistic understanding of rotavirus replication and identify precise VP2-binding sites on the polymerase surface that are critical for its enzymatic activation.IMPORTANCE Rotaviruses are important pathogens that cause severe gastroenteritis in the young of many animals. The viral polymerase VP1 mediates all stages of viral RNA synthesis, and it requires the core shell protein VP2 for its enzymatic activity. Yet, there are several gaps in knowledge about how VP2 engages and activates VP1. Here, we probed the functional significance of 5 distinct VP2 contact sites on VP1 that were revealed through previous structural studies. Specifically, we engineered alanine amino acid substitutions within each of the 5 VP1 regions and assayed the mutant polymerases for the capacity to synthesize RNA in the presence of VP2 in a test tube. Our results identified residues within 3 of the VP2 contact sites that are critical for robust polymerase activity. These results are important because they enhance the understanding of a key step of the rotavirus replication cycle.
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Proteínas do Capsídeo/genética , Proteínas Mutantes/química , RNA de Cadeia Dupla/química , RNA Viral/química , RNA Polimerase Dependente de RNA/química , Rotavirus , Sequência de Aminoácidos , Sítios de Ligação , Proteínas do Capsídeo/química , Proteínas do Capsídeo/metabolismo , Mutação com Perda de Função , Modelos Moleculares , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Ligação Proteica , Conformação Proteica , RNA de Cadeia Dupla/genética , RNA de Cadeia Dupla/metabolismo , RNA Viral/genética , RNA Viral/metabolismo , RNA Polimerase Dependente de RNA/genética , RNA Polimerase Dependente de RNA/metabolismo , Rotavirus/genética , Rotavirus/metabolismoRESUMO
BACKGROUND: Prevention of violence due to severe mental disorders in psychiatric hospitals may require intrusive, restrictive and coercive therapeutic practices. Research concerning appropriate use of such interventions is limited by lack of a system for description and measurement. We set out to devise and validate a tool for clinicians and secure hospitals to assess necessity and proportionality between imminent violence and restrictive practices including de-escalation, seclusion, restraint, forced medication and others. METHODS: In this retrospective observational cohort study, 28 patients on a 12 bed male admissions unit in a secure psychiatric hospital were assessed daily for six months. Data on adverse incidents were collected from case notes, incident registers and legal registers. Using the functional assessment sequence of antecedents, behaviours and consequences (A, B, C) we devised and applied a multivariate framework of structured professional assessment tools, common adverse incidents and preventive clinical interventions to develop a tool to analyse clinical practice. We validated by testing assumptions regarding the use of restrictive and intrusive practices in the prevention of violence in hospital. We aimed to provide a system for measuring contextual and individual factors contributing to adverse events and to assess whether the measured seriousness of threating and violent behaviours is proportionate to the degree of restrictive interventions used. General Estimating Equations tested preliminary models of contexts, decisions and pathways to interventions. RESULTS: A system for measuring adverse behaviours and restrictive, intrusive interventions for prevention had good internal consistency. Interventions were proportionate to seriousness of harmful behaviours. A 'Pareto' group of patients (5/28) were responsible for the majority (80%) of adverse events, outcomes and interventions. The seriousness of the precipitating events correlated with the degree of restrictions utilised to safely manage or treat such behaviours. CONCLUSION: Observational scales can be used for restrictive, intrusive or coercive practices in psychiatry even though these involve interrelated complex sequences of interactions. The DRILL tool has been validated to assess the necessity and demonstrate proportionality of restrictive practices. This tool will be of benefit to services when reviewing practices internally, for mandatory external reviewing bodies and for future clinical research paradigms.
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Transtornos Mentais , Saúde Mental , Liberdade , Hospitais Psiquiátricos , Humanos , Masculino , Restrição Física , Estudos RetrospectivosRESUMO
Reaction of 1,3-diazidopropane with an electron-rich Mn(II) precursor results in oxidation of the metal center to a Mn complex with concomitant assembly of the macrocyclic ligand into the 1,2,3,4,8,9,10,11-octaazacyclotetradeca-2,9-diene-1,4,8,11-tetraido (OIM) ligand. Although describable as a Werner Mn(V) complex, analysis by X-ray diffraction, magnetic measurements, X-ray photoelectron spectroscopy, cyclic voltammetry, and density functional theory calculations suggest an electronic structure consisting of a Mn(III) metal center with a noninnocent OIM diradical ligand. The resulting complex, (OIM)Mn(NH tBu), reacts via proton-coupled electron transfer (PCET) with phenols to form phenoxyl radicals, with dihydroanthracene to form anthracene, and with (2,4-di tert-butyltetrazolium-5-yl)amide to extrude a tetrazyl radical. PCET from the latter generates the isolable corresponding one-electron reduced compound with a neutral, zwitterionic axial 2,4-di tert-butyltetrazolium-5-yl)amido ligand. Electron paramagnetic resonance and density functional theoretical analyses suggest an electronic structure wherein the manganese atom remains Mn(III) and the OIM ligand has been reduced by one electron to a monoradical noninnocent ligand. The result indicates PCET processes whereby the proton is transferred to the axial ligand to extrude tBuNH2, the electron is transferred to the equatorial ligand, and the central metal remains relatively unperturbed.
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Complexos de Coordenação/química , Compostos Macrocíclicos/química , Manganês/química , Nitrogênio/química , Prótons , Transporte de Elétrons , Ligantes , Modelos Moleculares , Conformação MolecularRESUMO
New regimes of energy density in energetic materials may be achieved by replacement of oxidizing nitro groups with stronger oxidants such as oxychlorine species. We report the energetic material 1,3-di-tert-butyltetrazolium-5-imidoperchloratomanganese(II) 2, which crystallizes as an oligomeric cubane cluster. Bomb calorimetry on the amorphous, solvent-free phase gives an energy density of at least 40±3â MJ L- , higher than hydrocarbon combustion in air, more than twice that of traditional energetic nitramines, and ≈70 % higher than that of the unmetalated tetrazolium perchlorate salt without metal linkage. The effects of solid-state structure, charge, and lattice energy on the energy of 2 are discussed.
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Notch receptor-ligand interactions are critical for cell proliferation, differentiation and survival; however, the role of Notch signalling in psoriasis remains to be elucidated. Serum amyloid A (A-SAA) is an acute-phase protein with cytokine-like properties, regulates cell survival pathways and is implicated in many inflammatory conditions. To examine the role of Notch-1 signalling in the pathogenesis of psoriasis, Notch-1, DLL-4, Jagged-1, Hrt-1/Hrt-2, A-SAA, Factor VIII and vascular endothelial growth factor (VEGF) mRNA and/or protein expression in psoriasis skin biopsies, serum and dHMVEC were assessed by immunohistology, dual-immunofluorescence, real-time PCR, ELISA and Western blotting. A-SAA-induced angiogenesis and invasion in the presence of Notch-1 siRNA was assessed by matrigel tube formation assays and Transwell invasion assay. Increased Notch-1, its ligand DLL-4 and Hrt-1 expression were demonstrated in lesional skin compared with non-lesional skin, with greatest expression observed in the dermal vasculature (P < 0.05). Dual-immunofluorescent staining demonstrated co-localization of Notch-1 to endothelial cell marker Factor VIII. A significant increase in A-SAA levels was demonstrated in psoriasis serum compared with healthy control serum (P < 0.05), and A-SAA expression was higher in lesional skin compared with non-lesional. In dHMVEC, A-SAA significantly induced Jagged-1, Hrt-1 and VEGF mRNA expression (P < 0.05) and activated Notch-1 IC indicative of transcriptional regulation. In contrast, A-SAA significantly inhibited DLL-4 mRNA expression (P < 0.05). Finally A-SAA-induced angiogenesis and invasion were inhibited by Notch-1 siRNA (P < 0.05). Notch receptor-ligand interactions mediate vascular dysfunction in psoriasis and may represent a potential therapeutic target.
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Células Endoteliais/patologia , Neovascularização Patológica/patologia , Psoríase/patologia , Receptor Notch1/fisiologia , Adulto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Ligação ao Cálcio/biossíntese , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ciclo Celular/biossíntese , Proteínas de Ciclo Celular/genética , Células Cultivadas , Fator VIII/análise , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteína Jagged-1 , Masculino , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Microvasos/patologia , Pessoa de Meia-Idade , Psoríase/metabolismo , Interferência de RNA , RNA Mensageiro/biossíntese , RNA Interferente Pequeno/farmacologia , Receptor Notch1/antagonistas & inibidores , Receptor Notch1/genética , Proteínas Serrate-Jagged , Proteína Amiloide A Sérica/fisiologia , Transdução de Sinais , Adulto JovemRESUMO
BACKGROUND: In preparing novice anesthesiologists to perform their first ultrasound-guided axillary brachial plexus blockade, we hypothesized that virtual reality simulation-based training offers an additional learning benefit over standard training. We carried out pilot testing of this hypothesis using a prospective, single blind, randomized controlled trial. METHODS: We planned to recruit 20 anesthesiologists who had no experience of performing ultrasound-guided regional anesthesia. Initial standardized training, reflecting current best available practice was provided to all participating trainees. Trainees were randomized into one of two groups; (i) to undertake additional simulation-based training or (ii) no further training. On completion of their assigned training, trainees attempted their first ultrasound-guided axillary brachial plexus blockade. Two experts, blinded to the trainees' group allocation, assessed the performance of trainees using validated tools. RESULTS: This study was discontinued following a planned interim analysis, having recruited 10 trainees. This occurred because it became clear that the functionality of the available simulator was insufficient to meet our training requirements. There were no statistically significant difference in clinical performance, as assessed using the sum of a Global Rating Score and a checklist score, between simulation-based training [mean 32.9 (standard deviation 11.1)] and control trainees [31.5 (4.2)] (p = 0.885). CONCLUSIONS: We have described a methodology for assessing the effectiveness of a simulator, during its development, by means of a randomized controlled trial. We believe that the learning acquired will be useful if performing future trials on learning efficacy associated with simulation based training in procedural skills. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01965314. Registered October 17th 2013.
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Bloqueio do Plexo Braquial/métodos , Bloqueio do Plexo Braquial/normas , Competência Clínica/normas , Simulação por Computador/normas , Ultrassonografia de Intervenção/métodos , Ultrassonografia de Intervenção/normas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Desempenho Psicomotor/fisiologia , Método Simples-Cego , Adulto JovemRESUMO
OBJECTIVE: To investigate the relationship between acute-phase serum amyloid A (A-SAA) and joint destruction in inflammatory arthritis. METHODS: Serum A-SAA and C-reactive protein (CRP) levels, the erythrocyte sedimentation rate (ESR), and levels of matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-3, MMP-9, MMP-13, tissue inhibitor of metalloproteinases 1 (TIMP-1), vascular endothelial growth factor (VEGF), and type I and type II collagen-generated biomarkers C2C and C1,2C were measured at 0-3 months in patients with inflammatory arthritis commencing anti-tumor necrosis factor α (anti-TNFα) therapy and were correlated with 1-year radiographic progression. The effects of A-SAA on MMP/TIMP expression on RA fibroblast-like synoviocytes (FLS), primary human chondrocytes, and RA/psoriatic arthritis synovial explant cultures were assessed using real-time polymerase chain reaction, enzyme-linked immunosorbent assay, antibody protein arrays, and gelatin zymography. RESULTS: Serum A-SAA levels were significantly (P < 0.05) correlated with MMP-3, the MMP-3:TIMP-1 ratio, C1,2C, C2C, and VEGF. The baseline A-SAA level but not the ESR or the CRP level correlated with the 28-joint swollen joint count and was independently associated with 1-year radiographic progression (P = 0.038). A-SAA increased MMP-1, MMP-3, MMP-13, and MMP/TIMP expression in RA FLS and synovial explants (P < 0.05). In chondrocytes, A-SAA induced MMP-1, MMP-3, and MMP-13 messenger RNA and protein expression (all P < 0.01), resulting in a significant shift in MMP:TIMP ratios (P < 0.05). Gelatin zymography revealed that A-SAA induced MMP-2 and MMP-9 activity. Blockade of the A-SAA receptor SR-B1 (A-SAA receptor scavenger receptor-class B type 1) inhibited MMP-3, MMP-2, and MMP-9 expression in synovial explant cultures ex vivo. Importantly, we demonstrated that A-SAA has the ability to induce TNFα expression in RA synovial explant cultures (P < 0.05). CONCLUSION: A-SAA may be involved in joint destruction though MMP induction and collagen cleavage in vivo. The ability of A-SAA to regulate TNFα suggests that A-SAA signaling pathways may provide new therapeutic strategies for the treatment of inflammatory arthritis.
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Antirreumáticos/uso terapêutico , Artrite Reumatoide/metabolismo , Progressão da Doença , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Proteína Amiloide A Sérica/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adolescente , Adulto , Idoso , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Colágeno Tipo II/metabolismo , Feminino , Seguimentos , Articulações do Pé/diagnóstico por imagem , Articulação da Mão/diagnóstico por imagem , Humanos , Masculino , Metaloproteinases da Matriz/metabolismo , Pessoa de Meia-Idade , Radiografia , Líquido Sinovial/metabolismo , Membrana Sinovial/diagnóstico por imagem , Membrana Sinovial/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Proteins frequently function in high-order complexes. Defining protein-protein interactions is essential to acquiring a full understanding of their activity and regulation. Proximity biotinylation has emerged as a highly specific approach to capture transient and stable interactions in living cells or organisms. Proximity biotinylation exploits promiscuous biotinylating enzymes fused to a bait protein, resulting in the biotinylation of adjacent endogenous proteins. Biotinylated interactors are purified under very strict conditions and identified by mass spectrometry to obtain a high-confidence list of candidate binding partners. AirID is a recently described biotin ligase specifically engineered for proximity labeling. This protocol details proximity biotinylation by AirID, using protein complexes that form during a type I interferon response as an example. It covers the construction and validation of AirID fusion proteins and the enrichment and identification of biotinylated interactors. We describe a variation on the protocol using splitAirID. In this case, AirID is split into two inactive fragments and ligase activity is only restored upon dimerization of the bait proteins. This permits selective detection of proteins that interact with homo- or heterodimeric forms of the bait. The protocol considers design strategies, optimization, and the properties of different biotin ligases to identify optimal conditions for each experimental question. We also discuss common pitfalls and how to troubleshoot them. These approaches allow proximity biotinylation to be a powerful tool for defining protein interactomes. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Construction and functional validation of AirID fusion proteins Alternate Protocol: Construction and functional validation of splitAirID fusion proteins Support Protocol: Western blot for biotinylated proteins Basic Protocol 2: Biotinylation, enrichment, and identification of protein interactors.
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Biotina , Proteínas , Biotina/química , Biotinilação , Proteínas/química , Western Blotting , LigasesRESUMO
The failure of the immune response to clear the Hepatitis C virus (HCV) results in chronic inflammation that leads to liver cirrhosis. In general, women have a better prognosis than men and this may be associated with increased levels of anti-inflammatory mediators that are positively regulated by female sex hormones. Our aim was to determine if a cohort of Irish women who acquired infection through administration of HCV genotype 1b-contaminated anti-D immunoglobulin from a single source, had altered levels of circulating cytokine levels compared to women who spontaneously resolved infection, men with HCV infection or age-matched healthy controls. Twenty post-menopausal women and 20 men with chronic HCV infection (genotype 1), 20 post-menopausal women who resolved infection and age and sex-matched controls were recruited for the study. Levels of circulating cytokines were assessed by ELISA. Circulating IL-6, Oncostatin-M, TNF-α, CXCL10, CCL18, VEGF and GM-CSF did not differ between groups. Both men and women with HCV had significantly elevated levels of circulating Osteoprotegerin (OPG). However, male but not female HCV patients had elevated levels of circulating Matrix Metalloprotease-9 (MMP-9). An increased OPG: MMP-9 ratio in the circulation of females compared to males with chronic HCV may help protect against HCV-associated liver disease and explain the slow progress of liver disease in this cohort.
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Hepatite C Crônica/sangue , Hepatite C Crônica/enzimologia , Metaloproteinase 9 da Matriz/sangue , Osteoprotegerina/sangue , Pós-Menopausa/sangue , Idoso , Estudos de Casos e Controles , Citocinas/sangue , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Genótipo , Hepacivirus/genética , Humanos , Mediadores da Inflamação/sangue , Fígado/enzimologia , Fígado/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
If VR-based medical training and assessment is to improve patient care and safety (i.e. a genuine health gain), it has to be based on clinically relevant measurement of performance. Metrics on errors are particularly useful for capturing and correcting undesired behaviors before they occur in the operating room. However, translating clinically relevant metrics and errors into meaningful system design is a challenging process. This paper discusses how an existing task and error analysis was translated into the system design of a VR-based training and assessment environment for Ultrasound Guided Regional Anesthesia (UGRA).
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Anestesia por Condução/métodos , Anestesiologia/educação , Instrução por Computador/métodos , Injeções/métodos , Agulhas , Ultrassonografia de Intervenção/métodos , Interface Usuário-Computador , Anestesia por Condução/instrumentação , Anestésicos/administração & dosagem , Simulação por Computador , Humanos , Injeções/instrumentação , Modelos Biológicos , Ensino/métodosRESUMO
Rotaviruses are 11-segmented double-stranded RNA viruses and important causes of acute gastroenteritis in young children. To investigate the functions of specific viral proteins during the rotavirus lifecycle, temperature-sensitive (ts) mutants were previously created using a cultivatable simian strain (SA11) and chemical mutagenesis. These ts SA11 mutants replicate more efficiently at the permissive temperature of 31 °C than at the non-permissive temperature of 39 °C. Prototype strains SA11-tsC, SA11-tsF, and SA11-tsG were mapped to the genes encoding structural proteins VP1, VP2, and VP6, respectively, and putative ts lesions were identified using Sanger sequencing. However, additional background mutations in their genomes had hampered validation of the ts lesions and confounded their use in mechanistic studies. Here, we employed plasmid only-based reverse genetics to engineer recombinant (r) SA11 rotaviruses containing only the putative ts lesions of SA11-tsC (L138P change in VP1), SA11-tsF (A387D change in VP2) or SA11-tsG (S10T, D13H, and A121G changes in VP6). For simplicity, we refer to these newly-engineered, isogenic viruses as rSA11-tsVP1, rSA11-tsVP2, and rSA11-tsVP6. Single-cycle growth assays revealed that these mutants indeed exhibit ts phenotypes with significantly diminished titers (>1.5-logs) at 39 °C versus 31 °C. The rSA11 ts mutants proved genetically stable at the population-level following 3 sequential passages at 39 °C, but individual revertant clones were detected in plaque assays. Heat sensitivity experiments showed that pre-incubation of rSA11-tsVP1 or rSA11-tsVP2, but not rSA11-tsVP6, at 39 °C diminished replication at 31 °C. This result indicates that the ts lesions in VP1 and VP2 affect the incoming virion but those in VP6 affect a later stage of the viral lifecycle. In silico molecular dynamics simulations predicted temperature-dependent, long-range effects of the S10T, D13H, and/or A121G changes on the VP6 structure. Altogether, our results confirm the ts lesions of the original SA11-tsC, SA11-tsF, and SA11-tsG mutants, provide a new set of isogenic strains for investigating aspects of rotavirus replication, and shed light on how the ts lesions might impact VP1, VP2, or VP6 functions.
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Rotavirus , Engenharia Genética , Rotavirus/genética , Temperatura , Proteínas Virais/genética , VírionRESUMO
The domino Michael/Mannich (DMM) annulation reaction between an N-sulfinyl lithiodienamine and an electrophilic alkene is developed for the synthesis of chiral 2-amino cyclohexenes, a key building block in asymmetric synthesis. The DMM reaction proceeds at low temperature while maintaining the stereochemical fidelity. The product functionalized amino cyclohexenes, here obtained in 55-82% yield with diastereomeric ratios as high as >19:1.
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In this issue of Structure, Kaelber et al. (2020) use cryo-EM and synthetic decoy maps to reveal the patterning of 10 polymerase complexes within FAKV, a Reoviridae family member containing 9 genome segments. Their findings support a model for FAKV assembly that has implications for the entire Reoviridae family.
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Reoviridae , Microscopia Crioeletrônica , VírionRESUMO
Ward-based violence is the most significant cause of reported safety incidents at East London NHS Foundation Trust (ELFT). It impacts on patient and staff safety, well-being, clinical care and the broader hospital community in various direct and indirect ways. The contributing factors are varied and complex. Several factors differentiate the forensic setting, which has been identified as a particularly stressful work environment. Staff must constantly balance addressing therapeutic needs with robust risk management in a complex patient cohort. ELFT identified reducing inpatient physical violence on mental health wards as a major quality improvement (QI) priority. The aim was to use a QI methodology to reduce incidents of inpatient violence and aggression across two secure hospital sites by at least 30% between July 2016 and March 2018. Collaborative learning was central to this project. It sought to foster a culture of openness within the organisation around violence and to support service users and staff to work together to understand and address it. A QI methodology was applied in medium and low secure inpatient settings. A change bundle was tested for effectiveness, which included: safety huddles, safety crosses and weekly community safety discussions. Operational definitions for non-physical violence, physical violence and sexual harassment were developed and used. Reductions of 8% and 16.6% in rates of physical and non-physical violent incidents, respectively, were achieved and sustained. Compared with baseline, this equated to one less incident of physical and 17 less of non-physical violence per week averaged across seven wards. Three wards achieved at least a 30% reduction in incidents of physical violence per week. Five wards achieved at least a 30% reduction in incidents of non-physical violence per week. This collaborative brought significant improvements and a cultural shift towards openness around inpatient violence.
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Psiquiatria Legal/métodos , Melhoria de Qualidade , Violência no Trabalho/prevenção & controle , Psiquiatria Legal/normas , Psiquiatria Legal/tendências , Humanos , Londres , Gestão de Riscos/métodos , Medicina Estatal/organização & administração , Medicina Estatal/tendências , Violência no Trabalho/psicologia , Violência no Trabalho/tendênciasRESUMO
OBJECTIVE: We performed a randomized, controlled trial comparing low-dose ultrasound-guided axillary block with general anesthesia evaluating anesthetic and perioperative analgesic outcomes. METHODS: Patients were randomized to either ultrasound-guided axillary block or general anesthesia. Ultrasound-guided axillary block was performed using a needle-out-of-plane approach. Up to 5 mL of local anesthetic injectate (equal parts 2% lidocaine with 1:200,000 epinephrine and 0.5% bupivacaine with 7.5 mg/mL clonidine) was injected after identifying the median, ulnar, radial, and musculocutaneous nerves. A maximum of 20 mL local anesthetic injectate was used. General anesthesia was standardized to include induction with fentanyl and propofol, maintenance with sevoflurane in an oxygen/nitrous oxide mixture. Pain scores were measured in the recovery room and at 2, 6, 24, 48 h, and 7 days. Ability to bypass the recovery room and time to achieve hospital discharge criteria were also assessed. RESULTS: All ultrasound-guided axillary block patients achieved satisfactory anesthesia. The ultrasound-guided axillary block group had lower visual analog scale pain scores in the recovery room (0.3 [1.3] vs 55.8 [36.5], P < 0.001), and visual rating scale pain scores at 2 h (0.3 [1.3] vs 45 [29.6], P < 0.001), and at 6 h (1.1 [2.7] vs 4 [2.8], P < 0.01). All ultrasound-guided axillary block patients bypassed the recovery room and attained earlier hospital discharge criteria (30 min vs 120 min 30/240 P < 0.0001 median [range]). CONCLUSIONS: Ultrasound-guided axillary brachial plexus block with 20 mL local anesthetic mixture provided satisfactory anesthesia and superior analgesia after upper limb trauma surgery when compared with general anesthesia.