RESUMO
Archaea are uniquely adapted to thrive in harsh environments, and one of these adaptations involves the archaeal membrane lipids, which are characterized by their isoprenoid alkyl chains connected via ether linkages to glycerol 1-phosphate. The membrane lipids of the thermophilic and acidophilic euryarchaeota Thermoplasma volcanium are exclusively glycerol dibiphytanyl glycerol tetraethers. The first committed step in the biosynthetic pathway of these archaeal lipids is the formation of the ether linkage between glycerol 1-phosphate and geranylgeranyl diphosphate, and is catalyzed by the enzyme geranylgeranylglyceryl phosphate synthase (GGGPS). The 1.72â Å resolution crystal structure of GGGPS from T. volcanium (TvGGGPS) in complex with glycerol and sulfate is reported here. The crystal structure reveals TvGGGPS to be a dimer, which is consistent with the absence of the aromatic anchor residue in helix α5a that is required for hexamerization in other GGGPS homologs; the hexameric quaternary structure in GGGPS is thought to provide thermostability. A phylogenetic analysis of the Euryarchaeota and a parallel ancestral state reconstruction investigated the relationship between optimal growth temperature and the ancestral sequences. The presence of an aromatic anchor residue is not explained by temperature as an ecological parameter. An examination of the active site of the TvGGGPS dimer revealed that it may be able to accommodate longer isoprenoid substrates, supporting an alternative pathway of isoprenoid membrane-lipid synthesis.
Assuntos
Alquil e Aril Transferases/química , Proteínas Arqueais/química , Dimetilaliltranstransferase/química , Éteres Fosfolipídicos/metabolismo , Thermoplasma/enzimologia , Domínio Catalítico , Multimerização Proteica , Estrutura Quaternária de ProteínaRESUMO
The ability of 5-aminolaevulinic acid and some of its esterified derivatives to induce porphyrin accumulation has been examined in CaNT murine mammary carcinoma cells growing in culture and as tumours in vivo. Topical or intravenous administration of 5-aminolaevulinic acid-esters to mice bearing subcutaneous tumours produced lower porphyrin levels in the tumour than an equimolar dose of 5-aminolaevulinic acid. Reducing the dose of intravenous hexyl- or benzyl-ALA and topical hexyl-5-aminolaevulinic acid resulted in a dose-dependent reduction in porphyrin accumulation. A number of normal tissues accumulated higher concentrations of porphyrins than tumour tissue following intravenous administration of 5-aminolaevulinic acid-esters. Esterase activity in these normal tissues was greater than that in tumour tissue. In contrast to the situation in vivo, all of the 5-aminolaevulinic acid-esters examined were at least as effective as 5-aminolaevulinic acid when applied to cloned CaNT cells in vitro, with the drug concentration required for maximum porphyrin accumulation varying with ester chain-length. Tumour cells growing in culture released esterase activity into the medium. These findings suggest that the efficacy of 5-aminolaevulinic esters may vary depending on the esterase activity of the target tissue, and suggest caution when interpreting the findings of in vitro studies using these and similar prodrugs.
Assuntos
Ácido Aminolevulínico/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma/tratamento farmacológico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/biossíntese , Pró-Fármacos/uso terapêutico , Administração Cutânea , Ácido Aminolevulínico/administração & dosagem , Ácido Aminolevulínico/análogos & derivados , Ácido Aminolevulínico/farmacocinética , Ácido Aminolevulínico/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Carboxilesterase , Hidrolases de Éster Carboxílico/metabolismo , Carcinoma/metabolismo , Carcinoma/patologia , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Ésteres , Feminino , Injeções Intravenosas , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos CBA , Proteínas de Neoplasias/metabolismo , Fotoquimioterapia , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/farmacologia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Protoporfirinas/biossíntese , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
Intended to accommodate workers' personal needs and family commitments, FMLA has proved to be a headache for employers--even those with generous leave policies in place. Here are some tips avoiding the pitfalls.
Assuntos
Licença para Cuidar de Pessoa da Família/legislação & jurisprudência , Planos de Assistência de Saúde para Empregados/legislação & jurisprudência , Custos e Análise de Custo , Eficiência , Licença para Cuidar de Pessoa da Família/economia , Planos de Assistência de Saúde para Empregados/economia , Política Organizacional , Gestão de Recursos Humanos , Estados UnidosRESUMO
Provider-sponsored organizations say they keep third party players from meddling in the doctor-patient relationship. While their viability is uncertain, their focus on quality is raising the competitive stakes.
Assuntos
Redes Comunitárias/organização & administração , Relações Hospital-Paciente , Relações Médico-Paciente , Leis Antitruste , Redes Comunitárias/economia , Redes Comunitárias/normas , Atenção à Saúde/tendências , Competição Econômica/legislação & jurisprudência , Planos de Assistência de Saúde para Empregados/economia , Iowa , Minnesota , Garantia da Qualidade dos Cuidados de Saúde , Tennessee , Estados UnidosAssuntos
Prestação Integrada de Cuidados de Saúde , Hospitais , Habitação para Idosos , Idoso , Humanos , Massachusetts , Propriedade , Estados UnidosRESUMO
Will the IRS fix the MD recruitment rules? If hospitals are lucky, the rules on physician recruitment will all change soon. The IRS is about to come out with its first official pronouncement in this area in more than a decade; and hospitals, recruiters and lawyers are looking forward--with some concern--to the change.
Assuntos
Relações Comunidade-Instituição/economia , Hospitais Filantrópicos/legislação & jurisprudência , Corpo Clínico Hospitalar/legislação & jurisprudência , Seleção de Pessoal/legislação & jurisprudência , Impostos/legislação & jurisprudência , American Hospital Association , Relações Comunidade-Instituição/legislação & jurisprudência , Órgãos Governamentais , Planejamento Hospitalar/legislação & jurisprudência , Hospitais Filantrópicos/economia , Responsabilidade Legal , Política Organizacional , Planos de Incentivos Médicos/legislação & jurisprudência , Estados Unidos , Recursos HumanosRESUMO
Congress is debating the future of the popular, but expensive, Medicare program. The HMO community wants lawmakers to expand the options available to seniors.