RESUMEN
Critical mutations in the membrane-spanning domains of proteins cause many human diseases. We report the expression in Escherichia coli of helix-loop-helix segments of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel domain in milligram quantities. Analysis of gel migration patterns of these constructs, in conjunction with circular dichroism spectroscopy, demonstrate that a neutral-to-charged, CF-phenotypic point mutation of a hydrophobic residue (V232D) in the CFTR transmembrane (TM) helix 4 induces a hydrogen bond with neighboring wild type Gln 207 in TM helix 3. As an electrostatic crosslink within a hydrocarbon phase, such a hydrogen bond could alter the normal assembly and alignment of CFTR TM helices and/or impede their movement in response to substrate transport. Our results imply that membrane proteins may be vulnerable to loss of function through formation of membrane-buried interhelical hydrogen bonds by partnering of proximal polar side chains.
Asunto(s)
Membrana Celular/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/química , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Secuencia de Aminoácidos , Sustitución de Aminoácidos/genética , Membrana Celular/química , Dicroismo Circular , Simulación por Computador , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Detergentes/farmacología , Electroforesis en Gel de Poliacrilamida , Secuencias Hélice-Asa-Hélice , Humanos , Enlace de Hidrógeno , Modelos Moleculares , Datos de Secuencia Molecular , Peso Molecular , Fenotipo , Mutación Puntual/genética , Estructura Secundaria de Proteína/efectos de los fármacos , Estructura Terciaria de Proteína , Electricidad Estática , TermodinámicaRESUMEN
The history of the Forensic Psychiatric Institute (FPI) of British Columbia is reviewed through a description of the 3,500 remand admissions to the Institute between 1975 and 1990. Individuals charged with only minor offences and those who were certified under the Mental Health Act 1983 and subsequently had their charges stayed are examined in more detail. Results appear to suggest that these two groups are particularly vulnerable to the process of criminalization. The possible link between criminalization of the mentally ill and deinstitutionalization is explored.
Asunto(s)
Internamiento Obligatorio del Enfermo Mental/legislación & jurisprudencia , Derecho Penal/legislación & jurisprudencia , Psicología Criminal , Psiquiatría Forense/legislación & jurisprudencia , Hospitales Psiquiátricos/legislación & jurisprudencia , Colombia Británica , Humanos , Trastornos Mentales/diagnósticoRESUMEN
The current Canadian legislation regarding dangerous offenders is reviewed, with specific emphasis on the role of the required psychiatric testimony. It is suggested that, although this legislation as it is currently formulated could be viewed as an attempt to broaden the insanity defence, and permit the diversion of mentally ill offenders from a punitive to a therapeutic milieu, it enables the preventive detention of recidivist offenders. Some fundamental ethical issues which follow from this are identified, together with the issues which have dominated expert testimony in hearings held in British Columbia during the past 13 years.