RESUMO
Dominant mutations in ubiquitously expressed transfer RNA (tRNA) synthetase genes cause axonal peripheral neuropathy, accounting for at least six forms of Charcot-Marie-Tooth (CMT) disease. Genetic evidence in mouse and Drosophila models suggests a gain-of-function mechanism. In this study, we used in vivo, cell typespecific transcriptional and translational profiling to show that mutant tRNA synthetases activate the integrated stress response (ISR) through the sensor kinase GCN2 (general control nonderepressible 2). The chronic activation of the ISR contributed to the pathophysiology, and genetic deletion or pharmacological inhibition of Gcn2 alleviated the peripheral neuropathy. The activation of GCN2 suggests that the aberrant activity of the mutant tRNA synthetases is still related to translation and that inhibiting GCN2 or the ISR may represent a therapeutic strategy in CMT.
Assuntos
Doença de Charcot-Marie-Tooth/metabolismo , Glicina-tRNA Ligase/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Estresse Fisiológico , Tirosina-tRNA Ligase/metabolismo , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Animais , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/fisiopatologia , Modelos Animais de Doenças , Feminino , Deleção de Genes , Genes Dominantes , Glicina-tRNA Ligase/genética , Masculino , Camundongos , Camundongos Mutantes , Neurônios Motores/fisiologia , Biossíntese de Proteínas , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Medula Espinal/fisiopatologia , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genética , Estresse Fisiológico/fisiologia , Transcriptoma , Tirosina-tRNA Ligase/genéticaRESUMO
Sections of sterile all-silicone-, hydrogel/silver-all-silicone-, and hydrogel/silver-latex-Foley urinary catheters were exposed to suspensions of bacteria and Candida albicans associated with urinary tract infections. The adhesion of these microorganisms to the catheters was determined with a radiolabel-cell procedure and scanning electron microscopy. Anomalous data with the radiolabel procedure were produced with the hydrogel/silver-latex catheters for certain species. These aberrant data were related to adhesion on the untreated cut ends of the latex catheter. Radiolabel-cell-adhesion procedures that involve sections of coated materials may need to be supplemented with additional procedures such as scanning electron microscopy for valid interpretations of the data. Adhesion to the hydrogel/silver catheters by both Gram-positive- and Gram-negative bacteria most commonly associated with nosocomial urinary tract infections, including a strain of Pseudomonas aeruginosa noted for its superior adhesion capacity, was significantly lower than the adhesion to the control all-silicone catheter.
Assuntos
Aderência Bacteriana , Hidrogel de Polietilenoglicol-Dimetacrilato , Prata , Cateterismo Urinário/efeitos adversos , Infecções Urinárias/microbiologia , Candida albicans/patogenicidade , Bactérias Gram-Negativas/isolamento & purificação , Bactérias Gram-Negativas/patogenicidade , Bactérias Gram-Positivas/patogenicidade , Humanos , Técnicas In Vitro , Látex , Microscopia Eletrônica de Varredura , Silicones , Fatores de Tempo , Cateterismo Urinário/instrumentação , Infecções Urinárias/prevenção & controleAssuntos
Comportamento do Adolescente , Redes de Comunicação de Computadores , Promoção da Saúde , Adolescente , Atitude Frente a Saúde , Cognição , Participação da Comunidade , Tomada de Decisões , Liberdade , Educação em Saúde/métodos , Promoção da Saúde/métodos , Humanos , Aprendizagem , Assunção de Riscos , Abandono do Hábito de Fumar , Prevenção do Hábito de FumarRESUMO
The Persian Gulf War necessitated the activation of many Army Reserve and National Guard physicians, including a number in residency training. No prototype existed for the continued training of resident surgeons in a combat setting. The 159th Mobile Army Surgical Hospital (MASH) deployed in support of the Allied invasion of Iraq. A structured training program for two general surgery residents attached to the 159th MASH was developed and implemented. This program combined supervised operating room experience, perioperative management, morbidity and mortality conferences, and orthopedic grand rounds, all with careful professional documentation. A planned reading program could not be realized, due to the physical setting of wartime. Residents and attending staff interacted positively and the residents were able to continue their formal training as an integral part of the hospital. The model developed by the 159th MASH is a practical method of continuing structured resident training in a combat setting.
Assuntos
Cirurgia Geral/educação , Internato e Residência , Medicina Militar/educação , Militares , Guerra , Oriente Médio , Estados UnidosRESUMO
Partial misincorporation of Lys for Arg has been observed for the Arg residues of IGF-1 when the molecule is expressed in Escherichia coli using a synthetic gene with the low frequency AGA codon encoding all six Arg residues and yeast preferred codons encoding the remaining residues. The Lys for Arg substitution at these residues could not be detected when a gene containing E. coli preferred codons, with the codon CGT coding for all Arg residues, was used for the expression of the protein. Similarly, no misincorporation of Lys for Arg could be detected when a gene containing Escherichia coli preferred codons at all positions, except for an AGA codon at Arg (36), was utilized.