RESUMO
The study of a desmoglein 2 murine model of arrhythmogenic cardiomyopathy revealed cardiac inflammation as a key early event leading to fibrosis. Arrhythmogenic cardiomyopathy (AC) is an inherited heart muscle disorder leading to ventricular arrhythmias and heart failure due to abnormalities in the cardiac desmosome. We examined how loss of desmoglein 2 (Dsg2) in the young murine heart leads to development of AC. Apoptosis was an early cellular phenotype, and RNA sequencing analysis revealed early activation of inflammatory-associated pathways in Dsg2-null (Dsg2-/-) hearts at postnatal day 14 (2 weeks) that were absent in the fibrotic heart of adult mice (10 weeks). This included upregulation of iRhom2/ADAM17 and its associated pro-inflammatory cytokines and receptors such as TNFα, IL6R and IL-6. Furthermore, genes linked to specific macrophage populations were also upregulated. This suggests cardiomyocyte stress triggers an early immune response to clear apoptotic cells allowing tissue remodelling later on in the fibrotic heart. Our analysis at the early disease stage suggests cardiac inflammation is an important response and may be one of the mechanisms responsible for AC disease progression.
Assuntos
Arritmias Cardíacas/imunologia , Cardiomiopatias/imunologia , Desmogleína 2/metabolismo , Fibrose/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Inflamação/complicações , Animais , Modelos Animais de Doenças , Humanos , Inflamação/patologia , CamundongosRESUMO
In this paper a novel approach to the development of the architecture of a knowledge-based decision support system for the management of patients with cancer of the breast is described. Its initial design and subsequent realization in a prototype version was facilitated by examining closely the overall clinical task and identifying its associated activities and related knowledge. Implementation in KEE highlights the value of rigorous conceptual modelling that leads to a design able to assess treatment response and disease progression as well as providing specific therapy advice. The approach is general and may be applied to the development of decision support systems for other areas of cancer and medicine.
Assuntos
Inteligência Artificial , Neoplasias da Mama/diagnóstico , Técnicas de Apoio para a Decisão , Diagnóstico por Computador/instrumentação , Sistemas Inteligentes , Terapia Assistida por Computador/instrumentação , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Sistemas Computacionais , Feminino , Humanos , Estadiamento de Neoplasias , Prognóstico , SoftwareRESUMO
The condensation reactions of activated nucleotides, ImpN or 2-MeImpN, with the self-complementary ribo-octanucleotide GCGCGCGC or with the partially self-complementary heptanucleotide GCGCGCG were studied. The template-directed reaction of 2-MeImpC with the heptamer yields the 3'-5' octamer as the main product. All other reactions yield 2'-5'-linked octamers and pyrophosphates as major products. Surprisingly, 2-MeImpG facilitates the reaction of 2-MeImpC with the heptamer. Procedures for the analysis by gel electrophoresis of the oligomeric products obtained in reactions of this kind are described.
Assuntos
Oligorribonucleotídeos , Moldes Genéticos , Autorradiografia , Sequência de Bases , Indicadores e Reagentes , Oligorribonucleotídeos/síntese química , Radioisótopos de Fósforo , Relação Estrutura-AtividadeRESUMO
When aqueous solutions of adenosine-5'-mono-, di-, or triphosphates are treated with a water soluble carbodiimide the major product is the expected diadenosine-5'-5'-polyphosphate. The yields of these pyrophosphates are greatly increased in the presence of the Mg2+ ion. Adenosine-5'-tetraphosphate behaves differently. The major product is adenosine-5'-monophosphate. We believe that this hydrolysis occurs via a cyclic trimetaphosphate intermediate.
