Subject(s)
Bone Diseases/veterinary , Dog Diseases/physiopathology , Nervous System Diseases/veterinary , Orthopedics/veterinary , Posture , Animals , Bone Diseases/physiopathology , Bone Diseases/rehabilitation , Dog Diseases/therapy , Dogs , Mitral Valve Insufficiency , Nervous System Diseases/physiopathology , Nervous System Diseases/rehabilitationABSTRACT
The effects of hyperpnea on parenchymal lung mechanics are unknown, but they may contribute to the resultant airflow limitation commonly seen in asthma. To investigate these effects, we measured the following parameters in seven asthmatic and six normal subjects before and after 5 min of hyperpnea: specific conductance, upstream resistance, static compliance, the coefficient of retraction, lung volumes, lung hysteresis, and the ratio of maximal to partial flow rates (the M:P ratio, an indicator of the effect of deep inhalation on airflow, and a measure of relative airway and parenchymal hysteresis). In addition to a central effect on the airways, as shown by significant falls in specific conductance, hyperpnea in asthmatics, but not in normal subjects, resulted in significant increases in residual volume and pressure-volume hysteresis, suggestive of changes in parenchymal lung mechanics. The M:P ratio also increased in the asthmatics, consistent with greater increases in airway than in parenchymal hysteresis after hyperpnea. We conclude that hyperpnea has significant effects on the lung parenchyma that contribute to airflow limitation in asthmatics, and we hypothesize that these effects may be due to alterations in peripheral airway smooth muscle tone and surfactant function.
Subject(s)
Asthma/physiopathology , Respiratory Mechanics/physiology , Adult , Bronchial Provocation Tests , Bronchoconstriction/physiology , Bronchoconstrictor Agents , Case-Control Studies , Female , Humans , Male , Methacholine Chloride , Muscle, Smooth/physiopathology , Pulmonary Ventilation/physiologyABSTRACT
The ret oncogene frequently has been found activated in papillary thyroid carcinomas. A previous characterization of ret activation revealed recombination of its tyrosine kinase domain and sequences derived from an uncharacterized locus (D10S170). The mechanism leading to this recombination was identified as a paracentric inversion of the long arm of chromosome 10, inv(10)(q11.2q21), with the breakpoints occurring where ret and D10S170 were mapped. To further characterize the activation of ret in papillary thyroid carcinomas, we have now isolated and sequenced a second type of ret oncogenic rearrangement not involving the D10S170 locus. The nucleotide sequence indicated that the transforming activity was created by the fusion of the ret tyrosine kinase domain with part of the RI alpha regulatory subunit of protein kinase A (PKA). This is the first example of an oncogenic activity involving a PKA gene. PKA is the main intracellular cyclic AMP receptor, and its RI alpha subunit gene is located on chromosome 17q. RI alpha-ret transcripts encode two isoforms of the chimeric protein (p76 and p81), which display constitutive tyrosine phosphorylation as well as a tyrosine kinase enzymatic activity. Under nonreducing conditions, both isoforms are found in a dimeric configuration because of both homo- and heterodimer formation. Thus, the in vivo activation of ret in human papillary thyroid carcinomas is provided by the fusion of its tyrosine kinase domain with different genes and can be mediated by different mechanisms of gene rearrangement.
Subject(s)
Cell Transformation, Neoplastic/genetics , Drosophila Proteins , Protein Kinases/genetics , Protein-Tyrosine Kinases/genetics , Proto-Oncogene Proteins/genetics , Receptor Protein-Tyrosine Kinases , Thyroid Neoplasms/genetics , 3T3 Cells , Amino Acid Sequence , Animals , Base Sequence , Blotting, Western , Cloning, Molecular , DNA/genetics , Gene Expression Regulation , Gene Rearrangement , Mice , Molecular Sequence Data , Oligodeoxyribonucleotides/chemistry , Phosphotyrosine , Proto-Oncogene Proteins c-ret , Recombinant Fusion Proteins/genetics , Tyrosine/analogs & derivatives , Tyrosine/metabolismABSTRACT
We report the 9210 bp sequence from a segment of yeast chromosome III cloned from strain AB972 in lambda PM3270. Analysis of this sequence and its comparison with the one derived from the corresponding segment of strain XJ24-24A revealed that the AB972 region contains a duplication of about 2 kb and a Ty element, which are not found in XJ24-24A and cause a quite significant rearrangement of the whole region. We performed functional analysis of YCR28, the largest open reading frame we found in both AB972 and XJ24-24A. YCR28 encodes a putative protein of 512 amino acids with some similarities to yeast allontoate permease. Its disruption does not cause any detectable phenotype on rich medium or on allantoate medium, while we observed a strain-dependent effect on sensitivity to amino acid balance and to 3-aminotriazole, when cells were grown in synthetic medium.
