TSH receptor and Gs-alpha gene mutations in the pathogenesis of toxic thyroid adenomas--a note of caution

The detection of a constitutive activation of the AC cascade by TSH-R and Gs alpha mutations in a number of TTAs should not distract from the large gap in our understanding of the pathogenesis of thyroid tumors. TTAs form only a minor fraction of all thyroid nodules, and even within this small subgroup, activating mutations have been found regionally with a highly variable incidence. If activating mutations were the sole and only cause of TTAs, a homogeneous functional and morphological response of all thyrocytes would ensue. This, however, is not the case. Rather, severe disturbances of the Gs protein-AC cascade regularly occur in TTAs. Even within thyroids affected by activating TSH-R germline mutations, some cell clones proliferate at a faster rate than others, causing nodular growth with time. Moreover, not only functional, but also morphological heterogeneity very frequently evolves even in clonal adenomas. The natural heterogeneity among individual thyrocytes may account for a different functional and proliferative response among cells affected by identical mutations or any other gain-of-function event. The recent findings in toxic adenomas must be taken together with the fact that, in the large majority of all thyroid nodules, iodine metabolism is by no means enhanced, but diminished or absent and that, in this type of tumor, no consistent pattern of growth-stimulating mutational events has yet been identified. The nature, the precise temporal sequence and interaction of the genetic, cytogenetic, and environmental events that cause the very common and often autonomous nodular growth of only a few distinct cell populations within the human thyroid gland remain largely unknown.     

Differential K+ channel clustering activity of PSD-95 and SAP97, two related membrane-associated putative guanylate kinases

The molecular mechanisms underlying the clustering and localization of K+ channels in specific microdomains on the neuronal surface are largely unknown. The Shaker subclass of voltage-gated K+ channel alpha-subunits interact through their cytoplasmic C-terminus with a family of membrane-associated putative guanylate kinases, including PSD-95 and SAP97. We show here that heterologous coexpression of either sap97 or PSD-95 with various Shaker-type subunits results in the coclustering of these proteins with the K+ channels. Mutation of the C-terminal sequence (-ETDV) of the Shaker subunit Kv1.4 abolishes its binding to, and prevents its clustering with, SAP97 and PSD-95. Whereas PSD-95 induces plaque-like clusters of K+ channels at the cell surface; however, SAP97 coexpression results in the formation of large round intracellular aggregates into which both SAP97 and the K+ channel proteins are colocalized. The efficiency of surface clustering by PSD-95 varies with different Shaker subunits: striking Kv1.4 clustering occurs in > 60% of cotransfected cells, whereas Kv1.1 and Kv1.2 form convincing clusters with PSD-95 only in approximately 10% of cells.     

Computational study of packing a collagen-like molecule: quasi-hexagonal vs "Smith" collagen microfibril model

The lateral packing of a collagen-like molecule, CH3CO-(Gly-L-Pro-L-Pro)4-NHCH3, has been examined by energy minimization with the ECEPP/3 force field. Two current packing models, the Smith collagen microfibril twisted equilateral pentagonal model and the quasi-hexagonal packing model, have been extensively investigated. In treating the Smith microfibril model, energy minimization was carried out on various conformations including those with the symmetry of equivalent packing, i.e., in which the triple helices were arranged equivalently with respect to each other. Both models are based on the experimental observation of the characteristic axial periodicity, D = 67 nm, of light and dark bands, indicating that, if any superstructure exists, it should consist of five triple helices. The quasi-hexagonal packing structure is found to be energetically more favorable than the Smith microfibril model by as much as 31.2 kcal/mol of five triple helices. This is because the quasi-hexagonal packing geometry provides more nonbonded interaction possibilities between triple helices than does the Smith microfibril geometry. Our results are consistent with recent x-ray studies with synthetic collagen-like molecules and rat tail tendon, in which the data were interpreted as being consistent with either a quasi-hexagonal or a square-triangular structure.     

Restoration of masonry facades, renders and final coats in a severe climate

The restoration of relatively old masonry buildings, 1870-1920, represents about 119930 flats and offices in the 4-5 largest cities in Norway. Driving rain and a severe climate are the key factors for deterioration. The paper describes a case study at the city campus of the University of Oslo.