Resistance to thyroid hormone caused by a mutation in thyroid hormone receptor (TR)alpha 1 and TR alpha 2: clinical, biochemical, and genetic analyses of three related patients

Background The thyroid hormone receptor α gene (THRA) transcript is alternatively spliced to generate either thyroid hormone receptor (TR)α1 or a non-hormone-binding variant protein, TRα2, the function of which is unknown. Here, we describe the first patients identified with a mutation in THRA that affects both TRα1 and TRα2, and compare them with patients who have resistance to thyroid hormone owing to a mutation affecting only TRα1, to delineate the relative roles of TRα1 and TRα2. Methods We did clinical, biochemical, and genetic analyses of an index case and her two sons. We assessed physical and radiological features, thyroid function, physiological and biochemical markers of thyroid hormone action, and THRA sequence. Findings The patients presented in childhood with growth failure, developmental delay, and constipation, which improved after treatment with thyroxine, despite normal concentrations of circulating thyroid hormones. They had similar clinical (macrocephaly, broad faces, skin tags, motor dyspraxia, slow speech), biochemical (subnormal ratio of free thyroxine:free tri-iodothyronine [T3], low concentration of total reverse T3, high concentration of creatine kinase, mild anaemia), and radiological (thickened calvarium) features to patients with TRα1-mediated resistance to thyroid hormone, although our patients had a heterozygous mis-sense mutation (Ala263Val) in both TRα1 and TRα2 proteins. The Ala263Val mutant TRα1 inhibited the transcriptional function of normal receptor in a dominant-negative fashion. By contrast, function of Ala263Val mutant TRα2 matched its normal counterpart. In vitro, high concentrations of T3 restored transcriptional activity of Ala263Val mutant TRα1, and reversed the dominant-negative inhibition of its normal counterpart. High concentrations of T3 restored expression of thyroid hormone-responsive target genes in patient-derived blood cells. Interpretation TRα1 seems to be the principal functional product of the THRA gene. Thyroxine treatment alleviates hormone resistance in patients with mutations affecting this gene, possibly ameliorating the phenotype. These findings will help the diagnosis and treatment of other patients with resistance to thyroid hormone resulting from mutations in THRA. Funding Wellcome Trust, NIHR Cambridge Biomedical Research Centre, Marie Curie Actions, Foundation for Development of Internal Medicine in Europe

The H-sorption behaviour of ball-milled MgH2-5 mol.% FeF3 studied by in-situ small angle neutron scattering.

International audienceWe report on ball-milled MgH2 composite powder containing 5 mol.% FeF3, which were characterized by Small Angle Neutron Scattering (SANS) measurements carried out during in-situ H-2 absorption/desorption cycles. In the room temperature SANS curves for the as-milled powder, a power-law regime can be recognized for 0.02 angstrom(-1) < q < 0.15 angstrom(-1). Within this range, a linear fit yields a power-law scattering exponent alpha of about 2.4, indicating that the scattering entities can be associated with mass fractals with fractal dimension D approximate to 2.4. Scanning Electron Microscopy confirms the presence of powder particle aggregates and self-similarity features, which are characteristic of fractal structures. Upon cycling, a power-law regime is again observed for 0.02 angstrom(-1) < q < 0.15 angstrom(-1), alpha exhibiting values of about 3.5 and 4 after desorption and absorption, respectively. The former value can be related to surface fractals with fractal dimension D of about 2.5, whereas for alpha = 4 Porod's law is satisfied. This suggests the development, upon cycling, of a pore structure when Mg forms and its disappearance when MgH2 form

Additive Manufacturing of Cu Using Graphene-Oxide-Treated Powder

Additive manufacturing of Cu is interesting for many applications where high thermal and electric conductivity are required. A problem with printing of Cu with a laser-based process is the high reflectance of the powder for near-infrared wavelengths making it difficult to print components with a high density. In this study, we have investigated laser bed fusion (L-PBF) of Cu using graphene oxide (GO)-coated powder. The powder particles were coated in a simple wet-chemical process using electrostatic attractions between the GO and the powder surface. The coated powder exhibited a reduced reflectivity, which improved the printability and increased the densities from similar to 90% for uncoated powder to 99.8% using 0.1 wt% GO and a laser power of 500W. The coated Cu powders showed a tendency for balling using laser powers below 400 W, and increasing the GO concentration from 0.1 to 0.3 wt.% showed an increase in spattering and reduced density. Graphene-like sheet structures could be observed in the printed parts using scanning electron microscopy (SEM). Carbon-filled inclusions with sizes ranging from 10-200 nm could also be observed in the printed parts using transmission electron microscopy (TEM). The GO treatment yielded parts with higher hardness (75.7 HV) and electrical conductivity (77.8% IACS) compared to the parts printed with reference Cu powder

The H-sorption behaviour of ball-milled MgH2-5 mol.% FeF3 studied by in-situ small angle neutron scattering.

International audienceWe report on ball-milled MgH2 composite powder containing 5 mol.% FeF3, which were characterized by Small Angle Neutron Scattering (SANS) measurements carried out during in-situ H-2 absorption/desorption cycles. In the room temperature SANS curves for the as-milled powder, a power-law regime can be recognized for 0.02 angstrom(-1) < q < 0.15 angstrom(-1). Within this range, a linear fit yields a power-law scattering exponent alpha of about 2.4, indicating that the scattering entities can be associated with mass fractals with fractal dimension D approximate to 2.4. Scanning Electron Microscopy confirms the presence of powder particle aggregates and self-similarity features, which are characteristic of fractal structures. Upon cycling, a power-law regime is again observed for 0.02 angstrom(-1) < q < 0.15 angstrom(-1), alpha exhibiting values of about 3.5 and 4 after desorption and absorption, respectively. The former value can be related to surface fractals with fractal dimension D of about 2.5, whereas for alpha = 4 Porod's law is satisfied. This suggests the development, upon cycling, of a pore structure when Mg forms and its disappearance when MgH2 form

New Species of Virus-Coded Low-Molecular Weight Rna from Cells Infected with Adenovirus Type-2

A virus-coded low molecular weight RNA (5.2S), which migrates slightly faster on polyacrylamide gels than the well characterized adenovirus-specific 5.5S RNA, has been isolated from cells infected with adenovirus type 2