2,326 research outputs found

    A Genomic Point Mutation in the Extracellular Domain of the Thyrotropin Receptor in Patients with Graves’ Ophthalmopathy

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    Orbital and pretibial fibroblasts are targets of autoimmune attack in Graves' ophthalmopathy (GO) and pretibial dermopathy (PTD). The fibroblast autoantigen involved in these peripheral manifestations of Graves' disease and the reason for the association of GO and PTD with hyperthyroidism are unknown. RNA encoding the full-length extracellular domain of the TSH receptor has been demonstrated in orbital and dermal fibroblasts from patients with GO and normal subjects, suggesting a possible antigenic link between fibroblasts and thyrocytes. RNA was isolated from cultured orbital, pretibial, and abdominal fibroblasts obtained from patients with severe GO (n = 22) and normal subjects (n = 5). RNA was reverse transcribed, and the resulting cDNA was amplified by the polymerase chain reaction, using primers spanning overlapping regions of the entire extracellular domain of the TSH receptor. Nucleotide sequence analysis showed an A for C substitution in the first position of codon 52 in 2 of the patients, both of whom had GO, PTD, and acropachy. Genomic DNA isolated from the 2 affected patients, and not from an additional 12 normal subjects, revealed the codon 52 mutation by direct sequencing and AciI restriction enzyme digestions. In conclusion, we have demonstrated the presence of a genomic point mutation, leading to a threonine for proline amino acid shift in the predicted peptide, in the extracellular domain of the TSH receptor in two patients with severe GO, PTD, acropachy, and high thyroid-stimulating immunoglobulin levels. RNA encoding this mutant product was demonstrated in the fibroblasts of these patients. We suggest that the TSH receptor may be an important fibroblast autoantigen in GO and PTD, and that this mutant form of the receptor may have unique immunogenic properties

    Inelastic fingerprints of hydrogen contamination in atomic gold wire systems

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    We present series of first-principles calculations for both pure and hydrogen contaminated gold wire systems in order to investigate how such impurities can be detected. We show how a single H atom or a single H2 molecule in an atomic gold wire will affect forces and Au-Au atom distances under elongation. We further determine the corresponding evolution of the low-bias conductance as well as the inelastic contributions from vibrations. Our results indicate that the conductance of gold wires is only slightly reduced from the conductance quantum G0=2e^2/h by the presence of a single hydrogen impurity, hence making it difficult to use the conductance itself to distinguish between various configurations. On the other hand, our calculations of the inelastic signals predict significant differences between pure and hydrogen contaminated wires, and, importantly, between atomic and molecular forms of the impurity. A detailed characterization of gold wires with a hydrogen impurity should therefore be possible from the strain dependence of the inelastic signals in the conductance.Comment: 5 pages, 3 figures, Contribution to ICN+T2006, Basel, Switzerland, July-August 200

    Mathematical Model of Easter Island Society Collapse

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    In this paper we consider a mathematical model for the evolution and collapse of the Easter Island society, starting from the fifth century until the last period of the society collapse (fifteen century). Based on historical reports, the available primary sources consisted almost exclusively on the trees. We describe the inhabitants and the resources as an isolated system and both considered as dynamic variables. A mathematical analysis about why the structure of the Easter Island community collapse is performed. In particular, we analyze the critical values of the fundamental parameters driving the interaction humans-environment and consequently leading to the collapse. The technological parameter, quantifying the exploitation of the resources, is calculated and applied to the case of other extinguished civilization (Cop\'an Maya) confirming, with a sufficiently precise estimation, the consistency of the adopted model.Comment: 9 pages, 1 figure, final version published on EuroPhysics Letter

    Fuchsian convex bodies: basics of Brunn--Minkowski theory

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    The hyperbolic space \H^d can be defined as a pseudo-sphere in the (d+1)(d+1) Minkowski space-time. In this paper, a Fuchsian group Γ\Gamma is a group of linear isometries of the Minkowski space such that \H^d/\Gamma is a compact manifold. We introduce Fuchsian convex bodies, which are closed convex sets in Minkowski space, globally invariant for the action of a Fuchsian group. A volume can be associated to each Fuchsian convex body, and, if the group is fixed, Minkowski addition behaves well. Then Fuchsian convex bodies can be studied in the same manner as convex bodies of Euclidean space in the classical Brunn--Minkowski theory. For example, support functions can be defined, as functions on a compact hyperbolic manifold instead of the sphere. The main result is the convexity of the associated volume (it is log concave in the classical setting). This implies analogs of Alexandrov--Fenchel and Brunn--Minkowski inequalities. Here the inequalities are reversed

    Overcoming cross-cultural group work tensions: mixed student perspectives on the role of social relationships

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    As universities worldwide rapidly internationalise, higher education classrooms have become unique spaces for collaboration between students from different countries. One common way to encourage collaboration between diverse peers is through group work. However, previous research has highlighted that cross-cultural group work can be challenging and has hinted at potential social tensions. To understand this notion better, we have used robust quantitative tools in this study to select 20 participants from a larger classroom of 860 students to take part in an in-depth qualitative interview about cross-cultural group work experiences. Participant views on social tensions in cross-cultural group work were elicited using a unique mediating artefact method to encourage reflection and in-depth discussion. In our analysis of emergent interview themes, we compared student perspectives on the role of social relationships in group work by their academic performance level. Our findings indicated that all students interviewed desired the opportunity to form social relationships with their group work members, but their motivations for doing so varied widely by academic performance level

    Integrative proteomic analysis of the NMDA NR1 knockdown mouse model reveals effects on central and peripheral pathways associated with schizophrenia and autism spectrum disorders

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    Background: Over the last decade, the transgenic N-methyl-D-aspartate receptor (NMDAR) NR1-knockdown mouse (NR1neo-/-) has been investigated as a glutamate hypofunction model for schizophrenia. Recent research has now revealed that the model also recapitulates cognitive and negative symptoms in the continuum of other psychiatric diseases, particularly autism spectrum disorders (ASD). As previous studies have mostly focussed on behavioural readouts, a molecular characterisation of this model will help to identify novel biomarkers or potential drug targets. Methods. Here, we have used multiplex immunoassay analyses to investigate peripheral analyte alterations in serum of NR1neo-/- mice, as well as a combination of shotgun label-free liquid chromatography mass spectrometry, bioinformatic pathway analyses, and a shotgun-based 40-plex selected reaction monitoring (SRM) assay to investigate altered molecular pathways in the frontal cortex and hippocampus. All findings were cross compared to identify translatable findings between the brain and periphery. Results: Multiplex immunoassay profiling led to identification of 29 analytes that were significantly altered in sera of NR1neo-/- mice. The highest magnitude changes were found for neurotrophic factors (VEGFA, EGF, IGF-1), apolipoprotein A1, and fibrinogen. We also found decreased levels of several chemokines. Following this, LC-MS E profiling led to identification of 48 significantly changed proteins in the frontal cortex and 41 in the hippocampus. In particular, MARCS, the mitochondrial pyruvate kinase, and CamKII-alpha were affected. Based on the combination of protein set enrichment and bioinformatic pathway analysis, we designed orthogonal SRM-assays which validated the abnormalities of proteins involved in synaptic long-term potentiation, myelination, and the ERK-signalling pathway in both brain regions. In contrast, increased levels of proteins involved in neurotransmitter metabolism and release were found only in the frontal cortex and abnormalities of proteins involved in the purinergic system were found exclusively in the hippocampus. Conclusions: Taken together, this multi-platform profiling study has identified peripheral changes which are potentially linked to central alterations in synaptic plasticity and neuronal function associated with NMDAR-NR1 hypofunction. Therefore, the reported proteomic changes may be useful as translational biomarkers in human and rodent model drug discovery efforts
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