149 research outputs found
Mechanical properties of a lap joint under uniform clamping pressure
Equations were derived for the load deflection relations, the energy dissipation per cycle, and the instantaneous rate of dissipation for a lap joint idealized as two overlapping plates clamped together under a uniform clamping pressure
A study on range gated temporal reference acoustical holography Final technical report
Acoustical holographic imaging techniques for noninvasive visualization of soft tissue structures in ma
First principles theory of chiral dichroism in electron microscopy applied to 3d ferromagnets
Recently it was demonstrated (Schattschneider et al., Nature 441 (2006),
486), that an analogue of the X-ray magnetic circular dichroism (XMCD)
experiment can be performed with the transmission electron microscope (TEM).
The new phenomenon has been named energy-loss magnetic chiral dichroism (EMCD).
In this work we present a detailed ab initio study of the chiral dichroism in
the Fe, Co and Ni transition elements. We discuss the methods used for the
simulations together with the validity and accuracy of the treatment, which
can, in principle, apply to any given crystalline specimen. The dependence of
the dichroic signal on the sample thickness, accuracy of the detector position
and the size of convergence and collection angles is calculated.Comment: 9 pages, 6 figures, submitted to Physical Review
Functional consequence of a novel Y129C mutation in a patient with two contradictory melanocortin-2-receptor mutations
L F C and T-T C are supported by M R C Clinical Research Training
Fellowships (grant numbers G0600408, G0700581) and L A M by the
Wellcome Trust (grant number 076430/Z/05/7)
Experimental application of sum rules for electron energy loss magnetic chiral dichroism
We present a derivation of the orbital and spin sum rules for magnetic
circular dichroic spectra measured by electron energy loss spectroscopy in a
transmission electron microscope. These sum rules are obtained from the
differential cross section calculated for symmetric positions in the
diffraction pattern. Orbital and spin magnetic moments are expressed explicitly
in terms of experimental spectra and dynamical diffraction coefficients. We
estimate the ratio of spin to orbital magnetic moments and discuss first
experimental results for the Fe L_{2,3} edge.Comment: 11 pages, 2 figure
Missplicing due to a synonymous, T96= exonic substitution in the T-box transcription factor TBX19 resulting in isolated ACTH deficiency
Congenital isolated ACTH deficiency (IAD) is a rare condition characterised by low plasma ACTH and serum cortisol with
normal production of other pituitary hormones. TBX19 (also known as TPIT) is a T-box pituitary restricted transcription
factor important for POMC gene transcription and terminal differentiation of POMC-expressing cells. TBX19 gene mutations
have been shown to cause neonatal-onset congenital IAD. We report a neonate of Romanian origin, who presented at 15
h of life with respiratory arrest and hypoglycaemia which recurred over the following 2 weeks. Biochemical investigations
revealed IAD, with undetectable serum cortisol (cortisol < 1 μg/dL; normal range (NR): 7.8–26.2) and plasma ACTH levels
within the normal range (22.1 pg/mL; NR: 4.7–48.8). He responded to hydrocortisone treatment. Patient DNA was
analysed by a HaloPlex next-generation sequencing array targeting genes for adrenal insufficiency. A novel homozygous
synonymous mutation p.Thr96= (Chr1:168260482; c.288G>A; rs376493164; allele frequency 1 × 10−5, no homozygous) was
found in exon 2 of the TBX19 gene. The effect of this was assessed by an in vitro splicing assay, which revealed aberrant
splicing of exon 2 giving rise to a mutant mRNA transcript whereas the WT vector spliced exon 2 normally. This was
identified as the likely cause of IAD in the patient. The predicted protein product would be non-functional in keeping with
the complete loss of cortisol production and early presentation in the patient
Isolated Addison's disease is unlikely to be caused by mutations in MC2R, MRAP or STAR, three genes responsible for familial glucocorticoid deficiency
R P Dias is a Clinical Research Fellow funded by the Medical
Research Council
Neonatal presentation of familial glucocorticoid deficiency resulting from a novel splice mutation in the melanocortin 2 receptor accessory protein
This work was supported by a Medical Research Council/Academy of
Medical Sciences Clinician Scientist Fellowship to L F Chan (grant
number G0802796). L A Metherell is supported by a Medical Research
Council New Investigator Research Grant (grant number G0801265)
Identification and characterisation of a novel GHR defect disrupting the polypyrimidine tract and resulting in GH insensitivity
Objective GH insensitivity (GHI) is caused in the majority of cases by impaired function of the GH receptor (GHR). All but one known GHR mutation are in the coding sequence or the exon/intron boundaries. We identified and characterised the first intronic defect occurring in the polypyrimidine tract of the GHR in a patient with severe GHI.
Design We investigated the effect of the novel defect on mRNA splicing using an in vitro splicing assay and a cell transfection system.
Methods GHR was analysed by direct sequencing. To assess the effect of the novel defect, two heterologous minigenes (wild-type and mutant L1-GHR8-L2) were generated by inserting GHR exon 8 and its flanking wild-type or mutant intronic sequences into a well-characterised splicing reporter (Adml-par L1–L2). 32P-labelled pre-mRNA was generated from the two constructs and incubated in HeLa nuclear extracts or HEK293 cells.
Results Sequencing of the GHR revealed a novel homozygous defect in the polypyrimidine tract of intron 7 (IVS7-6T>A). This base change does not involve the highly conserved splice site sequences, and is not predicted in silico to affect GHR mRNA splicing. Nevertheless, skipping of exon 8 from the mutant L1-GHR8-L2 mRNA was clearly demonstrated in the in vitro splicing assay and in transfected HEK293 cells.
Conclusion Disruption of the GHR polypyrimidine tract causes aberrant mRNA splicing leading to a mutant GHR protein. This is predicted to lack its transmembrane and intracellular domains and, thus, be incapable of transducing a GH signal
Homozygous nonsense and frameshift mutations of the ACTH receptor in children with familial glucocorticoid deficiency (FGD) are not associated with long-term mineralocorticoid deficiency
Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid secretion. Mutations in the ACTH receptor (MC2R) account for approximately 25% of all FGD cases, but since these are usually missense mutations, a degree of receptor function is frequently retained. A recent report, however, suggested that disturbances in the renin-aldosterone axis were seen in some patients with potentially more severe MC2R mutations. Furthermore, MC2R knock out mice have overt aldosterone deficiency and hyperkalaemia despite preservation of a normal zona glomerulosa. We wished to determine whether a group of patients with severe nonsense mutations of the MC2R exhibited evidence of mineralocorticoid deficiency, thereby challenging the conventional diagnostic feature of FGD which might result in diagnostic misclassification
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