Uncoupled bone turnover in cystic fibrosis: bone markers and the PTH-vitamin D axis

No abstract

A polymorphism in the growth hormone (GH)-releasing hormone (GHRH) receptor gene is associated with elevated response to GHRH by human pituitary somatotrophinomas in vitro

A previous study has suggested that a G to A base change at position 169 of the GHRH-receptor gene in human somatotrophinomas is a mutation and confers hypersensitivity to GHRH. The alternative base converts codon 57 from GCG to AGC, resulting in replacement of alanine (Ala) with threonine (Thr). In the present study, two of five human GH-secreting somatotrophinomas were found to possess the codon 57 AGC sequence. The GCG allele was also detected, indicating heterozygosity. However, the patients' normal blood-derived DNA also yielded the same sequence pattern, indicating that the Ala=> Thr amino acid change is a normal polymorphism, and not a somatic mutation. Nevertheless, in vitro, the tumors possessing the Ala=> Thr amino acid change responded very strongly to GHRH in terms of cAMP formation, being increased 40- and 200-fold, in comparison to the 2-fold increases by tumors without the alternative GHRH-receptor sequence. Likewise, the in vitro response of GH secretion to GHRH was elevated. One of the two tumors with the alternative Thr residue, and the highest responder to GHRH, possessed a gsp muration, despite the fact that these defects are thought to reduce responsiveness to GHRH. These results fail to confirm that the GCG => AGC at codon 57 of the GHRH-receptor gene is a mutation, but do support the concept that the alternative form with Thr confers increased sensitivity to GHRH. (C) 2000 Academic Press.

Two-axis temperature-insensitive accelerometer based on multicore fiber Bragg gratings

We report a compact two-dimensional accelerometer based upon a simple fiber cantilever constructed from a short length of multicore optical fiber. Two-axis measurement is demonstrated up to 3 kHz. Differential measurement between fiber Bragg gratings written in the multicore fiber provides temperature- insensitive measurements.

Axis-alignment affects perceptual grouping: evidence from simultanagnosia

We examined the effect of grouping by the alignment of implicit axes on the perception of multiple shapes, using a patient (GK) who shows simultanagnosia as part of Blint's syndrome. Five experiments demonstrated that: (1) GK was better able to judge the orientation of a global configuration if the constituent local shapes were aligned with their major axes than if they were aligned with their edges; (2) this axis information was used implicitly, since GK was unable to discriminate between configurations of axis-aligned and edge-aligned shapes; (3) GK's sensitivity to axis-alignment persisted even when the orientations of local shapes were kept constant, indicating some form of cooperative effect between the local elements; (4) axis-alignment of shapes also facilitated his ability to discriminate single-item from multi-item configurations; (5) the effect of axis-alignment could be attributed, at least partially, to the degree to which there was matching between the orientations of local shapes and the global configuration. Taken together, the results suggest that axis-based grouping can support the selection of multiple objects.

Axis-based grouping reduces visual extinction

We examined the effects on extinction of grouping by collinearity of edges and grouping by alignment of internal axes of shapes, in a patient (GK) with simultanagnosia following bilateral parietal brain damage. GK’s visual extinction was reduced when items (equilateral triangles and angles) could be grouped by base alignment (i.e., collinearity) or by axis alignment, relative to a condition in which items were ungrouped. These grouping effects disappeared when inter-item spacing was increased, though factors such as display symmetry remained constant. Overall, the results suggest that, under some conditions, grouping by alignment of axes of symmetry can have an equal beneficial effect on visual extinction as edge-based grouping; thus, in the extinguished field, there is derivation of axis-based representations from the contours present.

Design methodology for the servo control of high speed multi-axis machinery (BL): decoupling and synchronisation of a generic machine by blockwise decentralised MIMO control

Traditional machinery for manufacturing processes are characterised by actuators powered and co-ordinated by mechanical linkages driven from a central drive. Increasingly, these linkages are replaced by independent electrical drives, each performs a different task and follows a different motion profile, co-ordinated by computers. A design methodology for the servo control of high speed multi-axis machinery is proposed, based on the concept of a highly adaptable generic machine model. In addition to the dynamics of the drives and the loads, the model includes the inherent interactions between the motion axes and thus provides a Multi-Input Multi-Output (MIMO) description. In general, inherent interactions such as structural couplings between groups of motion axes are undesirable and needed to be compensated. On the other hand, imposed interactions such as the synchronisation of different groups of axes are often required. It is recognised that a suitable MIMO controller can simultaneously achieve these objectives and reconciles their potential conflicts. Both analytical and numerical methods for the design of MIMO controllers are investigated. At present, it is not possible to implement high order MIMO controllers for practical reasons. Based on simulations of the generic machine model under full MIMO control, however, it is possible to determine a suitable topology for a blockwise decentralised control scheme. The Block Relative Gain array (BRG) is used to compare the relative strength of closed loop interactions between sub-systems. A number of approaches to the design of the smaller decentralised MIMO controllers for these sub-systems has been investigated. For the purpose of illustration, a benchmark problem based on a 3 axes test rig has been carried through the design cycle to demonstrate the working of the design methodology.

Receptor Activity Modifying Proteins (RAMPs) interact with the VPAC2 Receptor and CRF1 receptors and modulate their function

Background and Purpose Although it is established that the receptor activity modifying proteins (RAMPs) can interact with a number of GPCRs, little is known about the consequences of these interactions. Here the interaction of RAMPs with the glucagon-like peptide 1 receptor (GLP-1 receptor), the human vasoactive intestinal polypeptide/pituitary AC-Activating peptide 2 receptor (VPAC) and the type 1 corticotrophin releasing factor receptor (CRF) has been examined. Experimental Approach GPCRs were co-transfected with RAMPs in HEK 293S and CHO-K1 cells. Cell surface expression of RAMPs and GPCRs was examined by elisa. Where there was evidence for interactions, agonist-stimulated cAMP production, Ca mobilization and GTPγS binding to G, G, G and G were examined. The ability of CRF to stimulate adrenal corticotrophic hormone release in Ramp2 mice was assessed. Key Results The GLP-1 receptor failed to enhance the cell surface expression of any RAMP. VPAC enhanced the cell surface expression of all three RAMPs. CRF enhanced the cell surface expression of RAMP2; the cell surface expression of CRF was also increased. There was no effect on agonist-stimulated cAMP production. However, there was enhanced G-protein coupling in a receptor and agonist-dependent manner. The CRF: RAMP2 complex resulted in enhanced elevation of intracellular calcium to CRF and urocortin 1 but not sauvagine. In Ramp2 mice, there was a loss of responsiveness to CRF. Conclusions and Implications The VPAC and CRF receptors interact with RAMPs. This modulates G-protein coupling in an agonist-specific manner. For CRF, coupling to RAMP2 may be of physiological significance. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Recent advances in antidiabetic drug therapies targeting the enteroinsular axis

The enteroinsular axis (EIA) constitutes a physiological signalling system whereby intestinal endocrine cells secrete incretin hormones following feeding that potentiate insulin secretion and contribute to the regulation of blood glucose homeostasis. The two key hormones responsible are named glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Recent years have witnessed sustained development of antidiabetic therapies that exploit the EIA. Current clinical compounds divide neatly into two classes. One concerns analogues or mimetics of GLP-1, such as exenatide (Byetta) or liraglutide (NN2211). The other group comprises the gliptins (e.g. sitagliptin and vildagliptin) which boost endogenous incretin activity by inhibiting the enzyme dipeptidyl peptidase 4 (DPP 4) that degrades both GLP-1 and GIP. Ongoing research indicates that further incretin and gliptin compounds will become available for clinical use in the near future, offering comparable or improved efficacy. For incretin analogues there is the prospect of prolonged duration of action and alternative routes of administration. This review focuses on recent advances in pre-clinical research and their translation into clinical studies to provide future therapies for type 2 diabetes targeting the EIA. © 2009 Bentham Science Publishers Ltd.

Pituitary adenylate cyclase-activating polypeptide type 1 receptor (PAC1) gene is suppressed by transglutaminase 2 activation

Pituitary adenylate cyclase-activating polypeptide (PACAP) functions as a neuroprotective factor through the PACAP type 1 receptor, PAC1. In a previous work, we demonstrated that nerve growth factor augmented PAC1 gene expression through the activation of Sp1 via the Ras/MAPK pathway. We also observed that PAC1 expression in Neuro2a cells was transiently suppressed during in vitro ischemic conditions, oxygen-glucose deprivation (OGD). Because endoplasmic reticulum (ER) stress is induced by ischemia, we attempted to clarify how ER stress affects the expression of PAC1. Tunicamycin, which induces ER stress, significantly suppressed PAC1 gene expression, and salubrinal, a selective inhibitor of the protein kinase RNA-like endoplasmic reticulum kinase signaling pathway of ER stress, blocked the suppression. In luciferase reporter assay, we found that two Sp1 sites were involved in suppression of PAC1 gene expression due to tunicamycin or OGD. Immunocytochemical staining demonstrated that OGD-induced transglutaminase 2 (TG2) expression was suppressed by salubrinal or cystamine, a TG activity inhibitor. Further, the OGD-induced accumulation of cross-linked Sp1 in nuclei was suppressed by cystamine or salubrinal. Together with cystamine, R283, TG2-specific inhibitor, and siRNA specific for TG2 also ameliorated OGD-induced attenuation of PAC1 gene expression. These results suggest that Sp1 cross-linking might be crucial in negative regulation of PAC1 gene expression due to TG2 in OGD-induced ER stress. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

Two-axis accelerometer based on multicore fibre Bragg gratings

We report an accelerometer based upon a simple fibre cantilever constructed from a short length of multicore fibre(MCF) containing fibre Bragg gratings (FBGs). Two-axis measurement is demonstrated up to 3 kHz.