Ergopeptine-Sensitive Calcium-Dependent Protein Phosphorylation System in the Brain

We studied a protein phosphorylation system that is regulated by the dopamine-mimetic ergot bromocriptine. Bromocriptine was found to inhibit selectively the endogenous phosphorylation of a threonine residue(s) in 50,000- and 60,000-dalton proteins in a synaptosome fraction. The bromocriptine-sensitive phosphorylation is stimulated by calcium and by calmodulin, and occurs predominantly in the brain. The inhibitory effect of bromocriptine was not mimicked by 3,4-dihydroxyphenylethylamine or by any of the neurotransmitters and related agents tested, but was mimicked, although less effectively, by other ergots that contain peptide moieties. In the hippocampus, the brain region with the highest content of the 50,000- and 60,000-dalton proteins, the ergopeptine-sensitive protein phosphorylation appears to be localized to interneurons or cell bodies whose axons synapse outside the hippocampus. The results raise the possibility that some of the bromocriptine- and ergopeptine-induced pharmacological effects in the CNS may be mediated by the inhibition of the calcium/calmodulin-dependent phosphorylation of these specific proteins.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65208/1/j.1471-4159.1984.tb02758.x.pd

Development and validation of a generalised engineering methodology for thermal analysis of structural members in fire

Presented at 5th International Seminar on Fire & Explosion Hazards, Edinburgh 23-27 April 2007A novel methodology for generalising CFD-based approaches for thermal analysis of protected steelwork in fire has been developed, known as GeniSTELA. This is a quasi-3D approach with computation of a "steel temperature field" parameter in each computational cell. The methodology accommodates both uncertainties in the input parameters and possible variants to the specification by means of parallel calculations. A framework for the inclusion of temperature/time-dependent thermal properties, including the effects of moisture and intumescence, has been established. Indicative values of intumescent material properties have been obtained by means of cone calorimeter testing. These are dependent on initial thickness and exposure heat flux. GeniSTELA has been implemented as a submodel within the SOFIE RANS CFD code. The model is validated against measurements from the BRE large compartment fire tests, which involved well-instrumented post-flashover fires in a 12 x 12m compartment, including steel indicatives with and without protection. Sensitivity studies reveal the expected strong dependencies on structural member specification and properties of protection materials. The computational requirements are addressed, considering aspects such as the number of simultaneous cases and frequency of GeniSTELA call, in order to achieve a reasonable balance between fluid and solid-phase analyses. It is established that the model can be a practical tool, performing c. 10-100 simultaneous thermal calculations before becoming dominant. These steel temperature field predictions provided by GeniSTELA can provide far more flexibility in assessing the thermal response of structures to fire than is available via existing methods

Laminar Cortical Dynamics of 3D Surface Perception: Stratification, transparency, and Neon Color Spreading

How does the laminar organization of cortical circuitry in areas VI and V2 give rise to 3D percepts of stratification, transparency, and neon color spreading in response to 2D pictures and 3D scenes? Psychophysical experiments have shown that such 3D percepts are sensitive to whether contiguous image regions have the same relative contrast polarity (dark-light or lightdark), yet long-range perceptual grouping is known to pool over opposite contrast polarities. The ocularity of contiguous regions is also critical for neon color spreading: Having different ocularity despite the contrast relationship that favors neon spreading blocks the spread. In addition, half visible points in a stereogram can induce near-depth transparency if the contrast relationship favors transparency in the half visible areas. It thus seems critical to have the whole contrast relationship in a monocular configuration, since splitting it between two stereogram images cancels the effect. What adaptive functions of perceptual grouping enable it to both preserve sensitivity to monocular contrast and also to pool over opposite contrasts? Aspects of cortical development, grouping, attention, perceptual learning, stereopsis and 3D planar surface perception have previously been analyzed using a 3D LAMINART model of cortical areas VI, V2, and V4. The present work consistently extends this model to show how like-polarity competition between VI simple cells in layer 4 may be combined with other LAMINART grouping mechanisms, such as cooperative pooling of opposite polarities at layer 2/3 complex cells. The model also explains how the Metelli Rules can lead to transparent percepts, how bistable transparency percepts can arise in which either surface can be perceived as transparent, and how such a transparency reversal can be facilitated by an attention shift. The like-polarity inhibition prediction is consistent with lateral masking experiments in which two f1anking Gabor patches with the same contrast polarity as the target increase the target detection threshold when they approach the target. It is also consistent with LAMINART simulations of cortical development. Other model explanations and testable predictions will also be presented.Air Force Office of Naval Research (F49620-01-1-0397); Office of Naval Research (N00014-01-1-0624

Acupuncture for pain and osteoarthritis of the knee: a pilot study for an open parallel-arm randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>There is some evidence that acupuncture for pain and osteoarthritis (OA) of the knee is more than a placebo, and short term clinical benefits have been observed when acupuncture is compared to usual care. However there is insufficient evidence on whether clinical benefits of acupuncture are sustained over the longer term. In this study our key objectives are to inform the design parameters for a fully powered pragmatic randomised controlled trial. These objectives include establishing potential recruitment rates, appropriate validated outcome measures, attendance levels for acupuncture treatment, loss to follow up and the sample size for a full scale trial.</p> <p>Methods</p> <p>Potential participants aged over 50 with pain and osteoarthritis of the knee were identified from a GP database. Eligible patients were randomised to either 'acupuncture plus usual care' and 'usual care' alone, with allocation appropriately concealed. Acupuncture consisted of up to 10 sessions usually weekly. Outcome measures included Western Ontario and McMaster Universities (WOMAC) index with the sample size for a full scale trial determined from the variance.</p> <p>Results</p> <p>From the GP database of 15,927 patients, 335 potential trial participants were identified and invited to participate. After screening responses, 78 (23%) were identified as eligible and 30 patients who responded most promptly were randomised to 'acupuncture plus usual care' (15 patients) and 'usual care' alone (15 patients). Attendance for acupuncture appointments was high at 90% of the maximum. Although the trial was not powered to detect significant changes in outcome, the WOMAC pain index showed a statistically significant reduction at 3 months in the acupuncture group compared to usual care. This was not sustained at 12 months. The sample size for a fully powered two-arm trial was estimated to be 350.</p> <p>Conclusion</p> <p>This pilot study provided the evidence that a fully powered study to explore the longer term impact of acupuncture would be worthwhile, and relevant design features for such a trial were determined.</p> <p>Trial registration number</p> <p>ISRCTN25134802.</p

Sonic Hedgehog Signaling in Limb Development.

The gene encoding the secreted protein Sonic hedgehog (Shh) is expressed in the polarizing region (or zone of polarizing activity), a small group of mesenchyme cells at the posterior margin of the vertebrate limb bud. Detailed analyses have revealed that Shh has the properties of the long sought after polarizing region morphogen that specifies positional values across the antero-posterior axis (e.g., thumb to little finger axis) of the limb. Shh has also been shown to control the width of the limb bud by stimulating mesenchyme cell proliferation and by regulating the antero-posterior length of the apical ectodermal ridge, the signaling region required for limb bud outgrowth and the laying down of structures along the proximo-distal axis (e.g., shoulder to digits axis) of the limb. It has been shown that Shh signaling can specify antero-posterior positional values in limb buds in both a concentration- (paracrine) and time-dependent (autocrine) fashion. Currently there are several models for how Shh specifies positional values over time in the limb buds of chick and mouse embryos and how this is integrated with growth. Extensive work has elucidated downstream transcriptional targets of Shh signaling. Nevertheless, it remains unclear how antero-posterior positional values are encoded and then interpreted to give the particular structure appropriate to that position, for example, the type of digit. A distant cis-regulatory enhancer controls limb-bud-specific expression of Shh and the discovery of increasing numbers of interacting transcription factors indicate complex spatiotemporal regulation. Altered Shh signaling is implicated in clinical conditions with congenital limb defects and in the evolution of the morphological diversity of vertebrate limbs

Clinical development of new drug-radiotherapy combinations.

In countries with the best cancer outcomes, approximately 60% of patients receive radiotherapy as part of their treatment, which is one of the most cost-effective cancer treatments. Notably, around 40% of cancer cures include the use of radiotherapy, either as a single modality or combined with other treatments. Radiotherapy can provide enormous benefit to patients with cancer. In the past decade, significant technical advances, such as image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic radiotherapy, and proton therapy enable higher doses of radiotherapy to be delivered to the tumour with significantly lower doses to normal surrounding tissues. However, apart from the combination of traditional cytotoxic chemotherapy with radiotherapy, little progress has been made in identifying and defining optimal targeted therapy and radiotherapy combinations to improve the efficacy of cancer treatment. The National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) formed a Joint Working Group with representatives from academia, industry, patient groups and regulatory bodies to address this lack of progress and to publish recommendations for future clinical research. Herein, we highlight the Working Group's consensus recommendations to increase the number of novel drugs being successfully registered in combination with radiotherapy to improve clinical outcomes for patients with cancer.National Institute for Health ResearchThis is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/nrclinonc.2016.7

Lunch and journalism: The Wintec Press Club

This book is a collection of profiles from the past 20 speakers at the Wintec Press club written by Wintec's journalism students and edited by Wintec's writer in residence, Steve Braunias

The implications of compartment fire non-uniformity for the membrane action of reinforced concrete slabs

Maintaining structural stability is an integral component of building fire safety. Stability must be ensured to provide adequate time for safe egress of the buildings occupants, fire fighting operations and property protection. Structural fire engineering endeavours to design structures to withstand the effects of fire in order to achieve this objective. The behaviour of reinforced concrete in fire is not as well understood as other construction materials, such as steel. This is in part due to the complexity of concrete material behaviour and also due to concrete’s reputation of superior fire performance. Concrete technology is, however, continually evolving; structures are increasingly slender, more highly stressed and have higher compressive strengths. A more robust understanding of concrete’s behaviour in fire will enable predictions of the implications of changing concrete technology and also help to properly quantify the fire safety risk associated with concrete structures. A fundamental key to understanding structural fire performance is the relationship between the thermal environment induced by the fire and the structure. Significant thermal variation has been found experimentally to exist within fire compartments. Despite this the design of structures for fire almost universally assumes the compartment thermal environment to be homogeneous. In this thesis the implications of compartment fire non-uniformity for concrete structural behaviour is investigated to assess the validity of the uniform compartment temperature assumption. The investigation is conducted using numerical tools; a detailed review of the necessary background knowledge, material modelling of reinforced concrete, finite element modelling of reinforced concrete structures and compartment fire thermal variation is included. The behaviour of a two-way spanning reinforced concrete slab is used as a structural benchmark. The membrane behaviour exhibited by two-way spanning RC slabs at high temperatures has been previously studied under uniform thermal conditions. They therefore are an ideal benchmark for identifying the influence of non-uniform thermal environments for behaviour. The relationship between gas phase temperature variation and concrete thermal expansion behaviour, which is fundamental to understanding concrete high temperature structural behaviour, is first investigated. These preliminary studies provide the necessary fundamental understanding to identify the influence of gas phase temperature variation upon the membrane behaviour of reinforced concrete slabs. The individual influences of spatial and temporal variation upon slab membrane behaviour are investigated and the behaviour under non-uniform thermal variation contrasted with uniform thermal exposure behaviour. The influence of spatial variation of temperature is found to be strongly dependent upon the structural slenderness ratio. The tensile membrane action of slender slabs is particularly susceptible to the distorted slab deflection profiles induced by spatial variation of gas temperature. Conversely the compressive membrane behaviour of stocky slabs is found to be insensitive to the deformation effects induced by spatial variation of temperature. The influence upon slender slabs is demonstrated under a range of temporal variations indicating that the thermal response of concrete is sufficiently fast to be sensitive to realistically varying distributions of temperature. Contrasting behaviour induced by uniform and non-uniform thermal exposures indicates that uniform temperature assumptions provide both conservative and unconservative predictions of behaviour. The accuracy of the uniform temperature assumptions was also found to be dependent upon the type of fire, for example, fast hot and short cool fires. Additionally, the sensitivity of structural performance to deformations caused by spatial variation of temperature demonstrated in this thesis challenges the purely strength based focus of traditional structural fire engineering. Spalling is an important feature of concrete’s high temperature behaviour which is not currently explicitly addressed in design. The incorporation of spalling into structural analysis is not, however, straightforward. The influence of spalling upon behaviour has therefore been dealt with separately. A spalling design framework is developed to incorporate the effects of spalling into a structural analysis. Application of the framework to case studies demonstrates the potential for spalling to critically undermine the structural performance of concrete in fire. It also demonstrates how the framework can be used to quantify the effects of spalling and therefore account for these in the structural fire design addressing spalling risk in a rational manner.EThOS - Electronic Theses Online ServiceGBUnited Kingdo