Showing papers by "University of Leicester published in 2001"

The European Photon Imaging Camera on XMM-Newton: The pn-CCD camera

Abstract: The European Photon Imaging Camera (EPIC) consortium has provided the focal plane instruments for the three X-ray mirror systems on XMM-Newton. Two cameras with a reflecting grating spectrometer in the optical path are equipped with MOS type CCDs as focal plane detectors (Turner 2001), the telescope with the full photon flux operates the novel pn-CCD as an imaging X-ray spectrometer. The pn-CCD camera system was developed under the leadership of the Max-Planck-Institut fur extraterrestrische Physik (MPE), Garching. The concept of the pn-CCD is described as well as the dierent operational modes of the camera system. The electrical, mechanical and thermal design of the focal plane and camera is briefly treated. The in-orbit performance is described in terms of energy resolution, quantum eciency, time resolution, long term stability and charged particle background. Special emphasis is given to the radiation hardening of the devices and the measured and expected degradation due to radiation damage of ionizing particles in the rst 9 months of in orbit operation.

The European Photon Imaging Camera on XMM-Newton: The MOS cameras

Abstract: The EPIC focal plane imaging spectrometers on XMM-Newton use CCDs to record the images and spectra of celestial X-ray sources focused by the three X-ray mirrors. There is one camera at the focus of each mirror; two of the cameras contain seven MOS CCDs, while the third uses twelve PN CCDs, dening a circular eld of view of 30 0 diameter in each case. The CCDs were specially developed for EPIC, and combine high quality imaging with spectral resolution close to the Fano limit. A lter wheel carrying three kinds of X-ray transparent light blocking lter, a fully closed, and a fully open position, is tted to each EPIC instrument. The CCDs are cooled passively and are under full closed loop thermal control. A radio-active source is tted for internal calibration. Data are processed on-board to save telemetry by removing cosmic ray tracks, and generating X-ray event les; a variety of dierent instrument modes are available to increase the dynamic range of the instrument and to enable fast timing. The instruments were calibrated using laboratory X-ray beams, and synchrotron generated monochromatic X-ray beams before launch; in-orbit calibration makes use of a variety of celestial X-ray targets. The current calibration is better than 10% over the entire energy range of 0.2 to 10 keV. All three instruments survived launch and are performing nominally in orbit. In particular full eld-of-view coverage is available, all electronic modes work, and the energy resolution is close to pre-launch values. Radiation damage is well within pre-launch predictions and does not yet impact on the energy resolution. The scientic results from EPIC amply full pre-launch expectations.

The role of desires and anticipated emotions in goal-directed behaviours: broadening and deepening the theory of planned behaviour

Abstract: Building on the theory of planned behaviour (TPB), we develop a new model of purposive behaviour which suggests that desires are the proximal causes of intentions, and the traditional antecedents in the TPB work through desires. In addition, perceived consequences of goal achievement and goal failure are modelled as anticipated emotions, which also function as determinants of desires. The new model is tested in two studies: an investigation of bodyweight regulation by 108 Italians at the University of Rome and an investigation of effort expended in studying by 122 students at the University of Rome. Frequency and recency of past behaviour are controlled for in tests of hypotheses. The findings show that desires fully mediated the effects of attitudes, subjective norms, perceived behavioural control and anticipated emotions on intentions. Significantly greater amounts of variance are explained in intentions and behaviour by the new model in comparison to the TPB and variants of the TPB that include either anticipated emotions and/or past behaviour.

Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex.

Abstract: There is considerable interest in understanding patterns of linkage disequilibrium (LD) in the human genome, to aid investigations of human evolution and facilitate association studies in complex disease. The relative influences of meiotic crossover distribution and population history on LD remain unclear, however. In particular, it is uncertain to what extent crossovers are clustered into 'hot spots, that might influence LD patterns. As a first step to investigating the relationship between LD and recombination, we have analyzed a 216-kb segment of the class II region of the major histocompatibility complex (MHC) already characterized for familial crossovers. High-resolution LD analysis shows the existence of extended domains of strong association interrupted by patchwork areas of LD breakdown. Sperm typing shows that these areas correspond precisely to meiotic crossover hot spots. All six hot spots defined share a remarkably similar symmetrical morphology but vary considerably in intensity, and are not obviously associated with any primary DNA sequence determinants of hot-spot activity. These hot spots occur in clusters and together account for almost all crossovers in this region of the MHC. These data show that, within the MHC at least, crossovers are far from randomly distributed at the molecular level and that recombination hot spots can profoundly affect LD patterns.

Pharmacodynamic and Pharmacokinetic Study of Oral Curcuma Extract in Patients with Colorectal Cancer

Abstract: Curcuma spp. extracts, particularly the dietary polyphenol curcumin, prevent colon cancer in rodents. In view of the sparse information on the pharmacodynamics and pharmacokinetics of curcumin in humans, a dose-escalation pilot study of a novel standardized Curcuma extract in proprietary capsule form was performed at doses between 440 and 2200 mg/day, containing 36-180 mg of curcumin. Fifteen patients with advanced colorectal cancer refractory to standard chemotherapies received Curcuma extract daily for up to 4 months. Activity of glutathione S-transferase and levels of a DNA adduct (M(1)G) formed by malondialdehyde, a product of lipid peroxidation and prostaglandin biosynthesis, were measured in patients' blood cells. Oral Curcuma extract was well tolerated, and dose-limiting toxicity was not observed. Neither curcumin nor its metabolites were detected in blood or urine, but curcumin was recovered from feces. Curcumin sulfate was identified in the feces of one patient. Ingestion of 440 mg of Curcuma extract for 29 days was accompanied by a 59% decrease in lymphocytic glutathione S-transferase activity. At higher dose levels, this effect was not observed. Leukocytic M(1)G levels were constant within each patient and unaffected by treatment. Radiologically stable disease was demonstrated in five patients for 2-4 months of treatment. The results suggest that (a) Curcuma extract can be administered safely to patients at doses of up to 2.2 g daily, equivalent to 180 mg of curcumin; (b) curcumin has low oral bioavailability in humans and may undergo intestinal metabolism; and (c) larger clinical trials of Curcuma extract are merited.

Ultraluminous X-Ray Sources in External Galaxies

Abstract: We investigate models for the class of ultraluminous nonnuclear X-ray sources (i.e., ultraluminous compact X-ray sources [ULXs]) seen in a number of galaxies and probably associated with star-forming regions. Models in which the X-ray emission is assumed to be isotropic run into several difficulties. In particular, the formation of sufficient numbers of the required ultramassive black hole X-ray binaries is problematic, and the likely transient behavior of the resulting systems is not in good accord with observation. The assumption of mild X-ray beaming suggests instead that ULXs may represent a short-lived but extremely common stage in the evolution of a wide class of X-ray binaries. The best candidate for this is the phase of thermal-timescale mass transfer that is inevitable in many intermediate- and high-mass X-ray binaries. This in turn suggests a link with the Galactic microquasars. The short lifetimes of high-mass X-ray binaries would explain the association of ULXs with episodes of star formation. These considerations still allow the possibility that individual ULXs may contain extremely massive black holes.

Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia

Abstract: Background Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor β (TGF-β) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients. Methods We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-β–receptor proteins, including endoglin and activin-receptor–like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations. Results We identified suggestive linkage of pulmonary hypertension with hereditary hemo...

The HI Parkes All Sky Survey: southern observations, calibration and robust imaging

Abstract: The acquisition of HI Parkes All Shy Survey (HIPASS) southern sky data commenced at the Australia Telescope National Facility's Parkes 64-m telescope in 1997 February, and was completed in 2000 March. HIPASS is the deepest HI survey yet of the sky south of declination +2 degrees, and is sensitive to emission out to 170 h(75)(-1) Mpc. The characteristic root mean square noise in the survey images is 13.3 mJy. This paper describes the survey observations, which comprise 23 020 eight-degree scans of 9-min duration, and details the techniques used to calibrate and image the data. The processing algorithms are successfully designed to be statistically robust to the presence of interference signals, and are particular to imaging point (or nearly point) sources. Specifically, a major improvement in image quality is obtained by designing a median-gridding algorithm which uses the median estimator in place of the mean estimator.

Characterization of Metabolites of the Chemopreventive Agent Curcumin in Human and Rat Hepatocytes and in the Rat in Vivo, and Evaluation of Their Ability to Inhibit Phorbol Ester-induced Prostaglandin E2 Production

Abstract: Curcumin, the yellow pigment in turmeric, has been shown to prevent malignancies in a variety of tissues in rodents, especially in the intestinal tract. Pharmacological activities of curcumin in cells in situ germane to chemoprevention, such as inhibition of expression of cyclooxygenase-2 (COX-2), require drug concentrations in the 10(-5) - 10(-4) M range. The systemic bioavailability of curcumin is low, so that its pharmacological activity may be mediated, in part, by curcumin metabolites. To investigate this possibility, we compared curcumin metabolism in human and rat hepatocytes in suspension with that in rats in vivo. Analysis by high-performance liquid chromatography with detection at 420 and 280 nm permitted characterization of metabolites with both intact diferoylmethane structure and increased saturation of the heptatrienone chain. Chromatographic inferences were corroborated by mass spectrometry. The major metabolites in suspensions of human or rat hepatocytes were identified as hexahydrocurcumin and hexahydrocurcuminol. In rats, in vivo, curcumin administered i.v. (40 mg/kg) disappeared from the plasma within 1 h of dosing. After p.o. administration (500 mg/kg), parent drug was present in plasma at levels near the detection limit. The major products of curcumin biotransformation identified in rat plasma were curcumin glucuronide and curcumin sulfate whereas hexahydrocurcumin, hexahydrocurcuminol, and hexahydrocurcumin glucuronide were present in small amounts. To test the hypothesis that curcumin metabolites resemble their progenitor in that they can inhibit COX-2 expression, curcumin and four of its metabolites at a concentration of 20 microM were compared in terms of their ability to inhibit phorbol ester-induced prostaglandin E2 (PGE2) production in human colonic epithelial cells. Curcumin reduced PGE2 levels to preinduction levels, whereas tetrahydrocurcumin, previously shown to be a murine metabolite of curcumin, hexahydrocurcumin, and curcumin sulfate, had only weak PGE2 inhibitory activity, and hexahydrocurcuminol was inactive. The results suggest that (a) the major products of curcumin biotransformation by hepatocytes occur only at low abundance in rat plasma after curcumin administration; and (b) metabolism of curcumin by reduction or conjugation generates species with reduced ability to inhibit COX-2 expression. Because the gastrointestinal tract seems to be exposed more prominently to unmetabolized curcumin than any other tissue, the results support the clinical evaluation of curcumin as a colorectal cancer chemopreventive agent.

Emotion, Social Theory, and Social Structure: A Macrosociological Approach

Abstract: Emotion, Social Theory, and Social Structure takes sociology in a new direction. It examines key aspects of social structure by using a fresh understanding of emotions categories. Through that synthesis emerge new perspectives on rationality, class structure, social action, conformity, basic rights, and social change. As well as giving an innovative view of social processes, J. M. Barbalet's study also reveals unappreciated aspects of emotions by considering fear, resentment, vengefulness, shame, and confidence in the context of social structure. While much has been written on the social consequences of excessive or pathological emotions, this book demonstrates the centrality of emotions to routine operations of social interaction. Dr Barbalet also re-evaluates the nature of social theory, for once the importance of emotions to social processes becomes clear, the intellectual constitution of sociology, and therefore its history, must be rethought.

BMPR2 Haploinsufficiency as the Inherited Molecular Mechanism for Primary Pulmonary Hypertension

Abstract: Primary pulmonary hypertension (PPH) is a potentially lethal disorder, because the elevation of the pulmonary arterial pressure may result in right-heart failure. Histologically, the disorder is characterized by proliferation of pulmonary-artery smooth muscle and endothelial cells, by intimal hyperplasia, and by in situ thrombus formation. Heterozygous mutations within the bone morphogenetic protein type II receptor (BMPR-II) gene (BMPR2), of the transforming growth factor beta (TGF-beta) cell-signaling superfamily, have been identified in familial and sporadic cases of PPH. We report the molecular spectrum of BMPR2 mutations in 47 additional families with PPH and in three patients with sporadic PPH. Among the cohort of patients, we have identified 22 novel mutations, including 4 partial deletions, distributed throughout the BMPR2 gene. The majority (58%) of mutations are predicted to lead to a premature termination codon. We have also investigated the functional impact and genotype-phenotype relationships, to elucidate the mechanisms contributing to pathogenesis of this important vascular disease. In vitro expression analysis demonstrated loss of BMPR-II function for a number of the identified mutations. These data support the suggestion that haploinsufficiency represents the common molecular mechanism in PPH. Marked variability of the age at onset of disease was observed both within and between families. Taken together, these studies illustrate the considerable heterogeneity of BMPR2 mutations that cause PPH, and they strongly suggest that additional factors, genetic and/or environmental, may be required for the development of the clinical phenotype.

Diffusion tensor magnetic resonance imaging in multiple sclerosis

Abstract: Objectives: To quantify, using diffusion tensor imaging (DTI), the tissue damage in lesions and normal-appearing white matter (NAWM) from a large cohort of patients with MS and to investigate the magnitude of the correlation between DTI-derived metrics and clinical disability. Methods: Dual-echo and DTI scans were obtained from 78 patients with relapsing-remitting, secondary progressive, or primary progressive MS and from 20 normal control participants. Post-contrast T1-weighted images were also obtained from the patients. After creating mean diffusivity () and fractional anisotropy (FA) images and image coregistration, and FA values were measured for 4846 lesions (3207 nonenhancing T1-isointense, 1511 nonenhancing T1-hypointense, and 128 enhancing), 497 NAWM areas from patients, and 160 white matter areas from the controls. Results: The average lesion was higher and the average lesion FA was lower than the corresponding quantities of the NAWM ( p p p p = 0.01). Significant correlations were found between T1 and T2 lesion volume and and FA of lesions and NAWM. In the overall patient sample, a moderate correlation was also found between lesion and the Expanded Disability Status Scale score ( r = 0.28, p = 0.01). However, the r value of this correlation was 0.48 in patients with secondary progressive MS, whose disability was also correlated with average lesion FA ( r = −0.50). Conclusions The results of this study show that DTI is able to identify MS lesions with severe tissue damage and to detect changes in the NAWM. They also indicate that DTI-derived measures are correlated with clinical disability, especially in patients with secondary progressive MS, thus suggesting a role for DTI in monitoring advanced phases of the disease.

Chronic immune activation and inflammation as the cause of malignancy.

Abstract: Several chronic infections known to be associated with malignancy have established oncogenic properties. However the existence of chronic inflammatory conditions that do not have an established infective cause and are associated with the development of tumours strongly suggests that the inflammatory process itself provides the prerequisite environment for the development of malignancy. This environment includes upregulation of mediators of the inflammatory response such as cyclo-oxygenase (COX)-2 leading to the production of inflammatory cytokines and prostaglandins which themselves may suppress cell mediated immune responses and promote angiogenesis. These factors may also impact on cell growth and survival signalling pathways resulting in induction of cell proliferation and inhibition of apoptosis. Furthermore, chronic inflammation may lead to the production of reactive oxygen species and metabolites such as malondialdehyde within the affected cells that may in turn induce DNA damage and mutations and, as a result, be carcinogenic. Here it is proposed that the conditions provided by a chronic inflammatory environment are so essential for the progression of the neoplastic process that therapeutic intervention aimed at inhibiting inflammation, reducing angiogenesis and stimulating cell mediated immune responses may have a major role in reducing the incidence of common cancers.

Anxiety in High-Functioning Children with Autism

Abstract: High-functioning children with autism were compared with two control groups on measures of anxiety and social worries. Comparison control groups consisted of children with specific language impairment (SLI) and normally developing children. Each group consisted of 15 children between the ages of 8 and 12 years and were matched for age and gender. Children with autism were found to be most anxious on both measures. High anxiety subscale scores for the autism group were separation anxiety and obsessive-compulsive disorder. These findings are discussed within the context of theories of autism and anxiety in the general population of children. Suggestions for future research are made.

Discontinuous hp -Finite Element Methods for Advection-Diffusion-Reaction Problems

Abstract: We consider the hp-version of the discontinuous Galerkin finite element method (DGFEM) for second-order partial differential equations with nonnegative characteristic form. This class of equations includes second-order elliptic and parabolic equations, advection-reaction equations, as well as problems of mixed hyperbolic-elliptic-parabolic type. Our main concern is the error analysis of the method in the absence of streamline-diffusion stabilization. In the hyperbolic case, an hp-optimal error bound is derived; here, we consider only advection-reaction problems which satisfy a certain (standard) positivity condition. In the self-adjoint elliptic case, an error bound that is h-optimal and p-suboptimal by $\frac{1}{2}$ a power of p is obtained. These estimates are then combined to deduce an error bound in the general case. For elementwise analytic solutions the method exhibits exponential rates of convergence under p-refinement. The theoretical results are illustrated by numerical experiments.

Bayesian methods in meta-analysis and evidence synthesis.

Abstract: This paper reviews the use of Bayesian methods in meta-analysis. Whilst there has been an explosion in the use of meta-analysis over the last few years, driven mainly by the move towards evidence-based healthcare, so too Bayesian methods are being used increasingly within medical statistics. Whilst in many meta-analysis settings the Bayesian models used mirror those previously adopted in a frequentist formulation, there are a number of specific advantages conferred by the Bayesian approach. These include: full allowance for all parameter uncertainty in the model, the ability to include other pertinent information that would otherwise be excluded, and the ability to extend the models to accommodate more complex, but frequently occurring, scenarios. The Bayesian methods discussed are illustrated by means of a meta-analysis examining the evidence relating to electronic fetal heart rate monitoring and perinatal mortality in which evidence is available from a variety of sources.

Explaining the Diffusion of Knowledge Management: The Role of Fashion

Abstract: This paper provides evidence on the emergence and diffusion of the discourse of knowledge management. A literature review of the knowledge management and learning organization literatures demonstrates the lack of learning from one discourse to another and major differences in the concerns and issues that they address. At the same time, evidence on the level of interest in each discourse shows a tendency towards a normal curve distribution. Analytically, these findings suggest that the widespread diffusion of knowledge management might be explained in terms of the management fashion model. However, further consideration of the professionally-differentiated appropriation of knowledge management concepts by the information systems and human resource communities suggests that the fashion model provides only a partial explanation for the observed diffusion of knowledge management.

Structural, signalling and regulatory properties of the group I metabotropic glutamate receptors: prototypic family C G-protein-coupled receptors.

Abstract: In 1991 a new type of G-protein-coupled receptor (GPCR) was cloned, the type 1a metabotropic glutamate (mGlu) receptor, which, despite possessing the defining seven-transmembrane topology of the GPCR superfamily, bore little resemblance to the growing number of other cloned GPCRs. Subsequent studies have shown that there are eight mammalian mGlu receptors that, together with the calcium-sensing receptor, the GABA(B) receptor (where GABA is gamma-aminobutyric acid) and a subset of pheromone, olfactory and taste receptors, make up GPCR family C. Currently available data suggest that family C GPCRs share a number of structural, biochemical and regulatory characteristics, which differ markedly from those of the other GPCR families, most notably the rhodopsin/family A GPCRs that have been most widely studied to date. This review will focus on the group I mGlu receptors (mGlu1 and mGlu5). This subgroup of receptors is widely and differentially expressed in neuronal and glial cells within the brain, and receptor activation has been implicated in the control of an array of key signalling events, including roles in the adaptative changes needed for long-term depression or potentiation of neuronal synaptic connectivity. In addition to playing critical physiological roles within the brain, the mGlu receptors are also currently the focus of considerable attention because of their potential as drug targets for the treatment of a variety of neurological and psychiatric disorders.

Crystal structure of the anthrax lethal factor

Abstract: Lethal factor (LF) is a protein (relative molecular mass 90,000) that is critical in the pathogenesis of anthrax1,2,3. It is a highly specific protease that cleaves members of the mitogen-activated protein kinase kinase (MAPKK) family near to their amino termini, leading to the inhibition of one or more signalling pathways4,5,6. Here we describe the crystal structure of LF and its complex with the N terminus of MAPKK-2. LF comprises four domains: domain I binds the membrane-translocating component of anthrax toxin, the protective antigen (PA); domains II, III and IV together create a long deep groove that holds the 16-residue N-terminal tail of MAPKK-2 before cleavage. Domain II resembles the ADP-ribosylating toxin from Bacillus cereus, but the active site has been mutated and recruited to augment substrate recognition. Domain III is inserted into domain II, and seems to have arisen from a repeated duplication of a structural element of domain II. Domain IV is distantly related to the zinc metalloprotease family, and contains the catalytic centre; it also resembles domain I. The structure thus reveals a protein that has evolved through a process of gene duplication, mutation and fusion, into an enzyme with high and unusual specificity.

Nanoclusters deposited on surfaces

Abstract: Recently, films produced by depositing pre-formed mass-selected atomic clusters in the size range 1–10 nm have generated a great deal of attention. The ability to control the size, density and in some cases the morphology of the deposited particles allows unprecedented flexibility in the creation of new types of nanostructure. The technique enables research on the fundamental behaviour of matter at mesoscopic length scales and in addition has enormous potential in the creation of new materials whose properties can be widely varied. This review will describe the technology used to produce the particles and deposit them, and discuss the details of the landing on the surface and subsequent surface kinetics. The equilibrium structures and morphologies of the particles will be reviewed as also how the organisation of the particle assemblies is influenced by the particle–surface and inter-particle interactions. As a result of the reduced average atomic coordination, the quantum size effect and the modified screening response in nanoscale systems, the clusters display novel electronic and magnetic properties and these will be described for a range of elements including transition metals, noble and simple metals, and rare-earths. In addition to the native properties, the effect of the interaction with the substrate and other deposited particles will be explored. Finally, the work on coated particles and particles embedded in matrices will be reviewed and the potential to create new materials and devices will be discussed.

Experimental confirmation of the predicted shallow donor hydrogen state in zinc oxide.

Abstract: We confirm the recent prediction that interstitial protium may act as a shallow donor in zinc oxide, by direct spectroscopic observation of its muonium counterpart. On implantation into ZnO, positive muons---chemically analogous to protons in this context---form paramagnetic centers below about 40 K. The muon-electron contact hyperfine interaction, as well as the temperature and activation energy for ionization, imply a shallow level. Similar results for the cadmium chalcogenides suggest that such shallow donor states are generic to the II-VI compounds. The donor level depths should serve as a guide for the electrical activity of interstitial hydrogen.

Recruitment, activation and retention of caspases-9 and -3 by Apaf-1 apoptosome and associated XIAP complexes

Abstract: During apoptosis, release of cytochrome c initiates dATP-dependent oligomerization of Apaf-1 and formation of the apoptosome. In a cell-free system, we have addressed the order in which apical and effector caspases, caspases-9 and -3, respectively, are recruited to, activated and retained within the apoptosome. We propose a multi-step process, whereby catalytically active processed or unprocessed caspase-9 initially binds the Apaf-1 apoptosome in cytochrome c/dATP-activated lysates and consequently recruits caspase-3 via an interaction between the active site cysteine (C287) in caspase-9 and a critical aspartate (D175) in caspase-3. We demonstrate that XIAP, an inhibitor-of-apoptosis protein, is normally present in high molecular weight complexes in unactivated cell lysates, but directly interacts with the apoptosome in cytochrome c/dATP-activated lysates. XIAP associates with oligomerized Apaf-1 and/or processed caspase-9 and influences the activation of caspase-3, but also binds activated caspase-3 produced within the apoptosome and sequesters it within the complex. Thus, XIAP may regulate cell death by inhibiting the activation of caspase-3 within the apoptosome and by preventing release of active caspase-3 from the complex.

Methylation associated inactivation of RASSF1A from region 3p21.3 in lung, breast and ovarian tumours.

Abstract: Previously we analysed overlapping homozygous deletions in lung and breast tumours/tumour lines and defined a small region of 120 kb (part of LCTSGR1) at 3p21.3 that contained putative lung and breast cancer tumour suppressor gene(s) (TSG). Eight genes including RASSF1 were isolated from the minimal region. However, extensive mutation analysis in lung tumours and tumour lines revealed only rare inactivating mutations. Recently, de novo methylation at a CpG island associated with isoform A of RASSF1 (RASSF1A) was reported in lung tumours and tumour lines. To investigate RASSF1A as a candidate TSG for various cancers, we investigated: (a) RASSF1A methylation status in a large series of primary tumour and tumour lines; (b) chromosome 3p allele loss in lung tumours and (c) RASSF1 mutation analysis in breast tumours. RASSF1A promoter region CpG island methylation was detected in 72% of SCLC, 34% of NSCLC, 9% of breast, 10% of ovarian and 0% of primary cervical tumours and in 72% SCLC, 36% NSCLC, 80% of breast and 40% of ovarian tumour lines. In view of the lower frequency of RASSF1 methylation in primary breast cancers we proceeded to RASSF1 mutation analysis in 40 breast cancers. No mutations were detected, but six single nucleotide polymorphisms were identified. Twenty of 26 SCLC tumours with 3p21.3 allelic loss had RASSF1A methylation, while only six out of 22 NSCLC with 3p21.3 allele loss had RASSF1A methylation (P=0.0012), one out of five ovarian and none out of six cervical tumours with 3p21.3 loss had RASSF1A methylation. These results suggest that (a) RASSF1A inactivation by two hits (methylation and loss) is a critical step in SCLC tumourigenesis and (b) RASSF1A inactivation is of lesser importance in NSCLC, breast, ovarian and cervical cancers in which other genes within LCTSGR1 are likely to be implicated.

X-ray Spectral Variability and Rapid Variability of the Soft X-ray Spectrum Seyfert 1 Galaxies Ark 564 and Ton S180

Abstract: The bright, soft X-ray spectrum Seyfert 1 galaxies Ark 564 and Ton S180 were monitored for 35 days and 12 days with ASCA and RXTE (and EUVE for Ton S180). The short time scale (hours-days) variability patterns were very similar across energy bands, with no evidence of lags between any of the energy bands studied. The fractional variability amplitude was almost independent of energy band. It is difficult to simultaneously explain soft Seyferts stronger variability, softer spectra, and weaker energy-dependence of the variability relative to hard Seyferts. The soft and hard band light curves diverged on the longest time scales probed, consistent with the fluctuation power density spectra that showed relatively greater power on long time scales in the softest bands. The simplest explanation is that a relatively hard, rapidly-variable component dominates the total X-ray spectrum and a slowly-variable soft excess is present in the lowest energy channels of ASCA. Although it would be natural to identify the latter with an accretion disk and the former with a corona surrounding it, a standard thin disk could not get hot enough to radiate significantly in the ASCA band, and the observed variability time scales are much too short. The hard component may have a more complex shape than a pure power-law. The most rapid factor of 2 flares and dips occurred within ~1000 sec in Ark 564 and a bit more slowly in Ton S180. The speed of the luminosity changes rules out viscous or thermal processes and limits the size of the individual emission regions to <~15 Schwarzschild radii (and probably much less), that is, to either the inner disk or small regions in a corona.

XMM-EPIC observation of MCG-6-30-15: direct evidence for the extraction of energy from a spinning black hole?

Abstract: We present XMM-Newton European Photon Imaging Camera (EPIC) observations of the bright Seyfert 1 galaxy MCG 6-30-15, focusing on the broad Fe Kline at � 6keV and the associated reflection continuum, which is believed to originate from the inner accretion disk. We find these reflection features to be extremely broad and red-shifted, indicating its origin from the very most central regions of the accretion disk. It seems likely that we have caught this source in the "deep minimum" state first observed by Iwasawa et al. (1996). The implied central concentration of X-ray illumination is difficult to understand in any pure accretiondisk model. We suggest that we are witnessing the extraction and dissipation of rotational energy from a spinning black hole by magnetic fields connecting the black hole or plunging region to the disk.

Grid Power Quality with Variable-Speed Wind Turbines

Abstract: Grid connection of renewable energy sources is essential if they are to be effectively exploited, but grid connection brings problems of voltage fluctuation and harmonic distortion. In this paper, appropriate modeling and simulation techniques are discussed for studying the voltage fluctuation and harmonic distortion in a network to which variable speed wind turbines are connected. Case studies on a distribution network show that the voltage fluctuation and harmonic problems can be minimized with the proposed power electronics interface and control system while the wind energy conversion system captures the maximum power from the wind as wind speed varies. The studies have also demonstrated the ability of the advanced converter to assist the system voltage regulation.

Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci

Abstract: We have carried out a genome screen for atopic dermatitis (AD) and have identified linkage to AD on chromosomes 1q21, 17q25 and 20p These regions correspond closely with known psoriasis loci, as does a previously identified AD locus on chromosome 3q21 The results indicate that AD is influenced by genes with general effects on dermal inflammation and immunity