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Imprinting, characterized by unequal expression of the offspring's genes in a parent-of-origin dependent manner, has been functionally implicated in brain development and in psychiatric disorders. In this study, unambiguous distortion in paternal but not maternal transmission of the disease-associated single-nucleotide polymorphism (SNP) rs6556547 (T/G) clearly indicated the presence of parent-of-origin effect (POE) in the GABAA receptor β2 subunit gene (GABRB2). ‘Flipping’ of allelic mRNA expression in heterozygotes of SNP rs2229944 (C/T) and the observed two-tiered distribution of mRNA expression levels in heterozygotes of the disease-associated SNP rs1816071 (G/A) furnished important support for the occurrence of imprinting at GABRB2. Imprinting in effect introduced heterozygotes from different parents-of-origin endowed with dissimilar mRNA expression capabilities. The deficit of upper-tiered expressions accounted for the lowered mRNA expression levels in the schizophrenic heterozygotes. This pointed to the necessity of differentiating between two kinds of heterozygotes of different parental origins in disease association studies on GABRB2. Bisulfite sequencing revealed hypermethylation in the neighborhood of SNP rs1816071, and methylation differences between controls and schizophrenia patients. Notably, allele-specific methylation was observed at the disease-associated SNPs rs6556547 and rs1816071. These findings raised the possibility that CpG methylation status of these sites could have an impact on the expression of GABRB2 and the risk of schizophrenia. Furthermore, the occurrence of imprinting and allele-specific methylation in the schizophrenia candidate gene GABRB2 was compatible with the epigenetic hypothesis for schizophrenia pathophysiology, thereby calling for the need to explore the role of epigenetic factors in mediating susceptibility to schizophrenia.
Previously the GABA(A) receptor beta-2 subunit gene GABRB2 was found to be associated with schizophrenia (SCZ). for SNPs and haplotypes in GRBRB2, the associations with bipolar disorder (BPD), the functional consequences on GABRB2 expression and their relationship to demographic and clinical characteristics in BPD and SCZ remain to be elucidated.
Case-control analysis was performed for association study of GABRB2 with BPD, and its mRNA expression in postmortem BPD brains was examined using quantitative real-time PCR. Quantitative trait analysis was subsequently employed to assess the covariate effects of demographic and clinical characteristics on genotypic correlation of GABRB2 expression in SCZ and BPD.
Significant association of GABRB2 with BPD and reduction in GABRB2 mRNA expression in BPD brains were observed in the present study. Duration of illness (DOI) was found to be a significant covariate for the correlation of the disease-associated SNPs rs1816071, rs1816072 and rs187269 with GABRB2 expression in both SCZ and BPD. for individuals with homozygous major genotypes of these SNPs, while GABRB2 expression increased with age in the controls, it decreased with DOI and age in SCZ, and with DOI in BPD. with age of onset as covariate, these three SNPs were significantly correlated with antipsychotic dosage in SCZ.
These results have thus revealed correlations of GABRB2 SNPs and expression not only with the occurrence of SCZ and BPD, but also with the clinical characteristics of patients, therefore providing support for a shared etiological role played by the gene in both diseases.
Abnormal effort-based decision-making represents a potential mechanism underlying motivational deficits (amotivation) in psychotic disorders. Previous research identified effort allocation impairment in chronic schizophrenia and focused mostly on physical effort modality. No study has investigated cognitive effort allocation in first-episode psychosis (FEP).
Cognitive effort allocation was examined in 40 FEP patients and 44 demographically-matched healthy controls, using Cognitive Effort-Discounting (COGED) paradigm which quantified participants’ willingness to expend cognitive effort in terms of explicit, continuous discounting of monetary rewards based on parametrically-varied cognitive demands (levels N of N-back task). Relationship between reward-discounting and amotivation was investigated. Group differences in reward-magnitude and effort-cost sensitivity, and differential associations of these sensitivity indices with amotivation were explored.
Patients displayed significantly greater reward-discounting than controls. In particular, such discounting was most pronounced in patients with high levels of amotivation even when N-back performance and reward base amount were taken into consideration. Moreover, patients exhibited reduced reward-benefit sensitivity and effort-cost sensitivity relative to controls, and that decreased sensitivity to reward-benefit but not effort-cost was correlated with diminished motivation. Reward-discounting and sensitivity indices were generally unrelated to other symptom dimensions, antipsychotic dose and cognitive deficits.
This study provides the first evidence of cognitive effort-based decision-making impairment in FEP, and indicates that decreased effort expenditure is associated with amotivation. Our findings further suggest that abnormal effort allocation and amotivation might primarily be related to blunted reward valuation. Prospective research is required to clarify the utility of effort-based measures in predicting amotivation and functional outcome in FEP.
Expert judgement is frequently used within general insurance. It tends to be a method of last resort and used where data is sparse, non-existent or non-applicable to the problem under consideration. Whilst such judgements can significantly influence the end results, their quality is highly variable. The use of the term “expert judgement” itself can lend a generous impression of credibility to what may be a little more than a guess. Despite the increased emphasis placed on the importance of robust expert judgements in regulation, actuarial research to date has focussed on the more technical or data-driven methods, with less emphasis on how to use and incorporate softer information or how best to elicit judgements from others in a way that reduces cognitive biases. This paper highlights the research that the Getting Better Judgement Working Party has conducted in this area. Specifically, it covers the variable quality of expert judgement, both within and outside the regulatory context, and presents methods that may be applied to improve its formation. The aim of this paper is to arm the insurance practitioner with tools to distinguish between low-quality and high-quality judgements and improve the robustness of judgements accordingly, particularly for highly material circumstances.
Deficits in executive function (EF), impaired school functioning and altered white matter integrity in frontostriatal networks have been associated with attention-deficit/hyperactivity disorder (ADHD). However, relationships between impairments in these areas are unclear. Using a sample of youths with and without ADHD, this study examined the association between microstructural integrity of frontostriatal tracts and school dysfunction and the mediating roles of EF and ADHD symptoms in this association.
The sample included 32 Taiwanese youths with ADHD and 32 age-, sex-, handedness- and IQ-matched typically-developing (TD) youths. Participants were assessed using psychiatric interviews, parent reports on ADHD symptoms and school functioning, and EF measures from the Cambridge Neuropsychological Test Automated Battery (CANTAB). The frontostriatal tracts were reconstructed by diffusion spectrum imaging (DSI) tractography and were subdivided into four functionally distinct segments: caudate–dorsolateral, caudate–medial prefrontal, caudate–orbitofrontal and caudate–ventrolateral tracts.
Youths with ADHD, relative to TD youths, showed altered white matter integrity in all four bilateral pairs of frontostriatal tracts (decreased general fractional anisotropy, GFA), had poor attention, vigilance and response inhibition, and showed impaired school functioning. Altered microstructural integrity in frontostriatal tracts was significantly associated with school dysfunction, which was mediated by EF measures of attention/vigilance and response inhibition in addition to inattention and hyperactivity symptoms.
Our findings demonstrate an association between white matter integrity in the frontostriatal networks and school functioning and suggest that EF deficits and ADHD symptoms may be the mediating mechanisms for this association. Future research is needed to test the directionality and specificity of this finding.
To investigate the simultaneous occurrence of more than 1 Clostridium difficile ribotype in patients' stool samples at the time of diagnostic testing.
Stool samples submitted for diagnostic testing for the presence of toxigenic C. difficile were obtained for 102 unique patients. A total of 95 single colonies of C. difficile per stool sample were isolated on selective media, subcultured alongside negative (uninoculated) controls, and polymerase chain reaction (PCR) ribotyped using capillary gel electrophoresis.
Capillary-based PCR ribotyping was successful for 9,335 C. difficile isolates, yielding a median of 93 characterized isolates per stool sample (range, 69-95). More than 1 C. difficile ribotype was present in 16 of 102 (16%) C. difficile infection (CDI) cases; 2 of the 16 mixtures were composed of at least 3 ribotypes, while the remaining 14 were composed of at least 2.
Deep sampling of patient stool samples coupled with capillary-based PCR ribotyping identified a high rate of mixed CDI cases compared with previous estimates. Studies seeking to quantify the clinical significance of particular C. difficile ribotypes should account for mixed cases of disease.
The Australian Square Kilometre Array Pathfinder (ASKAP) will give us an unprecedented opportunity to investigate the transient sky at radio wavelengths. In this paper we present VAST, an ASKAP survey for Variables and Slow Transients. VAST will exploit the wide-field survey capabilities of ASKAP to enable the discovery and investigation of variable and transient phenomena from the local to the cosmological, including flare stars, intermittent pulsars, X-ray binaries, magnetars, extreme scattering events, interstellar scintillation, radio supernovae, and orphan afterglows of gamma-ray bursts. In addition, it will allow us to probe unexplored regions of parameter space where new classes of transient sources may be detected. In this paper we review the known radio transient and variable populations and the current results from blind radio surveys. We outline a comprehensive program based on a multi-tiered survey strategy to characterise the radio transient sky through detection and monitoring of transient and variable sources on the ASKAP imaging timescales of 5 s and greater. We also present an analysis of the expected source populations that we will be able to detect with VAST.
A survey of the Milky Way disk and the Magellanic System at the wavelengths of the 21-cm atomic hydrogen (H i) line and three 18-cm lines of the OH molecule will be carried out with the Australian Square Kilometre Array Pathfinder telescope. The survey will study the distribution of H i emission and absorption with unprecedented angular and velocity resolution, as well as molecular line thermal emission, absorption, and maser lines. The area to be covered includes the Galactic plane (|b| < 10°) at all declinations south of δ = +40°, spanning longitudes 167° through 360°to 79° at b = 0°, plus the entire area of the Magellanic Stream and Clouds, a total of 13 020 deg2. The brightness temperature sensitivity will be very good, typically σT≃ 1 K at resolution 30 arcsec and 1 km s−1. The survey has a wide spectrum of scientific goals, from studies of galaxy evolution to star formation, with particular contributions to understanding stellar wind kinematics, the thermal phases of the interstellar medium, the interaction between gas in the disk and halo, and the dynamical and thermal states of gas at various positions along the Magellanic Stream.
In this work, Dopant Segregated Schottky Barrier (DSSB) and Schottky Barrier (SB) vertical silicon nanowire (VSiNW) diodes were fabricated on p-type Si substrate using CMOS-compatible processes to investigate the effects of segregated dopants at the silicide/silicon interface and different annealing processes on nickel silicide formation in DSSB VSiNW diodes. With segregated dopants at the silicide/silicon interface, VSiNW diodes showed higher on-current, due to an enhanced carrier tunneling, and much lower leakage current. This can be attributed to the altered energy bands caused by the accumulated Arsenic dopants at the interface. Moreover, DSSB VSiNW diodes also gave ideality factor much closer to unity and exhibited lower electron SBH (ΦBn) than SB VSiNW diodes. This proved that interfacial accumulated dopants could impede the inhomogeneous nature of the Schottky diodes and simultaneously, minimize the effect of Fermi level pinning and ionization of surface defect states. Comparing the impact of different silicide formation annealing using DSSB VSiNW diodes, the 2-step anneal process reduces the silicide intrusion length within the SiNW by ~ 5X and the silicide interface was smooth along the (100) direction. Furthermore, the 2-step DSSB VSiNW diode also exhibited much lower leakage current and an ideality factor much closer to unity, as compared to 1-step DSSB VSiNW diode.
This study presents an analytical model for describing propagation of Rayleigh waves along the impermeable surface of an unsaturated poroelastic half-space. This model is based on the existence of the three modes of dilatational waves which employ the poroelastic equations developed for a porous medium containing two immiscible viscous compressible fluids (Lo, Sposito and Majer, ). In a two-fluid saturated medium, the three Rayleigh waves induced by the three dilatational waves can be expressed as R1, R2, and R3 waves in descending order of phase speed magnitude. As the excitation frequency and water saturation are given, the dispersion equation of a cubic polynomial can be solved numerically to obtain the phase speeds and attenuation coefficients of the R1, R2, and R3 waves. The numerical results show the phase speed of the R1 wave is frequency independent (non-dispersive). Comparatively, the R1 wave speed is 93 ∼ 95% of the shear wave speed, and 28% to 49% of the first dilatational wave speed for selected frequencies between 50Hz & 200Hz and relative water saturation ranging from 0.01 to 0.99. However, the R2 and R3 waves are dispersive at the frequencies examined. The ratios of R2 and R3 wave phase speeds to the second and third dilatational wave speeds fall between 56% and 90%. The R1 wave attenuates the least while the R3 wave has the highest attenuation coefficient. Furthermore, the phase speed of the R1 wave under an impermeable surface approaches 1.01 ∼ 1.37 times of the R1 wave under a permeable boundary. Impermeability has significant influence on the phase speeds and attenuation coefficients of the R1 and R2 waves at high water saturation due to the existence of confined fluids.
We observed several H ii regions in the dwarf irregular galaxy NGC 6822 using the infrared spectrograph on the Spitzer Space Telescope. Our aim is twofold: first, to examine the neon to sulfur abundance ratio in order to determine how much it may vary and whether or not, it is fairly ‘universal’; second, to discriminate and test the predicted ionizing spectral energy distribution between various stellar atmosphere models by comparing with our derivation of the ratio of fractional ionizations involving neon and sulfur. This work extends our previous similar studies of H ii regions in M83 and M33 to lower metallicities.
Changes in the cardiac β-adrenergic system in early stages of Trypanosoma cruzi infection have been described. Here, we studied an early (135 days post-infection–p.i.) and a late stage (365 days p.i.) of the cardiac chronic form of the experimental infection (Tulahuen or SGO-Z12 strains), determining plasma epinephrine and norepinephrine levels, β-receptor density, affinity and function, cardiac cAMP concentration and phosphodiesterase activity, cardiac contractility, and the presence of β-receptor autoantibodies. Tulahuen-infected mice presented lower epinephrine and norepinephrine levels; lower β-receptor affinity and density; a diminished norepinephrine response and higher cAMP levels in the early stage, and a basal contractility similar to non-infected controls in the early and augmented in the late stage. The Tulahuen strain induced autoantibodies with weak β-receptor interaction. SGO-Z12-infected mice presented lower norepinephrine levels and epinephrine levels that diminished with the evolution of the infection; lower β-receptor affinity and an increased density; unchanged epinephrine and norepinephrine response in the early and a diminished response in the late stage; higher cAMP levels and unchanged basal contractility. The SGO-Z12 isolate induced β-receptor autoantibodies with strong interaction with the β-receptors. None of the antibodies, however, acted a as β-receptor agonist. The present results demonstrate that this system is seriously compromised in the cardiac chronic stage of T. cruzi infection.
Carbon monoxide is an endogenous vasodilator gas produced by the enzyme heme oxygenase (HO). HO is expressed in human nasal mucosa, but its pathophysiological role in nasal inflammatory diseases is not fully understood. The aim of this study was to detect and compare the expression of HO-1 and -2 isoforms in nasal polyps with normal nasal mucosa.
Immunohistochemical analysis using antibodies specific for HO-1 and -2 was conducted on nasal polyps from nine patients with allergic nasal polyposis, and on normal nasal mucosa from six controls.
Intense HO-1 immunoreactivity was observed in nasal polyp epithelium but was absent in normal nasal mucosa. HO-2 staining was observed in respiratory epithelium, vascular endothelium and seromucous glands, with no difference observed between nasal polyps and normal nasal mucosa.
HO-1 expression is up-regulated in nasal polyp epithelium, supporting the theory that respiratory epithelium plays a role in the pathogenesis of nasal polyposis.
We report the use of nickel-platinum silicide (NiPtSi) as a source/drain (S/D) material for strain engineering in P-MOSFETs to improve drive current performance. The material and electrical characteristics of NiPtSi with various Pt concentrations was investigated and compared with those of NiSi. Ni0.95Pt0.05Si was selected for device integration. A 0.18 μm gate length P-MOSFET achieved a 22% gain in IDsat when Ni0.95Pt0.05Si S/D is employed instead of NiSi S/D. The enhancement is attributed to strain modification effects related to the nickel-platinum silicidation process.
Twenty-one Candida albicans isolates from three HIV-infected patients were collected over a period of 3 years and characterized for fluconazole susceptibility, infectivity and genetic relatedness. Fluconazole resistance was found in five isolates, four exhibited dose-dependent susceptibility and the remainder were fully susceptible to this agent. Pulsed-field gel electrophoresis of SfiI restriction digests of the genomic DNA from the isolates revealed that isolates from the same swab specimen were identical despite differences in susceptibility to fluconazole and isolates recovered over time from the three patients retained clonally related DNA fingerprints within each patient. This small-scale study confirms the persistence of oral colonization of C. albicans strains in HIV-infected patients. Clinical data also suggests that the primary infecting strain may become a persistent colonist in the oral cavity once the immune function of the patient has been restored.
This paper briefly describes the principle of operation and science goals of the AMANDA high energy neutrino telescope located at the South Pole, Antarctica. Results from an earlier phase of the telescope, called AMANDA-BIO, demonstrate both reliable operation and the broad astrophysical reach of this device, which includes searches for a variety of sources of ultrahigh energy neutrinos: generic point sources, Gamma-Ray Bursts and diffuse sources. The predicted sensitivity and angular resolution of the telescope were confirmed by studies of atmospheric muon and neutrino backgrounds. We also report on the status of the analysis from AMANDA-II, a larger version with far greater capabilities. At this stage of analysis, details of the ice properties and other systematic uncertainties of the AMANDA-II telescope are under study, but we have made progress toward critical science objectives. In particular, we present the first preliminary flux limits from AMANDA-II on the search for continuous emission from astrophysical point sources, and report on the search for correlated neutrino emission from Gamma Ray Bursts detected by BATSE before decommissioning in May 2000. During the next two years, we expect to exploit the full potential of AMANDA-II with the installation of a new data acquisition system that records full waveforms from the in-ice optical sensors.