We present new observational determinations of the evolution of the 2–10 keV X-ray luminosity function (XLF) of active galactic nuclei (AGN). We utilize data from a number of surveys including both ...the 2 Ms Chandra Deep Fields and the AEGIS-X 200 ks survey, enabling accurate measurements of the evolution of the faint end of the XLF. We combine direct, hard X-ray selection and spectroscopic follow-up or photometric redshift estimates at z < 1.2 with a rest-frame UV colour pre-selection approach at higher redshifts to avoid biases associated with catastrophic failure of the photometric redshifts. Only robust optical counterparts to X-ray sources are considered using a likelihood ratio matching technique. A Bayesian methodology is developed that considers redshift probability distributions, incorporates selection functions for our high-redshift samples and allows robust comparison of different evolutionary models. We statistically account for X-ray sources without optical counterparts to correct for incompleteness in our samples. We also account for Poissonian effects on the X-ray flux estimates and sensitivities and thus correct for the Eddington bias. We find that the XLF retains the same shape at all redshifts, but undergoes strong luminosity evolution out to z∼ 1, and an overall negative density evolution with increasing redshift, which thus dominates the evolution at earlier times. We do not find evidence that a luminosity-dependent density evolution, and the associated flattening of the faint-end slope, is required to describe the evolution of the XLF. We find significantly higher space densities of low-luminosity, high-redshift AGN than in prior studies, and a smaller shift in the peak of the number density to lower redshifts with decreasing luminosity. The total luminosity density of AGN peaks at z= 1.2 ± 0.1, but there is a mild decline to higher redshifts. We find that >50 per cent of black hole growth takes place at z > 1, with around half in LX < 1044 erg s−1 AGN.
Variability is a problem for the scalability of semiconductor quantum devices. The parameter space is large, and the operating range is small. Our statistical tuning algorithm searches for specific ...electron transport features in gate-defined quantum dot devices with a gate voltage space of up to eight dimensions. Starting from the full range of each gate voltage, our machine learning algorithm can tune each device to optimal performance in a median time of under 70 minutes. This performance surpassed our best human benchmark (although both human and machine performance can be improved). The algorithm is approximately 180 times faster than an automated random search of the parameter space, and is suitable for different material systems and device architectures. Our results yield a quantitative measurement of device variability, from one device to another and after thermal cycling. Our machine learning algorithm can be extended to higher dimensions and other technologies.
Genetic Control over the Resting Brain Glahn, D. C.; Winkler, A. M.; Kochunov, P. ...
Proceedings of the National Academy of Sciences - PNAS,
01/2010, Letnik:
107, Številka:
3
Journal Article, Web Resource
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The default-mode network, a coherent resting-state brain network, is thought to characterize basal neural activity. Aberrant defaultmode connectivity has been reported in a host of neurological and ...psychiatric illnesses and in persons at genetic risk for such illnesses. Whereas the neurophysiologic mechanisms that regulate defaultmode connectivity are unclear, there is growing evidence that genetic factors play a role. In this report, we estimate the importance of genetic effects on the default-mode network by examining covariation patterns in functional connectivity among 333 individuals from 29 randomly selected extended pedigrees. Heritability for default-mode functional connectivity was 0.424 ± 0.17 (P = 0.0046). Although neuroanatomic variation in this network was also heritable, the genetic factors that influence default-mode functional connectivity and gray-matter density seem to be distinct, suggesting that unique genes influence the structure and function of the network. In contrast, significant genetic correlations between regions within the network provide evidence that the same genetic factors contribute to variation in functional connectivity throughout the default mode. Specifically, the left parahippocampal region was genetically correlated with all other network regions. In addition, the posterior cingulate/precuneus region, medial prefrontal cortex, and right cerebellum seem to form a subnetwork. Default-mode functional connectivity is influenced by genetic factors that cannot be attributed to anatomic variation or a single region within the network. By establishing the heritability of default-mode functional connectivity, this experiment provides the obligatory evidence required before these measures can be considered as endophenotypes for psychiatric or neurological illnesses or to identify genes influencing intrinsic brain function.
Abstract Purpose Despite concerted actions to streamline care transitions, the journey from hospital to home remains hazardous for patients and caregivers. Remarkably little is known about the ...patient and caregiver experience during care transitions, the services they need, or the outcomes they value. The aims of this study were to (1) describe patient and caregiver experiences during care transitions and (2) characterize patient and caregiver desired outcomes of care transitions and the health services associated with them. Methods We interviewed 138 patients and 110 family caregivers recruited from 6 health networks across the United States. We conducted 34 homogenous focus groups (103 patients, 65 caregivers) and 80 key informant interviews (35 patients, 45 caregivers). Audio recordings were transcribed and analyzed using principles of grounded theory to identify themes and the relationship between them. Results Patients and caregivers identified 3 desired outcomes of care transition services: (1) to feel cared for and cared about by medical providers, (2) to have unambiguous accountability from the health care system, and (3) to feel prepared and capable of implementing care plans. Five care transition services or provider behaviors were linked to achieving these outcomes: (1) using empathic language and gestures, (2) anticipating the patient's needs to support self-care at home, (3) collaborative discharge planning, (4) providing actionable information, and (5) providing uninterrupted care with minimal handoffs. Conclusions Clear accountability, care continuity, and caring attitudes across the care continuum are important outcomes for patients and caregivers. When these outcomes are achieved, care is perceived as excellent and trustworthy. Otherwise, the care transition is experienced as transactional and unsafe, and leaves patients and caregivers feeling abandoned by the health care system.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
There is an increasing demand for accurate biomarkers for early non-invasive colorectal cancer detection. We employed a genome-scale marker discovery method to identify and verify candidate DNA ...methylation biomarkers for blood-based detection of colorectal cancer.
We used DNA methylation data from 711 colorectal tumors, 53 matched adjacent-normal colonic tissue samples, 286 healthy blood samples and 4,201 tumor samples of 15 different cancer types. DNA methylation data were generated by the Illumina Infinium HumanMethylation27 and the HumanMethylation450 platforms, which determine the methylation status of 27,578 and 482,421 CpG sites respectively. We first performed a multistep marker selection to identify candidate markers with high methylation across all colorectal tumors while harboring low methylation in healthy samples and other cancer types. We then used pre-therapeutic plasma and serum samples from 107 colorectal cancer patients and 98 controls without colorectal cancer, confirmed by colonoscopy, to verify candidate markers. We selected two markers for further evaluation: methylated THBD (THBD-M) and methylated C9orf50 (C9orf50-M). When tested on clinical plasma and serum samples these markers outperformed carcinoembryonic antigen (CEA) serum measurement and resulted in a high sensitive and specific test performance for early colorectal cancer detection.
Our systematic marker discovery and verification study for blood-based DNA methylation markers resulted in two novel colorectal cancer biomarkers, THBD-M and C9orf50-M. THBD-M in particular showed promising performance in clinical samples, justifying its further optimization and clinical testing.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Context:
Inadequate vitamin D status is common within elderly populations and may be implicated in the etiology of autoimmune disease and inflammation. Few studies have investigated the relationship ...between vitamin D status and age-related immune dysfunction in humans.
Objective:
The aim of this study was to investigate the association between vitamin D status and immune markers of inflammation in a large sample of older adults.
Design, Setting, and Participants:
An observational investigation of 957 Irish adults (>60 years of age) recruited in Northern Ireland (55°N latitude) as part of the Trinity Ulster Department of Agriculture aging cohort study.
Main Outcome Measure:
We measured serum 25-hydroxyvitamin D (25(OH)D) by liquid chromatography tandem mass spectrometry and serum cytokines IL-6, TNF-α, IL-10, and C-reactive protein (CRP) by ELISA.
Results:
Concentrations of IL-6, CRP, and the ratios of IL-6 to IL-10 and CRP to IL-10 were significantly higher in individuals with deficient (<25 nmol/L) serum 25(OH)D compared with those with sufficient (>75 nmol/L) status after adjustment for age, sex, and body mass index (P < .05). Vitamin D status was a significant predictor of the IL-6 to IL-10 cytokine ratio, and those participants defined as deficient were significantly more likely to have an IL-6 to IL-10 ratio >2:1 compared with those defined as sufficient.
Conclusions:
This study demonstrated significant associations between low vitamin D status and markers of inflammation (including the ratio of IL-6 to IL-10) within elderly adults. These findings suggest that an adequate vitamin D status may be required for optimal immune function, particularly within the older adult population.
This was a longitudinal study utilising the Irish Longitudinal Study on Ageing (n 3849 aged ≥ 50 years) and investigated the relationship between blood plasma folate and B12 levels at baseline (wave ...1) and incident depressive symptoms at 2 and 4 years (waves 2 and 3). A score ≥ 9 on the Center for Epidemiological Studies Depression Scale-8 at wave 2 or 3 was indicative of incident depressive symptoms. B12 status profiles (pmol/l) were defined as < 185, deficient low; 185 to < 258, low normal; > 258–601, normal and > 601 high. Folate status profiles (nmol/l) were defined as ≤ 10·0, deficient low; > 10–23·0, low normal; > 23·0–45·0, normal; >45·0, high. Logistic regression models were used to analyse the longitudinal associations. Both B12 and folate plasma concentrations were lower in the group with incident depressive symptoms v. non-depressed (folate: 21·4 v. 25·1 nmol/l; P = 0·0003; B12:315·7 v. 335·9 pmol/l; P = 0·0148). Regression models demonstrated that participants with deficient-low B12 status at baseline had a significantly higher likelihood of incident depression 4 years later (OR 1·51, 95 % CI 1·01, 2·27, P = 0·043). This finding remained robust after controlling for relevant covariates. No associations of folate status with incident depression were observed. Older adults with deficient-low B12 status had a 51 % increased likelihood of developing depressive symptoms over 4 years. The findings highlight the need to further explore the low-cost benefits of optimising vitamin B12 status for depression in older adults.
The tetrodotoxin-resistant sodium channel alpha subunit Nav1.8 is expressed exclusively in primary sensory neurons and is proposed to play an important role in sensitization of nociceptors. Here we ...compared visceral pain and referred hyperalgesia in Nav1.8-null mice and their wild-type littermates in five tests that differ in the degree to which behavior depends on spontaneous, ongoing firing in sensitized nociceptors. Nav1.8-null mice showed normal nociceptive behavior provoked by acute noxious stimulation of abdominal viscera (intracolonic saline or intraperitoneal acetylcholine). However, Nav1.8-null mutants showed weak pain and no referred hyperalgesia to intracolonic capsaicin, a model in which behavior is sustained by ongoing activity in nociceptors sensitized by the initial application. Nav1.8-null mice also showed blunted pain and hyperalgesia to intracolonic mustard oil, which sensitizes nociceptors but also provokes tissue damage. To distinguish between a possible role for Nav1.8 in ongoing activity per se and ongoing activity after sensitization in the absence of additional stimuli, we tried a visceral model of tonic noxious chemical stimulation, cyclophosphamide cystitis. Cyclophosphamide produces cystitis by gradual accumulation of toxic metabolites in the bladder. In this model, Nav1.8-null mice showed normal responses. There were no differences between null mutants and their normal littermates in tissue damage and inflammation evoked by any of the stimuli tested, suggesting that the behavioral differences are not secondary to impairment of inflammatory responses. We conclude that there is an essential role for Nav1.8 in mediating spontaneous activity in sensitized nociceptors.
Cannabinoids are analgesic in man, but their use is limited by their psychoactive properties. One way to avoid cannabinoid receptor subtype 1 (CB1R)-mediated central side-effects is to develop CB1R ...agonists with limited CNS penetration. Activation of peripheral CB1Rs has been proposed to be analgesic, but the relative contribution of peripheral CB1Rs to the analgesic effects of systemic cannabinoids remains unclear. Here we addressed this by exploring the analgesic properties and site of action of AZ11713908, a peripherally restricted CB1R agonist, in rodent pain models. Systemic administration of AZ11713908 produced robust efficacy in rat pain models, comparable to that produced by WIN 55, 212-2, a CNS-penetrant, mixed CB1R and CB2R agonist, but AZ11713908 generated fewer CNS side-effects than WIN 55, 212-in a rat Irwin test. Since AZ11713908 is also a CB2R inverse agonist in rat and a partial CB2R agonist in mouse, we tested the specificity of the effects in CB1R and CB2R knock-out (KO) mice. Analgesic effects produced by AZ11713908 in wild-type mice with Freund’s complete adjuvant-induced inflammation of the tail were completely absent in CB1R KO mice, but fully preserved in CB2R KO mice. An in vivo electrophysiological assay showed that the major site of action of AZ11713908 was peripheral. Similarly, intraplantar AZ11713908 was also sufficient to induce robust analgesia. These results demonstrate that systemic administration of AZ11713908, produced robust analgesia in rodent pain models via peripheral CB1R. Peripherally restricted CB1R agonists provide an interesting novel approach to analgesic therapy for chronic pain.
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