301 research outputs found

    Brain Activation by Visual Food-Related Stimuli and Correlations with Metabolic and Hormonal Parameters: A fMRI Study

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    Regional brain activity in 15 healthy, normal weight males during processing of visual food stimuli in a satiated and a hungry state was examined and correlated with neuroendocrine factors known to be involved in hunger and satiated states. Two functional Magnetic Resonance Imaging (fMRI) sessions were performed with a one week interval, after overnight fasting or 1 hour after a standardized meal. Blood samples and appetite assessment were obtained after each fMRI session. Main effects of processing food versus non-food stimuli were observed in the ventral visual stream, including the fusiform gyrus and hippocampal areas bilaterally, significantly more in the fasting state. Leptin concentration correlated negatively with activity in the left hippocampal area and right insula during the satiation condition. A positive correlation between ghrelin and "thought of food" hunger scores were found. The positive correlation between ghrelin and food related activation in the insula areas and the right hippocampus during fasting did not reach significance. Conclusion: The increased activation of food vs non-food pictures in the ventral visual stream reflects increased salience of food pictures when subjects are hungry. Leptin was associated with activations in areas involved in processing of new information and emotion. Β© Jakobsdottir et al

    Dense seismic network provides new insight into the 2007 Upptyppingar dyke intrusion

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    Factors such as network geometry, network size and phase-picking accuracy have significant\ud effects on the precision of seismic hypocentre locations. In turn, the precision of the hypocentral locations\ud dictates the degree to which morphological details within seismic swarms may be resolved. The Icelandic\ud national seismic network (SIL) is designed to monitor seismic activity across large expanses of Iceland in realtime\ud using automated earthquake detection and location software. Here we examine the performance of the\ud SIL network relative to a much denser, local network of seismometers deployed around the Askja volcano in\ud the Northern Volcanic Zone. A subset of earthquakes from the 2007–2008 dyke intrusion beneath Mt. Upptyppingar\ud is used to compare single- and multi-event hypocentral locations. Specifically, we highlight 288, high\ud signal-to-noise ratio events that occurred during an intensive sequence of earthquakes from 6–24 July 2007,\ud when the temporary Askja network was active. A careful refinement of phase onsets recorded by our wellconfigured,\ud dense network of receivers reveals hypocentres clustered tightly on a planar structure, interpreted\ud as a dyke dipping at 49. The root-mean-square (RMS) misfit to the plane (114 m) is only slightly greater than\ud the uncertainties in relative locations of the earthquakes themselves, and constitutes a three-fold reduction in\ud RMS misfit over SIL relative locations. The improved precision, facilitated predominantly by a more favourable\ud network size and configuration, permits a more detailed analysis of the intrusion

    Crustal structure beneath western and eastern Iceland from surface waves and receiver functions

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    We determine the crustal structures beneath 14 broad-band seismic stations, deployed in western, eastern, central and southern Iceland, using surface wave dispersion curves and receiver functions. We implement a method to invert receiver functions using constraints obtained from genetic algorithm inversion of surface waves. Our final models satisfy both data sets. The thickness of the upper crust, as defined by the velocity horizon Vs= 3.7 km sβˆ’1, is fairly uniform at ∼6.5–9 km beneath the Tertiary intraplate areas of western and eastern Iceland, and unusually thick at 11 km beneath station HOT22 in the far south of Iceland. The depth to the base of the lower crust, as defined by the velocity horizon Vs= 4.1 km sβˆ’1 is ∼20–26 km in western Iceland and ∼27–33 km in eastern Iceland. These results agree with those of explosion profiles that detect a thinner crust beneath western Iceland than beneath eastern Iceland. An earlier report of a substantial low-velocity zone beneath the Middle Volcanic Zone in the lower crust is confirmed by a similar observation beneath an additional station there. As was found in previous receiver function studies, the most reliable feature of the results is the clear division into an upper sequence that is a few kilometres thick where velocity gradients are high, and a lower, thicker sequence where velocity gradients are low. The transition to typical mantle velocities is variable, and may range from being very gradational to being relatively sharp and clear. A clear Moho, by any definition, is rarely seen, and there is thus uncertainty in estimates of the thickness of the crust in many areas. Although a great deal of seismic data are now available constraining the structures of the crust and upper mantle beneath Iceland, their geological nature is not well understood

    APOBEC3 mutational signatures are associated with extensive and diverse genomic instability across multiple tumour types

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    Background: The APOBEC3 (apolipoprotein B mRNA editing enzyme catalytic polypeptide 3) family of cytidine deaminases is responsible for two mutational signatures (SBS2 and SBS13) found in cancer genomes. APOBEC3 enzymes are activated in response to viral infection, and have been associated with increased mutation burden and TP53 mutation. In addition to this, it has been suggested that APOBEC3 activity may be responsible for mutations that do not fall into the classical APOBEC3 signatures (SBS2 and SBS13), through generation of double strand breaks.Previous work has mainly focused on the effects of APOBEC3 within individual tumour types using exome sequencing data. Here, we use whole genome sequencing data from 2451 primary tumours from 39 different tumour types in the Pan-Cancer Analysis of Whole Genomes (PCAWG) data set to investigate the relationship between APOBEC3 and genomic instability (GI). Results and conclusions: We found that the number of classical APOBEC3 signature mutations correlates with increased mutation burden across different tumour types. In addition, the number of APOBEC3 mutations is a significant predictor for six different measures of GI. Two GI measures (INDELs attributed to INDEL signatures ID6 and ID8) strongly suggest the occurrence and error prone repair of double strand breaks, and the relationship between APOBEC3 mutations and GI remains when SNVs attributed to kataegis are excluded. We provide evidence that supports a model of cancer genome evolution in which APOBEC3 acts as a causative factor in the development of diverse and widespread genomic instability through the generation of double strand breaks. This has important implications for treatment approaches for cancers that carry APOBEC3 mutations, and challenges the view that APOBECs only act opportunistically at sites of single stranded DNA

    Genetic and Functional Dissection of HTRA1 and LOC387715 in Age-Related Macular Degeneration

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    A common haplotype on 10q26 influences the risk of age-related macular degeneration (AMD) and encompasses two genes, LOC387715 and HTRA1. Recent data have suggested that loss of LOC387715, mediated by an insertion/deletion (in/del) that destabilizes its message, is causally related with the disorder. Here we show that loss of LOC387715 is insufficient to explain AMD susceptibility, since a nonsense mutation (R38X) in this gene that leads to loss of its message resides in a protective haplotype. At the same time, the common disease haplotype tagged by the in/del and rs11200638 has an effect on the transcriptional upregulation of the adjacent gene, HTRA1. These data implicate increased HTRA1 expression in the pathogenesis of AMD and highlight the importance of exploring multiple functional consequences of alleles in haplotypes that confer susceptibility to complex traits

    Using genetic variation and environmental risk factor data to identify individuals at high risk for age-related macular degeneration

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    A major goal of personalized medicine is to pre-symptomatically identify individuals at high risk for disease using knowledge of each individual's particular genetic profile and constellation of environmental risk factors. With the identification of several well-replicated risk factors for age-related macular degeneration (AMD), the leading cause of legal blindness in older adults, this previously unreachable goal is beginning to seem less elusive. However, recently developed algorithms have either been much less accurate than expected, given the strong effects of the identified risk factors, or have not been applied to independent datasets, leaving unknown how well they would perform in the population at large. We sought to increase accuracy by using novel modeling strategies, including multifactor dimensionality reduction (MDR) and grammatical evolution of neural networks (GENN), in addition to the traditional logistic regression approach. Furthermore, we rigorously designed and tested our models in three distinct datasets: a Vanderbilt-Miami (VM) clinic-based case-control dataset, a VM family dataset, and the population-based Age-related Maculopathy Ancillary (ARMA) Study cohort. Using a consensus approach to combine the results from logistic regression and GENN models, our algorithm was successful in differentiating between high- and low-risk groups (sensitivity 77.0%, specificity 74.1%). In the ARMA cohort, the positive and negative predictive values were 63.3% and 70.7%, respectively. We expect that future efforts to refine this algorithm by increasing the sample size available for model building, including novel susceptibility factors as they are discovered, and by calibrating the model for diverse populations will improve accuracy

    Genotype-informed estimation of risk of coronary heart disease based on genome-wide association data linked to the electronic medical record

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    <p>Abstract</p> <p>Background</p> <p>Susceptibility variants identified by genome-wide association studies (GWAS) have modest effect sizes. Whether such variants provide incremental information in assessing risk for common 'complex' diseases is unclear. We investigated whether measured and imputed genotypes from a GWAS dataset linked to the electronic medical record alter estimates of coronary heart disease (CHD) risk.</p> <p>Methods</p> <p>Study participants (<it>n </it>= 1243) had no known cardiovascular disease and were considered to be at high, intermediate, or low 10-year risk of CHD based on the Framingham risk score (FRS) which includes age, sex, total and HDL cholesterol, blood pressure, diabetes, and smoking status. Of twelve SNPs identified in prior GWAS to be associated with CHD, four were genotyped in the participants as part of a GWAS. Genotypes for seven SNPs were imputed from HapMap CEU population using the program MACH. We calculated a multiplex genetic risk score for each patient based on the odds ratios of the susceptibility SNPs and incorporated this into the FRS.</p> <p>Results</p> <p>The mean (SD) number of risk alleles was 12.31 (1.95), range 6-18. The mean (SD) of the weighted genetic risk score was 12.64 (2.05), range 5.75-18.20. The CHD genetic risk score was not correlated with the FRS (<it>P </it>= 0.78). After incorporating the genetic risk score into the FRS, a total of 380 individuals (30.6%) were reclassified into higher-(188) or lower-risk groups (192).</p> <p>Conclusion</p> <p>A genetic risk score based on measured/imputed genotypes at 11 susceptibility SNPs, led to significant reclassification in the 10-y CHD risk categories. Additional prospective studies are needed to assess accuracy and clinical utility of such reclassification.</p

    C2 and CFB Genes in Age-Related Maculopathy and Joint Action with CFH and LOC387715 Genes

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    Background: Age-related maculopathy (ARM) is a common cause of visual impairment in the elderly populations of industrialized countries and significantly affects the quality of life of those suffering from the disease. Variants within two genes, the complement factor H (CFH) and the poorly characterized LOC387715 (ARMS2), are widely recognized as ARM risk factors. CFH is important in regulation of the alternative complement pathway suggesting this pathway is involved in ARM pathogenesis. Two other complement pathway genes, the closely linked complement component receptor (C2) and complement factor B (CFB), were recently shown to harbor variants associated with ARM. Methods/Principal Findings: We investigated two SNPs in C2 and two in CFB in independent case-control and family cohorts of white subjects and found rs547154, an intronic SNP in C2, to be significantly associated with ARM in both our case-control (P-value 0.00007) and family data (P-value 0.00001). Logistic regression analysis suggested that accounting for the effect at this locus significantly (P-value 0.002) improves the fit of a genetic risk model of CFH and LOC387715 effects only. Modeling with the generalized multifactor dimensionality reduction method showed that adding C2 to the two-factor model of CFH and LOC387715 increases the sensitivity (from 63% to 73%). However, the balanced accuracy increases only from 71% to 72%, and the specificity decreases from 80% to 72%. Conclusions/Significance: C2/CFB significantly influences AMD susceptibility and although accounting for effects at this locus does not dramatically increase the overall accuracy of the genetic risk model, the improvement over the CFH-LOC387715 model is statistically significant. Β© 2008 Jakobsdottir et al

    Overexpression of HTRA1 Leads to Ultrastructural Changes in the Elastic Layer of Bruch's Membrane via Cleavage of Extracellular Matrix Components

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    Variants in the chromosomal region 10q26 are strongly associated with an increased risk for age-related macular degeneration (AMD). Two potential AMD genes are located in this region: ARMS2 and HTRA1 (high-temperature requirement A1). Previous studies have suggested that polymorphisms in the promotor region of HTRA1 result in overexpression of HTRA1 protein. This study investigated the role of HTRA1 overexpression in the pathogenesis of AMD. Transgenic Htra1 mice overexpressing the murine protein in the retinal pigment epithelium (RPE) layer of the retina were generated and characterized by transmission electron microscopy, immunofluorescence staining and Western Blot analysis. The elastic layer of Bruch's membrane (BM) in the Htra1 transgenic mice was fragmented and less continuous than in wild type (WT) controls. Recombinant HTRA1 lacking the N-terminal domain cleaved various extracellular matrix (ECM) proteins. Subsequent Western Blot analysis revealed an overexpression of fibronectin fragments and a reduction of fibulin 5 and tropoelastin in the RPE/choroid layer in transgenic mice compared to WT. Fibulin 5 is essential for elastogenesis by promoting elastic fiber assembly and maturation. Taken together, our data implicate that HTRA1 overexpression leads to an altered elastogenesis in BM through fibulin 5 cleavage. It highlights the importance of ECM related proteins in the development of AMD and links HTRA1 to other AMD risk genes such as fibulin 5, fibulin 6, ARMS2 and TIMP3

    Analysis of copy number variation at DMBT1 and age-related macular degeneration

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    BACKGROUND: DMBT1 is a gene that shows extensive copy number variation (CNV) that alters the number of bacteria-binding domains in the protein and has been shown to activate the complement pathway. It lies next to the ARMS2/HTRA1 genes in a region of chromosome 10q26, where single nucleotide variants have been strongly associated with age-related macular degeneration (AMD), the commonest cause of blindness in Western populations. Complement activation is thought to be a key factor in the pathogenesis of this condition. We sought to investigate whether DMBT1 CNV plays any role in the susceptibility to AMD. METHODS: We analysed long-range linkage disequilibrium of DMBT1 CNV1 and CNV2 with flanking single nucleotide polymorphisms (SNPs) using our previously published CNV and HapMap Phase 3 SNP data in the CEPH Europeans from Utah (CEU). We then typed a large cohort of 860 AMD patients and 419 examined age-matched controls for copy number at DMBT1 CNV1 and CNV2 and combined these data with copy numbers from a further 480 unexamined controls. RESULTS: We found weak linkage disequilibrium between DMBT1 CNV1 and CNV2 with the SNPs rs1474526 and rs714816 in the HTRA1/ARMS2 region. By directly analysing copy number variation, we found no evidence of association of CNV1 or CNV2 with AMD. CONCLUSIONS: We have shown that copy number variation at DMBT1 does not affect risk of developing age-related macular degeneration and can therefore be ruled out from future studies investigating the association of structural variation at 10q26 with AMD
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