413 research outputs found
Integrated Ultrasonic Transducer
The typical transducer considered consists of a piezoelectric film, and associated.electrodes, connected to one gate of a dual-gate field-effect transistor in the silicon wafer on which the piezoelectric film is situated. An individual transducer responds to various modes of excitation (flexural, surface, bulk) at frequencies which may range from far below one Hertz to hundreds of megahertz. The second gate of the field-effect transistor can be used for electrical amplitude control or for mixing purposes, Connection of a number of these small transducers together to form arrays permits realizing ultrasonic receiving devices having variable directivity, and progammable surface-wave signal processors
'Prechronous' metastasis in clear cell renal cell carcinoma: a case report
<p>Abstract</p> <p>Introduction</p> <p>Although metastatic carcinoma in the presence of an occult primary tumor is well recognized, underlying reasons for the failure of the primary tumor to manifest are uncertain. Explanations for this phenomenon have ranged from spontaneous regression of the primary tumor to early metastasis of the primary tumor before manifestation of a less aggressive primary tumor. We report a case of 'prechronous' metastasis arising from clear cell renal cell carcinoma, where metastatic disease initially manifested in the absence of a primary renal tumor, followed by aggressive growth of the primary renal lesion.</p> <p>Case presentation</p> <p>A 43-year-old Malay man initially presented to our facility with fever and cough. He subsequently underwent surgical resection of a 9 cm right-sided lung mass found on radiological examination. Histology showed a high-grade clear cell tumor with sarcomatoid differentiation, suggestive of a metastasis from clear cell renal cell carcinoma. However, no concurrent renal lesions were noted on computed tomographic evaluation at that time. Then, four months after lung resection, he presented with a subcutaneous mass in the left loin, as well as right loin discomfort. Computed tomography scanning revealed a 10 cm right renal mass, with renal vein and inferior vena cava invasion, as well as recurrent disease in the right thorax. Histological examination of the excised subcutaneous mass revealed a high-grade carcinoma consistent with clear cell renal cell carcinoma.</p> <p>Conclusions</p> <p>This is the first reported case of prechronous metastasis of renal cell carcinoma, with metastatic disease manifesting prior to the development of the primary lesion. The underlying mechanism is uncertain, but our patient's case provides anecdotal support for the early dissemination model of metastasis.</p
Decoherence, einselection, and the quantum origins of the classical
Decoherence is caused by the interaction with the environment. Environment
monitors certain observables of the system, destroying interference between the
pointer states corresponding to their eigenvalues. This leads to
environment-induced superselection or einselection, a quantum process
associated with selective loss of information. Einselected pointer states are
stable. They can retain correlations with the rest of the Universe in spite of
the environment. Einselection enforces classicality by imposing an effective
ban on the vast majority of the Hilbert space, eliminating especially the
flagrantly non-local "Schr\"odinger cat" states. Classical structure of phase
space emerges from the quantum Hilbert space in the appropriate macroscopic
limit: Combination of einselection with dynamics leads to the idealizations of
a point and of a classical trajectory. In measurements, einselection replaces
quantum entanglement between the apparatus and the measured system with the
classical correlation.Comment: Final version of the review, with brutally compressed figures. Apart
from the changes introduced in the editorial process the text is identical
with that in the Rev. Mod. Phys. July issue. Also available from
http://www.vjquantuminfo.or
Perinatal Tobacco Smoke Exposure Increases Vascular Oxidative Stress and Mitochondrial Damage in Non-Human Primates
Epidemiological studies suggest that events occurring during fetal and early childhood development influence disease susceptibility. Similarly, molecular studies in mice have shown that in utero exposure to cardiovascular disease (CVD) risk factors such as environmental tobacco smoke (ETS) increased adult atherogenic susceptibility and mitochondrial damage; however, the molecular effects of similar exposures in primates are not yet known. To determine whether perinatal ETS exposure increased mitochondrial damage, dysfunction and oxidant stress in primates, archived tissues from the non-human primate model Macaca mulatta (M. mulatta) were utilized. M. mulatta were exposed to low levels of ETS (1 mg/m3 total suspended particulates) from gestation (day 40) to early childhood (1 year), and aortic tissues were assessed for oxidized proteins (protein carbonyls), antioxidant activity (SOD), mitochondrial function (cytochrome oxidase), and mitochondrial damage (mitochondrial DNA damage). Results revealed that perinatal ETS exposure resulted in significantly increased oxidative stress, mitochondrial dysfunction and damage which were accompanied by significantly decreased mitochondrial antioxidant capacity and mitochondrial copy number in vascular tissue. Increased mitochondrial damage was also detected in buffy coat tissues in exposed M. mulatta. These studies suggest that perinatal tobacco smoke exposure increases vascular oxidative stress and mitochondrial damage in primates, potentially increasing adult disease susceptibility
Genome-Wide Linkage Analysis of Global Gene Expression in Loin Muscle Tissue Identifies Candidate Genes in Pigs
BACKGROUND: Nearly 6,000 QTL have been reported for 588 different traits in pigs, more than in any other livestock species. However, this effort has translated into only a few confirmed causative variants. A powerful strategy for revealing candidate genes involves expression QTL (eQTL) mapping, where the mRNA abundance of a set of transcripts is used as the response variable for a QTL scan. METHODOLOGY/PRINCIPAL FINDINGS: We utilized a whole genome expression microarray and an F(2) pig resource population to conduct a global eQTL analysis in loin muscle tissue, and compared results to previously inferred phenotypic QTL (pQTL) from the same experimental cross. We found 62 unique eQTL (FDR <10%) and identified 3 gene networks enriched with genes subject to genetic control involved in lipid metabolism, DNA replication, and cell cycle regulation. We observed strong evidence of local regulation (40 out of 59 eQTL with known genomic position) and compared these eQTL to pQTL to help identify potential candidate genes. Among the interesting associations, we found aldo-keto reductase 7A2 (AKR7A2) and thioredoxin domain containing 12 (TXNDC12) eQTL that are part of a network associated with lipid metabolism and in turn overlap with pQTL regions for marbling, % intramuscular fat (% fat) and loin muscle area on Sus scrofa (SSC) chromosome 6. Additionally, we report 13 genomic regions with overlapping eQTL and pQTL involving 14 local eQTL. CONCLUSIONS/SIGNIFICANCE: Results of this analysis provide novel candidate genes for important complex pig phenotypes
Predicting genome-wide DNA methylation using methylation marks, genomic position, and DNA regulatory elements
Background: Recent assays for individual-specific genome-wide DNA methylation
profiles have enabled epigenome-wide association studies to identify specific
CpG sites associated with a phenotype. Computational prediction of CpG
site-specific methylation levels is important, but current approaches tackle
average methylation within a genomic locus and are often limited to specific
genomic regions. Results: We characterize genome-wide DNA methylation patterns,
and show that correlation among CpG sites decays rapidly, making predictions
solely based on neighboring sites challenging. We built a random forest
classifier to predict CpG site methylation levels using as features neighboring
CpG site methylation levels and genomic distance, and co-localization with
coding regions, CGIs, and regulatory elements from the ENCODE project, among
others. Our approach achieves 91% -- 94% prediction accuracy of genome-wide
methylation levels at single CpG site precision. The accuracy increases to 98%
when restricted to CpG sites within CGIs. Our classifier outperforms
state-of-the-art methylation classifiers and identifies features that
contribute to prediction accuracy: neighboring CpG site methylation status, CpG
island status, co-localized DNase I hypersensitive sites, and specific
transcription factor binding sites were found to be most predictive of
methylation levels. Conclusions: Our observations of DNA methylation patterns
led us to develop a classifier to predict site-specific methylation levels that
achieves the best DNA methylation predictive accuracy to date. Furthermore, our
method identified genomic features that interact with DNA methylation,
elucidating mechanisms involved in DNA methylation modification and regulation,
and linking different epigenetic processes
Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels
Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets
Genome-Wide Association Study and Functional Characterization Identifies Candidate Genes for Insulin-Stimulated Glucose Uptake
Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in \u3e55,000 participants from three ancestry groups. We identified ten new loci (P \u3c 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits
Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care
Genetic drivers of heterogeneity in type 2 diabetes pathophysiology
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p
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