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  • 1
    Publication Date: 2018-07-03
    Description: Personalized dosimetry with high accuracy is becoming more important because of the growing interest in personalized medicine and targeted radionuclide therapy. Voxel-based dosimetry using dose point kernel or voxel S-value (VSV) convolution is available. However, these approaches do not consider the heterogeneity of the medium. Here, we propose a new method for whole-body voxel-based personalized dosimetry in heterogeneous media with nonuniform activity distributions—a method we refer to as the multiple VSV approach. Instead of using only a single VSV, as found in water, the method uses multiple numbers ( N ) of VSVs to cover media of various density ranges, as found in the whole body. Methods: The VSVs were precalculated using GATE Monte Carlo simulation and were convoluted with the time-integrated activity to generate density-specific dose maps. CT-based segmentation was performed to generate a binary mask image for each density region. The final dose map was acquired by the summation of N segmented density-specific dose maps. We tested several sets of VSVs with different densities: N = 1 (single water VSV), 4, 6, 8, 10, and 20. To validate the proposed method, phantom and patient studies were conducted and compared with the direct Monte Carlo approach, which was considered the ground truth. Finally, dosimetry on 10 patients was performed using the multiple VSV approach and compared with the single VSV and organ-based approaches. Errors at the voxel and organ levels were reported for 8 organs. Results: In the phantom and patient studies, the multiple VSV approach showed significant decreases in voxel-level errors, especially for the lung and bone regions. As the number of VSVs increased, voxel-level errors decreased, although some overestimations were observed at the lung boundaries. For the multiple VSVs ( N = 8), we achieved a voxel-level error of 2.06%. In the dosimetry study, our proposed method showed greatly improved results compared with single VSV and organ-based dosimetry. Errors at the organ level were –6.71%, 2.17%, and 227.46% for single VSV, multiple VSV, and organ-based dosimetry, respectively. Conclusion: The multiple VSV approach for heterogeneous media with nonuniform activity distributions offers fast personalized dosimetry at the whole-body level, yielding results comparable to those of the direct Monte Carlo approach.
    Print ISSN: 0022-3123
    Topics: Medicine
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  • 2
    Publication Date: 2018-11-01
    Description: A methionine substitution at lysine-27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits polycomb repressive complex 2 (PRC2) in a dominant-negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found that this interaction on chromatin is transient, with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-containing chromatin, suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to H3K27M, leading to the failure to spread H3K27me from PRC2 recruitment sites and consequently abrogating PRC2’s ability to establish H3K27me2-3 repressive chromatin domains. In turn, levels of polycomb antagonists such as H3K36me2 are elevated, suggesting a more global, downstream effect on the epigenome. Together, these findings reveal the conditions required for H3K27M-mediated PRC2 inhibition and reconcile seemingly paradoxical effects of H3K27M on PRC2 recruitment and activity.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 3
    Publication Date: 2011-05-27
    Description: Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis. Structural studies have identified phospholipids as potential LRH-1 ligands, but their functional relevance is unclear. Here we show that an unusual phosphatidylcholine species with two saturated 12 carbon fatty acid acyl side chains (dilauroyl phosphatidylcholine (DLPC)) is an LRH-1 agonist ligand in vitro. DLPC treatment induces bile acid biosynthetic enzymes in mouse liver, increases bile acid levels, and lowers hepatic triglycerides and serum glucose. DLPC treatment also decreases hepatic steatosis and improves glucose homeostasis in two mouse models of insulin resistance. Both the antidiabetic and lipotropic effects are lost in liver-specific Lrh-1 knockouts. These findings identify an LRH-1 dependent phosphatidylcholine signalling pathway that regulates bile acid metabolism and glucose homeostasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150801/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150801/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Jae Man -- Lee, Yoon Kwang -- Mamrosh, Jennifer L -- Busby, Scott A -- Griffin, Patrick R -- Pathak, Manish C -- Ortlund, Eric A -- Moore, David D -- DK-079638/DK/NIDDK NIH HHS/ -- R01 CA134873/CA/NCI NIH HHS/ -- R01 DK068804/DK/NIDDK NIH HHS/ -- R01 DK083572/DK/NIDDK NIH HHS/ -- R01 DK083572-02/DK/NIDDK NIH HHS/ -- T32 DK007696/DK/NIDDK NIH HHS/ -- U54 MH084512/MH/NIMH NIH HHS/ -- England -- Nature. 2011 May 25;474(7352):506-10. doi: 10.1038/nature10111.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21614002" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bile Acids and Salts/biosynthesis/metabolism/pharmacology ; Blood Glucose/metabolism ; Cell Line ; Disease Models, Animal ; Fatty Liver/drug therapy/enzymology ; HeLa Cells ; Homeostasis/drug effects ; Humans ; Hypoglycemic Agents/pharmacology ; Insulin Resistance/physiology ; Ligands ; Lipogenesis/drug effects ; Liver/drug effects/enzymology/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Phosphatidylcholines/*metabolism/pharmacology ; Protein Binding ; Receptors, Cytoplasmic and Nuclear/agonists/deficiency/genetics/*metabolism ; Signal Transduction/drug effects ; Triglycerides/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2014-11-11
    Description: Autophagy is an evolutionarily conserved catabolic process that recycles nutrients upon starvation and maintains cellular energy homeostasis. Its acute regulation by nutrient-sensing signalling pathways is well described, but its longer-term transcriptional regulation is not. The nuclear receptors peroxisome proliferator-activated receptor-alpha (PPARalpha) and farnesoid X receptor (FXR) are activated in the fasted and fed liver, respectively. Here we show that both PPARalpha and FXR regulate hepatic autophagy in mice. Pharmacological activation of PPARalpha reverses the normal suppression of autophagy in the fed state, inducing autophagic lipid degradation, or lipophagy. This response is lost in PPARalpha knockout (Ppara(-/-), also known as Nr1c1(-/-)) mice, which are partially defective in the induction of autophagy by fasting. Pharmacological activation of the bile acid receptor FXR strongly suppresses the induction of autophagy in the fasting state, and this response is absent in FXR knockout (Fxr(-/-), also known as Nr1h4(-/-)) mice, which show a partial defect in suppression of hepatic autophagy in the fed state. PPARalpha and FXR compete for binding to shared sites in autophagic gene promoters, with opposite transcriptional outputs. These results reveal complementary, interlocking mechanisms for regulation of autophagy by nutrient status.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267857/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267857/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Jae Man -- Wagner, Martin -- Xiao, Rui -- Kim, Kang Ho -- Feng, Dan -- Lazar, Mitchell A -- Moore, David D -- DK43806/DK/NIDDK NIH HHS/ -- P30 DK019525/DK/NIDDK NIH HHS/ -- P30DX56338-05A2/PHS HHS/ -- P39CA125123-04/CA/NCI NIH HHS/ -- R01 DK049780/DK/NIDDK NIH HHS/ -- R01 DK49780/DK/NIDDK NIH HHS/ -- R37 DK043806/DK/NIDDK NIH HHS/ -- S10RR027783-01A1/RR/NCRR NIH HHS/ -- U54HD-07495-39/HD/NICHD NIH HHS/ -- England -- Nature. 2014 Dec 4;516(7529):112-5. doi: 10.1038/nature13961. Epub 2014 Nov 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Division of Endocrinology, Diabetes, and Metabolism and the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19014, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25383539" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autophagy/genetics/*physiology ; Cell Line ; Cells, Cultured ; Fasting/physiology ; Gene Expression Regulation ; Hepatocytes/metabolism ; Liver/cytology/*metabolism/ultrastructure ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microtubule-Associated Proteins/genetics/metabolism ; PPAR alpha ; Receptors, Cytoplasmic and Nuclear/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2018-03-27
    Description: Objectives This study aimed to examine the associations between objectively assessed neighbourhood environmental attributes and depressive symptoms in Hong Kong Chinese older adults and the moderating effects of neighbourhood environmental attributes on the associations between living arrangements and depressive symptoms. Design Cross-sectional observational study. Setting Hong Kong. Participants 909 Hong Kong Chinese community dwellers aged 65+ years residing in preselected areas stratified by walkability and socioeconomic status. Exposure and outcome measures Attributes of participants’ neighbourhood environment were objectively assessed using geographic information systems and environmental audits. Depressive symptoms were measured using the Geriatric Depression Scale. Results Overall, pedestrian infrastructure (OR=1.025; P=0.008), connectivity (OR=1.039; P=0.002) and prevalence of public transport stops (OR=1.056; P=0.012) were positively associated with the odds of reporting depressive symptoms. Older adults living alone were at higher risk of reporting any depressive symptoms than those living with others (OR=1.497; P=0.039). This association was moderated by neighbourhood crowdedness, perceptible pollution, access to destinations and presence of people. Residing in neighbourhoods with lower levels of these attributes was associated with increased deleterious effects of living alone. Living in neighbourhoods with lower public transport density also increased the deleterious effects of living alone on the number of depressive symptoms. Those living alone and residing in neighbourhoods with higher levels of connectivity tended to report more depressive symptoms than their counterparts. Conclusions The level of access to destinations and social networks across Hong Kong may be sufficiently high to reduce the risk of depressive symptoms in older adults. Yet, exposure to extreme levels of public transport density and associated traffic volumes may increase the risk of depressive symptoms. The provision of good access to a variety of destinations, public transport and public open spaces for socialising in the neighbourhood may help reduce the risk of depressive symptoms in older adults who live alone.
    Keywords: Open access, Public health
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 6
    Publication Date: 2018-02-10
    Description: Justyna M. Meissner, Jay M. Bhatt, Eunjoo Lee, Melanie L. Styers, Anna A. Ivanova, Richard A. Kahn, and Elizabeth Sztul ADP-ribosylation factors (ARF) GTPases are activated by guanine nucleotide exchange factors (GEFs) to support cellular homeostasis. Key to understanding spatio-temporal regulation of ARF signaling is the mechanism of GEF recruitment to membranes. Small GEFs are recruited through phosphoinositide (PIP) binding by a pleckstrin homology (PH) domain downstream from the catalytic Sec7 domain (Sec7d). The large GEFs lack PH domains, and their recruitment mechanisms are poorly understood. We probed Golgi recruitment of GBF1, a GEF catalyzing ARF activation required for Golgi homeostasis. We show that the homology downstream of Sec7d-1 (HDS1) regulates Golgi recruitment of GBF1. We document that GBF1 binds phosphoinositides, preferentially PI3P, PI4P and PI(4,5)P 2 , and that lipid binding requires the HDS1 domain. Mutations within HDS1 that reduce GBF1 binding to specific PIPs in vitro inhibit GBF1 targeting to Golgi membranes in cells. Our data imply that HDS1 and PH domains are functionally analogous in that each uses lipid-based membrane information to regulate GEF recruitment. Lipid-based recruitment of GBF1 extends the paradigm of lipid regulation to small and large GEFs and suggests that lipid-based mechanisms evolved early during GEF diversification. This article has an associated First Person interview with the first author of the paper.
    Print ISSN: 0021-9533
    Electronic ISSN: 1477-9137
    Topics: Biology , Medicine
    Published by Company of Biologists
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  • 7
    ISSN: 1432-0630
    Keywords: PACS: 42.62; 85.60.J; 52.75.R
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: Abstract. Sapphire wafer is found to be scribed and cut freely by plasma from a metal surface on which a Q-switched Nd:YAG laser beam is focused through the wafer. The wafer is scribed enough to be cut using a Q-switched Nd:YAG laser with the average power of 5 W at atmospheric environment without a vacuum chamber. This method is successfully applied to split each device from a blue LED wafer including about 10000 blue LED devices grown on a sapphire wafer.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-0886
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract. Using polytene chromosomes of salivary gland cells of Chironomus tentans, phosphorylation state-sensitive antibodies and the transcription and protein kinase inhibitor 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole (DRB), we have visualized the chromosomal distribution of RNA polymerase II (pol II) with hypophosphorylated (pol IIA) and hyperphosphorylated (pol II0) carboxyl-terminal repeat domain (CTD). DRB blocks labeling of the CTD with 32Pi within minutes of its addition, and nuclear pol II0 is gradually converted to IIA; this conversion parallels the reduction in transcription of protein-coding genes. DRB also alters the chromosomal distribution of II0: there is a time-dependent clearance from chromosomes of phosphoCTD (PCTD) after addition of DRB, which coincides in time with the completion and release of preinitiated transcripts. Furthermore, the staining of smaller transcription units is abolished before that of larger ones. The staining pattern of chromosomes with anti-CTD antibodies is not detectably influenced by the DRB treatment, indicating that hypophosphorylated pol IIA is unaffected by the transcription inhibitor. Microinjection of synthetic heptapeptide repeats, anti-CTD and anti-PCTD antibodies into salivary gland nuclei hampered the transcription of BR2 genes, indicating the requirement for CTD and PCTD in transcription in living cells. The results demonstrate that in vivo the protein kinase effector DRB shows parallel effects on an early step in gene transcription and the process of pol II hyperphosphorylation. Our observations are consistent with the proposal that the initiation of productive RNA synthesis is CTD-phosphorylation dependent and also with the idea that the gradual dephosphorylation of transcribing pol II0 is coupled to the completion of nascent pol II gene transcripts.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-0797
    Source: Springer Online Journal Archives 1860-2000
    Topics: Process Engineering, Biotechnology, Nutrition Technology
    Notes: Abstract An off-line glucose analyzer, Yellow Springs Instrument (YSI) model 27 was modified and coupled to various peripheral components to produce a fast, fully automated system for the online determination of glucose concentration. The amount of time required to accomplish each measurement was in the order of two minutes. To demonstrate the utility of this system, various tests were performed. First, a stream containing known amounts of glucose was monitored on-line and the system was calibrated. The calibration curve was shown to be described by Michaelis-Menten kinetics. Once the system was properly calibrated, it was used to monitor the glucose concentration in the effluent stream of two different enzyme reactor systems. The glucose concentrations were within experimental error of those obtained via standard off-line techniques.
    Type of Medium: Electronic Resource
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