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Merging Orthovoltage X-Ray Minibeams spare the proximal tissues while producing a solid beam at the target.
Dilmanian FA, Krishnan S, McLaughlin WE, Lukaniec B, Baker JT, Ailawadi S, Hirsch KN, Cattell RF, Roy R, Helfer J, Kruger K, Spuhler K, He Y, Tailor R, Vassantachart A, Heaney DC, Zanzonico P, Gobbert MK, Graf JS, Nassimi JR, Fatemi NN, Schweitzer ME, Bangiyev L, Eley JG
(2019) Sci Rep 9: 1198
MeSH Terms: Brain Neoplasms, Computer Simulation, Gold, Humans, Metal Nanoparticles, Models, Biological, Monte Carlo Method, Radiography, Radiometry, Radiosurgery, Radiotherapy, Radiotherapy Dosage, X-Ray Therapy, X-Rays
Show Abstract · Added March 30, 2020
Conventional radiation therapy of brain tumors often produces cognitive deficits, particularly in children. We investigated the potential efficacy of merging Orthovoltage X-ray Minibeams (OXM). It segments the beam into an array of parallel, thin (~0.3 mm), planar beams, called minibeams, which are known from synchrotron x-ray experiments to spare tissues. Furthermore, the slight divergence of the OXM array make the individual minibeams gradually broaden, thus merging with their neighbors at a given tissue depth to produce a solid beam. In this way the proximal tissues, including the cerebral cortex, can be spared. Here we present experimental results with radiochromic films to characterize the method's dosimetry. Furthermore, we present our Monte Carlo simulation results for physical absorbed dose, and a first-order biologic model to predict tissue tolerance. In particular, a 220-kVp orthovoltage beam provides a 5-fold sharper lateral penumbra than a 6-MV x-ray beam. The method can be implemented in arc-scan, which may include volumetric-modulated arc therapy (VMAT). Finally, OXM's low beam energy makes it ideal for tumor-dose enhancement with contrast agents such as iodine or gold nanoparticles, and its low cost, portability, and small room-shielding requirements make it ideal for use in the low-and-middle-income countries.
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1 Members
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14 MeSH Terms
Identification of Phosphorylation Codes for Arrestin Recruitment by G Protein-Coupled Receptors.
Zhou XE, He Y, de Waal PW, Gao X, Kang Y, Van Eps N, Yin Y, Pal K, Goswami D, White TA, Barty A, Latorraca NR, Chapman HN, Hubbell WL, Dror RO, Stevens RC, Cherezov V, Gurevich VV, Griffin PR, Ernst OP, Melcher K, Xu HE
(2017) Cell 170: 457-469.e13
MeSH Terms: Amino Acid Sequence, Animals, Arrestins, Chromatography, Liquid, Humans, Mice, Models, Molecular, Phosphorylation, Rats, Rhodopsin, Sequence Alignment, Tandem Mass Spectrometry, X-Rays
Show Abstract · Added March 14, 2018
G protein-coupled receptors (GPCRs) mediate diverse signaling in part through interaction with arrestins, whose binding promotes receptor internalization and signaling through G protein-independent pathways. High-affinity arrestin binding requires receptor phosphorylation, often at the receptor's C-terminal tail. Here, we report an X-ray free electron laser (XFEL) crystal structure of the rhodopsin-arrestin complex, in which the phosphorylated C terminus of rhodopsin forms an extended intermolecular β sheet with the N-terminal β strands of arrestin. Phosphorylation was detected at rhodopsin C-terminal tail residues T336 and S338. These two phospho-residues, together with E341, form an extensive network of electrostatic interactions with three positively charged pockets in arrestin in a mode that resembles binding of the phosphorylated vasopressin-2 receptor tail to β-arrestin-1. Based on these observations, we derived and validated a set of phosphorylation codes that serve as a common mechanism for phosphorylation-dependent recruitment of arrestins by GPCRs.
Copyright © 2017 Elsevier Inc. All rights reserved.
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13 MeSH Terms
Rictor/mTORC2 deficiency enhances keratinocyte stress tolerance via mitohormesis.
Tassone B, Saoncella S, Neri F, Ala U, Brusa D, Magnuson MA, Provero P, Oliviero S, Riganti C, Calautti E
(2017) Cell Death Differ 24: 731-746
MeSH Terms: Acetylcysteine, Animals, Apoptosis, Cell Proliferation, Cells, Cultured, Cellular Senescence, Epirubicin, Glutamic Acid, Hyperplasia, Keratin-14, Keratinocytes, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Radiation Tolerance, Rapamycin-Insensitive Companion of mTOR Protein, Reactive Oxygen Species, Skin, Tetradecanoylphorbol Acetate, Transcriptome, X-Rays
Show Abstract · Added March 7, 2017
How metabolic pathways required for epidermal tissue growth and remodeling influence the ability of keratinocytes to survive stressful conditions is still largely unknown. The mechanistic target of rapamycin complex 2 (mTORC2) regulates growth and metabolism of several tissues, but its functions in epidermal cells are poorly defined. Rictor is an adaptor protein essential for mTORC2 activity. To explore the roles of mTORC2 in the epidermis, we have conditionally deleted rictor in mice via K14-Cre-mediated homologous recombination and found that its deficiency causes moderate tissue hypoplasia, reduced keratinocyte proliferation and attenuated hyperplastic response to TPA. Noteworthy, rictor-deficient keratinocytes displayed increased lifespan, protection from senescence, and enhanced tolerance to cellular stressors such as growth factors deprivation, epirubicin and X-ray in vitro and radioresistance in vivo. Rictor-deficient keratinocytes exhibited changes in global gene expression profiles consistent with metabolic alterations and enhanced stress tolerance, a shift in cell catabolic processes from glycids and lipids to glutamine consumption and increased production of mitochondrial reactive oxygen species (ROS). Mechanistically, the resiliency of rictor-deficient epidermal cells relies on these ROS increases, indicating stress resistance via mitohormesis. Thus, our findings reveal a new link between metabolic changes and stress adaptation of keratinocytes centered on mTORC2 activity, with potential implications in skin aging and therapeutic resistance of epithelial tumors.
2 Communities
1 Members
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22 MeSH Terms
Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser.
Kang Y, Zhou XE, Gao X, He Y, Liu W, Ishchenko A, Barty A, White TA, Yefanov O, Han GW, Xu Q, de Waal PW, Ke J, Tan MH, Zhang C, Moeller A, West GM, Pascal BD, Van Eps N, Caro LN, Vishnivetskiy SA, Lee RJ, Suino-Powell KM, Gu X, Pal K, Ma J, Zhi X, Boutet S, Williams GJ, Messerschmidt M, Gati C, Zatsepin NA, Wang D, James D, Basu S, Roy-Chowdhury S, Conrad CE, Coe J, Liu H, Lisova S, Kupitz C, Grotjohann I, Fromme R, Jiang Y, Tan M, Yang H, Li J, Wang M, Zheng Z, Li D, Howe N, Zhao Y, Standfuss J, Diederichs K, Dong Y, Potter CS, Carragher B, Caffrey M, Jiang H, Chapman HN, Spence JC, Fromme P, Weierstall U, Ernst OP, Katritch V, Gurevich VV, Griffin PR, Hubbell WL, Stevens RC, Cherezov V, Melcher K, Xu HE
(2015) Nature 523: 561-7
MeSH Terms: Animals, Arrestin, Binding Sites, Crystallography, X-Ray, Disulfides, Humans, Lasers, Mice, Models, Molecular, Multiprotein Complexes, Protein Binding, Reproducibility of Results, Rhodopsin, Signal Transduction, X-Rays
Show Abstract · Added February 15, 2016
G-protein-coupled receptors (GPCRs) signal primarily through G proteins or arrestins. Arrestin binding to GPCRs blocks G protein interaction and redirects signalling to numerous G-protein-independent pathways. Here we report the crystal structure of a constitutively active form of human rhodopsin bound to a pre-activated form of the mouse visual arrestin, determined by serial femtosecond X-ray laser crystallography. Together with extensive biochemical and mutagenesis data, the structure reveals an overall architecture of the rhodopsin-arrestin assembly in which rhodopsin uses distinct structural elements, including transmembrane helix 7 and helix 8, to recruit arrestin. Correspondingly, arrestin adopts the pre-activated conformation, with a ∼20° rotation between the amino and carboxy domains, which opens up a cleft in arrestin to accommodate a short helix formed by the second intracellular loop of rhodopsin. This structure provides a basis for understanding GPCR-mediated arrestin-biased signalling and demonstrates the power of X-ray lasers for advancing the frontiers of structural biology.
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15 MeSH Terms
Haplotypes of DNA repair and cell cycle control genes, X-ray exposure, and risk of childhood acute lymphoblastic leukemia.
Chokkalingam AP, Bartley K, Wiemels JL, Metayer C, Barcellos LF, Hansen HM, Aldrich MC, Guha N, Urayama KY, Scélo G, Chang JS, Month SR, Wiencke JK, Buffler PA
(2011) Cancer Causes Control 22: 1721-30
MeSH Terms: Case-Control Studies, Child, Preschool, DNA Repair, Genes, cdc, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, In Situ Hybridization, Fluorescence, Male, Polymorphism, Single Nucleotide, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Risk Factors, X-Rays
Show Abstract · Added February 26, 2014
BACKGROUND - Acute leukemias of childhood are a heterogeneous group of malignancies characterized by cytogenetic abnormalities, such as translocations and changes in ploidy. These abnormalities may be influenced by altered DNA repair and cell cycle control processes.
METHODS - We examined the association between childhood acute lymphoblastic leukemia (ALL) and 32 genes in DNA repair and cell cycle pathways using a haplotype-based approach, among 377 childhood ALL cases and 448 controls enrolled during 1995-2002.
RESULTS - We found that haplotypes in APEX1, BRCA2, ERCC2, and RAD51 were significantly associated with total ALL, while haplotypes in NBN and XRCC4, and CDKN2A were associated with structural and numerical change subtypes, respectively. In addition, we observed statistically significant interaction between exposure to 3 or more diagnostic X-rays and haplotypes of XRCC4 on risk of structural abnormality-positive childhood ALL.
CONCLUSIONS - These results support a role of altered DNA repair and cell cycle processes in the risk of childhood ALL, and show that this genetic susceptibility can differ by cytogenetic subtype and may be modified by exposure to ionizing radiation. To our knowledge, our study is the first to broadly examine the DNA repair and cell cycle pathways using a haplotype approach in conjunction with X-ray exposures in childhood ALL risk. If confirmed, future studies are needed to identify specific functional SNPs in the regions of interest identified in this analysis.
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1 Members
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14 MeSH Terms
Non-invasive predictors of human cortical bone mechanical properties: T(2)-discriminated H NMR compared with high resolution X-ray.
Horch RA, Gochberg DF, Nyman JS, Does MD
(2011) PLoS One 6: e16359
MeSH Terms: Biomechanical Phenomena, Bone and Bones, Fractures, Bone, Humans, Magnetic Resonance Spectroscopy, Predictive Value of Tests, Radiography, Stress, Mechanical, Tensile Strength, X-Rays
Show Abstract · Added October 31, 2013
Recent advancements in magnetic resonance imaging (MRI) have enabled clinical imaging of human cortical bone, providing a potentially powerful new means for assessing bone health with molecular-scale sensitivities unavailable to conventional X-ray-based diagnostics. To this end, (1)H nuclear magnetic resonance (NMR) and high-resolution X-ray signals from human cortical bone samples were correlated with mechanical properties of bone. Results showed that (1)H NMR signals were better predictors of yield stress, peak stress, and pre-yield toughness than were the X-ray derived signals. These (1)H NMR signals can, in principle, be extracted from clinical MRI, thus offering the potential for improved clinical assessment of fracture risk.
2 Communities
2 Members
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10 MeSH Terms
Medical radiation exposure and risk of retinoblastoma resulting from new germline RB1 mutation.
Bunin GR, Felice MA, Davidson W, Friedman DL, Shields CL, Maidment A, O'Shea M, Nichols KE, Leahey A, Dunkel IJ, Jubran R, Rodriguez-Galindo C, Schmidt ML, Weinstein JL, Goldman S, Abramson DH, Wilson MW, Gallie BL, Chan HS, Shapiro M, Cnaan A, Ganguly A, Meadows AT
(2011) Int J Cancer 128: 2393-404
MeSH Terms: Case-Control Studies, Female, Genes, Retinoblastoma, Germ-Line Mutation, Humans, Male, Neoplasms, Radiation-Induced, Pregnancy, Prenatal Exposure Delayed Effects, Radiation Dosage, Retinoblastoma, X-Rays
Show Abstract · Added March 27, 2014
Although ionizing radiation induces germline mutations in animals, human studies of radiation-exposed populations have not detected an effect. We conducted a case-control study of sporadic bilateral retinoblastoma, which results from a new germline RB1 mutation, to investigate gonadal radiation exposure of parents from medical sources before their child's conception. Parents of 206 cases from nine North American institutions and 269 controls participated; fathers of 184 cases and 223 friend and relative controls and mothers of 204 cases and 260 controls provided information in telephone interviews on their medical radiation exposure. Cases provided DNA for RB1 mutation testing. Of common procedures, lower gastrointestinal (GI) series conferred the highest estimated dose to testes and ovaries. Paternal history of lower GI series was associated with increased risk of retinoblastoma in the child [matched odds ratio (OR) = 3.6, 95% confidence interval (CI) = 1.2-11.2, two-sided p = 0.02], as was estimated total testicular dose from all procedures combined (OR for highest dose=3.9, 95% CI = 1.2-14.4, p = 0.02). Maternal history of lower GI series was also associated with increased risk (OR = 7.6, 95% CI = 2.8-20.7, p < 0.001) as was the estimated total dose (OR for highest dose = 3.0, 95% CI = 1.4-7.0, p = 0.005). The RB1 mutation spectrum in cases of exposed parents did not differ from that of other cases. Some animal and human data support our findings of an association of gonadal radiation exposure in men and women with new germline RB1 mutation detectable in their children, although bias, confounding, and/or chance may also explain the results.
Copyright © 2010 UICC.
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12 MeSH Terms
Reconstitution of Helicobacter pylori VacA toxin from purified components.
González-Rivera C, Gangwer KA, McClain MS, Eli IM, Chambers MG, Ohi MD, Lacy DB, Cover TL
(2010) Biochemistry 49: 5743-52
MeSH Terms: Antineoplastic Combined Chemotherapy Protocols, Cryoelectron Microscopy, Cyclophosphamide, Dactinomycin, Doxorubicin, HeLa Cells, Helicobacter pylori, Humans, Interleukin-2, Toxins, Biological, Vincristine, X-Rays
Show Abstract · Added May 7, 2013
Helicobacter pylori VacA is a pore-forming toxin that causes multiple alterations in human cells and contributes to the pathogenesis of peptic ulcer disease and gastric cancer. The toxin is secreted by H. pylori as an 88 kDa monomer (p88) consisting of two domains (p33 and p55). While an X-ray crystal structure for p55 exists and p88 oligomers have been visualized by cryo-electron microscopy, a detailed analysis of p33 has been hindered by an inability to purify this domain in an active form. In this study, we expressed and purified a recombinant form of p33 under denaturing conditions and optimized conditions for the refolding of the soluble protein. We show that refolded p33 can be added to purified p55 in trans to cause vacuolation of HeLa cells and inhibition of IL-2 production by Jurkat cells, effects identical to those produced by the p88 toxin from H. pylori. The p33 protein markedly enhances the cell binding properties of p55. Size exclusion chromatography experiments suggest that p33 and p55 assemble into a complex consistent with the size of a p88 monomer. Electron microscopy of these p33/p55 complexes reveals small rod-shaped structures that can convert to oligomeric flower-shaped structures in the presence of detergent. We propose that the oligomerization observed in these experiments mimics the process by which VacA oligomerizes when in contact with membranes of host cells.
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5 Members
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12 MeSH Terms
The Prp19 WD40 domain contains a conserved protein interaction region essential for its function.
Vander Kooi CW, Ren L, Xu P, Ohi MD, Gould KL, Chazin WJ
(2010) Structure 18: 584-93
MeSH Terms: Amino Acid Motifs, Crystallography, X-Ray, Eukaryota, Mutagenesis, Protein Structure, Tertiary, Proteins, RNA Splicing, Saccharomyces cerevisiae, Spliceosomes, Ubiquitin-Protein Ligases, X-Rays
Show Abstract · Added March 5, 2014
Prp19 is a member of the WD40 repeat family of E3 ubiquitin ligases and a conserved eukaryotic RNA splicing factor essential for activation and stabilization of the spliceosome. To understand the role of the WD40 repeat domain of Prp19 we have determined its structure using X-ray crystallography. The domain has a distorted seven bladed WD40 architecture with significant asymmetry due to irregular packing of blades one and seven into the core of the WD40 domain. Structure-based mutagenesis identified a highly conserved surface centered around blade five that is required for the physical interaction between Prp19 and Cwc2, another essential splicing factor. This region is found to be required for Prp19 function and yeast viability. Experiments in vitro and in vivo demonstrate that two molecules of Cwc2 bind to the Prp19 tetramer. These coupled structural and functional studies provide a model for the functional architecture of Prp19.
Copyright 2010 Elsevier Ltd. All rights reserved.
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4 Members
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11 MeSH Terms
Structural dynamics and single-stranded DNA binding activity of the three N-terminal domains of the large subunit of replication protein A from small angle X-ray scattering.
Pretto DI, Tsutakawa S, Brosey CA, Castillo A, Chagot ME, Smith JA, Tainer JA, Chazin WJ
(2010) Biochemistry 49: 2880-9
MeSH Terms: DNA, Single-Stranded, Humans, Molecular Dynamics Simulation, Protein Binding, Protein Conformation, Replication Protein A, Scattering, Small Angle, X-Rays
Show Abstract · Added May 30, 2013
Replication protein A (RPA) is the primary eukaryotic single-stranded DNA (ssDNA) binding protein utilized in diverse DNA transactions in the cell. RPA is a heterotrimeric protein with seven globular domains connected by flexible linkers, which enable substantial interdomain motion that is essential to its function. Small angle X-ray scattering (SAXS) experiments with two multidomain constructs from the N-terminus of the large subunit (RPA70) were used to examine the structural dynamics of these domains and their response to the binding of ssDNA. The SAXS data combined with molecular dynamics simulations reveal substantial interdomain flexibility for both RPA70AB (the tandem high-affinity ssDNA binding domains A and B connected by a 10-residue linker) and RPA70NAB (RPA70AB extended by a 70-residue linker to the RPA70N protein interaction domain). Binding of ssDNA to RPA70NAB reduces the interdomain flexibility between the A and B domains but has no effect on RPA70N. These studies provide the first direct measurements of changes in orientation of these three RPA domains upon binding ssDNA. The results support a model in which RPA70N remains structurally independent of RPA70AB in the DNA-bound state and therefore freely available to serve as a protein recruitment module.
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8 MeSH Terms