Recommendations for Clinical Pathology Data Generation, Interpretation, and Reporting in Target Animal Safety Studies for Veterinary Drug Development.

Science.gov (United States)

Siska, William; Gupta, Aradhana; Tomlinson, Lindsay; Tripathi, Niraj; von Beust, Barbara

Clinical pathology testing is routinely performed in target animal safety studies in order to identify potential toxicity associated with administration of an investigational veterinary pharmaceutical product. Regulatory and other testing guidelines that address such studies provide recommendations for clinical pathology testing but occasionally contain outdated analytes and do not take into account interspecies physiologic differences that affect the practical selection of appropriate clinical pathology tests. Additionally, strong emphasis is often placed on statistical analysis and use of reference intervals for interpretation of test article-related clinical pathology changes, with limited attention given to the critical scientific review of clinically, toxicologically, or biologically relevant changes. The purpose of this communication from the Regulatory Affairs Committee of the American Society for Veterinary Clinical Pathology is to provide current recommendations for clinical pathology testing and data interpretation in target animal safety studies and thereby enhance the value of clinical pathology testing in these studies.

The roles of pathology in targeted therapy of women with gynecologic cancers.

Science.gov (United States)

Murali, Rajmohan; Grisham, Rachel N; Soslow, Robert A

2018-01-01

The role of the pathologist in the multidisciplinary management of women with gynecologic cancer has evolved substantially over the past decade. Pathologists' evaluation of parameters such as pathologic stage, histologic subtype, grade and microsatellite instability, and their identification of patients at risk for Lynch syndrome have become essential components of diagnosis, prognostic assessment and determination of optimal treatment of affected women. Despite the use of multimodality treatment and combination cytotoxic chemotherapy, the prognosis of women with advanced-stage gynecologic cancer is often poor. Therefore, expanding the arsenal of available systemic therapies with targeted therapeutic agents is appealing. Anti-angiogenic therapies, immunotherapy and poly ADP ribose polymerase (PARP) inhibitors are now routinely used for the treatment of advanced gynecologic cancer, and many more are under investigation. Pathologists remain important in the clinical management of patients with targeted therapy, by identifying potentially targetable tumors on the basis of their pathologic phenotype, by assessing biomarkers that are predictive of response to targeted therapy (e.g. microsatellite instability, PD1/PDL1 expression), and by monitoring treatment response and resistance. Pathologists are also vital to research efforts exploring novel targeted therapies by identifying homogenous subsets of tumors for more reliable and meaningful analyses, and by confirming expression in tumor tissues of novel targets identified in genomic, epigenetic or other screening studies. In the era of precision gynecologic oncology, the roles of pathologists in the discovery, development and implementation of targeted therapeutic strategies remain as central as they are for traditional (surgery-chemotherapy-radiotherapy) management of women with gynecologic cancers. Copyright © 2017 Elsevier Inc. All rights reserved.

Study of the thermo-mechanical performances of the IFMIF-EVEDA Lithium Test Loop target assembly

Energy Technology Data Exchange (ETDEWEB)

Di Maio, P.A., E-mail: dimaio@din.unipa.it [Dipartimento dell' Energia, Universita di Palermo, Viale delle Scienze, 90128 Palermo (Italy); Arena, P.; Bongiovi, G. [Dipartimento dell' Energia, Universita di Palermo, Viale delle Scienze, 90128 Palermo (Italy); Giammusso, R.; Micciche, G.; Tincani, A. [ENEA C. R. Brasimone, 40032 Camugnano, Bologna (Italy)

2012-08-15

Highlights: Black-Right-Pointing-Pointer IFMIF-EVEDA target assembly thermo-mechanical behavior has been investigated. Black-Right-Pointing-Pointer Finite element method has been followed and a commercial code has been used. Black-Right-Pointing-Pointer Nominal, design and pressure test steady state scenarios and start-up transient conditions have been investigated. Black-Right-Pointing-Pointer Steady state results have shown that back-plate yielding may occur only under the design scenario. Black-Right-Pointing-Pointer Transient analysis has indicated that TA start-up lasts for {approx}60 h. - Abstract: Within the framework of the IFMIF R and D program and in close cooperation with ENEA-Brasimone, at the Department of Energy of the University of Palermo a research campaign has been launched to investigate the thermo-mechanical behavior of the target assembly under both steady state and start-up transient conditions. A theoretical approach based on the finite element method (FEM) has been followed and a well-known commercial code has been adopted. A realistic 3D FEM model of the target assembly has been set-up and optimized by running a mesh independency analysis. A proper set of loads and boundary conditions, mainly concerned with radiation heat transfer between the target assembly external walls and the inner walls of its containment vessel, have been considered and the target assembly thermo-mechanical behavior under nominal, design and pressure test steady state scenarios and start-up transient conditions has been investigated. Results are herewith reported and discussed.

A design concept of target-moderator-reflector assemblies for KENS-II

International Nuclear Information System (INIS)

Watanabe, N.

1991-01-01

A design concept of KENS-II target-moderator-reflector assemblies is described. One of the assemblies is dedicated to the cold neutron source, and the other, to the thermal and epithermal neutron source. A flux-trap type moderator-configuration was adopted with a vertical proton-beam injection scheme. All moderators for the cold neutron source are coupled liquid hydrogen moderators with premoderators. A new scheme of proton beam delivery is proposed. The new system can provide several times higher total performance than a reference system based on a traditional single assembly with all decoupled moderators in a wing geometry and with a horizontal proton-beam injection scheme. (author)

Targeted endothelial nanomedicine for common acute pathological conditions.

Science.gov (United States)

Shuvaev, Vladimir V; Brenner, Jacob S; Muzykantov, Vladimir R

2015-12-10

Endothelium, a thin monolayer of specialized cells lining the lumen of blood vessels is the key regulatory interface between blood and tissues. Endothelial abnormalities are implicated in many diseases, including common acute conditions with high morbidity and mortality lacking therapy, in part because drugs and drug carriers have no natural endothelial affinity. Precise endothelial drug delivery may improve management of these conditions. Using ligands of molecules exposed to the bloodstream on the endothelial surface enables design of diverse targeted endothelial nanomedicine agents. Target molecules and binding epitopes must be accessible to drug carriers, carriers must be free of harmful effects, and targeting should provide desirable sub-cellular addressing of the drug cargo. The roster of current candidate target molecules for endothelial nanomedicine includes peptidases and other enzymes, cell adhesion molecules and integrins, localized in different domains of the endothelial plasmalemma and differentially distributed throughout the vasculature. Endowing carriers with an affinity to specific endothelial epitopes enables an unprecedented level of precision of control of drug delivery: binding to selected endothelial cell phenotypes, cellular addressing and duration of therapeutic effects. Features of nanocarrier design such as choice of epitope and ligand control delivery and effect of targeted endothelial nanomedicine agents. Pathological factors modulate endothelial targeting and uptake of nanocarriers. Selection of optimal binding sites and design features of nanocarriers are key controllable factors that can be iteratively engineered based on their performance from in vitro to pre-clinical in vivo experimental models. Targeted endothelial nanomedicine agents provide antioxidant, anti-inflammatory and other therapeutic effects unattainable by non-targeted counterparts in animal models of common acute severe human disease conditions. The results of animal

pH-Sensitive Reversible Programmed Targeting Strategy by the Self-Assembly/Disassembly of Gold Nanoparticles.

Science.gov (United States)

Ma, Jinlong; Hu, Zhenpeng; Wang, Wei; Wang, Xinyu; Wu, Qiang; Yuan, Zhi

2017-05-24

A reversible programmed targeting strategy could achieve high tumor accumulation due to its long blood circulation time and high cellular internalization. Here, targeting ligand-modified poly(ethylene glycol) (PEG-ligand), dibutylamines (Bu), and pyrrolidinamines (Py) were introduced on the surface of gold nanoparticles (Au NPs) for reversible shielding/deshielding of the targeting ligands by pH-responsive self-assembly. Hydrophobic interaction and steric repulsion are the main driving forces for the self-assembly/disassembly of Au NPs. The precise self-assembly (pH ≥ 7.2) and disassembly (pH ≤ 6.8) of Au NPs with different ligands could be achieved by fine-tuning the modifying molar ratio of Bu and Py (R m ), which followed the formula R m = 1/(-0.0013X 2 + 0.0323X + 1), in which X is the logarithm of the partition coefficient of the targeting ligand. The assembled/disassembled behavior of Au NPs at pH 7.2 and 6.8 was confirmed by transmission electron microscopy and dynamic light scattering. Enzyme-linked immunosorbent assays and cellular uptake studies showed that the ligands could be buried inside the assembly and exposed when disassembled. More importantly, this process was reversible, which provides the possibility of prolonging blood circulation by shielding ligands associated with the NPs that were effused from tumor tissue.

Self-Assembled Smart Nanocarriers for Targeted Drug Delivery.

Science.gov (United States)

Cui, Wei; Li, Junbai; Decher, Gero

2016-02-10

Nanostructured drug-carrier systems promise numerous benefits for drug delivery. They can be engineered to precisely control drug-release rates or to target specific sites within the body with a specific amount of therapeutic agent. However, to achieve the best therapeutic effects, the systems should be designed for carrying the optimum amount of a drug to the desired target where it should be released at the optimum rate for a specified time. Despite numerous attempts, fulfilling all of these requirements in a synergistic way remains a huge challenge. The trend in drug delivery is consequently directed toward integrated multifunctional carrier systems, providing selective recognition in combination with sustained or triggered release. Capsules as vesicular systems enable drugs to be confined for controlled release. Furthermore, carriers modified with recognition groups can enhance the capability of encapsulated drug efficacy. Here, recent advances are reviewed regarding designing and preparing assembled capsules with targeting ligands or size controllable for selective recognition in drug delivery. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Novel tumor-targeting, self-assembling peptide nanofiber as a carrier for effective curcumin delivery

Directory of Open Access Journals (Sweden)

Liu J

2013-12-01

Full Text Available Jianfeng Liu, Jinjian Liu, Hongyan Xu, Yumin Zhang, Liping Chu, Qingfen Liu, Naling Song, Cuihong YangTianjin Key Laboratory of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, People's Republic of ChinaAbstract: The poor aqueous solubility and low bioavailability of curcumin restrict its clinical application for cancer treatment. In this study, a novel tumor-targeting nanofiber carrier was developed to improve the solubility and tumor-targeting ability of curcumin using a self-assembled Nap-GFFYG-RGD peptide. The morphologies of the peptide nanofiber and the curcumin-encapsulated nanofiber were visualized by transmission electron microscopy. The tumor-targeting activity of the curcumin-encapsulated Nap-GFFYG-RGD peptide nanofiber (f-RGD-Cur was studied in vitro and in vivo, using Nap-GFFYG-RGE peptide nanofiber (f-RGE-Cur as the control. Curcumin was encapsulated into the peptide nanofiber, which had a diameter of approximately 10–20 nm. Curcumin showed sustained-release behavior from the nanofibers in vitro. f-RGD-Cur showed much higher cellular uptake in αvβ3 integrin-positive HepG2 liver carcinoma cells than did non-targeted f-RGE-Cur, thereby leading to significantly higher cytotoxicity. Ex vivo studies further demonstrated that curcumin could accumulate markedly in mouse tumors after administration of f-RGD-Cur via the tail vein. These results indicate that Nap-GFFYG-RGD peptide self-assembled nanofibers are a promising hydrophobic drug delivery system for targeted treatment of cancer.Keywords: nanofiber, tumor-targeting, self-assembling, curcumin, drug delivery

Novel apigenin-loaded sodium hyaluronate nano-assemblies for targeting tumor cells.

Science.gov (United States)

Zhao, Ting; He, Yue; Chen, Huali; Bai, Yan; Hu, Wenjing; Zhang, Liangke

2017-12-01

We aimed to construct a novel nano-assembly carrying apigenin (APG), a hydrophobic drug, and to evaluate its in vitro targeting ability for A549 cells overexpressing CD44 receptors. The apigenin-loaded sodium hyaluronate nano-assemblies (APG/SH-NAs) were assembled by multiple non-covalent interactions between sodium hyaluronate (SH) and APG. The prepared APG/SH-NAs exhibited a small average size and narrow particle size distribution. In addition, satisfactory encapsulation efficiency and drug loading were obtained. The drug release curves indicated that APG/SH-NAs achieved a sustainable drug-release effect due to the presence of hydrophilic materials. The in vitro cytotoxicity of APG/SH-NAs against A549 cells and HepG2 cells was evaluated, and the results indicated that the prepared APG/SH-NA showed higher cytotoxicity compared to apigenin suspensions. When CD44 receptors on the surface of A549 cells were blocked by the addition of excess SH, the cytotoxicity of APG/SH-NA was significantly reduced. However, similar phenomena were not observed in HepG2 cells with relatively low CD44 receptor expression. The resulting APG/SH-NAs could efficiently facilitate the internalization of APG into A549 cells, which might be due to their high affinity for CD44 receptors. Moreover, the apoptotic rate of APG/SH-NAs through receptor-mediated endocytosis mechanism was higher than that of the other groups in A549 cells. Thus, such nano-assemblies were considered to be an effective transport system with excellent affinity for CD44 receptors to allow the SH-mediated targeted delivery of APG. Copyright © 2017. Published by Elsevier Ltd.

Role of targeted magnetic resonance imaging sequences in the surgical management of anterior skull base pathology.

Science.gov (United States)

Chawla, S; Bowman, J; Gandhi, M; Panizza, B

2017-01-01

The skull base is a highly complex anatomical region that provides passage for important nerves and vessels as they course into and out of the cranial cavity. Key to the management of pathology in this region is a thorough understanding of the anatomy, with its variations, and the relationship of various neurovascular structures to the pathology in question. Targeted high-resolution magnetic resonance imaging on high field strength magnets can enable the skull base surgeon to understand this intricate relationship and deal with the pathology from a position of relative advantage. With the help of case studies, this paper illustrates the application of specialised magnetic resonance techniques to study pathology of the orbital apex in particular. The fine anatomical detail provided gives surgeons the ability to design an endonasal endoscopic procedure appropriate to the anatomy of the pathology.

Molecular Imaging on the Cerebral Pathological Damage Target of Ketamine Dependence

Directory of Open Access Journals (Sweden)

YANG Hong-jie1,2;HU Shu1;JIA Shao-wei1;GAO Zhou1;WANG Tong3;ZHAO Zheng-qin1

2014-02-01

Full Text Available To study the cerebral pathological damage target which result from abusing ketamine through molecular imaging techniques， 20 cases of ketamine dependent patients looking for treatment at the Peking University Shenzhen Hospital and 31 healthy volunteers were included in this study, all of them got brain SPECT DAT imaging. The results were analyzed by SPSS 16.0. The bilateral caudate nucleus and putamen of healthy volunteers were roughly equally large, and the radioactive distribution of DAT in healthy volunteers were uniform and symmetrical. The bilateral corpora striatum showed typical “panda eyes” pattern. But the bilateral corpora striatum of ketamine dependent patients got smaller in shape, got disorders in pattern, and the radioactive distribution of DAT reduced or defected or even got disturbance and with much more non-specific radioactive. The V, m and Ra of bilateral corpora striatum in ketamine dependent patients were （21.03±3.15） cm3, （22.08±3.31） g and （5.37±1.08） %, respectively, which were significantly lower than the healthy volunteers (p<0.01. The cerebral pathological damage target which resulted from abusing ketamine was similar to those of compound codeine phosphate antitussive solution dependence, heroin dependence and MDMA dependence, all of these psychoactive substances damaged the function of DAT.

Targeting and Assembly of Components of the TOC Protein Import Complex at the Chloroplast Outer Envelope Membrane

Directory of Open Access Journals (Sweden)

Lynn G.L. Richardson

2014-06-01

Full Text Available The translocon at the outer envelope membrane of chloroplasts (TOC initiates the import of thousands of nuclear encoded preproteins required for chloroplast biogenesis and function. The multimeric TOC complex contains two GTP-regulated receptors, Toc34 and Toc159, which recognize the transit peptides of preproteins and initiate protein import through a β–barrel membrane channel, Toc75. Different isoforms of Toc34 and Toc159 assemble with Toc75 to form structurally and functionally diverse translocons, and the composition and levels of TOC translocons is required for the import of specific subsets of coordinately expressed proteins during plant growth and development. Consequently, the proper assembly of the TOC complexes is key to ensuring organelle homeostasis. This review will focus on our current knowledge of the targeting and assembly of TOC components to form functional translocons at the outer membrane. Our analyses reveal that the targeting of TOC components involves elements common to the targeting of other outer membrane proteins, but also include unique features that appear to have evolved to specifically facilitate assembly of the import apparatus.

Targeting and assembly of components of the TOC protein import complex at the chloroplast outer envelope membrane.

Science.gov (United States)

Richardson, Lynn G L; Paila, Yamuna D; Siman, Steven R; Chen, Yi; Smith, Matthew D; Schnell, Danny J

2014-01-01

The translocon at the outer envelope membrane of chloroplasts (TOC) initiates the import of thousands of nuclear encoded preproteins required for chloroplast biogenesis and function. The multimeric TOC complex contains two GTP-regulated receptors, Toc34 and Toc159, which recognize the transit peptides of preproteins and initiate protein import through a β-barrel membrane channel, Toc75. Different isoforms of Toc34 and Toc159 assemble with Toc75 to form structurally and functionally diverse translocons, and the composition and levels of TOC translocons is required for the import of specific subsets of coordinately expressed proteins during plant growth and development. Consequently, the proper assembly of the TOC complexes is key to ensuring organelle homeostasis. This review will focus on our current knowledge of the targeting and assembly of TOC components to form functional translocons at the outer membrane. Our analyses reveal that the targeting of TOC components involves elements common to the targeting of other outer membrane proteins, but also include unique features that appear to have evolved to specifically facilitate assembly of the import apparatus.

Commissioning a Rotating Target Wheel Assembly for Heavy Element Studies

Science.gov (United States)

Fields, L. D.; Bennett, M. E.; Mayorov, D. A.; Folden, C. M.

2013-10-01

The heaviest elements are produced artificially by fusing nuclei of light elements within an accelerator to form heavier nuclei. The most direct method to increase the production rate of nuclei is to increase the beam intensity, necessitating the use of a rotating target to minimize damage to the target by deposited heat. Such a target wheel was constructed for heavy element research at Texas A&M University, Cyclotron Institute, consisting of a wheel with three banana-shaped target cutouts. The target is designed to rotate at 1700 rpm, and a fiber optic cable provides a signal to trigger beam pulsing in order to avoid irradiating the spokes between target segments. Following minor mechanical modifications and construction of a dedicated electrical panel, the rotating target assembly was commissioned for a beam experiment. A 15 MeV/u beam of 20Ne was delivered from the K500 cyclotron and detected by a ruggedized silicon detector. The beam pulsing response time was characterized as a function of the rational frequency of the target wheel. Preliminary analysis suggests that the K500 is capable of pulsing at rates of up to 250 Hz, which is sufficient for planned future experiments. Funded by DOE and NSF-REU Program.

Detection of Alzheimer's amyloid beta aggregation by capturing molecular trails of individual assemblies

International Nuclear Information System (INIS)

Vestergaard, Mun'delanji; Hamada, Tsutomu; Saito, Masato; Yajima, Yoshifumi; Kudou, Monotori; Tamiya, Eiichi; Takagi, Masahiro

2008-01-01

Assembly of Amyloid beta (Aβ) peptides, in particular Aβ-42 is central to the formation of the amyloid plaques associated with neuro-pathologies such as Alzheimer's disease (AD). Molecular assembly of individual Aβ-42 species was observed using a simple fluorescence microscope. From the molecular movements (aka Brownian motion) of the individual peptide assemblies, we calculated a temporal evolution of the hydrodynamic radius (R H ) of the peptide at physiological temperature and pH. The results clearly show a direct relationship between R H of Aβ-42 and incubation period, corresponding to the previously reported peptide's aggregation kinetics. The data correlates highly with in solution-based label-free electrochemical detection of the peptide's aggregation, and Aβ-42 deposited on a solid surface and analysed using atomic force microscopy (AFM). To the best of our knowledge, this is the first analysis and characterisation of Aβ aggregation based on capturing molecular trails of individual assemblies. The technique enables both real-time observation and a semi-quantitative distribution profile of the various stages of Aβ assembly, at microM peptide concentration. Our method is a promising candidate for real-time observation and analysis of the effect of other pathologically-relevant molecules such as metal ions on pathways to Aβ oligomerisation and aggregation. The method is also a promising screening tool for AD therapeutics that target Aβ assembly.

Mapsembler, targeted and micro assembly of large NGS datasets on a desktop computer

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Peterlongo Pierre

2012-03-01

Full Text Available Abstract Background The analysis of next-generation sequencing data from large genomes is a timely research topic. Sequencers are producing billions of short sequence fragments from newly sequenced organisms. Computational methods for reconstructing whole genomes/transcriptomes (de novo assemblers are typically employed to process such data. However, these methods require large memory resources and computation time. Many basic biological questions could be answered targeting specific information in the reads, thus avoiding complete assembly. Results We present Mapsembler, an iterative micro and targeted assembler which processes large datasets of reads on commodity hardware. Mapsembler checks for the presence of given regions of interest that can be constructed from reads and builds a short assembly around it, either as a plain sequence or as a graph, showing contextual structure. We introduce new algorithms to retrieve approximate occurrences of a sequence from reads and construct an extension graph. Among other results presented in this paper, Mapsembler enabled to retrieve previously described human breast cancer candidate fusion genes, and to detect new ones not previously known. Conclusions Mapsembler is the first software that enables de novo discovery around a region of interest of repeats, SNPs, exon skipping, gene fusion, as well as other structural events, directly from raw sequencing reads. As indexing is localized, the memory footprint of Mapsembler is negligible. Mapsembler is released under the CeCILL license and can be freely downloaded from http://alcovna.genouest.org/mapsembler/.

Disulfide-induced self-assembled targets: A novel strategy for the label free colorimetric detection of DNAs/RNAs via unmodified gold nanoparticles

Science.gov (United States)

Shokri, Ehsan; Hosseini, Morteza; Davari, Mehdi D.; Ganjali, Mohammad R.; Peppelenbosch, Maikel P.; Rezaee, Farhad

2017-04-01

A modified non-cross-linking gold-nanoparticles (Au-NPs) aggregation strategy has been developed for the label free colorimetric detection of DNAs/RNAs based on self-assembling target species in the presence of thiolated probes. Two complementary thiol- modified probes, each of which specifically binds at one half of the target introduced SH groups at both ends of dsDNA. Continuous disulfide bond formation at 3‧ and 5‧ terminals of targets leads to the self-assembly of dsDNAs into the sulfur- rich and flexible products with different lengths. These products have a high affinity for the surface of Au-NPs and efficiently protect the surface from salt induced aggregation. To evaluate the assay efficacy, a small part of the citrus tristeza virus (CTV) genome was targeted, leading to a detection limit of about 5 × 10-9 mol.L-1 over a linear ranged from 20 × 10-9 to 10 × 10-7 mol.L-1. This approach also exhibits good reproducibility and recovery levels in the presence of plant total RNA or human plasma total circulating RNA extracts. Self-assembled targets can be then sensitively distinguished from non-assembled or mismatched targets after gel electrophoresis. The disulfide reaction method and integrating self-assembled DNAs/RNAs targets with bare AuNPs as a sensitive indicator provide us a powerful and simple visual detection tool for a wide range of applications.

Cellular imaging by targeted assembly of hot-spot SERS and photoacoustic nanoprobes using split-fluorescent protein scaffolds.

Science.gov (United States)

Köker, Tuğba; Tang, Nathalie; Tian, Chao; Zhang, Wei; Wang, Xueding; Martel, Richard; Pinaud, Fabien

2018-02-09

The in cellulo assembly of plasmonic nanomaterials into photo-responsive probes is of great interest for many bioimaging and nanophotonic applications but remains challenging with traditional nucleic acid scaffolds-based bottom-up methods. Here, we address this quandary using split-fluorescent protein (FP) fragments as molecular glue and switchable Raman reporters to assemble gold or silver plasmonic nanoparticles (NPs) into photonic clusters directly in live cells. When targeted to diffusing surface biomarkers in cancer cells, the NPs self-assemble into surface-enhanced Raman-scattering (SERS) nanoclusters having hot spots homogenously seeded by the reconstruction of full-length FPs. Within plasmonic hot spots, autocatalytic activation of the FP chromophore and near-field amplification of its Raman fingerprints enable selective and sensitive SERS imaging of targeted cells. This FP-driven assembly of metal colloids also yields enhanced photoacoustic signals, allowing the hybrid FP/NP nanoclusters to serve as contrast agents for multimodal SERS and photoacoustic microscopy with single-cell sensitivity.

Physico-Pathologic Mechanisms Involved in Neurodegeneration: Misfolded Protein-Plasma Membrane Interactions.

Science.gov (United States)

Shrivastava, Amulya Nidhi; Aperia, Anita; Melki, Ronald; Triller, Antoine

2017-07-05

Several neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, are characterized by prominent loss of synapses and neurons associated with the presence of abnormally structured or misfolded protein assemblies. Cell-to-cell transfer of misfolded proteins has been proposed for the intra-cerebral propagation of these diseases. When released, misfolded proteins diffuse in the 3D extracellular space before binding to the plasma membrane of neighboring cells, where they diffuse on a 2D plane. This reduction in diffusion dimension and the cell surface molecular crowding promote deleterious interactions with native membrane proteins, favoring clustering and further aggregation of misfolded protein assemblies. These processes open up new avenues for therapeutics development targeting the initial interactions of deleterious proteins with the plasma membrane or the subsequent pathological signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

Modular assembly of transposable element arrays by microsatellite targeting in the guayule and rice genomes.

Science.gov (United States)

Valdes Franco, José A; Wang, Yi; Huo, Naxin; Ponciano, Grisel; Colvin, Howard A; McMahan, Colleen M; Gu, Yong Q; Belknap, William R

2018-04-19

Guayule (Parthenium argentatum A. Gray) is a rubber-producing desert shrub native to Mexico and the United States. Guayule represents an alternative to Hevea brasiliensis as a source for commercial natural rubber. The efficient application of modern molecular/genetic tools to guayule improvement requires characterization of its genome. The 1.6 Gb guayule genome was sequenced, assembled and annotated. The final 1.5 Gb assembly, while fragmented (N 50  = 22 kb), maps > 95% of the shotgun reads and is essentially complete. Approximately 40,000 transcribed, protein encoding genes were annotated on the assembly. Further characterization of this genome revealed 15 families of small, microsatellite-associated, transposable elements (TEs) with unexpected chromosomal distribution profiles. These SaTar (Satellite Targeted) elements, which are non-autonomous Mu-like elements (MULEs), were frequently observed in multimeric linear arrays of unrelated individual elements within which no individual element is interrupted by another. This uniformly non-nested TE multimer architecture has not been previously described in either eukaryotic or prokaryotic genomes. Five families of similarly distributed non-autonomous MULEs (microsatellite associated, modularly assembled) were characterized in the rice genome. Families of TEs with similar structures and distribution profiles were identified in sorghum and citrus. The sequencing and assembly of the guayule genome provides a foundation for application of current crop improvement technologies to this plant. In addition, characterization of this genome revealed SaTar elements with distribution profiles unique among TEs. Satar targeting appears based on an alternative MULE recombination mechanism with the potential to impact gene evolution.

Potential functional and pathological side effects related to off-target pharmacological activity.

Science.gov (United States)

Lynch, James J; Van Vleet, Terry R; Mittelstadt, Scott W; Blomme, Eric A G

2017-09-01

Most pharmaceutical companies test their discovery-stage proprietary molecules in a battery of in vitro pharmacology assays to try to determine off-target interactions. During all phases of drug discovery and development, various questions arise regarding potential side effects associated with such off-target pharmacological activity. Here we present a scientific literature curation effort undertaken to determine and summarize the most likely functional and pathological outcomes associated with interactions at 70 receptors, enzymes, ion channels and transporters with established links to adverse effects. To that end, the scientific literature was reviewed using an on-line database, and the most commonly reported effects were summarized in tabular format. The resultant table should serve as a practical guide for research scientists and clinical investigators for the prediction and interpretation of adverse side effects associated with molecules interacting with components of this screening battery. Copyright © 2017 Elsevier Inc. All rights reserved.

A universal molecular translator for non-nucleic acid targets that enables dynamic DNA assemblies and logic operations.

Science.gov (United States)

Tang, Wei; Hu, Shichao; Wang, Huaming; Zhao, Yan; Li, Na; Liu, Feng

2014-11-28

A universal molecular translator based on the target-triggered DNA strand displacement was developed, which was able to convert various kinds of non-nucleic acid targets into a unique output DNA. This translation strategy was successfully applied in directing dynamic DNA assemblies and in realizing three-input logic gate operations.

Cardiac Fibroblasts Adopt Osteogenic Fates and Can Be Targeted to Attenuate Pathological Heart Calcification.

Science.gov (United States)

Pillai, Indulekha C L; Li, Shen; Romay, Milagros; Lam, Larry; Lu, Yan; Huang, Jie; Dillard, Nathaniel; Zemanova, Marketa; Rubbi, Liudmilla; Wang, Yibin; Lee, Jason; Xia, Ming; Liang, Owen; Xie, Ya-Hong; Pellegrini, Matteo; Lusis, Aldons J; Deb, Arjun

2017-02-02

Mammalian tissues calcify with age and injury. Analogous to bone formation, osteogenic cells are thought to be recruited to the affected tissue and induce mineralization. In the heart, calcification of cardiac muscle leads to conduction system disturbances and is one of the most common pathologies underlying heart blocks. However the cell identity and mechanisms contributing to pathological heart muscle calcification remain unknown. Using lineage tracing, murine models of heart calcification and in vivo transplantation assays, we show that cardiac fibroblasts (CFs) adopt an osteoblast cell-like fate and contribute directly to heart muscle calcification. Small-molecule inhibition of ENPP1, an enzyme that is induced upon injury and regulates bone mineralization, significantly attenuated cardiac calcification. Inhibitors of bone mineralization completely prevented ectopic cardiac calcification and improved post injury heart function. Taken together, these findings highlight the plasticity of fibroblasts in contributing to ectopic calcification and identify pharmacological targets for therapeutic development. Copyright © 2017 Elsevier Inc. All rights reserved.

Analysis of the thermomechanical behavior of the IFMIF bayonet target assembly under design loading scenarios

Energy Technology Data Exchange (ETDEWEB)

Bernardi, D., E-mail: davide.bernardi@enea.it [ENEA Brasimone, Camugnano, BO (Italy); Arena, P.; Bongiovì, G.; Di Maio, P.A. [Dipartimento di Energia, Ingegneria dell’Informazione e Modelli Matematici, Università di Palermo, Viale delle Scienze, Palermo (Italy); Frisoni, M. [ENEA Bologna, Via Martiri di Monte Sole 4, Bologna (Italy); Miccichè, G.; Serra, M. [ENEA Brasimone, Camugnano, BO (Italy)

2015-10-15

In the framework of the IFMIF Engineering Validation and Engineering Design Activities (IFMIF/EVEDA) phase, ENEA is responsible for the design of the European concept of the IFMIF lithium target system which foresees the possibility to periodically replace only the most irradiated and thus critical component (i.e., the backplate) while continuing to operate the rest of the target for a longer period (the so-called bayonet backplate concept). In this work, the results of the steady state thermomechanical analysis of the IFMIF bayonet target assembly under two different design loading scenarios (a “hot” scenario and a “cold” scenario) are briefly reported highlighting the relevant indications obtained with respect to the fulfillment of the design requirements. In particular, the analyses have shown that in the hot scenario the temperatures reached in the target assembly are within the material acceptable limits while in the cold scenario transition below the ductile to brittle transition temperature (DBTT) cannot be excluded. Moreover, results indicate that the contact between backplate and high flux test module is avoided and that the overall structural integrity of the system is assured in both scenarios. However, stress linearization analysis reveals that ITER Structural Design Criteria for In-vessel Components (SDC-IC) design rules are not always met along the selected paths at backplate middle plane section in the hot scenario, thus suggesting the need of a revision of the backplate design or a change of the operating conditions.

Platelet-derived growth factor-DD targeting arrests pathological angiogenesis by modulating glycogen synthase kinase-3beta phosphorylation.

Science.gov (United States)

Kumar, Anil; Hou, Xu; Lee, Chunsik; Li, Yang; Maminishkis, Arvydas; Tang, Zhongshu; Zhang, Fan; Langer, Harald F; Arjunan, Pachiappan; Dong, Lijin; Wu, Zhijian; Zhu, Linda Y; Wang, Lianchun; Min, Wang; Colosi, Peter; Chavakis, Triantafyllos; Li, Xuri

2010-05-14

Platelet-derived growth factor-DD (PDGF-DD) is a recently discovered member of the PDGF family. The role of PDGF-DD in pathological angiogenesis and the underlying cellular and molecular mechanisms remain largely unexplored. In this study, using different animal models, we showed that PDGF-DD expression was up-regulated during pathological angiogenesis, and inhibition of PDGF-DD suppressed both choroidal and retinal neovascularization. We also demonstrated a novel mechanism mediating the function of PDGF-DD. PDGF-DD induced glycogen synthase kinase-3beta (GSK3beta) Ser(9) phosphorylation and Tyr(216) dephosphorylation in vitro and in vivo, leading to increased cell survival. Consistently, GSK3beta activity was required for the antiangiogenic effect of PDGF-DD targeting. Moreover, PDGF-DD regulated the expression of GSK3beta and many other genes important for angiogenesis and apoptosis. Thus, we identified PDGF-DD as an important target gene for antiangiogenic therapy due to its pleiotropic effects on vascular and non-vascular cells. PDGF-DD inhibition may offer new therapeutic options to treat neovascular diseases.

Targeted nanodiamonds for identification of subcellular protein assemblies in mammalian cells

Science.gov (United States)

Lake, Michael P.; Bouchard, Louis-S.

2017-01-01

Transmission electron microscopy (TEM) can be used to successfully determine the structures of proteins. However, such studies are typically done ex situ after extraction of the protein from the cellular environment. Here we describe an application for nanodiamonds as targeted intensity contrast labels in biological TEM, using the nuclear pore complex (NPC) as a model macroassembly. We demonstrate that delivery of antibody-conjugated nanodiamonds to live mammalian cells using maltotriose-conjugated polypropylenimine dendrimers results in efficient localization of nanodiamonds to the intended cellular target. We further identify signatures of nanodiamonds under TEM that allow for unambiguous identification of individual nanodiamonds from a resin-embedded, OsO4-stained environment. This is the first demonstration of nanodiamonds as labels for nanoscale TEM-based identification of subcellular protein assemblies. These results, combined with the unique fluorescence properties and biocompatibility of nanodiamonds, represent an important step toward the use of nanodiamonds as markers for correlated optical/electron bioimaging. PMID:28636640

Targeted nanodiamonds for identification of subcellular protein assemblies in mammalian cells.

Directory of Open Access Journals (Sweden)

Michael P Lake

Full Text Available Transmission electron microscopy (TEM can be used to successfully determine the structures of proteins. However, such studies are typically done ex situ after extraction of the protein from the cellular environment. Here we describe an application for nanodiamonds as targeted intensity contrast labels in biological TEM, using the nuclear pore complex (NPC as a model macroassembly. We demonstrate that delivery of antibody-conjugated nanodiamonds to live mammalian cells using maltotriose-conjugated polypropylenimine dendrimers results in efficient localization of nanodiamonds to the intended cellular target. We further identify signatures of nanodiamonds under TEM that allow for unambiguous identification of individual nanodiamonds from a resin-embedded, OsO4-stained environment. This is the first demonstration of nanodiamonds as labels for nanoscale TEM-based identification of subcellular protein assemblies. These results, combined with the unique fluorescence properties and biocompatibility of nanodiamonds, represent an important step toward the use of nanodiamonds as markers for correlated optical/electron bioimaging.

Targeted nanodiamonds for identification of subcellular protein assemblies in mammalian cells.

Science.gov (United States)

Lake, Michael P; Bouchard, Louis-S

2017-01-01

Transmission electron microscopy (TEM) can be used to successfully determine the structures of proteins. However, such studies are typically done ex situ after extraction of the protein from the cellular environment. Here we describe an application for nanodiamonds as targeted intensity contrast labels in biological TEM, using the nuclear pore complex (NPC) as a model macroassembly. We demonstrate that delivery of antibody-conjugated nanodiamonds to live mammalian cells using maltotriose-conjugated polypropylenimine dendrimers results in efficient localization of nanodiamonds to the intended cellular target. We further identify signatures of nanodiamonds under TEM that allow for unambiguous identification of individual nanodiamonds from a resin-embedded, OsO4-stained environment. This is the first demonstration of nanodiamonds as labels for nanoscale TEM-based identification of subcellular protein assemblies. These results, combined with the unique fluorescence properties and biocompatibility of nanodiamonds, represent an important step toward the use of nanodiamonds as markers for correlated optical/electron bioimaging.

Hot target assembly at 14 UD Pelletron Accelerator Facility, BARC- TIFR, Mumbai

International Nuclear Information System (INIS)

Sharma, S.C.; Ramjilal; Ninawe, N.G.; Bhagwat, P.V.; Ahmeabadhai, P.; Kain, V.

2005-01-01

BARC-TIFR 14 UD Pelletron Accelerator Facility at Mumbai is operational since 1989 with progressively increased efficiency. The accelerator has been serving as major facility for heavy ion based research in India. There is an increased demand for high current proton beam, especially on heated targets for reactor physics based experiments. A proton beam setup is commissioned in the tower area of the existing facility itself, which provide proton beam of energy 2 MeV to 26 MeV with maximum 3 μA current. This setup is being used to produce radioisotopes and tracer packets. Proton beam of few MeV in μA current range is also needed to study radiation effects on metals at higher temperature, for use in reactors. For this purpose a hot target assembly has been designed and is being currently used at the Pelletron Accelerator

Ultra-high vacuum target assembly for charged particle irradiations in the materials research field

International Nuclear Information System (INIS)

Bressers, J.; Cassanelli, G.; Cat, R. de; Kohnen, H.; Gherardi, G.

1978-01-01

A target assembly designed for ion irradiation and ion implantation experiments on different particle accelerators is described. It consists of a target chamber separated from the beam line by a thin metal window, thus allowing implantations to be carried out under ultra-high vacuum conditions. Homogeneous in-depth distribution of the implanted ion species is realized by rotating the target about an axis perpendicular to the ion beam (rocking). The target holder is driven by means of a stepping motor with a constant step angle and a rocking device controller containing the required rocking angle-dwell time relation. Ion beam homogeneity over a sufficiently large target area is arrived at by transforming the Gaussian beam intensity profile into a flat beam intensity distribution by means of an electrostatic ring lens. The beam intensity profile is monitored by means of a specially designed ion beam monitor based on the Nipkov disc principle. A toroidal beam current monitoring transformer continuously measures the total beam current. Beam scanners and current measuring collimators complete the beam analysing equipment

Self-assembled silk sericin/poloxamer nanoparticles as nanocarriers of hydrophobic and hydrophilic drugs for targeted delivery

International Nuclear Information System (INIS)

Mandal, Biman B; Kundu, S C

2009-01-01

In recent times self-assembled micellar nanoparticles have been successfully employed in tissue engineering for targeted drug delivery applications. In this review, silk sericin protein from non-mulberry Antheraea mylitta tropical tasar silk cocoons was blended with pluronic F-127 and F-87 in the presence of solvents to achieve self-assembled micellar nanostructures capable of carrying both hydrophilic (FITC-inulin) and hydrophobic (anticancer drug paclitaxel) drugs. The fabricated nanoparticles were subsequently characterized for their size distribution, drug loading capability, cellular uptake and cytotoxicity. Nanoparticle sizes ranged between 100 and 110 nm in diameter as confirmed by dynamic light scattering. Rapid uptake of these particles into cells was observed in in vitro cellular uptake studies using breast cancer MCF-7 cells. In vitro cytotoxicity assay using paclitaxel-loaded nanoparticles against breast cancer cells showed promising results comparable to free paclitaxel drugs. Drug-encapsulated nanoparticle-induced apoptosis in MCF-7 cells was confirmed by FACS and confocal microscopic studies using Annexin V staining. Up-regulation of pro-apoptotic protein Bax, down-regulation of anti-apoptotic protein Bcl-2 and cleavage of regulatory protein PARP through Western blot analysis suggested further drug-induced apoptosis in cells. This study projects silk sericin protein as an alternative natural biomaterial for fabrication of self-assembled nanoparticles in the presence of poloxamer for successful delivery of both hydrophobic and hydrophilic drugs to target sites.

Self-assembled silk sericin/poloxamer nanoparticles as nanocarriers of hydrophobic and hydrophilic drugs for targeted delivery

Energy Technology Data Exchange (ETDEWEB)

Mandal, Biman B; Kundu, S C, E-mail: kundu@hijli.iitkgp.ernet.i [Department of Biotechnology, Indian Institute of Technology, Kharagpur 721302 (India)

2009-09-02

In recent times self-assembled micellar nanoparticles have been successfully employed in tissue engineering for targeted drug delivery applications. In this review, silk sericin protein from non-mulberry Antheraea mylitta tropical tasar silk cocoons was blended with pluronic F-127 and F-87 in the presence of solvents to achieve self-assembled micellar nanostructures capable of carrying both hydrophilic (FITC-inulin) and hydrophobic (anticancer drug paclitaxel) drugs. The fabricated nanoparticles were subsequently characterized for their size distribution, drug loading capability, cellular uptake and cytotoxicity. Nanoparticle sizes ranged between 100 and 110 nm in diameter as confirmed by dynamic light scattering. Rapid uptake of these particles into cells was observed in in vitro cellular uptake studies using breast cancer MCF-7 cells. In vitro cytotoxicity assay using paclitaxel-loaded nanoparticles against breast cancer cells showed promising results comparable to free paclitaxel drugs. Drug-encapsulated nanoparticle-induced apoptosis in MCF-7 cells was confirmed by FACS and confocal microscopic studies using Annexin V staining. Up-regulation of pro-apoptotic protein Bax, down-regulation of anti-apoptotic protein Bcl-2 and cleavage of regulatory protein PARP through Western blot analysis suggested further drug-induced apoptosis in cells. This study projects silk sericin protein as an alternative natural biomaterial for fabrication of self-assembled nanoparticles in the presence of poloxamer for successful delivery of both hydrophobic and hydrophilic drugs to target sites.

Intracellular targeting of CD44+ cells with self-assembling, protein only nanoparticles.

Science.gov (United States)

Pesarrodona, Mireia; Ferrer-Miralles, Neus; Unzueta, Ugutz; Gener, Petra; Tatkiewicz, Witold; Abasolo, Ibane; Ratera, Imma; Veciana, Jaume; Schwartz, Simó; Villaverde, Antonio; Vazquez, Esther

2014-10-01

CD44 is a multifunctional cell surface protein involved in proliferation and differentiation, angiogenesis and signaling. The expression of CD44 is up-regulated in several types of human tumors and particularly in cancer stem cells, representing an appealing target for drug delivery in the treatment of cancer. We have explored here several protein ligands of CD44 for the construction of self-assembling modular proteins designed to bind and internalize target cells. Among five tested ligands, two of them (A5G27 and FNI/II/V) drive the formation of protein-only, ring-shaped nanoparticles of about 14 nm that efficiently bind and penetrate CD44(+) cells by an endosomal route. The potential of these newly designed nanoparticles is evaluated regarding the need of biocompatible nanostructured materials for drug delivery in CD44-linked conditions. Copyright © 2014 Elsevier B.V. All rights reserved.

Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy

Science.gov (United States)

Spinazzola, Janelle M.; Kunkel, Louis M.

2016-01-01

Introduction Since the identification of the dystrophin gene in 1986, a cure for Duchenne muscular dystrophy (DMD) has yet to be discovered. Presently, there are a number of genetic-based therapies in development aimed at restoration and/or repair of the primary defect. However, growing understanding of the pathophysiological consequences of dystrophin absence has revealed several promising downstream targets for the development of therapeutics. Areas covered In this review, we discuss various strategies for DMD therapy targeting downstream consequences of dystrophin absence including loss of muscle mass, inflammation, fibrosis, calcium overload, oxidative stress, and ischemia. The rationale of each approach and the efficacy of drugs in preclinical and clinical studies are discussed. Expert opinion For the last 30 years, effective DMD drug therapy has been limited to corticosteroids, which are associated with a number of negative side effects. Our knowledge of the consequences of dystrophin absence that contribute to DMD pathology has revealed several potential therapeutic targets. Some of these approaches may have potential to improve or slow disease progression independently or in combination with genetic-based approaches. The applicability of these pharmacological therapies to DMD patients irrespective of their genetic mutation, as well as the potential benefits even for advanced stage patients warrants their continued investigation. PMID:28670506

Simulated nuclear reactor fuel assembly

International Nuclear Information System (INIS)

Berta, V.T.

1993-01-01

An apparatus for electrically simulating a nuclear reactor fuel assembly. It includes a heater assembly having a top end and a bottom end and a plurality of concentric heater tubes having electrical circuitry connected to a power source, and radially spaced from each other. An outer target tube and an inner target tube is concentric with the heater tubes and with each other, and the outer target tube surrounds and is radially spaced from the heater tubes. The inner target tube is surrounded by and radially spaced from the heater tubes and outer target tube. The top of the assembly is generally open to allow for the electrical power connection to the heater tubes, and the bottom of the assembly includes means for completing the electrical circuitry in the heater tubes to provide electrical resistance heating to simulate the power profile in a nuclear reactor. The embedded conductor elements in each heater tube is split into two halves for a substantial portion of its length and provided with electrical isolation such that each half of the conductor is joined at one end and is not joined at the other end

A targeted nanoglobular contrast agent from host-guest self-assembly for MR cancer molecular imaging.

Science.gov (United States)

Zhou, Zhuxian; Han, Zhen; Lu, Zheng-Rong

2016-04-01

The clinical application of nanoparticular Gd(III) based contrast agents for tumor molecular MRI has been hindered by safety concerns associated with prolonged tissue retention, although they can produce strong tumor enhancement. In this study, a targeted well-defined cyclodextrin-based nanoglobular contrast agent was developed through self-assembly driven by host-guest interactions for safe and effective cancer molecular MRI. Multiple β-cyclodextrins attached POSS (polyhedral oligomeric silsesquioxane) nanoglobule was used as host molecule. Adamantane-modified macrocyclic Gd(III) contrast agent, cRGD (cyclic RGDfK peptide) targeting ligand and fluorescent probe was used as guest molecules. The targeted host-guest nanoglobular contrast agent cRGD-POSS-βCD-(DOTA-Gd) specifically bond to αvβ3 integrin in malignant 4T1 breast tumor and provided greater contrast enhancement than the corresponding non-targeted agent. The agent also provided significant fluorescence signal in tumor tissue. The histological analysis of the tumor tissue confirmed its specific and effective targeting to αvβ3 integrin. The targeted imaging agent has a potential for specific cancer molecular MR and fluorescent imaging. Copyright © 2016 Elsevier Ltd. All rights reserved.

PET CT Thresholds for Radiotherapy Target Definition in Non-Small-Cell Lung Cancer: How Close are we to the Pathologic Findings?

International Nuclear Information System (INIS)

Wu Kailiang; Ung, Yee C.; Hornby, Jennifer

2010-01-01

Purpose: Optimal target delineation threshold values for positron emission tomography (PET) and computed tomography (CT) radiotherapy planning is controversial. In this present study, different PET CT threshold values were used for target delineation and then compared pathologically. Methods and Materials: A total of 31 non-small-cell lung cancer patients underwent PET CT before surgery. The maximal diameter (MD) of the pathologic primary tumor was obtained. The CT-based gross tumor volumes (GTV CT ) were delineated for CT window-level thresholds at 1,600 and -300 Hounsfield units (HU) (GTV CT1 ); 1,600 and -400 (GTV CT2 ); 1,600 and -450 HU (GTV CT3 ); 1,600 and -600 HU (GTV CT4 ); 1,200 and -700 HU (GTV CT5 ); 900 and -450 HU (GTV CT6 ); and 700 and -450 HU (GTV CT7 ). The PET-based GTVs (GTV PET ) were autocontoured at 20% (GTV 20 ), 30% (GTV 30 ), 40% (GTV 40 ), 45% (GTV 45 ), 50% (GTV 50 ), and 55% (GTV 55 ) of the maximal intensity level. The MD of each image-based GTV in three-dimensional orientation was determined. The MD of the GTV PET and GTV CT were compared with the pathologically determined MD. Results: The median MD of the GTV CT changed from 2.89 (GTV CT2 ) to 4.46 (GTV CT7 ) as the CT thresholds were varied. The correlation coefficient of the GTV CT compared with the pathologically determined MD ranged from 0.76 to 0.87. The correlation coefficient of the GTV CT1 was the best (r = 0.87). The median MD of GTV PET changed from 5.72cm to 2.67cm as the PET thresholds increased. The correlation coefficient of the GTV PET compared with the pathologic finding ranged from 0.51 to 0.77. The correlation coefficient of GTV 50 was the best (r = 0.77). Conclusion: Compared with the MD of GTV PET , the MD of GTV CT had better correlation with the pathologic MD. The GTV CT1 and GTV 50 had the best correlation with the pathologic results.

Positron emission tomography in amyotrophic lateral sclerosis: Towards targeting of molecular pathological hallmarks

Energy Technology Data Exchange (ETDEWEB)

Willekens, Stefanie M.A.; Weehaeghe, Donatienne van [University Hospitals Leuven and KU Leuven, Division of Nuclear Medicine, Department of Imaging and Pathology, Leuven (Belgium); Damme, Philip van [University Hospitals Leuven, Department of Neurology, Leuven (Belgium); KU Leuven, Department of Neurosciences, Experimental Neurology, Leuven (Belgium); Leuven Research Institute for Neuroscience and Disease (LIND), Leuven (Belgium); VIB, Vesalius Research Center, Laboratory of Neurobiology, Leuven (Belgium); Laere, Koen van [University Hospitals Leuven and KU Leuven, Division of Nuclear Medicine, Department of Imaging and Pathology, Leuven (Belgium); Leuven Research Institute for Neuroscience and Disease (LIND), Leuven (Belgium)

2017-03-15

During the past decades, extensive efforts have been made to expand the knowledge of amyotrophic lateral sclerosis (ALS). However, clinical translation of this research, in terms of earlier diagnosis and improved therapy, remains challenging. Since more than 30% of motor neurons are lost when symptoms become clinically apparent, techniques allowing non-invasive, in vivo detection of motor neuron degeneration are needed in the early, pre-symptomatic disease stage. Furthermore, it has become apparent that non-motor signs play an important role in the disease and there is an overlap with cognitive disorders, such as frontotemporal dementia (FTD). Radionuclide imaging, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), form an attractive approach to quantitatively monitor the ongoing neurodegenerative processes. Although [{sup 18}F]-FDG has been recently proposed as a potential biomarker for ALS, active targeting of the underlying pathologic molecular processes is likely to unravel further valuable disease information and may help to decipher the pathogenesis of ALS. In this review, we provide an overview of radiotracers that have already been applied in ALS and discuss possible novel targets for in vivo imaging of various pathogenic processes underlying ALS onset and progression. (orig.)

Positron emission tomography in amyotrophic lateral sclerosis: Towards targeting of molecular pathological hallmarks

International Nuclear Information System (INIS)

Willekens, Stefanie M.A.; Weehaeghe, Donatienne van; Damme, Philip van; Laere, Koen van

2017-01-01

During the past decades, extensive efforts have been made to expand the knowledge of amyotrophic lateral sclerosis (ALS). However, clinical translation of this research, in terms of earlier diagnosis and improved therapy, remains challenging. Since more than 30% of motor neurons are lost when symptoms become clinically apparent, techniques allowing non-invasive, in vivo detection of motor neuron degeneration are needed in the early, pre-symptomatic disease stage. Furthermore, it has become apparent that non-motor signs play an important role in the disease and there is an overlap with cognitive disorders, such as frontotemporal dementia (FTD). Radionuclide imaging, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), form an attractive approach to quantitatively monitor the ongoing neurodegenerative processes. Although ["1"8F]-FDG has been recently proposed as a potential biomarker for ALS, active targeting of the underlying pathologic molecular processes is likely to unravel further valuable disease information and may help to decipher the pathogenesis of ALS. In this review, we provide an overview of radiotracers that have already been applied in ALS and discuss possible novel targets for in vivo imaging of various pathogenic processes underlying ALS onset and progression. (orig.)

Multi-scale coarse-graining for the study of assembly pathways in DNA-brick self-assembly

Science.gov (United States)

Fonseca, Pedro; Romano, Flavio; Schreck, John S.; Ouldridge, Thomas E.; Doye, Jonathan P. K.; Louis, Ard A.

2018-04-01

Inspired by recent successes using single-stranded DNA tiles to produce complex structures, we develop a two-step coarse-graining approach that uses detailed thermodynamic calculations with oxDNA, a nucleotide-based model of DNA, to parametrize a coarser kinetic model that can reach the time and length scales needed to study the assembly mechanisms of these structures. We test the model by performing a detailed study of the assembly pathways for a two-dimensional target structure made up of 334 unique strands each of which are 42 nucleotides long. Without adjustable parameters, the model reproduces a critical temperature for the formation of the assembly that is close to the temperature at which assembly first occurs in experiments. Furthermore, the model allows us to investigate in detail the nucleation barriers and the distribution of critical nucleus shapes for the assembly of a single target structure. The assembly intermediates are compact and highly connected (although not maximally so), and classical nucleation theory provides a good fit to the height and shape of the nucleation barrier at temperatures close to where assembly first occurs.

Polyamine/salt-assembled microspheres coated with hyaluronic acid for targeting and pH sensing.

Science.gov (United States)

Zhang, Pan; Yang, Hui; Wang, Guojun; Tong, Weijun; Gao, Changyou

2016-06-01

The poly(allylamine hydrochloride)/trisodium citrate aggregates were fabricated and further covalently crosslinked via the coupling reaction of carboxylic sites on trisodium citrate with the amine groups on polyamine, onto which poly-L-lysine and hyaluronic acid were sequentially assembled, forming stable microspheres. The pH sensitive dye and pH insensitive dye were further labeled to enable the microspheres with pH sensing property. Moreover, these microspheres could be specifically targeted to HeLa tumor cells, since hyaluronic acid can specifically recognize and bind to CD44, a receptor overexpressed on many tumor cells. Quantitative pH measurement by confocal laser scanning microscopy demonstrated that the microspheres were internalized into HeLa cells, and accumulated in acidic compartments. By contrast, only a few microspheres were adhered on the NIH 3T3 cells surface. The microspheres with combined pH sensing property and targeting ability can enhance the insight understanding of the targeted drug vehicles trafficking after cellular internalization. Copyright © 2016 Elsevier B.V. All rights reserved.

Computed isotopic inventory and dose assessment for SRS fuel and target assemblies

International Nuclear Information System (INIS)

Chandler, M.C.; Ketusky, E.T.; Thoman, D.C.

1995-01-01

Past studies have identified and evaluated important radionuclide contributors to dose from reprocessed spent fuel sent to waste for Mark 16B and 22 fuel assemblies and for Mark 31 A and 31B target assemblies. Fission-product distributions after a 5- and 15-year decay time were calculated for a ''representative'' set of irradiation conditions (i.e., reactor power, irradiation time, and exposure) for each type of assembly. The numerical calculations were performed using the SHIELD/GLASS system of codes. The sludge and supernate source terms for dose were studied separately with the significant radionuclide contributors for each identified and evaluated. Dose analysis considered both inhalation and ingestion pathways: The inhalation pathway was analyzed for both evaporative and volatile releases. Analysis of evaporative releases utilized release fractions for the individual radionuclides as defined in the ICRP-30 by DOE guidance. A release fraction of unity was assumed for each radionuclide under volatile-type releases, which would encompass internally initiated events (e.g., fires, explosions), process-initiated events, and externally initiated events. Radionuclides which contributed at least 1% to the overall dose were designated as significant contributors. The present analysis extends and complements the past analyses through considering a broader spectrum of fuel types and a wider range of irradiation conditions. The results provide for a more thorough understanding of the influences of fuel composition and irradiation parameters on fission product distributions (at 2 years or more). Additionally, the present work allows for a more comprehensive evaluation of radionuclide contributions to dose and an estimation of the variability in the radionuclide composition of the dose source term that results from the spent fuel sent to waste encompassing a broad spectrum of fuel compositions and irradiation conditions

Intracellular Peptide Self-Assembly: A Biomimetic Approach for in Situ Nanodrug Preparation.

Science.gov (United States)

Du, Wei; Hu, Xiaomu; Wei, Weichen; Liang, Gaolin

2018-04-18

Most nanodrugs are preprepared by encapsulating or loading the drugs with nanocarriers (e.g., dendrimers, liposomes, micelles, and polymeric nanoparticles). However, besides the low bioavailability and fast excretion of the nanodrugs in vivo, nanocarriers often exhibit in vitro and in vivo cytotoxicity, oxidative stress, and inflammation. Self-assembly is a ubiquitous process in biology where it plays important roles and underlies the formation of a wide variety of complex biological structures. Inspired by some cellular nanostructures (e.g., actin filaments, microtubules, vesicles, and micelles) in biological systems which are formed via molecular self-assembly, in recent decades, scientists have utilized self-assembly of oligomeric peptide under specific physiological or pathological environments to in situ construct nanodrugs for lesion-targeted therapies. On one hand, peptide-based nanodrugs always have some excellent intrinsic chemical (specificity, intrinsic bioactivity, biodegradability) and physical (small size, conformation) properties. On the other hand, stimuli-regulated intracellular self-assembly of nanodrugs is quite an efficient way to accumulate the drugs in lesion location and can realize an in situ slow release of the drugs. In this review article, we provided an overview on recent design principles for intracellular peptide self-assembly and illustrate how these principles have been applied for the in situ preparation of nanodrugs at the lesion location. In the last part, we list some challenges underlying this strategy and their possible solutions. Moreover, we envision the future possible theranostic applications of this strategy.

The chaperonin-60 universal target is a barcode for bacteria that enables de novo assembly of metagenomic sequence data.

Science.gov (United States)

Links, Matthew G; Dumonceaux, Tim J; Hemmingsen, Sean M; Hill, Janet E

2012-01-01

Barcoding with molecular sequences is widely used to catalogue eukaryotic biodiversity. Studies investigating the community dynamics of microbes have relied heavily on gene-centric metagenomic profiling using two genes (16S rRNA and cpn60) to identify and track Bacteria. While there have been criteria formalized for barcoding of eukaryotes, these criteria have not been used to evaluate gene targets for other domains of life. Using the framework of the International Barcode of Life we evaluated DNA barcodes for Bacteria. Candidates from the 16S rRNA gene and the protein coding cpn60 gene were evaluated. Within complete bacterial genomes in the public domain representing 983 species from 21 phyla, the largest difference between median pairwise inter- and intra-specific distances ("barcode gap") was found from cpn60. Distribution of sequence diversity along the ∼555 bp cpn60 target region was remarkably uniform. The barcode gap of the cpn60 universal target facilitated the faithful de novo assembly of full-length operational taxonomic units from pyrosequencing data from a synthetic microbial community. Analysis supported the recognition of both 16S rRNA and cpn60 as DNA barcodes for Bacteria. The cpn60 universal target was found to have a much larger barcode gap than 16S rRNA suggesting cpn60 as a preferred barcode for Bacteria. A large barcode gap for cpn60 provided a robust target for species-level characterization of data. The assembly of consensus sequences for barcodes was shown to be a reliable method for the identification and tracking of novel microbes in metagenomic studies.

Tau Antibody Targeting Pathological Species Blocks Neuronal Uptake and Interneuron Propagation of Tau in Vitro.

Science.gov (United States)

Nobuhara, Chloe K; DeVos, Sarah L; Commins, Caitlin; Wegmann, Susanne; Moore, Benjamin D; Roe, Allyson D; Costantino, Isabel; Frosch, Matthew P; Pitstick, Rose; Carlson, George A; Hock, Christoph; Nitsch, Roger M; Montrasio, Fabio; Grimm, Jan; Cheung, Anne E; Dunah, Anthone W; Wittmann, Marion; Bussiere, Thierry; Weinreb, Paul H; Hyman, Bradley T; Takeda, Shuko

2017-06-01

The clinical progression of Alzheimer disease (AD) is associated with the accumulation of tau neurofibrillary tangles, which may spread throughout the cortex by interneuronal tau transfer. If so, targeting extracellular tau species may slow the spreading of tau pathology and possibly cognitive decline. To identify suitable target epitopes, we tested the effects of a panel of tau antibodies on neuronal uptake and aggregation in vitro. Immunodepletion was performed on brain extract from tau-transgenic mice and postmortem AD brain and added to a sensitive fluorescence resonance energy transfer-based tau uptake assay to assess blocking efficacy. The antibodies reduced tau uptake in an epitope-dependent manner: N-terminal (Tau13) and middomain (6C5 and HT7) antibodies successfully prevented uptake of tau species, whereas the distal C-terminal-specific antibody (Tau46) had little effect. Phosphorylation-dependent (40E8 and p396) and C-terminal half (4E4) tau antibodies also reduced tau uptake despite removing less total tau by immunodepletion, suggesting specific interactions with species involved in uptake. Among the seven antibodies evaluated, 6C5 most efficiently blocked uptake and subsequent aggregation. More important, 6C5 also blocked neuron-to-neuron spreading of tau in a unique three-chamber microfluidic device. Furthermore, 6C5 slowed down the progression of tau aggregation even after uptake had begun. Our results imply that not all antibodies/epitopes are equally robust in terms of blocking tau uptake of human AD-derived tau species. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Inverse design of multicomponent assemblies

Science.gov (United States)

Piñeros, William D.; Lindquist, Beth A.; Jadrich, Ryan B.; Truskett, Thomas M.

2018-03-01

Inverse design can be a useful strategy for discovering interactions that drive particles to spontaneously self-assemble into a desired structure. Here, we extend an inverse design methodology—relative entropy optimization—to determine isotropic interactions that promote assembly of targeted multicomponent phases, and we apply this extension to design interactions for a variety of binary crystals ranging from compact triangular and square architectures to highly open structures with dodecagonal and octadecagonal motifs. We compare the resulting optimized (self- and cross) interactions for the binary assemblies to those obtained from optimization of analogous single-component systems. This comparison reveals that self-interactions act as a "primer" to position particles at approximately correct coordination shell distances, while cross interactions act as the "binder" that refines and locks the system into the desired configuration. For simpler binary targets, it is possible to successfully design self-assembling systems while restricting one of these interaction types to be a hard-core-like potential. However, optimization of both self- and cross interaction types appears necessary to design for assembly of more complex or open structures.

Optimizing Transcriptome Assemblies for Eleusine indica Leaf and Seedling by Combining Multiple Assemblies from Three De Novo Assemblers

Directory of Open Access Journals (Sweden)

Shu Chen

2015-03-01

Full Text Available Due to rapid advances in sequencing technology, increasing amounts of genomic and transcriptomic data are available for plant species, presenting enormous challenges for biocomputing analysis. A crucial first step for a successful transcriptomics-based study is the building of a high-quality assembly. Here, we utilized three different de novo assemblers (Trinity, Velvet, and CLC and the EvidentialGene pipeline tr2aacds to assemble two optimized transcript sets for the notorious weed species, . Two RNA sequencing (RNA-seq datasets from leaf and aboveground seedlings were processed using three assemblers, which resulted in 20 assemblies for each dataset. The contig numbers and N50 values of each assembly were compared to study the effect of read number, k-mer size, and in silico normalization on assembly output. The 20 assemblies were then processed through the tr2aacds pipeline to remove redundant transcripts and to select the transcript set with the best coding potential. Each assembly contributed a considerable proportion to the final transcript combination with the exception of the CLC-k14. Thus each assembler and parameter set did assemble better contigs for certain transcripts. The redundancy, total contig number, N50, fully assembled contig number, and transcripts related to target-site herbicide resistance were evaluated for the EvidentialGene and Trinity assemblies. Comparing the EvidentialGene set with the Trinity assembly revealed improved quality and reduced redundancy in both leaf and seedling EvidentialGene sets. The optimized transcriptome references will be useful for studying herbicide resistance in and the evolutionary process in the three allotetraploid offspring.

Tumor Cell Invasion Can Be Blocked by Modulators of Collagen Fibril Alignment That Control Assembly of the Extracellular Matrix.

Science.gov (United States)

Grossman, Moran; Ben-Chetrit, Nir; Zhuravlev, Alina; Afik, Ran; Bassat, Elad; Solomonov, Inna; Yarden, Yosef; Sagi, Irit

2016-07-15

Abnormal architectures of collagen fibers in the extracellular matrix (ECM) are hallmarks of many invasive diseases, including cancer. Targeting specific stages of collagen assembly in vivo presents a great challenge due to the involvement of various crosslinking enzymes in the multistep, hierarchical process of ECM build-up. Using advanced microscopic tools, we monitored stages of fibrillary collagen assembly in a native fibroblast-derived 3D matrix system and identified anti-lysyl oxidase-like 2 (LOXL2) antibodies that alter the natural alignment and width of endogenic fibrillary collagens without affecting ECM composition. The disrupted collagen morphologies interfered with the adhesion and invasion properties of human breast cancer cells. Treatment of mice bearing breast cancer xenografts with the inhibitory antibodies resulted in disruption of the tumorigenic collagen superstructure and in reduction of primary tumor growth. Our approach could serve as a general methodology to identify novel therapeutics targeting fibrillary protein organization to treat ECM-associated pathologies. Cancer Res; 76(14); 4249-58. ©2016 AACR. ©2016 American Association for Cancer Research.

Self-assembling complexes of quantum dots and scFv antibodies for cancer cell targeting and imaging.

Directory of Open Access Journals (Sweden)

Tatiana A Zdobnova

Full Text Available Semiconductor quantum dots represent a novel class of fluorophores with unique physical and chemical properties which could enable a remarkable broadening of the current applications of fluorescent imaging and optical diagnostics. Complexes of quantum dots and antibodies are promising visualising agents for fluorescent detection of selective biomarkers overexpressed in tumor tissues. Here we describe the construction of self-assembling fluorescent complexes of quantum dots and anti-HER1 or anti-HER2/neu scFv antibodies and their interactions with cultured tumor cells. A binding strategy based on a very specific non-covalent interaction between two proteins, barnase and barstar, was used to connect quantum dots and the targeting antibodies. Such a strategy allows combining the targeting and visualization functions simply by varying the corresponding modules of the fluorescent complex.

Self-assembled Multifunctional DNA Nanoflowers for the Circumvention of Multidrug Resistance in Targeted Anticancer Drug Delivery.

Science.gov (United States)

Mei, Lei; Zhu, Guizhi; Qiu, Liping; Wu, Cuichen; Chen, Huapei; Liang, Hao; Cansiz, Sena; Lv, Yifan; Zhang, Xiaobing; Tan, Weihong

2015-11-01

Cancer chemotherapy has been impeded by side effects and multidrug resistance (MDR) partially caused by drug efflux from cancer cells, which call for targeted drug delivery systems additionally able to circumvent MDR. Here we report multifunctional DNA nanoflowers (NFs) for targeted drug delivery to both chemosensitive and MDR cancer cells and circumvent MDR in both leukemia and breast cancer cell models. NFs are self-assembled via liquid crystallization of DNA generated by Rolling Circle Replication, during which NFs are incorporated with aptamers for specific cancer cell recognition, fluorophores for bioimaging, and Doxorubicin (Dox)-binding DNA for drug delivery. NF sizes are tunable (down to ~200 nm in diameter), and the densely packed drug-binding motifs and porous intrastructures endow NFs with high drug loading capacity (71.4%, wt/wt). The Dox-loaded NFs (NF-Dox) are stable at physiological pH, yet drug release is facilitated in acidic or basic conditions. NFs deliver Dox into target chemosensitive and MDR cancer cells, preventing drug efflux and enhancing drug retention in MDR cells. Consequently, NF-Dox induces potent cytotoxicity in both target chemosensitive cells and MDR cells, but not nontarget cells, thus concurrently circumventing MDR and reducing side effects. Overall, these NFs are promising to circumvent MDR in targeted cancer therapy.

In situ assembly states of (Na+,K+)-pump ATPase in human erythrocytes. Radiation target size analyses

International Nuclear Information System (INIS)

Hah, J.; Goldinger, J.M.; Jung, C.Y.

1985-01-01

The in situ assembly state of the (Na+,K+)-pump ATPase of human erythrocytes was studied by applying the classical target theory to radiation inactivation data of the ouabain-sensitive sodium efflux and ATP hydrolysis. Erythrocytes and their extensively washed white ghosts were irradiated at -45 to -50 degrees C with an increasing dose of 1.5-MeV electron beam, and after thawing, the Na+-pump flux and/or enzyme activities were assayed. Each activity measured was reduced as a simple exponential function of radiation dose, from which a radiation sensitive mass (target size) was calculated. When intact cells were used, the target sizes for the pump and for the ATPase activities were equal and approximately 620,000 daltons. The target size for the ATPase activity was reduced to approximately 320,000 daltons if the cells were pretreated with digitoxigenin. When ghosts were used, the target size for the ATPase activity was again approximately 320,000 daltons. Our target size measurements together with other information available in literature suggest that (Na+,K+)-pump ATPase may exist in human erythrocytes either as a tetramer of alpha beta or as a dimer of alpha beta in tight association with other protein mass, probably certain glycolytic enzymes, and that this tetrameric or heterocomplex association is dissociable by digitoxigenin treatment or by extensive wash during ghost preparation

Disulfide-induced self-assembled targets : A novel strategy for the label free colorimetric detection of DNAs/RNAs via unmodified gold nanoparticles

NARCIS (Netherlands)

Shokri, Ehsan; Hosseini, Morteza; Davari, Mehdi D.; Ganjali, Mohammad R.; Peppelenbosch, Maikel P.; Rezaee, Farhad

2017-01-01

A modified non-cross-linking gold-nanoparticles (Au-NPs) aggregation strategy has been developed for the label free colorimetric detection of DNAs/RNAs based on self-assembling target species in the presence of thiolated probes. Two complementary thiol-modified probes, each of which specifically

Disulfide-induced self-assembled targets: A novel strategy for the label free colorimetric detection of DNAs/RNAs via unmodified gold nanoparticles

NARCIS (Netherlands)

Shokri, E. (Ehsan); M. Hosseini (Morteza); Davari, M.D. (Mehdi D.); Ganjali, M.R. (Mohammad R.); M.P. Peppelenbosch (Maikel); F. Rezaee (Farhad)

2017-01-01

textabstractA modified non-cross-linking gold-nanoparticles (Au-NPs) aggregation strategy has been developed for the label free colorimetric detection of DNAs/RNAs based on self-assembling target species in the presence of thiolated probes. Two complementary thiol- modified probes, each of which

Development and testing of a deuterium gas target assembly for neutron production via the H-2(d,n)He-3 reaction at a low-energy accelerator facility

International Nuclear Information System (INIS)

Feautrier, D.; Smith, D.L.

1992-03-01

This report describes the development and testing of a deuterium gas target intended for use at a low-energy accelerator facility to produce neutrons for basic research and various nuclear applications. The principle source reaction is H-2(d,n)He-3. It produces a nearly mono-energetic group of neutrons. However, a lower-energy continuum neutron spectrum is produced by the H-2(d;n,p)H-2 reaction and also by deuterons which strike various components in the target assembly. The present target is designed to achieve the following objectives: (1) minimize unwanted background neutron production from the target assembly, (2) provide a relatively low level of residual long-term activity within the target components, (3) have the capacity to dissipate up to 150 watts of beam power with good target longevity, and (4) possess a relatively modest target mass in order to minimize neutron scattering from the target components. The basic physical principles that have to be considered in designing an accelerator target are discussed and the major engineering features of this particular target design are outlined. The results of initial performance tests on this target are documented and some conclusions concerning the viability of the target design are presented

Enzyme sensitive smart inulin-dehydropeptide conjugate self-assembles into nanostructures useful for targeted delivery of ornidazole.

Science.gov (United States)

Shivhare, Kriti; Garg, Charu; Priyam, Ayushi; Gupta, Alka; Sharma, Ashwani Kumar; Kumar, Pradeep

2018-01-01

Molecular self-assembly of biodegradable amphiphilic polymers allows rational design of biocompatible nanomaterials for drug delivery. Use of substituted polysaccharides for such applications offers the ease of design and synthesis, and provides higher biofunctionality and biocompatibility to nanomaterials. The present work focuses on the synthesis, characterization and potential biomedical applications of self-assembled polysaccharide-based materials. We demonstrated that the synthesized amphiphilic inulin self-assembled in aqueous medium into nanostructures with average size in the range of 146-486nm and encapsulated hydrophobic therapeutic molecule, ornidazole. Hydrophophic dehydropeptide was conjugated with inulin via a biocompatible ester linkage. Dehydrophenylalanine, an unusual amino acid, was incorporated in the peptide to make it stable at a broader range of pH as well as against proteases. The resulting core-shell type of nanostructures could encapsulate ornidazole in the hydrophobic core and released it in a controlled fashion. By taking the advantage of inulin, which gets degraded in the colon by colonic bacteria, the effect of enzyme, inulinase, present in the microflora of the large intestine, on inulin-peptide degradation followed by drug release has been studied. Altogether, small peptide conjugated to inulin offers novel scaffold for the future design of nanostructures with potential applications in the field of targeted drug delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

Antiproton Target

CERN Multimedia

1980-01-01

Antiproton target used for the AA (antiproton accumulator). The first type of antiproton production target used from 1980 to 1982 comprised a rod of copper 3mm diameter and 120mm long embedded in a graphite cylinder that was itself pressed into a finned aluminium container. This assembly was air-cooled and it was used in conjunction with the Van der Meer magnetic horn. In 1983 Fermilab provided us with lithium lenses to replace the horn with a view to increasing the antiproton yield by about 30%. These lenses needed a much shorter target made of heavy metal - iridium was chosen for this purpose. The 50 mm iridium rod was housed in an extension to the original finned target container so that it could be brought very close to the entrance to the lithium lens. Picture 1 shows this target assembly and Picture 2 shows it mounted together with the lithium lens. These target containers had a short lifetime due to a combination of beam heating and radiation damage. This led to the design of the water-cooled target in...

Folate mediated self-assembled phytosterol-alginate nanoparticles for targeted intracellular anticancer drug delivery.

Science.gov (United States)

Wang, Jianting; Wang, Ming; Zheng, Mingming; Guo, Qiong; Wang, Yafan; Wang, Heqing; Xie, Xiangrong; Huang, Fenghong; Gong, Renmin

2015-05-01

Self-assembled core/shell nanoparticles (NPs) were synthesized from water-soluble alginate substituted by hydrophobic phytosterols. Folate, a cancer-cell-specific ligand, was conjugated to the phytosterol-alginate (PA) NPs for targeting folate-receptor-overexpressing cancer cells. The physicochemical properties of folate-phytosterol-alginate (FPA) NPs were characterized by nuclear magnetic resonance, transmission electron microscopy, dynamic light scattering, electrophoretic light scattering, and fluorescence spectroscopy. Doxorubicin (DOX), an anticancer drug, was entrapped inside prepared NPs by dialysis method. The identification of prepared FPA NPs to folate-receptor-overexpressing cancer cells (KB cells) was confirmed by cytotoxicity and folate competition assays. Compared to the pure DOX and DOX/PA NPs, the DOX/FPA NPs had lower IC50 value to KB cells because of folate-receptor-mediated endocytosis process and the cytotoxicity of DOX/FPA NPs to KB cells could be competitively inhibited by free folate. The cellular uptake and internalization of pure DOX and DOX/FPA NPs was confirmed by confocal laser scanning microscopy image and the higher intracellular uptake of drug for DOX/FPA NPs over pure DOX was observed. The FPA NPs had the potential as a promising carrier to target drugs to cancer cells overexpressing folate receptors and avoid cytotoxicity to normal tissues. Copyright © 2015 Elsevier B.V. All rights reserved.

Fuel assembly design for APR1400 with low CBC

Energy Technology Data Exchange (ETDEWEB)

Hah, Chang Joo, E-mail: changhah@kings.ac.kr [Department of NPP Engineering, KEPCO International Nuclear Graduate School, Ulsan (Korea, Republic of)

2015-04-29

APR 1400 is a PWR (Pressurized Water Reactor) with rated power of 3983 MWth and 241 assemblies. Recently, demand for extremely longer cycle up to 24 months is increasing with challenge of higher critical boron concentration (CBC). In this paper, assembly design method of selecting Gd-rods is introduced to reduce CBC. The purpose of the method is to lower the critical boron concentration of the preliminary core loading pattern (PLP), and consequently to achieve more negative or less positive moderator temperature coefficient (MTC). In this method, both the ratio of the number of low-Gd rod to the number of high-Gd rod (r) and assembly average Gd wt% (w) are the decision variables. The target function is the amount of soluble boron concentration reduction, which can be converted to Δk{sub TARGET}. A set of new designed fuel assembly satisfies an objective function, min [f=∑{sub i}(Δk{sub FA}−Δk{sub i})], and enables a final loading pattern to reach a target CBC. The constraints required to determine a set of Δk are physically realizable pair, (r,w), and the sum of Δk of new designed assemblies as close to Δk{sub TARGET} as possible. New Gd-bearing assemblies selected based on valid pairs of (r,w) are replaced with existing assemblies in a PLP. This design methodology is applied to Shin-Kori Unit 3 Cycle 1 used as a reference model. CASMO-3/MASTER code is used for depletion calculation. CASMO-3/MASTER calculations with new designed assemblies produce lower CBC than the expected CBC, proving that the proposed method works successful.

FABRICATION AND CHARACTERIZATION OF FAST IGNITION TARGETS

International Nuclear Information System (INIS)

HILL, D.W; CASTILLO, E; CHEN, K.C; GRANT, S.E; GREENWOOD, A.L; KAAE, J.L; NIKROO, A; PAGUIO, S.P; SHEARER, C; SMITH, J.N Jr.; STEPHENS, R.B; STEINMAN, D.A; WALL, J.

2003-09-01

OAK-B135 Fast ignition is a novel scheme for achieving laser fusion. A class of these targets involves cone mounted CH shells. The authors have been fabricating such targets with shells with a wide variety of diameters and wall thicknesses for several years at General Atomics. In addition, recently such shells were needed for implosion experiments at Laboratory for Laser Energetics (LLE) that for the first time were required to be gas retentive. Fabrication of these targets requires producing appropriate cones and shells, assembling the targets, and characterization of the assembled targets. The cones are produced using micromachining and plating techniques. The shells are fabricated using the depolymerizable mandrel technique followed by micromachining a hole for the cone. The cone and the shell then need to be assembled properly for gas retention and precisely in order to position the cone tip at the desired position within the shell. Both are critical for the fast ignition experiments. The presence of the cone in the shell creates new challenges in characterization of the assembled targets. Finally, for targets requiring a gas fill, the cone-shell assembly needs to be tested for gas retention and proper strength at the glue joint. This paper presents an overview of the developmental efforts and technical issues addressed during the fabrication of fast ignition targets

APT target-blanket fabrication development

Energy Technology Data Exchange (ETDEWEB)

Fisher, D.L.

1997-06-13

Concepts for producing tritium in an accelerator were translated into hardware for engineering studies of tritium generation, heat transfer, and effects of proton-neutron flux on materials. Small-scale target- blanket assemblies were fabricated and material samples prepared for these performance tests. Blanket assemblies utilize composite aluminum-lead modules, the two primary materials of the blanket. Several approaches are being investigated to produce large-scale assemblies, developing fabrication and assembly methods for their commercial manufacture. Small-scale target-blanket assemblies, designed and fabricated at the Savannah River Site, were place in Los Alamos Neutron Science Center (LANSCE) for irradiation. They were subjected to neutron flux for nine months during 1996-97. Coincident with this test was the development of production methods for large- scale modules. Increasing module size presented challenges that required new methods to be developed for fabrication and assembly. After development, these methods were demonstrated by fabricating and assembling two production-scale modules.

A highly sensitive label-free electrochemical aptasensor for interferon-gamma detection based on graphene controlled assembly and nuclease cleavage-assisted target recycling amplification.

Science.gov (United States)

Yan, Genping; Wang, Yonghong; He, Xiaoxiao; Wang, Kemin; Liu, Jinquan; Du, Yudan

2013-06-15

We report here a highly sensitive and label-free electrochemical aptasensing technology for detection of interferon-gamma (IFN-γ) based on graphene controlled assembly and enzyme cleavage-assisted target recycling amplification strategy. In this work, in the absence of IFN-γ, the graphene could not be assembled onto the 16-mercaptohexadecanoic acid (MHA) modified gold electrode because the IFN-γ binding aptamer was strongly adsorbed on the graphene due to the strong π-π interaction. Thus the electronic transmission was blocked (eT OFF). However, the presence of target IFN-γ and DNase I led to desorption of aptamer from the graphene surface and further cleavage of the aptamer, thereby releasing the IFN-γ. The released IFN-γ could then re-attack other aptamers on the graphene, resulting in the successive release of the aptamers from the graphene. At the same time, the "naked" graphene could be assembled onto the MHA modified gold electrode with hydrophobic interaction and π-conjunction, mediating the electron transfer between the electrode and the electroactive indicator. Then, measurable electrochemical signals were generated (eT ON), which was related to the concentration of the IFN-γ. By taking advantages of graphene and enzyme cleavage-assisted target recycling amplification, the developed label-free electrochemical aptasensing technology showed a linear response to concentration of IFN-γ range from 0.1 to 0.7 pM. The detection limit of IFN-γ was determined to be 0.065 pM. Moreover, this aptasensor shows good selectivity toward the target in the presence of other relevant proteins. Our strategy thus opens new opportunities for label-free and amplified detection of other kinds of proteins. Copyright © 2013 Elsevier B.V. All rights reserved.

Identification of Factors Promoting HBV Capsid Self-Assembly by Assembly-Promoting Antivirals.

Science.gov (United States)

Rath, Soumya Lipsa; Liu, Huihui; Okazaki, Susumu; Shinoda, Wataru

2018-02-26

Around 270 million individuals currently live with hepatitis B virus (HBV) infection. Heteroaryldihydropyrimidines (HAPs) are a family of antivirals that target the HBV capsid protein and induce aberrant self-assembly. The capsids formed resemble the native capsid structure but are unable to propagate the virus progeny because of a lack of RNA/DNA. Under normal conditions, self-assembly is initiated by the viral genome. The mode of action of HAPs, however, remains largely unknown. In this work, using molecular dynamics simulations, we attempted to understand the action of HAP by comparing the dynamics of capsid proteins with and without HAPs. We found that the inhibitor is more stable in higher oligomers. It retains its stability in the hexamer throughout 1 μs of simulation. Our results also show that the inhibitor might help in stabilizing the C-terminus, the HBc 149-183 arginine-rich domain of the capsid protein. The C-termini of dimers interact with each other, assisted by the HAP inhibitor. During capsid assembly, the termini are supposed to directly interact with the viral genome, thereby suggesting that the viral genome might work in a similar way to stabilize the capsid protein. Our results may help in understanding the underlying molecular mechanism of HBV capsid self-assembly, which should be crucial for exploring new drug targets and structure-based drug design.

Delayed brain radiation necrosis: pathological review and new molecular targets for treatment.

Science.gov (United States)

Furuse, Motomasa; Nonoguchi, Naosuke; Kawabata, Shinji; Miyatake, Shin-Ichi; Kuroiwa, Toshihiko

2015-12-01

Delayed radiation necrosis is a well-known adverse event following radiotherapy for brain diseases and has been studied since the 1930s. The primary pathogenesis is thought to be the direct damage to endothelial and glial cells, particularly oligodendrocytes, which causes vascular hyalinization and demyelination. This primary pathology leads to tissue inflammation and ischemia, inducing various tissue protective responses including angiogenesis. Macrophages and lymphocytes then infiltrate the surrounding areas of necrosis, releasing inflammatory cytokines such as interleukin (IL)-1α, IL-6, and tumor necrosis factor (TNF)-α. Microglia also express these inflammatory cytokines. Reactive astrocytes play an important role in angiogenesis, expressing vascular endothelial growth factor (VEGF). Some chemokine networks, like the CXCL12/CXCR4 axis, are upregulated by tissue inflammation. Hypoxia may mediate the cell-cell interactions among reactive astrocytes, macrophages, and microglial cells around the necrotic core. Recently, bevacizumab, an anti-VEGF antibody, has demonstrated promising results as an alternative treatment for radiation necrosis. The importance of VEGF in the pathophysiology of brain radiation necrosis is being recognized. The discovery of new molecular targets could facilitate novel treatments for radiation necrosis. This literature review will focus on recent work characterizing delayed radiation necrosis in the brain.

Research on Outfitting Virtual Assembly based on Ergonomics

Directory of Open Access Journals (Sweden)

Jiang Zuhua

2018-01-01

Full Text Available To improve the present situation where the assembly work of ship outfitting depends on manual experiential operation, the thesis, taking outfitting assembly operation as the research object and optimal assembly path as the target, puts forward the simulation method and procedure of outfitting virtual assembly considering operational posture, operational load, reachability and visibility and other ergonomic factors, taking pipe assembly operation of ship section as the application example. The results show that the method can obtain better assembly operation path, avoid interference of workers’ operation process and improve the efficiency of assembly operation.

Assembly and patterning of the vascular network of the vertebrate hindbrain

OpenAIRE

Fujita, Misato; Cha, Young R.; Pham, Van N.; Sakurai, Atsuko; Roman, Beth L.; Gutkind, J. Silvio; Weinstein, Brant M.

2011-01-01

The cranial vasculature is essential for the survival and development of the central nervous system and is important in stroke and other brain pathologies. Cranial vessels form in a reproducible and evolutionarily conserved manner, but the process by which these vessels assemble and acquire their stereotypic patterning remains unclear. Here, we examine the stepwise assembly and patterning of the vascular network of the zebrafish hindbrain. The major artery supplying the hindbrain, the basilar...

Concepts for fabrication of inertial fusion energy targets

Energy Technology Data Exchange (ETDEWEB)

Nobile, A. (Arthur), Jr.; Hoffer, J. K. (James K.); Gobby, P. L. (Peter L.); Steckle, W. P. (Warren P.), Jr.; Goodin, D. T. (Daniel T.); Besenbruch, G. E. (Gottfried E.); Schultz, K. R. (Kenneth R.)

2001-01-01

Future inertial fusion energy (IFE) power plants will have a Target Fabrication Facility (TFF) that must produce approximately 500,000 targets per day. To achieve a relatively low cost of electricity, the cost to produce these targets will need to be less than approximately $0.25 per target. In this paper the status on the development of concepts for a TFF to produce targets for a heavy ion fusion (HIF) reactor, such as HYLIFE II, and a laser direct drive fusion reactor such as Sombrero, is discussed. The baseline target that is produced in the HIF TFF is similar to the close-coupled indirect drive target designed by Callahan-Miller and Tabak at Lawrence Livermore Laboratory. This target consists of a cryogenic hohlraum that is made of a metal case and a variety of metal foams and metal-doped organic foams. The target contains a DT-filled CH capsule. The baseline direct drive target is the design developed by Bodner and coworkers at Naval Research Laboratory. HIF targets can be filled with DT before or after assembly of the capsule into the hohlraum. Assembly of targets before filling allows assembly operations to be done at room temperature, but tritium inventories are much larger due to the large volume that the hohlraum occupies in the fill system. Assembly of targets cold after filling allows substantial reduction in tritium inventory, but this requires assembly of targets at cryogenic temperature. A model being developed to evaluate the tritium inventories associated with each of the assembly and fill options indicates that filling targets before assembling the capsule into the hohlraum, filling at temperatures as high as possible, and reducing dead-volumes in the fill system as much as possible offers the potential to reduce tritium inventories to acceptable levels. Use of enhanced DT ice layering techniques, such as infrared layering can reduce tritium inventories significantly by reducing the layering time and therefore the number of capsules being layered

Physics analyses of an accelerator-driven sub-critical assembly

Science.gov (United States)

Naberezhnev, Dmitry G.; Gohar, Yousry; Bailey, James; Belch, Henry

2006-06-01

Physics analyses have been performed for an accelerator-driven sub-critical assembly as a part of the Argonne National Laboratory activity in preparation for a joint conceptual design with the Kharkov Institute of Physics and Technology (KIPT) of Ukraine. KIPT has a plan to construct an accelerator-driven sub-critical assembly targeted towards the medical isotope production and the support of the Ukraine nuclear industry. The external neutron source is produced either through photonuclear reactions in tungsten or uranium targets, or deuteron reactions in a beryllium target. KIPT intends using the high-enriched uranium (HEU) for the fuel of the sub-critical assembly. The main objective of this paper is to study the possibility of utilizing low-enriched uranium (LEU) fuel instead of HEU fuel without penalizing the sub-critical assembly performance, in particular the neutron flux level. In the course of this activity, several studies have been carried out to investigate the main choices for the system's parameters. The external neutron source has been characterized and a pre-conceptual target design has been developed. Several sub-critical configurations with different fuel enrichments and densities have been considered. Based on our analysis, it was shown that the performance of the LEU fuel is comparable with that of the HEU fuel. The LEU fuel sub-critical assembly with 200-MeV electron energy and 100-kW electron beam power has an average total flux of ˜2.50×10 13 n/s cm 2 in the irradiation channels. The corresponding total facility power is ˜204 kW divided into 91 and 113 kW deposited in the target and sub-critical assemblies, respectively.

Single molecule sequencing-guided scaffolding and correction of draft assemblies.

Science.gov (United States)

Zhu, Shenglong; Chen, Danny Z; Emrich, Scott J

2017-12-06

Although single molecule sequencing is still improving, the lengths of the generated sequences are inevitably an advantage in genome assembly. Prior work that utilizes long reads to conduct genome assembly has mostly focused on correcting sequencing errors and improving contiguity of de novo assemblies. We propose a disassembling-reassembling approach for both correcting structural errors in the draft assembly and scaffolding a target assembly based on error-corrected single molecule sequences. To achieve this goal, we formulate a maximum alternating path cover problem. We prove that this problem is NP-hard, and solve it by a 2-approximation algorithm. Our experimental results show that our approach can improve the structural correctness of target assemblies in the cost of some contiguity, even with smaller amounts of long reads. In addition, our reassembling process can also serve as a competitive scaffolder relative to well-established assembly benchmarks.

MiR-153 Regulates Amelogenesis by Targeting Endocytotic and Endosomal/lysosomal Pathways-Novel Insight into the Origins of Enamel Pathologies.

Science.gov (United States)

Yin, Kaifeng; Lin, Wenting; Guo, Jing; Sugiyama, Toshihiro; Snead, Malcolm L; Hacia, Joseph G; Paine, Michael L

2017-03-13

Amelogenesis imperfecta (AI) is group of inherited disorders resulting in enamel pathologies. The involvement of epigenetic regulation in the pathogenesis of AI is yet to be clarified due to a lack of knowledge about amelogenesis. Our previous genome-wide microRNA and mRNA transcriptome analyses suggest a key role for miR-153 in endosome/lysosome-related pathways during amelogenesis. Here we show that miR-153 is significantly downregulated in maturation ameloblasts compared with secretory ameloblasts. Within ameloblast-like cells, upregulation of miR-153 results in the downregulation of its predicted targets including Cltc, Lamp1, Clcn4 and Slc4a4, and a number of miRNAs implicated in endocytotic pathways. Luciferase reporter assays confirmed the predicted interactions between miR-153 and the 3'-UTRs of Cltc, Lamp1 (in a prior study), Clcn4 and Slc4a4. In an enamel protein intake assay, enamel cells transfected with miR-153 show a decreased ability to endocytose enamel proteins. Finally, microinjection of miR-153 in the region of mouse first mandibular molar at postnatal day 8 (PN8) induced AI-like pathologies when the enamel development reached maturity (PN12). In conclusion, miR-153 regulates maturation-stage amelogenesis by targeting key genes involved in the endocytotic and endosomal/lysosomal pathways, and disruption of miR-153 expression is a potential candidate etiologic factor contributing to the occurrence of AI.

MiR-153 Regulates Amelogenesis by Targeting Endocytotic and Endosomal/lysosomal Pathways–Novel Insight into the Origins of Enamel Pathologies

Science.gov (United States)

Yin, Kaifeng; Lin, Wenting; Guo, Jing; Sugiyama, Toshihiro; Snead, Malcolm L.; Hacia, Joseph G.; Paine, Michael L.

2017-01-01

Amelogenesis imperfecta (AI) is group of inherited disorders resulting in enamel pathologies. The involvement of epigenetic regulation in the pathogenesis of AI is yet to be clarified due to a lack of knowledge about amelogenesis. Our previous genome-wide microRNA and mRNA transcriptome analyses suggest a key role for miR-153 in endosome/lysosome-related pathways during amelogenesis. Here we show that miR-153 is significantly downregulated in maturation ameloblasts compared with secretory ameloblasts. Within ameloblast-like cells, upregulation of miR-153 results in the downregulation of its predicted targets including Cltc, Lamp1, Clcn4 and Slc4a4, and a number of miRNAs implicated in endocytotic pathways. Luciferase reporter assays confirmed the predicted interactions between miR-153 and the 3′-UTRs of Cltc, Lamp1 (in a prior study), Clcn4 and Slc4a4. In an enamel protein intake assay, enamel cells transfected with miR-153 show a decreased ability to endocytose enamel proteins. Finally, microinjection of miR-153 in the region of mouse first mandibular molar at postnatal day 8 (PN8) induced AI-like pathologies when the enamel development reached maturity (PN12). In conclusion, miR-153 regulates maturation-stage amelogenesis by targeting key genes involved in the endocytotic and endosomal/lysosomal pathways, and disruption of miR-153 expression is a potential candidate etiologic factor contributing to the occurrence of AI. PMID:28287144

Impaired decisional impulsivity in pathological videogamers.

Directory of Open Access Journals (Sweden)

Michael A Irvine

Full Text Available Pathological gaming is an emerging and poorly understood problem. Impulsivity is commonly impaired in disorders of behavioural and substance addiction, hence we sought to systematically investigate the different subtypes of decisional and motor impulsivity in a well-defined pathological gaming cohort.Fifty-two pathological gaming subjects and age-, gender- and IQ-matched healthy volunteers were tested on decisional impulsivity (Information Sampling Task testing reflection impulsivity and delay discounting questionnaire testing impulsive choice, and motor impulsivity (Stop Signal Task testing motor response inhibition, and the premature responding task. We used stringent diagnostic criteria highlighting functional impairment.In the Information Sampling Task, pathological gaming participants sampled less evidence prior to making a decision and scored fewer points compared with healthy volunteers. Gaming severity was also negatively correlated with evidence gathered and positively correlated with sampling error and points acquired. In the delay discounting task, pathological gamers made more impulsive choices, preferring smaller immediate over larger delayed rewards. Pathological gamers made more premature responses related to comorbid nicotine use. Greater number of hours played also correlated with a Motivational Index. Greater frequency of role playing games was associated with impaired motor response inhibition and strategy games with faster Go reaction time.We show that pathological gaming is associated with impaired decisional impulsivity with negative consequences in task performance. Decisional impulsivity may be a potential target in therapeutic management.

Development of a Natural Language Processing Engine to Generate Bladder Cancer Pathology Data for Health Services Research.

Science.gov (United States)

Schroeck, Florian R; Patterson, Olga V; Alba, Patrick R; Pattison, Erik A; Seigne, John D; DuVall, Scott L; Robertson, Douglas J; Sirovich, Brenda; Goodney, Philip P

2017-12-01

To take the first step toward assembling population-based cohorts of patients with bladder cancer with longitudinal pathology data, we developed and validated a natural language processing (NLP) engine that abstracts pathology data from full-text pathology reports. Using 600 bladder pathology reports randomly selected from the Department of Veterans Affairs, we developed and validated an NLP engine to abstract data on histology, invasion (presence vs absence and depth), grade, the presence of muscularis propria, and the presence of carcinoma in situ. Our gold standard was based on an independent review of reports by 2 urologists, followed by adjudication. We assessed the NLP performance by calculating the accuracy, the positive predictive value, and the sensitivity. We subsequently applied the NLP engine to pathology reports from 10,725 patients with bladder cancer. When comparing the NLP output to the gold standard, NLP achieved the highest accuracy (0.98) for the presence vs the absence of carcinoma in situ. Accuracy for histology, invasion (presence vs absence), grade, and the presence of muscularis propria ranged from 0.83 to 0.96. The most challenging variable was depth of invasion (accuracy 0.68), with an acceptable positive predictive value for lamina propria (0.82) and for muscularis propria (0.87) invasion. The validated engine was capable of abstracting pathologic characteristics for 99% of the patients with bladder cancer. NLP had high accuracy for 5 of 6 variables and abstracted data for the vast majority of the patients. This now allows for the assembly of population-based cohorts with longitudinal pathology data. Published by Elsevier Inc.

Target volume definition for external beam partial breast radiotherapy: Clinical, pathological and technical studies informing current approaches

International Nuclear Information System (INIS)

Kirby, Anna M.; Coles, Charlotte E.; Yarnold, John R.

2010-01-01

Partial breast irradiation (PBI) is currently under investigation in several phase III trials and, following a recent consensus statement, its use off-study may increase despite ongoing uncertainty regarding optimal target volume definition. We review the clinical, pathological and technical evidence for target volume definition in external beam partial breast irradiation (EB-PBI). The optimal method of tumour bed (TB) delineation requires X-ray CT imaging of implanted excision cavity wall markers. The definition of clinical target volume (CTV) as TB plus concentric 15 mm margins is based on the anatomical distribution of multifocal and multicentric disease around the primary tumour in mastectomy specimens, and the clinical locations of local tumour relapse (LR) after breast conservation surgery. If the majority of LR originate from foci of residual invasive and/or intraduct disease in the vicinity of the TB after complete microscopic resection, CTV margin logically takes account of the position of primary tumour within the surgical resection specimen. The uncertain significance of independent primary tumours as sources of preventable LR, and of wound healing responses in stimulating LR, increases the difficulties in defining optimal CTV. These uncertainties may resolve after long-term follow-up of current PBI trials. By contrast, a commonly used 10 mm clinical to planning target volume (PTV) margin has a stronger evidence base, although departmental set-up errors need to be confirmed locally. A CTV-PTV margin >10 mm may be required in women with larger breasts and/or large seromas, whilst the role of image-guided radiotherapy with or without TB markers in reducing CTV-PTV margins needs to be explored.

Impact analysis of spent fuel jacket assemblies

International Nuclear Information System (INIS)

Aramayo, G.A.

1994-01-01

As part of the analyses performed in support of the reracking of the High Flux Isotope Reactor pool, it became necessary to prove the structural integrity of the spent fuel jacket assemblies subjected to gravity drop that result from postulated accidents associated with the handling of these assemblies while submerged in the pool. The spent fuel jacket assemblies are an integral part of the reracking project, and serve to house fuel assemblies. The structure integrity of the jacket assemblies from loads that result from impact from a height of 10 feet onto specified targets has been performed analytically using the computer program LS-DYNA3D. Nine attitudes of the assembly at the time of impact have been considered. Results of the analyses show that there is no failure of the assemblies as a result of the impact scenarios considered

Inverse Problem in Self-assembly

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Tkachenko, Alexei

2012-02-01

By decorating colloids and nanoparticles with DNA, one can introduce highly selective key-lock interactions between them. This leads to a new class of systems and problems in soft condensed matter physics. In particular, this opens a possibility to solve inverse problem in self-assembly: how to build an arbitrary desired structure with the bottom-up approach? I will present a theoretical and computational analysis of the hierarchical strategy in attacking this problem. It involves self-assembly of particular building blocks (``octopus particles''), that in turn would assemble into the target structure. On a conceptual level, our approach combines elements of three different brands of programmable self assembly: DNA nanotechnology, nanoparticle-DNA assemblies and patchy colloids. I will discuss the general design principles, theoretical and practical limitations of this approach, and illustrate them with our simulation results. Our crucial result is that not only it is possible to design a system that has a given nanostructure as a ground state, but one can also program and optimize the kinetic pathway for its self-assembly.

Insulin dysfunction and Tau pathology

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Noura eEl Khoury

2014-02-01

Full Text Available The neuropathological hallmarks of Alzheimer's disease (AD include senile plaques of β-amyloid (Aβ peptides (a cleavage product of the Amyloid Precursor Protein, or APP and neurofibrillary tangles (NFT of hyperphosphorylated Tau protein assembled in paired helical filaments (PHF. NFT pathology is important since it correlates with the degree of cognitive impairment in AD.Only a small proportion of AD is due to genetic variants, whereas the large majority of cases (~99% is late onset and sporadic in origin. The cause of sporadic AD is likely to be multifactorial, with external factors interacting with biological or genetic susceptibilities to accelerate the manifestation of the disease.Insulin dysfunction, manifested by diabetes mellitus (DM might be such factor, as there is extensive data from epidemiological studies suggesting that DM is associated with an increased relative risk for AD. Type 1 diabetes (T1DM and type 2 diabetes (T2DM are known to affect multiple cognitive functions in patients. In this context, understanding the effects of diabetes on Tau pathogenesis is important since tau pathology show a strong relationship to dementia in AD, and to memory loss in normal aging and mild cognitive impairment.Here, we reviewed preclinical studies that link insulin dysfunction to Tau protein pathogenesis, one of the major pathological hallmarks of AD. We found more than 30 studies reporting on Tau phosphorylation in a mouse or rat model of insulin dysfunction. We also payed attention to potential sources of artifacts, such as hypothermia and anesthesia, that were demonstrated to results in Tau hyperphosphorylation and could major confounding experimental factors. We found that very few studies reported the temperature of the animals, and only a handful did not use anesthesia. Overall, most published studies showed that insulin dysfunction can promote Tau hyperphosphorylation and pathology, both directly and indirectly, through hypothermia.

Preliminary High-Throughput Metagenome Assembly

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Dusheyko, Serge; Furman, Craig; Pangilinan, Jasmyn; Shapiro, Harris; Tu, Hank

2007-03-26

Metagenome data sets present a qualitatively different assembly problem than traditional single-organism whole-genome shotgun (WGS) assembly. The unique aspects of such projects include the presence of a potentially large number of distinct organisms and their representation in the data set at widely different fractions. In addition, multiple closely related strains could be present, which would be difficult to assemble separately. Failure to take these issues into account can result in poor assemblies that either jumble together different strains or which fail to yield useful results. The DOE Joint Genome Institute has sequenced a number of metagenomic projects and plans to considerably increase this number in the coming year. As a result, the JGI has a need for high-throughput tools and techniques for handling metagenome projects. We present the techniques developed to handle metagenome assemblies in a high-throughput environment. This includes a streamlined assembly wrapper, based on the JGI?s in-house WGS assembler, Jazz. It also includes the selection of sensible defaults targeted for metagenome data sets, as well as quality control automation for cleaning up the raw results. While analysis is ongoing, we will discuss preliminary assessments of the quality of the assembly results (http://fames.jgi-psf.org).

Combined scanning probe and light scattering characterization of multi-stage self-assembly of targeted liposome-based delivery systems

International Nuclear Information System (INIS)

Farkas, N; Dagata, J A; Yang, C; Rait, A; Pirollo, K F; Chang, E H

2011-01-01

The mean size and size distribution of a targeted nanoparticle delivery system (NDS) strongly influences the intrinsic stability and functionality of this molecular complex, affects its performance as a systemic drug delivery platform and ultimately determines its efficacy toward early detection and treatment of cancer. Since its components undergo significant reorganization during multiple stages of self-assembly, it is essential to monitor the size and stability of the complex throughout the NDS formulation in order to ensure its potency and manufacturability prior to entering clinical trials. This work combines scanning probe microscopy (SPM) and dynamic light scattering (DLS) techniques to obtain quantitative and reliable size measurements of the NDS, and to investigate how variations in the NDS formulation or self-assembly process impact the size, structure and functionality of the complex with various therapeutic and diagnostic agent payloads. These combined SPM and DLS methods, when implemented at an early stage of the NDS formulation, present a potential measurement approach to facilitate drug discovery and development, optimization and quality control during manufacturing of the NDS

Generalized Modeling of the Human Lower Limb Assembly

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Cofaru, Ioana; Huzu, Iulia

2014-11-01

The main reason for creating a generalized assembly of the main bones of the lower human member is to create the premises of realizing a biomechanic assisted study which could be used for the study of the high range of varieties of pathologies that exist at this level. Starting from 3D CAD models of the main bones of the lower human member, which were realized in previous researches, in this study a generalized assembly system was developed, system in which are highlighted both the situation of an healthy subject and the situation of the situation of a subject affected by axial deviations. In order to achieve these purpose reference systems were created, systems that are in accordance with the mechanical axes and the anatomic axes of the lower member, which were later generally assembled in a manner that provides an easy customization option

Pathology informatics fellowship training: Focus on molecular pathology

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Diana Mandelker

2014-01-01

Full Text Available Background: Pathology informatics is both emerging as a distinct subspecialty and simultaneously becoming deeply integrated within the breadth of pathology practice. As specialists, pathology informaticians need a broad skill set, including aptitude with information fundamentals, information systems, workflow and process, and governance and management. Currently, many of those seeking training in pathology informatics additionally choose training in a second subspecialty. Combining pathology informatics training with molecular pathology is a natural extension, as molecular pathology is a subspecialty with high potential for application of modern biomedical informatics techniques. Methods and Results: Pathology informatics and molecular pathology fellows and faculty evaluated the current fellowship program′s core curriculum topics and subtopics for relevance to molecular pathology. By focusing on the overlap between the two disciplines, a structured curriculum consisting of didactics, operational rotations, and research projects was developed for those fellows interested in both pathology informatics and molecular pathology. Conclusions: The scope of molecular diagnostics is expanding dramatically as technology advances and our understanding of disease extends to the genetic level. Here, we highlight many of the informatics challenges facing molecular pathology today, and outline specific informatics principles necessary for the training of future molecular pathologists.

Pathology informatics fellowship training: Focus on molecular pathology.

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Mandelker, Diana; Lee, Roy E; Platt, Mia Y; Riedlinger, Gregory; Quinn, Andrew; Rao, Luigi K F; Klepeis, Veronica E; Mahowald, Michael; Lane, William J; Beckwith, Bruce A; Baron, Jason M; McClintock, David S; Kuo, Frank C; Lebo, Matthew S; Gilbertson, John R

2014-01-01

Pathology informatics is both emerging as a distinct subspecialty and simultaneously becoming deeply integrated within the breadth of pathology practice. As specialists, pathology informaticians need a broad skill set, including aptitude with information fundamentals, information systems, workflow and process, and governance and management. Currently, many of those seeking training in pathology informatics additionally choose training in a second subspecialty. Combining pathology informatics training with molecular pathology is a natural extension, as molecular pathology is a subspecialty with high potential for application of modern biomedical informatics techniques. Pathology informatics and molecular pathology fellows and faculty evaluated the current fellowship program's core curriculum topics and subtopics for relevance to molecular pathology. By focusing on the overlap between the two disciplines, a structured curriculum consisting of didactics, operational rotations, and research projects was developed for those fellows interested in both pathology informatics and molecular pathology. The scope of molecular diagnostics is expanding dramatically as technology advances and our understanding of disease extends to the genetic level. Here, we highlight many of the informatics challenges facing molecular pathology today, and outline specific informatics principles necessary for the training of future molecular pathologists.

Mitochondrial multifaceted dysfunction in schizophrenia; complex I as a possible pathological target.

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Ben-Shachar, Dorit

2017-09-01

Mitochondria are key players in various essential cellular processes beyond being the main energy supplier of the cell. Accordingly, they are involved in neuronal synaptic transmission, neuronal growth and sprouting and consequently neuronal plasticity and connectivity. In addition, mitochondria participate in the modulation of gene transcription and inflammation as well in physiological responses in health and disease. Schizophrenia is currently regarded as a neurodevelopmental disorder associated with impaired immune system, aberrant neuronal differentiation and abnormalities in various neurotransmitter systems mainly the dopaminergic, glutaminergic and GABAergic. Ample evidence has been accumulated over the last decade indicating a multifaceted dysfunction of mitochondria in schizophrenia. Indeed, mitochondrial deficit can be of relevance for the majority of the pathologies observed in this disease. In the present article, we overview specific deficits of the mitochondria in schizophrenia, with a focus on the first complex (complex I) of the mitochondrial electron transport chain (ETC). We argue that complex I, being a major factor in the regulation of mitochondrial ETC, is a possible key modulator of various functions of the mitochondria. We review biochemical, molecular, cellular and functional evidence for mitochondrial impairments and their possible convergence to impact in-vitro neuronal differentiation efficiency in schizophrenia. Mitochondrial function in schizophrenia may advance our knowledge of the disease pathophysiology and open the road for new treatment targets for the benefit of the patients. Copyright © 2016 Elsevier B.V. All rights reserved.

Real-time visualization of perforin nanopore assembly

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Leung, Carl; Hodel, Adrian W.; Brennan, Amelia J.; Lukoyanova, Natalya; Tran, Sharon; House, Colin M.; Kondos, Stephanie C.; Whisstock, James C.; Dunstone, Michelle A.; Trapani, Joseph A.; Voskoboinik, Ilia; Saibil, Helen R.; Hoogenboom, Bart W.

2017-05-01

Perforin is a key protein of the vertebrate immune system. Secreted by cytotoxic lymphocytes as soluble monomers, perforin can self-assemble into oligomeric pores of 10-20 nm inner diameter in the membranes of virus-infected and cancerous cells. These large pores facilitate the entry of pro-apoptotic granzymes, thereby rapidly killing the target cell. To elucidate the pathways of perforin pore assembly, we carried out real-time atomic force microscopy and electron microscopy studies. Our experiments reveal that the pore assembly proceeds via a membrane-bound prepore intermediate state, typically consisting of up to approximately eight loosely but irreversibly assembled monomeric subunits. These short oligomers convert to more closely packed membrane nanopore assemblies, which can subsequently recruit additional prepore oligomers to grow the pore size.

Breast MR biopsy: Pathological and radiological correlation

International Nuclear Information System (INIS)

Dratwa, Chloe; Chopier, Jocelyne; Jalaguier-Coudray, Aurelie; Thomassin-Piana, Jeanne; Gonin, Julie; Antoine, Martine; Trop, Isabelle; Darai, Emile; Thomassin-Naggara, Isabelle

2016-01-01

To identify pathological features for sample analysis of magnetic resonance imaging-guided vaccum-assisted breast biopsy (MRIgVaBB) to optimize radio pathological correlation and identify discordant benign result. Databases of two centres were queried to identify MRIgVaBB performed between January 2009 and February 2013. A cohort of 197 women (mean age: 54.5 years (24-77)) with 208 lesions was identified. We retrospectively analyzed all prebiopsy MRI examinations according to the new BI-RADS lexicon, and all biopsy samples to describe the lesion of interest, its interface with the surrounding breast tissue and other associated features. The malignancy rate was 26.0 % (54/208) with an underestimation rate of 15.67 % (5/32). A visible interface at pathology between a biopsied lesion and the surrounding breast tissue was more frequently identified in mass enhancement compared to NME or focus (p = 0.0003). Regional NME was correlated with a high degree of fibrosis (p = 0.001) and the presence of PASH (p = 0.0007). Linear or segmental NME was correlated with the presence of periductal mastitis (p = 0.0003). The description of a visible interface between the target lesion and the surrounding tissue is crucial to confirm the correct targeting of an MR mass or a NME. (orig.)

How the shapes of seeds can influence pathology.

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Melki, Ronald

2018-01-01

It is widely accepted that the loss of function of different cellular proteins following their aggregation into highly stable aggregates or the gain of pathologic function of the resulting macromolecular assemblies or both processes are tightly associated to distinct debilitating neurodegenerative diseases such as Alzheimer's, Parkinson's, Creutzfeldt-Jacob, Amyotrophic Lateral Sclerosis and Huntington's diseases. How the aggregation of one given protein leads to distinct diseases is unclear. Here, a structural-molecular explanation based on the ability of proteins such as α-synuclein or tau to form assemblies that differ by their intrinsic architecture, stability, seeding capacity, and surfaces is proposed to account for distinct synucleinopathies and tauopathies. The shape and surfaces of the seeds is proposed to define at the same time their seeding capacity, interactome and tropism for defined neuronal cells within the central nervous system. Copyright © 2017 Elsevier Inc. All rights reserved.

Muscle biopsies from human muscle diseases with myopathic pathology reveal common alterations in mitochondrial function.

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Sunitha, Balaraju; Gayathri, Narayanappa; Kumar, Manish; Keshava Prasad, Thottethodi Subrahmanya; Nalini, Atchayaram; Padmanabhan, Balasundaram; Srinivas Bharath, Muchukunte Mukunda

2016-07-01

Muscle diseases are clinically and genetically heterogeneous and manifest as dystrophic, inflammatory and myopathic pathologies, among others. Our previous study on the cardiotoxin mouse model of myodegeneration and inflammation linked muscle pathology with mitochondrial damage and oxidative stress. In this study, we investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies from muscle disease patients, represented by dysferlinopathy (dysfy) (dystrophic pathology; n = 43), polymyositis (PM) (inflammatory pathology; n = 24), and distal myopathy with rimmed vacuoles (DMRV) (distal myopathy; n = 31) were analyzed. Mitochondrial damage (ragged blue and COX-deficient fibers) was revealed in dysfy, PM, and DMRV cases by enzyme histochemistry (SDH and COX-SDH), electron microscopy (vacuolation and altered cristae) and biochemical assays (significantly increased ADP/ATP ratio). Proteomic analysis of muscle mitochondria from all three muscle diseases by isobaric tag for relative and absolute quantitation labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis demonstrated down-regulation of electron transport chain (ETC) complex subunits, assembly factors and Krebs cycle enzymes. Interestingly, 80 of the under-expressed proteins were common among the three pathologies. Assay of ETC and Krebs cycle enzyme activities validated the MS data. Mitochondrial proteins from muscle pathologies also displayed higher tryptophan (Trp) oxidation and the same was corroborated in the cardiotoxin model. Molecular modeling predicted Trp oxidation to alter the local structure of mitochondrial proteins. Our data highlight mitochondrial alterations in muscle pathologies, represented by morphological changes, altered mitochondrial proteome and protein oxidation, thereby establishing the role of mitochondrial damage in human muscle diseases. We investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies

Plasma membrane is the site of productive HIV-1 particle assembly.

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Nolwenn Jouvenet

2006-12-01

Full Text Available Recently proposed models that have gained wide acceptance posit that HIV-1 virion morphogenesis is initiated by targeting the major structural protein (Gag to late endosomal membranes. Thereafter, late endosome-based secretory pathways are thought to deliver Gag or assembled virions to the plasma membrane (PM and extracellular milieu. We present several findings that are inconsistent with this model. Specifically, we demonstrate that HIV-1 Gag is delivered to the PM, and virions are efficiently released into the extracellular medium, when late endosome motility is abolished. Furthermore, we show that HIV-1 virions are efficiently released when assembly is rationally targeted to the PM, but not when targeted to late endosomes. Recently synthesized Gag first accumulates and assembles at the PM, but a proportion is subsequently internalized via endocytosis or phagocytosis, thus accounting for observations of endosomal localization. We conclude that HIV-1 assembly is initiated and completed at the PM, and not at endosomal membranes.

Edaravone alleviates Alzheimer's disease-type pathologies and cognitive deficits.

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Jiao, Shu-Sheng; Yao, Xiu-Qing; Liu, Yu-Hui; Wang, Qing-Hua; Zeng, Fan; Lu, Jian-Jun; Liu, Jia; Zhu, Chi; Shen, Lin-Lin; Liu, Cheng-Hui; Wang, Ye-Ran; Zeng, Gui-Hua; Parikh, Ankit; Chen, Jia; Liang, Chun-Rong; Xiang, Yang; Bu, Xian-Le; Deng, Juan; Li, Jing; Xu, Juan; Zeng, Yue-Qin; Xu, Xiang; Xu, Hai-Wei; Zhong, Jin-Hua; Zhou, Hua-Dong; Zhou, Xin-Fu; Wang, Yan-Jiang

2015-04-21

Alzheimer's disease (AD) is one of most devastating diseases affecting elderly people. Amyloid-β (Aβ) accumulation and the downstream pathological events such as oxidative stress play critical roles in pathogenesis of AD. Lessons from failures of current clinical trials suggest that targeting multiple key pathways of the AD pathogenesis is necessary to halt the disease progression. Here we show that Edaravone, a free radical scavenger that is marketed for acute ischemic stroke, has a potent capacity of inhibiting Aβ aggregation and attenuating Aβ-induced oxidation in vitro. When given before or after the onset of Aβ deposition via i.p. injection, Edaravone substantially reduces Aβ deposition, alleviates oxidative stress, attenuates the downstream pathologies including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, synaptic dysfunction, and rescues the behavioral deficits of APPswe/PS1 mice. Oral administration of Edaravone also ameliorates the AD-like pathologies and memory deficits of the mice. These findings suggest that Edaravone holds a promise as a therapeutic agent for AD by targeting multiple key pathways of the disease pathogenesis.

Syntactic sequencing in Hebbian cell assemblies.

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Wennekers, Thomas; Palm, Günther

2009-12-01

Hebbian cell assemblies provide a theoretical framework for the modeling of cognitive processes that grounds them in the underlying physiological neural circuits. Recently we have presented an extension of cell assemblies by operational components which allows to model aspects of language, rules, and complex behaviour. In the present work we study the generation of syntactic sequences using operational cell assemblies timed by unspecific trigger signals. Syntactic patterns are implemented in terms of hetero-associative transition graphs in attractor networks which cause a directed flow of activity through the neural state space. We provide regimes for parameters that enable an unspecific excitatory control signal to switch reliably between attractors in accordance with the implemented syntactic rules. If several target attractors are possible in a given state, noise in the system in conjunction with a winner-takes-all mechanism can randomly choose a target. Disambiguation can also be guided by context signals or specific additional external signals. Given a permanently elevated level of external excitation the model can enter an autonomous mode, where it generates temporal grammatical patterns continuously.

Oxidative Stress and Mitochondrial Dysfunction across Broad-Ranging Pathologies: Toward Mitochondria-Targeted Clinical Strategies

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Giovanni Pagano

2014-01-01

Full Text Available Beyond the disorders recognized as mitochondrial diseases, abnormalities in function and/or ultrastructure of mitochondria have been reported in several unrelated pathologies. These encompass ageing, malformations, and a number of genetic or acquired diseases, as diabetes and cardiologic, haematologic, organ-specific (e.g., eye or liver, neurologic and psychiatric, autoimmune, and dermatologic disorders. The mechanistic grounds for mitochondrial dysfunction (MDF along with the occurrence of oxidative stress (OS have been investigated within the pathogenesis of individual disorders or in groups of interrelated disorders. We attempt to review broad-ranging pathologies that involve mitochondrial-specific deficiencies or rely on cytosol-derived prooxidant states or on autoimmune-induced mitochondrial damage. The established knowledge in these subjects warrants studies aimed at elucidating several open questions that are highlighted in the present review. The relevance of OS and MDF in different pathologies may establish the grounds for chemoprevention trials aimed at compensating OS/MDF by means of antioxidants and mitochondrial nutrients.

Computational Pathology

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Louis, David N.; Feldman, Michael; Carter, Alexis B.; Dighe, Anand S.; Pfeifer, John D.; Bry, Lynn; Almeida, Jonas S.; Saltz, Joel; Braun, Jonathan; Tomaszewski, John E.; Gilbertson, John R.; Sinard, John H.; Gerber, Georg K.; Galli, Stephen J.; Golden, Jeffrey A.; Becich, Michael J.

2016-01-01

Context We define the scope and needs within the new discipline of computational pathology, a discipline critical to the future of both the practice of pathology and, more broadly, medical practice in general. Objective To define the scope and needs of computational pathology. Data Sources A meeting was convened in Boston, Massachusetts, in July 2014 prior to the annual Association of Pathology Chairs meeting, and it was attended by a variety of pathologists, including individuals highly invested in pathology informatics as well as chairs of pathology departments. Conclusions The meeting made recommendations to promote computational pathology, including clearly defining the field and articulating its value propositions; asserting that the value propositions for health care systems must include means to incorporate robust computational approaches to implement data-driven methods that aid in guiding individual and population health care; leveraging computational pathology as a center for data interpretation in modern health care systems; stating that realizing the value proposition will require working with institutional administrations, other departments, and pathology colleagues; declaring that a robust pipeline should be fostered that trains and develops future computational pathologists, for those with both pathology and non-pathology backgrounds; and deciding that computational pathology should serve as a hub for data-related research in health care systems. The dissemination of these recommendations to pathology and bioinformatics departments should help facilitate the development of computational pathology. PMID:26098131

Brain and blood metabolite signatures of pathology and progression in Alzheimer disease: A targeted metabolomics study.

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Vijay R Varma

2018-01-01

Full Text Available The metabolic basis of Alzheimer disease (AD is poorly understood, and the relationships between systemic abnormalities in metabolism and AD pathogenesis are unclear. Understanding how global perturbations in metabolism are related to severity of AD neuropathology and the eventual expression of AD symptoms in at-risk individuals is critical to developing effective disease-modifying treatments. In this study, we undertook parallel metabolomics analyses in both the brain and blood to identify systemic correlates of neuropathology and their associations with prodromal and preclinical measures of AD progression.Quantitative and targeted metabolomics (Biocrates AbsoluteIDQ [identification and quantification] p180 assays were performed on brain tissue samples from the autopsy cohort of the Baltimore Longitudinal Study of Aging (BLSA (N = 44, mean age = 81.33, % female = 36.36 from AD (N = 15, control (CN; N = 14, and "asymptomatic Alzheimer's disease" (ASYMAD, i.e., individuals with significant AD pathology but no cognitive impairment during life; N = 15 participants. Using machine-learning methods, we identified a panel of 26 metabolites from two main classes-sphingolipids and glycerophospholipids-that discriminated AD and CN samples with accuracy, sensitivity, and specificity of 83.33%, 86.67%, and 80%, respectively. We then assayed these 26 metabolites in serum samples from two well-characterized longitudinal cohorts representing prodromal (Alzheimer's Disease Neuroimaging Initiative [ADNI], N = 767, mean age = 75.19, % female = 42.63 and preclinical (BLSA (N = 207, mean age = 78.68, % female = 42.63 AD, in which we tested their associations with magnetic resonance imaging (MRI measures of AD-related brain atrophy, cerebrospinal fluid (CSF biomarkers of AD pathology, risk of conversion to incident AD, and trajectories of cognitive performance. We developed an integrated blood and brain endophenotype score that summarized the relative importance of

Brain and blood metabolite signatures of pathology and progression in Alzheimer disease: A targeted metabolomics study

Science.gov (United States)

Oommen, Anup M.; Varma, Sudhir; Casanova, Ramon; An, Yang; O’Brien, Richard; Pletnikova, Olga; Kastenmueller, Gabi; Doraiswamy, P. Murali; Kaddurah-Daouk, Rima; Thambisetty, Madhav

2018-01-01

Background The metabolic basis of Alzheimer disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD pathogenesis are unclear. Understanding how global perturbations in metabolism are related to severity of AD neuropathology and the eventual expression of AD symptoms in at-risk individuals is critical to developing effective disease-modifying treatments. In this study, we undertook parallel metabolomics analyses in both the brain and blood to identify systemic correlates of neuropathology and their associations with prodromal and preclinical measures of AD progression. Methods and findings Quantitative and targeted metabolomics (Biocrates AbsoluteIDQ [identification and quantification] p180) assays were performed on brain tissue samples from the autopsy cohort of the Baltimore Longitudinal Study of Aging (BLSA) (N = 44, mean age = 81.33, % female = 36.36) from AD (N = 15), control (CN; N = 14), and “asymptomatic Alzheimer’s disease” (ASYMAD, i.e., individuals with significant AD pathology but no cognitive impairment during life; N = 15) participants. Using machine-learning methods, we identified a panel of 26 metabolites from two main classes—sphingolipids and glycerophospholipids—that discriminated AD and CN samples with accuracy, sensitivity, and specificity of 83.33%, 86.67%, and 80%, respectively. We then assayed these 26 metabolites in serum samples from two well-characterized longitudinal cohorts representing prodromal (Alzheimer’s Disease Neuroimaging Initiative [ADNI], N = 767, mean age = 75.19, % female = 42.63) and preclinical (BLSA) (N = 207, mean age = 78.68, % female = 42.63) AD, in which we tested their associations with magnetic resonance imaging (MRI) measures of AD-related brain atrophy, cerebrospinal fluid (CSF) biomarkers of AD pathology, risk of conversion to incident AD, and trajectories of cognitive performance. We developed an integrated blood and brain endophenotype score that

Pathologic mitoses and pathology of mitosis in tumorigenesis

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RG Steinbeck

2009-12-01

Full Text Available The gist of my hypothesis (.. is a certain abnormal chromatin constitution. Each process, which brings about this chromatin constitution, would result in the origin of a malignant tumour. Certainly, I consider irregularities with mitosis as the normal mode of the origin of an incorrectly assembled nucleus. This statement by Boveri (1914 has considered earlier observations of asymmetric divisions in human cancers (Hansemann, 1890. The hypothesis is based on the understanding of mitosis as an equational bipartition of the hereditary substance (Flemming, 1879; Roux, 1883. Latest since it was known that genes are located on chromosomes (Sturtevant, 1913, their balanced transport in anaphase appeared as a condition of correct somatic proliferation. True mitoses guarantee the constancy of terminally differentiated tissues. Politzer (1934 has performed X-ray experiments to investigate abnormal karyokinesis with regard to anomalous chromatin condensation, chromosome breakage, spindle malformation, and failure in cytokinesis. On the basis of light microscopy, further significant progress in understanding the pathology of mitosis was not possible. Tumour cases with reduced chromosome numbers seduced to the idea that mitotic activity is rather under cytoplasmic than under nuclear control (Koller, 1947.

Self-assembled nanomaterials for photoacoustic imaging

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Wang, Lei; Yang, Pei-Pei; Zhao, Xiao-Xiao; Wang, Hao

2016-01-01

In recent years, extensive endeavors have been paid to construct functional self-assembled nanomaterials for various applications such as catalysis, separation, energy and biomedicines. To date, different strategies have been developed for preparing nanomaterials with diversified structures and functionalities via fine tuning of self-assembled building blocks. In terms of biomedical applications, bioimaging technologies are urgently calling for high-efficient probes/contrast agents for high-performance bioimaging. Photoacoustic (PA) imaging is an emerging whole-body imaging modality offering high spatial resolution, deep penetration and high contrast in vivo. The self-assembled nanomaterials show high stability in vivo, specific tolerance to sterilization and prolonged half-life stability and desirable targeting properties, which is a kind of promising PA contrast agents for biomedical imaging. Herein, we focus on summarizing recent advances in smart self-assembled nanomaterials with NIR absorption as PA contrast agents for biomedical imaging. According to the preparation strategy of the contrast agents, the self-assembled nanomaterials are categorized into two groups, i.e., the ex situ and in situ self-assembled nanomaterials. The driving forces, assembly modes and regulation of PA properties of self-assembled nanomaterials and their applications for long-term imaging, enzyme activity detection and aggregation-induced retention (AIR) effect for diagnosis and therapy are emphasized. Finally, we conclude with an outlook towards future developments of self-assembled nanomaterials for PA imaging.

Self-assembled nanomaterials for photoacoustic imaging.

Science.gov (United States)

Wang, Lei; Yang, Pei-Pei; Zhao, Xiao-Xiao; Wang, Hao

2016-02-07

In recent years, extensive endeavors have been paid to construct functional self-assembled nanomaterials for various applications such as catalysis, separation, energy and biomedicines. To date, different strategies have been developed for preparing nanomaterials with diversified structures and functionalities via fine tuning of self-assembled building blocks. In terms of biomedical applications, bioimaging technologies are urgently calling for high-efficient probes/contrast agents for high-performance bioimaging. Photoacoustic (PA) imaging is an emerging whole-body imaging modality offering high spatial resolution, deep penetration and high contrast in vivo. The self-assembled nanomaterials show high stability in vivo, specific tolerance to sterilization and prolonged half-life stability and desirable targeting properties, which is a kind of promising PA contrast agents for biomedical imaging. Herein, we focus on summarizing recent advances in smart self-assembled nanomaterials with NIR absorption as PA contrast agents for biomedical imaging. According to the preparation strategy of the contrast agents, the self-assembled nanomaterials are categorized into two groups, i.e., the ex situ and in situ self-assembled nanomaterials. The driving forces, assembly modes and regulation of PA properties of self-assembled nanomaterials and their applications for long-term imaging, enzyme activity detection and aggregation-induced retention (AIR) effect for diagnosis and therapy are emphasized. Finally, we conclude with an outlook towards future developments of self-assembled nanomaterials for PA imaging.

Self-Assembly of Octopus Nanoparticles into Pre-Programmed Finite Clusters

Science.gov (United States)

Halverson, Jonathan; Tkachenko, Alexei

2012-02-01

The precise control of the spatial arrangement of nanoparticles (NP) is often required to take full advantage of their novel optical and electronic properties. NPs have been shown to self-assemble into crystalline structures using either patchy surface regions or complementary DNA strands to direct the assembly. Due to a lack of specificity of the interactions these methods lead to only a limited number of structures. An emerging approach is to bind ssDNA at specific sites on the particle surface making so-called octopus NPs. Using octopus NPs we investigate the inverse problem of the self-assembly of finite clusters. That is, for a given target cluster (e.g., arranging the NPs on the vertices of a dodecahedron) what are the minimum number of complementary DNA strands needed for the robust self-assembly of the cluster from an initially homogeneous NP solution? Based on the results of Brownian dynamics simulations we have compiled a set of design rules for various target clusters including cubes, pyramids, dodecahedrons and truncated icosahedrons. Our approach leads to control over the kinetic pathway and has demonstrated nearly perfect yield of the target.

LBNF 1.2 MW TARGET: CONCEPTUAL DESIGN & FABRICATION

Energy Technology Data Exchange (ETDEWEB)

Crowley, Cory F. [Fermilab; Ammigan, K. [Fermilab; Anderson, K. [Fermilab; Hartsell, B. [Fermilab; Hurh, P. [Fermilab; Hylen, J. [Fermilab; Zwaska, R. [Fermilab

2015-06-29

Fermilab’s Long-Baseline Neutrino Facility (LBNF) will utilize a modified design based on the NuMI low energy target that is reconfigured to accommodate beam operation at 1.2 MW. Achieving this power with a graphite target material and ancillary systems originally rated for 400 kW requires several design changes and R&D efforts related to material bonding and electrical isolation. Target cooling, structural design, and fabrication techniques must address higher stresses and heat loads that will be present during 1.2 MW operation, as the assembly will be subject to cyclic loads and thermal expansion. Mitigations must be balanced against compromises in neutrino yield. Beam monitoring and subsystem instrumentation will be updated and added to ensure confidence in target positioning and monitoring. Remote connection to the target hall support structure must provide for the eventual upgrade to a 2.4 MW target design, without producing excessive radioactive waste or unreasonable exposure to technicians during reconfiguration. Current designs and assembly layouts will be presented, in addition to current findings on processes and possibilities for prototype and final assembly fabrication.

LBNF 1.2 MW Target: Conceptual Design & Fabrication

Energy Technology Data Exchange (ETDEWEB)

Crowley, C. [Fermilab; Ammigan, K. [Fermilab; Anderson, K. [Fermilab; Hartsell, B. [Fermilab; Hurh, P. [Fermilab; Hylen, J. [Fermilab; Zwaska, R. [Fermilab

2015-06-01

Fermilab’s Long-Baseline Neutrino Facility (LBNF) will utilize a modified design based on the NuMI low energy target that is reconfigured to accommodate beam operation at 1.2 MW. Achieving this power with a graphite target material and ancillary systems originally rated for 400 kW requires several design changes and R&D efforts related to material bonding and electrical isolation. Target cooling, structural design, and fabrication techniques must address higher stresses and heat loads that will be present during 1.2 MW operation, as the assembly will be subject to cyclic loads and thermal expansion. Mitigations must be balanced against compromises in neutrino yield. Beam monitoring and subsystem instrumentation will be updated and added to ensure confidence in target positioning and monitoring. Remote connection to the target hall support structure must provide for the eventual upgrade to a 2.4 MW target design, without producing excessive radioactive waste or unreasonable exposure to technicians during reconfiguration. Current designs and assembly layouts will be presented, in addition to current findings on processes and possibilities for prototype and final assembly fabrication.

Curriculum Guidelines for Pathology and Oral Pathology.

Science.gov (United States)

Journal of Dental Education, 1985

1985-01-01

Guidelines for dental school pathology courses describe the interrelationships of general, systemic, and oral pathology; primary educational goals; prerequisites; a core curriculum outline and behavioral objectives for each type of pathology. Notes on sequencing, faculty, facilities, and occupational hazards are included. (MSE)

Plant pathology: monitoring a pathogen-targeted host protein.

Science.gov (United States)

Ellis, Jeff; Dodds, Peter

2003-05-13

A plant protein RIN4 is targeted and modified by bacterial pathogens as part of the disease process. At least two host resistance proteins monitor this pathogen interference and trigger the plant's defence responses.

Interleukin-22: immunobiology and pathology

Science.gov (United States)

Dudakov, Jarrod A.; Hanash, Alan M.; van den Brink, Marcel R.M.

2015-01-01

Interleukin-22 (IL-22) is a recently described IL-10 family cytokine that is produced by T-helper (Th)-17 cells, γδ T cells, NKT cells and newly described innate lymphoid cells (ILCs). Knowledge of IL-22 biology has rapidly evolved since its discovery in 2000, and a role for IL-22 has been identified in numerous tissues including the intestines, lung, liver, kidney, thymus, pancreas and skin. IL-22 primarily targets non-hematopoietic epithelial and stromal cells where it can promote proliferation and play a role in tissue regeneration. In addition, IL-22 regulates host defense at barrier surfaces. However, IL-22 has also been linked to several conditions involving inflammatory tissue pathology. In this review, we will assess the current understanding of this cytokine, including its physiologic and pathologic effects on epithelial cell function. PMID:25706098

Structural Aspects of Bacterial Outer Membrane Protein Assembly.

Science.gov (United States)

Calmettes, Charles; Judd, Andrew; Moraes, Trevor F

2015-01-01

The outer membrane of Gram-negative bacteria is predominantly populated by β-Barrel proteins and lipid anchored proteins that serve a variety of biological functions. The proper folding and assembly of these proteins is essential for bacterial viability and often plays a critical role in virulence and pathogenesis. The β-barrel assembly machinery (Bam) complex is responsible for the proper assembly of β-barrels into the outer membrane of Gram-negative bacteria, whereas the localization of lipoproteins (Lol) system is required for proper targeting of lipoproteins to the outer membrane.

Self-Assembled Polymeric Micelles Based on Hyaluronic Acid-g-Poly(d,l-lactide-co-glycolide) Copolymer for Tumor Targeting

Science.gov (United States)

Son, Gyung Mo; Kim, Hyun Yul; Ryu, Je Ho; Chu, Chong Woo; Kang, Dae Hwan; Park, Su Bum; Jeong, Young-IL

2014-01-01

Graft copolymer composed hyaluronic acid (HA) and poly(d,l-lactide-co-glycolide) (PLGA) (HAgLG) was synthesized for antitumor targeting via CD44 receptor of tumor cells. The carboxylic end of PLGA was conjugated with hexamethylenediamine (HMDA) to have amine end group in the end of chain (PLGA-amine). PLGA-amine was coupled with carboxylic acid of HA. Self-assembled polymeric micelles of HAgLG have spherical morphologies and their sizes were around 50–200 nm. Doxorubicin (DOX)-incorporated polymeric micelles were prepared by dialysis procedure. DOX was released over 4 days and its release rate was accelerated by the tumoric enzyme hyaluronidase. To assess targetability of polymeric micelles, CD44-positive HepG2 cells were employed treated with fluorescein isothiocyanate (FITC)-labeled polymeric micelles. HepG2 cells strongly expressed green fluorescence at the cell membrane and cytosol. However, internalization of polymeric micelles were significantly decreased when free HA was pretreated to block the CD44 receptor. Furthermore, the CD44-specific anticancer activity of HAgLG polymeric micelles was confirmed using CD44-negative CT26 cells and CD44-positive HepG2 cells. These results indicated that polymeric micelles of HaLG polymeric micelles have targetability against CD44 receptor of tumor cells. We suggest HAgLG polymeric micelles as a promising candidate for specific drug targeting. PMID:25216338

Self-Assembled Polymeric Micelles Based on Hyaluronic Acid-g-Poly(d,l-lactide-co-glycolide Copolymer for Tumor Targeting

Directory of Open Access Journals (Sweden)

Gyung Mo Son

2014-09-01

Full Text Available Graft copolymer composed hyaluronic acid (HA and poly(d,l-lactide-co-glycolide (PLGA (HAgLG was synthesized for antitumor targeting via CD44 receptor of tumor cells. The carboxylic end of PLGA was conjugated with hexamethylenediamine (HMDA to have amine end group in the end of chain (PLGA-amine. PLGA-amine was coupled with carboxylic acid of HA. Self-assembled polymeric micelles of HAgLG have spherical morphologies and their sizes were around 50–200 nm. Doxorubicin (DOX-incorporated polymeric micelles were prepared by dialysis procedure. DOX was released over 4 days and its release rate was accelerated by the tumoric enzyme hyaluronidase. To assess targetability of polymeric micelles, CD44-positive HepG2 cells were employed treated with fluorescein isothiocyanate (FITC-labeled polymeric micelles. HepG2 cells strongly expressed green fluorescence at the cell membrane and cytosol. However, internalization of polymeric micelles were significantly decreased when free HA was pretreated to block the CD44 receptor. Furthermore, the CD44-specific anticancer activity of HAgLG polymeric micelles was confirmed using CD44-negative CT26 cells and CD44-positive HepG2 cells. These results indicated that polymeric micelles of HaLG polymeric micelles have targetability against CD44 receptor of tumor cells. We suggest HAgLG polymeric micelles as a promising candidate for specific drug targeting.

Edaravone alleviates Alzheimer’s disease-type pathologies and cognitive deficits

Science.gov (United States)

Jiao, Shu-Sheng; Yao, Xiu-Qing; Liu, Yu-Hui; Wang, Qing-Hua; Zeng, Fan; Lu, Jian-Jun; Liu, Jia; Zhu, Chi; Shen, Lin-Lin; Liu, Cheng-Hui; Wang, Ye-Ran; Zeng, Gui-Hua; Parikh, Ankit; Chen, Jia; Liang, Chun-Rong; Xiang, Yang; Bu, Xian-Le; Deng, Juan; Li, Jing; Xu, Juan; Zeng, Yue-Qin; Xu, Xiang; Xu, Hai-Wei; Zhong, Jin-Hua; Zhou, Hua-Dong; Zhou, Xin-Fu; Wang, Yan-Jiang

2015-01-01

Alzheimer’s disease (AD) is one of most devastating diseases affecting elderly people. Amyloid-β (Aβ) accumulation and the downstream pathological events such as oxidative stress play critical roles in pathogenesis of AD. Lessons from failures of current clinical trials suggest that targeting multiple key pathways of the AD pathogenesis is necessary to halt the disease progression. Here we show that Edaravone, a free radical scavenger that is marketed for acute ischemic stroke, has a potent capacity of inhibiting Aβ aggregation and attenuating Aβ-induced oxidation in vitro. When given before or after the onset of Aβ deposition via i.p. injection, Edaravone substantially reduces Aβ deposition, alleviates oxidative stress, attenuates the downstream pathologies including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, synaptic dysfunction, and rescues the behavioral deficits of APPswe/PS1 mice. Oral administration of Edaravone also ameliorates the AD-like pathologies and memory deficits of the mice. These findings suggest that Edaravone holds a promise as a therapeutic agent for AD by targeting multiple key pathways of the disease pathogenesis. PMID:25847999

Layer-by-layer cell membrane assembly

Science.gov (United States)

Matosevic, Sandro; Paegel, Brian M.

2013-11-01

Eukaryotic subcellular membrane systems, such as the nuclear envelope or endoplasmic reticulum, present a rich array of architecturally and compositionally complex supramolecular targets that are as yet inaccessible. Here we describe layer-by-layer phospholipid membrane assembly on microfluidic droplets, a route to structures with defined compositional asymmetry and lamellarity. Starting with phospholipid-stabilized water-in-oil droplets trapped in a static droplet array, lipid monolayer deposition proceeds as oil/water-phase boundaries pass over the droplets. Unilamellar vesicles assembled layer-by-layer support functional insertion both of purified and of in situ expressed membrane proteins. Synthesis and chemical probing of asymmetric unilamellar and double-bilayer vesicles demonstrate the programmability of both membrane lamellarity and lipid-leaflet composition during assembly. The immobilized vesicle arrays are a pragmatic experimental platform for biophysical studies of membranes and their associated proteins, particularly complexes that assemble and function in multilamellar contexts in vivo.

Assembly constraints drive co-evolution among ribosomal constituents.

Science.gov (United States)

Mallik, Saurav; Akashi, Hiroshi; Kundu, Sudip

2015-06-23

Ribosome biogenesis, a central and essential cellular process, occurs through sequential association and mutual co-folding of protein-RNA constituents in a well-defined assembly pathway. Here, we construct a network of co-evolving nucleotide/amino acid residues within the ribosome and demonstrate that assembly constraints are strong predictors of co-evolutionary patterns. Predictors of co-evolution include a wide spectrum of structural reconstitution events, such as cooperativity phenomenon, protein-induced rRNA reconstitutions, molecular packing of different rRNA domains, protein-rRNA recognition, etc. A correlation between folding rate of small globular proteins and their topological features is known. We have introduced an analogous topological characteristic for co-evolutionary network of ribosome, which allows us to differentiate between rRNA regions subjected to rapid reconstitutions from those hindered by kinetic traps. Furthermore, co-evolutionary patterns provide a biological basis for deleterious mutation sites and further allow prediction of potential antibiotic targeting sites. Understanding assembly pathways of multicomponent macromolecules remains a key challenge in biophysics. Our study provides a 'proof of concept' that directly relates co-evolution to biophysical interactions during multicomponent assembly and suggests predictive power to identify candidates for critical functional interactions as well as for assembly-blocking antibiotic target sites. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Passive immunization targeting the N-terminal projection domain of tau decreases tau pathology and improves cognition in a transgenic mouse model of Alzheimer disease and tauopathies.

Science.gov (United States)

Dai, Chun-ling; Chen, Xia; Kazim, Syed Faraz; Liu, Fei; Gong, Cheng-Xin; Grundke-Iqbal, Inge; Iqbal, Khalid

2015-04-01

Intraneuronal accumulation of abnormally hyperphosphorylated tau in the brain is a histopathological hallmark of Alzheimer's disease and a family of related neurodegenerative disorders collectively called tauopathies. At present there is no effective treatment available for these progressive neurodegenerative diseases which are clinically characterized by dementia in mid to old-age. Here we report the treatment of 14-17-months-old 3xTg-AD mice with tau antibodies 43D (tau 6-18) and 77E9 (tau 184-195) to the N-terminal projection domain of tau or mouse IgG as a control by intraperitoneal injection once a week for 4 weeks, and the effects of the passive immunization on reduction of hyperphosphorylated tau, Aβ accumulation and cognitive performance in these animals. We found that treatment with tau antibodies 43D and 77E9 reduced total tau level, decreased tau hyperphosphorylated at Ser199, Ser202/Thr205 (AT8), Thr205, Ser262/356 (12E8), and Ser396/404 (PHF-1) sites, and a trend to reduce Aβ pathology. Most importantly, targeting N-terminal tau especially by 43D (tau 6-18) improved reference memory in the Morris water maze task in 3xTg-AD mice. We did not observe any abnormality in general physical characteristics of the treated animals with either of the two antibodies during the course of this study. Taken together, our studies demonstrate for the first time (1) that passive immunization targeting normal tau can effectively clear the hyperphosphorylated protein and possibly reduce Aβ pathology from the brain and (2) that targeting N-terminal projection domain of tau containing amino acid 6-18 is especially beneficial. Thus, targeting selective epitopes of N-terminal domain of tau may present a novel effective therapeutic opportunity for Alzheimer disease and other tauopathies.

MRI of pathology-proven peripheral nerve amyloidosis

International Nuclear Information System (INIS)

McKenzie, Gavin A.; Broski, Stephen M.; Howe, Benjamin M.; Spinner, Robert J.; Amrami, Kimberly K.; Dispenzieri, Angela; Ringler, Michael D.

2017-01-01

To highlight the MRI characteristics of pathologically proven amyloidosis involving the peripheral nervous system (PNS) and determine the utility of MRI in directing targeted biopsy for aiding diagnosis. A retrospective study was performed for patients with pathologically proven PNS amyloidosis who also underwent MRI of the biopsied or excised nerve. MRI signal characteristics, nerve morphology, associated muscular denervation changes, and the presence of multifocal involvement were detailed. Pathology reports were reviewed to determine subtypes of amyloid. Charts were reviewed to gather patient demographics, neurological symptoms and radiologist interpretation. Four men and three women with a mean age of 62 ± 11 years (range 46-76) were identified. All patients had abnormal findings on EMG with mixed sensorimotor neuropathy. All lesions demonstrated diffuse multifocal neural involvement with T1 hypointensity, T2 hyperintensity, and variable enhancement on MRI. One lesion exhibited superimposed T2 hypointensity. Six of seven patients demonstrated associated muscular denervation changes. Peripheral nerve amyloidosis is rare, and the diagnosis is difficult because of insidious symptom onset, mixed sensorimotor neurologic deficits, and the potential for a wide variety of nerves affected. On MRI, peripheral nerve involvement is most commonly characterized by T1 hypointensity, T2 hyperintensity, variable enhancement, maintenance of the fascicular architecture with fusiform enlargement, multifocal involvement and muscular denervation changes. While this appearance mimics other inflammatory neuropathies, MRI can readily detect neural changes and direct-targeted biopsy, thus facilitating early diagnosis and appropriate management. (orig.)

MRI of pathology-proven peripheral nerve amyloidosis

Energy Technology Data Exchange (ETDEWEB)

McKenzie, Gavin A.; Broski, Stephen M.; Howe, Benjamin M.; Spinner, Robert J.; Amrami, Kimberly K.; Dispenzieri, Angela; Ringler, Michael D. [Mayo Clinic, Department of Musculoskeletal Radiology, Rochester, MN (United States)

2017-01-15

To highlight the MRI characteristics of pathologically proven amyloidosis involving the peripheral nervous system (PNS) and determine the utility of MRI in directing targeted biopsy for aiding diagnosis. A retrospective study was performed for patients with pathologically proven PNS amyloidosis who also underwent MRI of the biopsied or excised nerve. MRI signal characteristics, nerve morphology, associated muscular denervation changes, and the presence of multifocal involvement were detailed. Pathology reports were reviewed to determine subtypes of amyloid. Charts were reviewed to gather patient demographics, neurological symptoms and radiologist interpretation. Four men and three women with a mean age of 62 ± 11 years (range 46-76) were identified. All patients had abnormal findings on EMG with mixed sensorimotor neuropathy. All lesions demonstrated diffuse multifocal neural involvement with T1 hypointensity, T2 hyperintensity, and variable enhancement on MRI. One lesion exhibited superimposed T2 hypointensity. Six of seven patients demonstrated associated muscular denervation changes. Peripheral nerve amyloidosis is rare, and the diagnosis is difficult because of insidious symptom onset, mixed sensorimotor neurologic deficits, and the potential for a wide variety of nerves affected. On MRI, peripheral nerve involvement is most commonly characterized by T1 hypointensity, T2 hyperintensity, variable enhancement, maintenance of the fascicular architecture with fusiform enlargement, multifocal involvement and muscular denervation changes. While this appearance mimics other inflammatory neuropathies, MRI can readily detect neural changes and direct-targeted biopsy, thus facilitating early diagnosis and appropriate management. (orig.)

A Prospective Pathologic Study to Define the Clinical Target Volume for Partial Breast Radiation Therapy in Women With Early Breast Cancer

Energy Technology Data Exchange (ETDEWEB)

Nguyen, Brandon T., E-mail: Brandon.Nguyen@act.gov.au [Department of Radiation Oncology, Peter MacCallum Cancer Centre, East Melbourne, Victoria (Australia); Canberra Hospital, Radiation Oncology Department, Garran, ACT (Australia); Deb, Siddhartha [Department of Anatomical Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria (Australia); Victorian Cancer Biobank, Cancer Council of Victoria, Carlton, Victoria (Australia); Fox, Stephen [Department of Anatomical Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria (Australia); Hill, Prudence [Department of Anatomical Pathology, St. Vincent' s Hospital Melbourne, Fitzroy, Victoria (Australia); Collins, Marnie [Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, East Melbourne, Victoria (Australia); Chua, Boon H. [Department of Radiation Oncology, Peter MacCallum Cancer Centre, East Melbourne, Victoria (Australia); University of Melbourne, Parkville, Victoria (Australia)

2012-12-01

Purpose: To determine an appropriate clinical target volume for partial breast radiation therapy (PBRT) based on the spatial distribution of residual invasive and in situ carcinoma after wide local excision (WLE) for early breast cancer or ductal carcinoma in situ (DCIS). Methods and Materials: We performed a prospective pathologic study of women potentially eligible for PBRT who had re-excision and/or completion mastectomy after WLE for early breast cancer or DCIS. A pathologic assessment protocol was used to determine the maximum radial extension (MRE) of residual carcinoma from the margin of the initial surgical cavity. Women were stratified by the closest initial radial margin width: negative (>1 mm), close (>0 mm and {<=}1 mm), or involved. Results: The study population was composed of 133 women with a median age of 59 years (range, 27-82 years) and the following stage groups: 0 (13.5%), I (40.6%), II (38.3%), and III (7.5%). The histologic subtypes of the primary tumor were invasive ductal carcinoma (74.4%), invasive lobular carcinoma (12.0%), and DCIS alone (13.5%). Residual carcinoma was present in the re-excision and completion mastectomy specimens in 55.4%, 14.3%, and 7.2% of women with an involved, close, and negative margin, respectively. In the 77 women with a noninvolved radial margin, the MRE of residual disease, if present, was {<=}10 mm in 97.4% (95% confidence interval 91.6-99.5) of cases. Larger MRE measurements were significantly associated with an involved margin (P<.001), tumor size >30 mm (P=.03), premenopausal status (P=.03), and negative progesterone receptor status (P=.05). Conclusions: A clinical target volume margin of 10 mm would encompass microscopic residual disease in >90% of women potentially eligible for PBRT after WLE with noninvolved resection margins.

A Prospective Pathologic Study to Define the Clinical Target Volume for Partial Breast Radiation Therapy in Women With Early Breast Cancer

International Nuclear Information System (INIS)

Nguyen, Brandon T.; Deb, Siddhartha; Fox, Stephen; Hill, Prudence; Collins, Marnie; Chua, Boon H.

2012-01-01

Purpose: To determine an appropriate clinical target volume for partial breast radiation therapy (PBRT) based on the spatial distribution of residual invasive and in situ carcinoma after wide local excision (WLE) for early breast cancer or ductal carcinoma in situ (DCIS). Methods and Materials: We performed a prospective pathologic study of women potentially eligible for PBRT who had re-excision and/or completion mastectomy after WLE for early breast cancer or DCIS. A pathologic assessment protocol was used to determine the maximum radial extension (MRE) of residual carcinoma from the margin of the initial surgical cavity. Women were stratified by the closest initial radial margin width: negative (>1 mm), close (>0 mm and ≤1 mm), or involved. Results: The study population was composed of 133 women with a median age of 59 years (range, 27-82 years) and the following stage groups: 0 (13.5%), I (40.6%), II (38.3%), and III (7.5%). The histologic subtypes of the primary tumor were invasive ductal carcinoma (74.4%), invasive lobular carcinoma (12.0%), and DCIS alone (13.5%). Residual carcinoma was present in the re-excision and completion mastectomy specimens in 55.4%, 14.3%, and 7.2% of women with an involved, close, and negative margin, respectively. In the 77 women with a noninvolved radial margin, the MRE of residual disease, if present, was ≤10 mm in 97.4% (95% confidence interval 91.6-99.5) of cases. Larger MRE measurements were significantly associated with an involved margin (P 30 mm (P=.03), premenopausal status (P=.03), and negative progesterone receptor status (P=.05). Conclusions: A clinical target volume margin of 10 mm would encompass microscopic residual disease in >90% of women potentially eligible for PBRT after WLE with noninvolved resection margins.

Real-time non-rigid target tracking for ultrasound-guided clinical interventions

NARCIS (Netherlands)

Zachiu, Cornel; Ries, Mario G; Ramaekers, Pascal; Guey, Jean-Luc; Moonen, Chrit T W; de Senneville, Baudouin Denis

2017-01-01

Biological motion is a problem for non- or mini-invasive interventions when conducted in mobile/deformable organs due to the targeted pathology moving/deforming with the organ. This may lead to high miss rates and/or incomplete treatment of the pathology. Therefore, real-time tracking of the target

Polysaccharide-based Noncovalent Assembly for Targeted Delivery of Taxol

Science.gov (United States)

Yang, Yang; Zhang, Ying-Ming; Chen, Yong; Chen, Jia-Tong; Liu, Yu

2016-01-01

The construction of synthetic straightforward, biocompatible and biodegradable targeted drug delivery system with fluorescent tracking abilities, high anticancer activities and low side effects is still a challenge in the field of biochemistry and material chemistry. In this work, we constructed targeted paclitaxel (Taxol) delivery nanoparticles composed of permethyl-β-cyclodextrin modified hyaluronic acid (HApCD) and porphyrin modified paclitaxel prodrug (PorTaxol), through host-guest and amphiphilic interactions. The obtained nanoparticles (HATXP) were biocompatible and enzymatic biodegradable due to their hydrophilic hyaluronic acid (HA) shell and hydrophobic Taxol core, and exhibited specific targeting internalization into cancer cells via HA receptor mediated endocytosis effects. The cytotoxicity experiments showed that the HATXP exhibited similar anticancer activities to, but much lower side effects than commercial anticancer drug Taxol. The present work would provide a platform for targeted paclitaxel drug delivery and a general protocol for the design of advanced multifunctional nanoscale biomaterials for targeted drug/gene delivery.

Pathology Gross Photography: The Beginning of Digital Pathology.

Science.gov (United States)

Rampy, B Alan; Glassy, Eric F

2015-06-01

The underutilized practice of photographing anatomic pathology specimens from surgical pathology and autopsies is an invaluable benefit to patients, clinicians, pathologists, and students. Photographic documentation of clinical specimens is essential for the effective practice of pathology. When considering what specimens to photograph, all grossly evident pathology, absent yet expected pathologic features, and gross-only specimens should be thoroughly documented. Specimen preparation prior to photography includes proper lighting and background, wiping surfaces of blood, removing material such as tubes or bandages, orienting the specimen in a logical fashion, framing the specimen to fill the screen, positioning of probes, and using the right-sized scale. Copyright © 2015 Elsevier Inc. All rights reserved.

DNA mediated assembly of lipid particles and uses therefor

DEFF Research Database (Denmark)

2007-01-01

The present invention relates to detection of target nucleic acids by targetnucleic acid induced liposome assembly. The invention provides oligonucleotides for use in detection and a method of detecting target nucleic acids.Other aspects of the invention are use of the oligonucleotide of the inve...

VEGF-A, cytoskeletal dynamics, and the pathological vascular phenotype

International Nuclear Information System (INIS)

Nagy, Janice A.; Senger, Donald R.

2006-01-01

Normal angiogenesis is a complex process involving the organization of proliferating and migrating endothelial cells (ECs) into a well-ordered and highly functional vascular network. In contrast, pathological angiogenesis, which is a conspicuous feature of tumor growth, ischemic diseases, and chronic inflammation, is characterized by vessels with aberrant angioarchitecture and compromised barrier function. Herein we review the subject of pathological angiogenesis, particularly that driven by vascular endothelial growth factor (VEGF-A), from a new perspective. We propose that the serious structural and functional anomalies associated with VEGF-A-elicited neovessels, reflect, at least in part, imbalances in the internal molecular cues that govern the ordered assembly of ECs into three dimensional vascular networks and preserve vessel barrier function. Adopting such a viewpoint widens the focus from solely on specific pro-angiogenic stimuli such as VEGF-A to include a key set of cytoskeletal regulatory molecules, the Rho GTPases, which are known to direct multiple aspects of vascular morphogenesis including EC motility, alignment, multi-cellular organization, as well as intercellular junction integrity. We offer this perspective to draw attention to the importance of endothelial cytoskeletal dynamics for proper neovascularization and to suggest new therapeutic strategies with the potential to improve the pathological vascular phenotype

The Japanese Society of Pathology Guidelines on the handling of pathological tissue samples for genomic research: Standard operating procedures based on empirical analyses.

Science.gov (United States)

Kanai, Yae; Nishihara, Hiroshi; Miyagi, Yohei; Tsuruyama, Tatsuhiro; Taguchi, Kenichi; Katoh, Hiroto; Takeuchi, Tomoyo; Gotoh, Masahiro; Kuramoto, Junko; Arai, Eri; Ojima, Hidenori; Shibuya, Ayako; Yoshida, Teruhiko; Akahane, Toshiaki; Kasajima, Rika; Morita, Kei-Ichi; Inazawa, Johji; Sasaki, Takeshi; Fukayama, Masashi; Oda, Yoshinao

2018-02-01

Genome research using appropriately collected pathological tissue samples is expected to yield breakthroughs in the development of biomarkers and identification of therapeutic targets for diseases such as cancers. In this connection, the Japanese Society of Pathology (JSP) has developed "The JSP Guidelines on the Handling of Pathological Tissue Samples for Genomic Research" based on an abundance of data from empirical analyses of tissue samples collected and stored under various conditions. Tissue samples should be collected from appropriate sites within surgically resected specimens, without disturbing the features on which pathological diagnosis is based, while avoiding bleeding or necrotic foci. They should be collected as soon as possible after resection: at the latest within about 3 h of storage at 4°C. Preferably, snap-frozen samples should be stored in liquid nitrogen (about -180°C) until use. When intending to use genomic DNA extracted from formalin-fixed paraffin-embedded tissue, 10% neutral buffered formalin should be used. Insufficient fixation and overfixation must both be avoided. We hope that pathologists, clinicians, clinical laboratory technicians and biobank operators will come to master the handling of pathological tissue samples based on the standard operating procedures in these Guidelines to yield results that will assist in the realization of genomic medicine. © 2018 The Authors. Pathology International published by Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.

Interaction of nucleosome assembly proteins abolishes nuclear localization of DGKζ by attenuating its association with importins

International Nuclear Information System (INIS)

Okada, Masashi; Hozumi, Yasukazu; Ichimura, Tohru; Tanaka, Toshiaki; Hasegawa, Hiroshi; Yamamoto, Masakazu; Takahashi, Nobuya; Iseki, Ken; Yagisawa, Hitoshi; Shinkawa, Takashi; Isobe, Toshiaki; Goto, Kaoru

2011-01-01

Diacylglycerol kinase (DGK) is involved in the regulation of lipid-mediated signal transduction through the metabolism of a second messenger diacylglycerol. Of the DGK family, DGKζ, which contains a nuclear localization signal, localizes mainly to the nucleus but translocates to the cytoplasm under pathological conditions. However, the detailed mechanism of translocation and its functional significance remain unclear. To elucidate these issues, we used a proteomic approach to search for protein targets that interact with DGKζ. Results show that nucleosome assembly protein (NAP) 1-like 1 (NAP1L1) and NAP1-like 4 (NAP1L4) are identified as novel DGKζ binding partners. NAP1Ls constitutively shuttle between the nucleus and the cytoplasm in transfected HEK293 cells. The molecular interaction of DGKζ and NAP1Ls prohibits nuclear import of DGKζ because binding of NAP1Ls to DGKζ blocks import carrier proteins, Qip1 and NPI1, to interact with DGKζ, leading to cytoplasmic tethering of DGKζ. In addition, overexpression of NAP1Ls exerts a protective effect against doxorubicin-induced cytotoxicity. These findings suggest that NAP1Ls are involved in a novel molecular basis for the regulation of nucleocytoplasmic shuttling of DGKζ and provide a clue to examine functional significance of its translocation under pathological conditions.

Pathology Assistant (C - Gamechanger Of Pathology Diagnostic

Directory of Open Access Journals (Sweden)

Asel Kudaybergenova

2016-06-01

When the competition ended, we received many favor- able reviews and we decided to start another project a little bit similar to the competition. Every month we show three interesting and difficult to diagnose cases provided by the leading Russian pathologists. The participants can look through the clinical data and digitized histological slides, and then discuss what they see among their professional society. There are 400  specialists  from  post  USSR countries.  Moreover, we get a few proposal of partnership to start a similar project in EU. And the last product in line is Pathology Assistant. It is a game changer. Pathology Assistant is a Digital Pathology©technology driven application for pathology diagnostics, tool to innovate pathology diagnostics in more simple, proven by analytical algo- rithm, automatically delivering anticipated support way. The service provides vast and structured database of validated cases, intuitive interface, fast and convenient system of analytical search. Pathology Assistant will streamline and simplify pathologist’s way to the right decision. Pathologists from Memorial Sloan Catering and biggest EU labs are working on preparing the con- tent for the project.  

Demonstration of Coupled Tiamat Single Assembly Calculations

Energy Technology Data Exchange (ETDEWEB)

Novascone, Stephen R. [Idaho National Lab. (INL), Idaho Falls, ID (United States); Hales, Jason D. [Idaho National Lab. (INL), Idaho Falls, ID (United States); Gardner, Russell [Idaho National Lab. (INL), Idaho Falls, ID (United States); Pawlowski, R. P. P. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Pastore, Giovanni [Idaho National Lab. (INL), Idaho Falls, ID (United States); Toth, Alex [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Clarno, Kevin T. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Collins, Benjamin S. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Stimpson, Shane G. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Powers, Jeffrey J. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

2017-06-01

This report corresponds to milestone L3:PHI.PCI.P15.03, which was originally intended to investigate the time discretization approaches with the newly developed fully coupled Tiamat capability, targeting single assembly problems.

The role of exercise dependence for the relationship between exercise behavior and eating pathology: mediator or moderator?

Science.gov (United States)

Cook, Brian J; Hausenblas, Heather A

2008-05-01

Our study examined the potential mediating or moderating effect of exercise dependence on the exercise-eating pathology relationship. Female university students (N = 330) completed Internet-based self-report measures of exercise behavior, exercise dependence, and eating pathology. Exercise dependence served as a mediator for the relationship between exercise and eating pathology. This unidirectional causal model suggests that an individual's pathological motivation or compulsion to exercise is the critical mediating component in the exercise-eating pathology relationship. The best target for removing the link between exercise behavior and eating pathology may be reformulating exercise dependence symptoms.

Progress on the SNS target station

International Nuclear Information System (INIS)

Carne, A.

1983-01-01

This review gives progress and modifications covering the last eighteen months, under the five broad areas of target, target assembly, control system, bulk shield and remote handling. Finally a discussion of additional facilities to the SNS is presented

An Overview of the Target Fabrication Operations at Lawrence Livermore National Laboratory

International Nuclear Information System (INIS)

Hibbard, R L; Bono, M J

2005-01-01

The Target Engineering team at Lawrence Livermore National Laboratory (LLNL) builds precision laser targets for the National Ignition Facility (NIF) and the Omega Laser in Rochester, NY, and other experimental facilities. The physics requirements demand precision in these targets, which creates a constant need for innovative manufacturing processes. As experimental diagnostics improve, there is greater demand for precision in fabrication, assembly, metrology, and documentation of as-built targets. The team specializes in meso-scale fabrication with core competencies in diamond turning, assembly, and metrology. Figure 1 shows a typical diamond turning center. The team builds over 200 laser targets per year in batches of five to fifteen targets. Thus, all are small-lot custom builds, and most are novel designs requiring engineering and process development. Component materials are metals, polymers and low density aerogel foams. Custom fixturing is used to locate parts on the Diamond Turning Machines (DTM) and assembly stations. This ensures parts can be repeatably located during manufacturing operations. Most target builds involve a series of fabricating one surface with features and then relocating the components on another fixture to finish the opposite side of the component. These components are then assembled to complete multiple-component targets. These targets are typically built one at a time. Cost and efficiency are issues with production of targets, and the team is developing batch processing techniques to meet precision target specifications and cost goals. Three example target builds will highlight some of the fabrication and material issues faced at LLNL. A low temperature Rayleigh Taylor target shows how multiple precision targets can be fabricated out of a single large disk. The ignition double shell targets highlight the required manufacturing complexity. A low density aerogel target highlights some material handling and assembly issues. The metrology

Hyb-Seq: Combining Target Enrichment and Genome Skimming for Plant Phylogenomics

Directory of Open Access Journals (Sweden)

Kevin Weitemier

2014-08-01

Full Text Available Premise of the study: Hyb-Seq, the combination of target enrichment and genome skimming, allows simultaneous data collection for low-copy nuclear genes and high-copy genomic targets for plant systematics and evolution studies. Methods and Results: Genome and transcriptome assemblies for milkweed (Asclepias syriaca were used to design enrichment probes for 3385 exons from 768 genes (>1.6 Mbp followed by Illumina sequencing of enriched libraries. Hyb-Seq of 12 individuals (10 Asclepias species and two related genera resulted in at least partial assembly of 92.6% of exons and 99.7% of genes and an average assembly length >2 Mbp. Importantly, complete plastomes and nuclear ribosomal DNA cistrons were assembled using off-target reads. Phylogenomic analyses demonstrated signal conflict between genomes. Conclusions: The Hyb-Seq approach enables targeted sequencing of thousands of low-copy nuclear exons and flanking regions, as well as genome skimming of high-copy repeats and organellar genomes, to efficiently produce genome-scale data sets for phylogenomics.

Assembly of viral genomes from metagenomes

Directory of Open Access Journals (Sweden)

Saskia L Smits

2014-12-01

Full Text Available Viral infections remain a serious global health issue. Metagenomic approaches are increasingly used in the detection of novel viral pathogens but also to generate complete genomes of uncultivated viruses. In silico identification of complete viral genomes from sequence data would allow rapid phylogenetic characterization of these new viruses. Often, however, complete viral genomes are not recovered, but rather several distinct contigs derived from a single entity, some of which have no sequence homology to any known proteins. De novo assembly of single viruses from a metagenome is challenging, not only because of the lack of a reference genome, but also because of intrapopulation variation and uneven or insufficient coverage. Here we explored different assembly algorithms, remote homology searches, genome-specific sequence motifs, k-mer frequency ranking, and coverage profile binning to detect and obtain viral target genomes from metagenomes. All methods were tested on 454-generated sequencing datasets containing three recently described RNA viruses with a relatively large genome which were divergent to previously known viruses from the viral families Rhabdoviridae and Coronaviridae. Depending on specific characteristics of the target virus and the metagenomic community, different assembly and in silico gap closure strategies were successful in obtaining near complete viral genomes.

Molecular Diagnostics in Pathology: Time for a Next-Generation Pathologist?

Science.gov (United States)

Fassan, Matteo

2018-03-01

- Comprehensive molecular investigations of mainstream carcinogenic processes have led to the use of effective molecular targeted agents in most cases of solid tumors in clinical settings. - To update readers regarding the evolving role of the pathologist in the therapeutic decision-making process and the introduction of next-generation technologies into pathology practice. - Current literature on the topic, primarily sourced from the PubMed (National Center for Biotechnology Information, Bethesda, Maryland) database, were reviewed. - Adequate evaluation of cytologic-based and tissue-based predictive diagnostic biomarkers largely depends on both proper pathologic characterization and customized processing of biospecimens. Moreover, increased requests for molecular testing have paralleled the recent, sharp decrease in tumor material to be analyzed-material that currently comprises cytology specimens or, at minimum, small biopsies in most cases of metastatic/advanced disease. Traditional diagnostic pathology has been completely revolutionized by the introduction of next-generation technologies, which provide multigene, targeted mutational profiling, even in the most complex of clinical cases. Combining traditional and molecular knowledge, pathologists integrate the morphological, clinical, and molecular dimensions of a disease, leading to a proper diagnosis and, therefore, the most-appropriate tailored therapy.

Dopamine Agonists and Pathologic Behaviors

Directory of Open Access Journals (Sweden)

Brendan J. Kelley

2012-01-01

Full Text Available The dopamine agonists ropinirole and pramipexole exhibit highly specific affinity for the cerebral dopamine D3 receptor. Use of these medications in Parkinson’s disease has been complicated by the emergence of pathologic behavioral patterns such as hypersexuality, pathologic gambling, excessive hobbying, and other circumscribed obsessive-compulsive disorders of impulse control in people having no history of such disorders. These behavioral changes typically remit following discontinuation of the medication, further demonstrating a causal relationship. Expression of the D3 receptor is particularly rich within the limbic system, where it plays an important role in modulating the physiologic and emotional experience of novelty, reward, and risk assessment. Converging neuroanatomical, physiological, and behavioral science data suggest the high D3 affinity of these medications as the basis for these behavioral changes. These observations suggest the D3 receptor as a therapeutic target for obsessive-compulsive disorder and substance abuse, and improved understanding of D3 receptor function may aid drug design of future atypical antipsychotics.

Mechanisms of Autoantibody-Induced Pathology

Directory of Open Access Journals (Sweden)

Ralf J. Ludwig

2017-05-01

Full Text Available Autoantibodies are frequently observed in healthy individuals. In a minority of these individuals, they lead to manifestation of autoimmune diseases, such as rheumatoid arthritis or Graves’ disease. Overall, more than 2.5% of the population is affected by autoantibody-driven autoimmune disease. Pathways leading to autoantibody-induced pathology greatly differ among different diseases, and autoantibodies directed against the same antigen, depending on the targeted epitope, can have diverse effects. To foster knowledge in autoantibody-induced pathology and to encourage development of urgently needed novel therapeutic strategies, we here categorized autoantibodies according to their effects. According to our algorithm, autoantibodies can be classified into the following categories: (1 mimic receptor stimulation, (2 blocking of neural transmission, (3 induction of altered signaling, triggering uncontrolled (4 microthrombosis, (5 cell lysis, (6 neutrophil activation, and (7 induction of inflammation. These mechanisms in relation to disease, as well as principles of autoantibody generation and detection, are reviewed herein.

Targeted modulation of reactive oxygen species in the vascular endothelium.

Science.gov (United States)

Shuvaev, Vladimir V; Muzykantov, Vladimir R

2011-07-15

'Endothelial cells lining vascular luminal surface represent an important site of signaling and injurious effects of reactive oxygen species (ROS) produced by other cells and endothelium itself in ischemia, inflammation and other pathological conditions. Targeted delivery of ROS modulating enzymes conjugated with antibodies to endothelial surface molecules (vascular immunotargeting) provides site-specific interventions in the endothelial ROS, unattainable by other formulations including PEG-modified enzymes. Targeting of ROS generating enzymes (e.g., glucose oxidase) provides ROS- and site-specific models of endothelial oxidative stress, whereas targeting of antioxidant enzymes SOD and catalase offers site-specific quenching of superoxide anion and H(2)O(2). These targeted antioxidant interventions help to clarify specific role of endothelial ROS in vascular and pulmonary pathologies and provide basis for design of targeted therapeutics for treatment of these pathologies. In particular, antibody/catalase conjugates alleviate acute lung ischemia/reperfusion injury, whereas antibody/SOD conjugates inhibit ROS-mediated vasoconstriction and inflammatory endothelial signaling. Encapsulation in protease-resistant, ROS-permeable carriers targeted to endothelium prolongs protective effects of antioxidant enzymes, further diversifying the means for targeted modulation of endothelial ROS. Copyright © 2011 Elsevier B.V. All rights reserved.

Minor Actinide Recycle in Sodium Cooled Fast Reactors Using Heterogeneous Targets

International Nuclear Information System (INIS)

Bays, Samuel; Medvedev, Pavel; Pope, Michael; Ferrer, Rodolfo; Forget, Benoit; Asgari, Mehdi

2009-01-01

This paper investigates the plausible design of transmutation target assemblies for minor actinides (MA) in Sodium Fast Reactors (SFR). A heterogeneous recycling strategy is investigated, whereby after each reactor pass, un-burned MAs from the targets are blended with MAs produced by the driver fuel and additional MAs from Spent Nuclear Fuel (SNF). A design iteration methodology was adopted for customizing the core design, target assembly design and matrix composition design. The overall design was constrained against allowable peak or maximum in-core performances. While respecting these criteria, the overall design was adjusted to reduce the total number of assemblies fabricated per refueling cycle. It was found that an inert metal-hydride MA-Zr-Hx target matrix gave the highest transmutation efficiency, thus allowing for the least number of targets to be fabricated per reactor cycle.

3D Surface Mapping of Capsule Fill-Tube Assemblies used in Laser-Driven Fusion Targets

Energy Technology Data Exchange (ETDEWEB)

Buice, E S; Alger, E T; Antipa, N A; Bhandarkar, S D; Biesiada, T A; Conder, A D; Dzenitis, E G; Flegel, M S; Hamza, A V; Heinbockel, C L; Horner, J; Johnson, M A; Kegelmeyer, L M; Meyer, J S; Montesanti, R C; Reynolds, J L; Taylor, J S; Wegner, P J

2011-02-18

This paper presents the development of a 3D surface mapping system used to measure the surface of a fusion target Capsule Fill-Tube Assembly (CFTA). The CFTA consists of a hollow Ge-doped plastic sphere, called a capsule, ranging in outer diameter between 2.2 mm and 2.6 mm and an attached 150 {micro}m diameter glass-core fill-tube that tapers down to a 10{micro} diameter at the capsule. The mapping system is an enabling technology to facilitate a quality assurance program and to archive 3D surface information of each capsule used in fusion ignition experiments that are currently being performed at the National Ignition Facility (NIF). The 3D Surface Mapping System is designed to locate and quantify surface features with a height of 50 nm and 300 nm in width or larger. Additionally, the system will be calibrated such that the 3D measured surface can be related to the capsule surface angular coordinate system to within 0.25 degree (1{sigma}), which corresponds to approximately 5 {micro}m linear error on the capsule surface.

3D Surface Mapping of Capsule Fill-Tube Assemblies used in Laser-Driven Fusion Targets

International Nuclear Information System (INIS)

Buice, E.S.; Alger, E.T.; Antipa, N.A.; Bhandarkar, S.D.; Biesiada, T.A.; Conder, A.D.; Dzenitis, E.G.; Flegel, M.S.; Hamza, A.V.; Heinbockel, C.L.; Horner, J.; Johnson, M.A.; Kegelmeyer, L.M.; Meyer, J.S.; Montesanti, R.C.; Reynolds, J.L.; Taylor, J.S.; Wegner, P.J.

2011-01-01

This paper presents the development of a 3D surface mapping system used to measure the surface of a fusion target Capsule Fill-Tube Assembly (CFTA). The CFTA consists of a hollow Ge-doped plastic sphere, called a capsule, ranging in outer diameter between 2.2 mm and 2.6 mm and an attached 150 (micro)m diameter glass-core fill-tube that tapers down to a 10(micro) diameter at the capsule. The mapping system is an enabling technology to facilitate a quality assurance program and to archive 3D surface information of each capsule used in fusion ignition experiments that are currently being performed at the National Ignition Facility (NIF). The 3D Surface Mapping System is designed to locate and quantify surface features with a height of 50 nm and 300 nm in width or larger. Additionally, the system will be calibrated such that the 3D measured surface can be related to the capsule surface angular coordinate system to within 0.25 degree (1σ), which corresponds to approximately 5 (micro)m linear error on the capsule surface.

Progress in FMIT test assembly development

International Nuclear Information System (INIS)

Opperman, E.K.; Vogel, M.A.; Shen, E.J.; Trego, A.L.

1983-08-01

Research and development supporting the completed design of the Fusion Materials Irradiation Test (FMIT) Facility is continuing at the Hanford Engineering Development Laboratory (HEDL) in Richland, Washington. The FMIT, a deuteron accelerator based (d + Li) neutron source, will produce an intense flux of high energy neutrons for use in radiation damage studies of fusion reactor materials. The most intense flux magnitude of greater than 10 15 n/cm 2 -s is located close to the neutron producing lithium target and is distributed within a volume about the size of an American football. The conceptual design and development of FMIT experiments called Test Assemblies has progressed over the past five years in parallel with the design of the FMIT. The paper will describe the recent accomplishments made in developing test assemblies appropriate for use in the limited volume close to the FMIT target where high neutron flux and heating rates and the associated spacial gradients significantly impact design considerations

GRAbB: Selective Assembly of Genomic Regions, a New Niche for Genomic Research.

Directory of Open Access Journals (Sweden)

Balázs Brankovics

2016-06-01

Full Text Available GRAbB (Genomic Region Assembly by Baiting is a new program that is dedicated to assemble specific genomic regions from NGS data. This approach is especially useful when dealing with multi copy regions, such as mitochondrial genome and the rDNA repeat region, parts of the genome that are often neglected or poorly assembled, although they contain interesting information from phylogenetic or epidemiologic perspectives, but also single copy regions can be assembled. The program is capable of targeting multiple regions within a single run. Furthermore, GRAbB can be used to extract specific loci from NGS data, based on homology, like sequences that are used for barcoding. To make the assembly specific, a known part of the region, such as the sequence of a PCR amplicon or a homologous sequence from a related species must be specified. By assembling only the region of interest, the assembly process is computationally much less demanding and may lead to assemblies of better quality. In this study the different applications and functionalities of the program are demonstrated such as: exhaustive assembly (rDNA region and mitochondrial genome, extracting homologous regions or genes (IGS, RPB1, RPB2 and TEF1a, as well as extracting multiple regions within a single run. The program is also compared with MITObim, which is meant for the exhaustive assembly of a single target based on a similar query sequence. GRAbB is shown to be more efficient than MITObim in terms of speed, memory and disk usage. The other functionalities (handling multiple targets simultaneously and extracting homologous regions of the new program are not matched by other programs. The program is available with explanatory documentation at https://github.com/b-brankovics/grabb. GRAbB has been tested on Ubuntu (12.04 and 14.04, Fedora (23, CentOS (7.1.1503 and Mac OS X (10.7. Furthermore, GRAbB is available as a docker repository: brankovics/grabb (https://hub.docker.com/r/brankovics/grabb/.

Hyb-Seq: Combining target enrichment and genome skimming for plant phylogenomics1

Science.gov (United States)

Weitemier, Kevin; Straub, Shannon C. K.; Cronn, Richard C.; Fishbein, Mark; Schmickl, Roswitha; McDonnell, Angela; Liston, Aaron

2014-01-01

• Premise of the study: Hyb-Seq, the combination of target enrichment and genome skimming, allows simultaneous data collection for low-copy nuclear genes and high-copy genomic targets for plant systematics and evolution studies. • Methods and Results: Genome and transcriptome assemblies for milkweed (Asclepias syriaca) were used to design enrichment probes for 3385 exons from 768 genes (>1.6 Mbp) followed by Illumina sequencing of enriched libraries. Hyb-Seq of 12 individuals (10 Asclepias species and two related genera) resulted in at least partial assembly of 92.6% of exons and 99.7% of genes and an average assembly length >2 Mbp. Importantly, complete plastomes and nuclear ribosomal DNA cistrons were assembled using off-target reads. Phylogenomic analyses demonstrated signal conflict between genomes. • Conclusions: The Hyb-Seq approach enables targeted sequencing of thousands of low-copy nuclear exons and flanking regions, as well as genome skimming of high-copy repeats and organellar genomes, to efficiently produce genome-scale data sets for phylogenomics. PMID:25225629

Development of the Triple Theta assembly station with machine vision feedback

International Nuclear Information System (INIS)

Schmidt, Derek William

2008-01-01

Increased requirements for tighter tolerances on assembled target components in complex three-dimensional geometries with only days to assemble complete campaigns require the implementation of a computer-controlled high-precision assembly station. Over the last year, an 11-axis computer-controlled assembly station has been designed and built with custom software to handle the multiple coordinate systems and automatically calculate all relational positions. Preliminary development efforts have also been done to explore the benefit of a machine vision feedback module with a dual-camera viewing system to automate certain basic features like crosshair calibration, component leveling, and component centering.

Pathology in Greece.

Science.gov (United States)

Sakellariou, S; Patsouris, E

2015-11-01

Pathology is the field of medicine that studies diseases. Ancient Greece hosted some of the earliest societies that laid the structural foundations of pathology. Initially, knowledge was based on observations but later on the key elements of pathology were established based on the dissection of animals and the autopsy of human cadavers. Christianized Greece under Ottoman rule (1453-1821) was not conducive to the development of pathology. After liberation, however, a series of events took place that paved the way for the establishment and further development of the specialty. The appointment in 1849 of two Professors of Pathology at the Medical School of Athens for didactical purposes proved to be the most important step in fostering the field of pathology in modern Greece. Presently in Greece there are seven university departments and 74 pathology laboratories in public hospitals, employing 415 specialized pathologists and 90 residents. The First Department of Pathology at the Medical School of Athens University is the oldest (1849) and largest in Greece, encompassing most pathology subspecialties.

In vitro reconstitution of chaperone-mediated human RISC assembly.

Science.gov (United States)

Naruse, Ken; Matsuura-Suzuki, Eriko; Watanabe, Mariko; Iwasaki, Shintaro; Tomari, Yukihide

2018-01-01

To silence target mRNAs, small RNAs and Argonaute (Ago) proteins need to be assembled into RNA-induced silencing complexes (RISCs). Although the assembly of Drosophila melanogaster RISC was recently reconstituted by Ago2, the Dicer-2/R2D2 heterodimer, and five chaperone proteins, the absence of a reconstitution system for mammalian RISC assembly has posed analytical challenges. Here we describe reconstitution of human RISC assembly using Ago2 and five recombinant chaperone proteins: Hsp90β, Hsc70, Hop, Dnaja2, and p23. Our data show that ATP hydrolysis by both Hsp90β and Hsc70 is required for RISC assembly of small RNA duplexes but not for that of single-stranded RNAs. The reconstitution system lays the groundwork for further studies of small RNA-mediated gene silencing in mammals. © 2018 Naruse et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

Targeted delivery and pH-responsive release of stereoisomeric anti-cancer drugs using β-cyclodextrin assemblied Fe{sub 3}O{sub 4} nanoparticles

Energy Technology Data Exchange (ETDEWEB)

Wang, Congli; Huang, Lizhen; Song, Shengmei; Saif, Bassam; Zhou, Yehong; Dong, Chuan; Shuang, Shaomin, E-mail: smshuang@sxu.edu.cn

2015-12-01

Graphical abstract: - Highlights: • β-Cyclodextrin assemblied magnetic Fe{sub 3}O{sub 4} nanoparticles (β-CD-MNPs) with good stability were successfully fabricated. • Stereoisomeric doxorubicin (DOX) and epirubicin (EPI) were used to explore the loading and release performance. • The loading properties of β-CD-MNPs were investigated using the Langmuir and Freundlich adsorption equilibrium models. • {sup 1}H NMR and the computer simulation were used to demonstrate the inclusion position between drug molecules and β-CD. - Abstract: The β-cyclodextrin assemblied magnetic Fe{sub 3}O{sub 4} nanoparticles (β-CD-MNPs) were successfully fabricated via a layer-by-layer method. Possessing an average size 14 nm, good stability and super-paramagnetic response (Ms 64 emu/g), the resultant nanocomposites could be served as a versatile biocompatible platform for selective loading, targeted delivery and pH-responsive release of stereoisomeric doxorubicin (DOX) and epirubicin (EPI). {sup 1}H-nuclear magnetic resonance ({sup 1}H NMR) and the computer simulation further give the evidence that partial anthracene ring of drug molecule is included by β-CD. In addition, non-toxic β-CD-MNPs have excellent biocompatibility on MCF-7 cells, and cellular uptake indicate that different amounts of DOX or EPI can be transported to targeting site and released from the internalized carriers. The results demonstrate that as-prepared β-CD-MNPs could be a very promising vehicle for DOX and EPI.

Next generation diagnostic molecular pathology: critical appraisal of quality assurance in Europe.

Science.gov (United States)

Dubbink, Hendrikus J; Deans, Zandra C; Tops, Bastiaan B J; van Kemenade, Folkert J; Koljenović, S; van Krieken, Han J M; Blokx, Willeke A M; Dinjens, Winand N M; Groenen, Patricia J T A

2014-06-01

Tumor evaluation in pathology is more and more based on a combination of traditional histopathology and molecular analysis. Due to the rapid development of new cancer treatments that specifically target aberrant proteins present in tumor cells, treatment decisions are increasingly based on the molecular features of the tumor. Not only the number of patients eligible for targeted precision medicine, but also the number of molecular targets per patient and tumor type is rising. Diagnostic molecular pathology, the discipline that determines the molecular aberrations present in tumors for diagnostic, prognostic or predictive purposes, is faced with true challenges. The laboratories have to meet the need of comprehensive molecular testing using only limited amount of tumor tissue, mostly fixed in formalin and embedded in paraffin (FFPE), in short turnaround time. Choices must be made for analytical methods that provide accurate, reliable and cost-effective results. Validation of the test procedures and results is essential. In addition, participation and good performance in internal (IQA) and external quality assurance (EQA) schemes is mandatory. In this review, we critically evaluate the validation procedure for comprehensive molecular tests as well as the organization of quality assurance and assessment of competence of diagnostic molecular pathology laboratories within Europe. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Alzheimer's disease pathological lesions activate the spleen tyrosine kinase.

Science.gov (United States)

Schweig, Jonas Elias; Yao, Hailan; Beaulieu-Abdelahad, David; Ait-Ghezala, Ghania; Mouzon, Benoit; Crawford, Fiona; Mullan, Michael; Paris, Daniel

2017-09-06

The pathology of Alzheimer's disease (AD) is characterized by dystrophic neurites (DNs) surrounding extracellular Aβ-plaques, microgliosis, astrogliosis, intraneuronal tau hyperphosphorylation and aggregation. We have previously shown that inhibition of the spleen tyrosine kinase (Syk) lowers Aβ production and tau hyperphosphorylation in vitro and in vivo. Here, we demonstrate that Aβ-overexpressing Tg PS1/APPsw, Tg APPsw mice, and tau overexpressing Tg Tau P301S mice exhibit a pathological activation of Syk compared to wild-type littermates. Syk activation is occurring in a subset of microglia and is age-dependently increased in Aβ-plaque-associated dystrophic neurites of Tg PS1/APPsw and Tg APPsw mice. In Tg Tau P301S mice, a pure model of tauopathy, activated Syk occurs in neurons that show an accumulation of misfolded and hyperphosphorylated tau in the cortex and hippocampus. Interestingly, the tau pathology is exacerbated in neurons that display high levels of Syk activation supporting a role of Syk in the formation of tau pathological species in vivo. Importantly, human AD brain sections show both pathological Syk activation in DNs around Aβ deposits and in neurons immunopositive for pathological tau species recapitulating the data obtained in transgenic mouse models of AD. Additionally, we show that Syk overexpression leads to increased tau accumulation and promotes tau hyperphosphorylation at multiple epitopes in human neuron-like SH-SY5Y cells, further supporting a role of Syk in the formation of tau pathogenic species. Collectively, our data show that Syk activation occurs following Aβ deposition and the formation of tau pathological species. Given that we have previously shown that Syk activation also promotes Aβ formation and tau hyperphosphorylation, our data suggest that AD pathological lesions may be self-propagating via a Syk dependent mechanism highlighting Syk as an attractive therapeutic target for the treatment of AD.

AA antiproton production target

CERN Multimedia

CERN PhotoLab

1979-01-01

The first version of the antiproton production target was a tungsten rod, 11 cm long and 3 mm in diameter. The rod was embedded in graphite, pressure-seated into an outer casing of stainless steel. At the entrance to the target assembly was a scintillator screen, imprinted with circles every 5 mm in radius, which allowed to precisely aim the 26 GeV high-intensity proton beam from the PS onto the centre of the target rod. The scintillator screen was a 1 mm thick plate of Cr-doped alumina. See also 7903034 and 7905091.

Targeted isolation, sequence assembly and characterization of two white spruce (Picea glauca BAC clones for terpenoid synthase and cytochrome P450 genes involved in conifer defence reveal insights into a conifer genome

Directory of Open Access Journals (Sweden)

Ritland Carol

2009-08-01

Full Text Available Abstract Background Conifers are a large group of gymnosperm trees which are separated from the angiosperms by more than 300 million years of independent evolution. Conifer genomes are extremely large and contain considerable amounts of repetitive DNA. Currently, conifer sequence resources exist predominantly as expressed sequence tags (ESTs and full-length (FLcDNAs. There is no genome sequence available for a conifer or any other gymnosperm. Conifer defence-related genes often group into large families with closely related members. The goals of this study are to assess the feasibility of targeted isolation and sequence assembly of conifer BAC clones containing specific genes from two large gene families, and to characterize large segments of genomic DNA sequence for the first time from a conifer. Results We used a PCR-based approach to identify BAC clones for two target genes, a terpene synthase (3-carene synthase; 3CAR and a cytochrome P450 (CYP720B4 from a non-arrayed genomic BAC library of white spruce (Picea glauca. Shotgun genomic fragments isolated from the BAC clones were sequenced to a depth of 15.6- and 16.0-fold coverage, respectively. Assembly and manual curation yielded sequence scaffolds of 172 kbp (3CAR and 94 kbp (CYP720B4 long. Inspection of the genomic sequences revealed the intron-exon structures, the putative promoter regions and putative cis-regulatory elements of these genes. Sequences related to transposable elements (TEs, high complexity repeats and simple repeats were prevalent and comprised approximately 40% of the sequenced genomic DNA. An in silico simulation of the effect of sequencing depth on the quality of the sequence assembly provides direction for future efforts of conifer genome sequencing. Conclusion We report the first targeted cloning, sequencing, assembly, and annotation of large segments of genomic DNA from a conifer. We demonstrate that genomic BAC clones for individual members of multi-member gene

Targeted isolation, sequence assembly and characterization of two white spruce (Picea glauca) BAC clones for terpenoid synthase and cytochrome P450 genes involved in conifer defence reveal insights into a conifer genome.

Science.gov (United States)

Hamberger, Björn; Hall, Dawn; Yuen, Mack; Oddy, Claire; Hamberger, Britta; Keeling, Christopher I; Ritland, Carol; Ritland, Kermit; Bohlmann, Jörg

2009-08-06

Conifers are a large group of gymnosperm trees which are separated from the angiosperms by more than 300 million years of independent evolution. Conifer genomes are extremely large and contain considerable amounts of repetitive DNA. Currently, conifer sequence resources exist predominantly as expressed sequence tags (ESTs) and full-length (FL)cDNAs. There is no genome sequence available for a conifer or any other gymnosperm. Conifer defence-related genes often group into large families with closely related members. The goals of this study are to assess the feasibility of targeted isolation and sequence assembly of conifer BAC clones containing specific genes from two large gene families, and to characterize large segments of genomic DNA sequence for the first time from a conifer. We used a PCR-based approach to identify BAC clones for two target genes, a terpene synthase (3-carene synthase; 3CAR) and a cytochrome P450 (CYP720B4) from a non-arrayed genomic BAC library of white spruce (Picea glauca). Shotgun genomic fragments isolated from the BAC clones were sequenced to a depth of 15.6- and 16.0-fold coverage, respectively. Assembly and manual curation yielded sequence scaffolds of 172 kbp (3CAR) and 94 kbp (CYP720B4) long. Inspection of the genomic sequences revealed the intron-exon structures, the putative promoter regions and putative cis-regulatory elements of these genes. Sequences related to transposable elements (TEs), high complexity repeats and simple repeats were prevalent and comprised approximately 40% of the sequenced genomic DNA. An in silico simulation of the effect of sequencing depth on the quality of the sequence assembly provides direction for future efforts of conifer genome sequencing. We report the first targeted cloning, sequencing, assembly, and annotation of large segments of genomic DNA from a conifer. We demonstrate that genomic BAC clones for individual members of multi-member gene families can be isolated in a gene-specific fashion. The

Fractalkine overexpression suppresses tau pathology in a mouse model of tauopathy.

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Nash, Kevin R; Lee, Daniel C; Hunt, Jerry B; Morganti, Josh M; Selenica, Maj-Linda; Moran, Peter; Reid, Patrick; Brownlow, Milene; Guang-Yu Yang, Clement; Savalia, Miloni; Gemma, Carmelina; Bickford, Paula C; Gordon, Marcia N; Morgan, David

2013-06-01

Alzheimer's disease is characterized by amyloid plaques, neurofibrillary tangles, glial activation, and neurodegeneration. In mouse models, inflammatory activation of microglia accelerates tau pathology. The chemokine fractalkine serves as an endogenous neuronal modulator to quell microglial activation. Experiments with fractalkine receptor null mice suggest that fractalkine signaling diminishes tau pathology, but exacerbates amyloid pathology. Consistent with this outcome, we report here that soluble fractalkine overexpression using adeno-associated viral vectors significantly reduced tau pathology in the rTg4510 mouse model of tau deposition. Furthermore, this treatment reduced microglial activation and appeared to prevent neurodegeneration normally found in this model. However, in contrast to studies with fractalkine receptor null mice, parallel studies in an APP/PS1 model found no effect of increased fractalkine signaling on amyloid deposition. These data argue that agonism at fractalkine receptors might be an excellent target for therapeutic intervention in tauopathies, including those associated with amyloid deposition. Copyright © 2013 Elsevier Inc. All rights reserved.

The Properties of the Massive Star-forming Galaxies with an Outside-in Assembly Mode

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Wang, Enci; Kong, Xu; Wang, Huiyuan; Wang, Lixin; Lin, Lin; Gao, Yulong; Liu, Qing

2017-08-01

Previous findings show that massive ({M}* > {10}10 {M}⊙ ) star-forming (SF) galaxies usually have an “inside-out” stellar mass assembly mode. In this paper, we have for the first time selected a sample of 77 massive SF galaxies with an “outside-in” assembly mode (called the “targeted sample”) from the Mapping Nearby Galaxies at the Apache Point Observatory (MaNGA) survey. For comparison, two control samples are constructed from the MaNGA sample matched in stellar mass: a sample of 154 normal SF galaxies and a sample of 62 quiescent galaxies. In contrast to normal SF galaxies, the targeted galaxies appear to be smoother and more bulge-dominated and have a smaller size and higher concentration, star formation rate, and gas-phase metallicity as a whole. However, they have a larger size and lower concentration than quiescent galaxies. Unlike the normal SF sample, the targeted sample exhibits a slightly positive gradient of the 4000 Å break and a pronounced negative gradient of Hα equivalent width. Furthermore, the median surface mass density profile is between those of the normal SF and quiescent samples, indicating that the gas accretion of quiescent galaxies is not likely to be the main approach for the outside-in assembly mode. Our results suggest that the targeted galaxies are likely in the transitional phase from normal SF galaxies to quiescent galaxies, with rapid ongoing central stellar mass assembly (or bulge growth). We discuss several possible formation mechanisms for the outside-in mass assembly mode.

Pathological jealousy and pathological love: Apples to apples or apples to oranges?

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Stravogiannis, Andrea Lorena da C; Kim, Hyoun S; Sophia, Eglacy C; Sanches, Cíntia; Zilberman, Monica L; Tavares, Hermano

2018-01-01

Pathological jealousy evokes emotions, thoughts, and behaviors that cause damage to social and interpersonal relationships. On the other hand, pathological love is the uncontrollable behavior of caring for a partner that results in neglecting the needs of the self. The aim of the present research was to assess the similarities and differences between the two psychopathologies of love. To this end, thirty-two individuals with pathological jealousy and 33 individuals with pathological love were compared on demographics, aspects of romantic relationship (jealousy, satisfaction, love style), psychiatric co-morbidities, personality and psychological characteristics (e.g., impulsivity). In a univariate analysis individuals with pathological jealousy were more likely to be in a current relationship and reported greater satisfaction. The avoidant attachment and the ludus love style were associated with pathological jealousy whereas the secure attachment and agape love style was associated with pathological love. Almost three-quarters (72.3%) of the sample met criteria for a current psychiatric disorder, however no differences emerged between the pathological jealousy and pathological love groups. In a binary logistic regression, relationship status and impairments in parenting significantly differentiated the groups. While both pathological jealousy and pathological love share similarities, they also present with unique differences, which may have important treatment implications. Copyright © 2017 Elsevier B.V. All rights reserved.

Pericentriolar Targeting of the Mouse Mammary Tumor Virus GAG Protein.

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Guangzhi Zhang

Full Text Available The Gag protein of the mouse mammary tumor virus (MMTV is the chief determinant of subcellular targeting. Electron microscopy studies show that MMTV Gag forms capsids within the cytoplasm and assembles as immature particles with MMTV RNA and the Y box binding protein-1, required for centrosome maturation. Other betaretroviruses, such as Mason-Pfizer monkey retrovirus (M-PMV, assemble adjacent to the pericentriolar region because of a cytoplasmic targeting and retention signal in the Matrix protein. Previous studies suggest that the MMTV Matrix protein may also harbor a similar cytoplasmic targeting and retention signal. Herein, we show that a substantial fraction of MMTV Gag localizes to the pericentriolar region. This was observed in HEK293T, HeLa human cell lines and the mouse derived NMuMG mammary gland cells. Moreover, MMTV capsids were observed adjacent to centrioles when expressed from plasmids encoding either MMTV Gag alone, Gag-Pro-Pol or full-length virus. We found that the cytoplasmic targeting and retention signal in the MMTV Matrix protein was sufficient for pericentriolar targeting, whereas mutation of the glutamine to alanine at position 56 (D56/A resulted in plasma membrane localization, similar to previous observations from mutational studies of M-PMV Gag. Furthermore, transmission electron microscopy studies showed that MMTV capsids accumulate around centrioles suggesting that, similar to M-PMV, the pericentriolar region may be a site for MMTV assembly. Together, the data imply that MMTV Gag targets the pericentriolar region as a result of the MMTV cytoplasmic targeting and retention signal, possibly aided by the Y box protein-1 required for the assembly of centrosomal microtubules.

New developments in digital pathology: from telepathology to virtual pathology laboratory.

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Kayser, Klaus; Kayser, Gian; Radziszowski, Dominik; Oehmann, Alexander

2004-01-01

To analyse the present status and future development of computerized diagnostic pathology in terms of work-flow integrative telepathology and virtual laboratory. Telepathology has left its childhood. The technical development of telepathology is mature, in contrast to that of virtual pathology. Two kinds of virtual pathology laboratories are emerging: a) those with distributed pathologists and distributed (>=1) laboratories associated to individual biopsy stations/surgical theatres, and b) distributed pathologists working in a centralized laboratory. Both are under technical development. Telepathology can be used for e-learning and e-training in pathology, as exemplarily demonstrated on Digital Lung Pathology Pathology (www.pathology-online.org). A virtual pathology institution (mode a) accepts a complete case with the patient's history, clinical findings, and (pre-selected) images for first diagnosis. The diagnostic responsibility is that of a conventional institution. The internet serves as platform for information transfer, and an open server such as the iPATH (http://telepath.patho.unibas.ch) for coordination and performance of the diagnostic procedure. The size of images has to be limited, and usual different magnifications have to be used. A group of pathologists is "on duty", or selects one member for a predefined duty period. The diagnostic statement of the pathologist(s) on duty is retransmitted to the sender with full responsibility. First experiences of a virtual pathology institution group working with the iPATH server (Dr. L. Banach, Dr. G. Haroske, Dr. I. Hurwitz, Dr. K. Kayser, Dr. K.D. Kunze, Dr. M. Oberholzer,) working with a small hospital of the Salomon islands are promising. A centralized virtual pathology institution (mode b) depends upon the digitalisation of a complete slide, and the transfer of large sized images to different pathologists working in one institution. The technical performance of complete slide digitalisation is still under

EAST machine assembly and its measurement system

International Nuclear Information System (INIS)

Wu, S.T.

2005-01-01

The EAST (HT-7U) superconducting tokamak consists of a superconducting poloidal field magnet system, a toroidal field magnet system, a vacuum vessel and in-vessel components, thermal shields and a cryostat vessel. The main parts of the machine have been delivered to ASIPP (Institute of Plasma Physics, Chinese Academy of Sciences) successionally from 2003. For its complicated constitution and precise requirement, a reasonable assembly procedure and measurement technique should be defined carefully. Before the assembly procedure, a reference frame has been set up with reference fiducial targets on the wall of the test hall by an industrial measurement system. After the torus of TF coils is formed, a new reference frame will be set up from the position of the TF torus. The vacuum vessel with all inner parts will be installed with reference of the new reference frame. The big size and mass of components, special configuration of the superconducting machine with tight installation tolerances of the HT-7U (EAST) machine result in complicated assembly procedure. The procedure had begun with the installation of the support frame and the base of cryostat vessel last year. In this paper, the requirements of the assembly precise for some key components of the machine are described. The reference frame for the assembly and maintenance is explained. The assembly procedure is introduced

Focusing on RISC assembly in mammalian cells.

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Hong, Junmei; Wei, Na; Chalk, Alistair; Wang, Jue; Song, Yutong; Yi, Fan; Qiao, Ren-Ping; Sonnhammer, Erik L L; Wahlestedt, Claes; Liang, Zicai; Du, Quan

2008-04-11

RISC (RNA-induced silencing complex) is a central protein complex in RNAi, into which a siRNA strand is assembled to become effective in gene silencing. By using an in vitro RNAi reaction based on Drosophila embryo extract, an asymmetric model was recently proposed for RISC assembly of siRNA strands, suggesting that the strand that is more loosely paired at its 5' end is selectively assembled into RISC and results in target gene silencing. However, in the present study, we were unable to establish such a correlation in cell-based RNAi assays, as well as in large-scale RNAi data analyses. This suggests that the thermodynamic stability of siRNA is not a major determinant of gene silencing in mammalian cells. Further studies on fork siRNAs showed that mismatch at the 5' end of the siRNA sense strand decreased RISC assembly of the antisense strand, but surprisingly did not increase RISC assembly of the sense strand. More interestingly, measurements of melting temperature showed that the terminal stability of fork siRNAs correlated with the positions of the mismatches, but not gene silencing efficacy. In summary, our data demonstrate that there is no definite correlation between siRNA stability and gene silencing in mammalian cells, which suggests that instead of thermodynamic stability, other features of the siRNA duplex contribute to RISC assembly in RNAi.

Focusing on RISC assembly in mammalian cells

International Nuclear Information System (INIS)

Hong Junmei; Wei Na; Chalk, Alistair; Wang Jue; Song, Yutong; Yi Fan; Qiao Renping; Sonnhammer, Erik L.L.; Wahlestedt, Claes; Liang Zicai; Du, Quan

2008-01-01

RISC (RNA-induced silencing complex) is a central protein complex in RNAi, into which a siRNA strand is assembled to become effective in gene silencing. By using an in vitro RNAi reaction based on Drosophila embryo extract, an asymmetric model was recently proposed for RISC assembly of siRNA strands, suggesting that the strand that is more loosely paired at its 5' end is selectively assembled into RISC and results in target gene silencing. However, in the present study, we were unable to establish such a correlation in cell-based RNAi assays, as well as in large-scale RNAi data analyses. This suggests that the thermodynamic stability of siRNA is not a major determinant of gene silencing in mammalian cells. Further studies on fork siRNAs showed that mismatch at the 5' end of the siRNA sense strand decreased RISC assembly of the antisense strand, but surprisingly did not increase RISC assembly of the sense strand. More interestingly, measurements of melting temperature showed that the terminal stability of fork siRNAs correlated with the positions of the mismatches, but not gene silencing efficacy. In summary, our data demonstrate that there is no definite correlation between siRNA stability and gene silencing in mammalian cells, which suggests that instead of thermodynamic stability, other features of the siRNA duplex contribute to RISC assembly in RNAi

Meningioangiomatosis: MR imaging and pathological correlation in two cases

International Nuclear Information System (INIS)

Kim, W.-Y.; Kim, W.S.; Cheon, J.-E.; Yeon, K.M.; Kim, I.-O.

2002-01-01

Meningioangiomatosis is a rare, benign neoplastic disorder involving the cortex and leptomeninges. The pathological findings are characterised by proliferation of meningothelial cells and leptomeningeal vessels and calcifications within the mass. We experienced two cases of pathologically confirmed meningioangiomatosis, one as a solitary cortical mass with calcification and the other as a cortical lesion manifested as extensive intracranial haemorrhage. On MRI, the first case showed an isointense cortical mass in the left frontal lobe and homogeneous enhancement on the contrast-enhanced study. The second case showed a target-like lesion with a peripheral dark signal rim on T2-weighted images accompanied by extensive haemorrhage in the adjacent frontal lobe and lateral ventricles. (orig.)

HIV-1 matrix dependent membrane targeting is regulated by Gag mRNA trafficking.

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Jing Jin

Full Text Available Retroviral Gag polyproteins are necessary and sufficient for virus budding. Productive HIV-1 Gag assembly takes place at the plasma membrane. However, little is known about the mechanisms by which thousands of Gag molecules are targeted to the plasma membrane. Using a bimolecular fluorescence complementation (BiFC assay, we recently reported that the cellular sites and efficiency of HIV-1 Gag assembly depend on the precise pathway of Gag mRNA export from the nucleus, known to be mediated by Rev. Here we describe an assembly deficiency in human cells for HIV Gag whose expression depends on hepatitis B virus (HBV post-transcriptional regulatory element (PRE mediated-mRNA nuclear export. PRE-dependent HIV Gag expressed well in human cells, but assembled with slower kinetics, accumulated intracellularly, and failed to associate with a lipid raft compartment where the wild-type Rev-dependent HIV-1 Gag efficiently assembles. Surprisingly, assembly and budding of PRE-dependent HIV Gag in human cells could be rescued in trans by co-expression of Rev-dependent Gag that provides correct membrane targeting signals, or in cis by replacing HIV matrix (MA with other membrane targeting domains. Taken together, our results demonstrate deficient membrane targeting of PRE-dependent HIV-1 Gag and suggest that HIV MA function is regulated by the trafficking pathway of the encoding mRNA.

Evaluation of GRCh38 and de novo haploid genome assemblies demonstrates the enduring quality of the reference assembly.

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Schneider, Valerie A; Graves-Lindsay, Tina; Howe, Kerstin; Bouk, Nathan; Chen, Hsiu-Chuan; Kitts, Paul A; Murphy, Terence D; Pruitt, Kim D; Thibaud-Nissen, Françoise; Albracht, Derek; Fulton, Robert S; Kremitzki, Milinn; Magrini, Vincent; Markovic, Chris; McGrath, Sean; Steinberg, Karyn Meltz; Auger, Kate; Chow, William; Collins, Joanna; Harden, Glenn; Hubbard, Timothy; Pelan, Sarah; Simpson, Jared T; Threadgold, Glen; Torrance, James; Wood, Jonathan M; Clarke, Laura; Koren, Sergey; Boitano, Matthew; Peluso, Paul; Li, Heng; Chin, Chen-Shan; Phillippy, Adam M; Durbin, Richard; Wilson, Richard K; Flicek, Paul; Eichler, Evan E; Church, Deanna M

2017-05-01

The human reference genome assembly plays a central role in nearly all aspects of today's basic and clinical research. GRCh38 is the first coordinate-changing assembly update since 2009; it reflects the resolution of roughly 1000 issues and encompasses modifications ranging from thousands of single base changes to megabase-scale path reorganizations, gap closures, and localization of previously orphaned sequences. We developed a new approach to sequence generation for targeted base updates and used data from new genome mapping technologies and single haplotype resources to identify and resolve larger assembly issues. For the first time, the reference assembly contains sequence-based representations for the centromeres. We also expanded the number of alternate loci to create a reference that provides a more robust representation of human population variation. We demonstrate that the updates render the reference an improved annotation substrate, alter read alignments in unchanged regions, and impact variant interpretation at clinically relevant loci. We additionally evaluated a collection of new de novo long-read haploid assemblies and conclude that although the new assemblies compare favorably to the reference with respect to continuity, error rate, and gene completeness, the reference still provides the best representation for complex genomic regions and coding sequences. We assert that the collected updates in GRCh38 make the newer assembly a more robust substrate for comprehensive analyses that will promote our understanding of human biology and advance our efforts to improve health. © 2017 Schneider et al.; Published by Cold Spring Harbor Laboratory Press.

Hierarchical self-assembly of magnetic nanoclusters for theranostics: Tunable size, enhanced magnetic resonance imagability, and controlled and targeted drug delivery.

Science.gov (United States)

Nguyen, Dai Hai; Lee, Jung Seok; Choi, Jong Hoon; Park, Kyung Min; Lee, Yunki; Park, Ki Dong

2016-04-15

Nanoparticle-based imaging and therapy are of interest for theranostic nanomedicine. In particular, superparamagnetic iron oxide (SPIO) nanoparticles (NPs) have attracted much attention in cancer imaging, diagnostics, and treatment because of their superior imagability and biocompatibility (approved by the Food and Drug Administration). Here, we developed SPIO nanoparticles (NPs) that self-assembled into magnetic nanoclusters (SAMNs) in aqueous environments as a theranostic nano-system. To generate multi-functional SPIO NPs, we covalently conjugated β-cyclodextrin (β-CD) to SPIO NPs using metal-adhesive dopamine groups. Polyethylene glycol (PEG) and paclitaxel (PTX) were hosted in the β-CD cavity through high affinity complexation. The core-shell structure of the magnetic nanoclusters was elucidated based on the condensed SPIO core and a PEG shell using electron microscopy and the composition was analyzed by thermogravimetric analysis (TGA). Our results indicate that nanocluster size could be readily controlled by changing the SPIO/PEG ratio in the assemblies. Interestingly, we observed a significant enhancement in magnetic resonance contrast due to the large cluster size and dense iron oxide core. In addition, tethering a tumor-targeting peptide to the SAMNs enhanced their uptake into tumor cells. PTX was efficiently loaded into β-CDs and released in a controlled manner when exposed to competitive guest molecules. These results strongly indicate that the SAMNs developed in this study possess great potential for application in image-guided cancer chemotherapy. In this study, we developed multi-functional SPIO NPs that self-assembled into magnetic nanoclusters (SAMNs) in aqueous conditions as a theranostic nano-system. The beta-cyclodextrin (β-CD) was immobilized on the surfaces of SPIO NPs and RGD-conjugated polyethylene glycol (PEG) and paclitaxel (PTX) were hosted in the β-CD cavity through high affinity complexation. We found that nanocluster size could be

The Gerda Phase II detector assembly

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Bode, Tobias; Schoenert, Stefan [Physik-Department E15, Technische Universitaet Muenchen (Germany); Schwingenheuer, Bernhard [Max-Planck-Institut fuer Kernphysik, Heidelberg (Germany); Collaboration: GERDA-Collaboration

2013-07-01

Phase II of the Gerda (Germanium Detector Array) experiment will continue the search for the neutrinoless double beta decay (0νββ) of {sup 76}Ge. Prerequisites for Phase II are an increased target mass and a reduced background index of < 10 {sup -3} cts/(keV.kg.yr). Major hardware upgrades to achieve these requirements are scheduled for 2013. They include the deployment of a new radio pure low mass detector assembly. The structural properties of available radio-pure materials and reduction of mass necessitate a change of the electrical contacting used to bias and read-out the detectors. The detector assembly design and the favored contacting solution are presented.

A Cryogenic Infrared Calibration Target

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Wollack, E. J.; Kinzer, R. E., Jr.; Rinehart, S. A.

2014-01-01

A compact cryogenic calibration target is presented that has a peak diffuse reflectance, R target. The resulting target assembly is lightweight, has a low-geometric profile, and has survived repeated thermal cycling from room temperature to approx.4 K. Basic design considerations, governing equations, and test data for realizing the structure described are provided. The optical properties of selected absorptive materials-Acktar Fractal Black, Aeroglaze Z306, and Stycast 2850 FT epoxy loaded with stainless steel powder-are characterized and presented

Interaction of nucleosome assembly proteins abolishes nuclear localization of DGK{zeta} by attenuating its association with importins

Energy Technology Data Exchange (ETDEWEB)

Okada, Masashi; Hozumi, Yasukazu [Department of Anatomy and Cell Biology, Yamagata University School of Medicine, Yamagata 990-9585 (Japan); Ichimura, Tohru [Department of Chemistry, Graduate School of Sciences and Engineering, Tokyo Metropolitan University, Hachioji 192-0397 (Japan); Tanaka, Toshiaki; Hasegawa, Hiroshi; Yamamoto, Masakazu; Takahashi, Nobuya [Department of Anatomy and Cell Biology, Yamagata University School of Medicine, Yamagata 990-9585 (Japan); Iseki, Ken [Department of Emergency and Critical Care Medicine, Yamagata University School of Medicine, Yamagata 990-9585 (Japan); Yagisawa, Hitoshi [Laboratory of Biological Signaling, Graduate School of Life Science, University of Hyogo, Hyogo 678-1297 (Japan); Shinkawa, Takashi; Isobe, Toshiaki [Department of Chemistry, Graduate School of Sciences and Engineering, Tokyo Metropolitan University, Hachioji 192-0397 (Japan); Goto, Kaoru, E-mail: kgoto@med.id.yamagata-u.ac.jp [Department of Anatomy and Cell Biology, Yamagata University School of Medicine, Yamagata 990-9585 (Japan)

2011-12-10

Diacylglycerol kinase (DGK) is involved in the regulation of lipid-mediated signal transduction through the metabolism of a second messenger diacylglycerol. Of the DGK family, DGK{zeta}, which contains a nuclear localization signal, localizes mainly to the nucleus but translocates to the cytoplasm under pathological conditions. However, the detailed mechanism of translocation and its functional significance remain unclear. To elucidate these issues, we used a proteomic approach to search for protein targets that interact with DGK{zeta}. Results show that nucleosome assembly protein (NAP) 1-like 1 (NAP1L1) and NAP1-like 4 (NAP1L4) are identified as novel DGK{zeta} binding partners. NAP1Ls constitutively shuttle between the nucleus and the cytoplasm in transfected HEK293 cells. The molecular interaction of DGK{zeta} and NAP1Ls prohibits nuclear import of DGK{zeta} because binding of NAP1Ls to DGK{zeta} blocks import carrier proteins, Qip1 and NPI1, to interact with DGK{zeta}, leading to cytoplasmic tethering of DGK{zeta}. In addition, overexpression of NAP1Ls exerts a protective effect against doxorubicin-induced cytotoxicity. These findings suggest that NAP1Ls are involved in a novel molecular basis for the regulation of nucleocytoplasmic shuttling of DGK{zeta} and provide a clue to examine functional significance of its translocation under pathological conditions.

VAGUE: a graphical user interface for the Velvet assembler.

Science.gov (United States)

Powell, David R; Seemann, Torsten

2013-01-15

Velvet is a popular open-source de novo genome assembly software tool, which is run from the Unix command line. Most of the problems experienced by new users of Velvet revolve around constructing syntactically and semantically correct command lines, getting input files into acceptable formats and assessing the output. Here, we present Velvet Assembler Graphical User Environment (VAGUE), a multi-platform graphical front-end for Velvet. VAGUE aims to make sequence assembly accessible to a wider audience and to facilitate better usage amongst existing users of Velvet. VAGUE is implemented in JRuby and targets the Java Virtual Machine. It is available under an open-source GPLv2 licence from http://www.vicbioinformatics.com/. torsten.seemann@monash.edu.

Structure and Pathology of Tau Protein in Alzheimer Disease

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Michala Kolarova

2012-01-01

Full Text Available Alzheimer's disease (AD is the most common type of dementia. In connection with the global trend of prolonging human life and the increasing number of elderly in the population, the AD becomes one of the most serious health and socioeconomic problems of the present. Tau protein promotes assembly and stabilizes microtubules, which contributes to the proper function of neuron. Alterations in the amount or the structure of tau protein can affect its role as a stabilizer of microtubules as well as some of the processes in which it is implicated. The molecular mechanisms governing tau aggregation are mainly represented by several posttranslational modifications that alter its structure and conformational state. Hence, abnormal phosphorylation and truncation of tau protein have gained attention as key mechanisms that become tau protein in a pathological entity. Evidences about the clinicopathological significance of phosphorylated and truncated tau have been documented during the progression of AD as well as their capacity to exert cytotoxicity when expressed in cell and animal models. This paper describes the normal structure and function of tau protein and its major alterations during its pathological aggregation in AD.

Fluorescence diagnosis of pre-invasive cervical pathology

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I. P. Aminodova

2015-01-01

Full Text Available Results of local fluorescence spectroscopy in 185 women with underlying and pre-invasive disease of cervix and high-risk HPV infection are represented. Fluorescence study was performed 2h after intravenous injection of fotoditazin in a dose of 1 mg/kg (wavelength 636.5 nm. Accumulation of the photosensitizer was estimated by diagnostic parameter (DP value, calculated as mean value of fluorescence scaled to each type of tissue. For normal tissues DP accounted for 0.6±0.4, showing accumulation of the photosensitizer. According to the study the medication did not also accumulate in retention cysts (DP 0.3±0.1, explaining low efficiency of photodynamic therapy for this pathology. The accumulation of fotoditazin depends significantly on type of pathologic tissue. In patients with inflammation, leukoplakia and CIN I accumulation of the photosensitizer in pathologic foci was negligible: DP accounted for 1.7±0.2, 1.8±0.2 and 2.1±0.3, respectively. In sites of endometriosis and CIN II DP was significantly higher and accounted for 8.3±2.1 and 14.1±4.1, respectively. The greatest accumulation of the photosensitizer was registered in sites of CIN III, squamous cell carcinoma and adenocarcinoma. Though DP value for these pathologies had almost no difference and accounted for 23.1±4.7, 22.7±1.8 and 23.3±1.4, respectively. For fluorescence diagnosis of severe dysplasia in 48% of patients borders of fluorescence regions were beyond lesions detected for extended colposcopy with additional areas of fluorescence. Targeted biopsy of these regions proved pathology in all patients: CIN II, CIN III, mild dysplasia or CIS. Thus, local spectroscopy allows to diagnosis multifocal lesions on cervix, to define correctly borders of lesion and consider excisional biopsy in-time.  

Correlation of magnetic resonance imaging findings of spinal intradural extramedullary schwannomas with pathologic findings

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Kim, Yeo Ju; Park, In Suh; Yoon, Seung Hwan; Choi, Suk Jin; Kim, Youn Jeong; Kang, Young Hye; Lee, Ha Young; Kim, Woo Chul; Han, Jun Gu; Cho, Soon Gu [Inha University Hospital, Incheon (Korea, Republic of)

2015-06-15

To evaluate the magnetic resonance imaging (MRI) findings of spinal intradural extramedullary schwannomas with pathologic correlation and to determine whether these schwannomas share the imaging features of schwannomas in the peripheral nerves. The MRIs of 17 cases of pathologically proven spinal intradural extramedullary schwannomas were reviewed retrospectively, and cystic changes, enhancement, and intratumoral hemorrhage of the tumors were evaluated. Imaging features known to be common findings of schwannoma in the peripheral nerves, such as encapsulation, the target sign, the fascicular sign, and visualization of entering or exiting nerve rootlets, were also evaluated. The histopathology of the tumors was correlated with the MRI findings. Cystic changes were detected in 14 cases by MRI and in 16 cases by pathology. The most common pattern of enhancement was a thick peripheral septal pattern (70.59%). Intratumoral hemorrhage was detected in four cases on MRI, but in all cases on pathology. Encapsulation was observed in all cases. The fascicular sign was seen in only four cases, and thickening of an exiting rootlet was visualized in one case. None of the cases showed the target sign. Spinal intradural extramedullary schwannomas were typical encapsulated cystic tumors and had few imaging features of schwannomas in the peripheral nerves.

Shortened outage duration and increased safety with head assembly upgrade packages

International Nuclear Information System (INIS)

Leanne, M.; Lisien, P.E.; Plute, K.; Duran, J.

2007-01-01

To significantly reduce outage critical path duration and personnel radiation exposure, and to increase personnel safety, Westinghouse Electric Co., LLC has designed and installed upgrades to the existing head assemblies of operating pressurized water reactors. These upgrades are known as Head Assembly Upgrade Packages (HAUPs) or Simplified Head Assemblies (SHAs). Custom configurations are created from a set of standard elements to optimize the design for each unique containment, head assembly configuration, and licensing basis. Two primary options are available for implementation: a full HAUP or targeted component and system upgrades. Plants may achieve much of the outage savings, dose reduction, and safety improvements even with a more limited hardware scope. A range of improvements can be offered from integral missile shields, to redesigned duct work, radiation shields, and cable layout and connection optimization. The hardware changes are customized to target the scope that adds the most value for a given plant. While combining upgrades with a reactor vessel head (RVH) replacement adds some flexibility, it is not necessary. Some plants have chosen to implement targeted upgrades prior to a replacement RVH outage and then complete the remainder of the full HAUP during the replacement RVH outage. Three-dimensional computer aided design tools are used in the conceptual and detailed design phases to identify and avoid interferences between existing and replacement plant components. State-of-the-art computational fluid dynamics models for control drive mechanism (CDM) cooling systems are used to demonstrate the ability to maintain or improve the original design performance while greatly simplifying the disassembly/re-assembly activities. Likewise, state-of-the-art finite element analysis methods allow optimization of structural components while meeting code limits for design basis accident conditions. (authors)

MicroRNA Dysregulation in Aging and Pathologies of the Skeletal Muscle.

Science.gov (United States)

McCormick, Rachel; Goljanek-Whysall, Katarzyna

2017-01-01

Skeletal muscle is one of the biggest organs of the body with important mechanistic and metabolic functions. Muscle homeostasis is controlled by environmental, genetic, and epigenetic factors. Indeed, MiRNAs, small noncoding RNAs robust regulators of gene expression, have and have been shown to regulate muscle homeostasis on several levels: through controlling myogenesis, muscle growth (hypertrophy) and atrophy, as well as interactions of muscle with other tissues. Given the large number of MiRNA target genes and the important role of MiRNAs in most physiological processes and various diseases, MiRNAs may have an enormous potential as therapeutic targets against numerous disorders, including pathologies of muscle. The purpose of this review is to present the current knowledge of the role of MiRNAs in skeletal muscle homeostasis and pathologies and the potential of MiRNAs as therapeutics for skeletal muscle wasting, with particular focus on the age- and disease-related loss of muscle mass and function. © 2017 Elsevier Inc. All rights reserved.

Geometric triangular chiral hexagon crystal-like complexes organization in pathological tissues biological collision order.

Directory of Open Access Journals (Sweden)

Jairo A Díaz

Full Text Available The present study describes and documents self-assembly of geometric triangular chiral hexagon crystal like complex organizations (GTCHC in human pathological tissues. The authors have found this architectural geometric expression at macroscopic and microscopic levels mainly in cancer processes. This study is based essentially on macroscopic and histopathologic analyses of 3000 surgical specimens: 2600 inflammatory lesions and 400 malignant tumours. Geometric complexes identified photographically at macroscopic level were located in the gross surgical specimen, and these areas were carefully dissected. Samples were taken to carry out histologic analysis. Based on the hypothesis of a collision genesis mechanism and because it is difficult to carry out an appropriate methodological observation in biological systems, the authors designed a model base on other dynamic systems to obtain indirect information in which a strong white flash wave light discharge, generated by an electronic device, hits over the lines of electrical conductance structured in helicoidal pattern. In their experimental model, the authors were able to reproduce and to predict polarity, chirality, helicoid geometry, triangular and hexagonal clusters through electromagnetic sequential collisions. They determined that similar events among constituents of extracelular matrix which drive and produce piezoelectric activity are responsible for the genesis of GTCHC complexes in pathological tissues. This research suggests that molecular crystals represented by triangular chiral hexagons derived from a collision-attraction event against collagen type I fibrils emerge at microscopic and macroscopic scales presenting a lateral assembly of each side of hypertrophy helicoid fibers, that represent energy flow in cooperative hierarchically chiral electromagnetic interaction in pathological tissues and arises as a geometry of the equilibrium in perturbed biological systems. Further

Geometric triangular chiral hexagon crystal-like complexes organization in pathological tissues biological collision order.

Science.gov (United States)

Díaz, Jairo A; Jaramillo, Natalia A; Murillo, Mauricio F

2007-12-12

The present study describes and documents self-assembly of geometric triangular chiral hexagon crystal like complex organizations (GTCHC) in human pathological tissues. The authors have found this architectural geometric expression at macroscopic and microscopic levels mainly in cancer processes. This study is based essentially on macroscopic and histopathologic analyses of 3000 surgical specimens: 2600 inflammatory lesions and 400 malignant tumours. Geometric complexes identified photographically at macroscopic level were located in the gross surgical specimen, and these areas were carefully dissected. Samples were taken to carry out histologic analysis. Based on the hypothesis of a collision genesis mechanism and because it is difficult to carry out an appropriate methodological observation in biological systems, the authors designed a model base on other dynamic systems to obtain indirect information in which a strong white flash wave light discharge, generated by an electronic device, hits over the lines of electrical conductance structured in helicoidal pattern. In their experimental model, the authors were able to reproduce and to predict polarity, chirality, helicoid geometry, triangular and hexagonal clusters through electromagnetic sequential collisions. They determined that similar events among constituents of extracelular matrix which drive and produce piezoelectric activity are responsible for the genesis of GTCHC complexes in pathological tissues. This research suggests that molecular crystals represented by triangular chiral hexagons derived from a collision-attraction event against collagen type I fibrils emerge at microscopic and macroscopic scales presenting a lateral assembly of each side of hypertrophy helicoid fibers, that represent energy flow in cooperative hierarchically chiral electromagnetic interaction in pathological tissues and arises as a geometry of the equilibrium in perturbed biological systems. Further interdisciplinary studies must

Nuclear localization of Schizosaccharomyces pombe Mcm2/Cdc19p requires MCM complex assembly.

Science.gov (United States)

Pasion, S G; Forsburg, S L

1999-12-01

The minichromosome maintenance (MCM) proteins MCM2-MCM7 are conserved eukaryotic replication factors that assemble in a heterohexameric complex. In fission yeast, these proteins are nuclear throughout the cell cycle. In studying the mechanism that regulates assembly of the MCM complex, we analyzed the cis and trans elements required for nuclear localization of a single subunit, Mcm2p. Mutation of any single mcm gene leads to redistribution of wild-type MCM subunits to the cytoplasm, and this redistribution depends on an active nuclear export system. We identified the nuclear localization signal sequences of Mcm2p and showed that these are required for nuclear targeting of other MCM subunits. In turn, Mcm2p must associate with other MCM proteins for its proper localization; nuclear localization of MCM proteins thus requires assembly of MCM proteins in a complex. We suggest that coupling complex assembly to nuclear targeting and retention ensures that only intact heterohexameric MCM complexes remain nuclear.

RISC assembly: Coordination between small RNAs and Argonaute proteins.

Science.gov (United States)

Kobayashi, Hotaka; Tomari, Yukihide

2016-01-01

Non-coding RNAs generally form ribonucleoprotein (RNP) complexes with their partner proteins to exert their functions. Small RNAs, including microRNAs, small interfering RNAs, and PIWI-interacting RNAs, assemble with Argonaute (Ago) family proteins into the effector complex called RNA-induced silencing complex (RISC), which mediates sequence-specific target gene silencing. RISC assembly is not a simple binding between a small RNA and Ago; rather, it follows an ordered multi-step pathway that requires specific accessory factors. Some steps of RISC assembly and RISC-mediated gene silencing are dependent on or facilitated by particular intracellular platforms, suggesting their spatial regulation. In this review, we summarize the currently known mechanisms for RISC assembly of each small RNA class and propose a revised model for the role of the chaperone machinery in the duplex-initiated RISC assembly pathway. This article is part of a Special Issue entitled: Clues to long noncoding RNA taxonomy1, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa. Copyright © 2015 Elsevier B.V. All rights reserved.

Calculation of Savannah River K Reactor Mark-22 assembly LOCA/ECS power limits

International Nuclear Information System (INIS)

Fischer, S.R.; Farman, R.F.; Birdsell, S.A.

1992-01-01

This paper summarizes the results of TRAC-PF1/MOD3 calculations of Mark-22 fuel assembly of loss-of-coolant accident/emergency cooling system (LOCA/ECS) power limits for the Savannah River Site (SRS) K Reactor. This effort was part of a larger effort undertaken by the Los Alamos National Laboratory for the US Department of Energy to perform confirmatory power limits calculations for the SRS K Reactor. A method using a detailed three-dimensional (3D) TRAC model of the Mark-22 fuel assembly was developed to compute LOCA/ECS power limits. Assembly power was limited to ensure that no point on the fuel assembly walls would exceed the local saturation temperature. The detailed TRAC model for the Mark-22 assembly consisted of three concentric 3D vessel components which simulated the two targets, two fuel tubes, and three main flow channels of the fuel assembly. The model included 100% eccentricity between the assembly annuli and a 20% power tilt. Eccentricity in the radial alignment of the assembly annuli arises because axial spacer ribs that run the length of the fuel and targets are used. Wall-shear, interfacial-shear, and wall heat-transfer correlations were developed and implemented in TRAC-PF1/MOD3 specifically for modeling flow and heat transfer in the narrow ribbed annuli encountered in the Mark-22 fuel assembly design. We established the validity of these new constitutive models using separate-effects benchmarks. TRAC system calculations of K Reactor indicated that the limiting ECS-phase accident is a double-ended guillonite break in a process water line at the pump discharge (i.e., a PDLOCA). The fuel assembly with the minimum cooling potential is identified from this system calculation. Detailed assembly calculations then were performed using appropriate boundary conditions obtained from this limiting system LOCA. Coolant flow rates and pressure boundary conditions were obtained from this system calculation and applied to the detailed assembly model

Cryogenic polarized-target facility. Progress report, July 1, 1981-June 30, 1982

International Nuclear Information System (INIS)

Gould, C.R.; Haase, D.G.

1982-01-01

The goal of this three-year research project is to build a cryogenically polarized target facility for measuring total neutron cross sections for polarized neutrons incident on polarized nuclei. The components of the system have been assembled at TUNL during the current contract period. These include the dilution-refrigerator support assembly, the dilution-refrigerator itself, the dewar, the beam line, the shielding cave for the neutron source, and the neutron-detector shield and rolling-cart assembly. The dilution refrigerator is presently undergoing testing at liquid-nitrogen and liquid-helium temperatures. Experiments with aluminum and copper targets are scheduled for the coming contract period

Amino Acid Availability Modulates Vacuolar H+-ATPase Assembly*

Science.gov (United States)

Stransky, Laura A.; Forgac, Michael

2015-01-01

The vacuolar H+-ATPase (V-ATPase) is an ATP-dependent proton pump composed of a peripheral ATPase domain (V1) and a membrane-integral proton-translocating domain (V0) and is involved in many normal and disease processes. An important mechanism of regulating V-ATPase activity is reversible assembly of the V1 and V0 domains. Increased assembly in mammalian cells occurs under various conditions and has been shown to involve PI3K. The V-ATPase is necessary for amino acid-induced activation of mechanistic target of rapamycin complex 1 (mTORC1), which is important in controlling cell growth in response to nutrient availability and growth signals. The V-ATPase undergoes amino acid-dependent interactions with the Ragulator complex, which is involved in recruitment of mTORC1 to the lysosomal membrane during amino acid sensing. We hypothesized that changes in the V-ATPase/Ragulator interaction might involve amino acid-dependent changes in V-ATPase assembly. To test this, we measured V-ATPase assembly by cell fractionation in HEK293T cells treated with and without amino acids. V-ATPase assembly increases upon amino acid starvation, and this effect is reversed upon readdition of amino acids. Lysosomes from amino acid-starved cells possess greater V-ATPase-dependent proton transport, indicating that assembled pumps are catalytically active. Amino acid-dependent changes in both V-ATPase assembly and activity are independent of PI3K and mTORC1 activity, indicating the involvement of signaling pathways distinct from those implicated previously in controlling assembly. By contrast, lysosomal neutralization blocks the amino acid-dependent change in assembly and reactivation of mTORC1 after amino acid starvation. These results identify an important new stimulus for controlling V-ATPase assembly. PMID:26378229

Teaching digital pathology: The international school of digital pathology and proposed syllabus

Directory of Open Access Journals (Sweden)

Vincenzo Della Mea

2017-01-01

Full Text Available Digital pathology is an interdisciplinary field where competency in pathology, laboratory techniques, informatics, computer science, information systems, engineering, and even biology converge. This implies that teaching students about digital pathology requires coverage, expertise, and hands-on experience in all these disciplines. With this in mind, a syllabus was developed for a digital pathology summer school aimed at professionals in the aforementioned fields, as well as trainees and doctoral students. The aim of this communication is to share the context, rationale, and syllabus for this school of digital pathology.

Heat-shock protein dysregulation is associated with functional and pathological TDP-43 aggregation

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Chang, Hsiang-Yu; Hou, Shin-Chen; Way, Tzong-Der; Wong, Chi-Huey; Wang, I.-Fan

2013-11-01

Conformational disorders are involved in various neurodegenerative diseases. Reactive oxygen species (ROS) are the major contributors to neurodegenerative disease; however, ROS that affect the structural changes in misfolded disease proteins have yet to be well characterized. Here we demonstrate that the intrinsic propensity of TDP-43 to aggregate drives the assembly of TDP-43-positive stress granules and soluble toxic TDP-43 oligomers in response to a ROS insult via a disulfide crosslinking-independent mechanism. Notably, ROS-induced TDP-43 protein assembly correlates with the dynamics of certain TDP-43-associated chaperones. The heat-shock protein (HSP)-90 inhibitor 17-AAG prevents ROS-induced TDP-43 aggregation, alters the type of TDP-43 multimers and reduces the severity of pathological TDP-43 inclusions. In summary, our study suggests that a common mechanism could be involved in the pathogenesis of conformational diseases that result from HSP dysregulation.

Preliminary results on the cryogenic target for FIREX project

International Nuclear Information System (INIS)

Iwamoto, A.; Maekawa, R.; Mito, T.; Okamoto, M.; Motojima, O.; Nakai, M.; Norimatsu, T.; Nagai, K.

2006-01-01

Preliminary tests on the cryogenic target for the fast ignition realization experiment (FIREX) project has been conducted. A foam shell method is proposed to realize its target design. A foam target consists of three parts: a foam shell, a conical laser guide and a liquid or gas feeder made of glass. The shell is a hollow sphere (500 μm in diameter) with a uniform and thin foam layer (about 20 μm in thickness). Epoxy resin is utilized to assemble the parts into the target. Liquid fuel is fed into the shell by the feeder and is soaked up by the foam material through capillarity. The fuel is then solidified. Regarding target fabrication, one of the concerns is the influence on various thermal contractions from the different materials when it is cooled down to cryogenic environment. This paper describes the result on the validity check at cryogenic environment and the demonstration of H 2 liquefaction using a dummy target instead of the foam target. Judging from these results, the target assembled in the same process as the dummy target is sure to be practicable for the FIREX project. (authors)

Organelle targeting: third level of drug targeting

Directory of Open Access Journals (Sweden)

Sakhrani NM

2013-07-01

Full Text Available Niraj M Sakhrani, Harish PadhDepartment of Cell and Molecular Biology, BV Patel Pharmaceutical Education and Research Development (PERD Centre, Gujarat, IndiaAbstract: Drug discovery and drug delivery are two main aspects for treatment of a variety of disorders. However, the real bottleneck associated with systemic drug administration is the lack of target-specific affinity toward a pathological site, resulting in systemic toxicity and innumerable other side effects as well as higher dosage requirement for efficacy. An attractive strategy to increase the therapeutic index of a drug is to specifically deliver the therapeutic molecule in its active form, not only into target tissue, nor even to target cells, but more importantly, into the targeted organelle, ie, to its intracellular therapeutic active site. This would ensure improved efficacy and minimize toxicity. Cancer chemotherapy today faces the major challenge of delivering chemotherapeutic drugs exclusively to tumor cells, while sparing normal proliferating cells. Nanoparticles play a crucial role by acting as a vehicle for delivery of drugs to target sites inside tumor cells. In this review, we spotlight active and passive targeting, followed by discussion of the importance of targeting to specific cell organelles and the potential role of cell-penetrating peptides. Finally, the discussion will address the strategies for drug/DNA targeting to lysosomes, mitochondria, nuclei and Golgi/endoplasmic reticulum.Keywords: intracellular drug delivery, cancer chemotherapy, therapeutic index, cell penetrating peptides

Deterministic assembly of linear gold nanorod chains as a platform for nanoscale applications

DEFF Research Database (Denmark)

Rey, Antje; Billardon, Guillaume; Loertscher, Emanuel

2013-01-01

target substrate, thus establishing a platform for a variety of nanoscale electronic and optical applications ranging from molecular electronics to optical and plasmonic devices. As a first example, electrical measurements are performed on contacted gold nanorod chains before and after their immersion......We demonstrate a method to assemble gold nanorods highly deterministically into a chain formation by means of directed capillary assembly. This way we achieved straight chains consisting of end-to-end aligned gold nanorods assembled in one specific direction with well-controlled gaps of similar...... to 6 nm between the individual constituents. We determined the conditions for optimum quality and yield of nanorod chain assembly by investigating the influence of template dimensions and assembly temperature. In addition, we transferred the gold nanorod chains from the assembly template onto a Si/SiO2...

Septin functions in organ system physiology and pathology.

Science.gov (United States)

Dolat, Lee; Hu, Qicong; Spiliotis, Elias T

2014-02-01

Human septins comprise a family of 13 genes that encode for >30 protein isoforms with ubiquitous and tissue-specific expressions. Septins are GTP-binding proteins that assemble into higher-order oligomers and filamentous polymers, which associate with cell membranes and the cytoskeleton. In the last decade, much progress has been made in understanding the biochemical properties and cell biological functions of septins. In parallel, a growing number of studies show that septins play important roles for the development and physiology of specific tissues and organs. Here, we review the expression and function of septins in the cardiovascular, immune, nervous, urinary, digestive, respiratory, endocrine, reproductive, and integumentary organ systems. Furthermore, we discuss how the tissue-specific functions of septins relate to the pathology of human diseases that arise from aberrations in septin expression.

The Danish Pathology Register

DEFF Research Database (Denmark)

Bjerregaard, Beth; Larsen, Ole B

2011-01-01

The National Board of Health, Denmark in 1997 published guidelines for reporting of pathology data and the Danish Pathology Register (DPR) was established.......The National Board of Health, Denmark in 1997 published guidelines for reporting of pathology data and the Danish Pathology Register (DPR) was established....

Pathological gambling and criminality.

Science.gov (United States)

Folino, Jorge Oscar; Abait, Patricia Estela

2009-09-01

To review research results on the relationship between pathological gambling and criminality, published in 2007 and 2008, in English and in Spanish. An important association between pathological gambling and criminality was confirmed in populations of anonymous gamblers, helpline callers and substance abusers. Helplines provide a timely service to gamblers who have not reached the maximum stages in the development of a pathological gambling pattern. Pathological gambling is associated with violence in couples and dysfunctional families. Inversely, violence is also an antecedent promoting vulnerability toward pathological gambling. Impulsiveness shows diverse relationships with pathological gambling and violence as well. A pathological gambler's involvement in crime is exceptionally considered without responsibility by justice, but it may be an indicator of the disorder severity and the need for special therapeutic tactics. While reviewing the present study, research work was published that contributed to a better understanding of the association between pathological gambling and criminality and went further into their complex relationship and the formulation of explanatory models related to impulsiveness.

Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains

Science.gov (United States)

Boluda, Susana; Iba, Michiyo; Zhang, Bin; Raible, Kevin M.; Lee, Virginia M-Y.; Trojanowski, John Q.

2015-01-01

Filamentous tau pathologies are hallmark lesions of several neurodegenerative tauopathies including Alzheimer’s disease (AD) and corticobasal degeneration (CBD) which show cell type-specific and topographically distinct tau inclusions. Growing evidence supports templated transmission of tauopathies through functionally interconnected neuroanatomical pathways suggesting that different self-propagating strains of pathological tau could account for the diverse manifestations of neurodegenerative tauopathies. Here, we describe the rapid and distinct cell type-specific spread of pathological tau following intracerebral injections of CBD or AD brain extracts enriched in pathological tau (designated CBD-Tau and AD-Tau, respectively) in young human mutant P301S tau transgenic (Tg) mice (line PS19) ~6–9 months before they show onset of mutant tau transgene-induced tau pathology. At 1 month post-injection of CBD-Tau, tau inclusions developed predominantly in oligodendrocytes of the fimbria and white matter near the injection sites with infrequent intraneuronal tau aggregates. In contrast, injections of AD-Tau in young PS19 mice induced tau pathology predominantly in neuronal perikarya with little or no oligodendrocyte involvement 1 month post-injection. With longer post-injection survival intervals of up to 6 months, CBD-Tau- and AD-Tau-induced tau pathology spread to different brain regions distant from the injection sites while maintaining the cell type-specific pattern noted above. Finally, CA3 neuron loss was detected 3 months post-injection of AD-Tau but not CBD-Tau. Thus, AD-Tau and CBD-Tau represent specific pathological tau strains that spread differentially and may underlie distinct clinical and pathological features of these two tauopathies. Hence, these strains could become targets to develop disease-modifying therapies for CBD and AD. PMID:25534024

Pitfalls in lung cancer molecular pathology: how to limit them in routine practice?

Science.gov (United States)

Ilie, M; Hofman, P

2012-01-01

New treatment options in advanced non-small cell lung carcinoma (NSCLC) targeting activating epidermal growth factor receptor (EGFR) gene mutations and other genetic alterations demonstrated the clinical significance of the molecular features of specific subsets of tumors. Therefore, the development of personalized medicine has stimulated the routine integration into pathology departments of somatic mutation testing. However, clinical mutation testing must be optimized and standardized with regard to histological profile, type of samples, pre-analytical steps, methodology and result reporting. Routine molecular testing in NSCLC is currently moving beyond EGFR mutational analysis. Recent progress of targeted therapies will require molecular testing for a wide panel of mutations for a personalized molecular diagnosis. As a consequence, efficient testing of multiple molecular abnormalities is an urgent requirement in thoracic oncology. Moreover, increasingly limited tumor sample becomes a major challenge for molecular pathology. Continuous efforts should be made for safe, effective and specific molecular analyses. This must be based on close collaboration between the departments involved in the management of lung cancer. In this review we explored the practical issues and pitfalls surrounding the routine implementation of molecular testing in NSCLC in a pathology laboratory.

Transmutation of uranium and thorium in the particle field of the Quinta sub-critical assembly

Science.gov (United States)

Hashemi-Nezhad, S. R.; Asquith, N. L.; Voronko, V. A.; Sotnikov, V. V.; Zhadan, Alina; Zhuk, I. V.; Potapenko, A.; Husak, Krystsina; Chilap, V.; Adam, J.; Baldin, A.; Berlev, A.; Furman, W.; Kadykov, M.; Khushvaktov, J.; Kudashkin, I.; Mar'in, I.; Paraipan, M.; Pronskih, V.; Solnyshkin, A.; Tyutyunnikov, S.

2018-03-01

The fission rates of natural uranium and thorium were measured in the particle field of Quinta, a 512 kg natural uranium target-blanket sub-critical assembly. The Quinta assembly was irradiated with deuterons of energy 4 GeV from the Nuclotron accelerator of the Joint Institute for Nuclear Research (JINR), Dubna, Russia. Fission rates of uranium and thorium were measured using Gamma spectroscopy and fission track techniques. The production rate of 239Np was also measured. The obtained experimental results were compared with Monte Carlo predictions using the MCNPX 2.7 code employing the physics and fission-evaporation models of INCL4-ABLA, CEM03.03 and LAQGSM03.03. Some of the neutronic characteristics of the Quinta are compared with the "Energy plus Transmutation (EpT)" subcritical assembly, which is composed of a lead target and natU blanket. This comparison clearly demonstrates the importance of target material, neutron moderator and reflector types on the performance of a spallation neutron driven subcritical system. As the dimensions of the Quinta are very close to those of an optimal multi-rod-uranium target, the experimental and Monte Carlo calculation results presented in this paper provide insights on the particle field within a uranium target as well as in Accelerator Driven Systems in general.

Oxidative Stress and Mitochondrial Dysfunction across Broad-Ranging Pathologies: Toward Mitochondria-Targeted Clinical Strategies

OpenAIRE

Pagano, Giovanni; Aiello Talamanca, Annarita; Castello, Giuseppe; Cordero, Mario D.; d'Ischia, Marco; Gadaleta, Maria Nicola; Pallardó, Federico V.; Petrović, Sandra; Tiano, Luca; Zatterale, Adriana

2014-01-01

Beyond the disorders recognized as mitochondrial diseases, abnormalities in function and/or ultrastructure of mitochondria have been reported in several unrelated pathologies. These encompass ageing, malformations, and a number of genetic or acquired diseases, as diabetes and cardiologic, haematologic, organ-specific (e.g., eye or liver), neurologic and psychiatric, autoimmune, and dermatologic disorders. The mechanistic grounds for mitochondrial dysfunction (MDF) along with the occurrence of...

Untangling dopamine-adenosine receptor-receptor assembly in experimental parkinsonism in rats

Directory of Open Access Journals (Sweden)

Víctor Fernández-Dueñas

2015-01-01

Full Text Available Parkinson’s disease (PD is a dopaminergic-related pathology in which functioning of the basal ganglia is altered. It has been postulated that a direct receptor-receptor interaction – i.e. of dopamine D2 receptor (D2R with adenosine A2A receptor (A2AR (forming D2R-A2AR oligomers – finely regulates this brain area. Accordingly, elucidating whether the pathology prompts changes to these complexes could provide valuable information for the design of new PD therapies. Here, we first resolved a long-standing question concerning whether D2R-A2AR assembly occurs in native tissue: by means of different complementary experimental approaches (i.e. immunoelectron microscopy, proximity ligation assay and TR-FRET, we unambiguously identified native D2R-A2AR oligomers in rat striatum. Subsequently, we determined that, under pathological conditions (i.e. in a rat PD model, D2R-A2AR interaction was impaired. Collectively, these results provide definitive evidence for alteration of native D2R-A2AR oligomers in experimental parkinsonism, thus conferring the rationale for appropriate oligomer-based PD treatments.

Self-assembly of silver nanoparticles and bacteriophage

Directory of Open Access Journals (Sweden)

Santi Scibilia

2016-03-01

Full Text Available Biohybrid nanostructured materials, composed of both inorganic nanoparticles and biomolecules, offer prospects for many new applications in extremely diverse fields such as chemistry, physics, engineering, medicine and nanobiotechnology. In the recent years, Phage display technique has been extensively used to generate phage clones displaying surface peptides with functionality towards organic materials. Screening and selection of phage displayed material binding peptides has attracted great interest because of their use for development of hybrid materials with multiple functionalities. Here, we present a self-assembly approach for the construction of hybrid nanostructured networks consisting of M13 P9b phage clone, specific for Pseudomonas aeruginosa, selected by Phage display technology, directly assembled with silver nanoparticles (AgNPs, previously prepared by pulsed laser ablation. These networks are characterized by UV–vis optical spectroscopy, scanning/transmission electron microscopies and Raman spectroscopy. We investigated the influence of different ions and medium pH on self-assembly by evaluating different phage suspension buffers. The assembly of these networks is controlled by electrostatic interactions between the phage pVIII major capsid proteins and the AgNPs. The formation of the AgNPs-phage networks was obtained only in two types of tested buffers at a pH value near the isoelectric point of each pVIII proteins displayed on the surface of the clone. This systematic study allowed to optimize the synthesis procedure to assembly AgNPs and bacteriophage. Such networks find application in the biomedical field of advanced biosensing and targeted gene and drug delivery. Keywords: Phage display, Silver nanoparticles, Self-assembly, Hybrid architecture, Raman spectroscopy

Bioinspired synthesis and self-assembly of hybrid organic–inorganic nanomaterials

Energy Technology Data Exchange (ETDEWEB)

Zhang, Honghu [Iowa State Univ., Ames, IA (United States)

2016-12-17

Nature is replete with complex organic–inorganic hierarchical materials of diverse yet specific functions. These materials are intricately designed under physiological conditions through biomineralization and biological self-assembly processes. Tremendous efforts have been devoted to investigating mechanisms of such biomineralization and biological self-assembly processes as well as gaining inspiration to develop biomimetic methods for synthesis and self-assembly of functional nanomaterials. In this work, we focus on the bioinspired synthesis and self-assembly of functional inorganic nanomaterials templated by specialized macromolecules including proteins, DNA and polymers. The in vitro biomineralization process of the magnetite biomineralizing protein Mms6 has been investigated using small-angle X-ray scattering. Templated by Mms6, complex magnetic nanomaterials can be synthesized on surfaces and in the bulk. DNA and synthetic polymers have been exploited to construct macroscopic two- and three-dimensional (2D and 3D) superlattices of gold nanocrystals. Employing X-ray scattering and spectroscopy techniques, the self-assembled structures and the self-assembly mechanisms have been studied, and theoretical models have been developed. Our results show that specialized macromolecules including proteins, DNA and polymers act as effective templates for synthesis and self-assembly of nanomaterials. These bottom-up approaches provide promising routes to fabricate hybrid organic–inorganic nanomaterials with rationally designed hierarchical structures, targeting specific functions.

Prevalence of Unique Pediatric Pathologies Encountered by Paramedic Students Across Age Groups.

Science.gov (United States)

Ernest, Eric V; Brazelton, Tom B; Carhart, Elliot D; Studnek, Jonathan R; Tritt, Patricia L; Philip, Genghis A; Burnett, Aaron M

2016-08-01

Introduction Traditionally, Emergency Medical Services (EMS) educators have divided the pediatric population into age groups to assist in targeting their clinical and didactic curriculum. Currently, the accrediting body for paramedic training programs requires student exposure to pediatric patients based entirely on age without specifying exposure to specific pathologies within each age stratification. Identifying which pathologies are most common within the different pediatric age groups would allow educators to design curriculum targeting the most prevalent pathologies in each age group and incorporating the physiologic and psychological developmental milestones commonly seen at that age. Hypothesis It was hypothesized that there are unique clusterings of pathologies, represented by paramedic student primary impressions, that are found in different age groups which can be used to target provider education. This is a retrospective review of prospectively collected data documented by paramedic students in the Fisdap (Field Internship Student Data Acquisition Project; Saint Paul, Minnesota USA) database over a one-year period. For the purposes of this study, pediatric patients were defined arbitrarily as those between the ages of 0-16 years. All paramedic student primary impressions recorded in Fisdap for patients aged 0-16 years were abstracted. Primary impression by age was calculated and graphed. The frequency of primary impression was then assessed for significance of trend by age with an alpha ≤.05 considered significant. The following primary impressions showed clinically and statistically significant variability in prevalence among different pediatric age groups: respiratory distress, medical-other, abdominal pain, seizure, overdose/poisoning, behavioral, and cardiac. In patients less than 13 years old, respiratory and other-medical were the most common two primary impressions and both decreased with age. In patients 5-16 years old, the prevalence of

An assembly of tritium production experiment

International Nuclear Information System (INIS)

Abe, Toshihiko

1981-01-01

An assembly for tritium production experiment, i.e. Tritium Extraction System (TREX) constructed as a small scale test facility for tritium production, and Tritium Removal System (TRS) attached to TREX, and the preliminary results of the experiments with them are described. The radiological safety of the process and operation is also an important consideration. Lithium-aluminum alloy was selected as the most promising target material. The following matters are involved in the scope of production technology: the selection of a target material and target preparation, reactor irradiation, the construction of a facility for the extraction of tritium from the irradiated target, the establishment of the optimum conditions of extraction, the purification, collection and storage of tritium, and the inspection of the product. The tritium production experiment at JAERI is yet on the initial stage; the development is to be continued with the stepwise increase of the scale of tritium production. (J.P.N.)

Distinct proteome pathology of circulating microparticles in systemic lupus erythematosus

DEFF Research Database (Denmark)

Østergaard, Ole; Nielsen, Christoffer Tandrup; Tanassi, Julia Tanas

2017-01-01

BACKGROUND: The pathogenesis of systemic lupus erythematosus (SLE) is poorly understood but has been linked to defective clearance of subcellular particulate material from the circulation. This study investigates the origin, formation, and specificity of circulating microparticles (MPs) in patien...... generation of MPs may partake in the pathology of SLE and that new diagnostic, monitoring, and treatment strategies targeting these processes may be advantageous....

Optimization of plutonium and minor actinide transmutation in an AP1000 fuel assembly via a genetic search algorithm

Energy Technology Data Exchange (ETDEWEB)

Washington, J., E-mail: jwashing@gmail.com; King, J., E-mail: kingjc@mines.edu

2017-01-15

Highlights: • We model a modified AP1000 fuel assembly in SCALE6.1. • We couple the NEWT module of SCALE to the MOGA module of DAKOTA. • Transmutation is optimized based on choice of coating and fuel. • Greatest transmutation achieved with PuZrO{sub 2}MgO fuel pins coated with Lu{sub 2}O{sub 3}. - Abstract: The average nuclear power plant produces twenty metric tons of used nuclear fuel per year, which contains approximately 95 wt% uranium, 1 wt% plutonium, and 4 wt% fission products and transuranic elements. Fast reactors are the preferred option for the transmutation of plutonium and minor actinides; however, an optimistic deployment time of at least 20 years indicates a need for a near-term solution. Previous simulation work demonstrated the potential to transmute transuranic elements in a modified light water reactor fuel pin. This study optimizes a quarter-assembly containing target fuels coated with spectral shift absorbers for the transmutation of plutonium and minor actinides in light water reactors. The spectral shift absorber coating on the target fuel pin tunes the neutron energy spectrum experienced by the target fuel. A coupled model developed using the NEWT module from SCALE 6.1 and a genetic algorithm module from the DAKOTA optimization toolbox provided performance data for the burnup of the target fuel pins in the present study. The optimization with the coupled NEWT/DAKOTA model proceeded in three stages. The first stage optimized a single-target fuel pin per quarter-assembly adjacent to the central instrumentation channel. The second stage evaluated a variety of quarter-assemblies with multiple target fuel pins from the first stage and the third stage re-optimized the pins in the optimal second stage quarter-assembly. An 8 wt% PuZrO{sub 2}MgO inert matrix fuel pin with a 1.44 mm radius and a 0.06 mm Lu{sub 2}O{sub 3} coating in a five target fuel pin per quarter-assembly configuration represents the optimal combination for the

Hyper bio assembler for 3D cellular systems

CERN Document Server

Arai, Fumihito; Yamato, Masayuki

2015-01-01

Hyper Bio Assembler for Cellular Systems is the first book to present a new methodology for measuring and separating target cells at high speed and constructing 3D cellular systems in vitro. This book represents a valuable resource for biologists, biophysicists and robotic engineers, as well as researchers interested in this new frontier area, offering a better understanding of the measurement, separation, assembly, analysis and synthesis of complex biological tissue, and of the medical applications of these technologies. This book is the outcome of the new academic fields of the Ministry of Education, Culture, Sports, Science and Technology’s Grant-in-Aid for Scientific Research in Japan.

Molecular pathology and thyroid FNA.

Science.gov (United States)

Poller, D N; Glaysher, S

2017-12-01

This review summarises molecular pathological techniques applicable to thyroid FNA. The molecular pathology of thyroid tumours is now fairly well understood. Molecular methods may be used as a rule-in test for diagnosis of malignancy in thyroid nodules, eg BRAF V600E point mutation, use of a seven-gene mutational panel (BRAF V600E, RAS genes, RET/PTC or PAX8/PPARG rearrangement), or as a comprehensive multigene next-generation sequencing panel, eg ThyroSeq v2. Molecular methods can also be applied as rule-out tests for malignancy in thyroid nodules, eg Afirma or ThyroSeq v2 or as markers of prognosis, eg TERT promoter mutation or other gene mutations including BRAF V600E, TP53 and AKT1, and as tests for newly defined tumour entities such as non-invasive follicular thyroid neoplasm with papillary like nuclei, or as a molecular marker(s) for targeted therapies. This review describes practical examples of molecular techniques as applied to thyroid FNA in routine clinical practice and the value of molecular diagnostics in thyroid FNA. It describes the range of molecular abnormalities identified in thyroid nodules and thyroid cancers with some practical applications of molecular methods to diagnosis and prognosis of thyroid nodules and thyroid cancer. © 2017 John Wiley & Sons Ltd.

Pathology in Undergraduate Training Program

Directory of Open Access Journals (Sweden)

Shiva Raj K.C.

2018-04-01

Full Text Available Pathology is a study of disease which deals with etiology, pathogenesis and morphological features and the associated clinical features. Pathology acts as a bridge that fills the gap between basic sciences and clinical medicine. With proper understanding of pathological processes, one can understand the disease process. In Nepal, since the beginning of medical school teaching, Pathology as a basic science discipline and is a component of the preclinical medical school curriculum.Pathology teaching in 19th century was vague, disorganized and very little, though precious. The lectures used to be conducted by surgeons. At Barts, surgeon Sir James Paget had taught surgical pathology. The real revolution in pathology teaching began in the early 1900s when, spurred on by increasing understanding of disease mechanisms, pathology began to be accepted as a specialty in its own right.During the early and mid of 20th century, pathology teaching was a part of clinical teaching with daily, autopsy demonstration. By the late 1980s, significant change had taken place. In many medical schools, debate started regarding relevance of vigorous preclinical teaching. Then system-based approach was incorporated and traditional preclinical course had been abandoned. With this pathology teaching also began to change with pathologists being involved in teaching histology, often alongside pathology to highlight its clinical relevance. In medical schools the pathology teaching time was cut. Autopsy demonstrations, which had been so popular with generations of medical students, were becoming irregular and less well attended.Though teaching of pathology in blocks to ‘avoid fragmentation’ has disappeared in western countries; it is still practice in Nepal. In western countries there was traditional practice of teaching general pathology in the first two years and systemic pathology in the clinical years. Now pathology teaching is integrated throughout the course. A

PEGylated Self-Assembled Nano-Bacitracin A: Probing the Antibacterial Mechanism and Real-Time Tracing of Target Delivery in Vivo.

Science.gov (United States)

Hong, Wei; Zhao, Yining; Guo, Yuru; Huang, Chengcheng; Qiu, Peng; Zhu, Jia; Chu, Chun; Shi, Hong; Liu, Mingchun

2018-04-04

Although nano-self-assemblies of hydrophobic-modified bacitracin A with poly(d,l-lactic- co-glycolic acid) (PLGA) (nano-BA PLGA ) have demonstrated promising antibacterial activities, the application of nano-BA PLGA was severely compromised by low water solubility. In this study, a series of PEGylated PLGA copolymers were selected to conjugate with the N-terminus of bacitracin A to construct PEGylated self-assembled nano-BAs and to further develop nano-self-assemblies of bacitracin A with strong antibacterial potency and high solubility. Compared with nano-BA PLGA , all PEGylated nano-BAs, except nano-BA 5k , exhibited strong antibacterial efficiency against both Gram-positive and Gram-negative bacteria by inducing loss of cytoplasmic membrane potential, membrane permeabilization, and leakage of calcein from artificial cell membranes. Studies elucidating the underlying mechanism of PEGylated nano-BAs against Gram-negative bacteria indicated that the strong hydrophobic and van der Waals interactions between PLGA and lipopolysaccharide (LPS) could bind, neutralize, and disassociate LPS, facilitating cellular uptake of the nanoparticles, which could destabilize the membrane, resulting in cell death. Moreover, PEGylated nano-BAs (nano-BA 12k ) with a longer PLGA block were expected to occupy a higher local density of BA mass on the surface and result in stronger hydrophobic and van der Waals interactions with LPS, which were responsible for the enhanced antibacterial activity against Gram-positive and emerging antibacterial activity against Gram-negative bacteria, respectively. In vivo imaging verified that PEGylated nano-BAs exhibited higher inflammatory tissue distribution and longer circulation time than nano-BA PLGA . Therefore, although PEGylation did not affect antibacterial activity, it is necessary for target delivery and resistance to clearance of the observed PEGylated nano-BAs. In vivo, nano-BA 12k also showed the highest therapeutic index against infection

Roles of PDE1 in Pathological Cardiac Remodeling and Dysfunction.

Science.gov (United States)

Chen, Si; Knight, Walter E; Yan, Chen

2018-04-23

Pathological cardiac hypertrophy and dysfunction is a response to various stress stimuli and can result in reduced cardiac output and heart failure. Cyclic nucleotide signaling regulates several cardiac functions including contractility, remodeling, and fibrosis. Cyclic nucleotide phosphodiesterases (PDEs), by catalyzing the hydrolysis of cyclic nucleotides, are critical in the homeostasis of intracellular cyclic nucleotide signaling and hold great therapeutic potential as drug targets. Recent studies have revealed that the inhibition of the PDE family member PDE1 plays a protective role in pathological cardiac remodeling and dysfunction by the modulation of distinct cyclic nucleotide signaling pathways. This review summarizes recent key findings regarding the roles of PDE1 in the cardiac system that can lead to a better understanding of its therapeutic potential.

Colorectal Cancers: An Update on Their Molecular Pathology.

Science.gov (United States)

Inamura, Kentaro

2018-01-20

Colorectal cancers (CRCs) are the third leading cause of cancer-related mortality worldwide. Rather than being a single, uniform disease type, accumulating evidence suggests that CRCs comprise a group of molecularly heterogeneous diseases that are characterized by a range of genomic and epigenomic alterations. This heterogeneity slows the development of molecular-targeted therapy as a form of precision medicine. Recent data regarding comprehensive molecular characterizations and molecular pathological examinations of CRCs have increased our understanding of the genomic and epigenomic landscapes of CRCs, which has enabled CRCs to be reclassified into biologically and clinically meaningful subtypes. The increased knowledge of the molecular pathological epidemiology of CRCs has permitted their evolution from a vaguely understood, heterogeneous group of diseases with variable clinical courses to characteristic molecular subtypes, a development that will allow the implementation of personalized therapies and better management of patients with CRC. This review provides a perspective regarding recent developments in our knowledge of the molecular and epidemiological landscapes of CRCs, including results of comprehensive molecular characterizations obtained from high-throughput analyses and the latest developments regarding their molecular pathologies, immunological biomarkers, and associated gut microbiome. Advances in our understanding of potential personalized therapies for molecularly specific subtypes are also reviewed.

Mixed Reload Design Using MOX and UOX Fuel Assemblies

International Nuclear Information System (INIS)

Ramon, Ramirez Sanchez J.; Perry, R.T.

2002-01-01

As part of the studies involved in plutonium utilization assessment for a Boiling Water Reactor, a conceptual design of MOX fuel was developed, this design is mechanically the same design of 10 X 10 BWR fuel assemblies but different fissile material. Several plutonium and gadolinium concentrations were tested to match the 18 months cycle length which is the current cycle length of LVNPP, a reference UO 2 assembly was modeled to have a full cycle length to compare results, an effective value of 0.97 for the multiplication factor was set as target for 470 Effective Full Power days for both cycles, here the gadolinium concentration was a key to find an average fissile plutonium content of 6.55% in the assembly. A reload of 124 fuel assemblies was assumed to simulate the complete core, several load fractions of MOX fuel mixed with UO 2 fresh fuel were tested to verify the shutdown margin, the UO 2 fuel meets the shutdown margin when 124 fuel assemblies are loaded into the core, but it does not happen when those 124 assemblies are replaced with MOX fuel assemblies, so the fraction of MOX was reduced step by step up to find a mixed load that meets both length cycle and shutdown margin. Finally the conclusion is that control rods losses some of their worth in presence of plutonium due to a more hardened neutron spectrum in MOX fuel and this fact limits the load of MOX fuel assemblies in the core, this results are shown in this paper. (authors)

Different Achilles Tendon Pathologies Show Distinct Histological and Molecular Characteristics

Directory of Open Access Journals (Sweden)

Franka Klatte-Schulz

2018-01-01

Full Text Available Reasons for the development of chronic tendon pathologies are still under debate and more basic knowledge is needed about the different diseases. The aim of the present study was therefore to characterize different acute and chronic Achilles tendon disorders. Achilles tendon samples from patients with chronic tendinopathy (n = 7, chronic ruptures (n = 6, acute ruptures (n = 13, and intact tendons (n = 4 were analyzed. The histological score investigating pathological changes was significantly increased in tendinopathy and chronic ruptures compared to acute ruptures. Inflammatory infiltration was detected by immunohistochemistry in all tendon pathology groups, but was significantly lower in tendinopathy compared to chronic ruptures. Quantitative real-time PCR (qRT-PCR analysis revealed significantly altered expression of genes related to collagens and matrix modeling/remodeling (matrix metalloproteinases, tissue inhibitors of metalloproteinases in tendinopathy and chronic ruptures compared to intact tendons and/or acute ruptures. In all three tendon pathology groups markers of inflammation (interleukin (IL 1β, tumor necrosis factor α, IL6, IL10, IL33, soluble ST2, transforming growth factor β1, cyclooxygenase 2, inflammatory cells (cluster of differentaition (CD 3, CD68, CD80, CD206, fat metabolism (fatty acid binding protein 4, peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein α, adiponectin, and innervation (protein gene product 9.5, growth associated protein 43, macrophage migration inhibitory factor were detectable, but only in acute ruptures significantly regulated compared to intact tendons. The study gives an insight into structural and molecular changes of pathological processes in tendons and might be used to identify targets for future therapy of tendon pathologies.

Go-no-go performance in pathological gamblers.

Science.gov (United States)

Kertzman, Semion; Lowengrub, Katherine; Aizer, Anat; Vainder, Michael; Kotler, Moshe; Dannon, Pinhas N

2008-10-30

Previous neuropsychological studies demonstrated various deficits of impulse control in pathological gamblers (PGs). However, there are limited data available on response-inhibition impairment among PGs. The present study attempted to assess response inhibition in untreated PGs (N=83), in comparison with normal subjects (N=84). Go/no-go and target-detection conditions of a computerized task were used as a measure of response-inhibition ability. A repeated measures analysis of covariance (ANCOVA-RM) was used with response time, variability of response time, and number of false alarms and misses as dependent measures; group (PG and controls) as the between-subjects measure; condition (target detection or go/no-go) and time slice (first and second in each condition) as repeated measures within-subject factors; and educational level as a covariate. Our results showed that PGs were significantly more impaired in both target detection and go/no-go task performance than controls. The PGs had significantly more false alarms and misses than controls, and they were slower and less consistent in their responses.

Molecular Pathology: A Requirement for Precision Medicine in Cancer.

Science.gov (United States)

Dietel, Manfred

2016-01-01

The increasing importance of targeting drugs and check-point inhibitors in the treatment of several tumor entities (breast, colon, lung, malignant melanoma, lymphoma, etc.) and the necessity of a companion diagnostic (HER2, (pan)RAS, EGFR, ALK, BRAF, ROS1, MET, PD-L1, etc.) is leading to new challenges for surgical pathology. Since almost all the biomarkers to be specifically detected are tissue based, a precise and reliable diagnostic is absolutely crucial. To meet this challenge surgical pathology has adapted a number of molecular methods (semi-quantitative immunohistochemistry, fluorescence in situ hybridization, PCR and its multiple variants, (pyro/Sanger) sequencing, next generation sequencing (amplicon, whole exome, whole genome), DNA arrays, methylation analyses, etc.) to be applicable for formalin-fixed paraffin-embedded tissue. Reading a patient's tissue as 'deeply' as possible and obtaining information on the morphological, genetic, proteomic and epigenetic background are the tasks of pathologists and molecular biologists and provide the clinicians with information relevant for precision medicine. Intensified cooperation between clinicians and pathologists will provide the basis of improved clinical drug selection and guide development of new cancer gene therapies and molecularly targeted drugs by research units and the pharmaceutical industry. © 2016 S. Karger GmbH, Freiburg.

Communication: Theoretical prediction of free-energy landscapes for complex self-assembly

Energy Technology Data Exchange (ETDEWEB)

Jacobs, William M.; Reinhardt, Aleks; Frenkel, Daan [Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW (United Kingdom)

2015-01-14

We present a technique for calculating free-energy profiles for the nucleation of multicomponent structures that contain as many species as building blocks. We find that a key factor is the topology of the graph describing the connectivity of the target assembly. By considering the designed interactions separately from weaker, incidental interactions, our approach yields predictions for the equilibrium yield and nucleation barriers. These predictions are in good agreement with corresponding Monte Carlo simulations. We show that a few fundamental properties of the connectivity graph determine the most prominent features of the assembly thermodynamics. Surprisingly, we find that polydispersity in the strengths of the designed interactions stabilizes intermediate structures and can be used to sculpt the free-energy landscape for self-assembly. Finally, we demonstrate that weak incidental interactions can preclude assembly at equilibrium due to the combinatorial possibilities for incorrect association.

Aging on a different scale--chronological versus pathology-related aging.

Science.gov (United States)

Melis, Joost P M; Jonker, Martijs J; Vijg, Jan; Hoeijmakers, Jan H J; Breit, Timo M; van Steeg, Harry

2013-10-01

In the next decades the elderly population will increase dramatically, demanding appropriate solutions in health care and aging research focusing on healthy aging to prevent high burdens and costs in health care. For this, research targeting tissue-specific and individual aging is paramount to make the necessary progression in aging research. In a recently published study we have attempted to make a step interpreting aging data on chronological as well as pathological scale. For this, we sampled five major tissues at regular time intervals during the entire C57BL/6J murine lifespan from a controlled in vivo aging study, measured the whole transcriptome and incorporated temporal as well as physical health aspects into the analyses. In total, we used 18 different age-related pathological parameters and transcriptomic profiles of liver, kidney, spleen, lung and brain and created a database that can now be used for a broad systems biology approach. In our study, we focused on the dynamics of biological processes during chronological aging and the comparison between chronological and pathology-related aging.

Robotically Assembled Aerospace Structures: Digital Material Assembly using a Gantry-Type Assembler

Science.gov (United States)

Trinh, Greenfield; Copplestone, Grace; O'Connor, Molly; Hu, Steven; Nowak, Sebastian; Cheung, Kenneth; Jenett, Benjamin; Cellucci, Daniel

2017-01-01

This paper evaluates the development of automated assembly techniques for discrete lattice structures using a multi-axis gantry type CNC machine. These lattices are made of discrete components called "digital materials." We present the development of a specialized end effector that works in conjunction with the CNC machine to assemble these lattices. With this configuration we are able to place voxels at a rate of 1.5 per minute. The scalability of digital material structures due to the incremental modular assembly is one of its key traits and an important metric of interest. We investigate the build times of a 5x5 beam structure on the scale of 1 meter (325 parts), 10 meters (3,250 parts), and 30 meters (9,750 parts). Utilizing the current configuration with a single end effector, performing serial assembly with a globally fixed feed station at the edge of the build volume, the build time increases according to a scaling law of n4, where n is the build scale. Build times can be reduced significantly by integrating feed systems into the gantry itself, resulting in a scaling law of n3. A completely serial assembly process will encounter time limitations as build scale increases. Automated assembly for digital materials can assemble high performance structures from discrete parts, and techniques such as built in feed systems, parallelization, and optimization of the fastening process will yield much higher throughput.

Tunneling nanotube (TNT)-mediated neuron-to neuron transfer of pathological Tau protein assemblies.

Science.gov (United States)

Tardivel, Meryem; Bégard, Séverine; Bousset, Luc; Dujardin, Simon; Coens, Audrey; Melki, Ronald; Buée, Luc; Colin, Morvane

2016-11-04

A given cell makes exchanges with its neighbors through a variety of means ranging from diffusible factors to vesicles. Cells use also tunneling nanotubes (TNTs), filamentous-actin-containing membranous structures that bridge and connect cells. First described in immune cells, TNTs facilitate HIV-1 transfer and are found in various cell types, including neurons. We show that the microtubule-associated protein Tau, a key player in Alzheimer's disease, is a bona fide constituent of TNTs. This is important because Tau appears beside filamentous actin and myosin 10 as a specific marker of these fine protrusions of membranes and cytosol that are difficult to visualize. Furthermore, we observed that exogenous Tau species increase the number of TNTs established between primary neurons, thereby facilitating the intercellular transfer of Tau fibrils. In conclusion, Tau may contribute to the formation and function of the highly dynamic TNTs that may be involved in the prion-like propagation of Tau assemblies.

Sequence assembly

DEFF Research Database (Denmark)

Scheibye-Alsing, Karsten; Hoffmann, S.; Frankel, Annett Maria

2009-01-01

Despite the rapidly increasing number of sequenced and re-sequenced genomes, many issues regarding the computational assembly of large-scale sequencing data have remain unresolved. Computational assembly is crucial in large genome projects as well for the evolving high-throughput technologies and...... in genomic DNA, highly expressed genes and alternative transcripts in EST sequences. We summarize existing comparisons of different assemblers and provide a detailed descriptions and directions for download of assembly programs at: http://genome.ku.dk/resources/assembly/methods.html....

Mitochondria mediate septin cage assembly to promote autophagy of Shigella.

Science.gov (United States)

Sirianni, Andrea; Krokowski, Sina; Lobato-Márquez, Damián; Buranyi, Stephen; Pfanzelter, Julia; Galea, Dieter; Willis, Alexandra; Culley, Siân; Henriques, Ricardo; Larrouy-Maumus, Gerald; Hollinshead, Michael; Sancho-Shimizu, Vanessa; Way, Michael; Mostowy, Serge

2016-07-01

Septins, cytoskeletal proteins with well-characterised roles in cytokinesis, form cage-like structures around cytosolic Shigella flexneri and promote their targeting to autophagosomes. However, the processes underlying septin cage assembly, and whether they influence S. flexneri proliferation, remain to be established. Using single-cell analysis, we show that the septin cages inhibit S. flexneri proliferation. To study mechanisms of septin cage assembly, we used proteomics and found mitochondrial proteins associate with septins in S. flexneri-infected cells. Strikingly, mitochondria associated with S. flexneri promote septin assembly into cages that entrap bacteria for autophagy. We demonstrate that the cytosolic GTPase dynamin-related protein 1 (Drp1) interacts with septins to enhance mitochondrial fission. To avoid autophagy, actin-polymerising Shigella fragment mitochondria to escape from septin caging. Our results demonstrate a role for mitochondria in anti-Shigella autophagy and uncover a fundamental link between septin assembly and mitochondria. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

Ethics and Professionalism in Pathology

Directory of Open Access Journals (Sweden)

R Baral

2016-03-01

Full Text Available Pathologists spend most of their professional lives beyond direct view of the public, mostly inside the four walls of the lab. It is the clinicians who face the wrath of the public when something goes wrong. However, with the growing awareness of the public into the decisive role played by the Pathologists in the definitive diagnosis of the disease, the pathologists will soon be the target of the aggrieved patients and relatives.1 The issue of ethics can be dealt when professionalism comes before profession. "Professionalism in medicine requires that physician serve the interests of the patient above his or her own selfinterest." Professionalism aspires to philanthropy, answerability, excellence, duty, service and respect for others. "Professionalism in Pathology is based on the same tenets, but has additional dimensions."The qualities of professionalism for pathologists include 1. Communication with the patients and the clinicians. A small phone call with the clinician will solve most of the clinical mysteries not written in the lab requisition forms; 2. Empathy and Compassion towards patients', colleagues', and laboratory personnel's culture, age, gender, and disabilities; 3. Demonstration of passion, respect and understanding towards the patients; 4. Adherence to guidelines and regulations of the regulatory and accrediting bodies; and 5.Profeciency and knowledge in one's work is valued by the patients more than the credentials, which also enables one to identify deficiencies in peer performance. The basic competencies of professionalism are vital to every pathology report, which in turn is the mirror of the ethics practiced by the pathologist. Evaluating oneself is perhaps the most important tool in maintaining professionalism in the practice of pathology. One colleague recently defined professionalism as “all the things one does when no one is watching,” thus placing personal integrity at the top of the list.

The Ignition Target for the National Ignition Facility

International Nuclear Information System (INIS)

Atherton, L J; Moses, E I; Carlisle, K; Kilkenny, J

2007-01-01

The National Ignition Facility (NIF) is a 192 beam Nd-glass laser facility presently under construction at Lawrence Livermore National Laboratory (LLNL) for performing inertial confinement fusion (ICF) and experiments studying high energy density (HED) science. When completed in 2009, NIF will be able to produce 1.8 MJ, 500 TW of ultraviolet light for target experiments that will create conditions of extreme temperatures (>10 8 K), pressures (10-GBar) and matter densities (> 100 g/cm 3 ). A detailed program called the National Ignition Campaign (NIC) has been developed to enable ignition experiments in 2010, with the goal of producing fusion ignition and burn of a deuterium-tritium (DT) fuel mixture in millimeter-scale target capsules. The first of the target experiments leading up to these ignition shots will begin in 2008. Targets for the National Ignition Campaign are both complex and precise, and are extraordinarily demanding in materials fabrication, machining, assembly, cryogenics and characterization. An overview of the campaign for ignition will be presented, along with technologies for target fabrication, assembly and metrology and advances in growth and x-ray imaging of DT ice layers. The sum of these efforts represents a quantum leap in target precision, characterization, manufacturing rate and flexibility over current state-of-the-art

Bacteriophage Assembly

Directory of Open Access Journals (Sweden)

Anastasia A. Aksyuk

2011-02-01

Full Text Available Bacteriophages have been a model system to study assembly processes for over half a century. Formation of infectious phage particles involves specific protein-protein and protein-nucleic acid interactions, as well as large conformational changes of assembly precursors. The sequence and molecular mechanisms of phage assembly have been elucidated by a variety of methods. Differences and similarities of assembly processes in several different groups of bacteriophages are discussed in this review. The general principles of phage assembly are applicable to many macromolecular complexes.

Device Assembly Facility (DAF) Glovebox Radioactive Waste Characterization

International Nuclear Information System (INIS)

Dominick, J L

2001-01-01

The Device Assembly Facility (DAF) at the Nevada Test Site (NTS) provides programmatic support to the Joint Actinide Shock Physics Experimental Research (JASPER) Facility in the form of target assembly. The target assembly activities are performed in a glovebox at DAF and include Special Nuclear Material (SNM). Currently, only activities with transuranic SNM are anticipated. Preliminary discussions with facility personnel indicate that primarily two distributions of SNM will be used: Weapons Grade Plutonium (WG-Pu), and Pu-238 enhanced WG-Pu. Nominal radionuclide distributions for the two material types are included in attachment 1. Wastes generated inside glove boxes is expected to be Transuranic (TRU) Waste which will eventually be disposed of at the Waste Isolation Pilot Plant (WIPP). Wastes generated in the Radioactive Material Area (RMA), outside of the glove box is presumed to be low level waste (LLW) which is destined for disposal at the NTS. The process knowledge quantification methods identified herein may be applied to waste generated anywhere within or around the DAF and possibly JASPER as long as the fundamental waste stream boundaries are adhered to as outlined below. The method is suitable for quantification of waste which can be directly surveyed with the Blue Alpha meter or swiped. An additional quantification methodology which requires the use of a high resolution gamma spectroscopy unit is also included and relies on the predetermined radionuclide distribution and utilizes scaling to measured nuclides for quantification

Flexible, Symmetry-Directed Approach To Assembling Protein Cages (Publisher’s Version Open Access)

Science.gov (United States)

2016-08-01

construction of enzyme nanoreactors, encapsulation of protein cargos, targeted drug delivery , and polyvalent display of epitopes, where atomic-level precision...Flexible, symmetry-directed approach to assembling protein cages Aaron Sciorea, Min Sub, Philipp Koldeweyc, Joseph D. Eschweilera, Kelsey A. Diffleya...approved June 10, 2016 (received for review April 15, 2016) The assembly of individual protein subunits into large-scale symmet- rical structures is

Epitope-Targeting of Tertiary Protein Structure Enables Target-Guided Synthesis of a Potent in Cell Inhibitor of Botulinum Neurotoxin**

OpenAIRE

Farrow, Blake; Wong, Michelle; Malette, Jacquie; Lai, Bert; Deyle, Kaycie M.; Das, Samir; Nag, Arundhati; Agnew, Heather D.; Heath, James R.

2015-01-01

Botulinum neurotoxin (BoNT) serotype A is the most lethal known toxin and has an occluded structure, which prevents direct inhibition of its active site before it enters the cytosol. Target-guided synthesis by in situ click chemistry is combined with synthetic epitope targeting to exploit the tertiary structure of the BoNT protein as a landscape for assembling a competitive inhibitor. A substrate-mimicking peptide macrocycle is used as a direct inhibitor of BoNT. An epitope-targeting in situ ...

A new series of HAPs as anti-HBV agents targeting at capsid assembly.

Science.gov (United States)

Yang, Xiu-yan; Xu, Xiao-qian; Guan, Hua; Wang, Li-li; Wu, Qin; Zhao, Guo-ming; Li, Song

2014-09-01

A series of novel Heteroaryldihydropyrimidines (HAPs) derivatives were designed and synthesized as potent inhibitors of HBV capsid assembly. These compounds were prepared from efforts to optimize an earlier series of HAPs, and compounds Mo1, Mo7, Mo8, Mo10, Mo12, and Mo13 demonstrated potent inhibition of HBV DNA replication at submicromolar range. Copyright © 2014. Published by Elsevier Ltd.

Herpesvirus capsid assembly and DNA packaging

Science.gov (United States)

Heming, Jason D.; Conway, James F.; Homa, Fred L.

2017-01-01

Herpes simplex virus type I (HSV-1) is the causative agent of several pathologies ranging in severity from the common cold sore to life-threatening encephalitic infection. During productive lytic infection, over 80 viral proteins are expressed in a highly regulated manner, resulting in the replication of viral genomes and assembly of progeny virions. The virion of all herpesviruses consists of an external membrane envelope, a proteinaceous layer called the tegument, and an icosahedral capsid containing the double-stranded linear DNA genome. The capsid shell of HSV-1 is built from four structural proteins: a major capsid protein, VP5, which forms the capsomers (hexons and pentons), the triplex consisting of VP19C and VP23 found between the capsomers, and VP26 which binds to VP5 on hexons but not pentons. In addition, the dodecameric pUL6 portal complex occupies one of the 12 capsid vertices, and the capsid vertex specific component (CVSC), a heterotrimer complex of pUL17, pUL25 and pUL36 binds specifically to the triplexes adjacent to each penton. The capsid is assembled in the nucleus where the viral genome is packaged into newly assembled closed capsid shells. Cleavage and packaging of replicated, concatemeric viral DNA requires the seven viral proteins encoded by the UL6, UL15, UL17, UL25, UL28, UL32, and UL33 genes. Considerable advances have been made in understanding the structure of the herpesvirus capsid and the function of several of the DNA packaging proteins by applying biochemical, genetic, and structural techniques. This review is a summary of recent advances with respect to the structure of the HSV-1 virion capsid and what is known about the function of the seven packaging proteins and their interactions with each other and with the capsid shell. PMID:28528442

Stem Cell Pathology.

Science.gov (United States)

Fu, Dah-Jiun; Miller, Andrew D; Southard, Teresa L; Flesken-Nikitin, Andrea; Ellenson, Lora H; Nikitin, Alexander Yu

2018-01-24

Rapid advances in stem cell biology and regenerative medicine have opened new opportunities for better understanding disease pathogenesis and the development of new diagnostic, prognostic, and treatment approaches. Many stem cell niches are well defined anatomically, thereby allowing their routine pathological evaluation during disease initiation and progression. Evaluation of the consequences of genetic manipulations in stem cells and investigation of the roles of stem cells in regenerative medicine and pathogenesis of various diseases such as cancer require significant expertise in pathology for accurate interpretation of novel findings. Therefore, there is an urgent need for developing stem cell pathology as a discipline to facilitate stem cell research and regenerative medicine. This review provides examples of anatomically defined niches suitable for evaluation by diagnostic pathologists, describes neoplastic lesions associated with them, and discusses further directions of stem cell pathology.

Architecture and roles of periplasmic adaptor proteins in tripartite efflux assemblies.

Directory of Open Access Journals (Sweden)

Vassiliy N. Bavro

2015-05-01

Full Text Available Recent years have seen major advances in the structural understanding of the different components of tripartite efflux assemblies, which encompass the multidrug efflux (MDR pumps and type I secretion systems. The majority of these investigations have focused on the role played by the inner membrane transporters and the outer membrane factor (OMF, leaving the third component of the system – the Periplasmic Adaptor Proteins (PAPs - relatively understudied. Here we review the current state of knowledge of these versatile proteins which, far from being passive linkers between the OMF and the transporter, emerge as active architects of tripartite assemblies, and play diverse roles in the transport process. Recognition between the PAPs and OMFs is essential for pump assembly and function, and targeting this interaction may provide a novel avenue for combating multidrug resistance. With the recent advances elucidating the drug-efflux and energetics of the tripartite assemblies, the understanding of the interaction between the OMFs and PAPs is the last piece remaining in the complete structure of the tripartite pump assembly puzzle.

Facility target insert shielding assessment

Energy Technology Data Exchange (ETDEWEB)

Mocko, Michal [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

2015-10-06

Main objective of this report is to assess the basic shielding requirements for the vertical target insert and retrieval port. We used the baseline design for the vertical target insert in our calculations. The insert sits in the 12”-diameter cylindrical shaft extending from the service alley in the top floor of the facility all the way down to the target location. The target retrieval mechanism is a long rod with the target assembly attached and running the entire length of the vertical shaft. The insert also houses the helium cooling supply and return lines each with 2” diameter. In the present study we focused on calculating the neutron and photon dose rate fields on top of the target insert/retrieval mechanism in the service alley. Additionally, we studied a few prototypical configurations of the shielding layers in the vertical insert as well as on the top.

The Oral Pathology Related Articles Published in Iranian Journal of Pathology from 2006 to 2015.

Science.gov (United States)

Shamim, Thorakkal

2016-01-01

There is a paucity of information about the oral pathology related articles published in a pathology journal. This study aimed to audit the oral pathology related articles published in Iranian Journal of Pathology (Iran J Pathol) from 2006 to 2015. Bibliometric analysis of issues of Iran J Pathol from 2006 to 2015 was performed using web-based search. The articles published were analyzed for type of article and individual topic of oral pathology. The articles published were also checked for authorship trends. Out of the total 49 published articles related to oral pathology, case reports (21) and original articles (18) contributed the major share. The highest number of oral pathology related articles was published in 2011, 2014 and 2015 with 8 articles each and the least published year was 2012 with 1 article. Among the oral pathology related articles published, spindle cell neoplasms (7) followed by salivary gland tumors (5), jaw tumors (4), oral granulomatous conditions (4), lymphomas (4), oral cancer (3) and odontogenic cysts (3) form the major attraction of the contributors. The largest numbers of published articles related to oral pathology were received from Tehran University of Medical Sciences; Tehran (7) followed by Mashhad University of Medical Sciences, Mashhad (6) and Shahid Beheshti University of Medical Sciences, Tehran (5). This paper may be considered as a baseline study for the bibliometric information regarding oral pathology related articles published in a pathology journal.

Actinide Sequestration Using Self-Assembled Monolayers on Mesoporous Supports

International Nuclear Information System (INIS)

Fryxell, Glen E.; Lin, Yuehe; Fiskum, Sandra K.; Birnbaum, Jerome C.; Wu, Hong; Kemner, K. M.; Kelly, Shelley

2005-01-01

Surfactant templated synthesis of mesoporous ceramics provides a versatile foundation upon which to create high efficiency environmental sorbents. These nanoporous ceramic oxides condense a huge amount of surface area into a very small volume. The ceramic oxide interface is receptive to surface functionalization through molecular self-assembly. The marriage of mesoporous ceramics with self-assembled monolayer chemistry creates a powerful new class of environmental sorbent materials called self-assembled monolayers on mesoporous supports (SAMMS). These SAMMS materials are highly efficient sorbents, whose interfacial chemistry can be fine-tuned to selectively sequester a specific target species, such as heavy metals, tetrahedral oxometallate anions and radionuclides. Details addressing the design, synthesis and characterization of SAMMS materials specifically designed to sequester actinides, of central importance to the environmental clean-up necessary after 40 years of weapons grade plutonium production, as well as evaluation of their binding affinities and kinetics are presented

Targeted disruption of the Hexa gene results in mice with biochemical and pathologic features of Tay-Sachs disease

Energy Technology Data Exchange (ETDEWEB)

Proia, R.L.; Yamanaka, S.; Johnson, M.D. [and others

1994-09-01

Tay-Sachs disease, the prototype of the G{sub M2} gangliosidoses, is a catastrophic neurodegenerative disorder of infancy. The disease is caused by mutations in the HEXA gene resulting in an absence of the lysosomal enzyme, {beta}-hexosaminidase A. As consequence of the enzyme deficiency, G{sub M2} ganglioside accumulates progressively, beginning early in fetal life, to excessive amounts in the central nervous system (CNS). Rapid mental and motor deterioration starting in the first year of life leads to death by 2 to 4 years of age. Through the targeted disruption of the Hexa gene in embryonic stem cells, we have produced mice with biochemical and neuropathologic features of Tay-Sachs disease. The mutant mice exhibited less than 1% of normal {beta}-hexosaminidase A activity and accumulated G{sub M2} ganglioside in their CNS in an age-dependent manner. The accumulated ganglioside was stored in neurons as membranous cytoplasmic bodies characteristically found in the neurons of Tay-Sachs disease patients. At three to five months of age the mutant mice showed no apparent defects in motor or memory function. These {beta}-hexosaminidase A deficient mice should be useful for devising strategies to introduce functional enzymes and genes into the CNS. This model may also be valuable for studying the biochemical and pathologic changes occurring during the course of the disease.

Self-assembled nanoparticles based on the c(RGDfk peptide for the delivery of siRNA targeting the VEGFR2 gene for tumor therapy

Directory of Open Access Journals (Sweden)

Liu L

2014-07-01

Full Text Available Li Liu,1 Xiaoxia Liu,1 Qian Xu,1 Ping Wu,2 Xialin Zuo,3 Jingjing Zhang,1 Houliang Deng,1 Zhuomin Wu,1 Aimin Ji1 1Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Pharmacy, Chengdu Integrated TCM & Western Medicine Hospital, Chengdu, People’s Republic of China; 3Institute of Neurosciences and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, People’s Republic of China Abstract: The clinical application of small interfering RNA (siRNA has been restricted by their poor intracellular uptake, low serum stability, and inability to target specific cells. During the last several decades, a great deal of effort has been devoted to exploring materials for siRNA delivery. In this study, biodegradable, tumor-targeted, self-assembled peptide nanoparticles consisting of cyclo(Arg–Gly–Asp–d–Phe–Lys-8–amino–3,6–dioxaoctanoic acid–β–maleimidopropionic acid (hereafter referred to as RPM were found to be an effective siRNA carrier both in vitro and in vivo. The nanoparticles were characterized based on transmission electron microscopy, circular dichroism spectra, and dynamic light scattering. In vitro analyses showed that the RPM/VEGFR2-siRNA exhibited negligible cytotoxicity and induced effective gene silencing. Delivery of the RPM/VEGFR2 (zebrafish-siRNA into zebrafish embryos resulted in inhibition of neovascularization. Administration of RPM/VEGFR2 (mouse-siRNA to tumor-bearing nude mice led to a significant inhibition of tumor growth, a marked reduction of vessels, and a downregulation of VEGFR2 (messenger RNA and protein in tumor tissue. Furthermore, the levels of IFN-α, IFN-γ, IL-12, and IL-6 in mouse serum, assayed via enzyme-linked immunosorbent assay, did not indicate any immunogenicity of the RPM/VEGFR2�

Fuel assemblies

International Nuclear Information System (INIS)

Nakatsuka, Masafumi.

1979-01-01

Purpose: To prevent scattering of gaseous fission products released from fuel assemblies stored in an fbr type reactor. Constitution; A cap provided with means capable of storing gas is adapted to amount to the assembly handling head, for example, by way of threading in a storage rack of spent fuel assemblies consisting of a bottom plate, a top plate and an assembly support mechanism. By previously eliminating the gas inside of the assembly and the cap in the storage rack, gaseous fission products upon loading, if released from fuel rods during storage, are stored in the cap and do not scatter in the storage rack. (Horiuchi, T.)

Self-assembled Nanomaterials for Chemotherapeutic Applications

Science.gov (United States)

Shieh, Aileen

The self-assembly of short designed peptides into functional nanostructures is becoming a growing interest in a wide range of fields from optoelectronic devices to nanobiotechnology. In the medical field, self-assembled peptides have especially attracted attention with several of its attractive features for applications in drug delivery, tissue regeneration, biological engineering as well as cosmetic industry and also the antibiotics field. We here describe the self-assembly of peptide conjugated with organic chromophore to successfully deliver sequence independent micro RNAs into human non-small cell lung cancer cell lines. The nanofiber used as the delivery vehicle is completely non-toxic and biodegradable, and exhibit enhanced permeability effect for targeting malignant tumors. The transfection efficiency with nanofiber as the delivery vehicle is comparable to that of the commercially available RNAiMAX lipofectamine while the toxicity is significantly lower. We also conjugated the peptide sequence with camptothecin (CPT) and observed the self-assembly of nanotubes for chemotherapeutic applications. The peptide scaffold is non-toxic and biodegradable, and drug loading of CPT is high, which minimizes the issue of systemic toxicity caused by extensive burden from the elimination of drug carriers. In addition, the peptide assembly drastically increases the solubility and stability of CPT under physiological conditions in vitro, while active CPT is gradually released from the peptide chain under the slight acidic tumor cell environment. Cytotoxicity results on human colorectal cancer cells and non-small cell lung cancer cell lines display promising anti-cancer properties compared to the parental CPT drug, which cannot be used clinically due to its poor solubility and lack of stability in physiological conditions. Moreover, the peptide sequence conjugated with 5-fluorouracil formed a hydrogel with promising topical chemotherapeutic applications that also display

Numerical Study for Turbulent Heat Transfer in Helical Wired Sub-channel Flow Regime of Duct-less Assembly in SFR

International Nuclear Information System (INIS)

You, Byunghyun; Jeong, Yong Hoon

2014-01-01

A fuel assembly had hexagonal structure adjacent to 6 fuel assemblies, which influence to the target fuel assembly due to elimination of duct. For calculating the influence, 6 additional channels were generated between the adjacent fuel assemblies and cross flow model was applied to the channels. The adjacent fuel assemblies were analyzed and the results were used in the additional channel as boundary condition of the target fuel assembly. To design the specifications of duct-less assembly, modified or brand-new thermal-hydraulic methodology is needed which is using MATRA-LMR and CFD codes in this study. The MATRA-LMR is a sub-channel analysis code for LMR that has been developed in Korea Atomic Energy Research Institute. It is designed to analyze a fuel assembly with wire-wrap and duct structure. However, the duct-less core is not able to be analyzed by the MATRA-LMR which doesn't consider cross flow between the fuel assemblies and effect of grid spacer. The code need improvement by editing source code to eliminate effect of duct and analyze pressure drop and mixing between the sub-channels caused by grid spacer and cross flow between the fuel assemblies. To validate reformed pressure drop model and cross flow model in MATRA-LMR, CFD analysis is performed. For verifying the results of CFD, LMR subchannel experimental data is benchmarked which is done by ORNL. The verified CFD for thermalhydraulic analysis calculated pressure drop and mixing caused by grid spacer and cross flow between fuel assemblies

Photoacoustic imaging of tumor targeting with biotin conjugated nanostructured phthalocyanine assemblies

Science.gov (United States)

Lee, Seunghyun; Li, Xingshu; Lee, Dayoung; Yoon, Juyoung; Kim, Chulhong

2018-02-01

Visualizing biological markers and delivering bioactive agents to living organisms are important to biological research. In recent decades, photoacoustic imaging (PAI) has been significantly improved in the area of molecular imaging, which provides high-resolution volume imaging with high optical absorption contrast. To demonstrate the ability of nanoprobes to target tumors using PAI, we synthesize convertible nanostructured agents with strong photothermal and photoacoustic properties and linked the nanoprobe with biotin to target tumors in small animal model. Interestingly, these nanoprobes allow partial to disassemble in the presence of targeted proteins that switchable photoactivity, thus the nanoprobes provides a fluorescent-cancer imaging with high signal-to-background ratios. The proposed nanoprobe produce a much stronger PA signal compared to the same concentration of methylene blue (MB), which is widely used in clinical study and contrast agent for PAI. The biotin conjugated nanoprobe has high selectivity for biotin receptor positive cancer cells such as A549 (human lung cancer). Then we subsequently examined the PA properties of the nanoprobe that are inherently suitable for in vivo PAI. After injecting of the nanoprobe via intravenous method, we observed the mice's whole body by PA imaging and acquired the PA signal near the cancer. The PA signal increased linearly with time after injection and the fluorescence signal near the cancer was confirmed by fluorescence imaging. The ability to target a specific cancer of the nanoprobe was well verified by PA imaging. This study provides valuable perspective on the advancement of clinical translations and in the design of tumor-targeting phototheranostic agents that could act as new nanomedicines.

Pathology of the vestibulocochlear nerve

Energy Technology Data Exchange (ETDEWEB)

De Foer, Bert [Department of Radiology, Sint-Augustinus Hospital, Oosterveldlaan 24, 2610 Wilrijk (Belgium)], E-mail: bert.defoer@GZA.be; Kenis, Christoph [Department of Radiology, Sint-Augustinus Hospital, Oosterveldlaan 24, 2610 Wilrijk (Belgium)], E-mail: christophkenis@hotmail.com; Van Melkebeke, Deborah [Department of Neurology, Sint-Augustinus Hospital, Oosterveldlaan 24, 2610 Wilrijk (Belgium)], E-mail: Deborah.vanmelkebeke@Ugent.be; Vercruysse, Jean-Philippe [University Department of ENT, Sint-Augustinus Hospital, Oosterveldlaan 24, 2610 Wilrijk (Belgium)], E-mail: jphver@yahoo.com; Somers, Thomas [University Department of ENT, Sint-Augustinus Hospital, Oosterveldlaan 24, 2610 Wilrijk (Belgium)], E-mail: Thomas.somers@GZA.be; Pouillon, Marc [Department of Radiology, Sint-Augustinus Hospital, Oosterveldlaan 24, 2610 Wilrijk (Belgium)], E-mail: marc.pouillon@GZA.be; Offeciers, Erwin [University Department of ENT, Sint-Augustinus Hospital, Oosterveldlaan 24, 2610 Wilrijk (Belgium)], E-mail: Erwin.offeciers@GZA.be; Casselman, Jan W. [Department of Radiology, AZ Sint-Jan AV Hospital, Ruddershove 10, Bruges (Belgium); Consultant Radiologist, Sint-Augustinus Hospital, Oosterveldlaan 24, 2610 Wilrijk (Belgium); Academic Consultent, University of Ghent (Belgium)], E-mail: jan.casselman@azbrugge.be

2010-05-15

There is a large scala of pathology affecting the vestibulocochlear nerve. Magnetic resonance imaging is the method of choice for the investigation of pathology of the vestibulocochlear nerve. Congenital pathology mainly consists of agenesis or hypoplasia of the vestibulocochlear nerve. Tumoral pathology affecting the vestibulocochlear nerve is most frequently located in the internal auditory canal or cerebellopontine angle. Schwannoma of the vestibulocochlear nerve is the most frequently found tumoral lesion followed by meningeoma, arachnoid cyst and epidermoid cyst. The most frequently encountered pathologies as well as some more rare entities are discussed in this chapter.

Pathology of the vestibulocochlear nerve

International Nuclear Information System (INIS)

De Foer, Bert; Kenis, Christoph; Van Melkebeke, Deborah; Vercruysse, Jean-Philippe; Somers, Thomas; Pouillon, Marc; Offeciers, Erwin; Casselman, Jan W.

2010-01-01

There is a large scala of pathology affecting the vestibulocochlear nerve. Magnetic resonance imaging is the method of choice for the investigation of pathology of the vestibulocochlear nerve. Congenital pathology mainly consists of agenesis or hypoplasia of the vestibulocochlear nerve. Tumoral pathology affecting the vestibulocochlear nerve is most frequently located in the internal auditory canal or cerebellopontine angle. Schwannoma of the vestibulocochlear nerve is the most frequently found tumoral lesion followed by meningeoma, arachnoid cyst and epidermoid cyst. The most frequently encountered pathologies as well as some more rare entities are discussed in this chapter.

Digital pathology in nephrology clinical trials, research, and pathology practice.

Science.gov (United States)

Barisoni, Laura; Hodgin, Jeffrey B

2017-11-01

In this review, we will discuss (i) how the recent advancements in digital technology and computational engineering are currently applied to nephropathology in the setting of clinical research, trials, and practice; (ii) the benefits of the new digital environment; (iii) how recognizing its challenges provides opportunities for transformation; and (iv) nephropathology in the upcoming era of kidney precision and predictive medicine. Recent studies highlighted how new standardized protocols facilitate the harmonization of digital pathology database infrastructure and morphologic, morphometric, and computer-aided quantitative analyses. Digital pathology enables robust protocols for clinical trials and research, with the potential to identify previously underused or unrecognized clinically useful parameters. The integration of digital pathology with molecular signatures is leading the way to establishing clinically relevant morpho-omic taxonomies of renal diseases. The introduction of digital pathology in clinical research and trials, and the progressive implementation of the modern software ecosystem, opens opportunities for the development of new predictive diagnostic paradigms and computer-aided algorithms, transforming the practice of renal disease into a modern computational science.

[Adolescent pathological gambling].

Science.gov (United States)

Petit, A; Karila, L; Lejoyeux, M

2015-05-01

Although experts have long thought that the problems of gambling involved only adults, recent studies tend to show that teenagers are also affected. The objective of this paper is to show the characteristics of pathological gambling in adolescents. This review focuses on the clinical features, prevalence, psychopathology, prevention and treatment of this disorder. A review of the medical literature was conducted, using PubMed, using the following keywords alone or combined: pathological gambling, dependence, addiction and adolescents. We selected 12 English articles from 1997 to 2014. Recent work estimate that between 4 and 8% of adolescents suffer from problem gambling, and the prevalence of pathological gambling is 2-4 times higher in adolescents than in adults. The term adolescent pathological gambler starts early around the age of 10-12 years, with a quick change of status from casual to that of problem gambler and player. Complications appear quickly and comorbidities are common. There is no curative pharmacological treatment approved by health authorities. Pathological gambling among adolescents has grown significantly in recent years and should be promptly taken care of. Further studies must be performed to improve our understanding of this problem among adolescents. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Molecular pathology and prostate cancer therapeutics: from biology to bedside.

Science.gov (United States)

Rodrigues, Daniel Nava; Butler, Lisa M; Estelles, David Lorente; de Bono, Johann S

2014-01-01

Prostate cancer (PCa) is the second most commonly diagnosed malignancy in men and has an extremely heterogeneous clinical behaviour. The vast majority of PCas are hormonally driven diseases in which androgen signalling plays a central role. The realization that castration-resistant prostate cancer (CRPC) continues to rely on androgen signalling prompted the development of new, effective androgen blocking agents. As the understanding of the molecular biology of PCas evolves, it is hoped that stratification of prostate tumours into distinct molecular entities, each with its own set of vulnerabilities, will be a feasible goal. Around half of PCas harbour rearrangements involving a member of the ETS transcription factor family. Tumours without this rearrangement include SPOP mutant as well as SPINK1-over-expressing subtypes. As the number of targeted therapy agents increases, it is crucial to determine which patients will benefit from these interventions and molecular pathology will be key in this respect. In addition to directly targeting cells, therapies that modify the tumour microenvironment have also been successful in prolonging the lives of PCa patients. Understanding the molecular aspects of PCa therapeutics will allow pathologists to provide core recommendations for patient management. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Increased Pathological Worry Levels in Patients with Alopecia Areata

Directory of Open Access Journals (Sweden)

Basak Sahin

2017-01-01

Full Text Available Aim: Alopecia Areata (AA is a type of hair loss that has been considered to have associations with various psychiatric disorders. In this study, we aimed to compare pathological worry levels between patients with AA and healthy controls (HC. Material and Method: Sixty-three patients with AA and 90 HCs were included in the present study after applying inclusion and exclusion criteria. The socio-demographic characteristics, some clinical characteristics, and the scores from the Penn State Worry Questionnaire (PSWQ were compared between groups. Results: The demographic characteristics were found to be similar between groups except for gender. The family history of AA was significantly higher in the AA group. The mean score of PSWQ in the AA group was 44.02 ± 11.59, compared to 39.71 ± 7.77 in the HC group. The mean score of PSWQ was significantly higher in the AA group (t=-3.27, p= 0.001.Discussion: The present study is the first to compare pathological worry between patients with AA and HCs. We suggest that pathological worry should be more thoroughly investigated in patients with AA to improve their quality of life. Also, this can be an effective approach to targeting the patients who may develop anxiety disorder.

Desmosome Assembly and Disassembly Are Membrane Raft-Dependent

Science.gov (United States)

Faundez, Victor; Koval, Michael; Mattheyses, Alexa L.; Kowalczyk, Andrew P.

2014-01-01

Strong intercellular adhesion is critical for tissues that experience mechanical stress, such as the skin and heart. Desmosomes provide adhesive strength to tissues by anchoring desmosomal cadherins of neighboring cells to the intermediate filament cytoskeleton. Alterations in assembly and disassembly compromise desmosome function and may contribute to human diseases, such as the autoimmune skin blistering disease pemphigus vulgaris (PV). We previously demonstrated that PV auto-antibodies directed against the desmosomal cadherin desmoglein 3 (Dsg3) cause loss of adhesion by triggering membrane raft-mediated Dsg3 endocytosis. We hypothesized that raft membrane microdomains play a broader role in desmosome homeostasis by regulating the dynamics of desmosome assembly and disassembly. In human keratinocytes, Dsg3 is raft associated as determined by biochemical and super resolution immunofluorescence microscopy methods. Cholesterol depletion, which disrupts rafts, prevented desmosome assembly and adhesion, thus functionally linking rafts to desmosome formation. Interestingly, Dsg3 did not associate with rafts in cells lacking desmosomal proteins. Additionally, PV IgG-induced desmosome disassembly occurred by redistribution of Dsg3 into raft-containing endocytic membrane domains, resulting in cholesterol-dependent loss of adhesion. These findings demonstrate that membrane rafts are required for desmosome assembly and disassembly dynamics, suggesting therapeutic potential for raft targeting agents in desmosomal diseases such as PV. PMID:24498201

Future-proofing pathology: the case for clinical adoption of digital pathology.

Science.gov (United States)

Williams, Bethany Jill; Bottoms, David; Treanor, Darren

2017-12-01

This document clarifies the strategic context of digital pathology adoption, defines the different use cases a healthcare provider may wish to consider as part of a digital adoption and summarises existing reasons for digital adoption and its potential benefits. The reader is provided with references to the relevant literature, and illustrative case studies. The authors hope this report will be of interest to healthcare providers, pathology managers, departmental heads, pathologists and biomedical scientists that are considering digital pathology, deployments or preparing business cases for digital pathology adoption in clinical settings. The information contained in this document can be shared and used in any documentation the reader wishes to present for their own institutional case for adoption report or business case. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Identification of clinical target areas in the brainstem of prion‐infected mice

Science.gov (United States)

Mirabile, Ilaria; Jat, Parmjit S.; Brandner, Sebastian

2015-01-01

Aims While prion infection ultimately involves the entire brain, it has long been thought that the abrupt clinical onset and rapid neurological decline in laboratory rodents relates to involvement of specific critical neuroanatomical target areas. The severity and type of clinical signs, together with the rapid progression, suggest the brainstem as a candidate location for such critical areas. In this study we aimed to correlate prion pathology with clinical phenotype in order to identify clinical target areas. Method We conducted a comprehensive survey of brainstem pathology in mice infected with two distinct prion strains, which produce different patterns of pathology, in mice overexpressing prion protein (with accelerated clinical onset) and in mice in which neuronal expression was reduced by gene targeting (which greatly delays clinical onset). Results We identified specific brainstem areas that are affected by prion pathology during the progression of the disease. In the early phase of disease the locus coeruleus, the nucleus of the solitary tract, and the pre‐Bötzinger complex were affected by prion protein deposition. This was followed by involvement of the motor and autonomic centres of the brainstem. Conclusions Neurodegeneration in the locus coeruleus, the nucleus of the solitary tract and the pre‐Bötzinger complex predominated and corresponded to the manifestation of the clinical phenotype. Because of their fundamental role in controlling autonomic function and the overlap with clinical signs in sporadic Creutzfeldt–Jakob disease, we suggest that these nuclei represent key clinical target areas in prion diseases. PMID:25311251

Nuclear performance of target-blanket assemblies for electronuclear fuel production

International Nuclear Information System (INIS)

Alsmiller, R.G. Jr.; Gabriel, T.A.; Barish, J.

1978-01-01

The results of calculations of high energy transport carried out to evaluate the nuclear performance of several of the designs that have been proposed for electronuclear fuel production are presented. Topics covered include: results for 1-GeV protons and 1-GeV deuterons incident on a lithium target surrounded by a 238 U blanket; results for 1 GeV protons and 1-GeV deuterons incident on a thorium salt; results for 1-GeV protons, incident on a gas-cooled system fueled by either 238 UO 2 or 232 ThO 2 ; and results for protons in the energy range 0.5 to 10 GeV incident on a very large natural uranium target

Next-Generation Pathology.

Science.gov (United States)

Caie, Peter D; Harrison, David J

2016-01-01

The field of pathology is rapidly transforming from a semiquantitative and empirical science toward a big data discipline. Large data sets from across multiple omics fields may now be extracted from a patient's tissue sample. Tissue is, however, complex, heterogeneous, and prone to artifact. A reductionist view of tissue and disease progression, which does not take this complexity into account, may lead to single biomarkers failing in clinical trials. The integration of standardized multi-omics big data and the retention of valuable information on spatial heterogeneity are imperative to model complex disease mechanisms. Mathematical modeling through systems pathology approaches is the ideal medium to distill the significant information from these large, multi-parametric, and hierarchical data sets. Systems pathology may also predict the dynamical response of disease progression or response to therapy regimens from a static tissue sample. Next-generation pathology will incorporate big data with systems medicine in order to personalize clinical practice for both prognostic and predictive patient care.

Noncanonical self-assembly of multifunctional DNA nanoflowers for biomedical applications.

Science.gov (United States)

Zhu, Guizhi; Hu, Rong; Zhao, Zilong; Chen, Zhuo; Zhang, Xiaobing; Tan, Weihong

2013-11-06

DNA nanotechnology has been extensively explored to assemble various functional nanostructures for versatile applications. Mediated by Watson-Crick base-pairing, these DNA nanostructures have been conventionally assembled through hybridization of many short DNA building blocks. Here we report the noncanonical self-assembly of multifunctional DNA nanostructures, termed as nanoflowers (NFs), and the versatile biomedical applications. These NFs were assembled from long DNA building blocks generated via rolling circle replication (RCR) of a designer template. NF assembly was driven by liquid crystallization and dense packaging of building blocks, without relying on Watson-Crick base-pairing between DNA strands, thereby avoiding the otherwise conventional complicated DNA sequence design. NF sizes were readily tunable in a wide range, by simply adjusting such parameters as assembly time and template sequences. NFs were exceptionally resistant to nuclease degradation, denaturation, or dissociation at extremely low concentration, presumably resulting from the dense DNA packaging in NFs. The exceptional biostability is critical for biomedical applications. By rational design, NFs can be readily incorporated with myriad functional moieties. All these properties make NFs promising for versatile applications. As a proof-of-principle demonstration, in this study, NFs were integrated with aptamers, bioimaging agents, and drug loading sites, and the resultant multifunctional NFs were demonstrated for selective cancer cell recognition, bioimaging, and targeted anticancer drug delivery.

High-power fused assemblies enabled by advances in fiber-processing technologies

Science.gov (United States)

Wiley, Robert; Clark, Brett

2011-02-01

The power handling capabilities of fiber lasers are limited by the technologies available to fabricate and assemble the key optical system components. Previous tools for the assembly, tapering, and fusion of fiber laser elements have had drawbacks with regard to temperature range, alignment capability, assembly flexibility and surface contamination. To provide expanded capabilities for fiber laser assembly, a wide-area electrical plasma heat source was used in conjunction with an optimized image analysis method and a flexible alignment system, integrated according to mechatronic principles. High-resolution imaging and vision-based measurement provided feedback to adjust assembly, fusion, and tapering process parameters. The system was used to perform assembly steps including dissimilar-fiber splicing, tapering, bundling, capillary bundling, and fusion of fibers to bulk optic devices up to several mm in diameter. A wide range of fiber types and diameters were tested, including extremely large diameters and photonic crystal fibers. The assemblies were evaluated for conformation to optical and mechanical design criteria, such as taper geometry and splice loss. The completed assemblies met the performance targets and exhibited reduced surface contamination compared to assemblies prepared on previously existing equipment. The imaging system and image analysis algorithms provided in situ fiber geometry measurement data that agreed well with external measurement. The ability to adjust operating parameters dynamically based on imaging was shown to provide substantial performance benefits, particularly in the tapering of fibers and bundles. The integrated design approach was shown to provide sufficient flexibility to perform all required operations with a minimum of reconfiguration.

Three-Dimensionally Engineered Normal Human Broncho-epithelial Tissue-Like Assemblies: Target Tissues for Human Respiratory Viral Infections

Science.gov (United States)

Goodwin, T. J.; McCarthy, M.; Lin, Y-H

2006-01-01

In vitro three-dimensional (3D) human broncho-epithelial (HBE) tissue-like assemblies (3D HBE TLAs) from this point forward referred to as TLAs were engineered in Rotating Wall Vessel (RWV) technology to mimic the characteristics of in vivo tissues thus providing a tool to study human respiratory viruses and host cell interactions. The TLAs were bioengineered onto collagen-coated cyclodextran microcarriers using primary human mesenchymal bronchial-tracheal cells (HBTC) as the foundation matrix and an adult human bronchial epithelial immortalized cell line (BEAS-2B) as the overlying component. The resulting TLAs share significant characteristics with in vivo human respiratory epithelium including polarization, tight junctions, desmosomes, and microvilli. The presence of tissue-like differentiation markers including villin, keratins, and specific lung epithelium markers, as well as the production of tissue mucin, further confirm these TLAs differentiated into tissues functionally similar to in vivo tissues. Increasing virus titers for human respiratory syncytial virus (wtRSVA2) and parainfluenza virus type 3 (wtPIV3 JS) and the detection of membrane bound glycoproteins over time confirm productive infections with both viruses. Therefore, TLAs mimic aspects of the human respiratory epithelium and provide a unique capability to study the interactions of respiratory viruses and their primary target tissue independent of the host's immune system.

Present status of the conceptual design of IFMIF target facility

International Nuclear Information System (INIS)

Katsuta, H.; Kato, Y.; Konishi, S.; Miyauchi, Y.; Smith, D.; Hua, T.; Green, L.; Benamati, G.; Cevolani, S.; Roehrig, H.; Schutz, W.

1998-01-01

The conceptual design activity (CDA) for the international fusion materials irradiation facility (IFMIF) has been conducted. For the IFMIF target facility, the conceptual designs of the following two main components have been performed. The design concept of IFMIF utilizes a high energy deuteron beam of 30-40 MeV and total current of 250 mA, impinging on a flowing lithium jet to produce high energy neutrons for irradiation of candidate fusion materials. (1) The target assembly: The kinetic energy of the deuteron beam is deposited on a Li-jet target and neutrons are produced through the d-Li stripping reaction in this target. The assembly is designed to get a stable lithium jet and to prevent the onset of lithium boiling. For 40-MeV deuteron beam (total current of 250 mA) and a beam footprint of 5 x 20 cm 2 lithium jet dimensions are designed to be 2.5 cm thick and 26 cm wide. The lithium jet parameters are given. (2) Lithium loop: The loop circulates the lithium to and from the target assembly and removes the heat deposited by the deuteron beam containing systems for maintaining the-high purity of the lithium required for radiological safety and to minimize corrosion. The maximum lithium flow rate is 130 l/s and the total lithium inventory is about 21 m 3 . The IFMIF policy requires that the lithium loop system be designed to guarantee no combustion of lithium in the event of a lithium leak. This can be achieved by use of multiple confinement of the lithium carrying components. The radioactive waste generated by the target facilities is estimated. (orig.)

n_TOF New target commissioning and beam characterization

CERN Multimedia

Igashira, M

A full characterization of the neutron beam and experimental conditions for measurement with the new spallation target installed at the n_TOF facility is proposed. In a first step, the behavior the target assembly under the proton beam irradiation will be investigated, in order to complete the target commissioning. Subsequently the neutron beam parameters required to analyze the physics measurements, i.e. neutron fluence, beam profile, energy resolution function and beam related backgrounds as a function of the neutron energy, will be determined.

Intracellular CXCR4+ cell targeting with T22-empowered protein-only nanoparticles

Directory of Open Access Journals (Sweden)

Unzueta U

2012-08-01

Full Text Available Ugutz Unzueta,1–3 María Virtudes Céspedes,3,4 Neus Ferrer-Miralles,1–3 Isolda Casanova,3,4 Juan Cedano,5 José Luis Corchero,1–3 Joan Domingo-Espín,1–3 Antonio Villaverde,1–3 Ramón Mangues,3,4 Esther Vázquez1–31Institut de Biotecnologia i de Biomedicina, 2Departamento de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, 3CIBER en Bioingeniería, Biomateriales y Nanomedicina, Bellaterra, Barcelona, 4Oncogenesis and Antitumor Drug Group, Biomedical Research Institute Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 5Laboratory of Immunology, Regional Norte, Universidad de la Republica, Salto, UruguayBackground: Cell-targeting peptides or proteins are appealing tools in nanomedicine and innovative medicines because they increase the local drug concentration and reduce potential side effects. CXC chemokine receptor 4 (CXCR4 is a cell surface marker associated with several severe human pathologies, including colorectal cancer, for which intracellular targeting agents are currently missing.Results: Four different peptides that bind CXCR4 were tested for their ability to internalize a green fluorescent protein-based reporter nanoparticle into CXCR4+ cells. Among them, only the 18 mer peptide T22, an engineered segment derivative of polyphemusin II from the horseshoe crab, efficiently penetrated target cells via a rapid, receptor-specific endosomal route. This resulted in accumulation of the reporter nanoparticle in a fully fluorescent and stable form in the perinuclear region of the target cells, without toxicity either in cell culture or in an in vivo model of metastatic colorectal cancer.Conclusion: Given the urgent demand for targeting agents in the research, diagnosis, and treatment of CXCR4-linked diseases, including colorectal cancer and human immunodeficiency virus infection, T22 appears to be a promising tag for the intracellular delivery of protein drugs, nanoparticles

Self-assembly of Archimedean tilings with enthalpically and entropically patchy polygons.

Science.gov (United States)

Millan, Jaime A; Ortiz, Daniel; van Anders, Greg; Glotzer, Sharon C

2014-03-25

Considerable progress in the synthesis of anisotropic patchy nanoplates (nanoplatelets) promises a rich variety of highly ordered two-dimensional superlattices. Recent experiments of superlattices assembled from nanoplates confirm the accessibility of exotic phases and motivate the need for a better understanding of the underlying self-assembly mechanisms. Here, we present experimentally accessible, rational design rules for the self-assembly of the Archimedean tilings from polygonal nanoplates. The Archimedean tilings represent a model set of target patterns that (i) contain both simple and complex patterns, (ii) are comprised of simple regular shapes, and (iii) contain patterns with potentially interesting materials properties. Via Monte Carlo simulations, we propose a set of design rules with general applicability to one- and two-component systems of polygons. These design rules, specified by increasing levels of patchiness, correspond to a reduced set of anisotropy dimensions for robust self-assembly of the Archimedean tilings. We show for which tilings entropic patches alone are sufficient for assembly and when short-range enthalpic interactions are required. For the latter, we show how patchy these interactions should be for optimal yield. This study provides a minimal set of guidelines for the design of anisostropic patchy particles that can self-assemble all 11 Archimedean tilings.

Controlled assembly of jammed colloidal shells on fluid droplets

Science.gov (United States)

Subramaniam, Anand Bala; Abkarian, Manouk; Stone, Howard A.

2005-07-01

Assembly of colloidal particles on fluid interfaces is a promising technique for synthesizing two-dimensional microcrystalline materials useful in fields as diverse as biomedicine, materials science, mineral flotation and food processing. Current approaches rely on bulk emulsification methods, require further chemical and thermal treatments, and are restrictive with respect to the materials used. The development of methods that exploit the great potential of interfacial assembly for producing tailored materials have been hampered by the lack of understanding of the assembly process. Here we report a microfluidic method that allows direct visualization and understanding of the dynamics of colloidal crystal growth on curved interfaces. The crystals are periodically ejected to form stable jammed shells, which we refer to as colloidal armour. We propose that the energetic barriers to interfacial crystal growth and organization can be overcome by targeted delivery of colloidal particles through hydrodynamic flows. Our method allows an unprecedented degree of control over armour composition, size and stability.

Sensor mount assemblies and sensor assemblies

Science.gov (United States)

Miller, David H [Redondo Beach, CA

2012-04-10

Sensor mount assemblies and sensor assemblies are provided. In an embodiment, by way of example only, a sensor mount assembly includes a busbar, a main body, a backing surface, and a first finger. The busbar has a first end and a second end. The main body is overmolded onto the busbar. The backing surface extends radially outwardly relative to the main body. The first finger extends axially from the backing surface, and the first finger has a first end, a second end, and a tooth. The first end of the first finger is disposed on the backing surface, and the tooth is formed on the second end of the first finger.

Using machine learning to parse breast pathology reports.

Science.gov (United States)

Yala, Adam; Barzilay, Regina; Salama, Laura; Griffin, Molly; Sollender, Grace; Bardia, Aditya; Lehman, Constance; Buckley, Julliette M; Coopey, Suzanne B; Polubriaginof, Fernanda; Garber, Judy E; Smith, Barbara L; Gadd, Michele A; Specht, Michelle C; Gudewicz, Thomas M; Guidi, Anthony J; Taghian, Alphonse; Hughes, Kevin S

2017-01-01

Extracting information from electronic medical record is a time-consuming and expensive process when done manually. Rule-based and machine learning techniques are two approaches to solving this problem. In this study, we trained a machine learning model on pathology reports to extract pertinent tumor characteristics, which enabled us to create a large database of attribute searchable pathology reports. This database can be used to identify cohorts of patients with characteristics of interest. We collected a total of 91,505 breast pathology reports from three Partners hospitals: Massachusetts General Hospital, Brigham and Women's Hospital, and Newton-Wellesley Hospital, covering the period from 1978 to 2016. We trained our system with annotations from two datasets, consisting of 6295 and 10,841 manually annotated reports. The system extracts 20 separate categories of information, including atypia types and various tumor characteristics such as receptors. We also report a learning curve analysis to show how much annotation our model needs to perform reasonably. The model accuracy was tested on 500 reports that did not overlap with the training set. The model achieved accuracy of 90% for correctly parsing all carcinoma and atypia categories for a given patient. The average accuracy for individual categories was 97%. Using this classifier, we created a database of 91,505 parsed pathology reports. Our learning curve analysis shows that the model can achieve reasonable results even when trained on a few annotations. We developed a user-friendly interface to the database that allows physicians to easily identify patients with target characteristics and export the matching cohort. This model has the potential to reduce the effort required for analyzing large amounts of data from medical records, and to minimize the cost and time required to glean scientific insight from these data.

New insights into molecular diagnostic pathology of primary liver cancer: Advances and challenges.

Science.gov (United States)

Cong, Wen-Ming; Wu, Meng-Chao

2015-11-01

Primary liver cancer (PLC) is one of the most common malignancies worldwide with increasing incidence and accounts for the third leading cause of cancer-related mortality. Traditional morphopathology primarily emphasizes qualitative diagnosis of PLC, which is not sufficient to resolve the major concern of increasing the long-term treatment efficacy of PLC in clinical management for the modern era. Since the beginning of the 21st century, molecular pathology has played an active role in the investigation of the evaluation of the metastatic potential of PLC, detection of drug targets, prediction of recurrence risks, analysis of clonal origins, evaluation of the malignancy trend of precancerous lesions, and determination of clinical prognosis. As a result, many new progresses have been obtained, and new strategies of molecular-pathological diagnosis have been formed. Moreover, the new types of pathobiological diagnosis indicator systems for PLC have been preliminarily established. These achievements provide valuable molecular pathology-based guide for clinical formulation of individualized therapy programs for PLC. This review article briefly summarizes some relevant progresses of molecular-pathological diagnosis of PLC from the perspective of clinical translational application other than basic experimental studies. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Molecular imaging with targeted contrast ultrasound.

Science.gov (United States)

Piedra, Mark; Allroggen, Achim; Lindner, Jonathan R

2009-01-01

Molecular imaging with contrast-enhanced ultrasound uses targeted microbubbles that are retained in diseased tissue. The resonant properties of these microbubbles produce acoustic signals in an ultrasound field. The microbubbles are targeted to diseased tissue by using certain chemical constituents in the microbubble shell or by attaching disease-specific ligands such as antibodies to the microbubble. In this review, we discuss the applications of this technique to pathological states in the cerebrovascular system including atherosclerosis, tumor angiogenesis, ischemia, intravascular thrombus, and inflammation. Copyright 2009 S. Karger AG, Basel.

High wall shear stress and spatial gradients in vascular pathology: a review.

Science.gov (United States)

Dolan, Jennifer M; Kolega, John; Meng, Hui

2013-07-01

Cardiovascular pathologies such as intracranial aneurysms (IAs) and atherosclerosis preferentially localize to bifurcations and curvatures where hemodynamics are complex. While extensive knowledge about low wall shear stress (WSS) has been generated in the past, due to its strong relevance to atherogenesis, high WSS (typically >3 Pa) has emerged as a key regulator of vascular biology and pathology as well, receiving renewed interests. As reviewed here, chronic high WSS not only stimulates adaptive outward remodeling, but also contributes to saccular IA formation (at bifurcation apices or outer curves) and atherosclerotic plaque destabilization (in stenosed vessels). Recent advances in understanding IA pathogenesis have shed new light on the role of high WSS in pathological vascular remodeling. In complex geometries, high WSS can couple with significant spatial WSS gradient (WSSG). A combination of high WSS and positive WSSG has been shown to trigger aneurysm initiation. Since endothelial cells (ECs) are sensors of WSS, we have begun to elucidate EC responses to high WSS alone and in combination with WSSG. Understanding such responses will provide insight into not only aneurysm formation, but also plaque destabilization and other vascular pathologies and potentially lead to improved strategies for disease management and novel targets for pharmacological intervention.

RNA Virus Evolution via a Quasispecies-Based Model Reveals a Drug Target with a High Barrier to Resistance

Directory of Open Access Journals (Sweden)

Richard J. Bingham

2017-11-01

Full Text Available The rapid occurrence of therapy-resistant mutant strains provides a challenge for anti-viral therapy. An ideal drug target would be a highly conserved molecular feature in the viral life cycle, such as the packaging signals in the genomes of RNA viruses that encode an instruction manual for their efficient assembly. The ubiquity of this assembly code in RNA viruses, including major human pathogens, suggests that it confers selective advantages. However, their impact on viral evolution cannot be assessed in current models of viral infection that lack molecular details of virus assembly. We introduce here a quasispecies-based model of a viral infection that incorporates structural and mechanistic knowledge of packaging signal function in assembly to construct a phenotype-fitness map, capturing the impact of this RNA code on assembly yield and efficiency. Details of viral replication and assembly inside an infected host cell are coupled with a population model of a viral infection, allowing the occurrence of therapy resistance to be assessed in response to drugs inhibiting packaging signal recognition. Stochastic simulations of viral quasispecies evolution in chronic HCV infection under drug action and/or immune clearance reveal that drugs targeting all RNA signals in the assembly code collectively have a high barrier to drug resistance, even though each packaging signal in isolation has a lower barrier than conventional drugs. This suggests that drugs targeting the RNA signals in the assembly code could be promising routes for exploitation in anti-viral drug design.

RNA Virus Evolution via a Quasispecies-Based Model Reveals a Drug Target with a High Barrier to Resistance.

Science.gov (United States)

Bingham, Richard J; Dykeman, Eric C; Twarock, Reidun

2017-11-17

The rapid occurrence of therapy-resistant mutant strains provides a challenge for anti-viral therapy. An ideal drug target would be a highly conserved molecular feature in the viral life cycle, such as the packaging signals in the genomes of RNA viruses that encode an instruction manual for their efficient assembly. The ubiquity of this assembly code in RNA viruses, including major human pathogens, suggests that it confers selective advantages. However, their impact on viral evolution cannot be assessed in current models of viral infection that lack molecular details of virus assembly. We introduce here a quasispecies-based model of a viral infection that incorporates structural and mechanistic knowledge of packaging signal function in assembly to construct a phenotype-fitness map, capturing the impact of this RNA code on assembly yield and efficiency. Details of viral replication and assembly inside an infected host cell are coupled with a population model of a viral infection, allowing the occurrence of therapy resistance to be assessed in response to drugs inhibiting packaging signal recognition. Stochastic simulations of viral quasispecies evolution in chronic HCV infection under drug action and/or immune clearance reveal that drugs targeting all RNA signals in the assembly code collectively have a high barrier to drug resistance, even though each packaging signal in isolation has a lower barrier than conventional drugs. This suggests that drugs targeting the RNA signals in the assembly code could be promising routes for exploitation in anti-viral drug design.

Remote handling for an ISIS target change

International Nuclear Information System (INIS)

Broome, T.A.; Holding, M.

1989-01-01

During 1987 two ISIS targets were changed. This document describes the main features of the remote handling aspects of the work. All the work has to be carried out using remote handling techniques. The radiation level measured on the surface of the reflector when the second target had been removed was about 800 mGy/h demonstrating that hands on operations on any part of the target reflector moderator assembly is not practical. The target changes were the first large scale operations in the Target Station Remote Handling Cell and a great deal was learned about both equipment and working practices. Some general principles emerged which are applicable to other active handling tasks on facilities like ISIS and these are discussed below. 8 figs

Haplotype assembly in polyploid genomes and identical by descent shared tracts.

Science.gov (United States)

Aguiar, Derek; Istrail, Sorin

2013-07-01

Genome-wide haplotype reconstruction from sequence data, or haplotype assembly, is at the center of major challenges in molecular biology and life sciences. For complex eukaryotic organisms like humans, the genome is vast and the population samples are growing so rapidly that algorithms processing high-throughput sequencing data must scale favorably in terms of both accuracy and computational efficiency. Furthermore, current models and methodologies for haplotype assembly (i) do not consider individuals sharing haplotypes jointly, which reduces the size and accuracy of assembled haplotypes, and (ii) are unable to model genomes having more than two sets of homologous chromosomes (polyploidy). Polyploid organisms are increasingly becoming the target of many research groups interested in the genomics of disease, phylogenetics, botany and evolution but there is an absence of theory and methods for polyploid haplotype reconstruction. In this work, we present a number of results, extensions and generalizations of compass graphs and our HapCompass framework. We prove the theoretical complexity of two haplotype assembly optimizations, thereby motivating the use of heuristics. Furthermore, we present graph theory-based algorithms for the problem of haplotype assembly using our previously developed HapCompass framework for (i) novel implementations of haplotype assembly optimizations (minimum error correction), (ii) assembly of a pair of individuals sharing a haplotype tract identical by descent and (iii) assembly of polyploid genomes. We evaluate our methods on 1000 Genomes Project, Pacific Biosciences and simulated sequence data. HapCompass is available for download at http://www.brown.edu/Research/Istrail_Lab/. Supplementary data are available at Bioinformatics online.

A modular platform for targeted RNAi therapeutics.

Science.gov (United States)

Kedmi, Ranit; Veiga, Nuphar; Ramishetti, Srinivas; Goldsmith, Meir; Rosenblum, Daniel; Dammes, Niels; Hazan-Halevy, Inbal; Nahary, Limor; Leviatan-Ben-Arye, Shani; Harlev, Michael; Behlke, Mark; Benhar, Itai; Lieberman, Judy; Peer, Dan

2018-03-01

Previous studies have identified relevant genes and signalling pathways that are hampered in human disorders as potential candidates for therapeutics. Developing nucleic acid-based tools to manipulate gene expression, such as short interfering RNAs 1-3 (siRNAs), opens up opportunities for personalized medicine. Yet, although major progress has been made in developing siRNA targeted delivery carriers, mainly by utilizing monoclonal antibodies (mAbs) for targeting 4-8 , their clinical translation has not occurred. This is in part because of the massive development and production requirements and the high batch-to-batch variability of current technologies, which rely on chemical conjugation. Here we present a self-assembled modular platform that enables the construction of a theoretically unlimited repertoire of siRNA targeted carriers. The self-assembly of the platform is based on a membrane-anchored lipoprotein that is incorporated into siRNA-loaded lipid nanoparticles that interact with the antibody crystallizable fragment (Fc) domain. We show that a simple switch of eight different mAbs redirects the specific uptake of siRNAs by diverse leukocyte subsets in vivo. The therapeutic potential of the platform is demonstrated in an inflammatory bowel disease model by targeting colon macrophages to reduce inflammatory symptoms, and in a Mantle Cell Lymphoma xenograft model by targeting cancer cells to induce cell death and improve survival. This modular delivery platform represents a milestone in the development of precision medicine.

A modular platform for targeted RNAi therapeutics

Science.gov (United States)

Kedmi, Ranit; Veiga, Nuphar; Ramishetti, Srinivas; Goldsmith, Meir; Rosenblum, Daniel; Dammes, Niels; Hazan-Halevy, Inbal; Nahary, Limor; Leviatan-Ben-Arye, Shani; Harlev, Michael; Behlke, Mark; Benhar, Itai; Lieberman, Judy; Peer, Dan

2018-01-01

Previous studies have identified relevant genes and signalling pathways that are hampered in human disorders as potential candidates for therapeutics. Developing nucleic acid-based tools to manipulate gene expression, such as short interfering RNAs1-3 (siRNAs), opens up opportunities for personalized medicine. Yet, although major progress has been made in developing siRNA targeted delivery carriers, mainly by utilizing monoclonal antibodies (mAbs) for targeting4-8, their clinical translation has not occurred. This is in part because of the massive development and production requirements and the high batch-to-batch variability of current technologies, which rely on chemical conjugation. Here we present a self-assembled modular platform that enables the construction of a theoretically unlimited repertoire of siRNA targeted carriers. The self-assembly of the platform is based on a membrane-anchored lipoprotein that is incorporated into siRNA-loaded lipid nanoparticles that interact with the antibody crystallizable fragment (Fc) domain. We show that a simple switch of eight different mAbs redirects the specific uptake of siRNAs by diverse leukocyte subsets in vivo. The therapeutic potential of the platform is demonstrated in an inflammatory bowel disease model by targeting colon macrophages to reduce inflammatory symptoms, and in a Mantle Cell Lymphoma xenograft model by targeting cancer cells to induce cell death and improve survival. This modular delivery platform represents a milestone in the development of precision medicine.

The effect of pathological gambling on families, marriages, and children.

Science.gov (United States)

Shaw, Martha C; Forbush, Kelsie T; Schlinder, Jessica; Rosenman, Eugene; Black, Donald W

2007-08-01

Pathological gambling (PG) is widely reported to have negative consequences on marriages, families, and children. Empirical evidence is only now accumulating but when put together with anecdotal information, the extent of these problems is clear. PG contributes to chaos and dysfunction within the family unit, disrupts marriages, leading to high rates of separation and divorce, and is associated with child abuse and neglect. Divorce rates are high, not surprising in light of reports that these marriages are often abusive. Research shows that the families of pathological gamblers are filled with members who gamble excessively, suffer from depressive or anxiety disorders, and misuse alcohol, drugs, or both. Families of persons with PG are also large, a variable independently related to family dysfunction. The authors review the evidence on the impact of PG on families, marriages, and offspring, and make recommendations for future research targeting these problems.

Target cells in internal dosimetry

Energy Technology Data Exchange (ETDEWEB)

Goessner, W

2003-07-01

Data related to radium induced bone sarcomas in humans are used as a model for defining target cells on bone surfaces and in the bone marrow. The differential distribution of radiation induced bone sarcoma types with a high ratio of non-bone producing, mainly fibroblastic tumours, challenges the ICRP concept that the bone lining cells are target cells. Multipotential mesenchymal stem cells are located within the range of alpha particles, and are the most likely target cells for the fibroblastic type of bone sarcoma. The histogenesis of bone sarcomas after irradiation with alpha emitters shows that their final histopathology is not dependent on a single target cell. Each target cell has a microenvironment, which has to be regarded as a synergistic morpho-functional tissue unit. For this the concept of 'histion', a term used in general pathology, is proposed. Interactions between target cells that have been hit by alpha-particles, leading to lethal, mutational or transformation events with all components of a 'histion', will prove critical to understanding the pathogenesis of both deterministic and stochastic late effects. (author)

Target cells in internal dosimetry

International Nuclear Information System (INIS)

Goessner, W.

2003-01-01

Data related to radium induced bone sarcomas in humans are used as a model for defining target cells on bone surfaces and in the bone marrow. The differential distribution of radiation induced bone sarcoma types with a high ratio of non-bone producing, mainly fibroblastic tumours, challenges the ICRP concept that the bone lining cells are target cells. Multipotential mesenchymal stem cells are located within the range of alpha particles, and are the most likely target cells for the fibroblastic type of bone sarcoma. The histogenesis of bone sarcomas after irradiation with alpha emitters shows that their final histopathology is not dependent on a single target cell. Each target cell has a microenvironment, which has to be regarded as a synergistic morpho-functional tissue unit. For this the concept of 'histion', a term used in general pathology, is proposed. Interactions between target cells that have been hit by alpha-particles, leading to lethal, mutational or transformation events with all components of a 'histion', will prove critical to understanding the pathogenesis of both deterministic and stochastic late effects. (author)

The nucleosome assembly activity of NAP1 is enhanced by Alien.

Science.gov (United States)

Eckey, Maren; Hong, Wei; Papaioannou, Maria; Baniahmad, Aria

2007-05-01

The assembly of nucleosomes into chromatin is essential for the compaction of DNA and inactivation of the DNA template to modulate and repress gene expression. The nucleosome assembly protein 1, NAP1, assembles nucleosomes independent of DNA synthesis and was shown to enhance coactivator-mediated gene expression, suggesting a role for NAP1 in transcriptional regulation. Here, we show that Alien, known to harbor characteristics of a corepressor of nuclear hormone receptors such as of the vitamin D receptor (VDR), binds in vivo and in vitro to NAP1 and modulates its activity by enhancing NAP1-mediated nucleosome assembly on DNA. Furthermore, Alien reduces the accessibility of the histones H3 and H4 for NAP1-promoted assembly reaction. This indicates that Alien sustains and reinforces the formation of nucleosomes. Employing deletion mutants of Alien suggests that different regions of Alien are involved in enhancement of NAP1-mediated nucleosome assembly and in inhibiting the accessibility of the histones H3 and H4. In addition, we provide evidence that Alien is associated with chromatin and with micrococcus nuclease-prepared nucleosome fractions and interacts with the histones H3 and H4. Furthermore, chromatin immunoprecipitation and reimmunoprecipitation experiments suggest that NAP1 and Alien localize to the endogenous CYP24 promoter in vivo, a VDR target gene. Based on these findings, we present here a novel pathway linking corepressor function with nucleosome assembly activity.

A Six Sigma Trial For Reduction of Error Rates in Pathology Laboratory.

Science.gov (United States)

Tosuner, Zeynep; Gücin, Zühal; Kiran, Tuğçe; Büyükpinarbaşili, Nur; Turna, Seval; Taşkiran, Olcay; Arici, Dilek Sema

2016-01-01

A major target of quality assurance is the minimization of error rates in order to enhance patient safety. Six Sigma is a method targeting zero error (3.4 errors per million events) used in industry. The five main principles of Six Sigma are defining, measuring, analysis, improvement and control. Using this methodology, the causes of errors can be examined and process improvement strategies can be identified. The aim of our study was to evaluate the utility of Six Sigma methodology in error reduction in our pathology laboratory. The errors encountered between April 2014 and April 2015 were recorded by the pathology personnel. Error follow-up forms were examined by the quality control supervisor, administrative supervisor and the head of the department. Using Six Sigma methodology, the rate of errors was measured monthly and the distribution of errors at the preanalytic, analytic and postanalytical phases was analysed. Improvement strategies were reclaimed in the monthly intradepartmental meetings and the control of the units with high error rates was provided. Fifty-six (52.4%) of 107 recorded errors in total were at the pre-analytic phase. Forty-five errors (42%) were recorded as analytical and 6 errors (5.6%) as post-analytical. Two of the 45 errors were major irrevocable errors. The error rate was 6.8 per million in the first half of the year and 1.3 per million in the second half, decreasing by 79.77%. The Six Sigma trial in our pathology laboratory provided the reduction of the error rates mainly in the pre-analytic and analytic phases.

Interactions within the yeast t-SNARE Sso1p that control SNARE complex assembly.

Science.gov (United States)

Munson, M; Chen, X; Cocina, A E; Schultz, S M; Hughson, F M

2000-10-01

In the eukaryotic secretory and endocytic pathways, transport vesicles shuttle cargo among intracellular organelles and to and from the plasma membrane. Cargo delivery entails fusion of the transport vesicle with its target, a process thought to be mediated by membrane bridging SNARE protein complexes. Temporal and spatial control of intracellular trafficking depends in part on regulating the assembly of these complexes. In vitro, SNARE assembly is inhibited by the closed conformation adopted by the syntaxin family of SNAREs. To visualize this closed conformation directly, the X-ray crystal structure of a yeast syntaxin, Sso1p, has been determined and refined to 2.1 A resolution. Mutants designed to destabilize the closed conformation exhibit accelerated rates of SNARE assembly. Our results provide insight into the mechanism of SNARE assembly and its intramolecular and intermolecular regulation.

Polymeric micelles for drug targeting.

Science.gov (United States)

Mahmud, Abdullah; Xiong, Xiao-Bing; Aliabadi, Hamidreza Montazeri; Lavasanifar, Afsaneh

2007-11-01

Polymeric micelles are nano-delivery systems formed through self-assembly of amphiphilic block copolymers in an aqueous environment. The nanoscopic dimension, stealth properties induced by the hydrophilic polymeric brush on the micellar surface, capacity for stabilized encapsulation of hydrophobic drugs offered by the hydrophobic and rigid micellar core, and finally a possibility for the chemical manipulation of the core/shell structure have made polymeric micelles one of the most promising carriers for drug targeting. To date, three generations of polymeric micellar delivery systems, i.e. polymeric micelles for passive, active and multifunctional drug targeting, have arisen from research efforts, with each subsequent generation displaying greater specificity for the diseased tissue and/or targeting efficiency. The present manuscript aims to review the research efforts made for the development of each generation and provide an assessment on the overall success of polymeric micellar delivery system in drug targeting. The emphasis is placed on the design and development of ligand modified, stimuli responsive and multifunctional polymeric micelles for drug targeting.

Statistical Use of Argonaute Expression and RISC Assembly in microRNA Target Identification

Science.gov (United States)

Stanhope, Stephen A.; Sengupta, Srikumar; den Boon, Johan; Ahlquist, Paul; Newton, Michael A.

2009-01-01

MicroRNAs (miRNAs) posttranscriptionally regulate targeted messenger RNAs (mRNAs) by inducing cleavage or otherwise repressing their translation. We address the problem of detecting m/miRNA targeting relationships in homo sapiens from microarray data by developing statistical models that are motivated by the biological mechanisms used by miRNAs. The focus of our modeling is the construction, activity, and mediation of RNA-induced silencing complexes (RISCs) competent for targeted mRNA cleavage. We demonstrate that regression models accommodating RISC abundance and controlling for other mediating factors fit the expression profiles of known target pairs substantially better than models based on m/miRNA expressions alone, and lead to verifications of computational target pair predictions that are more sensitive than those based on marginal expression levels. Because our models are fully independent of exogenous results from sequence-based computational methods, they are appropriate for use as either a primary or secondary source of information regarding m/miRNA target pair relationships, especially in conjunction with high-throughput expression studies. PMID:19779550

CERN neutrino project on target

CERN Multimedia

2005-01-01

Scientists at CERN announced the completion of the target assembly for the CERN neutrinos to Gran Sasso project, CNGS. On schedule for start-up in May 2006, CNGS will send a beam of neutrinos through the Earth to the Gran Sasso laboratory 730 km away in Italy in a bid to unravel the mysteries of nature's most elusive particles (½ page)

Hierarchical assembly of viral nanotemplates with encoded microparticles via nucleic acid hybridization.

Science.gov (United States)

Tan, Wui Siew; Lewis, Christina L; Horelik, Nicholas E; Pregibon, Daniel C; Doyle, Patrick S; Yi, Hyunmin

2008-11-04

We demonstrate hierarchical assembly of tobacco mosaic virus (TMV)-based nanotemplates with hydrogel-based encoded microparticles via nucleic acid hybridization. TMV nanotemplates possess a highly defined structure and a genetically engineered high density thiol functionality. The encoded microparticles are produced in a high throughput microfluidic device via stop-flow lithography (SFL) and consist of spatially discrete regions containing encoded identity information, an internal control, and capture DNAs. For the hybridization-based assembly, partially disassembled TMVs were programmed with linker DNAs that contain sequences complementary to both the virus 5' end and a selected capture DNA. Fluorescence microscopy, atomic force microscopy (AFM), and confocal microscopy results clearly indicate facile assembly of TMV nanotemplates onto microparticles with high spatial and sequence selectivity. We anticipate that our hybridization-based assembly strategy could be employed to create multifunctional viral-synthetic hybrid materials in a rapid and high-throughput manner. Additionally, we believe that these viral-synthetic hybrid microparticles may find broad applications in high capacity, multiplexed target sensing.

Design and fabrication of self-powered in-core neutron flux monitor assembly

International Nuclear Information System (INIS)

Chung, M.K.; Cho, S.W.; Kang, H.D.; Cho, K.K.; Cho, B.S.; Kang, S.S.

1980-01-01

This is the final report on the prototypical fabrication of an in-core neutron flux monitor detector assembly for a specific power reactor conducted by KAERI from July 1, 1978 to December 31, 1979. It is well known that power reactors require a large number of in-core neutron flux detector for reactor regulation and the structures of detector assemblies are different from reactor to reactor. Therefore, from the nature of this project, it should be noted here that the target model of the prototypical farbrication of an in-core neutron flux monitor detector assembly is a VFD-2 System for Wolsung CANDU. It is concluded that fabrication of in-core neutron flux monitor detector assembly for CANDU reactor is technically feasible and will bring economical benefit as much as 50 % of the unit price if they are fabricated in Korea by using partially materials which are available from local market. (author)

Heterogeneous chromatin target model

International Nuclear Information System (INIS)

Watanabe, Makoto

1996-01-01

The higher order structure of the entangled chromatin fibers in a chromosome plays a key role in molecular control mechanism involved in chromosome mutation due to ionizing radiations or chemical mutagens. The condensed superstructure of chromatin is not so rigid and regular as has been postulated in general. We have proposed a rheological explanation for the flexible network system ('chromatin network') that consists of the fluctuating assembly of nucleosome clusters linked with supertwisting DNA in a chromatin fiber ('Supertwisting Particulate Model'). We have proposed a 'Heterosensitive Target Model' for cellular radiosensitivity that is a modification of 'Heterogeneous Target Model'. The heterogeneity of chromatin target is derived from the highly condensed organization of chromatin segments consist of unstable and fragile sites in the fluctuating assembly of nucleosome clusters, namely 'supranucleosomal particles' or 'superbeads'. The models have been principally supported by our electron microscopic experiments employing 'surface - spreading whole - mount technique' since 1967. However, some deformation and artifacts in the chromatin structure are inevitable with these electron microscopic procedures. On the contrary, the 'atomic force microscope (AFM)' can be operated in liquid as well as in the air. A living specimen can be examined without any preparative procedures. Micromanipulation of the isolated chromosome is also possible by the precise positional control of a cantilever on the nanometer scale. The living human chromosomes were submerged in a solution of culture medium and observed by AFM using a liquid immersion cell. The surface - spreading whole - mount technique was applicable for this observation. The particulate chromatin segments of nucleosome clusters were clearly observed within mitotic human chromosomes in a living hydrated condition. These findings support the heterogeneity of chromatin target in a living cell. (J.P.N.)

The Rise of Forensic Pathology in Human Medicine: Lessons for Veterinary Forensic Pathology.

Science.gov (United States)

Pollanen, M S

2016-09-01

The rise of forensic pathology in human medicine has greatly contributed to the administration of justice, public safety and security, and medical knowledge. However, the evolution of human forensic pathology has been challenging. Veterinary forensic pathologists can learn from some of the lessons that have informed the growth and development of human forensic pathology. Three main observations have emerged in the past decade. First, wrongful convictions tell us to use a truth-seeking stance rather than an a priori "think dirty" stance when investigating obscure death. Second, missed homicides and concealed homicides tell us that training and certification are the beginning of reliable forensic pathology. Third, failure of a sustainable institutional arrangement that fosters a combination of service, research, and teaching will lead to stagnation of knowledge. Forensic pathology of humans and animals will flourish, help protect society, and support justice if we embrace a modern biomedical scientific model for our practice. We must build training programs, contribute to the published literature, and forge strong collaborative institutions. © The Author(s) 2016.

Imaging and Quantitation of a Succession of Transient Intermediates Reveal the Reversible Self-Assembly Pathway of a Simple Icosahedral Virus Capsid.

Science.gov (United States)

Medrano, María; Fuertes, Miguel Ángel; Valbuena, Alejandro; Carrillo, Pablo J P; Rodríguez-Huete, Alicia; Mateu, Mauricio G

2016-11-30

Understanding the fundamental principles underlying supramolecular self-assembly may facilitate many developments, from novel antivirals to self-organized nanodevices. Icosahedral virus particles constitute paradigms to study self-assembly using a combination of theory and experiment. Unfortunately, assembly pathways of the structurally simplest virus capsids, those more accessible to detailed theoretical studies, have been difficult to study experimentally. We have enabled the in vitro self-assembly under close to physiological conditions of one of the simplest virus particles known, the minute virus of mice (MVM) capsid, and experimentally analyzed its pathways of assembly and disassembly. A combination of electron microscopy and high-resolution atomic force microscopy was used to structurally characterize and quantify a succession of transient assembly and disassembly intermediates. The results provided an experiment-based model for the reversible self-assembly pathway of a most simple (T = 1) icosahedral protein shell. During assembly, trimeric capsid building blocks are sequentially added to the growing capsid, with pentamers of building blocks and incomplete capsids missing one building block as conspicuous intermediates. This study provided experimental verification of many features of self-assembly of a simple T = 1 capsid predicted by molecular dynamics simulations. It also demonstrated atomic force microscopy imaging and automated analysis, in combination with electron microscopy, as a powerful single-particle approach to characterize at high resolution and quantify transient intermediates during supramolecular self-assembly/disassembly reactions. Finally, the efficient in vitro self-assembly achieved for the oncotropic, cell nucleus-targeted MVM capsid may facilitate its development as a drug-encapsidating nanoparticle for anticancer targeted drug delivery.

Mobius Assembly: A versatile Golden-Gate framework towards universal DNA assembly.

Directory of Open Access Journals (Sweden)

Andreas I Andreou

Full Text Available Synthetic biology builds upon the foundation of engineering principles, prompting innovation and improvement in biotechnology via a design-build-test-learn cycle. A community-wide standard in DNA assembly would enable bio-molecular engineering at the levels of predictivity and universality in design and construction that are comparable to other engineering fields. Golden Gate Assembly technology, with its robust capability to unidirectionally assemble numerous DNA fragments in a one-tube reaction, has the potential to deliver a universal standard framework for DNA assembly. While current Golden Gate Assembly frameworks (e.g. MoClo and Golden Braid render either high cloning capacity or vector toolkit simplicity, the technology can be made more versatile-simple, streamlined, and cost/labor-efficient, without compromising capacity. Here we report the development of a new Golden Gate Assembly framework named Mobius Assembly, which combines vector toolkit simplicity with high cloning capacity. It is based on a two-level, hierarchical approach and utilizes a low-frequency cutter to reduce domestication requirements. Mobius Assembly embraces the standard overhang designs designated by MoClo, Golden Braid, and Phytobricks and is largely compatible with already available Golden Gate part libraries. In addition, dropout cassettes encoding chromogenic proteins were implemented for cost-free visible cloning screening that color-code different cloning levels. As proofs of concept, we have successfully assembled up to 16 transcriptional units of various pigmentation genes in both operon and multigene arrangements. Taken together, Mobius Assembly delivers enhanced versatility and efficiency in DNA assembly, facilitating improved standardization and automation.

Programmed Nanomaterial Assemblies in Large Scales: Applications of Synthetic and Genetically- Engineered Peptides to Bridge Nano-Assemblies and Macro-Assemblies

Energy Technology Data Exchange (ETDEWEB)

Matsui, Hiroshi

2014-09-09

Work is reported in these areas: Large-scale & reconfigurable 3D structures of precise nanoparticle assemblies in self-assembled collagen peptide grids; Binary QD-Au NP 3D superlattices assembled with collagen-like peptides and energy transfer between QD and Au NP in 3D peptide frameworks; Catalytic peptides discovered by new hydrogel-based combinatorial phage display approach and their enzyme-mimicking 2D assembly; New autonomous motors of metal-organic frameworks (MOFs) powered by reorganization of self-assembled peptides at interfaces; Biomimetic assembly of proteins into microcapsules on oil-in-water droplets with structural reinforcement via biomolecular recognition-based cross-linking of surface peptides; and Biomimetic fabrication of strong freestanding genetically-engineered collagen peptide films reinforced by quantum dot joints. We gained the broad knowledge about biomimetic material assembly from nanoscale to microscale ranges by coassembling peptides and NPs via biomolecular recognition. We discovered: Genetically-engineered collagen-like peptides can be self-assembled with Au NPs to generate 3D superlattices in large volumes (> μm{sup 3}); The assembly of the 3D peptide-Au NP superstructures is dynamic and the interparticle distance changes with assembly time as the reconfiguration of structure is triggered by pH change; QDs/NPs can be assembled with the peptide frameworks to generate 3D superlattices and these QDs/NPs can be electronically coupled for the efficient energy transfer; The controlled assembly of catalytic peptides mimicking the catalytic pocket of enzymes can catalyze chemical reactions with high selectivity; and, For the bacteria-mimicking swimmer fabrication, peptide-MOF superlattices can power translational and propellant motions by the reconfiguration of peptide assembly at the MOF-liquid interface.

Technologies using accelerator-driven targets under development at BNL

International Nuclear Information System (INIS)

Van Tuyle, G.J.

1994-01-01

Recent development work conducted at Brookhaven National Laboratory on technologies which use particle accelerator-driven targets is summarized. These efforts include development of the Spallation-Induced Lithium Conversion (SILC) Target for the Accelerator Production of Tritium (APT), the Accelerator-Driven Assembly for Plutonium Transformation (ADAPT) Target for the Accelerator-Based Conversion (ABC) of excess weapons plutonium. The PHOENIX Concept for the accelerator-driven transmutation of minor actinides and fission products from the waste stream of commercial nuclear power plants, and other potential applications

A comparison of reaction rate calculations using Endf/B-VII with critical assembly measurements

International Nuclear Information System (INIS)

Wilkerson, C.; Mac Innes, M.; Barr, D.; Trellue, H.; MacFarlane, R.; Chadwick, M.

2008-01-01

We present critical assembly reaction rate data, and modeling of the same using the recently released Endf/B-VII library. While some of the experimental measurements were performed as long as 50 years ago, the results have not been widely used/available outside of Los Alamos. Over the years, a variety of target foils were fabricated and placed in differing neutron spectrum/fluence environments within critical assemblies. Neutron-induced reactions such as (n,γ), (n,2n), and (n,f) on these targets were measured, typically referenced to 235 U(n,f) or 239 Pu(n,f). Because the cross section for the latter reactions are now well known, these experiments provide a rich data set for testing evaluated cross sections. Due to the large variety of critical assemblies that were historically available at Los Alamos, it was possible to make measurements in spectral environments ranging from hard (Pu Jezebel, center of Pu Flattop) through intermediate (Big Ten) to degraded (reflector region of Flattop). This broad range of configurations allows us to test both the cross section magnitudes and their energy dependencies. We will present data, along with reaction rate predictions using primarily MCNP5 in conjunction with Endf/B-VII, for a number of target nuclei, including iridium, isotopes of uranium (e.g., 233, 235, 237, 238), neptunium (237), plutonium (239), and americium (241). (authors)

Pathological video-gaming among Singaporean youth.

Science.gov (United States)

Choo, Hyekyung; Gentile, Douglas A; Sim, Timothy; Li, Dongdong; Khoo, Angeline; Liau, Albert K

2010-11-01

Increase in internet use and video-gaming contributes to public concern on pathological or obsessive play of video games among children and adolescents worldwide. Nevertheless, little is known about the prevalence of pathological symptoms in video-gaming among Singaporean youth and the psychometric properties of instruments measuring pathological symptoms in video-gaming. A total of 2998 children and adolescents from 6 primary and 6 secondary schools in Singapore responded to a comprehensive survey questionnaire on sociodemographic characteristics, video-gaming habits, school performance, somatic symptoms, various psychological traits, social functioning and pathological symptoms of video-gaming. After weighting, the survey data were analysed to determine the prevalence of pathological video-gaming among Singaporean youth and gender differences in the prevalence. The construct validity of instrument used to measure pathological symptoms of video-gaming was tested. Of all the study participants, 8.7% were classified as pathological players with more boys reporting more pathological symptoms than girls. All variables, including impulse control problem, social competence, hostility, academic performance, and damages to social functioning, tested for construct validity, were significantly associated with pathological status, providing good evidence for the construct validity of the instrument used. The prevalence rate of pathological video-gaming among Singaporean youth is comparable with that from other countries studied thus far, and gender differences are also consistent with the findings of prior research. The positive evidence of construct validity supports the potential use of the instrument for future research and clinical screening on Singapore children and adolescents' pathological video-gaming.

Modeling of a cyclotron target for the production of 11C with Geant4.

Science.gov (United States)

Chiappiniello, Andrea; Zagni, Federico; Infantino, Angelo; Vichi, Sara; Cicoria, Gianfranco; Morigi, Maria Pia; Marengo, Mario

2018-04-12

In medical cyclotron facilities, 11C is produced according to the 14N(p,α)11C reaction and widely employed in studies of prostate and brain cancers by Positron Emission Tomography. It is known from literature [1] that the 11C-target assembly shows a reduction in efficiency during time, meaning a decrease of activity produced at the end of bombardment. This effect might depend on aspects still not completely known. Possible causes of the loss of performance of the 11C-target assembly were addressed by Monte Carlo simulations. Geant4 was used to model the 11C-target assembly of a GE PETtrace cyclotron. The physical and transport parameters to be used in the energy range of medical applications were extracted from literature data and 11C routine productions. The Monte Carlo assessment of 11C saturation yield was performed varying several parameters such as the proton energy and the angle of the target assembly with respect to the proton beam. The estimated 11C saturation yield is in agreement with IAEA data at the energy of interest, while is about the 35% greater than experimental value. A more comprehensive modeling of the target system, including thermodynamic effect, is required. The energy absorbed in the inner layer of the target chamber was up to 46.5 J/mm2 under typical irradiation conditions. This study shows that Geant4 is potentially a useful tool to design and optimize targetry for PET radionuclide productions. Tests to choose the Geant4 physics libraries should be performed before using this tool with different energies and materials. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Targeting Integrin-β1 Impedes Cytokine-Induced Osteoclast ...

African Journals Online (AJOL)

but not in RANKL pathway. Given that, inflammatory cytokine secretions such as TNF-α are progressively implicated in pathological osteolysis, targeting this pathway may .... RANKL or TNF-alpha treated culture systems ... universal PCR Master Mix (Life Technologies,. USA). ... and developed using Super Signal West Dura.

Th and U fuel photofission study by NTD for AD-MSR subcritical assembly

Energy Technology Data Exchange (ETDEWEB)

Sajo-Bohus, Laszlo; Greaves, Eduardo D.; Barros, Haydn; Pino, Felix; Barrera, Maria T.; Farina, Fulvio [Universidad Simón Bolívar, Nuclear Physics Laboratory, Apdo 89000, Caracas 1080A (Venezuela, Bolivarian Republic of); Davila, Jesus [Física Médica C. A. and Universidad Central de Venezuela, Caracas (Venezuela, Bolivarian Republic of)

2015-07-23

During the last decade a considerable effort has been devoted for developing energy generating systems based on advanced nuclear technology within the design concepts of GEN-IV. Thorium base fuel systems such as accelerator driven nuclear reactors are one of the often mentioned attractive and affordable options. Several radiotherapy linear accelerators are on the market and due to their reliability, they could be employed as drivers for subcritical liquid fuel assemblies. Bremsstrahlung photons with energies above 5.5MeV, induce (γ,n) and (e,e’n) reactions in the W-target. Resulting gamma radiation and photo or fission neutrons may be absorbed in target materials such as thorium and uranium isotopes to induce sustained fission or nuclear transmutation in waste radioactive materials. Relevant photo driven and photo-fission reaction cross sections are important for actinides {sup 232}Th, {sup 238}U and {sup 237}Np in the radiotherapy machines energy range of 10-20 MV. In this study we employ passive nuclear track detectors (NTD) to determine fission rates and neutron production rates with the aim to establish the feasibility for gamma and photo-neutron driven subcritical assemblies. To cope with these objectives a 20 MV radiotherapy machine has been employed with a mixed fuel target. Results will support further development for a subcritical assembly employing a thorium containing liquid fuel. It is expected that acquired technological knowledge will contribute to the Venezuelan nuclear energy program.

Th and U fuel photofission study by NTD for AD-MSR subcritical assembly

Science.gov (United States)

Sajo-Bohus, Laszlo; Greaves, Eduardo D.; Davila, Jesus; Barros, Haydn; Pino, Felix; Barrera, Maria T.; Farina, Fulvio

2015-07-01

During the last decade a considerable effort has been devoted for developing energy generating systems based on advanced nuclear technology within the design concepts of GEN-IV. Thorium base fuel systems such as accelerator driven nuclear reactors are one of the often mentioned attractive and affordable options. Several radiotherapy linear accelerators are on the market and due to their reliability, they could be employed as drivers for subcritical liquid fuel assemblies. Bremsstrahlung photons with energies above 5.5MeV, induce (γ,n) and (e,e'n) reactions in the W-target. Resulting gamma radiation and photo or fission neutrons may be absorbed in target materials such as thorium and uranium isotopes to induce sustained fission or nuclear transmutation in waste radioactive materials. Relevant photo driven and photo-fission reaction cross sections are important for actinides 232Th, 238U and 237Np in the radiotherapy machines energy range of 10-20 MV. In this study we employ passive nuclear track detectors (NTD) to determine fission rates and neutron production rates with the aim to establish the feasibility for gamma and photo-neutron driven subcritical assemblies. To cope with these objectives a 20 MV radiotherapy machine has been employed with a mixed fuel target. Results will support further development for a subcritical assembly employing a thorium containing liquid fuel. It is expected that acquired technological knowledge will contribute to the Venezuelan nuclear energy program.

Information-optimal genome assembly via sparse read-overlap graphs.

Science.gov (United States)

Shomorony, Ilan; Kim, Samuel H; Courtade, Thomas A; Tse, David N C

2016-09-01

In the context of third-generation long-read sequencing technologies, read-overlap-based approaches are expected to play a central role in the assembly step. A fundamental challenge in assembling from a read-overlap graph is that the true sequence corresponds to a Hamiltonian path on the graph, and, under most formulations, the assembly problem becomes NP-hard, restricting practical approaches to heuristics. In this work, we avoid this seemingly fundamental barrier by first setting the computational complexity issue aside, and seeking an algorithm that targets information limits In particular, we consider a basic feasibility question: when does the set of reads contain enough information to allow unambiguous reconstruction of the true sequence? Based on insights from this information feasibility question, we present an algorithm-the Not-So-Greedy algorithm-to construct a sparse read-overlap graph. Unlike most other assembly algorithms, Not-So-Greedy comes with a performance guarantee: whenever information feasibility conditions are satisfied, the algorithm reduces the assembly problem to an Eulerian path problem on the resulting graph, and can thus be solved in linear time. In practice, this theoretical guarantee translates into assemblies of higher quality. Evaluations on both simulated reads from real genomes and a PacBio Escherichia coli K12 dataset demonstrate that Not-So-Greedy compares favorably with standard string graph approaches in terms of accuracy of the resulting read-overlap graph and contig N50. Available at github.com/samhykim/nsg courtade@eecs.berkeley.edu or dntse@stanford.edu Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Galaxy And Mass Assembly (GAMA): the G02 field, Herschel-ATLAS target selection and Data Release 3 arXiv

CERN Document Server

Baldry, I.K.; Brown, M.J.I.; Robotham, A.S.G.; Driver, S.P.; Dunne, L.; Alpaslan, M.; Brough, S.; Cluver, M.E.; Eardley, E.; Farrow, D.J.; Heymans, C.; Hildebrandt, H.; Hopkins, A.M.; Kelvin, L.S.; Loveday, J.; Moffett, A.J.; Norberg, P.; Owers, M.S.; Taylor, E.N.; Wright, A.H.; Bamford, S.P.; Bland-Hawthorn, J.; Bourne, N.; Bremer, M.N.; Colless, M.; Conselice, C.J.; Croom, S.M.; Davies, L.J.M.; Foster, C.; Grootes, M.W.; Holwerda, B.W.; Jones, D.H.; Kafle, P.R.; Kuijken, K.; Lara-Lopez, M.A.; Lopez-Sanchez, A.R.; Meyer, M.J.; Phillipps, S.; Sutherland, W.J.; van Kampen, E.; Wilkins, S.M.

We describe data release 3 (DR3) of the Galaxy And Mass Assembly (GAMA) survey. The GAMA survey is a spectroscopic redshift and multi-wavelength photometric survey in three equatorial regions each of 60.0 deg^2 (G09, G12, G15), and two southern regions of 55.7 deg^2 (G02) and 50.6 deg^2 (G23). DR3 consists of: the first release of data covering the G02 region and of data on H-ATLAS sources in the equatorial regions; and updates to data on sources released in DR2. DR3 includes 154809 sources with secure redshifts across four regions. A subset of the G02 region is 95.5% redshift complete to r<19.8 over an area of 19.5 deg^2, with 20086 galaxy redshifts, that overlaps substantially with the XXL survey (X-ray) and VIPERS (redshift survey). In the equatorial regions, the main survey has even higher completeness (98.5%), and spectra for about 75% of H-ATLAS filler targets were also obtained. This filler sample extends spectroscopic redshifts, for probable optical counterparts to H-ATLAS sub-mm sources, to 0.8 ma...

Stroop performance in pathological gamblers.

Science.gov (United States)

Kertzman, Semion; Lowengrub, Katherine; Aizer, Anat; Nahum, Zeev Ben; Kotler, Moshe; Dannon, Pinhas N

2006-05-30

Pathological gambling is a relatively prevalent psychiatric disorder that typically leads to severe family, social, legal, and occupational problems and is associated with a high rate of suicide attempts. Understanding the neurobiological basis of pathological gambling is a current focus of research, and emerging data have demonstrated that pathological gamblers may have impaired decision-making because of an inability to inhibit irrelevant information. In this study, we examined pathological gamblers by using the Stroop Color-Word Test, a neurocognitive task used to assess interference control. The "reverse" variant of the Stroop Color-Word Test was administered to a cohort of medication-free pathological gamblers (n=62) and a cohort of age-matched controls (n=83). In the reverse variant of the Stroop task, subjects are asked to read the meaning of the word rather than name the ink color. The reverse Stroop task was chosen because it highly discriminates ability to inhibit interference in a population of psychiatric patients. In our study, performance on the reverse Stroop task in the pathological gamblers was significantly slower and less accurate than in the healthy subjects. A new finding in our study was that for pathological gamblers, the average reaction time in the neutral condition (where the color names are displayed in black letters) was slower than the average reaction time in the incongruent condition (where the meaning of the color name and the color of the printed letters are different). This controlled study extends previous findings by showing that performance on the Stroop task is impaired in a sample of medication-free pathological gamblers.

Minor actinides incineration by loading moderated targets in fast reactor

International Nuclear Information System (INIS)

Wu Hongchun; Sato, Daisuke; Takeda, Toshikazu

2000-01-01

The effect of hydrogen concentration and loaded mass of minor actinides (MAs) in the target on the core performance and MAs transmutation rate was analyzed in this paper. An optimum core was proposed which has 96 MAs target assemblies of which MAs fuel pins per assembly is 38 with the composition ratio U/MA/Zr/H of 1/4/10/50. This optimized core offers good core performance and can transmute MAs very effectively, the transmutation rate was about 67% (939 kg) and the incinerate (transmute by fission) rate was about 35% (489 kg) through 3 years of reactor operation. It is about 2-3 times larger than current transmutation method that MAs are loaded homogeneously in the PWR and fast reactor core. (author)

Self-assembly of self-assembled molecular triangles

Indian Academy of Sciences (India)

While the solution state structure of 1 can be best described as a trinuclear complex, in the solidstate well-fashioned intermolecular - and CH- interactions are observed. Thus, in the solid-state further self-assembly of already self-assembled molecular triangle is witnessed. The triangular panels are arranged in a linear ...

Evaluation of nine popular de novo assemblers in microbial genome assembly.

Science.gov (United States)

Forouzan, Esmaeil; Maleki, Masoumeh Sadat Mousavi; Karkhane, Ali Asghar; Yakhchali, Bagher

2017-12-01

Next generation sequencing (NGS) technologies are revolutionizing biology, with Illumina being the most popular NGS platform. Short read assembly is a critical part of most genome studies using NGS. Hence, in this study, the performance of nine well-known assemblers was evaluated in the assembly of seven different microbial genomes. Effect of different read coverage and k-mer parameters on the quality of the assembly were also evaluated on both simulated and actual read datasets. Our results show that the performance of assemblers on real and simulated datasets could be significantly different, mainly because of coverage bias. According to outputs on actual read datasets, for all studied read coverages (of 7×, 25× and 100×), SPAdes and IDBA-UD clearly outperformed other assemblers based on NGA50 and accuracy metrics. Velvet is the most conservative assembler with the lowest NGA50 and error rate. Copyright © 2017. Published by Elsevier B.V.

Tailorable Exciton Transport in Doped Peptide–Amphiphile Assemblies

Energy Technology Data Exchange (ETDEWEB)

Solomon, Lee A. [Center; Sykes, Matthew E. [Center; Wu, Yimin A. [Center; Schaller, Richard D. [Center; Department; Wiederrecht, Gary P. [Center; Fry, H. Christopher [Center

2017-08-29

Light-harvesting biomaterials are an attractive target in photovoltaics, photocatalysis, and artificial photosynthesis. Through peptide self-assembly, complex nanostructures can be engineered to study the role of chromophore organization during light absorption and energy transport. To this end, we demonstrate the one-dimensional transport of excitons along naturally occurring, light-harvesting, Zn-protoporphyrin IX chromophores within self-assembled peptide-amphiphile nanofibers. The internal structure of the nanofibers induces packing of the porphyrins into linear chains. We find that this peptide assembly can enable long-range exciton diffusion, yet it also induces the formation of excimers between adjacent molecules, which serve as exciton traps. Electronic coupling between neighboring porphyrin molecules is confirmed by various spectroscopic methods. The exciton diffusion process is then probed through transient photoluminescence and absorption measurements and fit to a model for one-dimensional hopping. Because excimer formation impedes exciton hopping, increasing the interchromophore spacing allows for improved diffusivity, which we control through porphyrin doping levels. We show that diffusion lengths of over 60 nm are possible at low porphyrin doping, representing an order of magnitude improvement over the highest doping fractions.

Laser ``M'egajoule'' cryogenic target program: from target fabrication to conformation of the deuterium-tritium ice layer

Science.gov (United States)

Collier, Rémy; Durut, Frédéric; Reneaume, Benoît; Chicane, Cédric; Théobald, Marc; Breton, Olivier; Martin, Michel; Fleury, Emmanuel; Vincent-Viry, Olivier; Bachelet, Franck; Jeannot, Laurent; Geoffray, Isabelle; Botrel, Ronan; Dauteuil, Christophe; Hermerel, Cyril; Choux, Alexandre; Bednarczyk, Sophie; Legaie, Olivier

2008-11-01

For the French inertial confinement fusion (ICF) experiments, cryogenic target assemblies (CTAs) for the LMJ program are manufactured and filled at CEA Valduc (Dijon) in the cryogenic targets filling station (IRCC). They will be moved at about 20 K into a transport cryostat for cryogenic targets and will be driven from CEA/Valduc to CEA/CESTA (Bordeaux). Cryogenic targets will then be transferred by several cryogenic grippers on the cryogenic target positioner before shots. The CTA has to meet severe specifications and involves a lot of challenging tasks for its manufacture. To fill CTAs by permeation with deuterium-tritium (DT), the IRCC need to meet strict thermal, mechanical and dimensional specifications. To obtain a good combustion yield, a very homogenous DT ice layer and very smooth roughness at 1.5 K below the DT triple point are also required. This paper deals with the up to date main issues in the different fields of the LMJ cryogenic target program.

A conceptual design of assembly strategy and dedicated tools for assembly of 40o sector

International Nuclear Information System (INIS)

Park, H.K.; Nam, K.O.; Kim, D.J.; Ahn, H.J.; Lee, J.H.; Im, K.; Shaw, R.

2010-01-01

The International Thermanuclear Experimental Reactor (ITER) tokamak device is composed of 9 vacuum vessel (VV)/toroidal field coils (TFCs)/vacuum vessel thermal shields (VVTS) 40 o sectors. Each VV/TFCs/VVTS 40 o sector is made up of one 40 o VV, two 20 o TFCs and associated VVTS segments. The 40 o sectors are sub-assembled at assembly hall respectively and then nine 40 o sectors sub-assembled at assembly hall are finally assembled at tokamak in-pit hall. The assembly strategy and tools for the 40 o sector sub-assembly and final assembly should be developed to satisfy the basic assembly requirements of the ITER tokamak device. Accordingly, the purpose-built assembly tools should be designed and manufactured considering assembly plan, available space, cost, safety, easy operation, efficient maintenance, and so on. The 40 o sector assembly tools are classified into 2 groups. One group is the sub-assembly tools including upending tool, lifting tool, sub-assembly tool, VV supports and bracing tools used at assembly hall and the other group is the in-pit assembly tools including lifting tool, central column, radial beams and their supports. This paper describes the current status of the assembly strategy and major tools for the VV/TFCs/VVTS 40 o sector assembly at in-pit hall and assembly hall. The conceptual design of the major assembly tools and assembly process at assembly hall and tokamak in-pit hall are presented also.

The current and ideal state of anatomic pathology patient safety.

Science.gov (United States)

Raab, Stephen Spencer

2014-01-01

An anatomic pathology diagnostic error may be secondary to a number of active and latent technical and/or cognitive components, which may occur anywhere along the total testing process in clinical and/or laboratory domains. For the pathologist interpretive steps of diagnosis, we examine Kahneman's framework of slow and fast thinking to explain different causes of error in precision (agreement) and in accuracy (truth). The pathologist cognitive diagnostic process involves image pattern recognition and a slow thinking error may be caused by the application of different rationally-constructed mental maps of image criteria/patterns by different pathologists. This type of error is partly related to a system failure in standardizing the application of these maps. A fast thinking error involves the flawed leap from image pattern to incorrect diagnosis. In the ideal state, anatomic pathology systems would target these cognitive error causes as well as the technical latent factors that lead to error.

Integrated Pathology Informatics Enables High-Quality Personalized and Precision Medicine: Digital Pathology and Beyond.

Science.gov (United States)

Volynskaya, Zoya; Chow, Hung; Evans, Andrew; Wolff, Alan; Lagmay-Traya, Cecilia; Asa, Sylvia L

2018-03-01

- The critical role of pathology in diagnosis, prognosis, and prediction demands high-quality subspecialty diagnostics that integrates information from multiple laboratories. - To identify key requirements and to establish a systematic approach to providing high-quality pathology in a health care system that is responsible for services across a large geographic area. - This report focuses on the development of a multisite pathology informatics platform to support high-quality surgical pathology and hematopathology using a sophisticated laboratory information system and whole slide imaging for histology and immunohistochemistry, integrated with ancillary tools, including electron microscopy, flow cytometry, cytogenetics, and molecular diagnostics. - These tools enable patients in numerous geographic locations access to a model of subspecialty pathology that allows reporting of every specimen by the right pathologist at the right time. The use of whole slide imaging for multidisciplinary case conferences enables better communication among members of patient care teams. The system encourages data collection using a discrete data synoptic reporting module, has implemented documentation of quality assurance activities, and allows workload measurement, providing examples of additional benefits that can be gained by this electronic approach to pathology. - This approach builds the foundation for accurate big data collection and high-quality personalized and precision medicine.

Fuel injection assembly for use in turbine engines and method of assembling same

Science.gov (United States)

Berry, Jonathan Dwight; Johnson, Thomas Edward; York, William David; Uhm, Jong Ho

2015-12-15

A fuel injection assembly for use in a turbine engine is provided. The fuel injection assembly includes an end cover, an endcap assembly, a fluid supply chamber, and a plurality of tube assemblies positioned at the endcap assembly. Each of the tube assemblies includes housing having a fuel plenum and a cooling fluid plenum. The cooling fluid plenum is positioned downstream from the fuel plenum and separated from the fuel plenum by an intermediate wall. The plurality of tube assemblies also include a plurality of tubes that extends through the housing. Each of the plurality of tubes is coupled in flow communication with the fluid supply chamber and a combustion chamber positioned downstream from the tube assembly. The plurality of tube assemblies further includes an aft plate at a downstream end of the cooling fluid plenum. The plate includes at least one aperture.

PREFACE The physics of virus assembly The physics of virus assembly

Science.gov (United States)

Stockley, Peter G.; Twarock, Reidun

2010-12-01

Viruses are pathogens in every kingdom of life and are major causes of human disease and suffering. They are known to encompass a size range that overlaps with that of the smallest bacterial cells, and the largest viruses now seem to be hosts of their own viral pathogens. Recent genomic sequencing efforts show that many organisms have genes that are likely to be descended in evolution from viral progenitors. Even more astonishingly, analysis of the world's oceans has shown that some of the simplest viruses, the tailed dsDNA phages, are the most common biological entities on the planet, with estimates of their numbers ranging up to 1031, with ~ 1021 infection events every second, leading to a turnover of around 20% of the biomass in the sea every few days. These cycles of infection and lysis of oceanic bacteria and algae provide the nutrients for the smallest organisms lying at the bottom of the food chain. Without viruses, therefore, life on Earth would probably not be sustainable. These are remarkable facts for systems that are non-living in the strict sense, and are composed of simple materials—nucleic acids, proteins and lipids. Many viruses consist of little more than a protective protein coat surrounding their genomic nucleic acids, which can be either DNA or RNA. Their simplicity leads to highly symmetrical structures with protein containers based on helical or icosahedral lattices. Many simple viruses self-assemble rapidly and with great fidelity, and many groups are busy trying to exploit these properties to make virus-like particles for a wide range of applications, including targeted drug-delivery, medical imaging and even novel materials. This issue of Physical Biology contains a series of papers describing some of the latest experimental and theoretical research on viruses, their structures and assembly, as well as their regulated disassembly during infection. These range from a dissection of the in vivo assembly mechanism of a filamentous virus

Histamine modulation of the basal ganglia circuitry in the development of pathological grooming

Science.gov (United States)

Rapanelli, Maximiliano; Frick, Luciana

2017-01-01

Aberrant histaminergic function has been proposed as a cause of tic disorders. A rare mutation in the enzyme that produces histamine (HA), histidine decarboxylase (HDC), has been identified in patients with Tourette syndrome (TS). Hdc knockout mice exhibit repetitive behavioral pathology and neurochemical characteristics of TS, establishing them as a plausible model of tic pathophysiology. Where, when, and how HA deficiency produces these effects has remained unclear: whether the contribution of HA deficiency to pathogenesis is acute or developmental, and where in the brain the relevant consequences of HA deficiency occur. Here, we address these key pathophysiological questions, using anatomically and cellularly targeted manipulations in mice. We report that specific ablation or chemogenetic silencing of histaminergic neurons in the tuberomammillary nucleus (TMN) of the hypothalamus leads to markedly elevated grooming, a form of repetitive behavioral pathology, and to elevated markers of neuronal activity in both dorsal striatum and medial prefrontal cortex. Infusion of HA directly into the striatum reverses this behavioral pathology, confirming that acute HA deficiency mediates the effect. Bidirectional chemogenetic regulation reveals that dorsal striatum neurons activated after TMN silencing are both sufficient to produce repetitive behavioral pathology and necessary for the full expression of the effect. Chemogenetic activation of TMN-regulated medial prefrontal cortex neurons, in contrast, increases locomotion and not grooming. These data confirm the centrality of striatal regulation by neurotransmitter HA in the adult in the production of pathological grooming. PMID:28584117

AutoAssemblyD: a graphical user interface system for several genome assemblers.

Science.gov (United States)

Veras, Adonney Allan de Oliveira; de Sá, Pablo Henrique Caracciolo Gomes; Azevedo, Vasco; Silva, Artur; Ramos, Rommel Thiago Jucá

2013-01-01

Next-generation sequencing technologies have increased the amount of biological data generated. Thus, bioinformatics has become important because new methods and algorithms are necessary to manipulate and process such data. However, certain challenges have emerged, such as genome assembly using short reads and high-throughput platforms. In this context, several algorithms have been developed, such as Velvet, Abyss, Euler-SR, Mira, Edna, Maq, SHRiMP, Newbler, ALLPATHS, Bowtie and BWA. However, most such assemblers do not have a graphical interface, which makes their use difficult for users without computing experience given the complexity of the assembler syntax. Thus, to make the operation of such assemblers accessible to users without a computing background, we developed AutoAssemblyD, which is a graphical tool for genome assembly submission and remote management by multiple assemblers through XML templates. AssemblyD is freely available at https://sourceforge.net/projects/autoassemblyd. It requires Sun jdk 6 or higher.

Dysregulation of Prefrontal Cortex-Mediated Slow-Evolving Limbic Dynamics Drives Stress-Induced Emotional Pathology.

Science.gov (United States)

Hultman, Rainbo; Mague, Stephen D; Li, Qiang; Katz, Brittany M; Michel, Nadine; Lin, Lizhen; Wang, Joyce; David, Lisa K; Blount, Cameron; Chandy, Rithi; Carlson, David; Ulrich, Kyle; Carin, Lawrence; Dunson, David; Kumar, Sunil; Deisseroth, Karl; Moore, Scott D; Dzirasa, Kafui

2016-07-20

Circuits distributed across cortico-limbic brain regions compose the networks that mediate emotional behavior. The prefrontal cortex (PFC) regulates ultraslow (stress-related illnesses including major depressive disorder (MDD). To uncover the mechanism whereby stress-induced changes in PFC circuitry alter emotional networks to yield pathology, we used a multi-disciplinary approach including in vivo recordings in mice and chronic social defeat stress. Our network model, inferred using machine learning, linked stress-induced behavioral pathology to the capacity of PFC to synchronize amygdala and VTA activity. Direct stimulation of PFC-amygdala circuitry with DREADDs normalized PFC-dependent limbic synchrony in stress-susceptible animals and restored normal behavior. In addition to providing insights into MDD mechanisms, our findings demonstrate an interdisciplinary approach that can be used to identify the large-scale network changes that underlie complex emotional pathologies and the specific network nodes that can be used to develop targeted interventions. Copyright © 2016 Elsevier Inc. All rights reserved.

Advance in Targeted Immunotherapy for Graft-Versus-Host Disease

Directory of Open Access Journals (Sweden)

Lingling Zhang

2018-05-01

Full Text Available Graft-versus-host disease (GVHD is a serious and deadly complication of patients, who undergo hematopoietic stem cell transplantation (HSCT. Despite prophylactic treatment with immunosuppressive agents, 20–80% of recipients develop acute GVHD after HSCT. And the incidence rates of chronic GVHD range from 6 to 80%. Standard therapeutic strategies are still lacking, although considerable advances have been gained in knowing of the predisposing factors, pathology, and diagnosis of GVHD. Targeting immune cells, such as regulatory T cells, as well as tolerogenic dendritic cells or mesenchymal stromal cells (MSCs display considerable benefit in the relief of GVHD through the deletion of alloactivated T cells. Monoclonal antibodies targeting cytokines or signaling molecules have been demonstrated to be beneficial for the prevention of GVHD. However, these remain to be verified in clinical therapy. It is also important and necessary to consider adopting individualized treatment based on GVHD subtypes, pathological mechanisms involved and stages. In the future, it is hoped that the identification of novel therapeutic targets and systematic research strategies may yield novel safe and effective approaches in clinic to improve outcomes of GVHD further. In this article, we reviewed the current advances in targeted immunotherapy for the prevention of GVHD.

Contribution of oxidative stress to pathology in diaphragm and limb muscles with Duchenne muscular dystrophy.

Science.gov (United States)

Kim, Jong-Hee; Kwak, Hyo-Bum; Thompson, LaDora V; Lawler, John M

2013-02-01

Duchenne muscular dystrophy (DMD) is a degenerative skeletal muscle disease that makes walking and breathing difficult. DMD is caused by an X-linked (Xp21) mutation in the dystrophin gene. Dystrophin is a scaffolding protein located in the sarcolemmal cytoskeleton, important in maintaining structural integrity and regulating muscle cell (muscle fiber) growth and repair. Dystrophin deficiency in mouse models (e.g., mdx mouse) destabilizes the interface between muscle fibers and the extracellular matrix, resulting in profound damage, inflammation, and weakness in diaphragm and limb muscles. While the link between dystrophin deficiency with inflammation and pathology is multi-factorial, elevated oxidative stress has been proposed as a central mediator. Unfortunately, the use of non-specific antioxidant scavengers in mouse and human studies has led to inconsistent results, obscuring our understanding of the importance of redox signaling in pathology of muscular dystrophy. However, recent studies with more mechanistic approaches in mdx mice suggest that NAD(P)H oxidase and nuclear factor-kappaB are important in amplifying dystrophin-deficient muscle pathology. Therefore, more targeted antioxidant therapeutics may ameliorate damage and weakness in human population, thus promoting better muscle function and quality of life. This review will focus upon the pathobiology of dystrophin deficiency in diaphragm and limb muscle primarily in mouse models, with a rationale for development of targeted therapeutic antioxidants in DMD patients.

Theoretical and Experimental Research in Neutron Spectra and Nuclear Waste Transmutation on Fast Subcritical Assembly with MOX Fuel

Science.gov (United States)

Arkhipkin, D. A.; Buttsev, V. S.; Chigrinov, S. E.; Kutuev, R. Kh.; Polanski, A.; Rakhno, I. L.; Sissakian, A.; Zulkarneev, R. Ya.; Zulkarneeva, Yu. R.

2003-07-01

The paper deals with theoretical and experimental investigation of transmutation rates for a number of long-lived fission products and minor actinides, as well as with neutron spectra formed in a subcritical assembly driven with the following monodirectional beams: 660-MeV protons and 14-MeV neutrons. In this work, the main objective is the comparison of neutron spectra in the MOX assembly for different external driving sources: a 660-MeV proton accelerator and a 14-MeV neutron generator. The SAD project (JINR, Russia) has being discussed. In the context of this project, a subcritical assembly consisting of a cylindrical lead target surrounded by a cylindrical MOX fuel layer will be constructed. Present conceptual design of the subcritical assembly is based on the core with a nominal unit capacity of 15 kW (thermal). This corresponds to a multiplication coefficient, keff= 0.945, and an accelerator beam power of 0.5 kW. The results of theoretical investigations on the possibility of incinerating long-lived fission products and minor actinides in fast neutron spectrum and formation of neutron spectra with different hardness in subcritical systems based on the MOX subcritical assembly are discussed. Calculated neutron spectra emitted from a lead target irradiated by a 660-MeV protons are also presented.

Social cost of pathological gambling.

Science.gov (United States)

Ladouceur, R; Boisvert, J M; Pépin, M; Loranger, M; Sylvain, C

1994-12-01

Pathological gambling creates enormous problems for the afflicted individuals, their families, employers, and society, and has numerous disastrous financial consequences. The present study evaluates the financial burdens of pathological gambling by questioning pathological gamblers in treatment in Gamblers Anonymous (n=60; 56 males, 4 females; mean age = 40 years old) about personal debts, loss of productivity at work, illegal activities, medical costs and the presence of other dependencies. Results show that important debts, loss of productivity at work and legal problems are associated with pathological gambling. Discussion is formulated in terms of the social cost of adopting a liberal attitude toward the legalization of various gambling activities.

Systems pathology: a critical review.

Science.gov (United States)

Costa, Jose

2012-02-01

The technological advances of the last twenty years together with the dramatic increase in computational power have injected new life into systems-level thinking in Medicine. This review emphasizes the close relationship of Systems Pathology to Systems Biology and delineates the differences between Systems Pathology and Clinical Systems Pathology. It also suggests an algorithm to support the application of systems-level thinking to clinical research, proposes applying systems-level thinking to the health care systems and forecasts an acceleration of preventive medicine as a result of the coupling of personal genomics with systems pathology. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Assembly, alignment and test of the Transiting Exoplanet Survey Satellite (TESS) optical assemblies

Science.gov (United States)

Balonek, Gregory; Brown, Joshua J.; Andre, James E.; Chesbrough, Christian D.; Chrisp, Michael P.; Dalpiaz, Michael; Lennon, Joseph; Richards, B. C.; Clark, Kristin E.

2017-08-01

The Transiting Exoplanet Survey Satellite (TESS) will carry four visible waveband, seven-element, refractive F/1.4 lenses, each with a 34 degree diagonal field of view. This paper describes the methods used for the assembly, alignment and test of the four flight optical assemblies. Prior to commencing the build of the four flight optical assemblies, a Risk Reduction Unit (RRU) was successfully assembled and tested [1]. The lessons learned from the RRU were applied to the build of the flight assemblies. The main modifications to the flight assemblies include the inking of the third lens element stray light mitigation, tighter alignment tolerances, and diamond turning for critical mechanical surfaces. Each of the optical assemblies was tested interferometrically and measured with a low coherence distance measuring interferometer (DMI) to predict the optimal shim thickness between the lens assembly and detector before -75°C environmental testing. In addition to individual test data, environmental test results from prior assemblies allow for the exploration of marginal performance differences between each of the optical assemblies.

SWAP-Assembler: scalable and efficient genome assembly towards thousands of cores.

Science.gov (United States)

Meng, Jintao; Wang, Bingqiang; Wei, Yanjie; Feng, Shengzhong; Balaji, Pavan

2014-01-01

There is a widening gap between the throughput of massive parallel sequencing machines and the ability to analyze these sequencing data. Traditional assembly methods requiring long execution time and large amount of memory on a single workstation limit their use on these massive data. This paper presents a highly scalable assembler named as SWAP-Assembler for processing massive sequencing data using thousands of cores, where SWAP is an acronym for Small World Asynchronous Parallel model. In the paper, a mathematical description of multi-step bi-directed graph (MSG) is provided to resolve the computational interdependence on merging edges, and a highly scalable computational framework for SWAP is developed to automatically preform the parallel computation of all operations. Graph cleaning and contig extension are also included for generating contigs with high quality. Experimental results show that SWAP-Assembler scales up to 2048 cores on Yanhuang dataset using only 26 minutes, which is better than several other parallel assemblers, such as ABySS, Ray, and PASHA. Results also show that SWAP-Assembler can generate high quality contigs with good N50 size and low error rate, especially it generated the longest N50 contig sizes for Fish and Yanhuang datasets. In this paper, we presented a highly scalable and efficient genome assembly software, SWAP-Assembler. Compared with several other assemblers, it showed very good performance in terms of scalability and contig quality. This software is available at: https://sourceforge.net/projects/swapassembler.

Assembly tool design

International Nuclear Information System (INIS)

Kanamori, Naokazu; Nakahira, Masataka; Ohkawa, Yoshinao; Tada, Eisuke; Seki, Masahiro

1996-06-01

The reactor core of the International Thermonuclear Experimental Reactor (ITER) is assembled with a number of large and asymmetric components within a tight tolerance in order to assure the structural integrity for various loads and to provide the tritium confinement. In addition, the assembly procedure should be compatible with remote operation since the core structures will be activated by 14-MeV neutrons once it starts operation and thus personal access will be prohibited. Accordingly, the assembly procedure and tool design are quite essential and should be designed from the beginning to facilitate remote operation. According to the ITER Design Task Agreement, the Japan Atomic Energy Research Institute (JAERI) has performed design study to develop the assembly procedures and associated tool design for the ITER tokamak assembly. This report describes outlines of the assembly tools and the remaining issues obtained in this design study. (author)

Three-Dimensional Blood-Brain Barrier Model for in vitro Studies of Neurovascular Pathology

Science.gov (United States)

Cho, Hansang; Seo, Ji Hae; Wong, Keith H. K.; Terasaki, Yasukazu; Park, Joseph; Bong, Kiwan; Arai, Ken; Lo, Eng H.; Irimia, Daniel

2015-10-01

Blood-brain barrier (BBB) pathology leads to neurovascular disorders and is an important target for therapies. However, the study of BBB pathology is difficult in the absence of models that are simple and relevant. In vivo animal models are highly relevant, however they are hampered by complex, multi-cellular interactions that are difficult to decouple. In vitro models of BBB are simpler, however they have limited functionality and relevance to disease processes. To address these limitations, we developed a 3-dimensional (3D) model of BBB on a microfluidic platform. We verified the tightness of the BBB by showing its ability to reduce the leakage of dyes and to block the transmigration of immune cells towards chemoattractants. Moreover, we verified the localization at endothelial cell boundaries of ZO-1 and VE-Cadherin, two components of tight and adherens junctions. To validate the functionality of the BBB model, we probed its disruption by neuro-inflammation mediators and ischemic conditions and measured the protective function of antioxidant and ROCK-inhibitor treatments. Overall, our 3D BBB model provides a robust platform, adequate for detailed functional studies of BBB and for the screening of BBB-targeting drugs in neurological diseases.

PathBot: A Radiology-Pathology Correlation Dashboard.

Science.gov (United States)

Kelahan, Linda C; Kalaria, Amit D; Filice, Ross W

2017-12-01

Pathology is considered the "gold standard" of diagnostic medicine. The importance of radiology-pathology correlation is seen in interdepartmental patient conferences such as "tumor boards" and by the tradition of radiology resident immersion in a radiologic-pathology course at the American Institute of Radiologic Pathology. In practice, consistent pathology follow-up can be difficult due to time constraints and cumbersome electronic medical records. We present a radiology-pathology correlation dashboard that presents radiologists with pathology reports matched to their dictations, for both diagnostic imaging and image-guided procedures. In creating our dashboard, we utilized the RadLex ontology and National Center for Biomedical Ontology (NCBO) Annotator to identify anatomic concepts in pathology reports that could subsequently be mapped to relevant radiology reports, providing an automated method to match related radiology and pathology reports. Radiology-pathology matches are presented to the radiologist on a web-based dashboard. We found that our algorithm was highly specific in detecting matches. Our sensitivity was slightly lower than expected and could be attributed to missing anatomy concepts in the RadLex ontology, as well as limitations in our parent term hierarchical mapping and synonym recognition algorithms. By automating radiology-pathology correlation and presenting matches in a user-friendly dashboard format, we hope to encourage pathology follow-up in clinical radiology practice for purposes of self-education and to augment peer review. We also hope to provide a tool to facilitate the production of quality teaching files, lectures, and publications. Diagnostic images have a richer educational value when they are backed up by the gold standard of pathology.

Oxford Nanopore MinION Sequencing and Genome Assembly

Directory of Open Access Journals (Sweden)

Hengyun Lu

2016-10-01

Full Text Available The revolution of genome sequencing is continuing after the successful second-generation sequencing (SGS technology. The third-generation sequencing (TGS technology, led by Pacific Biosciences (PacBio, is progressing rapidly, moving from a technology once only capable of providing data for small genome analysis, or for performing targeted screening, to one that promises high quality de novo assembly and structural variation detection for human-sized genomes. In 2014, the MinION, the first commercial sequencer using nanopore technology, was released by Oxford Nanopore Technologies (ONT. MinION identifies DNA bases by measuring the changes in electrical conductivity generated as DNA strands pass through a biological pore. Its portability, affordability, and speed in data production makes it suitable for real-time applications, the release of the long read sequencer MinION has thus generated much excitement and interest in the genomics community. While de novo genome assemblies can be cheaply produced from SGS data, assembly continuity is often relatively poor, due to the limited ability of short reads to handle long repeats. Assembly quality can be greatly improved by using TGS long reads, since repetitive regions can be easily expanded into using longer sequencing lengths, despite having higher error rates at the base level. The potential of nanopore sequencing has been demonstrated by various studies in genome surveillance at locations where rapid and reliable sequencing is needed, but where resources are limited.

Drive piston assembly for a valve actuator assembly

Science.gov (United States)

Sun, Zongxuan

2010-02-23

A drive piston assembly is provided that is operable to selectively open a poppet valve. The drive piston assembly includes a cartridge defining a generally stepped bore. A drive piston is movable within the generally stepped bore and a boost sleeve is coaxially disposed with respect to the drive piston. A main fluid chamber is at least partially defined by the generally stepped bore, drive piston, and boost sleeve. First and second feedback chambers are at least partially defined by the drive piston and each are disposed at opposite ends of the drive piston. At least one of the drive piston and the boost sleeve is sufficiently configured to move within the generally stepped bore in response to fluid pressure within the main fluid chamber to selectively open the poppet valve. A valve actuator assembly and engine are also provided incorporating the disclosed drive piston assembly.

A method for normalizing pathology images to improve feature extraction for quantitative pathology

International Nuclear Information System (INIS)

Tam, Allison; Barker, Jocelyn; Rubin, Daniel

2016-01-01

Purpose: With the advent of digital slide scanning technologies and the potential proliferation of large repositories of digital pathology images, many research studies can leverage these data for biomedical discovery and to develop clinical applications. However, quantitative analysis of digital pathology images is impeded by batch effects generated by varied staining protocols and staining conditions of pathological slides. Methods: To overcome this problem, this paper proposes a novel, fully automated stain normalization method to reduce batch effects and thus aid research in digital pathology applications. Their method, intensity centering and histogram equalization (ICHE), normalizes a diverse set of pathology images by first scaling the centroids of the intensity histograms to a common point and then applying a modified version of contrast-limited adaptive histogram equalization. Normalization was performed on two datasets of digitized hematoxylin and eosin (H&E) slides of different tissue slices from the same lung tumor, and one immunohistochemistry dataset of digitized slides created by restaining one of the H&E datasets. Results: The ICHE method was evaluated based on image intensity values, quantitative features, and the effect on downstream applications, such as a computer aided diagnosis. For comparison, three methods from the literature were reimplemented and evaluated using the same criteria. The authors found that ICHE not only improved performance compared with un-normalized images, but in most cases showed improvement compared with previous methods for correcting batch effects in the literature. Conclusions: ICHE may be a useful preprocessing step a digital pathology image processing pipeline

A method for normalizing pathology images to improve feature extraction for quantitative pathology

Energy Technology Data Exchange (ETDEWEB)

Tam, Allison [Stanford Institutes of Medical Research Program, Stanford University School of Medicine, Stanford, California 94305 (United States); Barker, Jocelyn [Department of Radiology, Stanford University School of Medicine, Stanford, California 94305 (United States); Rubin, Daniel [Department of Radiology, Stanford University School of Medicine, Stanford, California 94305 and Department of Medicine (Biomedical Informatics Research), Stanford University School of Medicine, Stanford, California 94305 (United States)

2016-01-15

Purpose: With the advent of digital slide scanning technologies and the potential proliferation of large repositories of digital pathology images, many research studies can leverage these data for biomedical discovery and to develop clinical applications. However, quantitative analysis of digital pathology images is impeded by batch effects generated by varied staining protocols and staining conditions of pathological slides. Methods: To overcome this problem, this paper proposes a novel, fully automated stain normalization method to reduce batch effects and thus aid research in digital pathology applications. Their method, intensity centering and histogram equalization (ICHE), normalizes a diverse set of pathology images by first scaling the centroids of the intensity histograms to a common point and then applying a modified version of contrast-limited adaptive histogram equalization. Normalization was performed on two datasets of digitized hematoxylin and eosin (H&E) slides of different tissue slices from the same lung tumor, and one immunohistochemistry dataset of digitized slides created by restaining one of the H&E datasets. Results: The ICHE method was evaluated based on image intensity values, quantitative features, and the effect on downstream applications, such as a computer aided diagnosis. For comparison, three methods from the literature were reimplemented and evaluated using the same criteria. The authors found that ICHE not only improved performance compared with un-normalized images, but in most cases showed improvement compared with previous methods for correcting batch effects in the literature. Conclusions: ICHE may be a useful preprocessing step a digital pathology image processing pipeline.

Slot Machine Response Frequency Predicts Pathological Gambling

DEFF Research Database (Denmark)

Linnet, Jakob; Rømer Thomsen, Kristine; Møller, Arne

2013-01-01

. This study tested the hypothesis that response frequency is associated with symptom severity in pathological gambling. We tested response frequency among twenty-two pathological gambling sufferers and twenty-one non-problem gamblers on a commercially available slot machine, and screened for pathological...... in individuals with exacerbated pathological gambling symptoms. These findings may have important implications for detecting behaviors underlying pathological gambling....

RPA binds histone H3-H4 and functions in DNA replication-coupled nucleosome assembly.

Science.gov (United States)

Liu, Shaofeng; Xu, Zhiyun; Leng, He; Zheng, Pu; Yang, Jiayi; Chen, Kaifu; Feng, Jianxun; Li, Qing

2017-01-27

DNA replication-coupled nucleosome assembly is essential to maintain genome integrity and retain epigenetic information. Multiple involved histone chaperones have been identified, but how nucleosome assembly is coupled to DNA replication remains elusive. Here we show that replication protein A (RPA), an essential replisome component that binds single-stranded DNA, has a role in replication-coupled nucleosome assembly. RPA directly binds free H3-H4. Assays using a synthetic sequence that mimics freshly unwound single-stranded DNA at replication fork showed that RPA promotes DNA-(H3-H4) complex formation immediately adjacent to double-stranded DNA. Further, an RPA mutant defective in H3-H4 binding exhibited attenuated nucleosome assembly on nascent chromatin. Thus, we propose that RPA functions as a platform for targeting histone deposition to replication fork, through which RPA couples nucleosome assembly with ongoing DNA replication. Copyright © 2017, American Association for the Advancement of Science.

The Biological Side of Water-Soluble Arene Ruthenium Assemblies

Directory of Open Access Journals (Sweden)

Bruno Therrien

2014-01-01

Full Text Available This review article covers the synthetic strategies, structural aspects, and host-guest properties of ruthenium metalla-assemblies, with a special focus on their use as drug delivery vectors. The two-dimensional metalla-rectangles show interesting host-guest possibilities but seem less appropriate for being used as drug carriers. On the other hand, metalla-prisms allow encapsulation and possible targeted release of bioactive molecules and consequently show some potential as drug delivery vectors. The reactivity of these metalla-prisms can be fine-tuned to allow a fine control of the guest’s release. The larger metalla-cubes can be used to stabilize the formation of G-quadruplex DNA and can be used to encapsulate and release photoactive molecules such as porphins. These metalla-assemblies demonstrate great prospective in photodynamic therapy.

Assembly process of the ITER neutral beam injectors

Energy Technology Data Exchange (ETDEWEB)

Graceffa, J., E-mail: joseph.graceffa@iter.org [ITER Organization, Route de Vinon sur Verdon, 13115 Saint Paul lez Durance (France); Boilson, D.; Hemsworth, R.; Petrov, V.; Schunke, B.; Urbani, M. [ITER Organization, Route de Vinon sur Verdon, 13115 Saint Paul lez Durance (France); Pilard, V. [Fusion for Energy, C/ Josep Pla, n°2, Torres Diagonal Litoral, Edificio B3, 08019 Barcelona (Spain)

2013-10-15

main rail of the overhead crane associated with offset tooling when necessary. The overhead crane is used for the assembly of the components, and the final positioning of the beamline components and the beam source will be adjusted with respect to laser targets referring to the optimum beam axis and source position. This paper describes the installation tasks and the alignment and positioning solutions and the complexity of operations within the NB cell. Particular constraints on the HNB installation sequence due to the planned testing of the 1 MV high voltage supply are also described.

Measurement of fast assembly spectra using time-of-flight method

International Nuclear Information System (INIS)

Duquesne, Henry; Rotival, Michel; Schmitt, Andre; Allard, Christian; De Keyser, Albert; Hortsmann, Henri

1975-07-01

Measurement of neutron spectra made in fast subcritical assemblies HUG 3 and PHUG 3 (uranium-graphite and plutonium-graphite) utilizing time-of-flight techniques are described. The matrix were excited by the pulsed neutron source from the BCMN Linac beam impinging on a target of natural uranium. Details of the experimental procedure, safety studies, detector calibration and data reduction are given [fr

Pathology annual. Part 2

International Nuclear Information System (INIS)

Rosen, P.P.

1987-01-01

This book contains 11 selections. Some of the titles are: Applications of in situ DNA hybridization technology to diagnostic surgical pathology; Neoplasms associated with immune deficiencies; Chronic gastritis: The pathologists's role; Necrosis in lymph nodes; Pathologic changes of osteochondrodysplasia in infancy: A review; and Immunoglobulin light chain nephropathies

Imaging of Cerebrovascular Pathology in Animal Models of Alzheimer`s Disease

Directory of Open Access Journals (Sweden)

Jan eKlohs

2014-03-01

Full Text Available In Alzheimer’s disease (AD, vascular pathology may interact with neurodegeneration and thus aggravate cognitive decline. As the relationship between these two processes is poorly understood, research has been increasingly focused on understanding the link between cerebrovascular alterations and AD. This has at last been spurred by the engineering of transgenic animals, which display pathological features of AD and develop cerebral amyloid angiopathy to various degrees. Transgenic models are versatile for investigating the role of amyloid deposition and vascular dysfunction, and for evaluating novel therapeutic concepts. In addition, research has benefited from the development of novel imaging techniques, which are capable of characterizing vascular pathology in vivo. They provide vascular structural read-outs and have the ability to assess the functional consequences of vascular dysfunction as well as to visualize and monitor the molecular processes underlying these pathological alterations. This article focusses on recent in vivo small animal imaging studies addressing vascular aspects related to AD. With the technical advances of imaging modalities such as magnetic resonance, nuclear and microscopic imaging, molecular, functional and structural information related to vascular pathology can now be visualized in vivo in small rodents. Imaging vascular and parenchymal amyloid-β (Aβ deposition as well as Aβ transport pathways have been shown to be useful to characterize their dynamics and to elucidate their role in the development of cerebral amyloid angiopathy and AD. Structural and functional imaging read-outs have been employed to describe the deleterious affects of Aβ on vessel morphology, hemodynamics and vascular integrity. More recent imaging studies have also addressed how inflammatory processes partake in the pathogenesis of the disease. Moreover, imaging can be pivotal in the search for novel therapies targeting the vasculature.

Self-assembled Targeting of Cancer Cells by Iron(III)-doped, Silica Nanoparticles

OpenAIRE

Mitchell, K.K. Pohaku; Sandoval, S.; Cortes-Mateos, M. J.; Alfaro, J.G.; Kummel, A. C.; Trogler, W.C.

2014-01-01

Iron(III)-doped silica nanoshells are shown to possess an in vitro cell-receptor mediated targeting functionality for endocytosis. Compared to plain silica nanoparticles, iron enriched ones are shown to be target-specific, a property that makes them potentially better vehicles for applications, such as drug delivery and tumor imaging, by making them more selective and thereby reducing the nanoparticle dose. Iron(III) in the nanoshells can interact with endogenous transferrin, a serum protein ...

Native gel analysis for RISC assembly.

Science.gov (United States)

Kawamata, Tomoko; Tomari, Yukihide

2011-01-01

Small-interfering RNAs (siRNAs) and microRNAs (miRNAs) regulate expression of their target mRNAs via the RNA-induced silencing complex (RISC). A core component of RISC is the Argonaute (Ago) protein, which dictates the RISC function. In Drosophila, miRNAs and siRNAs are generally loaded into Ago1-containing RISC (Ago1-RISC) and Ago2-containing RISC (Ago2-RISC), respectively. We developed a native agarose gel system to directly detect Ago1-RISC, Ago2-RISC, and their precursor complexes. Methods presented here will provide powerful tools to biochemically dissect the RISC assembly pathways.

Recent advances in molecular pathology of craniopharyngioma [version 1; referees: 2 approved

Directory of Open Access Journals (Sweden)

Sarah Larkin

2017-07-01

Full Text Available Craniopharyngiomas are rare epithelial tumours arising along the path of the craniopharyngeal duct. Two major histological subtypes have been recognised, the papillary and the adamantinomatous. Craniopharyngiomas remain challenging tumours to manage and are associated with significant morbidities and mortality. Recent advances in the molecular pathology of these neoplasms have identified BRAF mutations in the papillary variant, offering promising options for targeted pharmacological treatment. The involvement of β-catenin and the Wnt pathway in the tumorigenesis of the adamantinomatous subtype has been previously established with the identification of stabilising mutations in exon 3 of CTNNB1. Further understanding of the pathogenesis of this subtype has been facilitated with the use of mouse models and xenograft experiments. It has been proposed that the clusters of cells with upregulated Wnt/β-catenin signalling induce tumour formation in a paracrine manner; the complex interactions occurring between different cell populations need to be further clarified for further expansion of this hypothesis. This review outlines recent key advances in our understanding of the molecular pathology of craniopharyngiomas and discusses some of the challenges that need to be overcome for the development of targeted therapies that will hopefully improve the management and the outcomes of these patients.

Hyb-Seq: combining target enrichment and genome skimming for plant phylogenomics

Science.gov (United States)

Kevin Weitemier; Shannon C.K. Straub; Richard C. Cronn; Mark Fishbein; Roswitha Schmickl; Angela McDonnell; Aaron. Liston

2014-01-01

• Premise of the study: Hyb-Seq, the combination of target enrichment and genome skimming, allows simultaneous data collection for low-copy nuclear genes and high-copy genomic targets for plant systematics and evolution studies. • Methods and Results: Genome and transcriptome assemblies for milkweed ( Asclepias syriaca ) were used to design enrichment probes for 3385...

Cross‐disease comparison of amyotrophic lateral sclerosis and spinal muscular atrophy reveals conservation of selective vulnerability but differential neuromuscular junction pathology

Science.gov (United States)

Nijssen, Jik; Frost‐Nylen, Johanna

2015-01-01

Neuromuscular junctions are primary pathological targets in the lethal motor neuron diseases spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). Synaptic pathology and denervation of target muscle fibers has been reported prior to the appearance of clinical symptoms in mouse models of both diseases, suggesting that neuromuscular junctions are highly vulnerable from the very early stages, and are a key target for therapeutic intervention. Here we examined neuromuscular pathology longitudinally in three clinically relevant muscle groups in mouse models of ALS and SMA in order to assess their relative vulnerabilities. We show for the first time that neuromuscular junctions of the extraocular muscles (responsible for the control of eye movement) were resistant to degeneration in endstage SMA mice, as well as in late symptomatic ALS mice. Tongue muscle neuromuscular junctions were also spared in both animal models. Conversely, neuromuscular junctions of the lumbrical muscles of the hind‐paw were vulnerable in both SMA and ALS, with a loss of neuronal innervation and shrinkage of motor endplates in both diseases. Thus, the pattern of selective vulnerability was conserved across these two models of motor neuron disease. However, the first evidence of neuromuscular pathology occurred at different timepoints of disease progression, with much earlier evidence of presynaptic involvement in ALS, progressing to changes on the postsynaptic side. Conversely, in SMA changes appeared concomitantly at the neuromuscular junction, suggesting that mechanisms of neuromuscular disruption are distinct in these diseases. J. Comp. Neurol. 524:1424–1442, 2016. © 2015 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc. PMID:26502195

Cellular retinoic acid bioavailability in various pathologies and its therapeutic implication.

Science.gov (United States)

Osanai, Makoto

2017-06-01

Retinoic acid (RA), an active metabolite of vitamin A, is a critical signaling molecule in various cell types. We found that RA depletion caused by expression of the RA-metabolizing enzyme CYP26A1 promotes carcinogenesis, implicating CYP26A1 as a candidate oncogene. Several studies of CYP26s have suggested that the biological effect of RA on target cells is primarily determined by "cellular RA bioavailability", which is defined as the RA level in an individual cell, rather than by the serum concentration of RA. Consistently, stellate cells store approximately 80% of vitamin A in the body, and the state of cellular RA bioavailability regulates their function. Based on the similarities between stellate cells and astrocytes, we demonstrated that retinal astrocytes regulate tight junction-based endothelial integrity in a paracrine manner. Since diabetic retinopathy is characterized by increased vascular permeability in its early pathogenesis, RA normalized retinal astrocytes that are compromised in diabetes, resulting in suppression of vascular leakiness. RA also attenuated the loss of the epithelial barrier in murine experimental colitis. The concept of "cellular RA bioavailability" in various diseases will be directed at understanding various pathologies caused by RA insufficiency, implying the potential feasibility of a therapeutic strategy targeting the stellate cell system. © 2017 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.

Self-assembled nanostructures

CERN Document Server

Zhang, Jin Z; Liu, Jun; Chen, Shaowei; Liu, Gang-yu

2003-01-01

Nanostructures refer to materials that have relevant dimensions on the nanometer length scales and reside in the mesoscopic regime between isolated atoms and molecules in bulk matter. These materials have unique physical properties that are distinctly different from bulk materials. Self-Assembled Nanostructures provides systematic coverage of basic nanomaterials science including materials assembly and synthesis, characterization, and application. Suitable for both beginners and experts, it balances the chemistry aspects of nanomaterials with physical principles. It also highlights nanomaterial-based architectures including assembled or self-assembled systems. Filled with in-depth discussion of important applications of nano-architectures as well as potential applications ranging from physical to chemical and biological systems, Self-Assembled Nanostructures is the essential reference or text for scientists involved with nanostructures.

A simple and efficient method for assembling TALE protein based on plasmid library.

Science.gov (United States)

Zhang, Zhiqiang; Li, Duo; Xu, Huarong; Xin, Ying; Zhang, Tingting; Ma, Lixia; Wang, Xin; Chen, Zhilong; Zhang, Zhiying

2013-01-01

DNA binding domain of the transcription activator-like effectors (TALEs) from Xanthomonas sp. consists of tandem repeats that can be rearranged according to a simple cipher to target new DNA sequences with high DNA-binding specificity. This technology has been successfully applied in varieties of species for genome engineering. However, assembling long TALE tandem repeats remains a big challenge precluding wide use of this technology. Although several new methodologies for efficiently assembling TALE repeats have been recently reported, all of them require either sophisticated facilities or skilled technicians to carry them out. Here, we described a simple and efficient method for generating customized TALE nucleases (TALENs) and TALE transcription factors (TALE-TFs) based on TALE repeat tetramer library. A tetramer library consisting of 256 tetramers covers all possible combinations of 4 base pairs. A set of unique primers was designed for amplification of these tetramers. PCR products were assembled by one step of digestion/ligation reaction. 12 TALE constructs including 4 TALEN pairs targeted to mouse Gt(ROSA)26Sor gene and mouse Mstn gene sequences as well as 4 TALE-TF constructs targeted to mouse Oct4, c-Myc, Klf4 and Sox2 gene promoter sequences were generated by using our method. The construction routines took 3 days and parallel constructions were available. The rate of positive clones during colony PCR verification was 64% on average. Sequencing results suggested that all TALE constructs were performed with high successful rate. This is a rapid and cost-efficient method using the most common enzymes and facilities with a high success rate.

Involvement of microRNAs in physiological and pathological processes in the lung

Directory of Open Access Journals (Sweden)

Kriegova Eva

2010-11-01

Full Text Available Abstract To date, at least 900 different microRNA (miRNA genes have been discovered in the human genome. These short, single-stranded RNA molecules originate from larger precursor molecules that fold to produce hairpin structures, which are subsequently processed by ribonucleases Drosha/Pasha and Dicer to form mature miRNAs. MiRNAs play role in the posttranscriptional regulation of about one third of human genes, mainly via degradation of target mRNAs. Whereas the target mRNAs are often involved in the regulation of diverse physiological processes ranging from developmental timing to apoptosis, miRNAs have a strong potential to regulate fundamental biological processes also in the lung compartment. However, the knowledge of the role of miRNAs in physiological and pathological conditions in the lung is still limited. This review, therefore, summarizes current knowledge of the mechanism, function of miRNAs and their contribution to lung development and homeostasis. Besides the involvement of miRNAs in pulmonary physiological conditions, there is evidence that abnormal miRNA expression may lead to pathological processes and development of various pulmonary diseases. Next, the review describes current state-of-art on the miRNA expression profiles in smoking-related diseases including lung cancerogenesis, in immune system mediated pulmonary diseases and fibrotic processes in the lung. From the current research it is evident that miRNAs may play role in the posttranscriptional regulation of key genes in human pulmonary diseases. Further studies are, therefore, necessary to explore miRNA expression profiles and their association with target mRNAs in human pulmonary diseases.

Slot Machine Response Frequency Predicts Pathological Gambling

DEFF Research Database (Denmark)

Linnet, Jakob; Rømer Thomsen, Kristine; Møller, Arne

2013-01-01

Slot machines are among the most addictive forms of gambling, and pathological gambling slot machine players represent the largest group of treatment seekers, accounting for 35% to 93% of the population. Pathological gambling sufferers have significantly higher response frequency (games / time......) on slot machines compared with non-problem gamblers, which may suggest increased reinforcement of the gambling behavior in pathological gambling. However, to date it is unknown whether or not the increased response frequency in pathological gambling is associated with symptom severity of the disorder....... This study tested the hypothesis that response frequency is associated with symptom severity in pathological gambling. We tested response frequency among twenty-two pathological gambling sufferers and twenty-one non-problem gamblers on a commercially available slot machine, and screened for pathological...

Overview of neutronic fuel assembly design and in-core fuel management

International Nuclear Information System (INIS)

Porsch, D.; Charlier, A.; Meier, G.; Mougniot, J.C.; Tsuda, K.

2000-01-01

The civil and military utilization of nuclear power results in stockpiles of spent fuel and separated plutonium. Recycling of the recovered plutonium in Light Water Reactors (LWR) is currently practiced in Belgium, France, Germany, and Switzerland, in Japan it is in preparation. Modern MOX fuel, with its optimized irradiation and reprocessing behavior, was introduced in 1981. Since then, about 1700 MOX fuel assemblies of different mechanical and neutronic design were irradiated in commercial LWRs and reached fuel assembly averaged exposures of up to 51.000 MWd/t HM. MOX fuel assemblies reloaded in PWR have an average fissile plutonium content of up to 4.8 w/o. For BWR, the average fissile plutonium content in actual reloads is 3.0 w/o. Targets for the MOX fuel assembly design are the compatibility to uranium fuel assemblies with respect to their mechanical fuel rod and fuel assembly design, they should have no impact on the flexibility of the reactor operation, and its reload should be economically feasible. In either cycle independent safety analyses or individually for each designed core it has to be demonstrated that recycling cores meet the same safety criteria as uranium cores. The safety criteria are determined for normal operation and for operational as well as design basis transients. Experience with realized MOX core loadings confirms the reliability of the applied modern design codes. Studies for reloads of advanced MOX assemblies in LWRs demonstrate the feasibility of a future development of the thermal plutonium recycling. New concepts for the utilization of plutonium are under consideration and reveal an attractive potential for further developments on the plutonium exploitation sector. (author)

Desain Sistem Pendeteksi untuk Citra Base Sub-assembly dengan Algoritma Backpropagation

Directory of Open Access Journals (Sweden)

Kasdianto Kasdianto

2017-04-01

Full Text Available Object identification technique using machine vision has been implemented in industrial of electronic manufacturers for years. This technique is commonly used for reject detection (for disqualified product based on existing standard or defect detection. This research aims to build a reject detector of sub-assembly condition which is differed by two conditions that are missing screw and wrong position screw using neural network backpropagation. The image taken using camera will be converted into grayscale before it is processed in backpropagation methods to generate a weight value. The experiment result shows that the network architecture with two layers has the most excellent accuracy level. Using learning rate of 0.5, target error 0.015%, and the number of node 1 of 100 and node 2 of 50, the successive rate for sub-assembly detection in right condition reached 99.02% while no error occurs in detecting the wrong condition of Sub-assembly (missing screw and wrong position screw.

Targeting VEGF in canine oxygen-induced retinopathy - a model for human retinopathy of prematurity.

Science.gov (United States)

McLeod, D Scott; Lutty, Gerard A

2016-01-01

Development of the dog superficial retinal vasculature is similar to the mechanism of human retinal vasculature development; they both develop by vasculogenesis, differentiation, and assembly of vascular precursors called angioblasts. Canine oxygen-induced retinopathy (OIR) was first developed by Arnall Patz in an effort to experimentally determine the effects of hyperoxia on the development of the retinal vasculature. The canine OIR model has many characteristics in common with human retinopathy of prematurity. Exposure of 1-day-old dogs to hyperoxia for 4 days causes a vaso-obliteration throughout the retina. Vasoproliferation, after the animals have returned to room air, is robust. The initial small preretinal neovascular formations anastomose to form large preretinal membranes that eventually cause tractional retinal folds. The end-stage pathology of the canine model is similar to stage IV human retinopathy of prematurity. Therefore, canine OIR is an excellent forum to evaluate the response to drugs targeting VEGF and its receptors. Evaluation of an antibody to VEGF-R2 and the VEGF-Trap demonstrated that doses should be titered down so that preretinal neovascularization is inhibited but retinal revascularization is able to proceed, vascularizing peripheral retina and preventing it from being a source of VEGF.

42 CFR 493.853 - Condition: Pathology.

Science.gov (United States)

2010-10-01

... 42 Public Health 5 2010-10-01 2010-10-01 false Condition: Pathology. 493.853 Section 493.853 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES... These Tests § 493.853 Condition: Pathology. The specialty of pathology includes, for purposes of...

Target developments program to prepare LMJ campaigns

Energy Technology Data Exchange (ETDEWEB)

Collier, R; Bachelet, F; Botrel, R; Breton, O; Chicanne, C; Dauteuil, C H; Durut, F; Fleury, E; Guillot, L; Hermerel, C; Jeannot, L; Legaie, O; Legay, G; Martin, M; Reneaume, B; Theobald, M; Vincent-Viry, O, E-mail: remy.collier@cea.f [Commissariat a l' Energie Atomique, Direction des Applications Militaires, Valduc, F-21120 Is-sur-Tille (France)

2010-08-01

To carry out laser plasma experiments on CEA laser facilities, a R and D program was set up and is still under way to deliver complex targets. For a decade, specific developments are also dedicated to 'Ligne d'Integration Laser' (LIL) in France and Omega facilities (USA). To prepare the targets intended for the first experiments on the Laser 'Megajoule' (LMJ) facility, new developments are required, such as cocktail hohlraum fabrication, gas barrier coating and foam shells developments. For fusion experiments on LMJ, an important program is also under way to elaborate the Cryogenic Target Assembly (CTA), to fill and transport the CTA and to study the conformation process of the DT layer.

Pathological fractures in children

Science.gov (United States)

De Mattos, C. B. R.; Binitie, O.; Dormans, J. P.

2012-01-01

Pathological fractures in children can occur as a result of a variety of conditions, ranging from metabolic diseases and infection to tumours. Fractures through benign and malignant bone tumours should be recognised and managed appropriately by the treating orthopaedic surgeon. The most common benign bone tumours that cause pathological fractures in children are unicameral bone cysts, aneurysmal bone cysts, non-ossifying fibromas and fibrous dysplasia. Although pathological fractures through a primary bone malignancy are rare, these should be recognised quickly in order to achieve better outcomes. A thorough history, physical examination and review of plain radiographs are crucial to determine the cause and guide treatment. In most benign cases the fracture will heal and the lesion can be addressed at the time of the fracture, or after the fracture is healed. A step-wise and multidisciplinary approach is necessary in caring for paediatric patients with malignancies. Pathological fractures do not have to be treated by amputation; these fractures can heal and limb salvage can be performed when indicated. PMID:23610658

The Nun Study: risk factors for pathology and clinical-pathologic correlations.

Science.gov (United States)

Mortimer, James A

2012-07-01

The Nun Study was the first cohort study to enroll and follow a large, well-defined population that included demented and non-demented participants, all of whom agreed to donate their brains for research. The inclusion of systematic neuropathologic analysis in this study has resulted in a greater understanding of the role of Alzheimer and vascular pathology in the expression of memory deficits and dementia and has provided data showing that biomarkers for the pathology may be evident many decades earlier in adult life. Findings related to neuropathology in this study have included the following: (1) Although clinical outcomes were strongly correlated with Alzheimer neuropathology, about one-third of the participants fulfilling criteria for neuropathologic Alzheimer's disease (AD) were not demented at the time of death. (2) Brain infarcts by themselves had little effect on cognitive status, but played an important role in increasing the risk of dementia associated with Alzheimer pathology. (3) Hippocampal volume was strongly correlated with Braak neurofibrillary stage even in participants with normal cognitive function. (4) A linguistic characteristic of essays written in early adult life, idea density, had a strong association with not only clinical outcomes in late life, but the severity of Alzheimer neuropathology as well. (5) The effect of apolipoprotein E-e4 on dementia was mediated through Alzheimer, but not vascular pathology.

Newnes electronics assembly handbook

CERN Document Server

Brindley, Keith

2013-01-01

Newnes Electronics Assembly Handbook: Techniques, Standards and Quality Assurance focuses on the aspects of electronic assembling. The handbook first looks at the printed circuit board (PCB). Base materials, basic mechanical properties, cleaning of assemblies, design, and PCB manufacturing processes are then explained. The text also discusses surface mounted assemblies and packaging of electromechanical assemblies, as well as the soldering process. Requirements for the soldering process; solderability and protective coatings; cleaning of PCBs; and mass solder/component reflow soldering are des

A methodological approach to studying resilience mechanisms: demonstration of utility in age and Alzheimer's disease-related brain pathology.

Science.gov (United States)

Wolf, Dominik; Fischer, Florian Udo; Fellgiebel, Andreas

2018-05-01

The present work aims at providing a methodological approach for the investigation of resilience factors and mechanisms in normal aging, Alzheimer's disease (AD) and other neurodegenerative disorders. By expanding and re-conceptualizing traditional regression approaches, we propose an approach that not only aims at identifying potential resilience factors but also allows for a differentiation between general and dynamic resilience factors in terms of their association with pathology. Dynamic resilience factors are characterized by an increasing relevance with increasing levels of pathology, while the relevance of general resilience factors is independent of the amount of pathology. Utility of the approach is demonstrated in age and AD-related brain pathology by investigating widely accepted resilience factors, including education and brain volume. Moreover, the approach is used to test hippocampal volume as potential resilience factor. Education and brain volume could be identified as general resilience factors against age and AD-related pathology. Beyond that, analyses highlighted that hippocampal volume may not only be disease target but also serve as a potential resilience factor in age and AD-related pathology, particularly at higher levels of tau-pathology (i.e. dynamic resilience factor). Given its unspecific and superordinate nature the approach is suitable for the investigation of a wide range of potential resilience factors in normal aging, AD and other neurodegenerative disorders. Consequently, it may find a wide application and thereby promote the comparability between studies.

Communication skills in diagnostic pathology.

Science.gov (United States)

Lehr, Hans-Anton; Bosman, Fred T

2016-01-01

Communication is an essential element of good medical practice also in pathology. In contrast to technical or diagnostic skills, communication skills are not easy to define, teach, or assess. Rules almost do not exist. In this paper, which has a rather personal character and cannot be taken as a set of guidelines, important aspects of communication in pathology are explored. This includes what should be communicated to the pathologist on the pathology request form, communication between pathologists during internal (interpathologist) consultation, communication around frozen section diagnoses, modalities of communication of a final diagnosis, with whom and how critical and unexpected findings should be communicated, (in-)adequate routes of communication for pathology diagnoses, who will (or might) receive pathology reports, and what should be communicated and how in case of an error or a technical problem. An earlier more formal description of what the responsibilities are of a pathologist as communicator and as collaborator in a medical team is added in separate tables. The intention of the paper is to stimulate reflection and discussion rather than to formulate strict rules.

Egr-1 mediated cardiac miR-99 family expression diverges physiological hypertrophy from pathological hypertrophy.

Science.gov (United States)

Ramasamy, Subbiah; Velmurugan, Ganesan; Rekha, Balakrishnan; Anusha, Sivakumar; Shanmugha Rajan, K; Shanmugarajan, Suresh; Ramprasath, Tharmarajan; Gopal, Pandi; Tomar, Dhanendra; Karthik, Karuppusamy V; Verma, Suresh Kumar; Garikipati, Venkata Naga Srikanth; Sudarsan, Rajan

2018-04-01

The physiological cardiac hypertrophy is an adaptive condition without myocyte cell death, while pathological hypertrophy is a maladaptive condition associated with myocyte cell death. This study explores the miRNome of α-2M-induced physiologically hypertrophied cardiomyocytes and the role of miRNA-99 family during cardiac hypertrophy. Physiological and pathological cardiac hypertrophy was induced in H9c2 cardiomyoblast cell lines using α-2M and isoproterenol respectively. Total RNA isolation and small RNA sequencing were executed for physiological hypertrophy model. The differentially expressed miRNAs and its target mRNAs were validated in animal models. Transcription factor binding sites were predicted in the promoter of specific miRNAs and validated by ChIP-PCR. Subsequently, the selected miRNA was functionally characterized by overexpression and silencing. The effects of silencing of upstream regulator and downstream target gene were studied. Analysis of small RNA reads revealed the differential expression of a large set of miRNAs during hypertrophy, of which miR-99 family was highly downregulated upon α-2M treatment. However, this miR-99 family expression was upregulated during pathological hypertrophy and confirmed in animal models. ChIP-PCR confirms the binding of Egr-1 transcription factor to the miR-99 promoter. Further, silencing of Egr-1 decreased the expression of miR-99. The overexpression or silencing of miR-99 diverges the physiological hypertrophy to pathological hypertrophy and vice versa by regulating Akt-1 pathway. Silencing of Akt-1 replicates the effect of overexpression of miR-99. The results proved Egr-1 mediated regulation of miR-99 family that plays a key role in determining the fate of cardiac hypertrophy by regulating Akt-1 signaling. Copyright © 2018 Elsevier Inc. All rights reserved.

Beyond typing and grading: target analysis in individualized therapy as a new challenge for tumour pathology.

Science.gov (United States)

Kreipe, Hans H; von Wasielewski, Reinhard

2007-01-01

In order to bring about its beneficial effects in oncology, targeted therapy depends on accurate target analysis. Whether cells of a tumour will be sensitive to a specific treatment is predicted by the detection of appropriate targets in cancer tissue by immunohistochemistry or molecular methods. In most instances this is performed by histopathologists. Reliability and reproducibility of tissue-based target analysis in histopathology require novel measures of quality assurance by internal and external controls. As a model for external quality assurance in targeted therapy an annual inter-laboratory trial has been set up in Germany applying tissue arrays with up to 60 mammary cancer samples which are tested by participants for expression of HER2/neu and steroid hormone receptors.

Evolution of the Pathology Residency Curriculum

Directory of Open Access Journals (Sweden)

Wesley Y. Naritoku MD, PhD

2016-10-01

Full Text Available The required medical knowledge and skill set for the pathologist of 2020 are different than in 2005. Pathology residency training curriculum must accordingly change to fulfill the needs of these ever-changing requirements. In order to make rational curricular adjustments, it is important for us to know the current trajectory of resident training in pathology—where we have been, what our actual current training curriculum is now—to understand how that might change in anticipation of meeting the needs of a changing patient and provider population and to fit within the evolving future biomedical and socioeconomic health-care setting. In 2013, there were 143 Accreditation Council for Graduate Medical Education-accredited pathology residency training programs in the United States, with approximately 2400 residents. There is diversity among residency training programs not only with respect to the number of residents but also in training venue(s. To characterize this diversity among pathology residency training programs, a curriculum survey was conducted of pathology residency program directors in 2013 and compared with a similar survey taken almost 9 years previously in 2005 to identify trends in pathology residency curriculum. Clinical pathology has not changed significantly in the number of rotations over 9 years; however, anatomic pathology has changed dramatically, with an increase in the number of surgical pathology rotations coupled with a decline in stand-alone autopsy rotations. With ever-expanding medical knowledge that the graduating pathology resident must know, it is necessary to (1 reflect upon what are the critical need subjects, (2 identify areas that have become of lesser importance, and then (3 prioritize training accordingly.

Evolution of the Pathology Residency Curriculum

Science.gov (United States)

Powell, Suzanne Z.; Black-Schaffer, W. Stephen

2016-01-01

The required medical knowledge and skill set for the pathologist of 2020 are different than in 2005. Pathology residency training curriculum must accordingly change to fulfill the needs of these ever-changing requirements. In order to make rational curricular adjustments, it is important for us to know the current trajectory of resident training in pathology—where we have been, what our actual current training curriculum is now—to understand how that might change in anticipation of meeting the needs of a changing patient and provider population and to fit within the evolving future biomedical and socioeconomic health-care setting. In 2013, there were 143 Accreditation Council for Graduate Medical Education-accredited pathology residency training programs in the United States, with approximately 2400 residents. There is diversity among residency training programs not only with respect to the number of residents but also in training venue(s). To characterize this diversity among pathology residency training programs, a curriculum survey was conducted of pathology residency program directors in 2013 and compared with a similar survey taken almost 9 years previously in 2005 to identify trends in pathology residency curriculum. Clinical pathology has not changed significantly in the number of rotations over 9 years; however, anatomic pathology has changed dramatically, with an increase in the number of surgical pathology rotations coupled with a decline in stand-alone autopsy rotations. With ever-expanding medical knowledge that the graduating pathology resident must know, it is necessary to (1) reflect upon what are the critical need subjects, (2) identify areas that have become of lesser importance, and then (3) prioritize training accordingly. PMID:28725779

Radiographic pathology for technologists

International Nuclear Information System (INIS)

Mace, J.D.; Kowalczyk, N.

1988-01-01

This book explains the fundamentals of disease mechanisms and relates this to the practice of radiologic science. Each chapter begins with a discussion of normal anatomy and physiology, then covers pathology and demonstrates how the pathology appears on film. Imaging modalities such as computed tomography, MRI, and ultrasound are also discussed. Clinical case studies are included

Endocrine pathology: past, present and future.

Science.gov (United States)

Asa, Sylvia L; Mete, Ozgur

2018-01-01

Endocrine pathology is the subspecialty of diagnostic pathology which deals with the diagnosis and characterisation of neoplastic and non-neoplastic diseases of the endocrine system. This relatively young subspecialty was initially focused mainly on thyroid and parathyroid pathology, with some participants also involved in studies of the pituitary, the endocrine pancreas, and the adrenal glands. However, the endocrine system involves much more than these traditional endocrine organs and the discipline has grown to encompass lesions of the dispersed neuroendocrine cells, including neuroendocrine tumours (NETs) of the lungs, gastrointestinal tract, thymus, breast and prostate, as well as paraganglia throughout the body, not just in the adrenals. Indeed, the production of hormones is the hallmark of the endocrine system, and some aspects of gynecological/testicular, bone and liver pathology also fall into the realm of this specialty. Many of the lesions that are the focus of this discipline are increasing in incidence and their pathology is becoming more complex with increased understanding of molecular pathology and a high incidence of familial disease. The future of endocrine pathology will demand a depth of understanding of structure, function, prognosis and prediction as pathologists play a key role in the multidisciplinary care team of patients with endocrine diseases. It is anticipated that new technologies will allow increased subspecialisation in pathology and growth of this important area of expertise. Copyright © 2017 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.

Fuel Assembly Damping Summary

Energy Technology Data Exchange (ETDEWEB)

Lee, Kanghee; Kang, Heungseok; Oh, Dongseok; Yoon, Kyungho; Kim, Hyungkyu; Kim, Jaeyong [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

2013-10-15

This paper summary the fuel assembly damping data in air/in still water/under flow, released from foreign fuel vendors, compared our data with the published data. Some technical issues in fuel assembly damping measurement testing are also briefly discussed. Understanding of each fuel assembly damping mechanisms according to the surrounding medium and flow velocity can support the fuel design improvement in fuel assembly dynamics and structural integrity aspect. Because the upgraded requirements of the newly-developed advanced reactor system will demands to minimize fuel design margin in integrity evaluation, reduction in conservatism of fuel assembly damping can contribute to alleviate the fuel design margin for sure. Damping is an energy dissipation mechanism in a vibrating mechanical structure and prevents a resonant structure from having infinite vibration amplitudes. The sources of fuel assembly damping are various from support friction to flow contribution, and it can be increased by the viscosity or drag of surrounding fluid medium or the average velocity of water flowing. Fuel licensing requires fuel design evaluation in transient or accidental condition. Dynamic response analysis of fuel assembly is to show fuel integrity and requires information on assembly-wise damping in dry condition and under wet or water flowing condition. However, damping measurement test for the full-scale fuel assembly prototype is not easy to carry out because of the scale (fuel prototype, test facility), unsteadiness of test data (scattering, random sampling and processing), instrumentation under water flowing (water-proof response measurement), and noise. LWR fuel technology division in KAERI is preparing the infra structure for damping measurement test of full-scale fuel assembly, to support fuel industries and related research activities. Here is a preliminary summary of fuel assembly damping, published in the literature. Some technical issues in fuel assembly damping

[Dual pathology].

Science.gov (United States)

Rougier, A

2008-05-01

Dual pathology is defined as the association of two potentially epileptogenic lesions, hippocampal (sclerosis, neuronal loss) and extrahippocampal (temporal or extratemporal). Epileptic activity may be generated by either lesion and the relative importance of every lesion's epileptogenicity conditions the surgical strategy adopted. Most frequently associated with hippocampal sclerosis are cortical dysplasias. The common physiopathology of the two lesions is not clearly established. Extrahippocampal lesions may be undetectable on MRI (microdysgenesis, for example) and ictal discharge patterns may vary among dual pathology patients. The surgical strategy depends on the location of the extrahippocampal lesion and its relative role in seizure generation; however, reported surgical results suggest that simultaneous resection of mesial temporal structures along with the extrahippocampal lesion should be performed.

The Biological Side of Water-Soluble Arene Ruthenium Assemblies

OpenAIRE

Therrien, Bruno; Furrer, Julien

2014-01-01

This review article covers the synthetic strategies, structural aspects, and host-guest properties of ruthenium metalla-assemblies, with a special focus on their use as drug delivery vectors. The two-dimensional metalla-rectangles show interesting host-guest possibilities but seem less appropriate for being used as drug carriers. On the other hand, metalla-prisms allow encapsulation and possible targeted release of bioactive molecules and consequently show some potential as drug delivery vect...

The Role of Brain-Reactive Autoantibodies in Brain Pathology and Cognitive Impairment

Directory of Open Access Journals (Sweden)

Simone Mader

2017-09-01

Full Text Available Antibodies to different brain proteins have been recently found to be associated with an increasing number of different autoimmune diseases. They need to penetrate the blood–brain barrier (BBB in order to bind antigens within the central nervous system (CNS. They can target either neuronal or non-neuronal antigen and result in damage either by themselves or in synergy with other inflammatory mediators. Antibodies can lead to acute brain pathology, which may be reversible; alternatively, they may trigger irreversible damage that persists even though the antibodies are no longer present. In this review, we will describe two different autoimmune conditions and the role of their antibodies in causing brain pathology. In systemic lupus erythematosus (SLE, patients can have double stranded DNA antibodies that cross react with the neuronal N-methyl-d-aspartate receptor (NMDAR, which have been recently linked to neurocognitive dysfunction. In neuromyelitis optica (NMO, antibodies to astrocytic aquaporin-4 (AQP4 are diagnostic of disease. There is emerging evidence that pathogenic T cells also play an important role for the disease pathogenesis in NMO since they infiltrate in the CNS. In order to enable appropriate and less invasive treatment for antibody-mediated diseases, we need to understand the mechanisms of antibody-mediated pathology, the acute and chronic effects of antibody exposure, if the antibodies are produced intrathecally or systemically, their target antigen, and what triggers their production. Emerging data also show that in utero exposure to some brain-reactive antibodies, such as those found in SLE, can cause neurodevelopmental impairment since they can penetrate the embryonic BBB. If the antibody exposure occurs at a critical time of development, this can result in irreversible damage of the offspring that persists throughout adulthood.

A Theoretical and Experimental Study of DNA Self-assembly

Science.gov (United States)

Chandran, Harish

providing detailed designs for local molecular computations that involve spatially contiguous molecules arranged on addressable substrates via enzyme-free DNA hybridization reaction cascades. We use the Visual DSD simulation software in conjunction with localized reaction rates obtained from biophysical modeling to create chemical reaction networks of localized hybridization circuits that are then model checked using the PRISM model checking software. We develop a DNA detection system employing the triggered self-assembly of a novel DNA dendritic nanostructure. Detection begins when a specific, single-stranded target DNA strand triggers a hybridization chain reaction between two distinct DNA hairpins. Each hairpin opens and hybridizes up to two copies of the other, and hence each layer of the growing dendritic nanostructure can in principle accommodate an exponentially increasing number of cognate molecules, generating a nanostructure with high molecular weight. We build linear activatable assemblies employing a novel protection/deprotection strategy to strictly enforce the direction of tiling assembly growth to ensure the robustness of the assembly process. Our system consists of two tiles that can form a linear co-polymer. These tiles, which are initially protected such that they do not react with each other, can be activated to form linear co-polymers via the use of a strand displacing enzyme.

Layer-by-layer assembled biopolymer microcapsule with separate layer cavities generated by gas-liquid microfluidic approach.

Science.gov (United States)

Wang, Yifeng; Zhou, Jing; Guo, Xuecheng; Hu, Qian; Qin, Chaoran; Liu, Hui; Dong, Meng; Chen, Yanjun

2017-12-01

In this work, a layer-by-layer (LbL) assembled biopolymer microcapsule with separate layer cavities is generated by a novel and convenient gas-liquid microfluidic approach. This approach exhibits combined advantages of microfluidic approach and LbL assembly method, and it can straightforwardly build LbL-assembled capsules in mild aqueous environments at room temperature. In particular, using this approach we can build the polyelectrolyte multilayer capsule with favorable cavities in each layer, and without the need for organic solvent, emulsifying agent, or sacrificial template. Various components (e.g., drugs, proteins, fluorescent dyes, and nanoparticles) can be respectively encapsulated in the separate layer cavities of the LbL-assembled capsules. Moreover, the encapsulated capsules present the ability as colorimetric sensors, and they also exhibit the interesting release behavior. Therefore, the LbL-assembled biopolymer capsule is a promising candidate for biomedical applications in targeted delivery, controlled release, and bio-detection. Copyright © 2017 Elsevier B.V. All rights reserved.

Review of laser mega joule target area: Design and processes

International Nuclear Information System (INIS)

Geitzholz, M.; Lanternier, C.

2006-01-01

The Laser Mega Joule (LMJ) target area is currently designed to achieve ignition and significant fusion gain in laboratory. LMJ will be composed of 240 identical large 370 mm * 370 mm square laser beams. These beams will focus 2 mega-joules of energy at the wavelength of 351 nm on the center of an experiment chamber. Design studies for target equipment are well advanced, target chamber and target holder (concrete) works have already begun. A detailed overview of the target area equipment is presented: target chamber, frame, diagnostic inserter manipulator, final optic assembly, dual diagnostic and laser reference, non cryogenic target positioner. Recent technical and architectural choices are detailed including safety transfers and alignment processes (target, laser and diagnostic). All this target equipment allows us to optimize shot chrono-gram, from target metrology to the shot, including calibration process. (authors)

Nanotized PPARα Overexpression Targeted to Hypertrophied Myocardium Improves Cardiac Function by Attenuating the p53-GSK3β-Mediated Mitochondrial Death Pathway.

Science.gov (United States)

Rana, Santanu; Datta, Ritwik; Chaudhuri, Ratul Datta; Chatterjee, Emeli; Chawla-Sarkar, Mamta; Sarkar, Sagartirtha

2018-05-09

Metabolic remodeling of cardiac muscles during pathological hypertrophy is characterized by downregulation of fatty acid oxidation (FAO) regulator, peroxisome proliferator-activated receptor alpha (PPARα). Thereby, we hypothesized that a cardiac-specific induction of PPARα might restore the FAO-related protein expression and resultant energy deficit. In the present study, consequences of PPARα augmentation were evaluated for amelioration of chronic oxidative stress, myocyte apoptosis, and cardiac function during pathological cardiac hypertrophy. Nanotized PPARα overexpression targeted to myocardium was done by a stearic acid-modified carboxymethyl-chitosan (CMC) conjugated to a 20-mer myocyte-targeted peptide (CMCP). Overexpression of PPARα ameliorated pathological hypertrophy and improved cardiac function. Augmented PPARα in hypertrophied myocytes revealed downregulated p53 acetylation (lys 382), leading to reduced apoptosis. Such cells showed increased binding of PPARα with p53 that in turn reduced interaction of p53 with glycogen synthase kinase-3β (GSK3β), which upregulated inactive phospho-GSK3β (serine [Ser]9) expression within mitochondrial protein fraction. Altogether, the altered molecular milieu in PPARα-overexpressed hypertrophy groups restored mitochondrial structure and function both in vitro and in vivo. Cardiomyocyte-targeted overexpression of a protein of interest (PPARα) by nanotized plasmid has been described for the first time in this study. Our data provide a novel insight towards regression of pathological hypertrophy by ameliorating mitochondrial oxidative stress in targeted PPARα-overexpressed myocardium. PPARα-overexpression during pathological hypertrophy showed substantial betterment of mitochondrial structure and function, along with downregulated apoptosis. Myocardium-targeted overexpression of PPARα during pathological cardiac hypertrophy led to an overall improvement of cardiac energy deficit and subsequent cardiac

EGFR and KRAS quality assurance schemes in pathology : generating normative data for molecular predictive marker analysis in targeted therapy

NARCIS (Netherlands)

Thunnissen, Erik; Bovée, Judith V M G; Bruinsma, Hans; van den Brule, Adriaan J C; Dinjens, Winand; Heideman, Daniëlle A M; Meulemans, Els; Nederlof, Petra; van Noesel, Carel; Prinsen, Clemens F M; Scheidel, Karen; van de Ven, Peter M; de Weger, Roel; Schuuring, Ed; Ligtenberg, Marjolijn

2011-01-01

Introduction The aim of this study was to compare the reproducibility of epidermal growth factor receptor (EGFR) immunohistochemistry (IHC), EGFR gene amplification analysis, and EGFR and KRAS mutation analysis among different laboratories performing routine diagnostic analyses in pathology in The

IL-1 as a target in inflammation.

Science.gov (United States)

Ito, Yuki; Kaneko, Naoe; Iwasaki, Tomoyuki; Morikawa, Shinnosuke; Kaneko, Kentaro; Masumoto, Junya

2015-03-16

Inflammation is a protective response to eliminate cytotoxic agents and pathogens. Various factors are thought to be involved in the pathological changes in tissues caused by inflammation. Interleukin 1, an inflammatory cytokine, is thought to have diverse physiological functions and to play an important role in inflammatory disease. In this review, we discuss interleukin-1 as a target of inflammatory disease.

Fuel assembly

International Nuclear Information System (INIS)

Abe, Hideaki; Sakai, Takao; Ishida, Tomio; Yokota, Norikatsu.

1992-01-01

The lower ends of a plurality of plate-like shape memory alloys are secured at the periphery of the upper inside of the handling head of a fuel assembly. As the shape memory alloy, a Cu-Zn alloy, a Ti-Pd alloy or a Fe-Ni alloy is used. When high temperature coolants flow out to the handling head, the shape memory alloy deforms by warping to the outer side more greatly toward the upper portion thereof with the temperature increase of the coolants. As the result, the shape of the flow channel of the coolants is changed so as to enlarge at the exit of the upper end of the fuel assembly. Then, the pressure loss of the coolants in the fuel assembly is decreased by the enlargement. Accordingly, the flow rate of the coolants in the fuel assembly is increased to lower the temperature of the coolants. Further, high temperature coolants and low temperature coolants are mixed sufficiently just above the fuel assembly. This can suppress the temperature fluctuation of the mixed coolants in the upper portion of the reactor core, thereby enabling to decrease a fatigue and failures of the structural components in the upper portion of the reactor core. (I.N.)

Soldering in electronics assembly

CERN Document Server

Judd, Mike

2013-01-01

Soldering in Electronics Assembly discusses several concerns in soldering of electronic assemblies. The book is comprised of nine chapters that tackle different areas in electronic assembly soldering. Chapter 1 discusses the soldering process itself, while Chapter 2 covers the electronic assemblies. Chapter 3 talks about solders and Chapter 4 deals with flux. The text also tackles the CS and SC soldering process. The cleaning of soldered assemblies, solder quality, and standards and specifications are also discussed. The book will be of great use to professionals who deal with electronic assem

Diagnostic imaging strategy for MDCT- or MRI-detected breast lesions: use of targeted sonography

International Nuclear Information System (INIS)

Nakano, Satoko; Ohtsuka, Masahiko; Mibu, Akemi; Karikomi, Masato; Sakata, Hitomi; Yamamoto, Masahiro

2012-01-01

Leading-edge technology such as magnetic resonance imaging (MRI) or computed tomography (CT) often reveals mammographically and ultrasonographically occult lesions. MRI is a well-documented, effective tool to evaluate these lesions; however, the detection rate of targeted sonography varies for MRI detected lesions, and its significance is not well established in diagnostic strategy of MRI detected lesions. We assessed the utility of targeted sonography for multidetector-row CT (MDCT)- or MRI-detected lesions in practice. We retrospectively reviewed 695 patients with newly diagnosed breast cancer who were candidates for breast conserving surgery and underwent MDCT or MRI in our hospital between January 2004 and March 2011. Targeted sonography was performed in all MDCT- or MRI-detected lesions followed by imaging-guided biopsy. Patient background, histopathology features and the sizes of the lesions were compared among benign, malignant and follow-up groups. Of the 695 patients, 61 lesions in 56 patients were detected by MDCT or MRI. The MDCT- or MRI-detected lesions were identified by targeted sonography in 58 out of 61 lesions (95.1%). Patients with pathological diagnoses were significantly older and more likely to be postmenopausal than the follow-up patients. Pathological diagnosis proved to be benign in 20 cases and malignant in 25. The remaining 16 lesions have been followed up. Lesion size and shape were not significantly different among the benign, malignant and follow-up groups. Approximately 95% of MDCT- or MRI-detected lesions were identified by targeted sonography, and nearly half of these lesions were pathologically proven malignancies in this study. Targeted sonography is a useful modality for MDCT- or MRI-detected breast lesions

Rapid fabrication and characterization of sine wave targets

International Nuclear Information System (INIS)

Day, R.D.; Armijo, E.; Gobby, P.; Hatch, D.; Rivera, G.; Salzer, L.; Townsend, J.

1997-01-01

The effect of surface perturbations on Inertial Confinement Fusion target performance is currently being researched at Los Alamos National Laboratory (LANL). These perturbations can cause hydrodynamic instabilities which in turn reduce the targets' yield. To systematically measure the growth of these instabilities requires targets to be produced which have perturbations of a known amplitude and spatial frequency. The authors have recently assembled hardware onto one of their diamond turning lathes which enables them to machine and measure these sine waves in about 15 minutes. This is a significant reduction in time from the two and one half hours required by the previous method. This paper discusses the hardware, how it works, and how well the system is working for them to produce these targets

Hip joint pathology

DEFF Research Database (Denmark)

Tijssen, M; van Cingel, R E H; de Visser, E

2017-01-01

The purpose of this retrospective cohort study was to (a) describe the clinical presentation of femoroacetabular impingement (FAI) and hip labral pathology; (b) describe the accuracy of patient history and physical tests for FAI and labral pathology as confirmed by hip arthroscopy. Patients (18......-65 years) were included if they were referred to a physical therapist to gather pre-operative data and were then diagnosed during arthroscopy. Results of pre-operative patient history and physical tests were collected and compared to arthroscopy. Data of 77 active patients (mean age: 37 years) were...

HaloPlex Targeted Resequencing for Mutation Detection in Clinical Formalin-Fixed, Paraffin-Embedded Tumor Samples.

Science.gov (United States)

Moens, Lotte N J; Falk-Sörqvist, Elin; Ljungström, Viktor; Mattsson, Johanna; Sundström, Magnus; La Fleur, Linnéa; Mathot, Lucy; Micke, Patrick; Nilsson, Mats; Botling, Johan

2015-11-01

In recent years, the advent of massively parallel next-generation sequencing technologies has enabled substantial advances in the study of human diseases. Combined with targeted DNA enrichment methods, high sequence coverage can be obtained for different genes simultaneously at a reduced cost per sample, creating unique opportunities for clinical cancer diagnostics. However, the formalin-fixed, paraffin-embedded (FFPE) process of tissue samples, routinely used in pathology departments, results in DNA fragmentation and nucleotide modifications that introduce a number of technical challenges for downstream biomolecular analyses. We evaluated the HaloPlex target enrichment system for somatic mutation detection in 80 tissue fractions derived from 20 clinical cancer cases with paired tumor and normal tissue available in both FFPE and fresh-frozen format. Several modifications to the standard method were introduced, including a reduced target fragment length and two strand capturing. We found that FFPE material can be used for HaloPlex-based target enrichment and next-generation sequencing, even when starting from small amounts of DNA. By specifically capturing both strands for each target fragment, we were able to reduce the number of false-positive errors caused by FFPE-induced artifacts and lower the detection limit for somatic mutations. We believe that the HaloPlex method presented here will be broadly applicable as a tool for somatic mutation detection in clinical cancer settings. Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

Multivalent protein assembly using monovalent self-assembling building blocks

NARCIS (Netherlands)

Petkau - Milroy, K.; Sonntag, M.H.; Colditz, A.; Brunsveld, L.

2013-01-01

Discotic molecules, which self-assemble in water into columnar supramolecular polymers, emerged as an alternative platform for the organization of proteins. Here, a monovalent discotic decorated with one single biotin was synthesized to study the self-assembling multivalency of this system in regard

Bearing assemblies, apparatuses, and motor assemblies using the same

Science.gov (United States)

Sexton, Timothy N.; Cooley, Craig H.; Knuteson, Cody W.

2015-12-29

Various embodiments of the invention relate to bearing assemblies, apparatuses and motor assemblies that include geometric features configured to impart a selected amount of heat transfer and/or hydrodynamic film formation. In an embodiment, a bearing assembly may include a plurality of superhard bearing pads distributed circumferentially about an axis. At least some of the plurality of superhard bearing pads may include a plurality of sub-superhard bearing elements defining a bearing surface. At least some of the plurality of sub-superhard bearing elements may be spaced from one another by one or more voids to impart a selected amount of heat transfer and hydrodynamic film formation thereon during operation. The bearing assembly may also include a support ring that carries the plurality of superhard bearing pads. In addition, at least a portion of the sub-superhard bearing elements may extend beyond the support ring.

A new method for discovering disease-specific MiRNA-target regulatory networks.

Directory of Open Access Journals (Sweden)

Miriam Baglioni

Full Text Available Genes and their expression regulation are among the key factors in the comprehension of the genesis and development of complex diseases. In this context, microRNAs (miRNAs are post-transcriptional regulators that play an important role in gene expression since they are frequently deregulated in pathologies like cardiovascular disease and cancer. In vitro validation of miRNA--targets regulation is often too expensive and time consuming to be carried out for every possible alternative. As a result, a tool able to provide some criteria to prioritize trials is becoming a pressing need. Moreover, before planning in vitro experiments, the scientist needs to evaluate the miRNA-target genes interaction network. In this paper we describe the miRable method whose purpose is to identify new potentially relevant genes and their interaction networks associate to a specific pathology. To achieve this goal miRable follows a system biology approach integrating together general-purpose medical knowledge (literature, Protein-Protein Interaction networks, prediction tools and pathology specific data (gene expression data. A case study on Prostate Cancer has shown that miRable is able to: 1 find new potential miRNA-targets pairs, 2 highlight novel genes potentially involved in a disease but never or little studied before, 3 reconstruct all possible regulatory subnetworks starting from the literature to expand the knowledge on the regulation of miRNA regulatory mechanisms.

Fuel assembly

International Nuclear Information System (INIS)

Gjertsen, R.K.; Bassler, E.A.; Huckestein, E.A.; Salton, R.B.; Tower, S.N.

1988-01-01

A fuel assembly adapted for use with a pressurized water nuclear reactor having capabilities for fluid moderator spectral shift control is described comprising: parallel arranged elongated nuclear fuel elements; means for providing for axial support of the fuel elements and for arranging the fuel elements in a spaced array; thimbles interspersed among the fuel elements adapted for insertion of a rod control cluster therewithin; means for structurally joining the fuel elements and the guide thimbles; fluid moderator control means for providing a volume of low neutron absorbing fluid within the fuel assembly and for removing a substantially equivalent volume of reactor coolant water therefrom, a first flow manifold at one end of the fuel assembly sealingly connected to a first end of the moderator control tubes whereby the first ends are commonly flow connected; and a second flow manifold, having an inlet passage and an outlet passage therein, sealingly connected to a second end of the moderator control tubes at a second end of the fuel assembly

Self assembly of organic nanostructures and dielectrophoretic assembly of inorganic nanowires.

Science.gov (United States)

Dholakia, Geetha; Kuo, Steven; Allen, E. L.

2007-03-01

Self assembly techniques enable the organization of organic molecules into nanostructures. Currently engineering strategies for efficient assembly and routine integration of inorganic nanoscale objects into functional devices is very limited. AC Dielectrophoresis is an efficient technique to manipulate inorganic nanomaterials into higher dimensional structures. We used an alumina template based sol-gel synthesis method for the growth of various metal oxide nanowires with typical diameters of 100-150 nm, ranging in length from 3-10 μm. Here we report the dielectrophoretic assembly of TiO2 nanowires, an important material for photocatalysis and photovoltaics, onto interdigitated devices. Self assembly in organic nanostructures and its dependence on structure and stereochemistry of the molecule and dielectrophoretic field dependence in the assembly of inorganic nanowires will be compared and contrasted. Tunneling spectroscopy and DOS of these nanoscale systems will also be discussed.

Project Plan Remote Target Fabrication Refurbishment Project

International Nuclear Information System (INIS)

Bell, Gary L.; Taylor, Robin D.

2009-01-01

was received in July 2009 under the Remote Target Fabrication Refurbishment Task of the Enhanced Utilization of Isotope Facilities project (Project Identification Code 2005230) funded by the American Recovery and Reinvestment Act of 2009. The goal of this project is to recover the capability to produce 4-5 curium targets for the irradiation period starting with HFIR cycle 427, currently scheduled to begin 2/17/10. Assuming success, the equipment would then be used to fabricate 6-7 additional targets to hold for the next irradiation campaign specified by the program. Specific objectives are the return to functionality of the Cubicle 3 Pellet Fabrication Line; Cubicle 2 Target Assembly equipment; and Cubicle 1 Target Inspection and Final Assembly system.

Design of a beam shaping assembly for an accelerator-based BNCT system

International Nuclear Information System (INIS)

Stichelbaut, F.; Forton, E.; Jongen, Y.

2006-01-01

A complete BNCT system based on a high-intensity proton accelerator is developed by the IBA company. The neutron beam is produced via the 7 Li(p,n) 7 Be reaction using a solid lithium target. The neutron energy spectrum is tailored with a beam shaping assembly surrounding the target. This device is the object of an extensive R and D project and is fully designed with the Monte Carlo simulation code MCNPX. The emphasis is put on the treatment quality, notably the radiation dose at the skin level, and the achievable neutron flux. (author)

Fire resistant PV shingle assembly

Science.gov (United States)

Lenox, Carl J.

2012-10-02

A fire resistant PV shingle assembly includes a PV assembly, including PV body, a fire shield and a connection member connecting the fire shield below the PV body, and a support and inter-engagement assembly. The support and inter-engagement assembly is mounted to the PV assembly and comprises a vertical support element, supporting the PV assembly above a support surface, an upper interlock element, positioned towards the upper PV edge, and a lower interlock element, positioned towards the lower PV edge. The upper interlock element of one PV shingle assembly is inter-engageable with the lower interlock element of an adjacent PV shingle assembly. In some embodiments the PV shingle assembly may comprise a ventilation path below the PV body. The PV body may be slidably mounted to the connection member to facilitate removal of the PV body.

Pathological gambling: a general overview.

Science.gov (United States)

Ashley, Larry L; Boehlke, Karmen K

2012-01-01

Throughout the course of history, gambling has been a popular activity across most cultures. In the United States, gambling has transitioned from early acceptance to prohibition to widespread proliferation. For most, gambling is a relaxing and recreational activity; however, for some individuals gambling becomes more than harmless fun. The most severe form of gambling, pathological gambling, is recognized as a mental health disorder. Pathological gambling is currently classified as an impulse control disorder in the DSM-IV-TR, but it shares many important features with substance use disorders, especially in terms of diagnostic criteria, clinical course, and treatment. Consequently, the DSM-V Task Force has suggested that pathological gambling be reclassified and included in a new category entitled "Addiction and Related Disorders." The category would include both substance-related and non-substance/behavioral addictions. This article provides a general overview of some of the available literature regarding pathological gambling and includes the presentation of a number of relevant topics including etiology, risk factors, comorbidity, prevention, and treatment. However, as with most complex, multifaceted, and multidimensional phenomena, more research is needed in order to improve both prevention and treatment efforts for pathological gambling.

Oral Pathology in Forensic Investigation.

Science.gov (United States)

Shamim, Thorakkal

2018-01-01

Forensic odontology is the subdiscipline of dentistry which analyses dental evidence in the interest of justice. Oral pathology is the subdiscipline of dentistry that deals with the pathology affecting the oral and maxillofacial regions. This subdiscipline is utilized for identification through oral and maxillofacial pathologies with associated syndromes, enamel rod patterns, sex determination using exfoliative cytology, identification from occlusal morphology of teeth, and deoxyribonucleic acid profiling from teeth. This subdiscipline is also utilized for age estimation studies which include Gustafson's method, incremental lines of Retzius, perikymata, natal line formation in teeth, neonatal line, racemization of collagen in dentin, cemental incremental lines, thickness of the cementum, and translucency of dentin. Even though the expertise of an oral pathologist is not taken in forensic investigations, this paper aims to discuss the role of oral pathology in forensic investigation.

Intraflagellar Transport (IFT) Role in Ciliary Assembly, Resorption and Signalling

DEFF Research Database (Denmark)

Pedersen, Lotte B; Rosenbaum, Joel L

2008-01-01

Cilia and flagella have attracted tremendous attention in recent years as research demonstrated crucial roles for these organelles in coordinating a number of physiologically and developmentally important signaling pathways, including the platelet-derived growth factor receptor (PDGFR) alpha, Sonic...... hedgehog, polycystin, and Wnt pathways. In addition, the realization that defective assembly or function of cilia can cause a plethora of diseases and developmental defects ("ciliopathies") has increased focus on the mechanisms by which these antenna-like, microtubular structures assemble. Ciliogenesis...... mechanisms and functions of IFT. In addition to a general, up-to-date description of IFT, we discuss mechanisms by which proteins are selectively targeted to the ciliary compartment, with special focus on the ciliary transition zone. Finally, we briefly review the role of IFT in cilia-mediated signaling...

The Pathology of an Autoimmune Astrocytopathy: Lessons Learned from Neuromyelitis Optica

Science.gov (United States)

Lucchinetti, Claudia F.; Guo, Yong; Popescu, Bogdan F. Gh.; Fujihara, Kazuo; Itoyama, Yasuto; Misu, Tatsuro

2014-01-01

Neuromyelitis optica (NMO) is a disabling autoimmune astrocytopathy characterized by typically severe and recurrent attacks of optic neuritis and longitudinally-extensive myelitis. Until recently, NMO was considered an acute aggressive variant of multiple sclerosis (MS), despite the fact that early studies postulated that NMO and MS may be two distinct diseases with a common clinical picture. With the discovery of a highly specific serum autoantibody (NMO-IgG), Lennon and colleagues provided the first unequivocal evidence distinguishing NMO from MS and other CNS inflammatory demyelinating disorders. The target antigen of NMO-IgG was confirmed to be aquaporin-4 (AQP4), the most abundant water channel protein in the central nervous system (CNS), mainly expressed on astrocytic foot processes at the blood brain barrier, subpial and subependymal regions. Pathological studies demonstrated that astrocytes were selectively targeted in NMO as evidenced by the extensive loss of immunoreactivities for the astrocytic proteins, AQP4 and glial fibrillary acidic protein (GFAP), as well as perivascular deposition of immunoglobulins and activation of complement even within lesions with a relative preservation of myelin. In support of these pathological findings, GFAP levels in the cerebrospinal fluid (CSF) during acute NMO exacerbations were found to be remarkably elevated in contrast to MS where CSF-GFAP levels did not substantially differ from controls. Additionally, recent experimental studies showed that AQP4 antibody is pathogenic, resulting in selective astrocyte destruction and dysfunction in vitro, ex vivo, and in vivo. These findings strongly suggest that NMO is an autoimmune astrocytopathy where damage to astrocytes exceeds both myelin and neuronal damage. This chapter will review recent neuropathological studies that have provided novel insights into the pathogenic mechanisms, cellular targets, as well as the spectrum of tissue damage in NMO. PMID:24345222

Specificity of Plasma Membrane Targeting by the Rous Sarcoma Virus Gag Protein

OpenAIRE

Scheifele, Lisa Z.; Rhoads, Jonathan D.; Parent, Leslie J.

2003-01-01

Budding of C-type retroviruses begins when the viral Gag polyprotein is directed to the plasma membrane by an N-terminal membrane-binding (M) domain. While dispersed basic amino acids within the M domain are critical for stable membrane association and consequent particle assembly, additional residues or motifs may be required for specific plasma membrane targeting and binding. We have identified an assembly-defective Rous sarcoma virus (RSV) Gag mutant that retains significant membrane affin...

Nuclear reactor fuel assembly

International Nuclear Information System (INIS)

Marmonier, Pierre; Mesnage, Bernard; Nervi, J.C.

1975-01-01

This invention refers to fuel assemblies for a liquid metal cooled fast neutron reactor. Each assembly is composed of a hollow vertical casing, of regular polygonal section, containing a bundle of clad pins filled with a fissile or fertile substance. The casing is open at its upper end and has a cylindrical foot at its lower end for positioning the assembly in a housing provided in the horizontal diagrid, on which the core assembly rests. A set of flat bars located on the external surface of the casing enables it to be correctly orientated in its housing among the other core assemblies [fr

Utilization management in anatomic pathology.

Science.gov (United States)

Lewandrowski, Kent; Black-Schaffer, Steven

2014-01-01

There is relatively little published literature concerning utilization management in anatomic pathology. Nonetheless there are many utilization management opportunities that currently exist and are well recognized. Some of these impact only the cost structure within the pathology department itself whereas others reduce charges for third party payers. Utilization management may result in medical legal liabilities for breaching the standard of care. For this reason it will be important for pathology professional societies to develop national utilization guidelines to assist individual practices in implementing a medically sound approach to utilization management. © 2013.

Cortical myoclonus and cerebellar pathology

NARCIS (Netherlands)

Tijssen, MAJ; Thom, M; Ellison, DW; Wilkins, P; Barnes, D; Thompson, PD; Brown, P

2000-01-01

Objective To study the electrophysiologic and pathologic findings in three patients with cortical myoclonus. In two patients the myoclonic ataxic syndrome was associated with proven celiac disease. Background: The pathologic findings in conditions associated with cortical myoclonus commonly involve

Cortical myoclonus and cerebellar pathology

NARCIS (Netherlands)

Tijssen, M. A.; Thom, M.; Ellison, D. W.; Wilkins, P.; Barnes, D.; Thompson, P. D.; Brown, P.

2000-01-01

OBJECTIVE: To study the electrophysiologic and pathologic findings in three patients with cortical myoclonus. In two patients the myoclonic ataxic syndrome was associated with proven celiac disease. BACKGROUND: The pathologic findings in conditions associated with cortical myoclonus commonly involve

Pathologic conditions in pregnancy

International Nuclear Information System (INIS)

Beomonte Zobel, B.; Tella, S.; Innacoli, M.; D'Archivio, C.; Cardone, G.; Masciocchi, C.; Gallucci, M.; Passariello, R.; Cappa, F.

1991-01-01

Soma authors suggested that MR imaging could rapresent an effective diagnostic alternative in the study of pathologic conditions of mother and fetus during pregnancy. To verify the actual role of MR imaging, we examined 20 patients in the 2nd and 3rd trimester of gestation, after a preliminary US examination. Fifteen patients presented fetal or placental pathologies; in 4 patients the onset of the pathologic condition occurred during pregnancy; in 1 case of US diagnosis of fetal ascites, MR findings were nornal and the newborn was healty. As for placental pathologies, our series included a case of placental cyst, two hematomas between placenta and uterine wall, and two cases of partial placenta previa. As for fetal malformation, we evaluated a case of omphalocele, one of Prune-Belly syndrome, a case of femoral asimmetry, one of thanatophoric dwarfism, a case of thoracopagus twins with cardiovascular abnormalities, two fetal hydrocephali, and three cases of pyelo-ureteral stenosis. As for maternal pathologies during pregnancy, we observed a case of subserous uterine fibromyoma, one of of right hydronephrosis, one of protrusion of lumbar invertebral disk, and a large ovarian cyst. In our experience, MR imaging exhibited high sensitivity and a large field of view, which were both useful in the investigation of the different conditions occurring during pregnancy. In the evaluation of fetal and placental abnormalities, especially during the 3rd trimester, the diagnostic yieldof MR imaging suggested it as a complementary technique to US for the evaluation of fetal malformation and of intrauterine growth retardation

Double-shell target fabrication workshop-2016 report

Energy Technology Data Exchange (ETDEWEB)

Wang, Y. Morris [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Oertel, John [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Farrell, Michael [General Atomics, San Diego, CA (United States); Baumann, Ted [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Huang, Haibo [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Nikroo, Abbas [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

2017-01-10

On June 30, 2016, over 40 representatives from Lawrence Livermore National Laboratory (LLNL), Los Alamos National Laboratory (LANL), General Atomics (GA), Laboratory for Laser Energetics (LLE), Schafer Corporation, and NNSA headquarter attended a double-shell (DS) target fabrication workshop at Livermore, California. Pushered-single-shell (PSS) and DS metalgas platforms potentially have a large impact on programmatic applications. The goal of this focused workshop is to bring together target fabrication scientists, physicists, and designers to brainstorm future PSS and DS target fabrication needs and strategies. This one-day workshop intends to give an overall view of historical information, recent approaches, and future research activities at each participating organization. Five topical areas have been discussed that are vital to the success of future DS target fabrications, including inner metal shells, foam spheres, outer ablators, fill tube assembly, and metrology.

Eye lens membrane junctional microdomains: a comparison between healthy and pathological cases

Energy Technology Data Exchange (ETDEWEB)

Buzhynskyy, Nikolay; Scheuring, Simon [Institut Curie, Equipe Inserm Avenir, UMR168-CNRS, 26 Rue d' Ulm, 75248 Paris Cedex 05 (France); Sens, Pierre [ESPCI, CNRS-UMR 7083, 75231 Paris (France); Behar-Cohen, Francine, E-mail: simon.scheuring@curie.fr [UMRS Inserm 872, Universite Paris Descartes, Centre de Recherches des Cordeliers, 15 rue de l' Ecole de Medecine, 75270 Paris Cedex 06 (France)

2011-08-15

The eye lens is a transparent tissue constituted of tightly packed fiber cells. To maintain homeostasis and transparency of the lens, the circulation of water, ions and metabolites is required. Junctional microdomains connect the lens cells and ensure both tight cell-to-cell adhesion and intercellular flow of fluids through a microcirculation system. Here, we overview membrane morphology and tissue functional requirements of the mammalian lens. Atomic force microscopy (AFM) has opened up the possibility of visualizing the junctional microdomains at unprecedented submolecular resolution, revealing the supramolecular assembly of lens-specific aquaporin-0 (AQP0) and connexins (Cx). We compare the membrane protein assembly in healthy lenses with senile and diabetes-II cataract cases and novel data of the lens membranes from a congenital cataract. In the healthy case, AQP0s form characteristic square arrays confined by connexons. In the cases of senile and diabetes-II cataract patients, connexons were degraded, leading to malformation of AQP0 arrays and breakdown of the microcirculation system. In the congenital cataract, connexons are present, indicating probable non-membranous grounds for lens opacification. Further, we discuss the energetic aspects of the membrane organization in junctional microdomains. The AFM hence becomes a biomedical nano-imaging tool for the analysis of single-membrane protein supramolecular association in healthy and pathological membranes.

Eye lens membrane junctional microdomains: a comparison between healthy and pathological cases

Science.gov (United States)

Buzhynskyy, Nikolay; Sens, Pierre; Behar-Cohen, Francine; Scheuring, Simon

2011-08-01

The eye lens is a transparent tissue constituted of tightly packed fiber cells. To maintain homeostasis and transparency of the lens, the circulation of water, ions and metabolites is required. Junctional microdomains connect the lens cells and ensure both tight cell-to-cell adhesion and intercellular flow of fluids through a microcirculation system. Here, we overview membrane morphology and tissue functional requirements of the mammalian lens. Atomic force microscopy (AFM) has opened up the possibility of visualizing the junctional microdomains at unprecedented submolecular resolution, revealing the supramolecular assembly of lens-specific aquaporin-0 (AQP0) and connexins (Cx). We compare the membrane protein assembly in healthy lenses with senile and diabetes-II cataract cases and novel data of the lens membranes from a congenital cataract. In the healthy case, AQP0s form characteristic square arrays confined by connexons. In the cases of senile and diabetes-II cataract patients, connexons were degraded, leading to malformation of AQP0 arrays and breakdown of the microcirculation system. In the congenital cataract, connexons are present, indicating probable non-membranous grounds for lens opacification. Further, we discuss the energetic aspects of the membrane organization in junctional microdomains. The AFM hence becomes a biomedical nano-imaging tool for the analysis of single-membrane protein supramolecular association in healthy and pathological membranes.

National Ignition Facility subsystem design requirements final optics assembly subsystem SSDR 1.8.7

International Nuclear Information System (INIS)

Adams, C.

1996-01-01

This SSDR establishes the performance, design, development and test requirements for the Final Optic Assembly (FOA). The FOA (WBS 1.8.7) as part of the Target Experimental System (1.8) includes vacuum windows, frequency conversion crystals, focus lens, debris shields and supporting mechanical equipment

A Case Study into Microbial Genome Assembly Gap Sequences and Finishing Strategies.

Science.gov (United States)

Utturkar, Sagar M; Klingeman, Dawn M; Hurt, Richard A; Brown, Steven D

2017-01-01

This study characterized regions of DNA which remained unassembled by either PacBio and Illumina sequencing technologies for seven bacterial genomes. Two genomes were manually finished using bioinformatics and PCR/Sanger sequencing approaches and regions not assembled by automated software were analyzed. Gaps present within Illumina assemblies mostly correspond to repetitive DNA regions such as multiple rRNA operon sequences. PacBio gap sequences were evaluated for several properties such as GC content, read coverage, gap length, ability to form strong secondary structures, and corresponding annotations. Our hypothesis that strong secondary DNA structures blocked DNA polymerases and contributed to gap sequences was not accepted. PacBio assemblies had few limitations overall and gaps were explained as cumulative effect of lower than average sequence coverage and repetitive sequences at contig termini. An important aspect of the present study is the compilation of biological features that interfered with assembly and included active transposons, multiple plasmid sequences, phage DNA integration, and large sequence duplication. Our targeted genome finishing approach and systematic evaluation of the unassembled DNA will be useful for others looking to close, finish, and polish microbial genome sequences.

Contact assembly of cell-laden hollow microtubes through automated micromanipulator tip locating

International Nuclear Information System (INIS)

Wang, Huaping; Shi, Qing; Guo, Yanan; Li, Yanan; Sun, Tao; Huang, Qiang; Fukuda, Toshio

2017-01-01

This paper presents an automated contact assembly method to fabricate a cell-laden microtube based on accurate locating of the micromanipulator tip. Essential for delivering nutrients in thick engineered tissues, a vessel-mimetic microtube can be precisely assembled through microrobotic contact biomanipulation. The biomanipulation is a technique to spatially order and immobilize cellular targets with high precision. However, due to image occlusion during contact, it is challenging to locate the micromanipulator tip for fully automated assembly. To achieve pixel-wise tracking and locating of the tip in contact, a particle filter algorithm integrated with a determined level set model is employed here. The model ensures precise convergence of the micromanipulator’s contour during occlusion. With the converged active contour, the algorithm is able to pixel-wisely separate the micromanipulator from the low-contrast background and precisely locate the tip with error around 1 pixel (2 µ m at 4  ×  magnification). As a result, the cell-laden microtube is automatically assembled at six layers/min, which is effective enough to fabricate vessel-mimetic constructs for vascularization in tissue engineering. (paper)

EB1 is required for primary cilia assembly in fibroblasts

DEFF Research Database (Denmark)

Schrøder, Jacob M; Schneider, Linda; Christensen, Søren T

2007-01-01

EB1 is a small microtubule (MT)-binding protein that associates preferentially with MT plus ends and plays a role in regulating MT dynamics. EB1 also targets other MT-associated proteins to the plus end and thereby regulates interactions of MTs with the cell cortex, mitotic kinetochores, and diff...... that localization of EB1 at the centriole/basal body is required for primary cilia assembly in fibroblasts....

Stackable Form-Factor Peripheral Component Interconnect Device and Assembly

Science.gov (United States)

Somervill, Kevin M. (Inventor); Ng, Tak-kwong (Inventor); Torres-Pomales, Wilfredo (Inventor); Malekpour, Mahyar R. (Inventor)

2013-01-01

A stackable form-factor Peripheral Component Interconnect (PCI) device can be configured as a host controller or a master/target for use on a PCI assembly. PCI device may comprise a multiple-input switch coupled to a PCI bus, a multiplexor coupled to the switch, and a reconfigurable device coupled to one of the switch and multiplexor. The PCI device is configured to support functionality from power-up, and either control function or add-in card function.

Self assembly of rectangular shapes on concentration programming and probabilistic tile assembly models.

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Kundeti, Vamsi; Rajasekaran, Sanguthevar

2012-06-01

Efficient tile sets for self assembling rectilinear shapes is of critical importance in algorithmic self assembly. A lower bound on the tile complexity of any deterministic self assembly system for an n × n square is [Formula: see text] (inferred from the Kolmogrov complexity). Deterministic self assembly systems with an optimal tile complexity have been designed for squares and related shapes in the past. However designing [Formula: see text] unique tiles specific to a shape is still an intensive task in the laboratory. On the other hand copies of a tile can be made rapidly using PCR (polymerase chain reaction) experiments. This led to the study of self assembly on tile concentration programming models. We present two major results in this paper on the concentration programming model. First we show how to self assemble rectangles with a fixed aspect ratio ( α:β ), with high probability, using Θ( α + β ) tiles. This result is much stronger than the existing results by Kao et al. (Randomized self-assembly for approximate shapes, LNCS, vol 5125. Springer, Heidelberg, 2008) and Doty (Randomized self-assembly for exact shapes. In: proceedings of the 50th annual IEEE symposium on foundations of computer science (FOCS), IEEE, Atlanta. pp 85-94, 2009)-which can only self assembly squares and rely on tiles which perform binary arithmetic. On the other hand, our result is based on a technique called staircase sampling . This technique eliminates the need for sub-tiles which perform binary arithmetic, reduces the constant in the asymptotic bound, and eliminates the need for approximate frames (Kao et al. Randomized self-assembly for approximate shapes, LNCS, vol 5125. Springer, Heidelberg, 2008). Our second result applies staircase sampling on the equimolar concentration programming model (The tile complexity of linear assemblies. In: proceedings of the 36th international colloquium automata, languages and programming: Part I on ICALP '09, Springer-Verlag, pp 235

Myofiber-specific TEAD1 overexpression drives satellite cell hyperplasia and counters pathological effects of dystrophin deficiency

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Southard, Sheryl; Kim, Ju-Ryoung; Low, SiewHui; Tsika, Richard W; Lepper, Christoph

2016-01-01

When unperturbed, somatic stem cells are poised to affect immediate tissue restoration upon trauma. Yet, little is known regarding the mechanistic basis controlling initial and homeostatic ‘scaling’ of stem cell pool sizes relative to their target tissues for effective regeneration. Here, we show that TEAD1-expressing skeletal muscle of transgenic mice features a dramatic hyperplasia of muscle stem cells (i.e. satellite cells, SCs) but surprisingly without affecting muscle tissue size. Super-numeral SCs attain a ‘normal’ quiescent state, accelerate regeneration, and maintain regenerative capacity over several injury-induced regeneration bouts. In dystrophic muscle, the TEAD1 transgene also ameliorated the pathology. We further demonstrate that hyperplastic SCs accumulate non-cell-autonomously via signal(s) from the TEAD1-expressing myofiber, suggesting that myofiber-specific TEAD1 overexpression activates a physiological signaling pathway(s) that determines initial and homeostatic SC pool size. We propose that TEAD1 and its downstream effectors are medically relevant targets for enhancing muscle regeneration and ameliorating muscle pathology. DOI: http://dx.doi.org/10.7554/eLife.15461.001 PMID:27725085

Assembling large, complex environmental metagenomes

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Howe, A. C. [Michigan State Univ., East Lansing, MI (United States). Microbiology and Molecular Genetics, Plant Soil and Microbial Sciences; Jansson, J. [USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Earth Sciences Division; Malfatti, S. A. [USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States); Tringe, S. G. [USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States); Tiedje, J. M. [Michigan State Univ., East Lansing, MI (United States). Microbiology and Molecular Genetics, Plant Soil and Microbial Sciences; Brown, C. T. [Michigan State Univ., East Lansing, MI (United States). Microbiology and Molecular Genetics, Computer Science and Engineering

2012-12-28

The large volumes of sequencing data required to sample complex environments deeply pose new challenges to sequence analysis approaches. De novo metagenomic assembly effectively reduces the total amount of data to be analyzed but requires significant computational resources. We apply two pre-assembly filtering approaches, digital normalization and partitioning, to make large metagenome assemblies more computationaly tractable. Using a human gut mock community dataset, we demonstrate that these methods result in assemblies nearly identical to assemblies from unprocessed data. We then assemble two large soil metagenomes from matched Iowa corn and native prairie soils. The predicted functional content and phylogenetic origin of the assembled contigs indicate significant taxonomic differences despite similar function. The assembly strategies presented are generic and can be extended to any metagenome; full source code is freely available under a BSD license.

Perinatal pathology: the role of the clinical pathological dialogue in problem solving

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Gavino Faa

2014-06-01

Full Text Available Pathologists and clinicians come together and exchange views, they instil in one another doubts, they break down barriers. Asphyxia, respiratory distress, sepsis, multi-organ failure (MOF, cerebral ischemia and neuroprotection, necrotizing enteritis, renal and biliary pathology (including congenital nephrotic syndrome, injury caused by drugs, cardiac decompensation, placental pathology, neonatal issues in mothers with tumor: these are the topics debated, in the true sense of the word, by perinatologists and pathologists. In some pathologies (e.g. MOF the pathophysiology is surprisingly the same in the neonate and the adult.  Different disciplines deal for example with immunohistochemistry and metabolomics with the processing of thousands of data in search of something that cannot be found with the classic criteria of anamnesis, objective examination, laboratory tests and imaging. Big data and information science promise to change the world. To come to grips with the extreme biological complexity of our organism and each of our organs, the completeness of enormous amounts of data is of extraordinary value if assessed holistically with the “omic” disciplines. Thus we have the possibility of understanding our extraordinary interindividual variability. The new technologies and their application do not diminish the role of physicians: on the contrary, they represent a formidable instrument for extending their diagnostic potential and make possible 5-P medicine: personalized, prospective, predictive, preventive, participatory.  Proceedings of the International Course on Perinatal Pathology (part of the 10th International Workshop on Neonatology · October 22nd-25th, 2014 · Cagliari (Italy · October 25th, 2014 · The role of the clinical pathological dialogue in problem solving Guest Editors: Gavino Faa, Vassilios Fanos, Peter Van Eyken

Dynamic release of nuclear RanGTP triggers TPX2-dependent microtubule assembly during the apoptotic execution phase.

Science.gov (United States)

Moss, David K; Wilde, Andrew; Lane, Jon D

2009-03-01

During apoptosis, the interphase microtubule network is dismantled then later replaced by a novel, non-centrosomal microtubule array. These microtubules assist in the peripheral redistribution of nuclear fragments in the apoptotic cell; however, the regulation of apoptotic microtubule assembly is not understood. Here, we demonstrate that microtubule assembly depends upon the release of nuclear RanGTP into the apoptotic cytoplasm because this process is blocked in apoptotic cells overexpressing dominant-negative GDP-locked Ran (T24N). Actin-myosin-II contractility provides the impetus for Ran release and, consequently, microtubule assembly is blocked in blebbistatin- and Y27632-treated apoptotic cells. Importantly, the spindle-assembly factor TPX2 (targeting protein for Xklp2), colocalises with apoptotic microtubules, and siRNA silencing of TPX2, but not of the microtubule motors Mklp1 and Kid, abrogates apoptotic microtubule assembly. These data provide a molecular explanation for the assembly of the apoptotic microtubule network, and suggest important similarities with the process of RanGTP- and TPX2-mediated mitotic spindle formation.

FROM PHYSIOLOGICAL TO PATHOLOGICAL METEOSENSITIVITY

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M. I. Yabluchanskiy

2013-12-01

Full Text Available This paper is dedicated to the problem of physiological and pathological meteosensitivity (meteodependency or meteopathy.We introduce and discuss the definition for individual meteodependency, define factors, mechanisms, clinical signs, diagnosis, and approaches to prophylaxy and treatment of individual pathological meteosensitivity.

Fragile X mental retardation protein stimulates ribonucleoprotein assembly of influenza A virus

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Zhou, Zhuo; Cao, Mengmeng; Guo, Yang; Zhao, Lili; Wang, Jingfeng; Jia, Xue; Li, Jianguo; Wang, Conghui; Gabriel, Gülsah; Xue, Qinghua; Yi, Yonghong; Cui, Sheng; Jin, Qi; Wang, Jianwei; Deng, Tao

2014-02-01

The ribonucleoprotein (RNP) of the influenza A virus is responsible for the transcription and replication of viral RNA in the nucleus. These processes require interplay between host factors and RNP components. Here, we report that the Fragile X mental retardation protein (FMRP) targets influenza virus RNA synthesis machinery and facilitates virus replication both in cell culture and in mice. We demonstrate that FMRP transiently associates with viral RNP and stimulates viral RNP assembly through RNA-mediated interaction with the nucleoprotein. Furthermore, the KH2 domain of FMRP mediates its association with the nucleoprotein. A point mutation (I304N) in the KH2 domain, identified from a Fragile X syndrome patient, disrupts the FMRP-nucleoprotein association and abolishes the ability of FMRP to participate in viral RNP assembly. We conclude that FMRP is a critical host factor used by influenza viruses to facilitate viral RNP assembly. Our observation reveals a mechanism of influenza virus RNA synthesis and provides insights into FMRP functions.

Nuclear fuel string assembly

International Nuclear Information System (INIS)

Ip, A.K.; Koyanagi, K.; Tarasuk, W.R.

1976-01-01

A method of fabricating rodded fuels suitable for use in pressure tube type reactors and in pressure vessel type reactors is described. Fuel rods are secured as an inner and an outer sub-assembly, each rod attached between mounting rings secured to the rod ends. The two sub-assemblies are telescoped together and positioned by spaced thimbles located between them to provide precise positioning while permittng differential axial movement between the sub-assemblies. Such sub-assemblies are particularly suited for mounting as bundle strings. The method provides particular advantages in the assembly of annular-section fuel pins, which includes booster fuel containing enriched fuel material. (LL)

Fuel assembly reconstitution

International Nuclear Information System (INIS)

Morgado, Mario M.; Oliveira, Monica G.N.; Ferreira Junior, Decio B.M.; Santos, Barbara O. dos; Santos, Jorge E. dos

2009-01-01

Fuel failures have been happened in Nuclear Power Plants worldwide, without lost of integrity and safety, mainly for the public, environment and power plants workers. The most common causes of these events are corrosion (CRUD), fretting and pellet cladding interaction. These failures are identified by increasing the activity of fission products, verified by chemical analyses of reactor coolant. Through these analyses, during the fourth operation cycle of Angra 2 Nuclear Power Plant, was possible to observe fuel failure indication. This indication was confirmed in the end of the cycle during the unloading of reactor core through leakage tests of fuel assembly, using the equipment called 'In Mast Sipping' and 'Box Sipping'. After confirmed, the fuel assembly reconstitution was scheduled, and happened in April, 2007, where was identified the cause and the fuel rod failure, which was substitute by dummy rods (zircaloy). The cause was fretting by 'debris'. The actions to avoid and prevent fuel assemblies failures are important. The goals of this work are to describe the methodology of fuel assembly reconstitution using the FARE (Fuel Assembly Reconstitution Equipment) system, to describe the results of this task in economic and security factors of the company and show how the fuel assembly failures are identified during operation and during the outage. (author)

Surgical Pathology Bootcamp: A Military Experience

Science.gov (United States)

2018-03-17

CAP 2018, Vancouver, British Columbia, Canada, March 17-23, 2018 14. ABSTRACT Surgical Pathology Bootcamp: A Military Experience Nathaniel Smith...REPORT TYPE 3. DATES COVERED (From - To) 17/03/2018 poster 03/17/2018-03/23/2018 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Surgical Pathology ...or its Components. Background A common complaint among pathology department faculty is the variable medical knowledge and histological experience

Biophysical characterization of the feline immunodeficiency virus p24 capsid protein conformation and in vitro capsid assembly.

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Jennifer Serrière

Full Text Available The Feline Immunodeficiency Virus (FIV capsid protein p24 oligomerizes to form a closed capsid that protects the viral genome. Because of its crucial role in the virion, FIV p24 is an interesting target for the development of therapeutic strategies, although little is known about its structure and assembly. We defined and optimized a protocol to overexpress recombinant FIV capsid protein in a bacterial system. Circular dichroism and isothermal titration calorimetry experiments showed that the structure of the purified FIV p24 protein was comprised mainly of α-helices. Dynamic light scattering (DLS and cross-linking experiments demonstrated that p24 was monomeric at low concentration and dimeric at high concentration. We developed a protocol for the in vitro assembly of the FIV capsid. As with HIV, an increased ionic strength resulted in FIV p24 assembly in vitro. Assembly appeared to be dependent on temperature, salt concentration, and protein concentration. The FIV p24 assembly kinetics was monitored by DLS. A limit end-point diameter suggested assembly into objects of definite shapes. This was confirmed by electron microscopy, where FIV p24 assembled into spherical particles. Comparison of FIV p24 with other retroviral capsid proteins showed that FIV assembly is particular and requires further specific study.

Formation of active inclusion bodies induced by hydrophobic self-assembling peptide GFIL8.

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Wang, Xu; Zhou, Bihong; Hu, Weike; Zhao, Qing; Lin, Zhanglin

2015-06-16

In the last few decades, several groups have observed that proteins expressed as inclusion bodies (IBs) in bacteria could still be biologically active when terminally fused to an appropriate aggregation-prone partner such as pyruvate oxidase from Paenibacillus polymyxa (PoxB). More recently, we have demonstrated that three amphipathic self-assembling peptides, an alpha helical peptide 18A, a beta-strand peptide ELK16, and a surfactant-like peptide L6KD, have properties that induce target proteins into active IBs. We have developed an efficient protein expression and purification approach for these active IBs by introducing a self-cleavable intein molecule. In this study, the self-assembling peptide GFIL8 (GFILGFIL) with only hydrophobic residues was analyzed, and this peptide effectively induced the formation of cytoplasmic IBs in Escherichia coli when terminally attached to lipase A and amadoriase II. The protein aggregates in cells were confirmed by transmission electron microscopy analysis and retained ~50% of their specific activities relative to the native counterparts. We constructed an expression and separation coupled tag (ESCT) by incorporating an intein molecule, the Mxe GyrA intein. Soluble target proteins were successfully released from active IBs upon cleavage of the intein between the GFIL8 tag and the target protein, which was mediated by dithiothreitol. A variant of GFIL8, GFIL16 (GFILGFILGFILGFIL), improved the ESCT scheme by efficiently eliminating interference from the soluble intein-GFIL8 molecule. The yields of target proteins at the laboratory scale were 3.0-7.5 μg/mg wet cell pellet, which is comparable to the yields from similar ESCT constructs using 18A, ELK16, or the elastin-like peptide tag scheme. The all-hydrophobic self-assembling peptide GFIL8 induced the formation of active IBs in E. coli when terminally attached to target proteins. GFIL8 and its variant GFIL16 can act as a "pull-down" tag to produce purified soluble proteins with

Genome-wide association study of pathological gambling.

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Lang, M; Leménager, T; Streit, F; Fauth-Bühler, M; Frank, J; Juraeva, D; Witt, S H; Degenhardt, F; Hofmann, A; Heilmann-Heimbach, S; Kiefer, F; Brors, B; Grabe, H-J; John, U; Bischof, A; Bischof, G; Völker, U; Homuth, G; Beutel, M; Lind, P A; Medland, S E; Slutske, W S; Martin, N G; Völzke, H; Nöthen, M M; Meyer, C; Rumpf, H-J; Wurst, F M; Rietschel, M; Mann, K F

2016-08-01

Pathological gambling is a behavioural addiction with negative economic, social, and psychological consequences. Identification of contributing genes and pathways may improve understanding of aetiology and facilitate therapy and prevention. Here, we report the first genome-wide association study of pathological gambling. Our aims were to identify pathways involved in pathological gambling, and examine whether there is a genetic overlap between pathological gambling and alcohol dependence. Four hundred and forty-five individuals with a diagnosis of pathological gambling according to the Diagnostic and Statistical Manual of Mental Disorders were recruited in Germany, and 986 controls were drawn from a German general population sample. A genome-wide association study of pathological gambling comprising single marker, gene-based, and pathway analyses, was performed. Polygenic risk scores were generated using data from a German genome-wide association study of alcohol dependence. No genome-wide significant association with pathological gambling was found for single markers or genes. Pathways for Huntington's disease (P-value=6.63×10(-3)); 5'-adenosine monophosphate-activated protein kinase signalling (P-value=9.57×10(-3)); and apoptosis (P-value=1.75×10(-2)) were significant. Polygenic risk score analysis of the alcohol dependence dataset yielded a one-sided nominal significant P-value in subjects with pathological gambling, irrespective of comorbid alcohol dependence status. The present results accord with previous quantitative formal genetic studies which showed genetic overlap between non-substance- and substance-related addictions. Furthermore, pathway analysis suggests shared pathology between Huntington's disease and pathological gambling. This finding is consistent with previous imaging studies. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Innovating undergraduate pathology education through public engagement.

Science.gov (United States)

Mukundu Nagesh, Navin; Chiva Giurca, Bogdan; Lishman, Suzy

2018-05-01

The trends in modern undergraduate medical education focus on a patient-centred approach through problem-based learning over the traditional modular curriculum. Integrating pathology into this style of learning has resulted in the dilution of core scientific principles which may have contributed to reduced understanding and interest in the subject. We aim to innovate pathology education by utilising National Pathology Week which is organised by the Royal College of Pathologists to develop the public engagement model which empowers students to learn pathology by teaching the public. Through this model, we hope to generate a greater interest in pathology at both undergraduate and postgraduate stages of education. We obtained funding from the Royal College of Pathologists to organise National Pathology Week at Exeter Medical School and the Royal Devon & Exeter Hospital. We involved 125 undergraduate student volunteers from health-related courses. We designed a curriculum aiming to educate both students and public on current topics such as cancer screening programmes, antibiotic resistance, diagnosis of inflammatory bowel disease and the role of pathologists. We hosted 15 pathologists, biomedical scientists and microbiologists to engage with students, share experiences and offer an insight into their careers. Through this project, we interacted with over 500 members of the public and 150 school students. The medical student volunteers developed a range of skills including competent use of microscopes to visualise pathology slides, effective communication with lay audiences to teach pathology and understanding of the clinical application of pathology. We believe the public engagement model of teaching undergraduate students has the potential to develop a greater interest in pathology whilst benefitting the wider community.

Integration of Molecular Pathology, Epidemiology, and Social Science for Global Precision Medicine

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Nishi, Akihiro; Milner, Danny A; Giovannucci, Edward L.; Nishihara, Reiko; Tan, Andy S.; Kawachi, Ichiro; Ogino, Shuji

2015-01-01

Summary The precision medicine concept and the unique disease principle imply that each patient has unique pathogenic processes resulting from heterogeneous cellular genetic and epigenetic alterations, and interactions between cells (including immune cells) and exposures, including dietary, environmental, microbial, and lifestyle factors. As a core method field in population health science and medicine, epidemiology is a growing scientific discipline that can analyze disease risk factors, and develop statistical methodologies to maximize utilization of big data on populations and disease pathology. The evolving transdisciplinary field of molecular pathological epidemiology (MPE) can advance biomedical and health research by linking exposures to molecular pathologic signatures, enhancing causal inference, and identifying potential biomarkers for clinical impact. The MPE approach can be applied to any diseases, although it has been most commonly used in neoplastic diseases (including breast, lung and colorectal cancers) because of availability of various molecular diagnostic tests. However, use of state-of-the-art genomic, epigenomic and other omic technologies and expensive drugs in modern healthcare systems increases racial, ethnic and socioeconomic disparities. To address this, we propose to integrate molecular pathology, epidemiology, and social science. Social epidemiology integrates the latter two fields. The integrative social MPE model can embrace sociology, economics and precision medicine, address global health disparities and inequalities, and elucidate biological effects of social environments, behaviors, and networks. We foresee advancements of molecular medicine, including molecular diagnostics, biomedical imaging, and targeted therapeutics, which should benefit individuals in a global population, by means of an interdisciplinary approach of integrative MPE and social health science. PMID:26636627

Integration of molecular pathology, epidemiology and social science for global precision medicine.

Science.gov (United States)

Nishi, Akihiro; Milner, Danny A; Giovannucci, Edward L; Nishihara, Reiko; Tan, Andy S; Kawachi, Ichiro; Ogino, Shuji

2016-01-01

The precision medicine concept and the unique disease principle imply that each patient has unique pathogenic processes resulting from heterogeneous cellular genetic and epigenetic alterations and interactions between cells (including immune cells) and exposures, including dietary, environmental, microbial and lifestyle factors. As a core method field in population health science and medicine, epidemiology is a growing scientific discipline that can analyze disease risk factors and develop statistical methodologies to maximize utilization of big data on populations and disease pathology. The evolving transdisciplinary field of molecular pathological epidemiology (MPE) can advance biomedical and health research by linking exposures to molecular pathologic signatures, enhancing causal inference and identifying potential biomarkers for clinical impact. The MPE approach can be applied to any diseases, although it has been most commonly used in neoplastic diseases (including breast, lung and colorectal cancers) because of availability of various molecular diagnostic tests. However, use of state-of-the-art genomic, epigenomic and other omic technologies and expensive drugs in modern healthcare systems increases racial, ethnic and socioeconomic disparities. To address this, we propose to integrate molecular pathology, epidemiology and social science. Social epidemiology integrates the latter two fields. The integrative social MPE model can embrace sociology, economics and precision medicine, address global health disparities and inequalities, and elucidate biological effects of social environments, behaviors and networks. We foresee advancements of molecular medicine, including molecular diagnostics, biomedical imaging and targeted therapeutics, which should benefit individuals in a global population, by means of an interdisciplinary approach of integrative MPE and social health science.

Magnetic resonance imaging of popliteal artery pathologies

International Nuclear Information System (INIS)

Holden, Andrew; Merrilees, Stephen; Mitchell, Nicola; Hill, Andrew

2008-01-01

This paper illustrates examples of popliteal artery pathologies imaged with contrast enhanced magnetic resonance angiography (CE-MRA) and magnetic resonance imaging (MRI) at a single tertiary referral centre. Popliteal artery pathologies were identified in 1710 patients referred over a 6-year period with symptoms suggesting lower limb arterial occlusive disease. Common pathologies such as atherosclerotic occlusive disease, thromboemboli and aneurysm disease are discussed as well as unusual pathologies such as cystic adventitial disease, mycotic aneurysm and arterial entrapment. The combination of CE-MRA and the excellent soft tissue resolution of MRI allow detailed evaluation of arterial and peri-arterial pathologies, and facilitate appropriate management decisions

Magnetic resonance imaging of popliteal artery pathologies

Energy Technology Data Exchange (ETDEWEB)

Holden, Andrew [Department of Radiology, Auckland City Hospital, Park Road, Grafton, Auckland 9 (New Zealand)], E-mail: andrewh@adhb.govt.nz; Merrilees, Stephen [Department of Radiology, Auckland City Hospital, Park Road, Grafton, Auckland 9 (New Zealand)], E-mail: smerrilees@adhb.govt.nz; Mitchell, Nicola [Department of Radiology, Auckland City Hospital, Park Road, Grafton, Auckland 9 (New Zealand)], E-mail: nmit010@ec.auckland.ac.nz; Hill, Andrew [Department of Vascular Surgery, Auckland City Hospital, Park Road, Grafton, Auckland 9 (New Zealand)], E-mail: ahill@adhb.govt.nz

2008-07-15

This paper illustrates examples of popliteal artery pathologies imaged with contrast enhanced magnetic resonance angiography (CE-MRA) and magnetic resonance imaging (MRI) at a single tertiary referral centre. Popliteal artery pathologies were identified in 1710 patients referred over a 6-year period with symptoms suggesting lower limb arterial occlusive disease. Common pathologies such as atherosclerotic occlusive disease, thromboemboli and aneurysm disease are discussed as well as unusual pathologies such as cystic adventitial disease, mycotic aneurysm and arterial entrapment. The combination of CE-MRA and the excellent soft tissue resolution of MRI allow detailed evaluation of arterial and peri-arterial pathologies, and facilitate appropriate management decisions.

Reflector-moderated critical assemblies

International Nuclear Information System (INIS)

Paxton, H.C.; Jarvis, G.A.; Byers, C.C.

1975-07-01

Experiments with reflector-moderated critical assemblies were part of the Rover Program at the Los Alamos Scientific Laboratory (LASL). These assemblies were characterized by thick D 2 O or beryllium reflectors surrounding large cavities that contained highly enriched uranium at low average densities. Because interest in this type of system has been revived by LASL Plasma Cavity Assembly studies, more detailed descriptions of the early assemblies than had been available in the unclassified literature are provided. (U.S.)

SWAP-Assembler 2: Optimization of De Novo Genome Assembler at Large Scale

Energy Technology Data Exchange (ETDEWEB)

Meng, Jintao; Seo, Sangmin; Balaji, Pavan; Wei, Yanjie; Wang, Bingqiang; Feng, Shengzhong

2016-08-16

In this paper, we analyze and optimize the most time-consuming steps of the SWAP-Assembler, a parallel genome assembler, so that it can scale to a large number of cores for huge genomes with the size of sequencing data ranging from terabyes to petabytes. According to the performance analysis results, the most time-consuming steps are input parallelization, k-mer graph construction, and graph simplification (edge merging). For the input parallelization, the input data is divided into virtual fragments with nearly equal size, and the start position and end position of each fragment are automatically separated at the beginning of the reads. In k-mer graph construction, in order to improve the communication efficiency, the message size is kept constant between any two processes by proportionally increasing the number of nucleotides to the number of processes in the input parallelization step for each round. The memory usage is also decreased because only a small part of the input data is processed in each round. With graph simplification, the communication protocol reduces the number of communication loops from four to two loops and decreases the idle communication time. The optimized assembler is denoted as SWAP-Assembler 2 (SWAP2). In our experiments using a 1000 Genomes project dataset of 4 terabytes (the largest dataset ever used for assembling) on the supercomputer Mira, the results show that SWAP2 scales to 131,072 cores with an efficiency of 40%. We also compared our work with both the HipMER assembler and the SWAP-Assembler. On the Yanhuang dataset of 300 gigabytes, SWAP2 shows a 3X speedup and 4X better scalability compared with the HipMer assembler and is 45 times faster than the SWAP-Assembler. The SWAP2 software is available at https://sourceforge.net/projects/swapassembler.

Controlled self assembly of collagen nanoparticle

Science.gov (United States)

Papi, Massimiliano; Palmieri, Valentina; Maulucci, Giuseppe; Arcovito, Giuseppe; Greco, Emanuela; Quintiliani, Gianluca; Fraziano, Maurizio; De Spirito, Marco

2011-11-01

In recent years carrier-mediated drug delivery has emerged as a powerful methodology for the treatment of various pathologies. The therapeutic index of traditional and novel drugs is enhanced via the increase of specificity due to targeting of drugs to a particular tissue, cell or intracellular compartment, the control over release kinetics, the protection of the active agent, or a combination of the above. Collagen is an important biomaterial in medical applications and ideal as protein-based drug delivery platform due to its special characteristics, such as biocompatibility, low toxicity, biodegradability, and weak antigenicity. While some many attempts have been made, further work is needed to produce fully biocompatible collagen hydrogels of desired size and able to release drugs on a specific target. In this article we propose a novel method to obtain spherical particles made of polymerized collagen surrounded by DMPC liposomes. The liposomes allow to control both the particles dimension and the gelling environment during the collagen polymerization. Furthermore, an optical based method to visualize and quantify each step of the proposed protocol is detailed and discussed.

Effects of Neurotrophic Support and Amyloid-Targeted Combined Therapy on Adult Hippocampal Neurogenesis in a Transgenic Model of Alzheimer's Disease.

Directory of Open Access Journals (Sweden)

Christopher D Morrone

Full Text Available Although it is recognized that multi-drug therapies may be necessary to combat AD, there is a paucity of preclinical proof of concept studies. We present a combination treatment paradigm, which temporally affects different aspects of Alzheimer's disease (AD-like pathology, specifically Aβ-toxicity and neurogenesis. At early stages of AD-like pathology, in TgCRND8 mice, we found that combating Aβ pathology with scyllo-inositol ameliorated deficits in neurogenesis. Older TgCRND8 mice with established amyloid load had decreased progenitor cell proliferation and survival compared to non-transgenic mice, regardless of scyllo-inositol treatment. The prolonged exposure to Aβ-pathology leads to deficits in the neurogenic niche, thus targeting Aβ alone is insufficient to rescue neurogenesis. To support the neurogenic niche, we combined scyllo-inositol treatment with leteprinim potassium (neotrofin, the latter of which stimulates neurotrophin expression. We show that the combination treatment of scyllo-inositol and neotrofin enhances neuronal survival and differentiation. We propose this proof of concept combination therapy of targeting Aβ-pathology and neurotrophin deficits as a potential treatment for AD.

Visualization of the Serratia Type VI Secretion System Reveals Unprovoked Attacks and Dynamic Assembly

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Amy J. Gerc

2015-09-01

Full Text Available The Type VI secretion system (T6SS is a bacterial nanomachine that fires toxic proteins into target cells. Deployment of the T6SS represents an efficient and widespread means by which bacteria attack competitors or interact with host organisms and may be triggered by contact from an attacking neighbor cell as a defensive strategy. Here, we use the opportunist pathogen Serratia marcescens and functional fluorescent fusions of key components of the T6SS to observe different subassemblies of the machinery simultaneously and on multiple timescales in vivo. We report that the localization and dynamic behavior of each of the components examined is distinct, revealing a multi-stage and dynamic assembly process for the T6SS machinery. We also show that the T6SS can assemble and fire without needing a cell contact trigger, defining an aggressive strategy that broadens target range and suggesting that activation of the T6SS is tailored to survival in specific niches.

Visualization of the Serratia Type VI Secretion System Reveals Unprovoked Attacks and Dynamic Assembly

Science.gov (United States)

Gerc, Amy J.; Diepold, Andreas; Trunk, Katharina; Porter, Michael; Rickman, Colin; Armitage, Judith P.; Stanley-Wall, Nicola R.; Coulthurst, Sarah J.

2015-01-01

Summary The Type VI secretion system (T6SS) is a bacterial nanomachine that fires toxic proteins into target cells. Deployment of the T6SS represents an efficient and widespread means by which bacteria attack competitors or interact with host organisms and may be triggered by contact from an attacking neighbor cell as a defensive strategy. Here, we use the opportunist pathogen Serratia marcescens and functional fluorescent fusions of key components of the T6SS to observe different subassemblies of the machinery simultaneously and on multiple timescales in vivo. We report that the localization and dynamic behavior of each of the components examined is distinct, revealing a multi-stage and dynamic assembly process for the T6SS machinery. We also show that the T6SS can assemble and fire without needing a cell contact trigger, defining an aggressive strategy that broadens target range and suggesting that activation of the T6SS is tailored to survival in specific niches. PMID:26387948

NMR imaging of osteoarticular pathology

International Nuclear Information System (INIS)

Frocrain, L.; Duvauferrier, R.; Gagey, N.

1987-01-01

NMR imaging is assuming an increasingly important role in the diagnosis of osteo-articular disorders. Semiological descriptions of the mean pathological disorders of the locomotor system are presented. Some investigation strategies are proposed to compare NMR imaging with other imaging techniques in various pathological states [fr

Claudin-Low Breast Cancer; Clinical & Pathological Characteristics.

Directory of Open Access Journals (Sweden)

Kay Dias

Full Text Available Claudin-low breast cancer is a molecular type of breast cancer originally identified by gene expression profiling and reportedly associated with poor survival. Claudin-low tumors have been recognised to preferentially display a triple-negative phenotype, however only a minority of triple-negative breast cancers are claudin-low. We sought to identify an immunohistochemical profile for claudin-low tumors that could facilitate their identification in formalin fixed paraffin embedded tumor material. First, an in silico collection of ~1600 human breast cancer expression profiles was assembled and all claudin-low tumors identified. Second, genes differentially expressed between claudin-low tumors and all other molecular subtypes of breast cancer were identified. Third, a number of these top differentially expressed genes were tested using immunohistochemistry for expression in a diverse panel of breast cancer cell lines to determine their specificity for claudin-low tumors. Finally, the immunohistochemical panel found to be most characteristic of claudin-low tumors was examined in a cohort of 942 formalin fixed paraffin embedded human breast cancers with >10 years clinical follow-up to evaluate the clinico-pathologic and survival characteristics of this tumor subtype. Using this approach we determined that claudin-low breast cancer is typically negative for ER, PR, HER2, claudin 3, claudin 4, claudin 7 and E-cadherin. Claudin-low tumors identified with this immunohistochemical panel, were associated with young age of onset, higher tumor grade, larger tumor size, extensive lymphocytic infiltrate and a circumscribed tumor margin. Patients with claudin-low tumors had a worse overall survival when compared to patients with luminal A type breast cancer. Interestingly, claudin-low tumors were associated with a low local recurrence rate following breast conserving therapy. In conclusion, a limited panel of antibodies can facilitate the identification of

A cryogenic infrared calibration target

Science.gov (United States)

Wollack, E. J.; Kinzer, R. E.; Rinehart, S. A.

2014-04-01

A compact cryogenic calibration target is presented that has a peak diffuse reflectance, R ⩽ 0.003, from 800 to 4800 cm-1 (12 - 2 μm). Upon expanding the spectral range under consideration to 400-10 000 cm-1 (25 - 1 μm) the observed performance gracefully degrades to R ⩽ 0.02 at the band edges. In the implementation described, a high-thermal-conductivity metallic substrate is textured with a pyramidal tiling and subsequently coated with a thin lossy dielectric coating that enables high absorption and thermal uniformity across the target. The resulting target assembly is lightweight, has a low-geometric profile, and has survived repeated thermal cycling from room temperature to ˜4 K. Basic design considerations, governing equations, and test data for realizing the structure described are provided. The optical properties of selected absorptive materials—Acktar Fractal Black, Aeroglaze Z306, and Stycast 2850 FT epoxy loaded with stainless steel powder—are characterized and presented.

Insulin Resistance as a Link between Amyloid-Beta and Tau Pathologies in Alzheimer’s Disease

Directory of Open Access Journals (Sweden)

Roger J. Mullins

2017-05-01

Full Text Available Current hypotheses and theories regarding the pathogenesis of Alzheimer’s disease (AD heavily implicate brain insulin resistance (IR as a key factor. Despite the many well-validated metrics for systemic IR, the absence of biomarkers for brain-specific IR represents a translational gap that has hindered its study in living humans. In our lab, we have been working to develop biomarkers that reflect the common mechanisms of brain IR and AD that may be used to follow their engagement by experimental treatments. We present two promising biomarkers for brain IR in AD: insulin cascade mediators probed in extracellular vesicles (EVs enriched for neuronal origin, and two-dimensional magnetic resonance spectroscopy (MRS measures of brain glucose. As further evidence for a fundamental link between brain IR and AD, we provide a novel analysis demonstrating the close spatial correlation between brain expression of genes implicated in IR (using Allen Human Brain Atlas data and tau and beta-amyloid pathologies. We proceed to propose the bold hypotheses that baseline differences in the metabolic reliance on glycolysis, and the expression of glucose transporters (GLUT and insulin signaling genes determine the vulnerability of different brain regions to Tau and/or Amyloid beta (Aβ pathology, and that IR is a critical link between these two pathologies that define AD. Lastly, we provide an overview of ongoing clinical trials that target IR as an angle to treat AD, and suggest how biomarkers may be used to evaluate treatment efficacy and target engagement.

Endocytic vesicle rupture is a conserved mechanism of cellular invasion by amyloid proteins.

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Flavin, William P; Bousset, Luc; Green, Zachary C; Chu, Yaping; Skarpathiotis, Stratos; Chaney, Michael J; Kordower, Jeffrey H; Melki, Ronald; Campbell, Edward M

2017-10-01

Numerous pathological amyloid proteins spread from cell to cell during neurodegenerative disease, facilitating the propagation of cellular pathology and disease progression. Understanding the mechanism by which disease-associated amyloid protein assemblies enter target cells and induce cellular dysfunction is, therefore, key to understanding the progressive nature of such neurodegenerative diseases. In this study, we utilized an imaging-based assay to monitor the ability of disease-associated amyloid assemblies to rupture intracellular vesicles following endocytosis. We observe that the ability to induce vesicle rupture is a common feature of α-synuclein (α-syn) assemblies, as assemblies derived from WT or familial disease-associated mutant α-syn all exhibited the ability to induce vesicle rupture. Similarly, different conformational strains of WT α-syn assemblies, but not monomeric or oligomeric forms, efficiently induced vesicle rupture following endocytosis. The ability to induce vesicle rupture was not specific to α-syn, as amyloid assemblies of tau and huntingtin Exon1 with pathologic polyglutamine repeats also exhibited the ability to induce vesicle rupture. We also observe that vesicles ruptured by α-syn are positive for the autophagic marker LC3 and can accumulate and fuse into large, intracellular structures resembling Lewy bodies in vitro. Finally, we show that the same markers of vesicle rupture surround Lewy bodies in brain sections from PD patients. These data underscore the importance of this conserved endocytic vesicle rupture event as a damaging mechanism of cellular invasion by amyloid assemblies of multiple neurodegenerative disease-associated proteins, and suggest that proteinaceous inclusions such as Lewy bodies form as a consequence of continued fusion of autophagic vesicles in cells unable to degrade ruptured vesicles and their amyloid contents.

Pathology of pulmonary aspergillomas

OpenAIRE

Shah Rajeev; Vaideeswar Pradeep; Pandit Shobhana

2008-01-01

Aspergilloma refers to a fungal ball formed by saprophytic overgrowth of Aspergillus species and is seen secondary to cavitatory/cystic respiratory diseases. Paucity of clinical and pathological data of aspergilloma in India prompted us to analyze cases of aspergilloma over 15 years. The clinical features were recorded in all and correlated with detailed pathological examination. Aspergillomas were identified in 41 surgical excisions or at autopsy. There was male predominance; half the patien...

[Correlation between iridology and general pathology].

Science.gov (United States)

Demea, Sorina

2002-01-01

The research proposal is to evaluate the association between certain irian signs and general pathology of studied patients. There were studied 57 hospitalized patients; there was taken over all their iris images, which were analyzed through iridological protocols; in the same time the pathology of these patients was noted from their records in the hospital, concordant with the clinical diagnosis; all these information were included in a database for a computerised processing. The correlations resulted from, shows a high connection between the irian constitution establish through iridological criteria and the existent pathology. Iris examination can be very useful for diagnosis of a certain general pathology, in a holistic approach of the patient.

Nanostructured nanoparticles of self-assembled lipid pro-drugs as a route to improved chemotherapeutic agents

Energy Technology Data Exchange (ETDEWEB)

Sagnella, Sharon M.; Gong, Xiaojuan; Moghaddam, Minoo J.; Conn, Charlotte E.; Kimpton, Kathleen; Waddington, Lynne J.; Krodkiewska, Irena; Drummond, Calum J. (CSIRO/MSE); (CSIRO/LW)

2014-09-24

We demonstrate that oral delivery of self-assembled nanostructured nanoparticles consisting of 5-fluorouracil (5-FU) lipid prodrugs results in a highly effective, target-activated, chemotherapeutic agent, and offers significantly enhanced efficacy over a commercially available alternative that does not self-assemble. The lipid prodrug nanoparticles have been found to significantly slow the growth of a highly aggressive mouse 4T1 breast tumour, and essentially halt the growth of a human MDA-MB-231 breast tumour in mouse xenografts. Systemic toxicity is avoided as prodrug activation requires a three-step, enzymatic conversion to 5-FU, with the third step occurring preferentially at the tumour site. Additionally, differences in the lipid prodrug chemical structure and internal nanostructure of the nanoparticle dictate the enzymatic conversion rate and can be used to control sustained release profiles. Thus, we have developed novel oral nanomedicines that combine sustained release properties with target-selective activation.

Ion source for ion beam deposition employing a novel electrode assembly

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Hayes, A. V.; Kanarov, V.; Yevtukhov, R.; Hegde, H.; Druz, B.; Yakovlevitch, D.; Cheesman, W.; Mirkov, V.

2000-02-01

A rf inductively coupled ion source employing a novel electrode assembly for focusing a broad ion beam on a relatively small target area was developed. The primary application of this ion source is the deposition of thin films used in the fabrication of magnetic sensors and optical devices. The ion optics consists of a three-electrode set of multiaperture concave dished grids with a beam extraction diameter of 150 mm. Also described is a variation in the design providing a beam extraction diameter of 120 mm. Grid hole diameters and grid spacing were optimized for low beamlet divergence and low grid impingement currents. The radius of curvature of the grids was optimized to obtain an optimally focused ion beam at the target location. A novel grid fabrication and mounting design was employed which overcomes typical limitations of such grid assemblies, particularly in terms of maintaining optimum beam focusing conditions after multiple cycles of operation. Ion beam generation with argon and xenon gases in energy ranges from 0.3 to 2.0 keV was characterized. For operation with argon gas, beam currents greater than 0.5 A were obtained with a beam energy of 800 eV. At optimal beam formation conditions, beam profiles at distances about equal to the radius of curvature were found to be close to Gaussian, with 99.9% of the beam current located within a 150 mm target diameter. Repeatability of the beam profile over long periods of operation is also reported.

Central pathology review with two-stage quality assurance for pathological response after neoadjuvant chemotherapy in the ARTemis Trial.

Science.gov (United States)

Thomas, Jeremy St John; Provenzano, Elena; Hiller, Louise; Dunn, Janet; Blenkinsop, Clare; Grybowicz, Louise; Vallier, Anne-Laure; Gounaris, Ioannis; Abraham, Jean; Hughes-Davies, Luke; McAdam, Karen; Chan, Stephen; Ahmad, Rizvana; Hickish, Tamas; Houston, Stephen; Rea, Daniel; Caldas, Carlos; Bartlett, John Ms; Cameron, David Allan; Hayward, Richard Laurence; Earl, Helena Margaret

2017-08-01

The ARTemis Trial tested standard neoadjuvant chemotherapy±bevacizumab in the treatment of HER2-negative early breast cancer. We compare data from central pathology review with report review and also the reporting behavior of the two central pathologists. Eight hundred women with HER2-negative early invasive breast cancer were recruited. Response to chemotherapy was assessed from local pathology reports for pathological complete response in breast and axillary lymph nodes. Sections from the original core biopsy and surgical excision were centrally reviewed by one of two trial pathologists blinded to the local pathology reports. Pathologists recorded response to chemotherapy descriptively and also calculated residual cancer burden. 10% of cases were double-reported to compare the central pathologists' reporting behavior. Full sample retrieval was obtained for 681 of the 781 patients (87%) who underwent surgery within the trial and were evaluable for pathological complete response. Four hundred and eighty-three (71%) were assessed by JSJT, and 198 (29%) were assessed by EP. Residual cancer burden calculations were possible in 587/681 (86%) of the centrally reviewed patients, as 94/681 (14%) had positive sentinel nodes removed before neoadjuvant chemotherapy invalidating residual cancer burden scoring. Good concordance was found between the two pathologists for residual cancer burden classes within the 65-patient quality assurance exercise (kappa 0.63 (95% CI: 0.57-0.69)). Similar results were obtained for the between-treatment arm comparison both from the report review and the central pathology review. For pathological complete response, report review was as good as central pathology review but for minimal residual disease, report review overestimated the extent of residual disease. In the ARTemis Trial central pathology review added little in the determination of pathological complete response but had a role in evaluating low levels of residual disease. Calculation