An analysis of interactions between fluorescently-tagged mutant and wild-type SOD1 in intracellular inclusions

By mechanisms yet to be discerned, the co-expression of high levels of wild-type human superoxide dismutase 1 (hSOD1) with variants of hSOD1 encoding mutations linked familial amyotrophic lateral sclerosis (fALS) hastens the onset of motor neuron degeneration in transgenic mice. Although it is known that spinal cords of paralyzed mice accumulate detergent insoluble forms of WT hSOD1 along with mutant hSOD1, it has been difficult to determine whether there is co-deposition of the proteins in inclusion structures.In the present study, we use cell culture models of mutant SOD1 aggregation, focusing on the A4V, G37R, and G85R variants, to examine interactions between WT-hSOD1 and misfolded mutant SOD1. In these studies, we fuse WT and mutant proteins to either yellow or red fluorescent protein so that the two proteins can be distinguished within inclusions structures.Although the interpretation of the data is not entirely straightforward because we have strong evidence that the nature of the fused fluorophores affects the organization of the inclusions that form, our data are most consistent with the idea that normal dimeric WT-hSOD1 does not readily interact with misfolded forms of mutant hSOD1. We also demonstrate the monomerization of WT-hSOD1 by experimental mutation does induce the protein to aggregate, although such monomerization may enable interactions with misfolded mutant SOD1. Our data suggest that WT-hSOD1 is not prone to become intimately associated with misfolded mutant hSOD1 within intracellular inclusions that can be generated in cultured cells

Highly accurate model for prediction of lung nodule malignancy with CT scans

Computed tomography (CT) examinations are commonly used to predict lung nodule malignancy in patients, which are shown to improve noninvasive early diagnosis of lung cancer. It remains challenging for computational approaches to achieve performance comparable to experienced radiologists. Here we present NoduleX, a systematic approach to predict lung nodule malignancy from CT data, based on deep learning convolutional neural networks (CNN). For training and validation, we analyze >1000 lung nodules in images from the LIDC/IDRI cohort. All nodules were identified and classified by four experienced thoracic radiologists who participated in the LIDC project. NoduleX achieves high accuracy for nodule malignancy classification, with an AUC of ~0.99. This is commensurate with the analysis of the dataset by experienced radiologists. Our approach, NoduleX, provides an effective framework for highly accurate nodule malignancy prediction with the model trained on a large patient population. Our results are replicable with software available at http://bioinformatics.astate.edu/NoduleX

Advanced High Temperature Reactor Systems and Economic Analysis

The Advanced High Temperature Reactor (AHTR) is a design concept for a large-output [3400 MW(t)] fluoride-salt-cooled high-temperature reactor (FHR). FHRs, by definition, feature low-pressure liquid fluoride salt cooling, coated-particle fuel, a high-temperature power cycle, and fully passive decay heat rejection. The AHTR's large thermal output enables direct comparison of its performance and requirements with other high output reactor concepts. As high-temperature plants, FHRs can support either high-efficiency electricity generation or industrial process heat production. The AHTR analysis presented in this report is limited to the electricity generation mission. FHRs, in principle, have the potential to be low-cost electricity producers while maintaining full passive safety. However, no FHR has been built, and no FHR design has reached the stage of maturity where realistic economic analysis can be performed. The system design effort described in this report represents early steps along the design path toward being able to predict the cost and performance characteristics of the AHTR as well as toward being able to identify the technology developments necessary to build an FHR power plant. While FHRs represent a distinct reactor class, they inherit desirable attributes from other thermal power plants whose characteristics can be studied to provide general guidance on plant configuration, anticipated performance, and costs. Molten salt reactors provide experience on the materials, procedures, and components necessary to use liquid fluoride salts. Liquid metal reactors provide design experience on using low-pressure liquid coolants, passive decay heat removal, and hot refueling. High temperature gas-cooled reactors provide experience with coated particle fuel and graphite components. Light water reactors (LWRs) show the potentials of transparent, high-heat capacity coolants with low chemical reactivity. Modern coal-fired power plants provide design experience with advanced supercritical-water power cycles. The current design activities build upon a series of small-scale efforts over the past decade to evaluate and describe the features and technology variants of FHRs. Key prior concept evaluation reports include the SmAHTR preconceptual design report,1 the PB-AHTR preconceptual design, and the series of early phase AHTR evaluations performed from 2004 to 2006. This report provides a power plant-focused description of the current state of the AHTR. The report includes descriptions and sizes of the major heat transport and power generation components. Component configuration and sizing are based upon early phase AHTR plant thermal hydraulic models. The report also provides a top-down AHTR comparative economic analysis. A commercially available advanced supercritical water-based power cycle was selected as the baseline AHTR power generation cycle both due to its superior performance and to enable more realistic economic analysis. The AHTR system design, however, has several remaining gaps, and the plant cost estimates consequently have substantial remaining uncertainty. For example, the enriched lithium required for the primary coolant cannot currently be produced on the required scale at reasonable cost, and the necessary core structural ceramics do not currently exist in a nuclear power qualified form. The report begins with an overview of the current, early phase, design of the AHTR plant. Only a limited amount of information is included about the core and vessel as the core design and refueling options are the subject of a companion report. The general layout of an AHTR system and site showing the relationship of the major facilities is then provided. Next is a comparative evaluation of the AHTR anticipated performance and costs. Finally, the major system design efforts necessary to bring the AHTR design to a pre-conceptual level are then presented

AHTR Mechanical, Structural, and Neutronic Preconceptual Design

This report provides an overview of the mechanical, structural, and neutronic aspects of the Advanced High Temperature Reactor (AHTR) design concept. The AHTR is a design concept for a large output Fluoride salt cooled High-temperature Reactor (FHR) that is being developed to enable evaluation of the technology hurdles remaining to be overcome prior to FHRs becoming a commercial reactor class. This report documents the incremental AHTR design maturation performed over the past year and is focused on advancing the design concept to a level of a functional, self-consistent system. The AHTR employs plate type coated particle fuel assemblies with rapid, off-line refueling. Neutronic analysis of the core has confirmed the viability of a 6-month 2-batch cycle with 9 weight-percent enriched uranium fuel. Refueling is intended to be performed automatically under visual guidance using dedicated robotic manipulators. The present design intent is for used fuel to be stored inside of containment for at least 6 months and then transferred to local dry wells for intermediate term, on-site storage. The mechanical and structural concept development effort has included an emphasis on transportation and constructability to minimize construction costs and schedule. The design intent is that all components be factory fabricated into rail transportable modules that are assembled into subsystems at an on-site workshop prior to being lifted into position using a heavy-lift crane in an open-top style construction. While detailed accident identification and response sequence analysis has yet to be performed, the design concept incorporates multiple levels of radioactive material containment including fully passive responses to all identified design basis or non-very-low frequency beyond design basis accidents. Key building design elements include: 1) below grade siting to minimize vulnerability to aircraft impact, 2) multiple natural circulation decay heat rejection chimneys, 3) seismic base isolation, and 4) decay heat powered back-up electricity generation. The report provides a preconceptual design of the manipulators, the fuel transfer system, and the salt transfer loops. The mechanical handling of the fuel and how it is accomplished without instrumentation inside the salt is described within the report. All drives for the manipulators reside outside the reactor top flange. The design has also taken into account the transportability of major components and how they will be assembled on sit

Field-induced spin density wave in (TMTSF)2_2NO3_3

Interlayer magnetoresistance of the Bechgaard salt (TMTSF)$_2$NO$_3$ is investigated up to 50 teslas under pressures of a few kilobars. This compound, the Fermi surface of which is quasi two-dimensional at low temperature, is a semi metal under pressure. Nevertheless, a field-induced spin density wave is evidenced at 8.5 kbar above $\sim$ 20 T. This state is characterized by a drastically different spectrum of the quantum oscillations compared to the low pressure spin density wave state.Comment: to be published in Phys. Rev. B 71 (2005

Cancer targeting with biomolecules: a comparative study of photodynamic therapy efficacy using antibody or lectin conjugated phthalocyanine-PEG gold nanoparticles

The functionalisation of therapeutic nanoparticle constructs with cancer-specific biomolecules can enable selective tumour accumulation and targeted treatment. Water soluble gold nanoparticles (ca. 4 nm) stabilised by a mixed monolayer of a hydrophobic zinc phthalocyanine photosensitiser (C11Pc) and hydrophilic polyethylene glycol (PEG) have been prepared. The C11Pc-PEG gold nanoparticle constructs were further functionalised with jacalin, a lectin specific for the cancer-associated Thomsen–Friedenreich (T) carbohydrate antigen, or with monoclonal antibodies specific for the human epidermal growth factor receptor-2 (HER-2). The two biofunctionalised nanoparticle conjugates produced similar levels of singlet oxygen upon irradiation at 633 nm. Importantly, both nanoparticle conjugates demonstrated extensive, yet comparable, phototoxicity in HT-29 colorectal adenocarcinoma cells (80–90%) and in SK-BR-3 breast adenocarcinoma cells (>99%). Non-conjugated C11Pc-PEG gold nanoparticles were only minimally phototoxic. Lysosomal colocalisation studies performed with the HT-29 colon cancer cells and the SK-BR-3 breast cancer cells revealed that both nanoparticle conjugates were partially localised within acidic organelles, which is typical of receptor-mediated endocytosis. The similarity of the targeted PDT efficacy of the two biofunctionalised C11Pc-PEG gold nanoparticles is discussed with respect to targeting ligand binding affinity and cell surface antigen density as key determinants of targeting efficiency. This study highlights how targeting small cell-surface molecules, such as the T antigen, can mediate a selective photodynamic treatment response which is similar to that achieved when targeting overexpressed protein receptors, such as HER-2. The high prevalence of the T antigen present on the cellular surface of primary tumours emphasises the broad potential applications for lectin-targeted therapies

Safety and Nonsafety Communications and Interactions in International Nuclear Power Plants

Current industry and NRC guidance documents such as IEEE 7-4.3.2, Reg. Guide 1.152, and IEEE 603 do not sufficiently define a level of detail for evaluating interdivisional communications independence. The NRC seeks to establish criteria for safety systems communications that can be uniformly applied in evaluation of a variety of safety system designs. This report focuses strictly on communication issues related to data sent between safety systems and between safety and nonsafety systems. Further, the report does not provide design guidance for communication systems nor present detailed failure modes and effects analysis (FMEA) results for existing designs. This letter report describes communications between safety and nonsafety systems in nuclear power plants outside the United States. A limited study of international nuclear power plants was conducted to ascertain important communication implementations that might have bearing on systems proposed for licensing in the United States. This report provides that following information: 1.communications types and structures used in a representative set of international nuclear power reactors, and 2.communications issues derived from standards and other source documents relevant to safety and nonsafety communications. Topics that are discussed include the following: communication among redundant safety divisions, communications between safety divisions and nonsafety systems, control of safety equipment from a nonsafety workstation, and connection of nonsafety programming, maintenance, and test equipment to redundant safety divisions during operation. Information for this report was obtained through publicly available sources such as published papers and presentations. No proprietary information is represented

Preoptic leptin signaling modulates energy balance independent of body temperature regulation

© Yu et al. The adipokine leptin acts on the brain to regulate energy balance but specific functions in many brain areas remain poorly understood. Among these, the preoptic area (POA) is well known to regulate core body temperature by controlling brown fat thermogenesis, and we have previously shown that glutamatergic, long-form leptin receptor (Lepr)-expressing neurons in the POA are stimulated by warm ambient temperature and suppress energy expenditure and food intake. Here we further investigate the role of POA leptin signaling in body weight regulation and its relationship to body temperature regulation in mice. We show that POA Lepr signaling modulates energy expenditure in response to internal energy state, and thus contributes to body weight homeostasis. However, POA leptin signaling is not involved in ambient temperature-dependent metabolic adaptations. Our study reveals a novel cell population through which leptin regulates body weight

Pre-Conceptual Design of a Fluoride-Salt-Cooled Small Modular Advanced High Temperature Reactor (SmAHTR)

This document presents the results of a study conducted at Oak Ridge National Laboratory during 2010 to explore the feasibility of small modular fluoride salt-cooled high temperature reactors (FHRs). A preliminary reactor system concept, SmATHR (for Small modular Advanced High Temperature Reactor) is described, along with an integrated high-temperature thermal energy storage or salt vault system. The SmAHTR is a 125 MWt, integral primary, liquid salt cooled, coated particle-graphite fueled, low-pressure system operating at 700 C. The system employs passive decay heat removal and two-out-of-three , 50% capacity, subsystem redundancy for critical functions. The reactor vessel is sufficiently small to be transportable on standard commercial tractor-trailer transport vehicles. Initial transient analyses indicated the transition from normal reactor operations to passive decay heat removal is accomplished in a manner that preserves robust safety margins at all times during the transient. Numerous trade studies and trade-space considerations are discussed, along with the resultant initial system concept. The current concept is not optimized. Work remains to more completely define the overall system with particular emphasis on refining the final fuel/core configuration, salt vault configuration, and integrated system dynamics and safety behavior