The orphan nuclear receptor, NOR-1, is a target of beta-adrenergic signaling in skeletal muscle

beta-Adrenergic receptor (beta-AR) agonists induce Nur77 mRNA expression in the C2C12 skeletal muscle cell culture model and elicit skeletal muscle hypertrophy. We previously demonstrated that Nur77 (NR4A1) is involved in lipolysis and gene expression associated with the regulation of lipid homeostasis. Subsequently it was demonstrated by another group that beta-AR agonists and cold exposure-induced Nur77 expression in brown adipocytes and brown adipose tissue, respectively. Moreover, NOR-1 (NR4A3) was hyperinduced by cold exposure in the nur77(-/-) animal model. These studies underscored the importance of understanding the role of NOR-1 in skeletal muscle. In this context we observed 30-480 min of beta-AR agonist treatment significantly and transiently increased expression of the orphan nuclear receptor NOR-1 in both mouse skeletal muscle tissue (plantaris) and C2C12 skeletal muscle cells. Specific beta(2)-and beta(3)-AR agonists had similar effects as the pan-agonist and were blocked by the beta-AR antagonist propranolol. Moreover, in agreement with these observations, isoprenaline also significantly increased the activity of the NOR-1 promoter. Stable exogenous expression of a NOR-1 small interfering RNA (but not the negative control small interfering RNA) in skeletal muscle cells significantly repressed endogenous NOR-1 mRNA expression and led to changes in the expression of genes involved in the control of lipid use and muscle mass underscored by a dramatic increase in myostatin mRNA expression. Concordantly the myostatin promoter was repressed by NOR-1 expression. In conclusion, NOR-1 is highly responsive to beta-adrenergic signaling and regulates the expression of genes controlling fatty acid use and muscle mass.

WASOP, a qualitative methodology for waste minimization: systems thinking, HAZOP principles and nuclear waste

Purpose – The international nuclear community continues to face the challenge of managing both the legacy waste and the new wastes that emerge from ongoing energy production. The UK is in the early stages of proposing a new convention for its nuclear industry, that is: waste minimisation through closely managing the radioactive source which creates the waste. This paper proposes a new technique (called waste and source material operability study (WASOP)) to qualitatively analyse a complex, waste-producing system to minimise avoidable waste and thus increase the protection to the public and the environment. Design/methodology/approach – WASOP critically considers the systemic impact of up and downstream facilities on the minimisation of nuclear waste in a facility. Based on the principles of HAZOP, the technique structures managers' thinking on the impact of mal-operations in interlinking facilities in order to identify preventative actions to reduce the impact on waste production of those mal-operations.' Findings – WASOP was tested with a small group of experienced nuclear regulators and was found to support their qualitative examination of waste minimisation and help them to work towards developing a plan of action. Originality/value – Given the newness of this convention, the wider methodology in which WASOP sits is still in development. However, this paper communicates the latest thinking from nuclear regulators on decision-making methodology for supporting waste minimisation and is hoped to form part of future regulatory guidance. WASOP is believed to have widespread potential application to the minimisation of many other forms of waste, including that from other energy sectors and household/general waste.

Elasto-plastic impact of fine particles and fragmentation of small agglomerates

Surface deposition of dense aerosol particles is of major concern in the nuclear industry for safety assessment. This study presents theoretical investigations and computer simulations of single gas-born U3O8 particles impacting with the in-reactor surface and the fragmentation of small agglomerates. A theoretical model for elasto-plastic spheres has been developed and used to analyse the force-displacement and force-time relationships. The impulse equations, based on Newton's second law, are applied to govern the tangential bouncing behaviour. The theoretical model is then incorporated into the Distinct Element Method code TRUBAL in order to perform computer simulated tests of particle collisions. A comparison of simulated results with both theoretical predictions and experimental measurements is provided. For oblique impacts, the results in terms of the force-displacement relationship, coefficients of restitution, trajectory of the impacting particle, and distribution of kinetic energy and work done during the process of impact are presented. The effects of Poisson's ratio, friction, plastic deformation and initial particle rotation on the bouncing behaviour are also discussed. In the presence of adhesion an elasto-plastic collision model, which is an extension to the JKR theory, is developed. Based on an energy balance equation the critical sticking velocity is obtained. For oblique collisions computer simulated results are used to establish a set of criteria determining whether or not the particle bounces off the target plate. For impact velocities above the critical sticking value, computer simulated results for the coefficients of restitution and rebound angles of the particle are presented. Computer simulations of fracture/fragmentation resulting from agglomerate-wall impact have also been performed, where two randomly generated agglomerates (one monodisperse, the other polydisperse), each consisting of 50 primary particles are used. The effects of impact angle, local structural arrangements close to the impact point, and plastic deformation at the contacts on agglomerate damage are examined. The simulated results show a significant difference in agglomerate strength between the two assemblies. The computer data also shows that agglomerate damage resulting from an oblique impact is determined by the normal velocity component rather than the impact speed.

A nanoliter volume nuclear magnetic resonance (NMR) system using tunneling magneto-resistive (TMR) sensors to recognize biomolecules

The need to incorporate advanced engineering tools in biology, biochemistry and medicine is in great demand. Many of the existing instruments and tools are usually expensive and require special facilities.^ With the advent of nanotechnology in the past decade, new approaches to develop devices and tools have been generated by academia and industry. ^ One such technology, NMR spectroscopy, has been used by biochemists for more than 2 decades to study the molecular structure of chemical compounds. However, NMR spectrometers are very expensive and require special laboratory rooms for their proper operation. High magnetic fields with strengths in the order of several Tesla make these instruments unaffordable to most research groups.^ This doctoral research proposes a new technology to develop NMR spectrometers that can operate at field strengths of less than 0.5 Tesla using an inexpensive permanent magnet and spin dependent nanoscale magnetic devices. This portable NMR system is intended to analyze samples as small as a few nanoliters.^ The main problem to resolve when downscaling the variables is to obtain an NMR signal with high Signal-To-Noise-Ratio (SNR). A special Tunneling Magneto-Resistive (TMR) sensor design was developed to achieve this goal. The minimum specifications for each component of the proposed NMR system were established. A complete NMR system was designed based on these minimum requirements. The goat was always to find cost effective realistic components. The novel design of the NMR system uses technologies such as Direct Digital Synthesis (DDS), Digital Signal Processing (DSP) and a special Backpropagation Neural Network that finds the best match of the NMR spectrum. The system was designed, calculated and simulated with excellent results.^ In addition, a general method to design TMR Sensors was developed. The technique was automated and a computer program was written to help the designer perform this task interactively.^

Weak electron scattering for the 3He-3H transition and the weak nuclear form factors

We calculate the differential cross section for weak electron scattering reaction, e + 3He-' 3H + ve, for energies from 100 MeV to 6 GeV as a function of outgoing nucleus angle from 0 to n/2 radians. We find that the differential cross section at low [q2] increases with electron energy from 0.1 GeV to 6.0 GeV, such that the peak value at 6.0 GeV is approximately 3.2 x 10-40 cm 2 / ster, a factor of 10 larger than the peak value at 0.1 GeV. We also find that the width of the peak falls very rapidly with increasing electron energy. At high [q2] we find that the differential cross section falls by approximately three orders of magnitude making experimental observation at this time unlikely. The contributions of the individual form factors are obtained for electron energies of 0.5GeV and 2.0 GeV. It is found that at low [q2] the form factors, FA(q2) and Fv(q2), make contributions of similar size to the differential cross section and might be simultaneously determined , but for the case of FM(q2) we find that the contribution is too small to determine. It is also found that at large [q2] values, the contribution of FM(q2) is substantially enhanced , but that the cross section is probably too small to enable a direct determination of FM(q2).

Going it alone? North Korea’s adaptability as a small power in a changing world

This article uses small states scholarship to map North Korea’s evolution from a post-colonial small state to a system-influencing state due to its nuclear weapons programme. The framework allows for contributions to: (1) The DPRK literature which in some parts has suggested the future collapse of the state, (2) The small states literature that suggests they can only survive if they integrate larger political and/or economic units, (3) The mainstream IR literature and its dominant realist streak that considers great powers and their will as the main drivers in contemporary world politics.

Determination of Biomolecular Interdomain Motions using Nuclear Magnetic Resonance

Biological macromolecules can rearrange interdomain orientations when binding to various partners. Interdomain dynamics serve as a molecular mechanism to guide the transitions between orientations. However, our understanding of interdomain dynamics is limited because a useful description of interdomain motions requires an estimate of the probabilities of interdomain conformations, increasing complexity of the problem.

Staphylococcal protein A (SpA) has five tandem protein-binding domains and four interdomain linkers. The domains enable Staphylococcus aureus to evade the host immune system by binding to multiple host proteins including antibodies. Here, I present a study of the interdomain motions of two adjacent domains in SpA. NMR spin relaxation experiments identified a 6-residue flexible interdomain linker and interdomain motions. To quantify the anisotropy of the distribution of interdomain orientations, we measured residual dipolar couplings (RDCs) from the two domains with multiple alignments. The N-terminal domain was directly aligned by a lanthanide ion and not influenced by interdomain motions, so it acted as a reference frame to achieve motional decoupling. We also applied {\it de novo} methods to extract spatial dynamic information from RDCs and represent interdomain motions as a continuous distribution on the 3D rotational space. Significant anisotropy was observed in the distribution, indicating the motion populates some interdomain orientations more than others. Statistical thermodynamic analysis of the observed orientational distribution suggests that it is among the energetically most favorable orientational distributions for binding to antibodies. Thus, the affinity is enhanced by a pre-posed distribution of interdomain orientations while maintaining the flexibility required for function.

The protocol described above can be applied to other biological systems in general. Protein molecule calmodulin and RNA molecule trans-activation response element (TAR) also have intensive interdomain motions with relative small intradomain dynamics. Their interdomain motions were studied using our method based on published RDC data. Our results were consistent with literature results in general. The differences could be due to previous studies' use of physical models, which contain assumptions about potential energy and thus introduced non-experimental information into the interpretations.

Evaluating laser-driven Bremsstrahlung radiation sources for imaging and analysis of nuclear waste packages

A small scale sample nuclear waste package, consisting of a 28 mm diameter uranium penny encased in grout, was imaged by absorption contrast radiography using a single pulse exposure from an X-ray source driven by a high-power laser. The Vulcan laser was used to deliver a focused pulse of photons to a tantalum foil, in order to generate a bright burst of highly penetrating X-rays (with energy >500 keV), with a source size of <0.5 mm. BAS-TR and BAS-SR image plates were used for image capture, alongside a newly developed Thalium doped Caesium Iodide scintillator-based detector coupled to CCD chips. The uranium penny was clearly resolved to sub-mm accuracy over a 30 cm2 scan area from a single shot acquisition. In addition, neutron generation was demonstrated in situ with the X-ray beam, with a single shot, thus demonstrating the potential for multi-modal criticality testing of waste materials. This feasibility study successfully demonstrated non-destructive radiography of encapsulated, high density, nuclear material. With recent developments of high-power laser systems, to 10 Hz operation, a laser-driven multi-modal beamline for waste monitoring applications is envisioned.

Refining the diagnosis and EGFR status of non-small cell lung carcinoma in biopsy and cytologic material, using a panel of mucin staining, TTF-1, cytokeratin 5/6, and P63, and EGFR mutation analysis.

INTRODUCTION: The dichotomization of non-small cell carcinoma (NSCLC) subtype into squamous (SQCC) and adenocarcinoma (ADC) has become important in recent years and is increasingly required with regard to management. The aim of this study was to determine the utility of a panel of commercially available antibodies in refining the diagnosis on small biopsies and also to determine whether cytologic material is suitable for somatic EGFR genotyping in a prospectively analyzed series of patients undergoing investigation for suspected lung cancer. METHODS: Thirty-two consecutive cases of NSCLC were first tested using a panel comprising cytokeratin 5/6, P63, thyroid transcription factor-1, 34betaE12, and a D-PAS stain for mucin, to determine their value in refining diagnosis of NSCLC. After this test phase, two further pathologists independently reviewed the cases using a refined panel that excluded 34betaE12 because of its low specificity for SQCC, and refinement of diagnosis and concordance were assessed. Ten cases of ADC, including eight derived from cytologic samples, were sent for EGFR mutation analysis. RESULTS: There was refinement of diagnosis in 65% of cases of NSCLC to either SQCC or ADC in the test phase. This included 10 of 13 cases where cell pellets had been prepared from transbronchial needle aspirates. Validation by two further pathologists with varying expertise in lung pathology confirmed increased refinement and concordance of diagnosis. All samples were adequate for analysis, and they all showed a wild-type EGFR genotype. CONCLUSION: A panel comprising cytokeratin 5/6, P63, thyroid transcription factor-1, and a D-PAS stain for mucin increases diagnostic accuracy and agreement between pathologists when faced with refining a diagnosis of NSCLC to SQCC or ADC. These small samples, even cell pellets derived from transbronchial needle aspirates, seem to be adequate for EGFR mutation analysis.

Docking of HIV-1 Vpr to the nuclear envelope is mediated by the interaction with the nucleoporin hCG1

The HIV-1 genome contains several genes coding for auxiliary proteins, including the small Vpr protein. Vpr affects the integrity of the nuclear envelope and participates in the nuclear translocation of the preintegration complex containing the viral DNA. Here, we show by photobleaching experiments performed on living cells expressing a Vpr-green fluorescent protein fusion that the protein shuttles between the nucleus and the cytoplasm, but a significant fraction is concentrated at the nuclear envelope, supporting the hypothesis that Vpr interacts with components of the nuclear pore complex. An interaction between HIV-1 Vpr and the human nucleoporin CG1 (hCG1) was revealed in the yeast two-hybrid system, and then confirmed both in vitro and in transfected cells. This interaction does not involve the FG repeat domain of hCG1 but rather the N-terminal region of the protein. Using a nuclear import assay based on digitonin-permeabilized cells, we demonstrate that hCG1 participates in the docking of Vpr at the nuclear envelope. This association of Vpr with a component of the nuclear pore complex may contribute to the disruption of the nuclear envelope and to the nuclear import of the viral DNA.

Specific Filters Applied in Nuclear Medicine Services

In Nuclear Medicine, radioiodine, in various chemical forms, is a key tracer used in diagnostic practices and/or therapy. Due to its high volatility, medical professionals may incorporate radioactive iodine during the preparation of the dose to be administered to the patient. In radioactive iodine therapy doses ranging from 3.7 to 7.4GBq per patient are employed. Thus, aiming at reducing the risk of occupational contamination, we developed a low cost filter to be installed at the exit of the exhaust system where doses of radioactive iodine are fractionated, using domestic technology. The effectiveness of radioactive iodine retention by silver impregnated silica [10%] crystals and natural activated carbon was verified using radiotracer techniques. The results showed that natural activated carbon is effective for I2 capture for a large or small amount of substrate but its use is restricted due to its low flash point (150º C). Besides, when poisoned by organic solvents, this flash point may become lower, causing explosions if absorbing large amounts of nitrates. To hold the CH3I gas, it was necessary to increase the volume of natural activated carbon since it was not absorbed by SiO2 + Ag crystals. We concluded that, for an exhaust flow range of (306 4) m3/h, a double stage filter using SiO2 + Ag in the first stage and natural activated carbon in the second is sufficient to meet radiological safety requirements.

Nuclear-follower foraging associations among Characiformes fishes and Potamotrygonidae rays in clean waters environments of Teles Pires and Xingu rivers basins, Midwest Brazil

Por meio de observações sub e supra-aquáticas foram registradas associações alimentares do tipo nuclear-seguidor entre três espécies de peixes characiformes - Chalceus epakros, Hemiodus semitaeniatus e Hemiodus unimaculatus - e uma espécie de raia de água doce - Potamotrygon orbignyi - nas bacias dos rios Teles Pires e Xingu, no Centro-Oeste do Brasil. Os peixes teleósteos foram observados seguindo as raias quando estas revolviam o substrato à procura de invertebrados, formando discretas nuvens de sedimento. Essas situações atraíram os peixes que se aproximaram das raias para se alimentar de pequenas presas e outros tipos de alimentos expostos desta forma. Esse é um típico exemplo de relação comensal onde um participante é beneficiado enquanto o outro não é prejudicado e representa o segundo registro na literatura de associação alimentar do tipo nuclear-seguidor entre raias potamotrigonídeas e peixes teleósteos, demonstrando o potencial de estudos naturalísticos para a descoberta de novas interações envolvendo espécies de peixes de água doce.

FABRICATION, CHARACTERIZATION, AND IRRADIATION OF AN AUSTENITIC OXIDE DISPERSION STRENGTHENED STEEL SUITED FOR NEXT GENERATION NUCLEAR APPLICATIONS

As nuclear energy systems become more advanced, the materials encompassing them need to perform at higher temperatures for longer periods of time. In this Master’s thesis we experiment with an oxide dispersion strengthened (ODS) austenitic steel that has been recently developed. ODS materials have a small concentration of nano oxide particles dispersed in their matrix, and typically have higher strength and better extreme temperature creep resistance characteristics than ordinary steels. However, no ODS materials have ever been installed in a commercial power reactor to date. Being a newer research material, there are many unanswered phenomena that need to be addressed regarding the performance under irradiation. Furthermore, due to the ODS material traditionally needing to follow a powder metallurgy fabrication route, there are many processing parameters that need to be optimized before achieving a nuclear grade material specification. In this Master’s thesis we explore the development of a novel ODS processing technology conducted in Beijing, China, to produce solutionized bulk ODS samples with ~97% theoretical density. This is done using relatively low temperatures and ultra high pressure (UHP) equipment, to compact the mechanically alloyed (MA) steel powder into bulk samples without any thermal phase change influence or oxide precipitation. By having solutionized bulk ODS samples, transmission electron microscopy (TEM) observation of nano oxide precipitation within the steel material can be studied by applying post heat treatments. These types of samples will be very useful to the science and engineering community, to answer questions regarding material powder compacting, oxide synthesis, and performance. Subsequent analysis performed at Queen’s University included X-ray diffraction (XRD) and inductively coupled plasma optical emission spectrometry (ICP-OES). Additional TEM in-situ 1MeV Kr2+ irradiation experiments coupled with energy dispersive X-ray (EDX) techniques, were also performed on large (200nm+) non-stoichiometric oxides embedded within the austenite steel grains, in an attempt to quantify the elemental compositional changes during high temperature (520oC) heavy ion irradiation.

Small polarons in spin-orbit coupled osmates

Small polarons (SP) have been thoroughly investigated in 3d transition metal oxides and they have been found to play a crucial role in physical phenomena such as charge transport, colossal magnetoresistance and surface reactivity. However, our knowledge about these quasi-particles in 5d systems remains very limited, since the more delocalised nature of the 5d orbitals reduces the strength of the Electronic Correlation (EC), making SP formation in these compounds rather unexpected. Nevertheless, the Spin-Orbit coupled Dirac-Mott insulator Ba2NaOsO6 (BNOO) represents a good candidate for enabling polaron formation in a relativistic background, due to the relatively large EC (U ∼ 3 eV) and Jahn-Teller activity. Moreover, anomalous peaks in Nuclear Magnetic Resonance (NMR) spectroscopy experiments suggest the presence of thermally activated SP dynamics when BNOO is doped with Ca atoms. We investigate SP formation in BNOO both from an electronic and structural point of view by means of fully relativistic first principles calculations. Our numerical simulations predict a stable SP ground state and agree on the value of 810 K for the dynamical process peak found by NMR experiments.

Egfr Activating Mutations And Their Association With Response To Platinum-doublet Chemotherapy In Brazilian Non-small Cell Lung Cancer Patients.

The aim of the study was to analyze the frequency of epidermal growth factor receptor (EGFR) mutations in Brazilian non-small cell lung cancer patients and to correlate these mutations with response to benefit of platinum-based chemotherapy in non-small cell lung cancer (NSCLC). Our cohort consisted of prospective patients with NSCLCs who received chemotherapy (platinum derivates plus paclitaxel) at the [UNICAMP], Brazil. EGFR exons 18-21 were analyzed in tumor-derived DNA. Fifty patients were included in the study (25 with adenocarcinoma). EGFR mutations were identified in 6/50 (12 %) NSCLCs and in 6/25 (24 %) adenocarcinomas; representing the frequency of EGFR mutations in a mostly self-reported White (82.0 %) southeastern Brazilian population of NSCLCs. Patients with NSCLCs harboring EGFR exon 19 deletions or the exon 21 L858R mutation were found to have a higher chance of response to platinum-paclitaxel (OR 9.67 [95 % CI 1.03-90.41], p = 0.047). We report the frequency of EGFR activating mutations in a typical southeastern Brazilian population with NSCLC, which are similar to that of other countries with Western European ethnicity. EGFR mutations seem to be predictive of a response to platinum-paclitaxel, and additional studies are needed to confirm or refute this relationship.