The solution of Poisson-like equations defined on a complex geometry is required for gyrokinetic simulations, which are important for the modelling of plasma turbulence in nuclear fusion devices such ...as the ITER tokamak. In this paper, we compare three existing solvers finely tuned to solve this problem, in terms of the accuracy of the solution, and their computational efficiency. We also consider practical implementation aspects, including the parallel efficiency of the code, potentially enabling an integration of the solvers in a state-of-the-art first-principle gyrokinetic simulation framework. The first, the Spline FEM solver, uses C1 polar splines to construct a finite elements method which solves the equation on curvilinear coordinates. The resulting linear system is solved using a conjugate gradient method. The second, the GMGPolar solver, uses a symmetric finite difference method to discretise the differential equation. The resulting linear system is solved using a tailored geometric multigrid scheme, with a combination of zebra circle and radial line smoothers, together with an implicit extrapolation scheme. The third, the Embedded Boundary solver, uses a finite volumes method on Cartesian coordinates with an embedded boundary scheme. The resulting linear system is solved using a multigrid scheme. The Spline FEM solver is shown to be the most accurate. The GMGPolar solver is shown to use the least memory. The Embedded Boundary solver is shown to be the fastest in most cases. All three solvers are shown to be capable of solving the equation on a realistic non-analytical geometry. The Embedded Boundary solver is additionally used to attempt to solve an X-point geometry.
•Solver comparison for the gyrokinetic Poisson-like equation on complex geometry.•High-order spline FEM solver based on C1 polar splines and conjugate gradient.•Curvilinear finite difference method using multigrid with low memory footprint.•Embedded boundary scheme with fast multigrid for simple X-point geometry.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Large-scale and high throughput approaches increasingly play an essential role in the study of biological systems, which are per se highly complex. Therefore, they need to be examined by these ...extensive methods to receive information about the large genomic and proteomic networks. In plant biology, this purpose has a strong support through the accessability of the complete genome sequence of the model plant Arabidopsis thaliana. This brief review intends to focus on the basics and the state-of-the-art of these high-throughput technologies and their application to plant proteomics. It describes protein microarrays, the use of antibodies, 2-DE and MS methods and the yeast two hybrid system, which are emerging as the major technologies for plant proteomics.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The panel focused largely on the management of this complex disease and derived prudent, practical, and contemporary treatment strategies for the many subgroups of patients comprising the broad HCM ...disease spectrum. Because of the relatively low prevalence of HCM in general cardiologic practice (50), its diverse presentation, and mechanisms of death and disability and skewed patterns of patient referral (7,11,13,36-38,42,51-59), the level of evidence governing management decisions for drugs or devices has often been derived from non-randomized and retrospective investigations. Large-scale controlled and randomized study designs, such as those that have provided important answers regarding the management of coronary artery disease (CAD) and congestive heart failure (60-62), have generally not been available in HCM as a result of these factors. ...treatment strategies have necessarily evolved based on available data that have frequently been observational in design, sometimes obtained in relatively small patient groups, or derived from the accumulated clinical experience of individual investigators, and reasonable inferences drawn from other cardiac diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Dengue virus (DENV) and West Nile virus (WNV) are arthropod-transmitted flaviviruses that cause systemic vascular leakage and encephalitis syndromes, respectively, in humans. However, the viral ...factors contributing to these specific clinical disorders are not completely understood. Flavivirus nonstructural protein 1 (NS1) is required for replication, expressed on the cell surface, and secreted as a soluble glycoprotein, reaching high levels in the blood of infected individuals. Extracellular DENV NS1 and WNV NS1 interact with host proteins and cells, have immune evasion functions, and promote endothelial dysfunction in a tissue-specific manner. To characterize how differences in DENV NS1 and WNV NS1 might function in pathogenesis, we generated WNV NS1 variants with substitutions corresponding to residues found in DENV NS1. We discovered that the substitution NS1-P101K led to reduced WNV infectivity in the brain and attenuated lethality in infected mice, although the virus replicated efficiently in cell culture and peripheral organs and bound at wild-type levels to brain endothelial cells and complement components. The P101K substitution resulted in reduced NS1 antigenemia in mice, and this was associated with reduced WNV spread to the brain. Because exogenous administration of NS1 protein rescued WNV brain infectivity in mice, we conclude that circulating WNV NS1 facilitates viral dissemination into the central nervous system and impacts disease outcomes.
Flavivirus NS1 serves as an essential scaffolding molecule during virus replication but also is expressed on the cell surface and is secreted as a soluble glycoprotein that circulates in the blood of infected individuals. Although extracellular forms of NS1 are implicated in immune modulation and in promoting endothelial dysfunction at blood-tissue barriers, it has been challenging to study specific effects of NS1 on pathogenesis without disrupting its key role in virus replication. Here, we assessed WNV NS1 variants that do not affect virus replication and evaluated their effects on pathogenesis in mice. Our characterization of WNV NS1-P101K suggests that the levels of NS1 in the circulation facilitate WNV dissemination to the brain and affect disease outcomes. Our findings facilitate understanding of the role of NS1 during flavivirus infection and support antiviral strategies for targeting circulating forms of NS1.
Abstract The glycoprotein envelope of alphaviruses consists of two proteins, E1 and E2. E1 is responsible for fusion and E2 is responsible for receptor binding. An atomic structure is available for ...E1, but one for E2 has not been reported. In this study, transposon linker-insertion mutagenesis was used to probe the function of different domains of E2. A library of mutants, containing 19 amino acid insertions in the E2 glycoprotein sequence of the prototype alphavirus, Sindbis virus (SINV), was generated. Fifty-seven independent E2 insertions were characterized, of which more than half (67%) gave rise to viable virus. The wild-type-like mutants identify regions that accommodate insertions without perturbing virus production and can be used to insert targeting moieties to direct SINV to specific receptors. The defective and lethal mutants give insight into regions of E2 important for protein stability, transport to the cell membrane, E1–E2 contacts, and receptor binding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pastoralism is rarely viewed as a major future form of land use, because of well-documented cases of rangeland degradation, attributed to irrational overstocking by pastoralists, and the subsequent ...losses of ecosystem services. However, pastoralists were actually encouraged to settle and adopt such strategies, copied from rangelands with higher and more reliable rainfall. This curtailed mobility resulted in a shift from opportunistic and extensive land use to more intensive and settled forms of use. The purpose of this review is to examine the link between pastoralism and the provision of ecosystem services by rangelands, focusing on biodiversity conservation and carbon sequestration. Pastoralists employ several techniques to manage rangeland resources, including mobility, herding, corralling, grazing reserves and the use of fire. With these strategies, pastoralists have contributed to the enhancement of rangeland biodiversity and the long-term conservation of important wildlife habitats. Pastoralists also possess detailed knowledge of rangeland plants and their uses, which could be valuable in the assessment, conservation and utilisation of rangeland biodiversity. Similarly, traditional pastoral rangeland management practices, such as the use of seasonal grassland reserves and livestock mobility, influence vegetation composition, coverage and abundance in rangelands and offer tools for biomass and soil carbon restoration, contributing to the mitigation of climate change. However, various internal and external factors have curtailed traditional management practices and livestock mobility, breaking the co-evolved balance of vegetation, wildlife and land use, thus exposing rangeland to continued livestock pressure, which often leads to degradation. Rather than abandoning pastoralism, the revitalisation of traditional practices and indigenous knowledge is vital to secure sustainable livelihoods for millions of pastoralists and to maintain rangeland biodiversity and ecosystem services.
Metal-supported SOFCs with power densities above 700 mW/cm2 at 750oC were fabricated by atmospheric plasma spraying, which can be readily automated and scaled for larger cell areas and production ...volumes, with no cell sintering requirement. Porous stainless steel substrates were dip-coated to protect against oxidation and chromium loss, followed by fabrication of the functional layers. Preliminary performance in hydrogen was found to be stable for 200 hours, with longer durability tests ongoing. Cells with modified anodes can achieve performances close to those of standard cells operating in hydrogen, with no evidence of coking in TGA methane experiments. Fabrication of anodes for hydrocarbon fuels and the results of scaling up from button cells to 5cm x 5cm cells are discussed.
Abstract Objectives The management of developmental anomalies of the ossicular chain and otic capsule in stapes surgery tests the otologist's diagnostic skills and flexibility in technique and ...prosthesis choice. We review our experience in managing various incudostapedial developmental anomalies discovered during middle ear exploration for suspected otosclerosis in adult patients. Design A retrospective case-series review was used. Setting The study was set at a military tertiary referral center. Patients and other Participants A review of 185 stapes procedures yielded 8 cases of identified congenital anomalies of the stapes or incudostapedial complex including congenital absence of the oval window with malformed incus and stapes, columellar-type stapes with promontory fixation, stapes superstructure fixation to the fallopian canal, and malformed incus with stapes superstructure fixation to the promontory. Interventions The developmental anatomy and surgical technique in each case were reviewed. The surgical technique used in each case varied depending on the specific ossicular abnormality found and whether both the stapes and incus were affected. Main outcome measures Comparison of preoperative and postoperative audiometric testing results was performed. Results All 8 ears (7 patients) that underwent a stapes procedure for either an isolated congenital stapes anomaly or a combined incudostapedial anomaly had a favorable hearing outcome, with 7 ears improving to within 10-dB and 1 ear to within 13-dB air-bone gap on postoperative audiometry. Conclusions Despite unanticipated findings of congenital anomalies of the stapes and incus during middle ear exploration for conductive hearing loss, a flexible management approach can lead to successful hearing outcomes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The human double minute (HDM)-2 E3 ubiquitin ligase plays a key role in p53 turnover and has been validated preclinically as a target in multiple myeloma (MM) and mantle cell lymphoma (MCL). HDM-2 ...inhibitors are entering clinical trials, and we therefore sought to understand potential mechanisms of resistance in lymphoid models. Wild-type p53 H929 MM and Granta-519 MCL cells resistant to MI-63 or Nutlin were generated by exposing them to increasing drug concentrations. MI-63-resistant H929 and Granta-519 cells were resistant to Nutlin, whereas Nutlin-resistant cells displayed cross-resistance to MI-63. These cells also showed cross-resistance to bortezomib, doxorubicin, cisplatin, and melphalan, but remained sensitive to the small molecule inhibitor RITA (reactivation of p53 and induction of tumor cell apoptosis). HDM-2 inhibitor-resistant cells harbored increased p53 levels, but neither genotoxic nor nongenotoxic approaches to activate p53 induced HDM-2 or p21. Resequencing revealed wild-type HDM-2, but mutations were found in the p53 DNA binding and dimerization domains. In resistant cells, RITA induced a G(2)-M arrest, upregulation of p53 targets HDM-2, PUMA, and NOXA, and PARP cleavage. Combination regimens with RITA and MI-63 resulted in enhanced cell death compared with RITA alone. These findings support the possibility that p53 mutation could be a primary mechanism of acquired resistance to HDM-2 inhibitors in MCL and MM. Furthermore, they suggest that simultaneous restoration of p53 function and HDM-2 inhibition is a rational strategy for clinical translation.
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