A hybrid global surrogate modeling software for nuclear reactor cross section estimation

Nuclear fuel cycle (NFC) simulators track the amount and composition of materials as they move through facilities such as mines, fuel fabrication plants, and nuclear reactors. A major task of a NFC simulator is to calculate the evolution of compositions of batches of nuclear materials as they are transmuted in reactors, decay, and are blended with other batches to create reactor fuel or be reprocessed or disposed. Codes used for NFC simulation that utilize intermediate data saved in databases which are calculated ahead of time are attractive since their fidelity can be improved by investing more resources in expanding their databases. Shifting the computational work ahead of the reactor simulation like this allows the fidelity to be improved without sacrificing runtime computational cost. This dissertation describes a method that attempts to maximize the fidelity increase per unit time invested during this precomputation step. Unlike previous work in the reactor simulation field, this methodology does not limit the number and type of runtime simulation inputs. NUDGE (NUclear Database GEneration software) is an implementation of this methodology. The methodology has two main steps where new data is added to databases. First is exploration, where inputs to the database are selected to be as uniformly distributed as possible within the problem input domain. Second step is exploitation, where output information is utilized to inform the selection of the next point to run. An improvement to exploitation, named Voronoi Cell Adjustment, is described in this dissertation and implemented in NUDGE. This improvement has been shown to benefit the average fidelity increase during database building. A study of the scaling of the methodology, a comparison of error metrics, and an exploration of optimal values for several key parameters in the methodology are presented. NUDGE has also been used to create a global surrogate model of a NFC simulation software (named XSgen). This model shows better performance compared to models generated by other established methods under equal constraints.Mechanical Engineerin

Investigating the brain in mouse models of Duchenne muscular dystrophy

PhD ThesisDuchenne muscular dystrophy (DMD) is an X-linked recessive muscle wasting disease caused by mutations in the DMD gene, which encodes the large cytoskeletal protein dystrophin. Alongside severe muscle pathology, one-third of DMD patients exhibit cognitive problems ranging from reduced verbal intelligence to severe autism. There is conclusive evidence that the muscle pathology exhibited by DMD patients is progressive, yet it remains unknown whether the cognitive impairments in DMD are also progressive. Previous studies have highlighted a cognitive impairment in the mdx mouse model of DMD, but no studies have investigated if this cognitive impairment worsens with age. We assessed the consequences of dystrophin deficiency on brain morphology and cognitive function in two dystrophin-deficient mouse models (mdx and Cmah-/-mdx mice). The overall project aim was to identify outcome measures to monitor central nervous system (CNS) pathology non-invasively in DMD mice. Magnetic resonance imaging (MRI) identified a total brain volume increase in DMD mice, alongside morphological changes in brain ventricles. Behavioural testing revealed a deficit in hippocampal spatial learning and memory, particularly long-term memory, in mdx mice, which appears to progressively worsen with age. Immunoblotting identified a progressive reduction of aquaporin-4 (AQP4) expression, the major water channel of the CNS, in DMD mice. Moreover, contrast enhancing MRI and Evans blue extravasation demonstrated a progressive impairment in blood-brain barrier (BBB) integrity in mdx mice. Proteomic profiling of the mdx cerebellum identified changes in expression of mitochondrial subunit complexes, suggestive of changes in mitochondrial function. Additionally, elevated levels of inflammatory markers were identified and confirmed in the mdx cerebellum. Our studies suggest that dystrophin deficiency causes a progressive cognitive impairment in mdx mice. We also present evidence showing that changes in osmotic equilibrium may be involved in the pathogenesis of DMD, with reductions in AQP4 expression and BBB disruptions. We speculate that some of the changes in the mdx cerebellar proteome, in comparison to wild type mice, iii serve as compensatory mechanisms whilst others may contribute directly to cognitive dysfunction in DMD. These results support a role for dystrophin in normal brain morphology and cognitive function.Medical Research Council UK

Serial single-cell profiling analysis of metastatic TNBC during Nab-paclitaxel and pembrolizumab treatment

Purpose: Immunotherapy has recently been shown to improve outcomes for advanced PD-L1-positive triple-negative breast cancer (TNBC) in the Impassion130 trial, leading to FDA approval of the first immune checkpoint inhibitor in combination with taxane chemotherapy. To further develop predictive biomarkers and improve therapeutic efficacy of the combination, interrogation of the tumor immune microenvironment before therapy as well as during each component of treatment is crucial. Here we use single-cell RNA sequencing (scRNA-seq) on tumor biopsies to assess immune cell changes from two patients with advanced TNBC treated in a prospective trial at predefined serial time points, before treatment, on taxane chemotherapy and on chemo-immunotherapy. Methods: Both patients (one responder and one progressor) received the trial therapy, in cycle 1 nab-paclitaxel given as single agent, in cycle 2 nab-paclitaxel in combination with pembrolizumab. Tumor core biopsies were obtained at baseline, 3 weeks (after cycle 1, chemotherapy alone) and 6 weeks (after cycle 2, chemo-immunotherapy). Single-cell RNA sequencing (scRNA-seq) of both cancer cells and infiltrating immune cells isolated were performed from fresh tumor core biopsy specimens by 10 × chromium sequencing. Results: ScRNA-seq analysis showed significant baseline heterogeneity of tumor-infiltrating immune cell populations between the two patients as well as modulation of the tumor microenvironment by chemotherapy and immunotherapy. In the responding patient there was a population of PD-1high-expressing T cells which significantly decreased after nab-paclitaxel plus pembrolizumab treatment as well as a presence of tissue-resident memory T cells (TRM). In contrast, tumors from the patient with rapid disease progression showed a prevalent and persistent myeloid compartment. Conclusions: Our study provides a deep cellular analysis of on-treatment changes during chemo-immunotherapy for advanced TNBC, demonstrating not only feasibility of single-cell analyses on serial tumor biopsies but also the heterogeneity of TNBC and differences in on-treatment changes in responder versus progressor

Fluence based neutron balance approach using spatial flux calculations

textThis thesis describes the addition of spatially dependent power sharing to a methodology for calculating the input and output isotopics and burnup of nuclear reactors within a nuclear fuel cycle simulator. This methodology carries out neutron balance and depletion calculations by using pre-calculated fluence-based libraries. These libraries track the transmutation and neutron economy evolution of unit masses of isotopes available in input fuel. The current work generalizes the method to simulate reactors that contain more than one type of fuel in their core, for instance breeders with a driver-blanket configuration. To achieve this, spatial flux calculations are used to determine the fluence-dependent relative average flux inside macroscopic spatial regions. These fluxes are then used to determine the relative average power of macroscopic spatial regions as well as to more accurately calculate region-specific transmutation rates. The paper presents several cases where the fluence based approach alone would not have been sufficient to determine results.Mechanical Engineerin

On the feasibility of numerical analysis of large creep problems

SIGLEAvailable from British Library Document Supply Centre- DSC:DX92407 / BLDSC - British Library Document Supply CentreGBUnited Kingdo