An Upgraded Photoinjector for the Argonne Wakefield Accelerator

The Argonne Wakefield Accelerator (AWA) is planning an upgrade of the drive-beam accelerator’s photoinjector, the driving force of electron generation. The upgrade’s main goal is to improve beam brightness using linear accelerating cavities and a radiofrequency-gun cavity. In the process of this upgrade, one of the beam focusing solenoids is being redesigned. A beam dynamics optimization is performed for two new solenoid designs, with considerations for producing low-charge (∼ 1 nC) electron bunches as well as operations at higher charges (∼ 50 nC). This project focuses on the optimization study for both the low- and high-charge regimes, exploring the impact of different solenoid designs on the beam dynamics

Investigating the relationship between income and subjective well-being in South Africa.

M.Dev.Studies University of KwaZulu-Natal, Durban 2013.Conventional approaches to the analysis of human well-being use money-metric measures such as income or consumption. However, they are heavily criticised for relying on a limited understanding of well-being. In recent decades, subjective measures of well-being have been increasingly presented as providing a more inclusive and holistic perspective of well-being. Using data from the National Income Dynamics Study (NIDS), this dissertation examines the relationship between income, a common money-metric measure of well-being, and life satisfaction, a key indicator of subjective well-being. The results show that income and life satisfaction exhibit a weak but significant positive relationship, one which is stronger at lower levels of income. In addition to income, the analysis identifies a number of other significant correlates of subjective well-being. Furthermore, several differences in the correlates of income and life satisfaction are detected. These results highlight how subjective well-being measures can include information about people’s lived experiences in ways that are not fully captured in objective money-metric measures

Evaluation Of Covert Plutonium Production From Unconventional Uranium Sources

The potential for a relatively non-advanced nation to covertly acquire a significant quantity of weapons-grade plutonium using a gas-cooled, natural uranium-fueled reactor based on relatively primitive early published designed is evaluated in this article. The economic and technical issues that would influence the design decisions of a covert 239Pu production program are considered. Several unconventional uranium acquisition approaches were explored. Methods for extracting uranium from enrichment tails, seawater, and coal ash sources were considered. The evaluation indicated that uranium extraction from coal ash or insitu leaching from underground deposits could be performed in economical manner that might be difficult to detect by the international community. These two methods were estimated to be within the technical capabilities of an under-developed national. Calculations performed using the Monte Carlo N-Particle code (MCNP) showed that extracting uranium from enrichment tails would not be a technically feasible source for reactor fuel fabrication because the 235U concentration inside the enrichment tails would not be high enough to maintain criticality in the relatively unsophisticated reactor design considered. The SCALE code package was used to perform reactor physics and depletion calculations used to evaluate the effect of different combinations of uranium irradiation time and reactor power density had on plutonium production rates and isotope concentrations. The results of these simulations were used to estimate the desirability of the modeled plutonium for use in a weapon with published materials attractiveness figures of merit. All the modeled reactor conditions produced material that was highly attractive for use in a nuclear weapon. Historical examples of early gas-cooled reactors were used to examine the complexity associate with building various gas-cooled reactor designs. These examples were compared to simulated reactor conditions. The choices that a covert unsophisticated nuclear weapons program might consider when designing a reactor were evaluated. An air-cooled design was found to be a simple and cost effective solution for a group interested in producing a small number of significant quantities (8 kg) of plutonium

A generalization of the maximum likelihood expectation maximization (MLEM) method: Masked-MLEM

Objective.In our previous work on image reconstruction for single-layer collimatorless scintigraphy, we developed the min-min weighted robust least squares (WRLS) optimization algorithm to address the challenge of reconstructing images when both the system matrix and the projection data are uncertain. Whereas the WRLS algorithm has been successful in two-dimensional (2D) reconstruction, expanding it to three-dimensional (3D) reconstruction is difficult since the WRLS optimization problem is neither smooth nor strongly-convex. To overcome these difficulties and achieve robust image reconstruction in the presence of system uncertainties and projection noise, we propose a generalized iterative method based on the maximum likelihood expectation maximization (MLEM) algorithm, hereinafter referred to as the Masked-MLEM algorithm.Approach.In the Masked-MLEM algorithm, only selected subsets ('masks') from the system matrix and the projection contribute to the image update to satisfy the constraints imposed by the system uncertainties. We validate the Masked-MLEM algorithm and compare it to the standard MLEM algorithm using experimental data obtained from both collimated and uncollimated imaging instruments, including parallel-hole collimated SPECT, 2D collimatorless scintigraphy, and 3D collimatorless tomography. Additionally, we conduct comprehensive Monte Carlo simulations for 3D collimatorless tomography to further validate the effectiveness of the Masked-MLEM algorithm in handling different levels of system uncertainties.Main results.The Masked-MLEM and standard MLEM reconstructions are similar in cases with negligible system uncertainties, whereas the Masked-MLEM algorithm outperforms the standard MLEM algorithm when the system matrix is an approximation. Importantly, the Masked-MLEM algorithm ensures reliable image reconstruction across varying levels of system uncertainties.Significance.With a good choice of system uncertainty and without requiring accurate knowledge of the actual system matrix, the Masked-MLEM algorithm yields more robust image reconstruction than the standard MLEM algorithm, effectively reducing the likelihood of erroneously reconstructing higher activities in regions without radioactive sources

Coded aperture and Compton imaging for the development of 225Ac‐based radiopharmaceuticals

BackgroundTargeted alpha-particle therapy (TAT) has great promise as a cancer treatment. Arguably the most promising TAT radionuclide that has been proposed is 225 Ac. The development of 225 Ac-based radiopharmaceuticals has been hampered due to the lack of effective means to study the daughter redistribution of these agents in small animals at the preclinical stage.PurposeThe ability to directly image the daughters, namely 221 Fr and 213 Bi, via their gamma-ray emissions would be a boon for preclinical studies. That said, conventional medical imaging modalities, including single photon emission computed tomography (SPECT) based on nonmultiplexed collimation, cannot be employed due to sensitivity limitations.MethodsAs an alternative, we propose the use of both coded aperture and Compton imaging with the former modality suited to the 218-keV gamma-ray emission of 221 Fr and the latter suited to the 440-keV gamma-ray emission of 213 Bi.ResultsThis work includes coded aperture images of 221 Fr and Compton images of 213 Bi in tumor-bearing mice injected with 225 Ac-based radiopharmaceuticals.ConclusionsThese results are the first demonstration of visualizing and quantifying the 225 Ac daughters in small animals through the application of coded aperture and Compton imaging

Coded Aperture and Compton Imaging for the Development of 225^{225}Ac-based Radiopharmaceuticals

Targeted alpha-particle therapy (TAT) has great promise as a cancer treatment. Arguably the most promising TAT radionuclide that has been proposed is $^{225}$Ac. The development of $^{225}$Ac-based radiopharmaceuticals has been hampered due to the lack of effective means to study the daughter redistribution of these agents in small animals at the preclinical stage. The ability to directly image the daughters, namely $^{221}$Fr and $^{213}$Bi, via their gamma-ray emissions would be a boon for preclinical studies. That said, conventional medical imaging modalities, including single photon emission computed tomography (SPECT) based on pinhole collimation, cannot be employed due to sensitivity limitations. As an alternative, we propose the use of both coded aperture and Compton imaging with the former modality suited to the 218-keV gamma-ray emission of $^{221}$Fr and the latter suited to the 440-keV gamma-ray emission of $^{213}$Bi. This work includes coded aperture images of $^{221}$Fr and Compton images of $^{213}$Bi in tumor-bearing mice injected with $^{225}$Ac-based radiopharmaceuticals. These results are the first demonstration of visualizing and quantifying the $^{225}$Ac daughters in small animals via coded aperture and Compton imaging and serve as a stepping stone for future radiopharmaceutical studies

Modeling the Compton Camera Response for Extended Voxel Sources

The analysis and interpretation of coincidence events in a Compton camera requires the comparison of the expected rates of observed events from sources with various emission rates, energy spectra and spatial distributions. Radioactive source distributions are often represented by the activity distributed among numerous voxels; each voxel having uniform internal activity and spectra within a cube. In this paper a mathematical model is constructed that predicts the expected rate of coincident Compton events from the rate of emissions from a single voxel source. This detailed model incorporates (1) the finite voxel size, (2) the blurring of the “Compton cone” by the limitations of energy resolution in the detectors and (3) the uncertainty in the Compton cone-axis due to the limited spatial resolution and ‘lever-arm’ separation between the coincident interactions. The resultant rates can be used to generate the system response matrix for source reconstruction and, therefore, are directly applicable in list-mode MLEM source reconstruction algorithms

A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability

43 p.-5 fig.Despite the approval of several multikinase inhibitors that target SRC and the overwhelming evidence of the role of SRC in the progression and resistance mechanisms of many solid malignancies, inhibition of its kinase activity has thus far failed to improve patient outcomes. Here we report the small molecule eCF506 locks SRC in its native inactive conformation, thereby inhibiting both enzymatic and scaffolding functions that prevent phosphorylation and complex formation with its partner FAK. This unprecedented mechanism of action resulted in highly potent and selective pathway inhibition, in culture and in vivo. Treatment with eCF506 resulted in increased antitumor efficacy and tolerability in syngeneic murine cancer models, demonstrating significant therapeutic advantages over existing SRC/ABL inhibitors. Therefore, this novel mode of inhibiting SRC could lead to improved treatment of SRC-associated disorders.C.T. thanks the CMVM of the University of Edinburgh (Principal's scholarship). D.L. acknowledges support from the Spanish Ministry of Science, Innovation and Universities for the Spanish State Research Agency Retos Grant RTI2018-099318-B-I00, cofunded by the European Regional Development Fund (FEDER). E.R.W., J.C.D. and K.G.M. are funded by CRUK. J.R.L.O. acknowledges support from the Molecular Interactions Facility funds at the CIB-CSIC. T.V. is funded by H2020-MSCA-IF-2016-749299. RCM thanks the support from the Vice Rectorate for Research of the University of Granada. X.-F.L. and B.-Z.Q. are funded by a CRUK Career Development Fellowship (C49791/A17367). B.-Z.Q. also acknowledges support from an ERC Starting Grant (716379). C.S, M.C.F. and V.G.B are funded by CRUK Programme Grant C157/A15703. N.O.C. and A.U.B are grateful to the CMVM of the University of Edinburgh and Wellcome Trust for financial support (ISSF3).Peer reviewe

A fluorogenic probe for granzyme B enables in-biopsy evaluation and screening of response to anticancer immunotherapies

Immunotherapy promotes the attack of cancer cells by the immune system; however, it is difficult to detect early responses before changes in tumor size occur. Here, we report the rational design of a fluorogenic peptide able to detect picomolar concentrations of active granzyme B as a biomarker of immune-mediated anticancer action. Through a series of chemical iterations and molecular dynamics simulations, we synthesize a library of FRET peptides and identify probe H5 with an optimal fit into granzyme B. We demonstrate that probe H5 enables the real-time detection of T cell-mediated anticancer activity in mouse tumors and in tumors from lung cancer patients. Furthermore, we show image-based phenotypic screens, which reveal that the AKT kinase inhibitor AZD5363 shows immune-mediated anticancer activity. The reactivity of probe H5 may enable the monitoring of early responses to anticancer treatments using tissue biopsies

The Intrinsic Substrate Specificity of the Human Tyrosine Kinome

Phosphorylation of proteins on tyrosine (Tyr) residues evolved in metazoan organisms as a mechanism of coordinating tissue growth1. Multicellular eukaryotes typically have more than 50 distinct protein Tyr kinases that catalyse the phosphorylation of thousands of Tyr residues throughout the proteome1-3. How a given Tyr kinase can phosphorylate a specific subset of proteins at unique Tyr sites is only partially understood4-7. Here we used combinatorial peptide arrays to profile the substrate sequence specificity of all human Tyr kinases. Globally, the Tyr kinases demonstrate considerable diversity in optimal patterns of residues surrounding the site of phosphorylation, revealing the functional organization of the human Tyr kinome by substrate motif preference. Using this information, Tyr kinases that are most compatible with phosphorylating any Tyr site can be identified. Analysis of mass spectrometry phosphoproteomic datasets using this compendium of kinase specificities accurately identifies specific Tyr kinases that are dysregulated in cells after stimulation with growth factors, treatment with anti-cancer drugs or expression of oncogenic variants. Furthermore, the topology of known Tyr signalling networks naturally emerged from a comparison of the sequence specificities of the Tyr kinases and the SH2 phosphotyrosine (pTyr)-binding domains. Finally we show that the intrinsic substrate specificity of Tyr kinases has remained fundamentally unchanged from worms to humans, suggesting that the fidelity between Tyr kinases and their protein substrate sequences has been maintained across hundreds of millions of years of evolution