Variational Integrators for Reduced Magnetohydrodynamics

Reduced magnetohydrodynamics is a simplified set of magnetohydrodynamics equations with applications to both fusion and astrophysical plasmas, possessing a noncanonical Hamiltonian structure and consequently a number of conserved functionals. We propose a new discretisation strategy for these equations based on a discrete variational principle applied to a formal Lagrangian. The resulting integrator preserves important quantities like the total energy, magnetic helicity and cross helicity exactly (up to machine precision). As the integrator is free of numerical resistivity, spurious reconnection along current sheets is absent in the ideal case. If effects of electron inertia are added, reconnection of magnetic field lines is allowed, although the resulting model still possesses a noncanonical Hamiltonian structure. After reviewing the conservation laws of the model equations, the adopted variational principle with the related conservation laws are described both at the continuous and discrete level. We verify the favourable properties of the variational integrator in particular with respect to the preservation of the invariants of the models under consideration and compare with results from the literature and those of a pseudo-spectral code.Comment: 35 page

Development And Characterization Of Novel Raf Dimer Inhibitors To Target Brafv600e Inhibitor Resistance

ABSTRACT BRAF is a notable oncoprotein within the MAPK signaling pathway, which is a pathway that sends a signal from the surface of a cell to the nucleus of a cell via phosphorylation cascades. This pathway regulates cell growth, differentiation, and survival. BRAF is known to be mutated in about 50% of melanomas, and less frequently in a wide variety of other cancers, making BRAF a bona-fide target for therapy. In melanoma, a single V600E activation segment mutation (BRAFV600E) accounts for ~90% of BRAF mutant malignant tumors. BRAFV600E selective inhibitors, such as vemurafenib, extend the survival of patients in the clinic, however most patients develop drug resistance and progress at a median of 6 months. One mode of resistance is “paradoxical activation” of RAF heterodimers. In this mechanism, a drug-bound BRAF protomer dimerizes with either BRAFWT or CRAFWT, allosterically stimulating kinase activity and leading to hyper-activation of the MAPK pathway. The first part of this thesis involves my efforts to develop bivalent BRAF inhibitors to target paradoxical activation of active RAF dimers. We successfully chemically linked two BRAFV600E selective vemurafenib inibitors and found that this bivalent inhibitor stabilized an inactive face-to-face BRAF dimer conformation. We then extended this strategy to pan-RAF inhibitor TAK632 to target BRAFWT and CRAFWT in cells. Interestingly, this bivalent molecule was unable to “trap” two BRAF molecules in the same face-to-face conformation as the bivalent vemurafenib inhibitor, but also uncovered that the monovalent TAK632 depends on induction of active conformation BRAF dimers to be able to potently inhibit RAF. The last part of this thesis involved the development of a high throughput screen to discover novel inhibitors that can disrupt the complex between BRAF and its downstream substrate MEK. We were able to design a high throughput TR-FRET assay to identify 15 novel inhibitors that can inhibit BRAF/MEK dimerization. Together, our studies identify novel RAF dimer inhibitors that can be used as chemical probes to further understand BRAF signaling through RAF dimerization in melanoma and other BRAF-related cancers. These studies also highlight a novel method of targeting paradoxical activation and RAF dimerization for melanoma therapy

The Maritime Revival: Antimodernity, class, and culture, 1870--1940

Between 1870 and 1940, Americans redefined their perceptions, ideas, and cultural meanings of seafaring under sail. The Maritime Revival---a cultural phenomenon that took the workaday nineteenth-century maritime world and converted it into an archetypical exercise in essential Americanism---selectively picked stories, symbols, and specific lifestyles and elevated them to heroic status. Part of larger nineteenth-century revivalism, the Maritime Revival created an image of seafaring that was a small subset of the entire experience-as-lived. By the 1930s, Americans recognized a heroic, but lost, golden age of sailing ships that did not correspond to the maritime world that had once been a ubiquitous part of American life. This dissertation draws on American tonnage statistics, the writings of adventure-seeking young sailors, visual arts, and maritime preservation movements to illuminate how and why the Maritime Revival developed and matured between the Centennial and World War II. A conservative group of old-stock Americans believed seafaring represented essential American cultural values, and incorporated its symbols and aesthetics into a heritage movement. If initially engineered by eastern elites to insulate themselves from social changes, the Maritime Revival\u27s redefined image of seafaring appealed to middle- and working-class Americans. Many responded enthusiastically, and used it to participate in a culture cast as essentially American and patriotically important. Popular art, literature, historic ships, and museums celebrated square-riggers, and the romance and sublimity of the oceans. A variety of cultural forms, from fine arts to kitsch and advertisements, diffused the ideas of the Maritime Revival throughout American culture to people of all social classes. Not every piece of cultural output associated with ships and the sea, nor every aspect of contemporary maritime industry, nor every mariner, were part of the Maritime Revival. Some Americans embraced modernizing marine worlds, but Maritime Revivalists looked backwards to lament a passing era and acted to preserve the material and intellectual culture of seafaring\u27s past. In so doing, they helped ease their own transition into the modern world, and created popularized images of sailors, ships, and lifestyles that profoundly influenced how Americans remembered the maritime past for most of the twentieth century

Ureteroscopic laser treatment of upper urinary tract neoplasms.

BACKGROUND: Endoscopic management of upper urinary tract transitional cell carcinoma has assumed an important role in diagnosis and treatment. The introduction of small diameter rigid and flexible ureteroscopes has permitted access to the upper tract. Biopsy techniques have been developed for accurate diagnosis, and the addition of lasers has given the urologists an excellent tool for treatment. METHODS: Medical literature available relative to the endoscopic laser treatment of upper tract neoplasms has been reviewed. RESULTS: Ureteroscopic treatment has been characterized by good success with high recurrence rates, both in the upper tract and in the bladder. Bladder recurrence rates are similar to those seen after surgical treatment of upper tract tumors. Surveillance has been ureteroscopic since the other diagnostic options are inadequate. The holmium and neodymium:YAG lasers are the devices most commonly used now for the endoscopic treatment of upper tract tumors. CONCLUSION: Ureteroscopic treatment of upper tract neoplasms usually with ablation and resection using the neodymium and holmium: YAG lasers is a current acceptable procedure. This should be considered as one of the options in tumor treatment

Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential.

BackgroundMetastatic prostate cancer (PC) is highly lethal. The ability to identify primary tumors capable of dissemination is an unmet need in the quest to understand lethal biology and improve patient outcomes. Previous studies have linked chromosomal instability (CIN), which generates aneuploidy following chromosomal missegregation during mitosis, to PC progression. Evidence of CIN includes broad copy number alterations (CNAs) spanning > 300 base pairs of DNA, which may also be measured via RNA expression signatures associated with CNA frequency. Signatures of CIN in metastatic PC, however, have not been interrogated or well defined. We examined a published 70-gene CIN signature (CIN70) in untreated and castration-resistant prostate cancer (CRPC) cohorts from The Cancer Genome Atlas (TCGA) and previously published reports. We also performed transcriptome and CNA analysis in a unique cohort of untreated primary tumors collected from diagnostic prostate needle biopsies (PNBX) of localized (M0) and metastatic (M1) cases to determine if CIN was linked to clinical stage and outcome.MethodsPNBX were collected from 99 patients treated in the VA Greater Los Angeles (GLA-VA) Healthcare System between 2000 and 2016. Total RNA was extracted from high-grade cancer areas in PNBX cores, followed by RNA sequencing and/or copy number analysis using OncoScan. Multivariate logistic regression analyses permitted calculation of odds ratios for CIN status (high versus low) in an expanded GLA-VA PNBX cohort (n = 121).ResultsThe CIN70 signature was significantly enriched in primary tumors and CRPC metastases from M1 PC cases. An intersection of gene signatures comprised of differentially expressed genes (DEGs) generated through comparison of M1 versus M0 PNBX and primary CRPC tumors versus metastases revealed a 157-gene "metastasis" signature that was further distilled to 7-genes (PC-CIN) regulating centrosomes, chromosomal segregation, and mitotic spindle assembly. High PC-CIN scores correlated with CRPC, PC-death and all-cause mortality in the expanded GLA-VA PNBX cohort. Interestingly, approximately 1/3 of M1 PNBX cases exhibited low CIN, illuminating differential pathways of lethal PC progression.ConclusionsMeasuring CIN in PNBX by transcriptome profiling is feasible, and the PC-CIN signature may identify patients with a high risk of lethal progression at the time of diagnosis

Dimensional regularization applied to nuclear matter with a zero--range interaction

We apply the dimensional regularization procedure to treat an ultraviolet divergence occurring in the framework of the nuclear many-body problem. We consider the second--order correction (beyond the mean-field approximation) to the equation of state of nuclear matter with a zero-range effective interaction. The unphysical ultraviolet divergence that is generated at second order by the zero range of the interaction is removed by the regularization technique and the regularized equation of state (mean-field + second-order contributions) is adjusted to a reference equation of state. The main practical advantage of this procedure, with respect to a cutoff regularization, is to provide a unique set of parameters for the adjusted effective interaction. This occurs because the regularized second-order correction does not contain any cutoff dependence. The encouraging results found in this work indicate that such an elegant technique to generate regularized effective interactions is likely to be applied in future to finite nuclei in the framework of beyond mean-field models.Comment: 11 figures. Revised versio

Bitemporal Complex Event Processing of Web Event Advertisements

Abstract. The web is the largest bulletin board of the world. Events of all types, from flight arrivals to business meetings, are announced on this board. Tracking and reacting to such event announcements, however, is a tedious manual task, only slightly alleviated by email or similar notifications. Announcements are published with human readers in mind, and updates or delayed announcements are frequent. These characteristics have hampered attempts at automatic tracking. PEACE provides the first integrated framework for event processing on top of web event ads. Given a schema of events to be tracked, the framework populates this schema through compact wrappers for event announcement sources. These wrappers produce events including updates and retractions. PEACE then queries these events to detect complex events, often combining announcements from multiple sources. To deal with updates and delayed announcements, PEACE's schemas are bitemporal so as to distinguish between occurrence and detection time. This allows complex event specifications to track updates and to react to differences in occurrence and detection time. Our evaluation shows that extracting the event from an announcement dominates the processing of PEACE and that the complex event processor deals with several event announcement sources even with moderate resources. We further show, that simple restrictions on the complex event specifications suffice to guarantee that PEACE only requires a constant buffer to process arbitrarily many event announcements

PEACE-ful Web Event Extraction and Processing

Abstract. PEACE, our proposed tool, integrates complex event processing and web extraction into a unified framework to handle web event advertisements and to run a notification service atop. Its bitemporal schemata distinguish occurrence and detection time, enabling PEACE to deal with updates and delayed announcements, as often occurring on the web. To consolidate the arising event streams, PEACE combines simple events into complex ones. Depending on their occurrence and detection time, these complex events trigger actions to be executed. We demonstrate PEACE's capabilities with a business trip scenario, involving as raw events business trips, flight bookings, scheduled flights, and flight arrivals and departures. These events are scrapped from the web and combined into complex events, triggering actions to be executed, such as updating facebook status messages. Our demonstrator records and reruns event sequences at different speeds to show the system dealing with complex scenarios spanning several days