Algebraic Monte Carlo precedure reduces statistical analysis time and cost factors

Algebraic Monte Carlo procedure statistically analyzes performance parameters in large, complex systems. The individual effects of input variables can be isolated and individual input statistics can be changed without having to repeat the entire analysis

Commercialization of the land remote sensing system: An examination of mechanisms and issues

In September 1982 the Secretary of Commerce was authorized (by Title II of H.R. 5890 of the 97th Congress) to plan and provide for the management and operation of the civil land remote sensing satellite systems, to provide for user fees, and to plan for the transfer of the ownership and operation of future civil operational land remote sensing satellite systems to the private sector. As part of the planning for transfer, a number of approaches were to be compared including wholly private ownership and operation of the system by an entity competitively selected, mixed government/private ownership and operation, and a legislatively-chartered privately-owned corporation. The results of an analysis and comparison of a limited number of financial and organizational approaches for either transfer of the ownership and operation of the civil operational land remote sensing program to the private sector or government retention are presented

Einstein's "Zur Elektrodynamik..." (1905) Revisited, with Some Consequences

Einstein, in his "Zur Elektrodynamik bewegter Korper", gave a physical (operational) meaning to "time" of a remote event in describing "motion" by introducing the concept of "synchronous stationary clocks located at different places". But with regard to "place" in describing motion, he assumed without analysis the concept of a system of co-ordinates. In the present paper, we propose a way of giving physical (operational) meaning to the concepts of "place" and "co-ordinate system", and show how the observer can define both the place and time of a remote event. Following Einstein, we consider another system "in uniform motion of translation relatively to the former". Without assuming "the properties of homogeneity which we attribute to space and time", we show that the definitions of space and time in the two systems are linearly related. We deduce some novel consequences of our approach regarding faster-than-light observers and particles, "one-way" and "two-way" velocities of light, symmetry, the "group property" of inertial reference frames, length contraction and time dilatation, and the "twin paradox". Finally, we point out a flaw in Einstein's argument in the "Electrodynamical Part" of his paper and show that the Lorentz force formula and Einstein's formula for transformation of field quantities are mutually consistent. We show that for faster-than-light bodies, a simple modification of Planck's formula for mass suffices. (Except for the reference to Planck's formula, we restrict ourselves to Physics of 1905.)Comment: 55 pages, 4 figures, accepted for publication in "Foundations of Physics

Targeting Ref-1/APE1 Pathway Inhibition in Pancreatic Cancer Using APX3330 for Clinical Trials

poster abstractPancreatic ductal adenocarcinoma is the 4th leading cause of cancer-related mortality in the US. Most patients present with advanced disease and ~95% die within five years, most surviving under six months. Targeted therapies offer modest improvement in survival, albeit at an increase in side effects and unwanted toxicities. Ref-1 regulates transcription factors involved in pancreatic cancer cell survival signaling due to its redox-coactivator activity, such as HIF-1α, NFκB, NRF2 and STAT3. High expression levels of Ref-1 indicate decreased survival in PDAC and other cancers. APX3330, a specific Ref-1 inhibitor, has been shown in multiple in vitro and in vivo pancreatic cancer models to be effective in reducing tumor growth and metastases. The safety and dose administration of APX3330 have been previously established, including toxicology, phase I, and phase II clinical evaluation in non-cancer patients in Japan (Eisai). We have partnered with ApeX Therapeutics to develop APX3330 for cancer treatment (phase I trial anticipated early 2016). We studied interactions of Ref-1, APX3330, convergent pathways; i.e. HIF-1α and STAT3, and downstream targets like CAIX. We performed in vivo studies demonstrating single and combination effects of APX3330 with Gemcitabine (Gem) showing significantly decreased tumor volume in the combination treatments. We also tested single and combination studies of APX3330 in an ex vivo 3-D tumor-stroma model system using patient derived tumor cells along with patient derived cancer-associated fibroblasts. We used the CAIX inhibitor SLC-0111 and JAK2 inhibitor, Ruxolitinib; both in clinical trials. In our system, APX3330 decreases the tumor area and intensity in a dose-dependent manner. The combination of APX3330 with Gem demonstrated an additive enhancement effect in the tumor, and APX3330 with SLC-0111/Ruxolitinib enhanced tumor killing. These data demonstrate APX3330 single agent efficacy in our 3D patient model and enhanced tumor killing when pathways regulated by Ref-1, HIF-1 and STAT3 are blocked

Solar Contamination in Extreme-precision Radial-velocity Measurements: Deleterious Effects and Prospects for Mitigation

Solar contamination, due to moonlight and atmospheric scattering of sunlight, can cause systematic errors in stellar radial velocity (RV) measurements that significantly detract from the ~10 cm s−1 sensitivity required for the detection and characterization of terrestrial exoplanets in or near habitable zones of Sun-like stars. The addition of low-level spectral contamination at variable effective velocity offsets introduces systematic noise when measuring velocities using classical mask-based or template-based cross-correlation techniques. Here we present simulations estimating the range of RV measurement error induced by uncorrected scattered sunlight contamination. We explore potential correction techniques, using both simultaneous spectrometer sky fibers and broadband imaging via coherent fiber imaging bundles, that could reliably reduce this source of error to below the photon-noise limit of typical stellar observations. We discuss the limitations of these simulations, the underlying assumptions, and mitigation mechanisms. We also present and discuss the components designed and built into the NEID (NN-EXPLORE Exoplanet Investigations with Doppler spectroscopy) precision RV instrument for the WIYN 3.5 m telescope, to serve as an ongoing resource for the community to explore and evaluate correction techniques. We emphasize that while "bright time" has been traditionally adequate for RV science, the goal of 10 cm s−1 precision on the most interesting exoplanetary systems may necessitate access to darker skies for these next-generation instruments

Uncertainty quantification through bayesian analysis for a fixed bed experiment of carbon capture using polyethylenimine (PEI) solid sorbents

With greenhouse gas emissions becoming a major concern and topic for research over the past decade, much effort has been supplied into the progress of reducing these emissions. Carbon dioxide concentration has increased over past 60 years. A major source of this emission is post combustion coal power plants. In order to reduce these emissions, many carbon capture and storage technologies are being researched and developed. A major issue confronting this research is investigating these technologies on multiple scales. For example, solid sorbents experience phenomena on a quantum and macroscopic scale. Thus a bridge must be made between these two scales.;This thesis investigates a fixed bed experiment, proposes a model for both the flow and adsorption of CO2 & H2O, and then quantifies the uncertainty of parameter estimations made with comparing the model to data. The model and uncertainty quantification was implemented in a C++ tool set. The power of this tool set lies in the ability to extract more information out of bench scale experiments than traditional optimization methods. This leads to better predictions in modeling a larger (process) scale, better understanding of the mathematical model used at the bench scale, and information to design better bench scale experiments to reduce the uncertainty.;The results of this analysis with the proposed model showed the posterior predictions covering the real data set. In other words, the posterior distribution includes a set of parameters that are the true values. Information on the certainty of each parameter estimation was also obtained in this analysis

Is it feasible to deliver a complex intervention to improve the outcome of falls in people with dementia? A protocol for the DIFRID feasibility study

Background: People with dementia (PWD) experience ten times as many incident falls as people without dementia. Little is known about how best to deliver services to people with dementia following a fall. We used an integrated, mixed-methods approach to develop a new intervention which combines theory generated via a realist synthesis and data on current provision and pathways, gathered through a prospective observational study as well as qualitative interviews, focus groups, and ethnographic observation. This intervention is to be tested in a feasibility study in the UK National Health Service. Methods: People living with dementia in one of three geographical areas will be eligible for the study if they experience a fall requiring healthcare attention and have an informal carer. Potential participants will be identified by community services (primary care, paramedics, telecare), secondary care (ED; facilitated discharge services; rehabilitation outreach teams) and research case registers. Participants will receive a complex multidisciplinary intervention focused on their goals and interests for up to 12 weeks. The intervention will be delivered by occupational therapists, physiotherapists and rehabilitation support workers. Feasibility outcomes will include recruitment and retention, suitability and acceptability of outcome measures and acceptability, feasibility and fidelity of intervention components. PWD outcome measures will include number of falls, Montreal Cognitive Assessment (MOCA), European Quality of Life Instrument (EQ-5D-5L), Quality of Life–Alzheimer’s Disease Scale (QOL-AD), Modified Falls Efficacy Scale (MFES) and Goal Attainment Scaling (GAS). PWD outcome measures completed by an informal carer will include Disability Assessment for Dementia (DAD), EQ-5D-5L Proxy, QoL-AD Proxy and a Health Utilisation Questionnaire (HUQ), The carer outcome measure will be the Zarit Burden Interview (ZBI). An embedded process evaluation will explore barriers and facilitators to recruitment and intervention delivery. Discussion: The study results will inform whether and how a larger multicentre RCT should be undertaken. A full RCT would have the potential to show how outcomes can be improved for people with dementia who have fallen. Ethics and dissemination: The National Research Ethics Service Committee Newcastle and North Tyneside 2 approved the feasibility study. Trial registration: International Standard Randomised Controlled Trial Registry Registration number: ISRCTN41760734 Date of registration: 16/11/201

Chromosomes. CENP-C reshapes and stabilizes CENP-A nucleosomes at the centromere

Inheritance of each chromosome depends upon its centromere. A histone H3 variant, centromere protein A (CENP-A), is essential for epigenetically marking centromere location. We find that CENP-A is quantitatively retained at the centromere upon which it is initially assembled. CENP-C binds to CENP-A nucleosomes and is a prime candidate to stabilize centromeric chromatin. Using purified components, we find that CENP-C reshapes the octameric histone core of CENP-A nucleosomes, rigidifies both surface and internal nucleosome structure, and modulates terminal DNA to match the loose wrap that is found on native CENP-A nucleosomes at functional human centromeres. Thus, CENP-C affects nucleosome shape and dynamics in a manner analogous to allosteric regulation of enzymes. CENP-C depletion leads to rapid removal of CENP-A from centromeres, indicating their collaboration in maintaining centromere identity.NIH grants: (GM082989, CA186430, GM008275, GM008216, GM007229); American Heart Association predoctoral fellowship; American Cancer Society postdoctoral fellowship; NSF grant: (agreement DMR-0944772)

Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related mortality in the United States. Aggressive treatment regimens have not changed the disease course, and the median survival has just recently reached a year. Several mechanisms are proposed to play a role in PDAC therapeutic resistance, including hypoxia, which creates a more aggressive phenotype with increased metastatic potential and impaired therapeutic efficacy. AP Endonuclease-1/Redox Effector Factor 1 (APE1/Ref-1) is a multifunctional protein possessing a DNA repair function in base excision repair and the ability to reduce oxidized transcription factors, enabling them to bind to their DNA target sequences. APE1/Ref-1 regulates several transcription factors involved in survival mechanisms, tumor growth, and hypoxia signaling. Here, we explore the mechanisms underlying PDAC cell responses to hypoxia and modulation of APE1/Ref-1 redox signaling activity, which regulates the transcriptional activation of hypoxia-inducible factor 1 alpha (HIF1α). Carbonic anhydrase IX (CA9) is regulated by HIF1α and functions as a part of the cellular response to hypoxia to regulate intracellular pH, thereby promoting cell survival. We hypothesized that modulating APE1/Ref-1 function will block activation of downstream transcription factors, STAT3 and HIF1α, interfering with the hypoxia-induced gene expression. We demonstrate APE1/Ref-1 inhibition in patient-derived and established PDAC cells results in decreased HIF1α–mediated induction of CA9. Furthermore, an ex vivo three-dimensional tumor coculture model demonstrates dramatic enhancement of APE1/Ref-1–induced cell killing upon dual targeting of APE1/Ref-1 and CA9. Both APE1/Ref-1 and CA9 are under clinical development; therefore, these studies have the potential to direct novel PDAC therapeutic treatment