An Analysis of the Effects of Low Energy Electron Radiation of Al\u3csub\u3ex\u3c/sub\u3eGa\u3csub\u3e1-x\u3c/sub\u3eN/GaN Modulation-Doped Field-Effect Transistors

The effects of radiation on AlxGa1-xN/GaN MODFETs is an area of increasing interest to the USAF as these devices become developed and integrated in satellite-based systems Irradiation is also a valuable tool for analyzing the quantum-level characteristics and properties that are responsible for device operation AlxGa1-xN/GaN MODFETs were fabricated and irradiated at liquid nitrogen temperatures by 0,45-1,2MeV electrons up to doses of 6*1016 e/cm2. Following irradiation, low temperature I-V measurements were recorded providing dose-dependent measurements Temperature-dependent I-V measurements were also made during room temperature annealing following irradiation I-V measurements indicate radiation-induced changes occur in these devices creating increased gate and drain currents These increased currents are only maintained at low temperatures (T \u3c 300 K), It is believed that the increase in gate current is caused by an increase in the electron trap concentration of the AlxGa1-xN/GaN layer, This increase in trap concentration directly increases the trap-assisted tunneling current resulting in the observed increase in gate current The mechanism causing the increase in drain current is unknown, Several theories explaining this increase are presented along with the additional research necessary to illuminate the correct theory, This is the first experiment involving electron radiation of AlxGa1-xN/GaN MODFETs

Engineered Surfaces to Control Secondary Electron Yield for Multipactor Suppression

A significant problem for satellites, vacuum electron devices, and particle accelerators is multipactor: an avalanche of electrons caused by recurring secondary electron emission (SEE) in a time-varying electric field. The consequences of multipactor range from temporary to permanent device failure. This research studied how surface topography can be engineered to minimize SEE and suppress multipactor. Two new semi-empirical models (one based on a 2D pore, the other based on a 3D pore) were developed to predict the secondary electron yield (SEY) of a porous surface based on pore aspect ratio and porosity. The models were validated with experimental SEY measurements of microporous gold surfaces. The more accurate 3D model predicts that a porous gold surface with pore aspect ratios = 2.0 and porosity = 0.5 will control the maximum SEY to near unity, providing a multipactor-resistant surface. Both the SEY models and experimental results confirm the understanding that the ability of a porous surface to control SEY is not dependent on pore size

Engineered surfaces to control secondary electron emission for multipactor suppression

A significant problem for space-based systems is multipactor - an avalanche of electrons caused by repeated secondary electron emission (SEE). The consequences of multipactor range from altering the operation of radio frequency (RF) devices to permanent device damage. Existing efforts to suppress multipactor rely heavily on limiting power levels below a multipactor threshold [1]. This research applies surface micromachining techniques to create porous surfaces to control the secondary electron yield (SEY) of a material for multipactor suppression. Surface characteristics of interest include pore aspect ratio and density. A discussion is provided on the advantage of using electroplating (vice etching) to create porous surfaces for studying the relationships between SEY and pore aspect ratio & density (i.e. porosity). Preventing multipactor through SEY reduction will allow power level restrictions to be eased, leading to more powerful and capable space-based systems

Surface Feature Engineering through Nanosphere Lithography

How surface geometries can be selectively manipulated through nanosphere lithography (NSL) is discussed. Self-assembled monolayers and multilayers of nanospheres have been studied for decades and have been applied to lithography for almost as long. When compared to the most modern, state-of-the-art techniques, NSL offers comparable feature resolution with many advantages over competing technologies

NADPH oxidases regulate cell growth and migration in myeloid cells transformed by oncogenic tyrosine kinases

Transformation by tyrosine kinase oncogenes in myeloid malignancies, including BCR-ABL in chronic myeloid leukemia, FLT3ITD in acute myeloid leukemia (AML) or JAK2V617F in myeloproliferative neoplasms (MPN), is associated with increased growth and cytoskeletal abnormalities. Using targeted approaches against components of the superoxide-producing NADPH-oxidases, including NOX2, NOX4 and the common p22phox subunit of NOX1-4, myeloid cells were found to display reduced cell growth and spontaneous migration. Consistent with a role of NOX as regulators of membrane proximal signaling events in non-phagocytic cells, NOX2 and NOX4 were not involved in the excess production of intracellular reactive oxygen species and did not significantly increase oxygen consumption. All NOX family members are controlled in part through levels of the rate-limiting substrate NADPH, which was found to be significantly elevated in tyrosine kinase oncogene transformed cells. Also, reduced phosphorylation of the actin filament crosslinking protein MARCKS in response to suppression of p22phox hints at a novel effector of NOX signaling. MARCKS was also found to be required for increased migration. Overall, these data suggest a model whereby NOX links metabolic NADPH production to cellular events that directly contribute to transformation

Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasms

The transforming JAK2V617F kinase is frequently associated with myeloproliferative neoplasms (MPNs) and thought to be instrumental for the overproduction of myeloid lineage cells. Several small molecule drugs targeting JAK2 are currently in clinical development for treatment in these diseases. We performed a high-throughput in vitro screen to identify point mutations in JAK2V617F that would be predicted to have potential clinical relevance and associated with drug resistance to the JAK2 inhibitor ruxolitinib (INCB018424). Seven libraries of mutagenized JAK2V617F cDNA were screened to specifically identify mutations in the predicted drug-binding region that would confer resistance to ruxolitinib, using a BaF3 cell-based assay. We identified 5 different non-synonymous point mutations that conferred drug resistance. Cells containing mutations had a 9 to 33-fold higher EC50 for ruxolitinib compared to native JAK2V617F. Our results further indicated that these mutations also conferred cross-resistance to all JAK2 kinase inhibitors tested, including AZD1480, TG101348, lestaurtinib (CEP-701) and CYT-387. Surprisingly, introduction of the ‘gatekeeper’ mutation (M929I) in JAK2V617F affected only ruxolitinib sensitivity (4-fold increase in EC50). These results suggest that JAK2 inhibitors currently in clinical trials may be prone to resistance as a result of point mutations and caution should be exercised when administering these drugs

Modeling Micro-porous Surfaces for Secondary Electron Emission Control to Suppress Multipactor

This work seeks to understand how the topography of a surface can be engineered to control secondary electron emission (SEE) for multipactor suppression. Two unique, semi-empirical models for the secondary electron yield (SEY) of a micro-porous surface are derived and compared. The first model is based on a two-dimensional (2D) pore geometry. The second model is based on a three-dimensional (3D) pore geometry. The SEY of both models is shown to depend on two categories of surface parameters: chemistry and topography. An important parameter in these models is the probability of electron emissions to escape the surface pores. This probability is shown by both models to depend exclusively on the aspect ratio of the pore (the ratio of the pore height to the pore diameter). The increased accuracy of the 3D model (compared to the 2D model) results in lower electron escape probabilities with the greatest reductions occurring for aspect ratios less than two. In order to validate these models, a variety of micro-porous gold surfaces were designed and fabricated using photolithography and electroplating processes. The use of an additive metal-deposition process (instead of the more commonly used subtractive metal-etch process) provided geometrically ideal pores which were necessary to accurately assess the 2D and 3D models. Comparison of the experimentally measured SEY data with model predictions from both the 2D and 3D models illustrates the improved accuracy of the 3D model. For a micro-porous gold surface consisting of pores with aspect ratios of two and a 50% pore density, the 3D model predicts that the maximum total SEY will be one. This provides optimal engineered surface design objectives to pursue for multipactor suppression using gold surfaces. © 2017 Author(s)

An Innovative Non-Pharmacologic Treatment for Delusional Misidentification in Persons with Major Neurocognitive Disorder

Misidentification delusions are false, fixed beliefs that assign an incorrect identity to a previously familiar or unfamiliar person or place. Such delusions are common in several neuropsychiatric disorders and place a particular burden on individuals with Major Neurocognitive Disorder and their caregivers. No standard pharmacologic or non-pharmacologic treatment approaches have been shown to be consistently effective in addressing this problem. We describe two caregiver-care recipient dyads in which an innovative non-pharmacologic, digital intervention reduced delusional misidentification, improved care recipient behavior, and decreased caregiver burden

Structure of a pseudokinase domain switch that controls oncogenic activation of Jak kinases

The V617F mutation in the Jak2 pseudokinase domain causes myeloproliferative neoplasms, and the equivalent mutation in Jak1 (V658F) is found in T-cell leukemias. Crystal structures of wild type and V658F mutant human Jak1 pseudokinase reveal a conformational switch that remodels a linker segment encoded by exon 12, which is also a site of mutations in Jak2. This switch is required for V617F-mediated Jak2 activation, and possibly for physiologic Jak activation

Acute myeloid leukemia cells require 6-phosphogluconate dehydrogenase for cell growth and NADPH-dependent metabolic reprogramming

Acute myeloid leukemia (AML) cells are highly dependent on glycolytic pathways to generate metabolic energy and support cell growth, hinting at specific, targetable vulnerabilities as potential novel targets for drug development. Elevated levels of NADPH, a central metabolic factor involved in redox reactions, are common in myeloid leukemia cells, but the significance or biochemical basis underlying this increase is unknown. Using a small molecule analog that efficiently inhibits NADPH-producing enzymes, we found that AML cells require NADPH homeostasis for cell growth. We also found that inhibiting NADPH production through knockdown of 6-phosphogluconate dehydrogenase (6PGD) within the pentose phosphate pathway was sufficient to reduce cell growth and lactate production, a measure of metabolic reprogramming. Further, inhibition of 6PGD activity reduced NADH levels and enzymatic activity of the oxidized NADH-dependent sirtuin-1. Targeting 6PGD and NADPH production was sufficient to block growth of AML cell lines resistant to the chemotherapeutics daunorubicin and cytarabine. Importantly, stromal cell-mediated resistance to targeted inhibition of oncogenic FLT3 kinase activity by quizartinib was circumvented by 6PGD knockdown. Overall, these data suggest that the dependency of AML cells on NADPH to permit increased glycolytic flux creates a potential vulnerability of possible therapeutic benefit, since much of the enhanced production of NADPH is dependent on the activity of a single enzyme, 6PGD