Emerging role of nuclear factor erythroid 2-related factor 2 in the mechanism of action and resistance to anticancer therapies

Nuclear factor E2-related factor 2 (NRF2), a transcription factor, is a master regulator of an array of genes related to oxidative and electrophilic stress that promote and maintain redox homeostasis. NRF2 function is well studied in in vitro, animal and general physiology models. However, emerging data has uncovered novel functionality of this transcription factor in human diseases such as cancer, autism, anxiety disorders and diabetes. A key finding in these emerging roles has been its constitutive upregulation in multiple cancers promoting pro-survival phenotypes. The survivability pathways in these studies were mostly explained by classical NRF2 activation involving KEAP-1 relief and transcriptional induction of reactive oxygen species (ROS) neutralizing and cytoprotective drug-metabolizing enzymes (phase I, II, III and 0). Further, NRF2 status and activation is associated with lowered cancer therapeutic efficacy and the eventual emergence of therapeutic resistance. Interestingly, we and others have provided further evidence of direct NRF2 regulation of anticancer drug targets like receptor tyrosine kinases and DNA damage and repair proteins and kinases with implications for therapy outcome. This novel finding demonstrates a renewed role of NRF2 as a key modulatory factor informing anticancer therapeutic outcomes, which extends beyond its described classical role as a ROS regulator. This review will provide a knowledge base for these emerging roles of NRF2 in anticancer therapies involving feedback and feed forward models and will consolidate and present such findings in a systematic manner. This places NRF2 as a key determinant of action, effectiveness and resistance to anticancer therapy

Simple Max-Min Ant Systems and the Optimization of Linear Pseudo-Boolean Functions

With this paper, we contribute to the understanding of ant colony optimization (ACO) algorithms by formally analyzing their runtime behavior. We study simple MAX-MIN ant systems on the class of linear pseudo-Boolean functions defined on binary strings of length 'n'. Our investigations point out how the progress according to function values is stored in pheromone. We provide a general upper bound of O((n^3 \log n)/ \rho) for two ACO variants on all linear functions, where (\rho) determines the pheromone update strength. Furthermore, we show improved bounds for two well-known linear pseudo-Boolean functions called OneMax and BinVal and give additional insights using an experimental study.Comment: 19 pages, 2 figure

Finite difference time domain modeling of steady state scattering from jet engines with moving turbine blades

The approach chosen to model steady state scattering from jet engines with moving turbine blades is based upon the Finite Difference Time Domain (FDTD) method. The FDTD method is a numerical electromagnetic program based upon the direct solution in the time domain of Maxwell's time dependent curl equations throughout a volume. One of the strengths of this method is the ability to model objects with complicated shape and/or material composition. General time domain functions may be used as source excitations. For example, a plane wave excitation may be specified as a pulse containing many frequencies and at any incidence angle to the scatterer. A best fit to the scatterer is accomplished using cubical cells in the standard cartesian implementation of the FDTD method. The material composition of the scatterer is determined by specifying its electrical properties at each cell on the scatterer. Thus, the FDTD method is a suitable choice for problems with complex geometries evaluated at multiple frequencies. It is assumed that the reader is familiar with the FDTD method

Note and Comment

The Rule of Certainty in Damages and the Value of a Chance; Is a Bank Check an Assignment Pro Tanto of the Fund on Deposit?; The Finger-Print Case; Right of Husband to Recover Alimony Independent of an Action for Divorce

Note and Comment

The Latest Step in the Expansion of the Commerce Clause of the Federal Constitution; The Right of a Trustee of a Bankrupt Partnership to Administer the Individual Estate of an Unadjudicated Partner Against His Will or Consent; Presumption in Favor of Reply Letters; A Novel Case Upon the Question of What Constitutes Former Jeopard

Dynamic response of full-scale sandwich composite structures subject to air-blast loading

Glass-fibre reinforced polymer (GFRP) sandwich structures (1.6 m × 1.3 m) were subject to 30 kg charges of C4 explosive at stand-off distances 8–14 m. Experiments provide detailed data for sandwich panel response, which are often used in civil and military structures, where air-blast loading represents a serious threat. High-speed photography, with digital image correlation (DIC), was employed to monitor the deformation of these structures during the blasts. Failure mechanisms were revealed in the DIC data, confirmed in post-test sectioning. The experimental data provides for the development of analytical and computational models. Moreover, it underlines the importance of support boundary conditions with regards to blast mitigation. These findings were analysed further in finite element simulations, where boundary stiffness was, as expected, shown to strongly influence the panel deformation. In-depth parametric studies are ongoing to establish the hierarchy of the various factors that influence the blast response of sandwich composite structures

Deformation and rupture of armour grade steel under localised blast loading

A series of 30 blast experiments were conducted on monolithic steel panels of two armour grade steels. The two steels evaluated were a high hardness armour (HHA) and a rolled homogenous armour (RHA). Tests were conducted at two standoff distances using a fixed charge diameter. The charge weight was varied to produce specific magnitudes of blast loading and to isolate the rupture threshold of each material. The results indicated that the HHA steel, generally reserved for ballistic protection, outperformed a more ductile RHA steel in terms of both its deformation resistance and rupture threshold. Optical and scanning electron microscopy was utilised for fractographic analysis of the ruptured plates. The failure of the steels in this investigation was found to be initiated by slant shear fracture with little to no localised thinning. This is in contrast to the tensile instability and ductile tearing predicted by established theories of plate rupture for mild steels under blast loading. The deformation and rupture of the candidate steels was analysed for all experimental conditions and compared to current empirical models based on a non-dimensional impulse parameter. While deformation behaviour is well predicted, the blast rupture threshold of the armour grade steels is poorly captured by current empirical modelling approaches. The identified shear fracture mode leads to lower energy absorption capabilities of the material compared to more ductile tensile failure