Silencing E3 Ubiqutin ligase ITCH as a potential therapy to enhance chemotherapy efficacy in p53 mutant neuroblastoma cells

P53 mutations are responsible for drug-resistance of tumour cells which impacts on the efficacy of treatment. Alternative tumour suppressor pathways need to be explored to treat p53- deficient tumours. The E3 ubiquitin ligase, ITCH, negatively regulates the tumour suppressor protein TP73, providing a therapeutic target to enhance the sensitivity of the tumour cells to the treatment. In the present study, two p53-mutant neuroblastoma cell lines were used as in vitro models. Using immunostaining, western blot and qPCR methods, we firstly identified that ITCH was expressed on p53-mutant neuroblastoma cell lines. Transfection of these cell lines with ITCH siRNA could effectively silence the ITCH expression, and result in the stabilization of TP73 protein, which mediated the apoptosis of the neuroblastoma cells upon irradiation treatment. Finally, in vivo delivery of the ITCH siRNA using nanoparticles to the neuroblastoma xenograft mouse model showed around 15–20% ITCH silencing 48 hours after transfection. Our data suggest that ITCH could be silenced both in vitro and in vivo using nanoparticles, and silencing of ITCH sensitizes the tumour cells to irradiation treatment. This strategy could be further explored to combine the chemotherapy/radiotherapy treatment to enhance the therapeutic effects on p53-deficient neuroblastoma

Optimized bolted joint

A method is disclosed for joining segments of the skin of an aircraft. The ends of the skin are positioned in close proximity or abutt each other. The skin is of constant thickness throughout the joint and is sandwiched between splice plates, which taper in thickness from the last to the first bolt rows in order to reduce the stiffness of the splice plate and thereby reduce the load transfer at the location where bypass loads are the highest

Amplitude squeezed light from a laser

Intensity squeezed light was successfully generated using semiconductor lasers with sub-Poissonian pumping. Control of the pumping statistics is crucial and is achieved by a large series resistor which regulates the pump current; its sub-Poissonian statistics are then transferred to the laser output. The sub-Poissonian pumping of other laser systems is not so simple, however, and their potential as squeezed states sources is apparently diminished. We consider a conventional laser incoherently pumped well above threshold, and allow for pump depletion of the ground state. In this regime, sub-Poissonian photon statistics and squeezed amplitude fluctuations are produced

The Emerging Nature of Participation in Multispecies Interaction Design

Interactive technology has become integral part of daily life for both humans and animals, with animals often interacting with technologized environments on behalf of humans. For some, animals' participation in the design process is essential to design technology that can adequately support their activities. For others, animals' inability to understand and control design activities inevitably stands in the way of multispecies participatory practices. Here, we consider the essential elements of participation within interspecies interactions and illustrate its emergence, in spite of contextual constraints and asymmetries. To move beyond anthropomorphic notions of participation, and consequent anthropocentric practices, we propose a broader participatory model based on indexical semiosis, volition and choice; and we highlight dimensions that could define inclusive participatory practices more resilient to the diversity of understandings and goals among part-taking agents, and better able to account for the contribution of diverse, multispecies agents in interaction design and beyond

Adjoint error estimation and spatial adaptivity for EHL-like models

The use of adjoint error estimation techniques is described for a model problem that is a simplified version of an EHL line contact. Quantities of interest, such as friction, may be dependent upon the accuracy of the Solution in some parts of the domain more than in others. The use of an inexpensive extra solve to calculate an adjoint solution is described for estimating the intergrid error in the value of friction calculated, and as a basis for local refinement. It is demonstrated that this enables an accurate estimate for the quantity of interest to be obtained from a less accurate solution of the model problem

Critical joints in large composite aircraft structure

A program was conducted at Douglas Aircraft Company to develop the technology for critical structural joints of composite wing structure that meets design requirements for a 1990 commercial transport aircraft. The prime objective of the program was to demonstrate the ability to reliably predict the strength of large bolted composite joints. Ancillary testing of 180 specimens generated data on strength and load-deflection characteristics which provided input to the joint analysis. Load-sharing between fasteners in multirow bolted joints was computed by the nonlinear analysis program A4EJ. This program was used to predict strengths of 20 additional large subcomponents representing strips from a wing root chordwise splice. In most cases, the predictions were accurate to within a few percent of the test results. In some cases, the observed mode of failure was different than anticipated. The highlight of the subcomponent testing was the consistent ability to achieve gross-section failure strains close to 0.005. That represents a considerable improvement over the state of the art

Shuttle Ground Operations Efficiencies/Technologies Study (SGOE/T). Volume 5: Technical Information Sheets (TIS)

The Technology Information Sheet was assembled in database format during Phase I. This document was designed to provide a repository for information pertaining to 144 Operations and Maintenance Instructions (OMI) controlled operations in the Orbiter Processing Facility (OPF), Vehicle Assembly Building (VAB), and PAD. It provides a way to accumulate information about required crew sizes, operations task time duration (serial and/or parallel), special Ground Support Equipment (GSE). required, and identification of a potential application of existing technology or the need for the development of a new technolgoy item

Shuttle Ground Operations Efficiencies/Technologies (SGOE/T) study. Volume 1: Executive summary

Methods and technolgoy were defined to reduce the overall operations cost of a major space program. Space Shuttle processing at Kennedy Space Center (KSC) was designed as the working model that would be the source of the operational information. Methods of improving efficiency of ground operations were assessed and technology elements that could reduce cost identified. Emphasis is on: (1) specific technology items and (2) management approaches required to develop and support efficient ground operations. Prime study results are to be recommendations on how to achieve more efficient operations and identification of existing or new technology that would make vehicle processing in both the current program and future programs more efficient and, therefore, less costly

Shuttle Ground Operations Efficiencies/Technologies (SGOE/T) study. Volume 2: Ground Operations evaluation

The Ground Operations Evaluation describes the breath and depth of the various study elements selected as a result of an operational analysis conducted during the early part of the study. Analysis techniques used for the evaluation are described in detail. Elements selected for further evaluation are identified; the results of the analysis documented; and a follow-on course of action recommended. The background and rationale for developing recommendations for the current Shuttle or for future programs is presented