Autophagy supports PDGFRA-dependent brain tumour development by modulating oncogenic signalling

Autophagy is a highly conserved catabolic process which sequesters intracellular substrates for lysosomal degradation. Whilst autophagy-related proteins have been shown to regulate the signalling and trafficking of some receptor tyrosine kinases, the relevance of this during cancer development is unclear. Here, we uncover a novel role for autophagy in regulating PDGFRA signalling and levels. We find that PDGFRA can be targeted to autophagic degradation through the activity of the autophagy cargo receptor, p62. As a result, short term autophagy inhibition leads to elevated intracellular levels of PDGFRA but an unexpected defect in PDGFA-mediated downstream signalling due to perturbed trafficking of the receptor. Defective PDGFRA signalling led to a reduction in receptor levels during prolonged autophagy inhibition suggesting that cells adapt to autophagy inhibition by downregulating receptor expression. Importantly, PDGFA-driven gliomagenesis in mice was disrupted when autophagy was inhibited. Activation of PI3K/AKT signalling through Pten mutation overrides the need for autophagy during tumour development upon PDGFRA activation highlighting a genotype-specific role for autophagy during tumourigenesis. In summary, our data provide a novel mechanism by which cells require autophagy for optimal oncogenic signalling that drives tumour formation

Seamless Bead to Microarray Screening: Rapid Identification of the Highest Affinity Protein Ligands from Large Combinatorial Libraries

SummarySeveral approaches have been developed for screening combinatorial libraries or collections of synthetic molecules for agonists or antagonists of protein function, each with its own advantages and limitations. In this report, we describe an experimental platform that seamlessly couples massively parallel bead-based screening of one-bead one-compound combinatorial libraries with microarray-based quantitative comparisons of the binding affinities of the many hits isolated from the bead library. Combined with other technical improvements, this technique allows the rapid identification of the best protein ligands in combinatorial libraries containing millions of compounds without the need for labor-intensive resynthesis of the hits

Maximal surface group representations in isometry groups of classical Hermitian symmetric spaces

Higgs bundles and non-abelian Hodge theory provide holomorphic methods with which to study the moduli spaces of surface group representations in a reductive Lie group G. In this paper we survey the case in which G is the isometry group of a classical Hermitian symmetric space of non-compact type. Using Morse theory on the moduli spaces of Higgs bundles, we compute the number of connected components of the moduli space of representations with maximal Toledo invariant.Comment: v2: added due credits to the work of Burger, Iozzi and Wienhard. v3: corrected count of connected components for G=SU(p,q) (p \neq q); added due credits to the work of Xia and Markman-Xia; minor corrections and clarifications. 31 page

Role of Peroxisome Proliferator-Activated Receptor Gamma and Its Ligands in the Treatment of Hematological Malignancies

Peroxisome proliferator-activated receptor gamma (PPARγ) is a multifunctional transcription factor with important regulatory roles in inflammation, cellular growth, differentiation, and apoptosis. PPARγ is expressed in a variety of immune cells as well as in numerous leukemias and lymphomas. Here, we review recent studies that provide new insights into the mechanisms by which PPARγ ligands influence hematological malignant cell growth, differentiation, and survival. Understanding the diverse properties of PPARγ ligands is crucial for the development of new therapeutic approaches for hematological malignancies

Cellular Models of Aggregation-Dependent Template-Directed Proteolysis to Characterize Tau Aggregation Inhibitors for Treatment of Alzheimer's Disease

Copyright © 2015, The American Society for Biochemistry and Molecular Biology. Acknowledgements-We thank Drs Timo Rager and Rolf Hilfiker (Solvias, Switzerland) for polymorph analyses.Peer reviewedPublisher PD

Space-Based Telemetry And Range Safety Flight Demonstration #1

The basic ability of STARS to maintain a satellite communications link with TDRSS satellites during dynamic aircraft flights was successfully demonstrated during FD 1. The Range Safety and Range User systems' link margins were measured. The ability to acquire/reacquire and maintain lock between a high-dynamic vehicle and a satellite-based system was demonstrated. The Range Safety system simultaneously received and processed command links from space and ground transmitters and provided near real-time Range Safety telemetry to DFRC, which then sent it in near real time to KSC, GSFC, and WFF for monitoring. The GPS receiver maintained track except during extremely dynamic maneuvers. The Range User system sent data at three different data rates. There were excellent cooperation and support from the different Centers, contractors, and Ranges. A large amount of data was recorded and extensive post-flight analysis was performed. The Range User TDRSS link margin met or exceeded the predicted performance at three different data rates. The Range Safety launch-head link margins generally agreed with the predicted performance. The UPS positions and velocities agreed with those from tracking radar to within about 20 m and a few rn/s. The link margins for the Range Safety TDRSS telemetry link were less than expected. The link margin for one TDRSS command link LPT channel was occasionally much less than the other. Additional post-flight testing has yet to identify the root causes of these results. There were many lessons learned from this first set of test flights. The most important one is that more time and testing are needed for each step to deal with the inevitable problems. It is vital that these lessons be among the primary areas of study that will carry over from FD#1 to FD#2, which is currently scheduled for early FY05 at DFRC and will use a specially designed Ku-band phased array antenna for the Range User system. The next series of flight demonstrations scheduled for late 2004 at DFRC will incorporate many lessons learned from FD#1. A specially designed Ku-band phased array antenna will be used with the Range User system. A test flight on a hypersonic vehicle is planned by the end of 2006

Laser-Induced Fabrication of Metallic Interlayers and Patterns in Polyimide Films

Self-metallizing polyimide films are created by doping polyamic acid solutions with metallic ions and solubilizing agents. Upon creating a film, the film is exposed to coherent light for a specific time and then cured. The resulting film has been found to have a metallic surface layer and a metallic subsurface layer (interlayer). The layer separating the metallic layer has a uniform dispersion of small metal particulates within the polymer. The layer below the interlayer has larger metal particulates uniformly distributed within the polymer. By varying the intensity or time of exposure to the coherent light, three-dimensional control of metal formation within the film is provided