Enzymatic degradation ofRNAcauses widespread protein aggregation in cell and tissue lysates

Most proteins in cell and tissue lysates are soluble. We show here that in lysate from human neurons, more than 1,300 proteins are maintained in a soluble and functional state by association with endogenous RNA, as degradation of RNA invariably leads to protein aggregation. The majority of these proteins lack conventional RNA‐binding domains. Using synthetic oligonucleotides, we identify the importance of nucleic acid structure, with single‐stranded pyrimidine‐rich bulges or loops surrounded by double‐stranded regions being particularly efficient in the maintenance of protein solubility. These experiments also identify an apparent one‐to‐one protein‐nucleic acid stoichiometry. Furthermore, we show that protein aggregates isolated from brain tissue from Amyotrophic Lateral Sclerosis patients can be rendered soluble after refolding by both RNA and synthetic oligonucleotides. Together, these findings open new avenues for understanding the mechanism behind protein aggregation and shed light on how certain proteins remain soluble

Microglia promote glioblastoma via mTOR-mediated immunosuppression of the tumour microenvironment

Tumour-associated microglia/macrophages (TAM) are the most numerous non-neoplastic populations in the tumour microenvironment in glioblastoma multiforme (GBM), the most common malignant brain tumour in adulthood. The mTOR pathway, an important regulator of cell survival/proliferation, is upregulated in GBM, but little is known about the potential role of this pathway in TAM. Here, we show that GBM-initiating cells induce mTOR signalling in the microglia but not bone marrow-derived macrophages in both in vitro and in vivo GBM mouse models. mTOR-dependent regulation of STAT3 and NF-jB activity promotes an immunosuppressive microglial phenotype. This hinders effector T-cell infiltration, proliferation and immune reactivity, thereby contributing to tumour immune evasion and promoting tumour growth in mouse models. The translational value of our results is demonstrated in whole transcriptome datasets of human GBM and in a novel in vitro model, whereby expandedpotential stem cells (EPSC)-derived microglia-like cells are conditioned by syngeneic patient-derived GBM-initiating cells. These results raise the possibility that microglia could be the primary target of mTOR inhibition, rather than the intrinsic tumour cells in GB

Black Holes as Effective Geometries

Gravitational entropy arises in string theory via coarse graining over an underlying space of microstates. In this review we would like to address the question of how the classical black hole geometry itself arises as an effective or approximate description of a pure state, in a closed string theory, which semiclassical observers are unable to distinguish from the "naive" geometry. In cases with enough supersymmetry it has been possible to explicitly construct these microstates in spacetime, and understand how coarse-graining of non-singular, horizon-free objects can lead to an effective description as an extremal black hole. We discuss how these results arise for examples in Type II string theory on AdS_5 x S^5 and on AdS_3 x S^3 x T^4 that preserve 16 and 8 supercharges respectively. For such a picture of black holes as effective geometries to extend to cases with finite horizon area the scale of quantum effects in gravity would have to extend well beyond the vicinity of the singularities in the effective theory. By studying examples in M-theory on AdS_3 x S^2 x CY that preserve 4 supersymmetries we show how this can happen.Comment: Review based on lectures of JdB at CERN RTN Winter School and of VB at PIMS Summer School. 68 pages. Added reference

Kerr/CFT, dipole theories and nonrelativistic CFTs

We study solutions of type IIB supergravity which are SL(2,R) x SU(2) x U(1)^2 invariant deformations of AdS_3 x S^3 x K3 and take the form of products of self-dual spacelike warped AdS_3 and a deformed three-sphere. One of these backgrounds has been recently argued to be relevant for a derivation of Kerr/CFT from string theory, whereas the remaining ones are holographic duals of two-dimensional dipole theories and their S-duals. We show that each of these backgrounds is holographically dual to a deformation of the DLCQ of the D1-D5 CFT by a specific supersymmetric (1,2) operator, which we write down explicitly in terms of twist operators at the free orbifold point. The deforming operator is argued to be exactly marginal with respect to the zero-dimensional nonrelativistic conformal (or Schroedinger) group - which is simply SL(2,R)_L x U(1)_R. Moreover, in the supergravity limit of large N and strong coupling, no other single-trace operators are turned on. We thus propose that the field theory duals to the backgrounds of interest are nonrelativistic CFTs defined by adding the single Schroedinger-invariant (1,2) operator mentioned above to the original CFT action. Our analysis indicates that the rotating extremal black holes we study are best thought of as finite right-moving temperature (non-supersymmetric) states in the above-defined supersymmetric nonrelativistic CFT and hints towards a more general connection between Kerr/CFT and two-dimensional non-relativistic CFTs.Comment: 48+8 pages, 4 figures; minor corrections and references adde

Anti-cancer effects and mechanism of actions of aspirin analogues in the treatment of glioma cancer

INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-κB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS – 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma

Comparative epigenetic analysis of tumour initiating cells and syngeneic EPSC-derived neural stem cells in glioblastoma

Epigenetic mechanisms which play an essential role in normal developmental processes, such as self-renewal and fate specification of neural stem cells (NSC) are also responsible for some of the changes in the glioblastoma (GBM) genome. Here we develop a strategy to compare the epigenetic and transcriptional make-up of primary GBM cells (GIC) with patient-matched expanded potential stem cell (EPSC)-derived NSC (iNSC). Using a comparative analysis of the transcriptome of syngeneic GIC/iNSC pairs, we identify a glycosaminoglycan (GAG)-mediated mechanism of recruitment of regulatory T cells (Tregs) in GBM. Integrated analysis of the transcriptome and DNA methylome of GBM cells identifies druggable target genes and patient-specific prediction of drug response in primary GIC cultures, which is validated in 3D and in vivo models. Taken together, we provide a proof of principle that this experimental pipeline has the potential to identify patient-specific disease mechanisms and druggable targets in GBM

c-MYC overexpression induces choroid plexus papillomas through a T-cell mediated inflammatory mechanism

Medical Research Council UK (G0800020, 85704)Centre of Excellence award from Brain Tumour ResearchBritish Neuropathological Society gran