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-κB 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 expanded-potential 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 GBM

Active learning and optimal climate policy

This paper develops a climate-economy model with uncertainty, irreversibility, and active learning. Whereas previous papers assume learning from one observation per period, or experiment with control variables to gain additional information, this paper considers active learning from investment in monitoring, specifically in improved observations of the global mean temperature. We find that the decision maker invests a significant amount of money in climate research, far more than the current level, in order to increase the rate of learning about climate change. This helps the decision maker make improved decisions. The level of uncertainty decreases more rapidly in the active learning model than in the passive learning model with only temperature observations. As the uncertainty about climate change is smaller, active learning reduces the optimal carbon tax. The greater the risk, the larger is the effect of learning. The method proposed here is applicable to any dynamic control problem where the quality of monitoring is a choice variable, for instance, the precision at which we observe GDP, unemployment, or the quality of education

Biomechanical spinal growth modulation and progressive adolescent scoliosis – a test of the 'vicious cycle' pathogenetic hypothesis: Summary of an electronic focus group debate of the IBSE

There is no generally accepted scientific theory for the causes of adolescent idiopathic scoliosis (AIS). As part of its mission to widen understanding of scoliosis etiology, the International Federated Body on Scoliosis Etiology (IBSE) introduced the electronic focus group (EFG) as a means of increasing debate on knowledge of important topics. This has been designated as an on-line Delphi discussion. The text for this debate was written by Dr Ian A Stokes. It evaluates the hypothesis that in progressive scoliosis vertebral body wedging during adolescent growth results from asymmetric muscular loading in a "vicious cycle" (vicious cycle hypothesis of pathogenesis) by affecting vertebral body growth plates (endplate physes). A frontal plane mathematical simulation tested whether the calculated loading asymmetry created by muscles in a scoliotic spine could explain the observed rate of scoliosis increase by measuring the vertebral growth modulation by altered compression. The model deals only with vertebral (not disc) wedging. It assumes that a pre-existing scoliosis curve initiates the mechanically-modulated alteration of vertebral body growth that in turn causes worsening of the scoliosis, while everything else is anatomically and physiologically 'normal' The results provide quantitative data consistent with the vicious cycle hypothesis. Dr Stokes' biomechanical research engenders controversy. A new speculative concept is proposed of vertebral symphyseal dysplasia with implications for Dr Stokes' research and the etiology of AIS. What is not controversial is the need to test this hypothesis using additional factors in his current model and in three-dimensional quantitative models that incorporate intervertebral discs and simulate thoracic as well as lumbar scoliosis. The growth modulation process in the vertebral body can be viewed as one type of the biologic phenomenon of mechanotransduction. In certain connective tissues this involves the effects of mechanical strain on chondrocytic metabolism a possible target for novel therapeutic intervention

Beyond equilibrium climate sensitivity

ISSN:1752-0908ISSN:1752-089

Investigating the psychometric properties of the Suicide Stroop Task

Behavioral measures are increasingly used to assess suicidal thoughts and behaviors. Some measures, such as the Suicide Stroop Task, have yielded mixed findings in the literature. An understudied feature of these behavioral measures has been their psychometric properties, which may affect the probability of detecting significant effects and reproducibility. In the largest investigation of its kind, we tested the internal consistency and concurrent validity of the Suicide Stroop Task in its current form, drawing from seven separate studies (N = 875 participants, 64% female, aged 12 to 81 years). Results indicated that the most common Suicide Stroop scoring approach, interference scores, yielded unacceptably low internal consistency (rs = -.09-.13) and failed to demonstrate concurrent validity. Internal consistency coefficients for mean reaction times (RTs) to each stimulus type ranged from rs = .93-.94. All scoring approaches for suicide-related interference demonstrated poor classification accuracy (AUCs = .52-.56) indicating that scores performed near chance in their ability to classify suicide attempters from nonattempters. In the case of mean RTs, we did not find evidence for concurrent validity despite our excellent reliability findings, highlighting that reliability does not guarantee a measure is clinically useful. These results are discussed in the context of the wider implications for testing and reporting psychometric properties of behavioral measures in mental health research.status: publishe