The tumor suppressor CIC directly regulates MAPK pathway genes via histone deacetylation

Abstract Oligodendrogliomas are brain tumors accounting for approximately 10% of all central nervous system cancers. CIC is a transcription factor that is mutated in most patients with oligodendrogliomas; these mutations are believed to be a key oncogenic event in such cancers. Analysis of the Drosophila melanogaster ortholog of CIC, Capicua, indicates that CIC loss phenocopies activation of the EGFR/RAS/MAPK pathway, and studies in mammalian cells have demonstrated a role for CIC in repressing the transcription of the PEA3 subfamily of ETS transcription factors. Here, we address the mechanism by which CIC represses transcription and assess the functional consequences of CIC inactivation. Genome-wide binding patterns of CIC in several cell types revealed that CIC target genes were enriched for MAPK effector genes involved in cell-cycle regulation and proliferation. CIC binding to target genes was abolished by high MAPK activity, which led to their transcriptional activation. CIC interacted with the SIN3 deacetylation complex and, based on our results, we suggest that CIC functions as a transcriptional repressor through the recruitment of histone deacetylases. Independent single amino acid substitutions found in oligodendrogliomas prevented CIC from binding its target genes. Taken together, our results show that CIC is a transcriptional repressor of genes regulated by MAPK signaling, and that ablation of CIC function leads to increased histone acetylation levels and transcription at these genes, ultimately fueling mitogen-independent tumor growth. Significance: Inactivation of CIC inhibits its direct repression of MAPK pathway genes, leading to their increased expression and mitogen-independent growth. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4114/F1.large.jpg. Cancer Res; 78(15); 4114–25. ©2018 AACR.</jats:p

Advancing Biomedical Image Retrieval: Development and Analysis of a Test Collection

Objective: Develop and analyze results from an image retrieval test collection. Methods: After participating research groups obtained and assessed results from their systems in the image retrieval task of Cross-Language Evaluation Forum, we assessed the results for common themes and trends. In addition to overall performance, results were analyzed on the basis of topic categories (those most amenable to visual, textual, or mixed approaches) and run categories (those employing queries entered by automated or manual means as well as those using visual, textual, or mixed indexing and retrieval methods). We also assessed results on the different topics and compared the impact of duplicate relevance judgments. Results: A total of 13 research groups participated. Analysis was limited to the best run submitted by each group in each run category. The best results were obtained by systems that combined visual and textual methods. There was substantial variation in performance across topics. Systems employing textual methods were more resilient to visually oriented topics than those using visual methods were to textually oriented topics. The primary performance measure of mean average precision (MAP) was not necessarily associated with other measures, including those possibly more pertinent to real users, such as precision at 10 or 30 images. Conclusions: We developed a test collection amenable to assessing visual and textual methods for image retrieval. Future work must focus on how varying topic and run types affect retrieval performance. Users' studies also are necessary to determine the best measures for evaluating the efficacy of image retrieval system

Incidence of and Risk Factors for Sick Sinus Syndrome in the General Population

AbstractBackgroundLittle is known about the incidence of and risk factors for sick sinus syndrome (SSS), a common indication for pacemaker implantation.ObjectivesThis study sought to describe the epidemiology of SSS.MethodsThis analysis included 20,572 participants (mean baseline age 59 years, 43% male) in the ARIC (Atherosclerosis Risk In Communities) study and the CHS (Cardiovascular Health Study), who at baseline were free of prevalent atrial fibrillation and pacemaker therapy, had a heart rate of ≥50 beats/min unless using beta blockers, and were identified as of white or black race. Incident SSS cases were identified by hospital discharge International Classification of Disease-revision 9-Clinical Modification code 427.81 and validated by medical record review.ResultsDuring an average 17 years of follow-up, 291 incident SSS cases were identified (unadjusted rate 0.8 per 1,000 person-years). Incidence increased with age (hazard ratio [HR]: 1.73; 95% confidence interval [CI]: 1.47 to 2.05 per 5-year increment), and blacks had a 41% lower risk of SSS than whites (HR: 0.59; 95% CI: 0.37 to 0.98). Incident SSS was associated with greater baseline body mass index, height, N-terminal pro–B-type natriuretic peptide, and cystatin C, with longer QRS interval, with lower heart rate, and with prevalent hypertension, right bundle branch block, and cardiovascular disease. We project that the annual number of new SSS cases in the United States will increase from 78,000 in 2012 to 172,000 in 2060.ConclusionsBlacks have a lower risk of SSS than whites, and several cardiovascular risk factors were associated with incident SSS. With the aging of the population, the number of Americans with SSS will increase dramatically over the next 50 years

Neutral Evolution as Diffusion in phenotype space: reproduction with mutation but without selection

The process of `Evolutionary Diffusion', i.e. reproduction with local mutation but without selection in a biological population, resembles standard Diffusion in many ways. However, Evolutionary Diffusion allows the formation of local peaks with a characteristic width that undergo drift, even in the infinite population limit. We analytically calculate the mean peak width and the effective random walk step size, and obtain the distribution of the peak width which has a power law tail. We find that independent local mutations act as a diffusion of interacting particles with increased stepsize.Comment: 4 pages, 2 figures. Paper now representative of published articl

Development of a Fuel Quantity based Engine Control Unit Software Architecture

&nbsp; &nbsp;Conventionally diesel engines are controlled in open loop with maps based on engine speed and throttle position wherein fuel quantity is indirectly fixed using the rail pressure and injection duration maps with engine speed and throttle position as the independent variables which are measured by the respective sensors. In this work an engine control unit (ECU) software architecture where fuel quantity is directly specified in relation to the driver demand was implemented by modifying the control logic of a throttle position based framework. A desired fuel quantity for a given engine speed and throttle position was mapped from base line experiments on the reference engine. Injection durations and rail pressure required for this quantity was mapped on a fuel injector calibration test bench. The final calculation of injection duration in the new architecture is calculated using the fuel injector model. This enables determination of fuel quantity injected at any moment which directly indicates the torque produced by the engine at a given speed enabling smoke limited fuelling calculations and easing the implementation of control functions like all-speed governing

Stochastic Cellular Automata Model for Stock Market Dynamics

In the present work we introduce a stochastic cellular automata model in order to simulate the dynamics of the stock market. A direct percolation method is used to create a hierarchy of clusters of active traders on a two dimensional grid. Active traders are characterised by the decision to buy, (+1), or sell, (-1), a stock at a certain discrete time step. The remaining cells are inactive,(0). The trading dynamics is then determined by the stochastic interaction between traders belonging to the same cluster. Most of the stylized aspects of the financial market time series are reproduced by the model.Comment: 17 pages and 7 figure

Parameter Estimation Error Dependency on the Acquisition Protocol in Diffusion Kurtosis Imaging

Mono-exponential kurtosis model is routinely fitted on diffusion weighted, magnetic resonance imaging data to describe non-Gaussian diffusion. Here, the purpose was to optimize acquisitions for this model to minimize the errors in estimating diffusion coefficient and kurtosis. Similar to a previous study, covariance matrix calculations were used, and coefficients of variation in estimating each parameter of this model were calculated. The acquisition parameter, b values, varied in discrete grids to find the optimum ones that minimize the coefficient of variation in estimating the two non-Gaussian parameters. Also, the effect of variation of the target values on the optimized values was investigated. Additionally, the results were benchmarked with Monte Carlo noise simulations. Simple correlations were found between the optimized b values and target values of diffusion and kurtosis. For small target values of the two parameters, there is higher chance of having significant errors; this is caused by maximum b value limits imposed by the scanner than the mathematical bounds. The results here, cover a wide range of parameters D and K so that they could be used in many directionally averaged diffusion weighted cases such as head and neck, prostate, etc

The Middle Way: East Asian masters students’ perceptions of critical argumentation in U.K. universities.

The paper explores the learning experiences of East Asian masters students in dealing with Western academic norms of critical thinking in classroom debate and assignment writing. The research takes a cultural approach, and employs grounded theory and case study methodology, the aims being for students to explain their perceptions of their personal learning journeys. The data suggest that the majority of students interviewed rejected full academic acculturation into Western norms of argumentation. They instead opted for a ‘Middle Way’ that synergizes the traditional cultural academic values held by many East Asian students with those elements of Western academic norms that are perceived to be aligned with these. This is a relatively new area of research which represents a challenge for British lecturers and students