Real-time state estimation of laboratory flows

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Earth, Atmospheric, and Planetary Sciences, 2007."June 2007."Includes bibliographical references (p. 51).In this project, we use a real time computer model to simulate a differentially heated laboratory annulus. The laboratory annulus allows us to study chaotic flows typical of the atmosphere. Our objective is to bring the numerical model into close alignment with the laboratory system. Parameter estimation and data assimilation of real time model runs with the tank experiment can be used to improve numerical model fidelity, provided the model operates in real time and the model parameters are in acceptable regimes. We describe how to modify the default configuration of the MITgcm to tackle this new problem. We also run laboratory experiments. Using an iterative process, we update the model parameters (such as diffusion and viscosity), and observe that in at least some regimes, there is excellent agreement between observations and simulations. Much of this effort required the development of infrastructure, which is discussed in this document. Finally, we create and test a complete, real-time system, with data sent across the network from a parallel computer running the numerical model to the laboratory computer, where data assimilation takes place. We further modify the model to allow it to pause mid-run, and restart with the most recent state estimates of velocity and temperature.by Scott Stransky.S.M

A realtime observatory for laboratory simulation of planetary flows

Motivated by the large-scale circulation of the atmosphere and ocean, we develop a system that uses observations from a laboratory analog to constrain, in real time, a numerical simulation of the laboratory flow. This system provides a tool to rapidly prototype new methods for state and parameter estimation, and facilitates the study of prediction, predictability, and transport of geophysical fluids where observations or numerical simulations would not independently suffice. A computer vision system is used to extract measurements of the physical simulation. Observations are used to constrain the model-state of the MIT General Circulation Model in a probabilistic, ensemble based assimilation approach. Using a combination of parallelism, domain decomposition and an efficient scheme to select ensembles of model-states, we show that estimates that effectively track the fluid state can be produced. To the best of our knowledge this is the first such observatory for laboratory analogs of planetary circulation that functions in real time.National Science Foundation (U.S.) (CNS-0540259)National Science Foundation (U.S.) (grant CNS-0540248

Report of the Regional Co-ordination Meeting for the North Sea and Eastern Arctic (RCM NS&EA) 2015

The RCM NS&EA met 31st August - 4th September 2015 at den Haag, Netherlands with 27 participants form 11 member states and autonomous regions attending, including representatives of ICES and the Commission. National correspondents from Spain, UK, Denmark, Lithuania, Germany, Sweden and the Netherlands were present. The meeting was co-chaired by Katja Ringdahl (Sweden) and Alastair Pout (Scotland). The RCM N&SEA considered the recommendations from the 11th Liasion meeting and summaries were presented of the work of expert groups and end users for the 2014-15 period to the plenary session of the meeting. The expert groups included WGCATCH, PGDATA, WKISCON2, WKRDB 2014-01, RDB–SC, STECF and the Zagreb meeting on transversal variables. ICES, as a main end user, provided feedback. A summary was presented of the progress in the regional coordination project (fishPi). This project involves over 40 participants from 12 members states from NS&EA, NA and Baltic regions, two external statistical experts, and ICES. The project has a wide scope of regional cooperation issues including sampling designs, data formats, code lists, PETS, stomach sampling, small scale and recreational sampling, and data quality software production. It has a budget of €400,000, and a one year time line and with a planned completion date of April 2016. A project with identical aims is running in paralleled in the Mediterranean and Black Sea regions The majority of the ToRs of the RCM NS&EA were addressed by three subgroups: one concerned with data analysis, one with the landing obligation, and one with issues particularly related to role and work of national correspondents

Medulloblastoma Exome Sequencing Uncovers Subtype-Specific Somatic Mutations

Medulloblastomas are the most common malignant brain tumors in children1. Identifying and understanding the genetic events that drive these tumors is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma based on transcriptional and copy number profiles2–5. Here, we utilized whole exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas exhibit low mutation rates consistent with other pediatric tumors, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR, and LDB1, novel findings in medulloblastoma. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant but not wild type beta-catenin. Together, our study reveals the alteration of Wnt, Hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic beta-catenin signaling in medulloblastoma

Comprehensive analysis of cancer-associated somatic mutations in class I HLA genes

Detection of somatic mutations in human leukocyte antigen (HLA) genes using whole-exome sequencing (WES) is hampered by the high polymorphism of the HLA loci, which prevents alignment of sequencing reads to the human reference genome. We describe a computational pipeline that enables accurate inference of germline alleles of class I HLA-A, B and C genes and subsequent detection of mutations in these genes using the inferred alleles as a reference. Analysis of WES data from 7,930 pairs of tumor and healthy tissue from the same patient revealed 298 nonsilent HLA mutations in tumors from 266 patients. These 298 mutations are enriched for likely functional mutations, including putative loss-of-function events. Recurrence of mutations suggested that these \u27hotspot\u27 sites were positively selected. Cancers with recurrent somatic HLA mutations were associated with upregulation of signatures of cytolytic activity characteristic of tumor infiltration by effector lymphocytes, supporting immune evasion by altered HLA function as a contributory mechanism in cancer

Mutational heterogeneity in cancer and the search for new cancer genes

Major international projects are now underway aimed at creating a comprehensive catalog of all genes responsible for the initiation and progression of cancer. These studies involve sequencing of matched tumor–normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here, we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false positive findings that overshadow true driver events. Here, we show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumor-normal pairs and discover extraordinary variation in (i) mutation frequency and spectrum within cancer types, which shed light on mutational processes and disease etiology, and (ii) mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and allow true cancer genes to rise to attention

Parallel genome-scale loss of function screens in 216 cancer cell lines for the identification of context-specific genetic dependencies

Using a genome-scale, lentivirally delivered shRNA library, we performed massively parallel pooled shRNA screens in 216 cancer cell lines to identify genes that are required for cell proliferation and/or viability. Cell line dependencies on 11,000 genes were interrogated by 5 shRNAs per gene. The proliferation effect of each shRNA in each cell line was assessed by transducing a population of 11M cells with one shRNA-virus per cell and determining the relative enrichment or depletion of each of the 54,000 shRNAs after 16 population doublings using Next Generation Sequencing. All the cell lines were screened using standardized conditions to best assess differential genetic dependencies across cell lines. When combined with genomic characterization of these cell lines, this dataset facilitates the linkage of genetic dependencies with specific cellular contexts (e.g., gene mutations or cell lineage). To enable such comparisons, we developed and provided a bioinformatics tool to identify linear and nonlinear correlations between these features

Genomic and transcriptomic characterisation of undifferentiated pleomorphic sarcoma of bone

This is an accepted manuscript of an article published by Wiely in The Journal of Pathology on 27/12/2018, available online: https://doi.org/10.1002/path.5176 The accepted version of the publication may differ from the final published version.Undifferentiated pleomorphic sarcoma of bone (UPSb), is a rare primary bone sarcoma that lacks a specific line of differentiation. There is very little information about the genetic alterations leading to tumourigenesis or malignant transformation. Distinguishing between UPSb and other malignant bone sarcomas, including dedifferentiated chondrosarcoma and osteosarcoma, can be challenging due to overlapping features. To explore the genomic and transcriptomic landscape of UPSb tumours, whole-exome sequencing (WES) and RNA Sequencing (RNA-Seq) were performed on UPSb tumours. All tumours lacked hotspot mutations in IDH1/2 132 or 172 codons, thereby excluding the diagnosis of dedifferentiated chondrosarcoma. Recurrent somatic mutations in TP53 were identified in 4/14 samples (29%). Moreover, recurrent mutations in histone chromatin remodelling genes, including H3F3A, ATRX and DOT1L, were identified in 5/14 samples (36%), highlighting the potential role of deregulated chromatin remodelling pathways in UPSb tumourigenesis. The majority of recurrent mutations in chromatin remodelling genes identified here are reported in COSMIC, including the H3F3A G35 and K36 hotspot residues. Copy number alteration analysis identified gains and losses in genes that have been previously altered in UPSb or UPS of soft tissue. Eight somatic gene fusions were identified by RNA-Seq, two of which, CLTC-VMP1 and FARP1-STK24, were reported previously in multiple cancers. Five gene fusions were genomically characterised. Hierarchical clustering analysis, using RNA-Seq data, distinctly clustered UPSb tumours from osteosarcoma and other sarcomas, thus molecularly distinguishing UPSb from other sarcomas. RNA-Seq expression profiling analysis and quantitative RT-PCR showed an elevated expression in FGF23 which can be a potential molecular biomarker in UPSb. To our knowledge, this study represents the first comprehensive WES and RNA-Seq analysis of UPSb tumours revealing novel protein-coding recurrent gene mutations, gene fusions and identifying a potential UPSb molecular biomarker, thereby broadening the understanding of the pathogenic mechanisms and highlighting the possibility of developing novel targeted therapeutics

Report of the Regional Co-ordination Meeting for the North Sea and Eastern Arctic (RCM NS&EA) 2016

The Regional Coordination Meeting NS&EA met in Edinburgh from 5th to 9th September 2016. Thirty four participants from 12 members states, representatives from Commission and ICES were in attendance. The meeting was largely devoted to subgroup work relating to regional sampling, cost sharing models, data needs and the sampling of anadromous and catadromous specie

Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH -Mutant Molecular Profiles

Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance