Single-cell genomic variation induced by mutational processes in cancer

How cell-to-cell copy number alterations that underpin genomic instability1 in human cancers drive genomic and phenotypic variation, and consequently the evolution of cancer2, remains understudied. Here, by applying scaled single-cell whole-genome sequencing3 to wild-type, TP53-deficient and TP53-deficient;BRCA1-deficient or TP53-deficient;BRCA2-deficient mammary epithelial cells (13,818 genomes), and to primary triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSC) cells (22,057 genomes), we identify three distinct 'foreground' mutational patterns that are defined by cell-to-cell structural variation. Cell- and clone-specific high-level amplifications, parallel haplotype-specific copy number alterations and copy number segment length variation (serrate structural variations) had measurable phenotypic and evolutionary consequences. In TNBC and HGSC, clone-specific high-level amplifications in known oncogenes were highly prevalent in tumours bearing fold-back inversions, relative to tumours with homologous recombination deficiency, and were associated with increased clone-to-clone phenotypic variation. Parallel haplotype-specific alterations were also commonly observed, leading to phylogenetic evolutionary diversity and clone-specific mono-allelic expression. Serrate variants were increased in tumours with fold-back inversions and were highly correlated with increased genomic diversity of cellular populations. Together, our findings show that cell-to-cell structural variation contributes to the origins of phenotypic and evolutionary diversity in TNBC and HGSC, and provide insight into the genomic and mutational states of individual cancer cells

Cytomapper: an R/bioconductor package for visualisation of highly multiplexed imaging data

SUMMARY: Highly multiplexed imaging technologies enable spatial profiling of dozens of biomarkers in situ. Here we describe cytomapper, a computational tool written in R, that enables visualisation of pixel- and cell-level information obtained by multiplexed imaging. To illustrate its utility, we analysed 100 images obtained by imaging mass cytometry from a cohort of type 1 diabetes patients. In addition, cytomapper includes a Shiny application that allows hierarchical gating of cells based on marker expression and visualisation of selected cells in corresponding images. AVAILABILITY AND IMPLEMENTATION: The cytomapper package can be installed via https://www.bioconductor.org/packages/release/bioc/html/cytomapper.html. Code for analysis and further instructions can be found at https://github.com/BodenmillerGroup/cytomapper_publication. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online

Energizing the Future: Implementing Intentional Islanding on the Texas Power Grid

As technology evolves and the electric load changes, electric grids need to be modified to accommodate new threats and resources. One such threat is the increase of natural disasters due to climate change. Electrical grids around the globe need to be carefully designed to withstand disasters such as hurricanes, tornadoes, blizzards, fires, and droughts.This paper focuses specifically on the Texas grid, as it is a stand-alone interconnection and has a synthetic model designed in PowerWorld to aid in the development of research. In the event of a natural disaster powerful enough to take out a few sizeable generators in one section of Texas, the whole state is vulnerable to blackout. In order to avoid this, Texas (and all grids) could implement intentional or “adaptive” islanding. The National Academies Report,Enhancing the Resilience of the Nation's Electricity System, describes adaptive islanding as, “The concept [of] predefining how to break apart the system in response to system events, by matching clusters of load and generation.” The following paper includes simulations of such on the synthetic grid modeled in PowerWorld. The results show that islanding the Texas grid successfully protects the state from a complete blackout, and maintains full functionality for both halves in the absence of an event.Therefore, this paper concludes that all grids should prepare an islanding plan in case of a natural disaster and coordinate with utilities to plan transmission lines which lend themselves to islanding

Energizing the Future: Implementing Intentional Islanding on the Texas Power Grid

As technology evolves and the electric load changes, electric grids need to be modified to accommodate new threats and resources. One such threat is the increase of natural disasters due to climate change. Electrical grids around the globe need to be carefully designed to withstand disasters such as hurricanes, tornadoes, blizzards, fires, and droughts.This paper focuses specifically on the Texas grid, as it is a stand-alone interconnection and has a synthetic model designed in PowerWorld to aid in the development of research. In the event of a natural disaster powerful enough to take out a few sizeable generators in one section of Texas, the whole state is vulnerable to blackout. In order to avoid this, Texas (and all grids) could implement intentional or “adaptive” islanding. The National Academies Report,Enhancing the Resilience of the Nation's Electricity System, describes adaptive islanding as, “The concept [of] predefining how to break apart the system in response to system events, by matching clusters of load and generation.” The following paper includes simulations of such on the synthetic grid modeled in PowerWorld. The results show that islanding the Texas grid successfully protects the state from a complete blackout, and maintains full functionality for both halves in the absence of an event.Therefore, this paper concludes that all grids should prepare an islanding plan in case of a natural disaster and coordinate with utilities to plan transmission lines which lend themselves to islanding

Clonal transcriptomics identifies mechanisms of chemoresistance and empowers rational design of combination therapies

Tumour heterogeneity is thought to be a major barrier to successful cancer treatment due to the presence of drug resistant clonal lineages. However, identifying the characteristics of such lineages that underpin resistance to therapy has remained challenging. Here, we utilise clonal transcriptomics with WILD-seq; Wholistic Interrogation of Lineage Dynamics by sequencing, in mouse models of triple-negative breast cancer (TNBC) to understand response and resistance to therapy, including BET bromodomain inhibition and taxane-based chemotherapy. These analyses revealed oxidative stress protection by NRF2 as a major mechanism of taxane resistance and led to the discovery that our tumour models are collaterally sensitive to asparagine deprivation therapy using the clinical stage drug L-asparaginase after frontline treatment with docetaxel. In summary, clonal transcriptomics with WILD-seq identifies mechanisms of resistance to chemotherapy that are also operative in patients and pin points asparagine bioavailability as a druggable vulnerability of taxane-resistant lineages

Die Umsetzung des neuen überregionalen Lehrplans (2014) im Fremdsprachenunterricht an finnischen Grundschulen : Eine Umfrage an Lehrende zur Übergangszeit der Lehrplanreform

Tässä tutkielmassa tarkasteltiin yläkoulun kieltenopettajien näkemyksiä vuonna 2014 julkaistuista uusista peruskoulun opetussuunnitelman perusteista sekä laajemmin opetussuunnitelmauudistuksen vaikutuksesta koulutyöhön. Uutta opetussuunnitelmaa ja vuonna 2012 julkaistua uutta peruskoulun tuntijakoa kohtaan on esitetty ennalta kritiikkiä etenkin kielten osalta. Uuden tuntijaon myötä yläkoulusta alakouluun siirtyy mm. yksi A-kielen vuosiviikkotunti ja ruotsin kielen alkamista varhaistetaan alkamaan kuudennelta luokalta. Uudistukset toteutetaan siirtymäajan mukaisesti, jossa alakoulu on siirtynyt opetussuunnitelmaan ja uuteen tuntijakoon syksyllä 2016 ja yläkoulu siirtyy niihin porrastetusti vuosien 2017-2019 aikana. Tutkimuksen aineisto kerättiin opettajilta kyselyn ja kahden haastattelun avulla. Kyselyiden analysointimenetelmänä käytettiin sisällönanalyysin sekä laadullisia että määrällisiä menetelmiä. Siten aineistosta voitiin laadullisen analysoinnin lisäksi selvittää, mitkä teemat toistuivat opettajien vastauksissa. Haastatteluilla kerätyillä tiedoilla täydennettiin ja syvennettiin kyselyiden pohjalta tehtyjä johtopäätöksiä. Tutkimuksella voitiin tuottaa tietoa opettajien näkemyksistä opetussuunnitelma-uudistuksen siirtymäajan aikana. Tärkeimpiä tuloksia olivat selkeät erot niin opettajien aktiivisuudessa paikallisessa opetussuunnitelmatyössä kuin myös asenteissa uutta opetussuunnitelmaa kohtaan. Näiden erojen syntyyn vaikuttivat osaltaan opetuksen järjestäjän vapaudet paikallisesti päätettävissä asioissa sekä yksittäisten opettajien vapaus toteuttaa omaa opetustaan. Toisaalta opettajien ammattitaito korostui opetuksen räätälöinnissa tarpeen mukaan ja opetusmateriaalien kriittisessä arvioinnissa, toisaalta aineistossa ilmeni kritiikkiä toisten opettajien osallistumattomuutta kohtaan sekä opetussuunnitelmauudistuksen merkityksen kyseenalaistamista. Opettajien tukemisessa todettiin olevan etenkin käytännön toteutukseen, arviointiin ja tietotekniikkaan sekä sen hallintaan liittyen puutteita. Etenkin vähemmän valmistelutyöhön osallistuneiden tukemisen ja resurssien riittävyyden todettiin olevan ensiarvoisen tärkeitä uudistuksen toteutumisen kannalta. Lisäksi tutkimuksessa ilmeni viitteitä siitä, että siirtymävaiheessa keskitytään sisällön ohella vahvasti uudistuksen ulkoisiin muutoksiin, kuten tuntijakoon, digitalisaatioon, yhteistyöhön ja arviointiin. Esimerkiksi kielten korostumista opetussuunnitelmassa tuotiin vain vähän esiin, kun taas muutoksia kielten tuntijaossa kritisoitiin vahvasti. Kieltenopettajat olivat huolissaan esimerkiksi peruskoulun oppilaiden kielitaidon kaventumisesta uuden tuntijaon myötä, toisaalta kritiikin taustalla voitiin todeta olevan osittain myös pelkoa oman työn aseman heikkenemisestä. Sisällöllisistä asioista tuotiin esiin mm. oppilaan aseman vahvistumista, erilaisia työtapoja sekä useita tavoitteita

scQUEST: Quantifying tumor ecosystem heterogeneity from mass or flow cytometry data

With mass and flow cytometry, millions of single-cell profiles with dozens of parameters can be measured to comprehensively characterize complex tumor ecosystems. Here, we present scQUEST, an open-source Python library for cell type identification and quantification of tumor ecosystem heterogeneity in patient cohorts. We provide a step-by-step protocol on the application of scQUEST on our previously generated human breast cancer single-cell atlas using mass cytometry and discuss how it can be adapted and extended for other datasets and analyses. For complete details on the use and execution of this protocol, please refer to Wagner et al. (2019)