522 research outputs found
A New Performance : Exploring the possibilities and difficulties related to the inclusion of the voice in violin playing
No full textThis thesis seeks to explore the many possibilities that lie within the incorporation of the voice alongside playing the violin. This territory is still very unknown, and the author believes that many new artistic possibilities and tools are yet to be discovered.The attempts made seek to understand the difficulties and limitations of the incorporation of the voice, while discovering its bountiful treasures."Terje Vigen" by Ivar BøksleArrangement by Olav Eirik LølandViolin and vocal - Olav Eirik LølandKonserten börjar efter två minuter.</p
Seismic stratigraphy of the Eirik Drift, southern Greenland margin: tracking North Atlantic bottom water flow since the Eocene
No full textEirik Drift is a detached giant elongated drift which extends a total length of 360 km, located off the southern margin of Greenland, approximately 100 km south of Cape Farewell, Greenland in the North Atlantic Ocean. Eirik Drift is controlled by the influence of deep contour currents resulting from the movement of the deep Western Boundary Undercurrent (WBUC). The WBUC is a dominant constituent of North Atlantic Deep Water (NADW), the lower limb of the global thermohaline circulation (THC) system, which transports sediments, nutrients, and temperature regimes across the Atlantic Ocean. Understanding the origins, distribution, and development of Eirik Drift is critical to reliably placing proxy data into a larger context of sedimentation, ocean circulation, global climate and using these histories as analogs of recent changes in global climate. This study examined the seismic stratigraphy of Eirik Drift using multi-channel seismic (MCS) profiles collected in the summer of 2002 during cruise KN166-14 of the R/V Knorr and tied it to the lithology, sedimentation rates, and downhole data of four Ocean Drilling sites: Ocean Drilling Program (ODP) Leg 105 Site 646, and International Ocean Discovery Program (IODP) Expedition Sites U1305, U1306 and U1307. This analysis concludes that drift building began at 7.5 Ma and continues to the present. The drift’s morphology shows significant sedimentation and drift building occurred throughout the Pliocene, then slowed during the Pleistocene, as shown through mapped patterns of sediment accumulation in time and space. Over this time, the WBUC has migrated with varying intensity (i.e., modifications in velocity and/or and buoyancy relating to climate regimes), modifying the shape and distribution of the drift, due to measured changes in sediment supply, ocean circulation, and atmospheric conditions. This finding is consistent with other measurements and models of the history of WBUC and North Atlantic Ocean circulation and atmospheric conditions.M.S.Includes bibliographical reference
Tracking deep-water flow on Eirik drift over the past 160 kyr: linking deep-water changes to freshwater fluxes
No full textThis dissertation uses surface and deep ocean proxies to understand changes in North Atlantic deep-water production associated with periods of increased freshwater input throughout the Late Pleistocene and Holocene. Coring sites on Eirik Drift have long-term sedimentation rates exceeding 15 cm/kyr., allowing for paleoceanographic reconstructions on Milankovitch and millennial time scales.
The transition from glacial North Atlantic Intermediate Water (gNAIW) of marine isotope chron (MIC) 2 to North Atlantic Deep Water (NADW) during the Holocene is examined in Chapter 1. Early Holocene (9000-10,500 ka), sedimentation rates in core 21GGC (3471 m) are >100 cm/kyr., indicating gNAIW winnowed upstream glacial sediments, depositing at 21GGC. Enhanced sediment deposition persisted until ~9ka when long-term rates leveled off at 40 cm/kyr., indicating NADW density had stabilized. From 8.6 to 8.2 ka, catastrophic drainage of glacial Lake Agassiz poured freshwater into the North Atlantic disrupting deep-ocean circulation.
Chapter 2 focuses on the past 160 kyr at Site 1306 (2272 m) on the Eirik Drift where highest sedimentation rates occurred during MIC 2- 5d. Mean sortable silt (SS) and ?18O of N. pachyderma (s) are inversely related during this interval, indicating that changes in surface conditions above the Eirik Drift are propagated into the deep ocean. During the past 40 kyr., SS decreases are concomitant with instances of surface ocean freshening. These intervals correlate with Heinrich Events, suggesting that massive ice flows released
from the continents altered deep ocean circulation.
The final chapter examines deep-ocean response during Terminations 1 and 2. Higher insolation forcing across Termination 2 is postulated to promote rapid melting of continental glaciers, leaving little opportunity for continental storage of freshwater. Conversely, lower insolation across Termination 1 allowed continental ice to linger, allowing for the routing and rapid release of freshwater creating abrupt climate reversals (H1, YD and 8.2 kyr Event). Deep-ocean circulation during MIC 5e loses buoyancy in a fashion similar to the Holocene; however, maximum flow velocities are curtailed for ~7 kyr after the onset of interglacial conditions. This lag is best explained by the melting of Greenland into areas of NCW convection due to increased insolation forcing.Ph.D.Includes bibliographical references.by Samuel Straker Henderso
Unravelling haematopoietic stem cell dysfunction in isolated Del(5q) myelodysplastic syndromes
No full textMyelodysplastic syndromes (MDS) represent a heterogeneous group of haematological malignancies. A subgroup of MDS patients are characterized by heterozygous deletion of the long arm of chromosome 5, Del(5q), as the only karyotypic abnormality. The commonly deleted region (CDR) on chromosome 5 contains approximately forty-two genes and haploinsufficiency of one or more of these genes is thought to be the basis for Del(5q) MDS pathogenesis.
The 5q deletion originates in the Hematopoietic Stem Cell (HSC) compartment and Del(5q) HSCs have a clonal advantage, outcompeting healthy HSCs in the bone marrow of patients. Although they have a competitive advantage in situ, Del(5q) HSCs perform poorly in functional stem cell assays in vitro and in vivo.
A mouse model of Del(5q) MDS, the Cd74-Nid67 model, carries a heterozygous deletion of eight genes located within the CDR. Cd74-Nid67 haploinsufficiency causes macrocytic anaemia and bone marrow dysplasia in mice. However, the impact of Cd74-Nid67 haploinsufficiency on HSC function has not previously been investigated.
The results presented, herein, demonstrate that haploinsufficiency of Cd74-Nid67 has a significant impact on HSC self-renewal and repopulation potential. Furthermore, two genes within this region, Rps14 and Rbm22, are identified as likely candidates responsible for Cd74-Nid67 HSC dysfunction. Finally, we demonstrate that Cd74-Nid67 HSC dysfunction is driven by a P53-dependent mechanism.
This study provides important insights into the mechanistic basis for disease development and propagation, which may facilitate the development of improved therapeutic avenues for Del(5q) MDS patients
Investigating the specific roles of the growth factor kit ligand in the regulation of murine haematopoiesis
No full textCharacterisation and targeting of stem cells in myelodysplastic syndromes
No full textUnderstanding which cells within a cancer are responsible for its initiation and propagation is vital if we are to achieve cure. If cancer stem cells are the only population able to sustain a tumour long term, designing therapeutic strategies to target this population will give medical science the best chance of long-term cure. Significant controversy remains over the existence of cancer stem cells, predominantly due to the lack of a sensitive human cancer stem cell assay. This thesis investigates whether two haematological malignancies, myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML) can only be driven by rare and distinct cancer stem cells. We have demonstrated that low and intermediate-1 risk MDS is driven solely by the stem cell (Lin- CD34+ CD38- CD90+ CD45RA-) by developing a novel genetic approach, tracing all somatic mutations and karyotypic abnormalities back to this population. Prior to this study, very little was known about the clonal architecture of CMML. By performing detailed phenotypic, functional, molecular and genetic analysis of patients with CMML, we were able to demonstrate that the most likely candidate driver cell in these patients was also the stem cell rather than any of the down-stream progenitors. Currently, effective therapeutic strategies for MDS or CMML are very limited. Allogeneic stem cell transplantation is the only potential cure and not suitable for most patients. Cancer stem cells, including MDS stem cells are known to be highly quiescent and selectively resistant to therapy. Having demonstrated that both MDS and CMML were driven by stem cells, we developed a novel therapeutic targeting strategy. Using the thrombopoietin receptor agonist, Romiplostim, we were able to activate stem cells and enhance their subsequent sensitivity to chemotherapy dramatically. This approach may facilitate improved remission rates and prevent cancer stem cell driven relapse in many diseases
The emergence and early fate decisions of stem and progenitor cells in the haematopoietic system
No full textThe alternative road map describes the separation of lympho-myeloid and myeloid-megakaryocyte-erythroid (myeloid-Mk-E) lineages as the earliest haematopoietic commitment event. However, a number of aspects of this lineage restriction process remain poorly understood. Herein this work identified a lympho-myeloid restricted progenitor in the embryo, which resembles the adult LMPP, and demonstrated that lymphoid lineage restriction is initiated prior to definitive haematopoiesis, much earlier than previously appreciated. In vivo fate mapping showed that lympho-myeloid progenitors significantly contribute to steady state myelopoiesis in the embryo. The early thymic progenitor (ETP) as most primitive cell in the thymus was characterised and demonstrated to sustain B, T and myeloid but not Mk potentials at the single cell level. The ETP therefore largely resembles the cellular properties of lympho-myeloid progenitors in bone marrow and foetal liver, which points to these cells as candidate thymus seeding progenitors (TSP). Furthermore the existence of a putative Mk progenitor was explored within the LSKCD150+CD48+Gata1pos compartment of a Gata1 reporter mouse providing the basis for a future prospective characterisation. Finally, this work evaluated the earliest lineage restriction of von Willebrand factor (Vwf)-EGFP+ and EGFP- haematopoietic stem cells (HSCs) through in vitro paired daughter fate mapping. Single Vwf+ HSCs showed heterogeneous Mk priming and more frequently sustained Mk potential after cell division. Moreover, analysis of lineage priming between daughter cells revealed the asymmetric expression of key lineage determinants and stem cell regulators, which might be employed as reporters for future fate mapping studies
Unravelling the molecular and cellular mechanisms of fetal B cell lymphopoiesis to help understand childhood leukaemia
No full textChildhood Leukaemia accounts for nearly one in three of all childhood cancers, with approximately 400 cases diagnosed in the UK every year. Initial genetic lesions in paediatric and infant B cell leukaemias occur in utero in fetal haematopoietic progenitors. Despite the importance of understanding fetal B cell lymphopoiesis in relation to the aetiology of leukaemia, fetal B cell development remains poorly characterised. We hypothesised that by understanding and characterising murine fetal B cell lymphopoiesis, we would gain insights into the development of childhood leukaemias. In chapter III of this thesis I show that the first immune restricted cells with B cell potential in the mouse emerge in the E9.5 vascular plexus of the yolk sac. Subsequently, in chapter IV, I use a Mb1-cre fate mapping approach to show that progenitors which are entirely restricted to the B cell lineage can be detected as early as E12.5 in the fetal liver (FL), prior to the cell surface expression of CD19. In chapter V, I investigate B cell progenitors in the E14.5 FL, applying an advanced B cell staging originally developed for the adult bone marrow, modified to include the key lymphoid cytokine receptors IL-7Rα, KIT and FLT3. I identify and functionally and molecularly characterise a rare CD19+ B cell progenitor that expresses FLT3 and peaks in frequency in late gestation embryos. I further show that FLT3+ CD19+ adult Pro B cells demonstrate an increased engraftment when transplanted into recipient mice compared to CD19+FLT3- Pro B cells. Finally in chapter VI, I apply our new understanding of fetal B cell lymphopoiesis to characterise B cell progenitors in a mouse that expresses the TEL-AML1 translocation, an oncogene associated with 25% of paediatric B cell leukaemias. We find that the novel FLT3+ CD19+ ProB cell progenitor identified here is expanded in the fetal liver of E14.5 TEL-AML1 embryos, giving a new developmental insight into the functional impact of this oncogene
Using Author Profiling to Determine the Age Group of an Author
No full textDenne masteroppgaven utforsker hvordan fastslå aldersgruppen til en forfatter. I hovedsak om forfatteren er et barn, som vil si under 18 år, eller voksen, 25 år og oppover. Videre er målet å undersøke hvilke tekstlige trekk som best korrelerer med alderen til en forfatter, over flere genrer. Til slutt, vil vi utforske om det vil være tilstrekkelig å kun bruke en felles modell for å predikere alderen over flere domener, eller om hver enkelt genre trenger en individuell modell. For å få svar på disse spørsmålene, har datasett fra tidligere forsking innenfor feltet forfatterprofilering, blitt samlet inn. Disse datasettene inneholder bloggdata, sosial mediatekster og Twitterdata. Videre har flere eksperimenter blitt utført på disse datasettene, der vi brukte maskinlærings algoritmer ofte brukt til klassifisering, samt ofte brukte språkgjenkjennelsesmetoder. Eksperimentene som ble utført ble gjort på individuelle datasett, i tillegg til kombinerte datasett.
Resultatene viser at det er mulig å fastslå aldersgruppen til forfattere basert på hvordan de skriver, med relativ høy treffsikkerhet. Videre viser også resultatene fra eksperimentene at lineær kernel SVM (Support Vector Machine) produserte de beste resultatene, med tanke på treffsikkerhet, presisjon og recall score, og den kombinerte verdien. Det erflere tekstlige trekk som ernyttige til å skille tekstene fra de forskjellige aldersgruppene og genere fra hverandre. Noen av disse er TF-IDF (Term Frequency - Inverse Document Frequency), LIWC (Linguistic Inquiry and Word Count), n-grams, PoS (Part of Speech) tagging og frekvensen stilistiske språklige trekk. Til slutt, viser resultatene at modellene som er trent på kombinerte sett med genre, gjorde det betraktelig dårligere enn modeller som bare var trent på individuelle domener.This thesis investigates how to determine the age group of an author, mainly if the author is a child, below the age of 18, or an adult, above the age of 25. Furthermore, the goal is to explore which textual features across different genres best correlate with the age of an author. Lastly, we want to investigate if a single model would be sufficient to predict age across various genres, or if the different domains need an individual model. To answer these questions, several data sets, previously used in author profiling research, have been collected. The data sets gathered contain blog texts, social media data and Twitter data. Furthermore, numerous experiments are implemented using commonly used machine learning classification algorithms and language recognition methods. The experiments are performed on individual genre data sets, as well as combined domains.
The results showed that it is possible to determine the age group of authors with relative accuracy, based on how they write. Results also reveal that the linear kernel SVM (Support Vector Machine) produces the best results throughout the experiments, in regards to overall prediction accuracy, precision and recall score, and the combined measure. Moreover, some of the textual features that are effective in distinguishing text written by the different age groups across the genres are TF-IDF (Term Frequency - Inverse Document Frequency), LIWC (Linguistic Inquiry and Word Count), n-grams, PoS (Part of Speech) tagging and stylistic language frequencies. Additionally, the results show that the models that are trained on a combined set of genres underperformed compared to models that trained only on a single domain
Clonal dynamics of TEL-AML1+ childhood ALL: an in vivo model
No full textETV6–RUNX1 gene fusion is an early or initiating genetic lesion of Childhood Acute Lymphoblastic Leukaemia, followed, in disease progression, by a modest number of recurrent or "driver" copy number alterations. Among patients diagnosed with this particular cytogenetic subtype of ALL cure rate reaches over 80% . However, treatment protocols are extremely demanding, and the molecular mechanisms driving drug-resistance and relapse in the remaining 10% of patient are still unknown. Recently a genetic signature of subclones arranged in a complex non-linear or branching architecture has been identified in this leukaemia, pioneering similar observations in many other cancer types. At present, most reports of this intratumor diversity represent static, in-depth snapshots of clonal diversity of tumours at a given time. "Real-time" longitudinal and spatial analysis of subclonal evolutionary dynamics is required to understand the functional characteristics of individual subclones. Such approach also promises to reveal the overall clinical relevance of this phenomenon. This project therefore aims to understand whether genetically distinct subclones are also functionally different, particularly with respect to chemoresistance. A mouse model that allows for the independent exposure of the same tumour to treatment multiple times, and the tracking of clonal dynamics by mean of a selected pool of genetic markers was established. While the analysis is still ongoing, preliminary data confirm that tumours generated from the same inoculum are highly similar in their genetic makeup across recipients, that multiple clones within a tumour can survive chemotherapy, but sensitivity of clones equally represented within the bulk can vary, and unexpectedly that spatially segregated subclones can be identified in this model of liquid cancer. The complete analysis of the collected samples by mFISH as well as by single cell whole genome sequencing will provide unprecedented insight into the impact of cytotoxic treatment on intratumour genetic heterogeneity, and might reveal novel mechanisms of chemoresistance and relapse. Additionally, a lentiviral overexpression system was designed to endogenously manipulate clonal interactions through the restored expression of TEL and PAX5 in primary cells from patients, and evaluate their impact on clonal relationships and hierarchies and to validate the results obtained from the first part of the study. Lentiviral vectors for TEL and PAX5 second hit overexpression were produced and tested by Western blot and qPCR. The TEL vectors were adopted in a preliminary in vivo experiment, showing no effect on overall engraftment ability
- …
