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Whole-genome sequencing (WGS) is becoming widely used in clinical medicine in diagnostic contexts and to inform treatment choice. Here we evaluate the potential of the Oxford Nanopore Technologies (ONT) MinION long-read sequencer for routine WGS by sequencing the reference sample NA12878 and the genome of an individual with ataxia-pancytopenia syndrome and severe immune dysregulation. We develop and apply a novel reference panel-free analytical method to infer and then exploit phase information which improves single-nucleotide variant (SNV) calling performance from otherwise modest levels. In the clinical sample, we identify and directly phase two non-synonymous de novo variants in SAMD9L , (OMIM #159550) inferring that they lie on the same paternal haplotype. Whilst consensus SNV-calling error rates from ONT data remain substantially higher than those from short-read methods, we demonstrate the substantial benefits of analytical innovation. Ongoing improvements to base-calling and SNV-calling methodology must continue for nanopore sequencing to establish itself as a primary method for clinical WGS. Nanopore sequencing technology generates longer reads than current technologies, but with more errors. Here, the authors develop new analytical tools to improve accuracy and evaluate the potential of nanopore sequencing for clinical human genomics.

Recent advances in throughput and accuracy mean that the Oxford Nanopore Technologies PromethION platform is a now a viable solution for genome sequencing. Much of the validation of bioinformatic tools for this long-read data has focussed on calling germline variants (including structural variants). Somatic variants are outnumbered many-fold by germline variants and their detection is further complicated by the effects of tumour purity/subclonality. Here, we evaluate the extent to which Nanopore sequencing enables detection and analysis of somatic variation. We do this through sequencing tumour and germline genomes for a patient with diffuse B-cell lymphoma and comparing results with 150 bp short-read sequencing of the same samples. Calling germline single nucleotide variants (SNVs) from specific chromosomes of the long-read data achieved good specificity and sensitivity. However, results of somatic SNV calling highlight the need for the development of specialised joint calling algorithms. We find the comparative genome-wide performance of different tools varies significantly between structural variant types, and suggest long reads are especially advantageous for calling large somatic deletions and duplications. Finally, we highlight the utility of long reads for phasing clinically relevant variants, confirming that a somatic 1.6 Mb deletion and a p.(Arg249Met) mutation involving TP53 are oriented in trans .

Magnetic memory and logic technologies promise greater energy efficiency and speed than conventional, semiconductor-based electronics. To date, electrical current has been used to operate such devices, although voltage-control may be a more efficient way to control magnetisation. One route to achieving voltage control of magnetisation is to use a hybrid piezoelectric/ferromagnetic device in which a voltage applied to the piezoelectric induces a strain in the ferromagnetic layer, which in turn induces a magnetic anisotropy. In this thesis such hybrid devices are used to investigate the control of magnetisation by inducing uniaxial anisotropy in the ferromagnetic layer. One material that shows promise for use as the ferromagnetic layer is Fe81Ga19. This material is attractive since it contains no rare earth elements, and in bulk crystals has been shown to be highly magnetically responsive to strain. This thesis investigates the magnetic properties of epitaxial Fe81Ga19 thin films grown by molecular beam epitaxy and it is demonstrated that these thin films retain the attractive magnetostrictive properties previously observed in bulk crystals. The presence of strong cubic magnetocrystalline anisotropy in the layers is exploited to demonstrate the non-volatile switching of magnetisation using strain-induced anisotropy in the absence of an applied magnetic field. This thesis shows also the manipulation of magnetic anisotropies and control of the configuration of magnetic domains and domain walls in Fe81Ga19 at a range of different lateral dimensions, from50 μm to 1 μm. It is shown that as the lateral dimensions of the device structures studied are reduced the domain configuration appears more regular, and that strain-induced anisotropy is more able to control these domains. In wires around 1 μm in width it is shown that growth strain relaxation by lithographic patterning induces sufficient anisotropy to cause a change in the domain configuration of the wire studied. Finally, this thesis begins to investigate how inverse magnetostriction can be used to tune the behaviour of domain walls in wires 1 μm wide and narrower. Experimental control of the field required to depin a vortex domain wall from a notch in a 1 μm wide Co wire is demonstrated. Using micromagnetic simulations it is shown that a large degree of control over the depinning of domain walls from notches in wires 1 μm wide and narrower is possible. The influence of in plane uniaxial magnetic anisotropy on the domain wall velocity in wires supporting in plane transverse domain walls driven by an external magnetic field is also investigated. Work previously done on the effect of uniaxial anisotropy on domain wall velocities close to Walker breakdown is extended in this thesis and in investigating the velocity and structure at driving magnetic fields far above walker Breakdown a second peak in domain wall velocity is observed, a phenomenon previously observed in wide wires, and wires under the influence of a transverse magnetic field.

Geochemical analyses of Holocene coastal sediments from eastern England were made to better understand the cycling of organic carbon and nutrients in the coastal zone in the past, present and future. Sediments and peat were deposited in freshwater marshes, saltmarshes and intertidal mud- and sand-flat environments that were much more extensive during the Holocene than they are at present. The reduction in these areas, largely through human activities, has decreased the potential annual accumulation and storage of organic carbon, nitrogen and phosphorus associated with sediments. While the carbon and nitrogen contents of modem intertidal environments are similar to Holocene intertidal areas, phosphorus is enriched in modem sediments by up to a factor of two. Budgets of nitrogen and phosphorus cycling in Fenland, eastern England, suggest that the Holocene estuaries in this area were sinks of nutrients from the North Sea despite nitrogen isotopic evidence suggesting that nitrogen buried in freshwater marshes was predominantly terrestrially derived. The present-day estuaries are sources of nutrients to the North Sea as riverine loads and atmospheric deposition are much higher than during the Holocene and sedimentation is also greatly reduced. The southern North Sea is probably autotrophic, in contrast to the coastal zone global average which is heterotrophic. The major differences between these two areas are: 1) the global coastal zone receives much greater loads of riverine particulate matter than the southern North Sea, and 2) sedimentation in the global coastal zone occurs in large river deltas which are absent from the relatively small European estuaries, thus much of the sediment supplied to the North Sea is exported to the shelf edge. Approximately 4x 109 t C, 0.3 x 109 tN and 0.1 x 109 tP are currently stored in fine-grained Holocene sediments in the southern North Sea coastal zone.

For any group G and generating set X we shall be primarily concerned with three sets of words over X: the word problem, the reduced word problem, and the irreducible word problem. We explain the relationships between these three sets of words and give necessary and sufficient conditions for a language to be the word problem (or the reduced word problem) of a group. We prove that the groups which have context-free reduced word problem with respect to some finite monoid generating set are exactly the context-free groups, thus proving a conjecture of Haring-Smith. We also show that, if a group G has finite irreducible word problem with respect to a monoid generating set X, then the reduced word problem of G with respect to X is simple. In addition, we show that the reduced word problem is recursive (or recursively enumerable) precisely when the word problem is recursive. The irreducible word problem corresponds to the set of words on the left hand side of a special rewriting system which is confluent on the equivalence class containing the identity. We show that the class of groups which have monoid presentations by means of finite special []-confluent string-rewriting systems strictly contains the class of plain groups (the groups which are free products of a finitely generated free group and finitely many finite groups), and that any group which has an infinite cyclic central subgroup can be presented by such a string-rewriting system if and only if it is the direct product of an infinite cyclic group and a finite cyclic group.

For any group G and generating set X we shall be primarily concerned with three sets of words over X: the word problem, the reduced word problem, and the irreducible word problem. We explain the relationships between these three sets of words and give necessary and sufficient conditions for a language to be the word problem (or the reduced word problem) of a group.We prove that the groups which have context-free reduced word problem with respect to some finite monoid generating set are exactly the context-free groups, thus proving a conjecture of Haring-Smith. We also show that, if a group G has finite irreducible word problem with respect to a monoid generating set X, then the reduced word problem of G with respect to X is simple. In addition, we show that the reduced word problem is recursive (or recursively enumerable) precisely when the word problem is recursive.The irreducible word problem corresponds to the set of words on the left hand side of a special rewriting system which is confluent on the equivalence class containing the identity. We show that the class of groups which have monoid presentations by means of finite special [ ]-confluent string-rewriting systems strictly contains the class of plain groups (the groups which are free products of a finitely generated free group and finitely many finite groups), and that any group which has an infinite cyclic central subgroup can be presented by such a string-rewriting system if and only if it is the direct product of an infinite cyclic group and a finite cyclic group.

Abstract Chronic lymphocytic leukaemia (CLL) is characterised by considerable clinical and biological heterogeneity, with specific recurrent genomic alterations, including TP53 mutations, deletions of chromosome 17p, and IgHV mutational status, impacting on response to chemo-immunotherapy and targeted agents. Consequently, diagnostic screening for these predictive biomarkers is recommended in both national and international clinical guidelines. Current conventional methods, including fluorescent in-situ hybridisation and Sanger sequencing, exhibit shortcomings in terms of cost, speed and sensitivity, and even second-generation sequencing methods encounter technical limitations imposed by short-read lengths and bio-informatics analysis. The MinION platform from Oxford Nanopore Technologies generates exceptionally long (1-100kbp) read lengths in a short period of time and at low cost, making it a good candidate for diagnostic testing. In this paper, we present a nanopore-based CLL-specific screening assay, to simultaneously screen for both TP53 mutations and del17p13.1, as well as determining the IgHV mutation status for a single patient in one sequencing run. We sequenced 11 CLL patients and were able to generate a full diagnostic dataset for all. We identified somatic SNVs and indels in the coding region of TP53, and demonstrate that, following error correction of the data, we could accurately define the somatically hypermutated IgHV region in all patients. We also demonstrated the ability of the MinION platform to detect large-scale genomic deletions through low-coverage whole-genome sequencing. We conclude that nanopore sequencing has the potential to provide accurate, low-cost and rapid diagnostic information, which could be applied to other cancer types.

Recent advances in throughput and accuracy mean that the Oxford Nanopore Technologies (ONT) PromethION platform is a now a viable solution for genome sequencing. Much of the validation of bioinformatic tools for this long-read data has focussed on calling germline variants (including structural variants). Somatic variants are outnumbered many-fold by germline variants and their detection is further complicated by the effects of tumour purity/subclonality. Here, we evaluate the extent to which Nanopore sequencing enables genome-wide detection and analysis of somatic variation. We do this through sequencing tumour and germline genomes for a patient with diffuse B-cell lymphoma and comparing results with 150bp short-read sequencing of the same samples. Calling germline single nucleotide variants (SNVs) from the long-read data achieved good specificity and sensitivity. However, results of somatic SNV calling highlight the need for the development of specialized joint calling algorithms. We find the comparative performance of different tools varies significantly between structural variant types, and suggest long reads are especially advantageous for calling large somatic deletions and duplications. Finally, we highlight the utility of long reads for phasing clinically relevant variants, confirming that a somatic 1.6Mb deletion and a p.(Arg249Met) mutation involving TP53 are oriented in trans.

German Text Crimes offers new perspectives on scandals and legal actions implicating writers of German literature since the 1950s. A wide range of topics not all involve codified law, but all test relations between state power, civil society, media industries and artistic license.

CURRENT NSW Champion rowers, Robyn Cragg and Yvonne Collings, were first declared Australian champions in the women's pairs late in 2005.