Genetic regulation of mouse liver metabolite levels.

We profiled and analyzed 283 metabolites representing eight major classes of molecules including Lipids, Carbohydrates, Amino Acids, Peptides, Xenobiotics, Vitamins and Cofactors, Energy Metabolism, and Nucleotides in mouse liver of 104 inbred and recombinant inbred strains. We find that metabolites exhibit a wide range of variation, as has been previously observed with metabolites in blood serum. Using genome-wide association analysis, we mapped 40% of the quantified metabolites to at least one locus in the genome and for 75% of the loci mapped we identified at least one candidate gene by local expression QTL analysis of the transcripts. Moreover, we validated 2 of 3 of the significant loci examined by adenoviral overexpression of the genes in mice. In our GWAS results, we find that at significant loci the peak markers explained on average between 20 and 40% of variation in the metabolites. Moreover, 39% of loci found to be regulating liver metabolites in mice were also found in human GWAS results for serum metabolites, providing support for similarity in genetic regulation of metabolites between mice and human. We also integrated the metabolomic data with transcriptomic and clinical phenotypic data to evaluate the extent of co-variation across various biological scales

Modelling of psoriasis patient flows for the reconfiguration of secondary care services and treatments

This paper describes work in collaboration with a large dermatology directorate in South Wales to map out current patient flow and activity levels for psoriasis management. Psoriasis is a chronic skin disease which often has a high impact on patient quality of life. Clinical services for patients with moderate to severe psoriasis tend to be located in secondary care hospitals. The range of services that were studied, their geographical location in relation to the distribution of population, and the population demographics in this health board were not unique; similar profiles for these factors can be found throughout the NHS in England and Wales. The model was created to analyse patient flow through different therapies, with the aim of maximising throughput of patients, eliminating bottlenecks, improving patient access to services and improving patient safety. It was shown that reducing waiting times and improving access to phototherapy would lower overall service costs, as fewer patients would subsequently require systemic and biologic therapies. The model has been used to quantify how recent year-on-year increases in overall spend on psoriasis treatments might be slowed and eventually halted. This would require reallocation of notional cost-savings generated by reducing the rate of increase in the drug spend to fund the development of a more balanced and accessible network of more basic psoriasis services

A modal ambiguity in for-infinitival relative clauses

This squib presents two puzzles related to an ambiguity found in for-infinitival relative clauses (FIRs). FIRs invariably receive a modal interpretation even in the absence of any overt modal verb. The modal interpretation seems to come in two distinct types, which can be paraphrased by finite relative clauses employing the modal auxiliaries should and could. The two puzzles presented here arise because the availability of the two readings is constrained by factors that are not otherwise known to affect the interpretation of a relative clause. Specifically, we show, first, that “strong” determiners require the FIR to be interpreted as a SHOULD-relative while “weak” determiners allow both interpretations (the Determiner-Modal Generalization). Secondly, we observe that the COULD-interpretation requires a raising (internally headed) structure for the FIR, while the SHOULD-interpretation is compatible with either a raising or a more standard matching (externally headed) structure (the Raising/Matching Generalization)

Secondary predication and the distribution of raising to object

In Den Dikken (2017b) arguments are presented for a predicational approach to hyperraising and copy raising constructions in which the ‘raised’ DP serves as the subject of the matrix clause. In this sequel, I show that hyperraising and copy raising also occur in secondary predication constructions embedded under propositional attitude verbs such as consider. An examination of the properties of these hyperraising and copy raising to object constructions leads to the conclusion that overt subject-toobject raising (‘object shift’) definitely exists in English but is obligatory only for subjects of small-clause complements of verbs. Apart from yielding a clearer perspective on the distribution of overt object shift in English, the study also delivers a unified account of a variety of restrictions on the subject of the non-finite complement of propositional attitude verbs

'Tough'-constructions and their derivation

This article addresses the syntax of the notorious 'tough' (-movement) construction (TC) in English. TCs exhibit a range of apparently contradictory empirical properties suggesting that their derivation involves the application of both A-movement and A'-movement operations. Given that within previous Principles and Parameters models TCs have remained “unexplained and in principle unexplainable” (Holmberg 2000: 839) due to incompatibility with constraints on theta-assignment, locality, and Case, this article argues that the phase-based implementation of the Minimalist program (Chomsky 2000, 2001, 2004) permits a reanalysis of null wh-operators capable of circumventing the previous theoretical difficulties. Essentially, 'tough'-movement consists of A-moving a constituent out of a “complex” null operator which has already undergone A'-movement, a “smuggling” construction in the terms of Collins (2005a,b

On the Topic of Pseudoclefts

This paper presents arguments in favor of a pseudocleft analysis of a certain class of sentences in Malagasy, despite the lack of an overt wh-element. It is shown that voice morphology on the verb creates an operator-variable relationship much like the one created by wh-movement in free relatives in English and other languages. The bulk of the paper argues in favor of an inversion analysis of specificational pseudoclefts in Malagasy: a predicate DP is fronted to a topic position from within a small clause constituent. Moreover, it is shown that the same inversion occurs in equative and specificational sentences in Malagasy, which suggests that these types of sentences share the same syntactic structure. The proposed analysis also provides support for the view that specificational pseudoclefts have a topic \u3e focus structure, where the wh-clause has been overtly topicalized

Exome Sequencing Reveals Comprehensive Genomic Alterations across Eight Cancer Cell Lines

It is well established that genomic alterations play an essential role in oncogenesis, disease progression, and response of tumors to therapeutic intervention. The advances of next-generation sequencing technologies (NGS) provide unprecedented capabilities to scan genomes for changes such as mutations, deletions, and alterations of chromosomal copy number. However, the cost of full-genome sequencing still prevents the routine application of NGS in many areas. Capturing and sequencing the coding exons of genes (the “exome”) can be a cost-effective approach for identifying changes that result in alteration of protein sequences. We applied an exome-sequencing technology (Roche Nimblegen capture paired with 454 sequencing) to identify sequence variation and mutations in eight commonly used cancer cell lines from a variety of tissue origins (A2780, A549, Colo205, GTL16, NCI-H661, MDA-MB468, PC3, and RD). We showed that this technology can accurately identify sequence variation, providing ∼95% concordance with Affymetrix SNP Array 6.0 performed on the same cell lines. Furthermore, we detected 19 of the 21 mutations reported in Sanger COSMIC database for these cell lines. We identified an average of 2,779 potential novel sequence variations/mutations per cell line, of which 1,904 were non-synonymous. Many non-synonymous changes were identified in kinases and known cancer-related genes. In addition we confirmed that the read-depth of exome sequence data can be used to estimate high-level gene amplifications and identify homologous deletions. In summary, we demonstrate that exome sequencing can be a reliable and cost-effective way for identifying alterations in cancer genomes, and we have generated a comprehensive catalogue of genomic alterations in coding regions of eight cancer cell lines. These findings could provide important insights into cancer pathways and mechanisms of resistance to anti-cancer therapies

Negation and the functional sequence

There exists a general restriction on admissible functional sequences which prevents adjacent identical heads. We investigate a particular instantiation of this restriction in the domain of negation. Empirically, it manifests itself as a restriction the stacking of multiple negative morphemes. We propose a principled account of this restriction in terms of the general ban on immediately consecutive identical heads in the functional sequence on the one hand, and the presence of a Neg feature inside negative morphemes on the other hand. The account predicts that the stacking of multiple negative morphemes should be possible provided they are separated by intervening levels of structure. We show that this prediction is borne out