Phosphorylation is a cellular process that modifies proteins, and thereby regulates the cellular fates of more than two-thirds of all proteins. This dynamic process is carried out by protein kinases, which phosphorylate specific proteins to regulate a variety of downstream cellular mechanisms, including development and functioning of the nervous system. SRPK is one such protein kinase that phosphorylates proteins to control gene expression, the cell cycle, and cell survival in neurons. Previous work from the lab has demonstrated that SRPK phosphorylates RNF12/RLIM, a member of the E3 ligase family of enzymes that control protein destruction. SRPK phosphorylation of RNF12 controls destruction of proteins involved in gene expression, to regulate expression of neuronal genes. Patient mutations in the gene encoding RNF12 cause Tonne-Kalscheuer syndrome (TOKAS), an intellectual disability disorder. SRPK also phosphorylates other E3 ligases that have important functions in the nervous system. These include RNF10, which is linked to control of protein translation, formation of neurons, and protecting neurons with a myelin sheath. In this project, I aim to understand how SRPK phosphorylation controls RNF10 and to understand the downstream consequences for development and functioning of neurons in the nervous system.

The main goal of typing is to prevent the occurrence of execution errors during the running of a program. Milner formalised the idea, showing that ``well-typed programs cannot go wrong''. In practice, type structures provide a fundamental technique of reducing programmer errors. At their strongest, they cover most of the properties of interest to the verification community. A major trend in the development of functional languages is improvement in expressiveness of the underlying type system, e.g., in terms of Dependent Types, Type Classes, Generalised Algebraic Types (GADTs), Dependent Type Classes and Canonical Structures. Milner-style decidable type inference does not always suffice for such extensions (e.g. the principal type may no longer exist), and deciding well-typedness sometimes requires computation additional to compile-time type inference. Implementations of new type inference algorithms include a variety of first-order decision procedures, notably Unification and Logic Programming (LP), Constraint LP, LP embedded into interactive tactics (Coq's eauto), and LP supplemented by rewriting. Recently, a strong claim has been made by Gonthier et al that, for richer type systems, LP-style type inference is more efficient and natural than traditional tactic-driven proof development. A second major trend is parallelism: the absence of side-effects makes it easy to evaluate sub-expressions in parallel. Powerful abstraction mechanisms of function composition and higher-order functions play important roles in parallelisation. Three major parallel languages are Eden (explicit parallelism) Parallel ML (implicit parallelism) and Glasgow parallel Haskell (semi-explicit parallelism). Control parallelism in particular distinguishes functional languages. Type inference and parallelism are rarely considered together in the literature. As type inference becomes more sophisticated and takes a bigger role in the overall program development, sequential type inference is bound to become a bottle-neck for language parallelisation. Our new Coalgebraic Logic Programming (CoALP) offers both extra expressiveness (corecursion) and parallelism in one algorithm. We propose to use CoALP in place of LP tools currently used in type inference. With the mentioned major developments in Corecursion, Parallelism, and Typeful (functional) programming it has become vital for these disjoint communities to combine their efforts: enriched type theories rely more and more on the new generation of LP languages; coalgebraic semantics has become influential in language design; and parallel dialects of languages have huge potential in applying common techniques across the FP/LP programming paradigm. This project is unique in bringing together local and international collaborators working in the three communities. The number of supporters the project has speaks better than words about the timeliness of our agenda. The project will impact on two streams of EPSRC's strategic plan: "Programming Languages and Compilers" and "Verification and Correctness". The project is novel in aspects of Theory (coalgebraic study of (co)recursive computations arising in automated proof-search); Practice (implementation of the new language CoALP and its embedding in type-inference tools); and Methodology (Mixed corecursion and parallelism).

To maintain their genetic integrity, eukaryotic cells must segregate their chromosomes properly to opposite poles during mitosis. The unravelling of the mechanisms that ensure high-fidelity chromosome segregation should improve our understanding of various human diseases such as cancers and congenital disorders (e.g. Down syndrome), which are characterized by chromosome instability and aneuploidy. Sister chromatid segregation during mitosis mainly depends on the forces generated by microtubules that attach to kinetochores. For proper chromosome segregation, kinetochores must interact with spindle microtubules efficiently and this interaction must develop correctly to achieve proper chromosome segregation in the subsequent anaphase. Our research goal is to discover and characterize the molecular mechanisms by which cells regulate these vital processes of kinetochore-microtubule interactions. We investigate the kinetochore-microtubule interactions in budding yeast because of the amenable genetics and detailed proteomic information in this organism. The basic principles of kinetochore-microtubule interactions are similar in yeast and vertebrate cells. Because of this conservation of basic mechanisms, it is likely that results from the yeast system will be of direct relevance to chromosome segregation mechanisms in human cells.