Symplectic structures on right-angled Artin groups: between the mapping class group and the symplectic group

We define a family of groups that include the mapping class group of a genus g surface with one boundary component and the integral symplectic group Sp(2g,Z). We then prove that these groups are finitely generated. These groups, which we call mapping class groups over graphs, are indexed over labeled simplicial graphs with 2g vertices. The mapping class group over the graph Gamma is defined to be a subgroup of the automorphism group of the right-angled Artin group A_Gamma of Gamma. We also prove that the kernel of the map Aut A_Gamma to Aut H_1(A_Gamma) is finitely generated, generalizing a theorem of Magnus.Comment: 45 page

Peak reduction and finite presentations for automorphism groups of right-angled Artin groups

We generalize the peak-reduction algorithm (Whitehead's theorem) for free groups to a theorem about a general right-angled Artin group A_Gamma. As an application, we find a finite presentation for the automorphism group Aut A_Gamma that generalizes McCool's presentation for the automorphism group of a finite rank free group. We also give consider a stronger generalization of peak-reduction, giving a counterexample and proving a special case.Comment: 41 page

The modular compilation of effects

The introduction of new features to a programming language often requires that its compiler goes to the effort of ensuring they are introduced in a manner that does not interfere with the existing code base. Engineers frequently find themselves changing code that has already been designed, implemented and (ideally) proved correct, which is bad practice from a software engineering point of view. This thesis addresses the issue of constructing a compiler for a source language that is modular in the computational features that it supports. Utilising a minimal language that allows us to demonstrate the underlying techniques, we go on to introduce a significant range of effectful features in a modular manner, showing that their syntax can be compiled independently, and that source languages containing multiple features can be compiled by making use of a fold. In the event that new features necessitate changes in the underlying representation of either the source language or that of the compiler, we show that our framework is capable of incorporating these changes with minimal disruption. Finally, we show how the framework we have developed can be used to define both modular evaluators and modular virtual machines

The modular compilation of effects

The introduction of new features to a programming language often requires that its compiler goes to the effort of ensuring they are introduced in a manner that does not interfere with the existing code base. Engineers frequently find themselves changing code that has already been designed, implemented and (ideally) proved correct, which is bad practice from a software engineering point of view. This thesis addresses the issue of constructing a compiler for a source language that is modular in the computational features that it supports. Utilising a minimal language that allows us to demonstrate the underlying techniques, we go on to introduce a significant range of effectful features in a modular manner, showing that their syntax can be compiled independently, and that source languages containing multiple features can be compiled by making use of a fold. In the event that new features necessitate changes in the underlying representation of either the source language or that of the compiler, we show that our framework is capable of incorporating these changes with minimal disruption. Finally, we show how the framework we have developed can be used to define both modular evaluators and modular virtual machines

Phosphorylation-dependent assembly of DNA damage response systems and the central roles of TOPBP1

The cellular response to DNA damage (DDR) that causes replication collapse and/or DNA double strand breaks, is characterised by a massive change in the post-translational modifications (PTM) of hundreds of proteins involved in the detection and repair of DNA damage, and the communication of the state of damage to the cellular systems that regulate replication and cell division. A substantial proportion of these PTMs involve targeted phosphorylation, which among other effects, promotes the formation of multiprotein complexes through the specific binding of phosphorylated motifs on one protein, by specialised domains on other proteins. Understanding the nature of these phosphorylation mediated interactions allows definition of the pathways and networks that coordinate the DDR, and helps identify new targets for therapeutic intervention that may be of benefit in the treatment of cancer, where DDR plays a key role. In this review we summarise the present understanding of how phosphorylated motifs are recognised by BRCT domains, which occur in many DDR proteins. We particularly focus on TOPBP1 – a multi-BRCT domain scaffold protein with essential roles in replication and the repair and signalling of DNA damage

Phosphorylation-dependent assembly and coordination of the DNA damage checkpoint apparatus by Rad4TopBP1

The BRCT-domain protein Rad4(TopBP1) facilitates activation of the DNA damage checkpoint in Schizosaccharomyces pombe by physically coupling the Rad9-Rad1-Hus1 clamp, the Rad3(ATR) -Rad26(ATRIP) kinase complex, and the Crb2(53BP1) mediator. We have now determined crystal structures of the BRCT repeats of Rad4(TopBP1), revealing a distinctive domain architecture, and characterized their phosphorylation-dependent interactions with Rad9 and Crb2(53BP1). We identify a cluster of phosphorylation sites in the N-terminal region of Crb2(53BP1) that mediate interaction with Rad4(TopBP1) and reveal a hierarchical phosphorylation mechanism in which phosphorylation of Crb2(53BP1) residues Thr215 and Thr235 promotes phosphorylation of the noncanonical Thr187 site by scaffolding cyclin-dependent kinase (CDK) recruitment. Finally, we show that the simultaneous interaction of a single Rad4(TopBP1) molecule with both Thr187 phosphorylation sites in a Crb2(53BP1) dimer is essential for establishing the DNA damage checkpoint

Structural basis for recruitment of the CHK1 DNA damage kinase by the CLASPIN scaffold protein

CHK1 is a protein kinase that functions downstream of activated ATR to phosphorylate multiple targets as part of intra-S and G2/M DNA damage checkpoints. Its role in allowing cells to survive replicative stress has made it an important target for anti-cancer drug discovery. Activation of CHK1 by ATR depends on their mutual interaction with CLASPIN, a natively unstructured protein that interacts with CHK1 through a cluster of phosphorylation sites in its C-terminal half. We have now determined the crystal structure of the kinase domain of CHK1 bound to a high-affinity motif from CLASPIN. Our data show that CLASPIN engages a conserved site on CHK1 adjacent to the substrate-binding cleft, involved in phosphate sensing in other kinases. The CLASPIN motif is not phosphorylated by CHK1, nor does it affect phosphorylation of a CDC25 substrate peptide, suggesting that it functions purely as a scaffold for CHK1 activation by ATR

Artificial neural network approaches for fluorescence lifetime imaging techniques

A novel high-speed fluorescence lifetime imaging (FLIM) analysis method based on artificial neural networks (ANN) has been proposed. In terms of image generation, the proposed ANN-FLIM method does not require iterative searching procedures or initial conditions, and it can generate lifetime images at least 180-fold faster than conventional least squares curve-fitting software tools. The advantages of ANN-FLIM were demonstrated on both synthesized and experimental data, showing that it has great potential to fuel current revolutions in rapid FLIM technologies

Phosphorylation-mediated interactions with TOPBP1 couple 53BP1 and 9-1-1 to control the G1 DNA damage checkpoint

Coordination of the cellular response to DNA damage is organised by multi-domain 'scaffold' proteins, including 53BP1 and TOPBP1, which recognise post-translational modifications such as phosphorylation, methylation and ubiquitylation on other proteins, and are themselves carriers of such regulatory signals. Here we show that the DNA damage checkpoint regulating S-phase entry is controlled by a phosphorylation-dependent interaction of 53BP1 and TOPBP1. BRCT domains of TOPBP1 selectively bind conserved phosphorylation sites in the N-terminus of 53BP1. Mutation of these sites does not affect formation of 53BP1 or ATM foci following DNA damage, but abolishes recruitment of TOPBP1, ATR and CHK1 to 53BP1 damage foci, abrogating cell cycle arrest and permitting progression into S-phase. TOPBP1 interaction with 53BP1 is structurally complimentary to its interaction with RAD9-RAD1-HUS1, allowing these damage recognition factors to bind simultaneously to the same TOPBP1 molecule and cooperate in ATR activation in the G1 DNA damage checkpoint

How will climate change pathways and mitigation options alter incidence of vector-borne diseases? A framework for leishmaniasis in South and Meso-America

The enormous global burden of vector-borne diseases disproportionately affects poor people in tropical, developing countries. Changes in vector-borne disease impacts are often linked to human modification of ecosystems as well as climate change. For tropical ecosystems, the health impacts of future environmental and developmental policy depend on how vector-borne disease risks trade off against other ecosystem services across heterogeneous landscapes. By linking future socio-economic and climate change pathways to dynamic land use models, this study is amongst the first to analyse and project impacts of both land use and climate change on continental-scale patterns in vector-borne diseases. Models were developed for cutaneous and visceral leishmaniasis in the Americas—ecologically complex sand fly borne infections linked to tropical forests and diverse wild and domestic mammal hosts. Both diseases were hypothesised to increase with available interface habitat between forest and agricultural or domestic habitats and with mammal biodiversity. However, landscape edge metrics were not important as predictors of leishmaniasis. Models including mammal richness were similar in accuracy and predicted disease extent to models containing only climate and land use predictors. Overall, climatic factors explained 80% and land use factors only 20% of the variance in past disease patterns. Both diseases, but especially cutaneous leishmaniasis, were associated with low seasonality in temperature and precipitation. Since such seasonality increases under future climate change, particularly under strong climate forcing, both diseases were predicted to contract in geographical extent to 2050, with cutaneous leishmaniasis contracting by between 35% and 50%. Whilst visceral leishmaniasis contracted slightly more under strong than weak management for carbon, biodiversity and ecosystem services, future cutaneous leishmaniasis extent was relatively insensitive to future alternative socio-economic pathways. Models parameterised at narrower geographical scales may be more sensitive to land use pattern and project more substantial changes in disease extent under future alternative socio-economic pathways