Sequent Calculus in the Topos of Trees

Nakano's "later" modality, inspired by G\"{o}del-L\"{o}b provability logic, has been applied in type systems and program logics to capture guarded recursion. Birkedal et al modelled this modality via the internal logic of the topos of trees. We show that the semantics of the propositional fragment of this logic can be given by linear converse-well-founded intuitionistic Kripke frames, so this logic is a marriage of the intuitionistic modal logic KM and the intermediate logic LC. We therefore call this logic $\mathrm{KM}_{\mathrm{lin}}$. We give a sound and cut-free complete sequent calculus for $\mathrm{KM}_{\mathrm{lin}}$ via a strategy that decomposes implication into its static and irreflexive components. Our calculus provides deterministic and terminating backward proof-search, yields decidability of the logic and the coNP-completeness of its validity problem. Our calculus and decision procedure can be restricted to drop linearity and hence capture KM.Comment: Extended version, with full proof details, of a paper accepted to FoSSaCS 2015 (this version edited to fix some minor typos

The structure of the RbBP5 β-propeller domain reveals a surface with potential nucleic acid binding sites

The multi-protein complex WRAD, formed by WDR5, RbBP5, Ash2L and Dpy30, binds to the MLL SET domain to stabilize the catalytically active conformation required for histone H3K4 methylation. In addition, the WRAD complex contributes to the targeting of the activated complex to specific sites on chromatin. RbBP5 is central to MLL catalytic activation, by making critical contacts with the other members of the complex. Interestingly its only major structural domain, a canonical WD40 repeat -propeller, is not implicated in this function. Here, we present the structure of the RbBP5 -propeller domain revealing a distinct, feature rich surface, dominated by clusters of Arginine residues. Our nuclear magnetic resonance binding data supports the hypothesis that in addition to the role of RbBP5 in catalytic activation, its -propeller domain is a platform for the recruitment of the MLL complexes to chromatin targets through its direct interaction with nucleic acids

Foundation Expenses and Compensation: How Operating Characteristics Influence Spending

This report examines the impact of a broader range of operating charateristics on the spending patterns of the 10,000 largest independent, corporate, and community foundations by giving. It provides an overview of the composition of expenses of the three types of foundations and documents how major differences in foundations' operating characteristics have an impact on their expense levels. The appendices include the methodology of the study, the list of variables as well as benchmarking tables

A cryptic RNA-binding domain mediates Syncrip recognition and exosomal partitioning of miRNA targets

Exosomal miRNA transfer is a mechanism for cell-cell communication that is important in the immune response, in the functioning of the nervous system and in cancer. Syncrip/hnRNPQ is a highly conserved RNA-binding protein that mediates the exosomal partition of a set of miRNAs. Here, we report that Syncrip's amino-terminal domain, which was previously thought to mediate protein-protein interactions, is a cryptic, conserved and sequence-specific RNA-binding domain, designated NURR (N-terminal unit for RNA recognition). The NURR domain mediates the specific recognition of a short hEXO sequence defining Syncrip exosomal miRNA targets, and is coupled by a non-canonical structural element to Syncrip's RRM domains to achieve high-affinity miRNA binding. As a consequence, Syncrip-mediated selection of the target miRNAs implies both recognition of the hEXO sequence by the NURR domain and binding of the RRM domains 5′ to this sequence. This structural arrangement enables Syncrip-mediated selection of miRNAs with different seed sequences. © 2018 The Author(s)

Specification and verification of atomic operations in GPGPU programs

We propose a specification and verification technique based on separation logic to reason about data race freedom and functional correctness of GPU kernels that use atomic operations as synchronisation mechanism. Our approach exploits the notion of resource invariant from Concurrent Separation Logic (CSL) to capture the behaviour of atomic operations. However, because of the different memory levels in the GPU architecture, we adapt this notion of resource invariant to these memory levels, i.e., group resource invariants capture the behaviour of atomic operations that access locations in local memory, while kernel resource invariants capture the behaviour of atomic operations that access locations in global memory. We show soundness of our approach and we provide tool support that enables us to verify kernels from standard benchmarks suites

Lin28a uses distinct mechanisms of binding to RNA and affects positively and negatively miRNA levels

Lin28a inhibits the biogenesis of let-7 miRNAs by triggering the polyuridylation and degradation of their precursors by terminal uridylyltransferases TUT4/7 and 3'-5' exoribonuclease Dis3l2, respectively. Previously, we showed that Lin28a also controls the production of neuro-specific miRNA-9 via a polyuridylation-independent mechanism. Here we reveal that the sequences and structural characteristics of pre-let-7 and pre-miRNA-9 are eliciting two distinct modes of binding to Lin28a. We present evidence that Dis3l2 controls miRNA-9 production. Finally, we show that the constitutive expression of untagged Lin28a during neuronal differentiation in vitro positively and negatively affects numerous other miRNAs. Our findings shed light on the role of Lin28a in differentiating cells and on the ways in which one RNA-binding protein can perform multiple roles in the regulation of RNA processing

IMP1 KH1 and KH2 domains create a structural platform with unique RNA recognition and re-modelling properties

IGF2 mRNA-binding protein 1 (IMP1) is a key regulator of messenger RNA (mRNA) metabolism and transport in organismal development and, in cancer, its mis-regulation is an important component of tumour metastasis. IMP1 function relies on the recognition of a diverse set of mRNA targets that is mediated by the combinatorial action of multiple RNA-binding domains. Here, we dissect the structure and RNA-binding properties of two key RNA-binding domains of IMP1, KH1 and KH2, and we build a kinetic model for the recognition of RNA targets. Our data and model explain how the two domains are organized as an intermolecular pseudo-dimer and that the important role they play in mRNA target recognition is underpinned by the high RNA-binding affinity and fast kinetics of this KH1KH2-RNA recognition unit. Importantly, the high-affinity RNA-binding by KH1KH2 is achieved by an inter-domain coupling 50-fold stronger than that existing in a second pseudo-dimer in the protein, KH3KH4. The presence of this strong coupling supports a role of RNA re-modelling in IMP1 recognition of known cancer targets