Genetic Covariance Structure of Reading, Intelligence and Memory in Children

This study investigates the genetic relationship among reading performance, IQ, verbal and visuospatial working memory (WM) and short-term memory (STM) in a sample of 112, 9-year-old twin pairs and their older siblings. The relationship between reading performance and the other traits was explained by a common genetic factor for reading performance, IQ, WM and STM and a genetic factor that only influenced reading performance and verbal memory. Genetic variation explained 83% of the variation in reading performance; most of this genetic variance was explained by variation in IQ and memory performance. We hypothesize, based on these results, that children with reading problems possibly can be divided into three groups: (1) children low in IQ and with reading problems; (2) children with average IQ but a STM deficit and with reading problems; (3) children with low IQ and STM deficits; this group may experience more reading problems than the other two

A dependent nominal type theory

Nominal abstract syntax is an approach to representing names and binding pioneered by Gabbay and Pitts. So far nominal techniques have mostly been studied using classical logic or model theory, not type theory. Nominal extensions to simple, dependent and ML-like polymorphic languages have been studied, but decidability and normalization results have only been established for simple nominal type theories. We present a LF-style dependent type theory extended with name-abstraction types, prove soundness and decidability of beta-eta-equivalence checking, discuss adequacy and canonical forms via an example, and discuss extensions such as dependently-typed recursion and induction principles

Intra-tumoural extra-cellular pH: a useful parameter of response to chemotherapy in syngeneic tumour lines

Reliable surrogate markers of response to anticancer therapy remain a desirable tool for preclinical modelling and clinical practice in oncology. Clinical evaluation is relatively unreliable when attempting to assess rapidly and prospectively the outcome of treatment. Fluxes in released or circulating tumour marker levels are a useful but inconsistent marker of cytotoxic response. Serial measurement of circulating tumour cells appears to have some utility as a surrogate marker, but assay systems are expensive, and many cancers are not associated with the presence of circulating tumour cells. Because tissue breakdown is associated with release of nucleic acids and other cellular products, we reasoned that serial measurement of intra-tumoural pH may correlate with the extent of tumour lysis, and thus with outcomes of cytotoxic chemotherapy. Doxorubicin-sensitive and doxorubicin-resistant sublines of P388 murine monocytic leukaemia in C57BL/6 mice were treated with increasing concentrations of doxorubicin. Tumours were serially measured by conventional bi-dimensional methods and pH was sampled using a bevelled tip electrode. Mean and median pH changes were statistically different in responsive and resistant tumours, and amplitude of change correlated with long-term responses to doxorubicin. Serial sampling of pH in tumour masses may provide a useful surrogate of long-term response to chemotherapy

Pre-emptive and therapeutic adoptive immunotherapy for nasopharyngeal carcinoma: Phenotype and effector function of T cells impact on clinical response

published_or_final_versio

Exploiting Symmetries When Proving Equivalence Properties for Security Protocols

International audienceVerification of privacy-type properties for cryptographic protocols in an active adversarial environment, modelled as a behavioural equivalence in concurrent-process calculi, exhibits a high computational complexity. While undecidable in general, for some classes of common cryptographic primitives the problem is coNEXP-complete when the number of honest participants is bounded.In this paper we develop optimisation techniques for verifying equivalences, exploiting symmetries between the two processes under study. We demonstrate that they provide a significant (several orders of magnitude) speed-up in practice, thus increasing the size of the protocols that can be analysed fully automatically

Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers

We address whether combinations with a pan-RAF inhibitor (RAFi) would be effective in KRAS mutant pancreatic ductal adenocarcinoma (PDAC). Chemical library and CRISPR genetic screens identify combinations causing apoptotic anti-tumor activity. The most potent combination, concurrent inhibition of RAF (RAFi) and ERK (ERKi), is highly synergistic at low doses in cell line, organoid, and rat models of PDAC, whereas each inhibitor alone is only cytostatic. Comprehensive mechanistic signaling studies using reverse phase protein array (RPPA) pathway mapping and RNA sequencing (RNA-seq) show that RAFi/ERKi induced insensitivity to loss of negative feedback and system failures including loss of ERK signaling, FOSL1, and MYC; shutdown of the MYC transcriptome; and induction of mesenchymal-to-epithelial transition. We conclude that low-dose vertical inhibition of the RAF-MEK-ERK cascade is an effective therapeutic strategy for KRAS mutant PDAC.Peer reviewe

Visitor expenditure estimation for grocery store location planning: a case study of Cornwall

Visitor expenditure is an important driver of demand in many local economies, supporting a range of services and facilities which may not be viable based solely on residential demand. In areas where self-catering accommodation is prevalent visitor demand makes up a considerable proportion of sales and revenue within grocery stores, yet this form of visitor consumption is commonly overlooked in supply and demand-side estimates of visitor spend. As such, store location planning in tourist resorts, decisions about local service provision and the local economic impacts of tourism are based on very limited demand-side estimates of visitor spend. Using Cornwall, South West England as a study area, we outline a methodology and data sources to estimate small-area visitor grocery spend. We use self-catering accommodation provision, utilisation and visitor expenditure rates as key factors driving visitor spend. We identify that the use of visitor accommodation accounts for the spatial and temporal complexities of visitor demand that may be overlooked when using alternative approaches, such as the up-scaling of residential demand. Using a spatial interaction model, we demonstrate that our expenditure estimates can be used to generate store level revenue estimation within tourist resorts, and we make a number of recommendations for service provision and store location planning in these areas

In Vitro Selection of a DNA-Templated Small-Molecule Library Reveals a Class of Macrocyclic Kinase Inhibitors

DNA-templated organic synthesis enables the translation of DNA sequences into synthetic small-molecule libraries suitable for in vitro selection. Previously, we described the DNA-templated multistep synthesis of a 13 824-membered small-molecule macrocycle library. Here, we report the discovery of small molecules that modulate the activity of kinase enzymes through the in vitro selection of this DNA-templated small-molecule macrocycle library against 36 biomedically relevant protein targets. DNA encoding selection survivors was amplified by PCR and identified by ultra-high-throughput DNA sequencing. Macrocycles corresponding to DNA sequences enriched upon selection against several protein kinases were synthesized on a multimilligram scale. In vitro assays revealed that these macrocycles inhibit (or activate) the kinases against which they were selected with IC50 values as low as 680 nM. We characterized in depth a family of macrocycles enriched upon selection against Src kinase, and showed that inhibition was highly dependent on the identity of macrocycle building blocks as well as on backbone conformation. Two macrocycles in this family exhibited unusually strong Src inhibition selectivity even among kinases closely related to Src. One macrocycle was found to activate, rather than inhibit, its target kinase, VEGFR2. Taken together, these results establish the use of DNA-templated synthesis and in vitro selection to discover small molecules that modulate enzyme activities, and also reveal a new scaffold for selective ATP-competitive kinase inhibition.Chemistry and Chemical Biolog