Site-Selective Cross-Coupling of Remote Chlorides Enabled by Electrostatically-Directed Palladium Catalysis

Control of site-selectivity in chemical reactions that occur remote from existing functionality remains a major challenge in synthetic chemistry. We describe a strategy that enables three of the most commonly used cross-coupling processes to occur with high site-selectivity on dichloroarenes which bear acidic functional groups. We have achieved this by repurposing an established sulfonylated phosphine ligand to exploit its inherent bifunctionality. Mechanistic studies suggest that the sulfonate group engages in attractive electrostatic interactions with the associated cation of deprotonated substrate, guiding cross-coupling to the chloride at the arene meta-position. This counterintuitive combination of anionic ligand and anionic substrate demonstrates an alternative design principle when considering applying non-covalent interactions to direct catalysis.We are grateful to AstraZeneca for PhD studentships through the AZ‐Cambridge PhD program (W.A.G. and R.P.), the Royal Society for a University Research Fellowship (R.J.P.), the EPSRC (EP/N005422/1) and the ERC (StG 757381)

A population genetic analysis of antifolate resistance in Plasmodium falciparum in Southeast Africa

This thesis is a description of the effects of Sulphadoxine/Pyrimethamine (SP) selection on the genome of Plasmodium Jalciparum. Antimalarial resistance in P. Jalciparum to the antifolate combination of SP is conferred by a series of substitutions that alter the active sites of the target enzymes dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS). Different combinations of substitutions result in differing levels of drug insensitivity as shown by both in vitro studies and association with treatment failure. In southeast Africa, where the samples taken for this study originate, the two most highly resistant dhfr and dhps alleles are the triple mutant (N51I+C59R+Sl08N) and the double mutant (A437G+K540E) ,respectively. A molecular population genetic analytic approach is applied to examine the emergence and spread of SP resistant mutations in Africa. We observe that differences in the frequencies of the resistance alleles between southeast African populations broadly reflect heterogeneity in drug selection history across the region. We find that this exists despite strongly homogenising gene flow. Selection for a favourable allele can have effects on neutral loci flanking the selected site. A selective sweep occurs when neutral flanking loci hitchhike with the selected allele as it increases in frequency, reducing genetic diversity along the chromosome in the population. The hitchhiking alleles indicate the ancestry of the selected allele and has shown that alleles at dhfr and dhps comprised of multiples of mutations have emerged rarely in east African parasite populations (Roper et al. 2003). The thesis is the first description of the full extent of the selective sweeps around three dhfr and dhps resistance alleles in southeast Africa. The thesis contains analysis of the changes that occur to a selective sweep over time and in populations with contrasting recombination rates and selection histories. Through use of a deterministic model we identify that gene flow plays an important role in establishing the frequency of the resistance allele at values greater than l/Ne, the frequency of a de novo mutation

An investigation of the performance of a new Mechanical thrombectomy device using Bond Graph modelling: application to the extraction of blood clots in the middle cerebral artery

A number of thrombectomy devices using a variety of methods have now been developed to facilitate clot removal. We present research involving one such experimental device recently developed in the UK, called a ‘GP’ Thrombus Aspiration Device (GPTAD). This device has the potential to bring about the extraction of a thrombus. Although the device is at a relatively early stage of development, the results look encouraging. In this work, we present an analysis and modeling of the GPTAD by means of the bond graph technique; it seems to be a highly effective method of simulating the device under a variety of conditions. Such modeling is useful in optimizing the GPTAD and predicting the result of clot extraction. The aim of this simulation model is to obtain the minimum pressure necessary to extract the clot and to verify that both the pressure and the time required to complete the clot extraction are realistic for use in clinical situations, and are consistent with any experimentally obtained data. We therefore consider aspects of rheology and mechanics in our modeling

Diverse functions of clusterin promote and protect against the development of pulmonary fibrosis.

Pulmonary fibrosis is a progressive scarring disorder of the lung with dismal prognosis and no curative therapy. Clusterin, an extracellular chaperone and regulator of cell functions, is reduced in bronchoalveolar lavage fluid of patients with pulmonary fibrosis. However, its distribution and role in normal and fibrotic human lung are incompletely characterized. Immunohistochemical localization of clusterin revealed strong staining associated with fibroblasts in control lung and morphologically normal areas of fibrotic lung but weak or undetectable staining in fibrotic regions and particularly fibroblastic foci. Clusterin also co-localized with elastin in vessel walls and additionally with amorphous elastin deposits in fibrotic lung. Analysis of primary lung fibroblast isolates in vitro confirmed the down-regulation of clusterin expression in fibrotic compared with control lung fibroblasts and further demonstrated that TGF-β1 is capable of down-regulating fibroblast clusterin expression. shRNA-mediated down-regulation of clusterin did not affect TGF-β1-induced fibroblast-myofibroblast differentiation but inhibited fibroblast proliferative responses and sensitized to apoptosis. Down-regulation of clusterin in fibrotic lung fibroblasts at least partly due to increased TGF-β1 may therefore represent an appropriate but insufficient response to limit fibroproliferation. Reduced expression of clusterin in the lung may also limit its extracellular chaperoning activity contributing to dysregulated deposition of extracellular matrix proteins

Legume based plant mixtures for delivery of multiple ecosystem services: An overview of benefits

As costs for mineral fertilizers rise, legume-based leys are recognised as a potential alternative nitrogen source for crops. Here we demonstrate that including species-rich legume-based leys in the rotation helps to maximize synergies between agricultural productivity and other ecosystem services. By using functionally diverse plant species mixtures these services can be optimised and fine-tuned to regional and farm-specific needs. Field experiments run over three years at multiple locations showed that the stability of ley performance was greater in multi-species mixtures than in legume monocultures. In addition, mixing different legume species in the ley helps to suppress both early and late weeds. Further, combining complementary phenologies of different legume species extended forage availability for key pollinator species. Finally, widening the range of legume species increases opportunities to build short term leys into rotations on conventional farms via cover cropping or undersowing

Comparison of individual-level and population-level risk factors for rhinoconjunctivitis, asthma, and eczema in the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three

Background Symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema in children cluster at both the individual and population levels. Objectives To assess individual-level and school-level risk factors for symptoms of rhinoconjunctivitis and compare them to corresponding associations with symptoms of asthma and eczema in Phase Three of the International Study of Asthma and Allergies in Childhood. Methods We studied 116,863 children aged 6–7 years from 2163 schools in 59 centres and 22 countries and 224,436 adolescents aged 13–14 years from 2037 schools in 97 centres in 41 countries. Multilevel logistic regression models were fitted with random intercepts for school, centre, and country, adjusting for sex and maternal education at the child level. Associations between symptoms and a range of lifestyle and environmental risk factors were assessed for both the child's exposure and mean exposure at the school. Models were fitted for rhinoconjunctivitis, asthma, and eczema singly (unimorbidity) and for combinations of these conditions (multimorbidity). Results Generally, associations between symptoms and exposures at the school level were similar in direction and magnitude to those at the child level. Associations with multimorbidity were stronger than for unimorbidity, particularly in individuals with symptoms of all three diseases, but risk factor associations found in conventional single disease analyses persisted among children with only one condition, after excluding multimorbid groups. Comparisons of individuals with only one disease showed that many risk factor associations were consistent across the three conditions. More strongly associated with asthma were low birthweight, cat exposure in infancy, and current maternal smoking. Current paracetamol use was more strongly associated with asthma and rhinoconjunctivitis than eczema. Breastfeeding was more strongly associated with eczema than asthma or rhinoconjunctivitis. The direction and magnitude of most risk factor associations were similar in affluent and non-affluent countries, although notable exceptions include farm animal contact in infancy and larger sibships, which were associated with increased risk of rhinoconjunctivitis in non-affluent countries but reduced risk in affluent countries. In both age groups, current paracetamol use increased risk of each disease to a greater extent in affluent countries than in non-affluent countries. Effects of paracetamol and antibiotics in infancy were more consistent between richer and poorer settings. Conclusions Most of the environmental and lifestyle correlates of rhinoconjunctivitis, asthma and eczema in childhood display similarity across the three conditions, even in less affluent settings where allergic sensitisation is less likely to explain the concordant epidemiological patterns

A nullimorphic ERLIN2 mutation defines a complicated hereditary spastic paraplegia locus (SPG18)

Hereditary Spastic Paraplegia (HSP) is a clinically and genetically heterogeneous group of neurological disorders that are characterized by progressive spasticity of the lower extremities. We describe an extended consanguineous Saudi family in which HSP is linked to SPG18, a previously reported autosomal recessive locus, and show that it is associated with a nullimorphic deletion of ERLIN2, a component of endoplasmic reticulum associated degradation. This finding adds to the growing diversity of cellular functions that are now known to be involved in the maintenance of the corticospinal tract neurons

Spin and Statistics and First Principles

It was shown in the early Seventies that, in Local Quantum Theory (that is the most general formulation of Quantum Field Theory, if we leave out only the unknown scenario of Quantum Gravity) the notion of Statistics can be grounded solely on the local observable quantities (without assuming neither the commutation relations nor even the existence of unobservable charged field operators); one finds that only the well known (para)statistics of Bose/Fermi type are allowed by the key principle of local commutativity of observables. In this frame it was possible to formulate and prove the Spin and Statistics Theorem purely on the basis of First Principles. In a subsequent stage it has been possible to prove the existence of a unique, canonical algebra of local field operators obeying ordinary Bose/Fermi commutation relations at spacelike separations. In this general guise the Spin - Statistics Theorem applies to Theories (on the four dimensional Minkowski space) where only massive particles with finite mass degeneracy can occur. Here we describe the underlying simple basic ideas, and briefly mention the subsequent generalisations; eventually we comment on the possible validity of the Spin - Statistics Theorem in presence of massless particles, or of violations of locality as expected in Quantum Gravity.Comment: Survey based on a talk given at the Meeting on "Theoretical and experimental aspects of the spin - statistics connection and related symmetries", Trieste, Italy - October 21-25, 200