Facile kinetic induction of a dihydropyridide to pyrrolide ring contraction

A sterically demanding N-aryl carbodiimide reacts with magnesium 1,4-dihydropyridides to initiate heterocyclic ring contraction and pyrrolide formation under unprecedentedly mild conditions.</p

Autoimmune hypercalcemia due to autoantibodies against the calcium-sensing receptor

Context Autoimmune hypocalciuric hypercalcemia (AHH) is an acquired disorder caused by the presence of blocking autoantibodies against the calcium-sensing receptor (CaSR). Few cases of this condition have been described to date in the literature. Objective The objectives of this study were to describe two patients in whom the presence of AHH was suspected and to assess the patients for the presence of CaSR antibodies. Methods CaSR antibodies were detected and characterised by immunoprecipitation assays, CaSR peptide ELISAs, and functional assays based on the calcium-stimulated accumulation of inositol-1-phosphate in a mammalian cell line expressing the CaSR. Results Both patients presented with an acquired form of hypocalciuric hypercalcemia. Mutational analyses of CASR, GNA11 and AP2S1 for familial hypocalciuric hypercalcemia, were negative. According to the presence of Hashimoto’s disease in one patient and latent autoimmune diabetes of adulthood and thyroid autoimmunity in the other, AHH was suspected. Immunoprecipitation assays detected CaSR antibodies in both patients. Analysis of the antibody binding sites revealed two main epitopes at amino acids 41-69 and 114-126. Preincubation with purified CaSR antibodies against epitope 114-126 resulted in a significant decrease in inositol-1-phophate accumulation upon calcium-stimulation of mammalian cells expressing the CaSR, suggesting that the antibodies had receptor-blocking activity. Conclusions AHH is to be suspected in patients with an acquired biochemical pattern of PTH-dependant hypocalciuric hypercalcemia, especially in those with other concomitant autoimmune diseases. Diagnosis by means of detecting CaSR antibodies may help to better characterise this probably under-reported condition

Synthesis and structural comparisons of NHC-alanes

N-heterocyclic Carbenes (NHCs) are widely used in organometallic chemistry. Here, we examine the role of NHCs in the stabilisation of aluminium hydrides, AlH3, also known as alanes. This includes an assessment of the various synthetic strategies, comparisons of structural parameters and theoretical insight. Based on percent buried volume (%Vbur) parameters we report the largest and smallest NHC alanes to date, with noted differences in their observed stability in both the solution and solid state

Learning from patients : trainers' use of narratives for learning and teaching

There is a growing interest in how doctors learn from narratives about individual cases, reflected, for example, in the use of e-portfolios. This study aimed to evaluate how GP trainers conceptualised 'learning from patients', and what use they currently made of narrative recounts in training. Thematic analysis (TA) and corpus-linguistic (CL) analysis, with data collected from a convenience sample of trainers in the UK, Ireland, and Spain. GP trainers in the three settings were contacted, and volunteers recruited (22 in UK, 24 in Ireland, and 16 in Spain). Volunteers were interviewed and asked to offer a narrative about 'a patient you learned from' and whether they used narratives as a training device. There were no differences between settings. Trainers described an engaged and personal relationship with patients. They described learning about themselves, the human condition, and about how to live and die well. Their narratives were structured in various ways. At times, they led to precise conclusions: at times, they were perceived as meaningful, but resisting analysis. As regards teaching through narrative, it was reported as commonly used, but present practice appears ad hoc rather than planned. The lack of difference between settings suggests a degree of commonality about how trainers perceive learning and teaching in the areas explored, but cannot be generalised further. The level of personal engagement was more than anticipated, and suggests the label 'doctor-patient relationship', as the term is used, may not be adequate to describe the nature of some interactions

Synthesis and reactivity of an aluminium n-heterocyclic aminal

Tethered N-heterocyclic carbenes (NHCs) are an emerging class of ligand, as they feature all the desirable aspects of NHCs (ease of synthesis, high tunabilty) but also enable metal-ligand cooperativity when combined with Lewis acidic metal centres due to the donor-acceptor nature of the complexes formed. Herein we report a simple ethoxy-tethered NHC for the stabilisation of Al(III) hydrides, resulting in the unexpected formation of a bicyclic N-heterocyclic aminal (1). Compound 1 behaves as a metal hydride, capable of reducing benzophenone and carbodiimide to yield compounds 2 and 3, respectively. Furthermore, we show that 1 behaves as an efficient catalyst in the dehydrocoupling of amine-boranes due to the hemilabile nature of the supporting ligand

The perseverance of Pacioli's goods inventory accounting system

This paper details sources of the 'undoubtedly strange' (Yamey, 1994a, p.119) system of goods inventory records described in Pacioli’s 1494 bookkeeping treatise and traces the longevity and widespread use of this early perpetual inventory recording (EPIR) system in English language texts. By doing so and contrasting this system with the bookkeeping treatment of modern texts, it is shown that the EPIR system persisted as the dominant form of goods inventory accounting for between 400 and 500 years and that the reasons for its demise are worthy of further consideration and research

Variant of TYR and Autoimmunity Susceptibility Loci in Generalized Vitiligo.

BACKGROUND Generalized vitiligo is an autoimmune disease characterized by melanocyte loss, which results in patchy depigmentation of skin and hair, and is associated with an elevated risk of other autoimmune diseases. METHODS To identify generalized vitiligo susceptibility loci, we conducted a genomewide association study. We genotyped 579,146 single-nucleotide polymorphisms (SNPs) in 1514 patients with generalized vitiligo who were of European-derived white (CEU) ancestry and compared the genotypes with publicly available control genotypes from 2813 CEU persons. We then tested 50 SNPs in two replication sets, one comprising 677 independent CEU patients and 1106 CEU controls and the other comprising 183 CEU simplex trios with generalized vitiligo and 332 CEU multiplex families. RESULTS We detected significant associations between generalized vitiligo and SNPs at several loci previously associated with other autoimmune diseases. These included genes encoding major-histocompatibility-complex class I molecules (P=9.05×10−23) and class II molecules (P=4.50×10−34), PTPN22 (P=1.31×10−7), LPP (P=1.01×10−11), IL2RA (P=2.78×10−9), UBASH3A (P=1.26×10−9), and C1QTNF6 (P=2.21×10−16). We also detected associations between generalized vitiligo and SNPs in two additional immune-related loci, RERE (P=7.07×10−15) and GZMB (P=3.44×10−8), and in a locus containing TYR (P=1.60×10−18), encoding tyrosinase. CONCLUSIONS We observed associations between generalized vitiligo and markers implicating multiple genes, some associated with other autoimmune diseases and one (TYR) that may mediate target-cell specificity and indicate a mutually exclusive relationship between susceptibility to vitiligo and susceptibility to melanoma

Common variants in FOXP1 are associated with generalized vitiligo

In a recent genome-wide association study of generalized vitiligo, we identified ten confirmed susceptibility loci. By testing additional loci that showed suggestive association in the genome-wide study, using two replication cohorts of European descent, we observed replicated association of generalized vitiligo with variants at 3p13 encompassing FOXP1 (rs17008723, combined P = 1.04 × 10−8) and with variants at 6q27 encompassing CCR6 (rs6902119, combined P = 3.94 × 10−7)

Candidate-gene based GWAS identifies reproducible DNA markers for metabolic pyrethroid resistance from standing genetic variation in East African Anopheles gambiae.

Metabolic resistance to pyrethroid insecticides is widespread in Anopheles mosquitoes and is a major threat to malaria control. DNA markers would aid predictive monitoring of resistance, but few mutations have been discovered outside of insecticide-targeted genes. Isofemale family pools from a wild Ugandan Anopheles gambiae population, from an area where operational pyrethroid failure is suspected, were genotyped using a candidate-gene enriched SNP array. Resistance-associated SNPs were detected in three genes from detoxification superfamilies, in addition to the insecticide target site (the Voltage Gated Sodium Channel gene, Vgsc). The putative associations were confirmed for two of the marker SNPs, in the P450 Cyp4j5 and the esterase Coeae1d by reproducible association with pyrethroid resistance in multiple field collections from Uganda and Kenya, and together with the Vgsc-1014S (kdr) mutation these SNPs explained around 20% of variation in resistance. Moreover, the >20 Mb 2La inversion also showed evidence of association with resistance as did environmental humidity. Sequencing of Cyp4j5 and Coeae1d detected no resistance-linked loss of diversity, suggesting selection from standing variation. Our study provides novel, regionally-validated DNA assays for resistance to the most important insecticide class, and establishes both 2La karyotype variation and humidity as common factors impacting the resistance phenotype

Synthesis and reactivity of bis-tris(pyrazolyl)borate lanthanide-aluminium heterobimetallic trihydride complexes

Molecular heterobimetallic hydride complexes of lanthanides (Ln) and main group (MG) metals exhibit chemical properties unique from their monometallic counterparts and are highly reactive species, making their synthesis and isolation challenging. Herein, molecular Ln/Al heterobimetallic trihydrides [Ln(Tp)2(μ-H)2Al(H)(Nʹʹ)] 2-Ln (Ln = Y, Sm, Dy, Yb; Tp = hydrotris(1-pyrazolyl)borate; Nʹʹ = N(SiMe3)2) have been synthesised by facile insertion of aminoalane [Me3N•AlH3] into the Ln–N amide bonds of [Ln(Tp)2(Nʹʹ)] 1-Ln. Thus, providing a simple synthetic strategy to access a range of Ln/Al hydrides. Reactivity studies demonstrate that 2-Ln is a heterobimetallic hydride, with evidence for the cooperative nature of 2-Ln shown by the catalytic amine-borane dehydrocoupling under ambient conditions in contrast to its monomeric counterparts