Definitive crystal structure of 1,1'-bis[1,2-dicarba-<i>clos</i>o-dodecaborane(11)]

In the title compound, C4H22B20, the two {1,2-closo-C2B10H11} cages are linked across a centre of inversion with a C—C distance of 1.5339 (11) Å. By careful analysis of the structure, it is established that the non-linking cage C atom is equally disordered over cage vertices 2 and 3

Crystal structure of 1,1'-bis[1,7-dicarba-<i>closo</i>-dodecaborane(11)]

In the title compound, C4H22B20, the two {1,7-closo-C2B10H11} cages are linked across a centre of inversion, with C—C = 1.5401 (16) Å. The position of the second non-linking cage C atom was established unambiguously by geometric and crystallographic methods and there is no evidence of C/B disorder

Steric <i>versus</i> electronic factors in metallacarborane isomerisation: nickelacarboranes with 3,1,2-, 4,1,2- and 2,1,8-NiC₂B₉ architectures and pendant carborane groups, derived from 1,1′-bis(o-carborane)

Nickelacarborane derivatives of 1,1′-bis(o-carborane) allow comment on the factors important in the isomerisation of metallacarboranes.</p

Developing nitrosocarborane chemistry

New nitrosocarboranes or their hydroxylamine or Diels–Alder cycloadducts have been prepared and fully characterised.</p

Double deboronation and homometalation of 1,1'-bis(ortho-carborane)

Diastereomeric diruthenium and dicobalt species derived from double deboronation and metalation of 1,1′-bis(ortho-carborane) have been prepared and characterised.</p

Unprecedented flexibility of the 1,1′-bis(o-carborane) ligand:catalytically-active species stabilised by B-agostic B–H⇀Ru interactions

The compound (p-cymene)Ru[(C2B10H10)2], an effective Lewis acid catalyst, is the precursor to a number of products in which the 1,1′-bis(o-carborane) unit displays an unprecedented range of ligating modes.</p

Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn’s Disease

Inflammatory bowel disease (IBD), clinically defined as Crohn’s disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in genetically susceptible hosts. Pediatric onset IBD represents ≥ 25% of all IBD diagnoses and often presents with intestinal stricturing, perianal disease, and failed response to conventional treatments. NOD2 was the first and is the most replicated locus associated with adult IBD, to date. However, its role in pediatric onset IBD is not well understood. We performed whole-exome sequencing on a cohort of 1,183 patients with pediatric onset IBD (ages 0–18.5 years). We identified 92 probands with biallelic rare and low frequency NOD2 variants accounting for approximately 8% of our cohort, suggesting a Mendelian inheritance pattern of disease. Additionally, we investigated the contribution of recessive inheritance of NOD2 alleles in adult IBD patients from a large clinical population cohort. We found that recessive inheritance of NOD2 variants explains ~ 7% of cases in this adult IBD cohort, including ~ 10% of CD cases, confirming the observations from our pediatric IBD cohort. Exploration of EHR data showed that several of these adult IBD patients obtained their initial IBD diagnosis before 18 years of age, consistent with early onset disease. While it has been previously reported that carriers of more than one NOD2 risk alleles have increased susceptibility to Crohn’s Disease (CD), our data formally demonstrate that recessive inheritance of NOD2 alleles is a mechanistic driver of early onset IBD, specifically CD, likely due to loss of NOD2 protein function. Collectively, our findings show that recessive inheritance of rare and low frequency deleterious NOD2 variants account for 7–10% of CD cases and implicate NOD2 as a Mendelian disease gene for early onset Crohn’s Disease

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis