Photochemistry of riboflavin

Résumé Le spectre d'absorption, les caractéristiques luminescentes et photochimiques de la riboflavine sont présentés. L'interprétation des données expérimentales d'autres auteurs sur la décomposition photochimique de l'eau sensibilisée par la riboflavine est critiquée. Il faut distinguer deux cas: dans les réactions photochimiques qui ont lieu en l'absence de donneurs d'électrons ajoutés, la portion ribosique de la riboflavine se comporte en donneuse d'électrons et elle est détruité. Par contre, en présence de donneurs d'électrons adjoutés, la riboflavine agit comme véritable photosensibilisateur et n'est pas consumée dans l'ensemble de la réaction photochimique.     

Sur la biosynthèse des constituants amers des Simarubacées

Summary The biosynthesis of glaucarubinone (IXa) and glaucarubolone (IXb), the bitter constituents ofSimarouba glauca (Simaroubaceae), has been investigated with the help of [2-¹⁴C] mevalonic acid lactone. The results so far obtained are consistent with the scheme involving a tetracyclic triterpene of the apoeuphol type as a precursor of these bitter substances.

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Avec la collaboration technique de Mlle A.Merrien.     

Mechanisms of drug inhibition of signalling molecules

The emergence of tumour-specific, molecularly targeted agents signifies a paradigm shift in cancer therapy, with less reliance on drugs that non-discriminately kill tumour and host cells. Although the diversity of targets giving rise to this new generation of anticancer drugs has expanded, many challenges persist in the design of effective treatment regimens. The complex interplay of signal-transduction pathways further complicates the customization of cancer treatments to target single mechanisms. However, despite uncertainty over precise or dominant mechanisms of action, especially for compounds targeting multiple gene products, emerging agents are producing significant therapeutic advances against a broad range of human cancers.     

A novel self-promoted Morita-Baylis-Hillman-like dimerization

While stable in CH₂Cl₂, hexane or THF, in the presence of MeOH, self-promoted dimerization of the triarylphosphine-alkene 1, a ligand for Pd-catalyzed reactions, produced an unusual racemic bis(phosphine) 2 in high yield. The reaction of 2 with Pd(dba)₂, followed by oxidative addition of p-IC₆H₄NO₂, yielded a trans-chelated Pd(II) aryl iodide complex.     

PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans

Ichthyoses comprise a heterogeneous group of genodermatoses characterized by abnormal desquamation over the whole body, for which the genetic causes of several human forms remain unknown. We used a spontaneous dog model in the golden retriever breed, which is affected by a lamellar ichthyosis resembling human autosomal recessive congenital ichthyoses (ARCI), to carry out a genome-wide association study. We identified a homozygous insertion-deletion (indel) mutation in PNPLA1 that leads to a premature stop codon in all affected golden retriever dogs. We subsequently found one missense and one nonsense mutation in the catalytic domain of human PNPLA1 in six individuals with ARCI from two families. Further experiments highlighted the importance of PNPLA1 in the formation of the epidermal lipid barrier. This study identifies a new gene involved in human ichthyoses and provides insights into the localization and function of this yet uncharacterized member of the PNPLA protein family.     

The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous autosomal recessive disorder characterized by recurrent infections of the respiratory tract associated with the abnormal function of motile cilia. Approximately half of individuals with PCD also have alterations in the left-right organization of their internal organ positioning, including situs inversus and situs ambiguous (Kartagener's syndrome). Here, we identify an uncharacterized coiled-coil domain containing a protein, CCDC40, essential for correct left-right patterning in mouse, zebrafish and human. In mouse and zebrafish, Ccdc40 is expressed in tissues that contain motile cilia, and mutations in Ccdc40 result in cilia with reduced ranges of motility. We further show that CCDC40 mutations in humans result in a variant of PCD characterized by misplacement of the central pair of microtubules and defective assembly of inner dynein arms and dynein regulatory complexes. CCDC40 localizes to motile cilia and the apical cytoplasm and is required for axonemal recruitment of CCDC39, disruption of which underlies a similar variant of PCD.     

Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3

We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.     

Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis

Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2-24.2 and show that the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-β pathway that is essential for TGF-β signal transmission. SMAD3 mutations lead to increased aortic expression of several key players in the TGF-β pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-β pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis.     

Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon

Kras is commonly mutated in colon cancers, but mutations in Nras are rare. We have used genetically engineered mice to determine whether and how these related oncogenes regulate homeostasis and tumorigenesis in the colon. Expression of K-Ras(G12D) in the colonic epithelium stimulated hyperproliferation in a Mek-dependent manner. N-Ras(G12D) did not alter the growth properties of the epithelium, but was able to confer resistance to apoptosis. In the context of an Apc-mutant colonic tumor, activation of K-Ras led to defects in terminal differentiation and expansion of putative stem cells within the tumor epithelium. This K-Ras tumor phenotype was associated with attenuated signaling through the MAPK pathway, and human colon cancer cells expressing mutant K-Ras were hypersensitive to inhibition of Raf, but not Mek. These studies demonstrate clear phenotypic differences between mutant Kras and Nras, and suggest that the oncogenic phenotype of mutant K-Ras might be mediated by noncanonical signaling through Ras effector pathways.