Null alleles of ABCG2 encoding the breast cancer resistance protein define the new blood group system Junior

The breast cancer resistance protein, also known as ABCG2, is one of the most highly studied ATP-binding cassette (ABC) transporters because of its ability to confer multidrug resistance. The lack of information on the physiological role of ABCG2 in humans severely limits cancer chemotherapeutic approaches targeting this transporter. We report here that ABCG2 comprises the molecular basis of a new blood group system (Junior, Jr) and that individuals of the Jr(a-) blood type have inherited two null alleles of ABCG2. We identified five frameshift and three nonsense mutations in ABCG2. We also show that the prevalence of the Jr(a-) blood type in the Japanese and European Gypsy populations is related to the p.Gln126* and p.Arg236* protein alterations, respectively. The identification of ABCG2(-/-) (Jr(a-)) individuals who appear phenotypically normal is an essential step toward targeting ABCG2 in cancer and also in understanding the physiological and pharmacological roles of this promiscuous transporter in humans.     

Abdominal obesity and metabolic syndrome

Metabolic syndrome is associated with abdominal obesity, blood lipid disorders, inflammation, insulin resistance or full-blown diabetes, and increased risk of developing cardiovascular disease. Proposed criteria for identifying patients with metabolic syndrome have contributed greatly to preventive medicine, but the value of metabolic syndrome as a scientific concept remains controversial. The presence of metabolic syndrome alone cannot predict global cardiovascular disease risk. But abdominal obesity - the most prevalent manifestation of metabolic syndrome - is a marker of 'dysfunctional adipose tissue', and is of central importance in clinical diagnosis. Better risk assessment algorithms are needed to quantify diabetes and cardiovascular disease risk on a global scale.     

Thresholded consensus for n-trees

A class of (multiple) consensus methods for n-trees (dendroids, hierarchical classifications) is studied. This class constitutes an extension of the so-called median consensus in the sense that we get two numbersm andm such that: If a clusterX occurs ink n-trees of a profileP, withk m, then it occurs in every consensus n-tree ofP. IfX occurs ink n-trees ofP, withm k <m, then it may, or may not, belong to a consensus n-tree ofP. IfX occurs ink n-trees ofP, withk <m then it cannot occur in any consensus n-tree ofP. If these conditions are satisfied, the multiconsensus function is said to be thresholded by the pair (m,m). Two results are obtained. The first one characterizes the pairs of numbers that can be viewed as thresholds for some consensus function. The second one provides a characterization of thresholded consensus methods. As an application a characterization of the quota rules is provided.

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Resume Cet article traite d'une classe de méthodes de consensus (multiples) entre des classifications hiérarchiques. Cette classe est une généralisation du consensus médian dans las mesure oú elle est constituée des méthodes c pour lesquelles il existe deux nombresm etm tels que: Si une classeX appartient ák hiérarchies d'un profilP, aveck m, alorsX appartient á chaque hiérarchie consensus deP. SiX appartient ák hiérarchies deP, avecm k <m, alorsX, peut, ou non, appartenir à une hiérarchie consensus deP. SiX appartient àk hiérarchies deP, aveck <m, alorsX n'appartient á aucune hiérarchie consensus deP. On dit alors que le couple (m,m) est un seuil pour c. Deux résultats sont obtenus. Le premier caractérise les couples de nombres qui sont des seuils de consensus. Le second caractérise les consensus admettant un seuil. Une caractérisation de la régle des quotas est déduite de ce second résultat.

     

Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia

The past decade has seen great advances in unraveling the biological basis of hereditary ataxias. Molecular studies of spinocerebellar ataxias (SCA) have extended our understanding of dominant ataxias. Causative genes have been identified for a few autosomal recessive ataxias: Friedreich's ataxia, ataxia with vitamin E deficiency, ataxia telangiectasia, recessive spastic ataxia of Charlevoix-Saguenay and ataxia with oculomotor apraxia type 1 (refs. 6,7) and type 2 (ref. 8). Nonetheless, genes remain unidentified for most recessive ataxias. Additionally, pure cerebellar ataxias, which represent up to 20% of all ataxias, remain poorly studied with only two causative dominant genes being described: CACNA1A (ref. 9) and SPTBN2 (ref. 10). Here, we report a newly discovered form of recessive ataxia in a French-Canadian cohort and show that SYNE1 mutations are causative in all of our kindreds, making SYNE1 the first identified gene responsible for a recessively inherited pure cerebellar ataxia.     

NP-hard Approximation Problems in Overlapping Clustering

L_p -norm (p < ∞). These problems also correspond to the approximation by a strongly Robinson dissimilarity or by a dissimilarity fulfilling the four-point inequality (Bandelt 1992; Diatta and Fichet 1994). The results are extended to circular strongly Robinson dissimilarities, indexed k-hierarchies (Jardine and Sibson 1971, pp. 65-71), and to proper dissimilarities satisfying the Bertrand and Janowitz (k + 2)-point inequality (Bertrand and Janowitz 1999). Unidimensional scaling (linear or circular) is reinterpreted as a clustering problem and its hardness is established, but only for the L ₁ norm.     

X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation

Pentameric ligand-gated ion channels from the Cys-loop family mediate fast chemo-electrical transduction, but the mechanisms of ion permeation and gating of these membrane proteins remain elusive. Here we present the X-ray structure at 2.9 A resolution of the bacterial Gloeobacter violaceus pentameric ligand-gated ion channel homologue (GLIC) at pH 4.6 in an apparently open conformation. This cationic channel is known to be permanently activated by protons. The structure is arranged as a funnel-shaped transmembrane pore widely open on the outer side and lined by hydrophobic residues. On the inner side, a 5 A constriction matches with rings of hydrophilic residues that are likely to contribute to the ionic selectivity. Structural comparison with ELIC, a bacterial homologue from Erwinia chrysanthemi solved in a presumed closed conformation, shows a wider pore where the narrow hydrophobic constriction found in ELIC is removed. Comparative analysis of GLIC and ELIC reveals, in concert, a rotation of each extracellular beta-sandwich domain as a rigid body, interface rearrangements, and a reorganization of the transmembrane domain, involving a tilt of the M2 and M3 alpha-helices away from the pore axis. These data are consistent with a model of pore opening based on both quaternary twist and tertiary deformation.