Cell-specific ATP7A transport sustains copper-dependent tyrosinase activity in melanosomes

Copper is a cofactor for many cellular enzymes and transporters. It can be loaded onto secreted and endomembrane cuproproteins by translocation from the cytosol into membrane-bound organelles by ATP7A or ATP7B transporters, the genes for which are mutated in the copper imbalance syndromes Menkes disease and Wilson disease, respectively. Endomembrane cuproproteins are thought to incorporate copper stably on transit through the trans-Golgi network, in which ATP7A accumulates by dynamic cycling through early endocytic compartments. Here we show that the pigment-cell-specific cuproenzyme tyrosinase acquires copper only transiently and inefficiently within the trans-Golgi network of mouse melanocytes. To catalyse melanin synthesis, tyrosinase is subsequently reloaded with copper within specialized organelles called melanosomes. Copper is supplied to melanosomes by ATP7A, a cohort of which localizes to melanosomes in a biogenesis of lysosome-related organelles complex-1 (BLOC-1)-dependent manner. These results indicate that cell-type-specific localization of a metal transporter is required to sustain metallation of an endomembrane cuproenzyme, providing a mechanism for exquisite spatial control of metalloenzyme activity. Moreover, because BLOC-1 subunits are mutated in subtypes of the genetic disease Hermansky-Pudlak syndrome, these results also show that defects in copper transporter localization contribute to hypopigmentation, and hence perhaps other systemic defects, in Hermansky-Pudlak syndrome.     

Individual differences in non-verbal number acuity correlate with maths achievement

Human mathematical competence emerges from two representational systems. Competence in some domains of mathematics, such as calculus, relies on symbolic representations that are unique to humans who have undergone explicit teaching. More basic numerical intuitions are supported by an evolutionarily ancient approximate number system that is shared by adults, infants and non-human animals-these groups can all represent the approximate number of items in visual or auditory arrays without verbally counting, and use this capacity to guide everyday behaviour such as foraging. Despite the widespread nature of the approximate number system both across species and across development, it is not known whether some individuals have a more precise non-verbal 'number sense' than others. Furthermore, the extent to which this system interfaces with the formal, symbolic maths abilities that humans acquire by explicit instruction remains unknown. Here we show that there are large individual differences in the non-verbal approximation abilities of 14-year-old children, and that these individual differences in the present correlate with children's past scores on standardized maths achievement tests, extending all the way back to kindergarten. Moreover, this correlation remains significant when controlling for individual differences in other cognitive and performance factors. Our results show that individual differences in achievement in school mathematics are related to individual differences in the acuity of an evolutionarily ancient, unlearned approximate number sense. Further research will determine whether early differences in number sense acuity affect later maths learning, whether maths education enhances number sense acuity, and the extent to which tertiary factors can affect both.     

Conjugated action of two species-specific invasion proteins for fetoplacental listeriosis

The ability to cross host barriers is an essential virulence determinant of invasive microbial pathogens. Listeria monocytogenes is a model microorganism that crosses human intestinal and placental barriers, and causes severe maternofetal infections by an unknown mechanism. Several studies have helped to characterize the bacterial invasion proteins InlA and InlB. However, their respective species specificity has complicated investigations on their in vivo role. Here we describe two novel and complementary animal models for human listeriosis: the gerbil, a natural host for L. monocytogenes, and a knock-in mouse line ubiquitously expressing humanized E-cadherin. Using these two models, we uncover the essential and interdependent roles of InlA and InlB in fetoplacental listeriosis, and thereby decipher the molecular mechanism underlying the ability of a microbe to target and cross the placental barrier.     

Common antigenic properties of a g-type (goose) and a c-type (duck) egg white lysozyme: Antibody responses in rabbits and mice

Embden goose (GEWL) and Barbary duck (DEWL) egg white lysozymes possess different amino acid sequences corresponding to the g-type and c-type, respectively. GEWL was shown to be a better immunogen than DEWL in both rabbits and mice. The antigenicity of the two lysozymes was tested using different technique (i.e. indirect ELISA, inhibition tests and immunoabsorption experiments). Injection of either GEWL or DEWL into rabbits and mice induced both specific antibodies and cross-reacting antibodies. Moreover, anti-GEWL antibodies, in contrast to anti-DEWL antibodies, did not cross-react with hen egg white lysozyme (HEWL), a c-type lysozyme. While the structure of GEWL was not modified after binding to plastic, DEWL was denaturated, but it did keep some native epitopes. It was concluded that g-type and c-type lysozymes, which have different amino acid sequences, exhibit strong common antigenic properties.     

Variation in FTO contributes to childhood obesity and severe adult obesity

We identified a set of SNPs in the first intron of the FTO (fat mass and obesity associated) gene on chromosome 16q12.2 that is consistently strongly associated with early-onset and severe obesity in both adults and children of European ancestry with an experiment-wise P value of 1.67 x 10(-26) in 2,900 affected individuals and 5,100 controls. The at-risk haplotype yields a proportion of attributable risk of 22% for common obesity. We conclude that FTO contributes to human obesity and hence may be a target for subsequent functional analyses.     

Genomic analysis of Bartonella identifies type IV secretion systems as host adaptability factors

The bacterial genus Bartonella comprises 21 pathogens causing characteristic intraerythrocytic infections. Bartonella bacilliformis is a severe pathogen representing an ancestral lineage, whereas the other species are benign pathogens that evolved by radial speciation. Here, we have used comparative and functional genomics to infer pathogenicity genes specific to the radiating lineage, and we suggest that these genes may have facilitated adaptation to the host environment. We determined the complete genome sequence of Bartonella tribocorum by shotgun sequencing and functionally identified 97 pathogenicity genes by signature-tagged mutagenesis. Eighty-one pathogenicity genes belong to the core genome (1,097 genes) of the radiating lineage inferred from genome comparison of B. tribocorum, Bartonella henselae and Bartonella quintana. Sixty-six pathogenicity genes are present in B. bacilliformis, and one has been lost by deletion. The 14 pathogenicity genes specific for the radiating lineage encode two laterally acquired type IV secretion systems, suggesting that these systems have a role in host adaptability.     

Huntington’s disease: from huntingtin function and dysfunction to therapeutic strategies

Huntington’s disease (HD) is a neurodegenerative disorder that usually starts in middle age and is characterized by involuntary movements (chorea), personality changes and dementia, leading to death within 10–20 years. The defective gene in HD contains a trinucleotide CAG repeat expansion within its coding region that expresses a polyglutamine repeat in the protein huntingtin. Together with the characteristic formation of aggregates in HD, aberrant protein interactions and several post-translational modifications affect huntingtin during disease progression and lead to the dysfunction and death of selective neurons in the brains of patients. The exact molecular mechanisms by which mutant huntingtin induces cell death are not completely understood but may involve the gain of new toxic functions and the loss of the beneficial properties of huntingtin. This review focuses on the cellular functions in which huntingtin is involved and how a better understanding of pathogenic pathways can lead to new therapeutic approaches. Received 24 May 2006; received after revision 5 July 2006; accepted 23 August 2006     

In vivo effects of immunostimulating lipopeptides on mouse liver microsomal cytochromes P-450 and on paracetamol-induced toxicity

Immunomodulating lipopeptides lauroyl-L-Ala-gamma-D-Glu-LL-A2pmNH2-Gly (RP 44.102) and lauroyl-L-Ala-gamma-D-Glu-LL-A2pmNH2 (RP 56.142) were found to protect mice against the hepatotoxicity of paracetamol, which is due to cytochrome P-450 dependent formation of toxic metabolites and radicals. In fact they decreased the amount of hepatic microsomal cytochrome P-450, and the level of CCl4-induced lipid peroxidation. In contrast lauroyl-L-Ala-gamma-D-Glu-DD-A2pmNH2 (RP 53.204), which only differs by the configuration of the two chiral carbons of A2pm (diaminopimelic acid) and is not an immunomodulating agent, failed to protect against poisoning by paracetamol and had no effect on the level of hepatic cytochrome P-450 or the microsomal CCl4-induced lipid peroxidation. This provides a clear connection between the immunostimulating properties of a compound and its effects on xenobiotic biotransformations.     

Sister chromatid exchanges in lymphocytes of normal and alcoholic subjects

The effects of alcohol consumption, cigarette smoking and age on sister chromatid exchangen (SCE) frequency in human lymphocytes were assessed by means of multiple linear regression. An increase in SCE rates was associated with alcohol consumption (p=0.0001), smoking (p=0.0231), and, to a small extent (p=0.057), age. These three confounding factors explain 48% of the inter-personal variation in SCE rates among subjects studied.We are grateful to Dr D. Krapavickaité for performing, the statistical analysis, and to Mrs V. Navickiené for technical assistance. We also wish to thank Dr B. Lambert (Stockholm, Sweden) for his valuable suggestions.     

Reaction of pyridoxal-5′-phosphate with γ-carboxyglutamic acid

Summary Pyridoxal-5-phosphate (PLP) reacts with -carboxyglutamic acid (Gla) to form a stable complex absorbing at 325 nm. It is suggested that a condensation occurs in which the formyl group of PLP reacts with the -amino group and the carbon atom of Gla to give a pyrrolidine derivative.