Susceptibility to leprosy is associated with PARK2 and PACRG

Leprosy is caused by Mycobacterium leprae and affects about 700,000 individuals each year. It has long been thought that leprosy has a strong genetic component, and recently we mapped a leprosy susceptibility locus to chromosome 6 region q25-q26 (ref. 3). Here we investigate this region further by using a systematic association scan of the chromosomal interval most likely to harbour this leprosy susceptibility locus. In 197 Vietnamese families we found a significant association between leprosy and 17 markers located in a block of approx. 80 kilobases overlapping the 5' regulatory region shared by the Parkinson's disease gene PARK2 and the co-regulated gene PACRG. Possession of as few as two of the 17 risk alleles was highly predictive of leprosy. This was confirmed in a sample of 975 unrelated leprosy cases and controls from Brazil in whom the same alleles were strongly associated with leprosy. Variants in the regulatory region shared by PARK2 and PACRG therefore act as common risk factors for leprosy.     

Suppression of pup retrieving behavior in rats following administration ofl-Δ9-Tetrahydrocannabinol

Résumé Le comportement des femelles rat rapportant ses petits au nid a été fortement influencé par le L- ⁹ A des doses de 20 mg/kg il s'est complètement arrêté.     

Development of tolerance toΔ 9-THC in the frog

Résumé Après injections bi-journalières de ⁹-THC à des grenouilles, nous avons calculé la durée de la perte du réflexe de redressement. La tolérance au ⁹-THC fut évidente après la seconde injection et, après la troisième, aucun effect ne fut visible. Ceci suggère que la tolérance se développe par le ⁹-THC, et non par ses métabolites, puisque les grenouilles n'ont pas de système enzymatique d'hydroxylation.     

The hematopoietic stem-cell niche in health and leukemia

Research in the last decade has shown that hematopoietic stem cells (HSCs) interact with and are modulated by a complex multicellular microenvironment in the bone marrow, which includes both the HSC progeny and multiple non-hematopoietic cell types. Intense work is gradually throwing light on the composition of the HSC niche and the molecular cues exchanged between its components, which has implications for HSC production, maintenance and expansion. In addition, it has become apparent that bidirectional interactions between leukemic cells and their niche play a previously unrecognized role in the initiation and development of hematological malignancies. Consequently, targeting of the malignant niche holds considerable promise for more specific antileukemic therapies. Here we summarize the latest insights into HSC niche biology and recent work showing multiple connections between hematological malignancy and alterations in the bone marrow microenvironment.     

Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations

Mutations involving gains of glycosylation have been considered rare, and the pathogenic role of the new carbohydrate chains has never been formally established. We identified three children with mendelian susceptibility to mycobacterial disease who were homozygous with respect to a missense mutation in IFNGR2 creating a new N-glycosylation site in the IFNgammaR2 chain. The resulting additional carbohydrate moiety was both necessary and sufficient to abolish the cellular response to IFNgamma. We then searched the Human Gene Mutation Database for potential gain-of-N-glycosylation missense mutations; of 10,047 mutations in 577 genes encoding proteins trafficked through the secretory pathway, we identified 142 candidate mutations ( approximately 1.4%) in 77 genes ( approximately 13.3%). Six mutant proteins bore new N-linked carbohydrate moieties. Thus, an unexpectedly high proportion of mutations that cause human genetic disease might lead to the creation of new N-glycosylation sites. Their pathogenic effects may be a direct consequence of the addition of N-linked carbohydrate.     

Modulation of A-type potassium channels by a family of calcium sensors

In the brain and heart, rapidly inactivating (A-type) voltage-gated potassium (Kv) currents operate at subthreshold membrane potentials to control the excitability of neurons and cardiac myocytes. Although pore-forming alpha-subunits of the Kv4, or Shal-related, channel family form A-type currents in heterologous cells, these differ significantly from native A-type currents. Here we describe three Kv channel-interacting proteins (KChIPs) that bind to the cytoplasmic amino termini of Kv4 alpha-subunits. We find that expression of KChIP and Kv4 together reconstitutes several features of native A-type currents by modulating the density, inactivation kinetics and rate of recovery from inactivation of Kv4 channels in heterologous cells. All three KChIPs co-localize and co-immunoprecipitate with brain Kv4 alpha-subunits, and are thus integral components of native Kv4 channel complexes. The KChIPs have four EF-hand-like domains and bind calcium ions. As the activity and density of neuronal A-type currents tightly control responses to excitatory synaptic inputs, these KChIPs may regulate A-type currents, and hence neuronal excitability, in response to changes in intracellular calcium.     

Chronopharmacology ofΔ 9-tetrahydrocannabinol hypothermia in mice

Résumé La température rectale de souris ayant subi une unique injection de ⁹THC (injection administrée soit le matin, soit l'après-midi, ou soit durant la nuit) a été mesurée 1, 2 et 4 h suivant cette injection. Chez les animaux, injectés l'après-midi, l'abaissement de température était maximal, mais il fut minimal chez les animaux injectés de nuit.     

A tree · a window · a hill; generalization of nearest-neighbor interchange in phylogenetic optimization

The method of nearest-neighbor interchange effects local improvements in a binary tree by replacing a 4-subtree by one of its two alternatives if this improves the objective function. We extend this to k-subtrees to reduce the number of local optima. Possible sequences of k-subtrees to be examined are produced by moving a window over the tree, incorporating one edge at a time while deactivating another. The direction of this movement is chosen according to a hill-climbing strategy. The algorithm includes a backtracking component. Series of simulations of molecular evolution data/parsimony analysis are carried out, fork=4, ..., 8, contrasting the hill-climbing strategy to one based on a random choice of next window, and comparing two stopping rules. Increasing window sizek is found to be the most effective way of improving the local optimum, followed by the choice of hill-climbing over the random strategy. A suggestion for achieving higher values ofk is based on a recursive use of the hill-climbing strategy.Acknowledgments: This work was supported in part by grants to the first author from the Natural Sciences and Engineering Research Council (Canada) and theFonds pour la formation de chercheurs et l'aide à la recherche (Québec), and to the third author from the Danish Research Council. The first author is a fellow of the Canadian Institute for Advanced Research. Much of the research was carried out in the spring of 1991 while the first author was visiting the University of Geneva; warmest thanks are due Professor Claude Weber for this opportunity.     

Proteolytic control of TGF-β co-receptor activity by BMP-1/tolloid-like proteases revealed by quantitative iTRAQ proteomics

The metalloproteinase BMP-1 (bone morphogenetic protein-1) plays a major role in the control of extracellular matrix (ECM) assembly and growth factor activation. Most of the growth factors activated by BMP-1 are members of the TGF-β superfamily known to regulate multiple biological processes including embryonic development, wound healing, inflammation and tumor progression. In this study, we used an iTRAQ (isobaric tags for relative and absolute quantification)-based quantitative proteomic approach to reveal the release of proteolytic fragments from the cell surface or the ECM by BMP-1. Thirty-eight extracellular proteins were found in significantly higher or lower amounts in the conditioned medium of HT1080 cells overexpressing BMP-1 and thus, could be considered as candidate substrates. Strikingly, three of these new candidates (betaglycan, CD109 and neuropilin-1) were TGF-β co-receptors, also acting as antagonists when released from the cell surface, and were chosen for further substrate validation. Betaglycan and CD109 proved to be directly cleaved by BMP-1 and the corresponding cleavage sites were extensively characterized using a new mass spectrometry approach. Furthermore, we could show that the ability of betaglycan and CD109 to interact with TGF-β was altered after cleavage by BMP-1, leading to increased and prolonged SMAD2 phosphorylation in BMP-1-overexpressing cells. Betaglycan processing was also observed in primary corneal keratocytes, indicating a general and novel mechanism by which BMP-1 directly affects signaling by controlling TGF-β co-receptor activity. The proteomic data have been submitted to ProteomeXchange with the identifier PXD000786 and doi: 10.6019/PXD000786.