Cellular mechanisms responsible for cell-to-cell spreading of prions

Prions are infectious agents that cause fatal neurodegenerative diseases. Current evidence indicates that they are essentially composed of an abnormally folded protein (PrP^Sc). These abnormal aggregated PrP^Sc species multiply in infected cells by recruiting and converting the host PrP^C protein into new PrP^Sc. How prions move from cell to cell and progressively spread across the infected tissue is of crucial importance and may provide experimental opportunity to delay the progression of the disease. In infected cells, different mechanisms have been identified, including release of infectious extracellular vesicles and intercellular transfer of PrP^Sc-containing organelles through tunneling nanotubes. These findings should allow manipulation of the intracellular trafficking events targeting PrP^Sc in these particular subcellular compartments to experimentally address the relative contribution of these mechanisms to in vivo prion pathogenesis. In addition, such information may prompt further experimental strategies to decipher the causal roles of protein misfolding and aggregation in other human neurodegenerative diseases.     

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.     

Rough Sets and Three Valued Connectives Extended Abstract

<正>1 Introduction In[5]we investigated the significance of some truth-functional three valued logics of ill-known sets described by pairs of disjoint(or pairs of nested) subsets.In particular,we referred to the case of rough sets showing that if from a mathematical standpoint we obtain sound results,the interpretation with respect to     

Abnormal sensitivity to erythropoietin in the erythroblast precursors in Vaquez disease]

Marrow specimens of patients with polycythemia vera rise to erythrocytic colonies in vitro without addition of erythropoietin to the culture. This behavior was never observed with marrow cells of normal subjects or secondary erythrocytosis. These results indicate that the sensitivity of some erythrocytic progenitor cells to erythropoietin is altered in polycythemia vera.     

A star in a 15.2-year orbit around the supermassive black hole at the centre of the Milky Way

Many galaxies are thought to have supermassive black holes at their centres-more than a million times the mass of the Sun. Measurements of stellar velocities and the discovery of variable X-ray emission have provided strong evidence in favour of such a black hole at the centre of the Milky Way, but have hitherto been unable to rule out conclusively the presence of alternative concentrations of mass. Here we report ten years of high-resolution astrometric imaging that allows us to trace two-thirds of the orbit of the star currently closest to the compact radio source (and massive black-hole candidate) Sagittarius A*. The observations, which include both pericentre and apocentre passages, show that the star is on a bound, highly elliptical keplerian orbit around Sgr A*, with an orbital period of 15.2 years and a pericentre distance of only 17 light hours. The orbit with the best fit to the observations requires a central point mass of (3.7 +/- 1.5) x 10(6) solar masses (M(*)). The data no longer allow for a central mass composed of a dense cluster of dark stellar objects or a ball of massive, degenerate fermions.     

Near-infrared flares from accreting gas around the supermassive black hole at the Galactic Centre

Recent measurements of stellar orbits provide compelling evidence that the compact radio source Sagittarius A* (refs 4, 5) at the Galactic Centre is a 3.6-million-solar-mass black hole. Sgr A* is remarkably faint in all wavebands other than the radio region, however, which challenges current theories of matter accretion and radiation surrounding black holes. The black hole's rotation rate is not known, and therefore neither is the structure of space-time around it. Here we report high-resolution infrared observations of Sgr A* that reveal 'quiescent' emission and several flares. The infrared emission originates from within a few milliarcseconds of the black hole, and traces very energetic electrons or moderately hot gas within the innermost accretion region. Two flares exhibit a 17-minute quasi-periodic variability. If the periodicity arises from relativistic modulation of orbiting gas, the emission must come from just outside the event horizon, and the black hole must be rotating at about half of the maximum possible rate.     

Astrocladistics: A Phylogenetic Analysis of Galaxy Evolution II. Formation and Diversification of Galaxies

This series of papers is intended to evaluate astrocladistics in reconstructing phylogenies of galaxies. The objective of this second paper is to formalize the concept of galaxy formation and to identify the processes of diversification. We show that galaxy diversity can be expected to organize itself in a hierarchy. In order to better understand the role of mergers, we have selected a sample of 43 galaxies from the GALICS database built from simulations with a hybrid model for galaxy formation studies. These simulated galaxies, described by 119 characters and considered as representing still undefined classes, have experienced different numbers of merger events during evolution. Our cladistic analysis yields a robust tree that proves the existence of a hierarchy. Mergers, like interactions (not taken into account in the GALICS simulations), are probably a strong driver for galaxy diversification. Our result shows that mergers participate in a branching type of evolution, but do not seem to play the role of an evolutionary clock.     

A petunia ABC protein controls strigolactone-dependent symbiotic signalling and branching

Strigolactones were originally identified as stimulators of the germination of root-parasitic weeds that pose a serious threat to resource-limited agriculture. They are mostly exuded from roots and function as signalling compounds in the initiation of arbuscular mycorrhizae, which are plant-fungus symbionts with a global effect on carbon and phosphate cycling. Recently, strigolactones were established to be phytohormones that regulate plant shoot architecture by inhibiting the outgrowth of axillary buds. Despite their importance, it is not known how strigolactones are transported. ATP-binding cassette (ABC) transporters, however, are known to have functions in phytohormone translocation. Here we show that the Petunia hybrida ABC transporter PDR1 has a key role in regulating the development of arbuscular mycorrhizae and axillary branches, by functioning as a cellular strigolactone exporter. P. hybrida pdr1 mutants are defective in strigolactone exudation from their roots, resulting in reduced symbiotic interactions. Above ground, pdr1 mutants have an enhanced branching phenotype, which is indicative of impaired strigolactone allocation. Overexpression of Petunia axillaris PDR1 in Arabidopsis thaliana results in increased tolerance to high concentrations of a synthetic strigolactone, consistent with increased export of strigolactones from the roots. PDR1 is the first known component in strigolactone transport, providing new opportunities for investigating and manipulating strigolactone-dependent processes.