Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity

Mutations in SPINK5, encoding the serine protease inhibitor LEKTI, cause Netherton syndrome, a severe autosomal recessive genodermatosis. Spink5(-/-) mice faithfully replicate key features of Netherton syndrome, including altered desquamation, impaired keratinization, hair malformation and a skin barrier defect. LEKTI deficiency causes abnormal desmosome cleavage in the upper granular layer through degradation of desmoglein 1 due to stratum corneum tryptic enzyme and stratum corneum chymotryptic enzyme-like hyperactivity. This leads to defective stratum corneum adhesion and resultant loss of skin barrier function. Profilaggrin processing is increased and implicates LEKTI in the cornification process. This work identifies LEKTI as a key regulator of epidermal protease activity and degradation of desmoglein 1 as the primary pathogenic event in Netherton syndrome.     

Intragenic tandem repeats generate functional variability

Tandemly repeated DNA sequences are highly dynamic components of genomes. Most repeats are in intergenic regions, but some are in coding sequences or pseudogenes. In humans, expansion of intragenic triplet repeats is associated with various diseases, including Huntington chorea and fragile X syndrome. The persistence of intragenic repeats in genomes suggests that there is a compensating benefit. Here we show that in the genome of Saccharomyces cerevisiae, most genes containing intragenic repeats encode cell-wall proteins. The repeats trigger frequent recombination events in the gene or between the gene and a pseudogene, causing expansion and contraction in the gene size. This size variation creates quantitative alterations in phenotypes (e.g., adhesion, flocculation or biofilm formation). We propose that variation in intragenic repeat number provides the functional diversity of cell surface antigens that, in fungi and other pathogens, allows rapid adaptation to the environment and elusion of the host immune system.     

Discovery of the triple asteroidal system 87 Sylvia

After decades of speculation, the existence of binary asteroids has been observationally confirmed, with examples in all minor planet populations. However, no triple systems have hitherto been discovered. Here we report the unambiguous detection of a triple asteroidal system in the main belt, composed of a 280-km primary (87 Sylvia) and two small moonlets orbiting at 710 and 1,360 km. We estimate their orbital elements and use them to refine the shape of the primary body. Both orbits are equatorial, circular and prograde, suggesting a common origin. Using the orbital information to estimate its mass and density, 87 Sylvia appears to have a rubble-pile structure with a porosity of 25-60 per cent. The system was most probably formed through the disruptive collision of a parent asteroid, with the new primary resulting from accretion of fragments, while the moonlets are formed from the debris, as has been predicted previously.     

Critical introductory notes on farming systems research in developing third world agriculture

In Third World agricultural research of household-managed production units, the systems approach is applied in the form of Farming Systems Research (FSR). Several authors reviewed here have criticized the way in which this is done. It appears that most of them neglect the fact that most FSR belongs to the hard systems approach. The problem context (the household production unit and its surrounding socioeconomic system), however, consists of sense-giving subjects, which have conflicting goals and interests. Their thinking and behavior are determined largely by power relations. Therefore, in FSR, the hard systems approach should be discarded and a critical alternative approach should be developed instead.     

Being human: Religion: bound to believe?

Atheism will always be a harder sell than religion, Pascal Boyer explains, because a slew of cognitive traits predispose us to faith.     

Historical phenology: grape ripening as a past climate indicator

French records of grape-harvest dates in Burgundy were used to reconstruct spring-summer temperatures from 1370 to 2003 using a process-based phenology model developed for the Pinot Noir grape. Our results reveal that temperatures as high as those reached in the 1990s have occurred several times in Burgundy since 1370. However, the summer of 2003 appears to have been extraordinary, with temperatures that were probably higher than in any other year since 1370.     

The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy

Neutral lipid storage disease comprises a heterogeneous group of autosomal recessive disorders characterized by systemic accumulation of triglycerides in cytoplasmic droplets. Here we report a neutral lipid storage disease subgroup characterized by mild myopathy, absence of ichthyosis and mutations in both alleles of adipose triglyceride lipase (PNPLA2, also known as ATGL). Three of these mutations are predicted to lead to a truncated ATGL protein with an intact patatin domain containing the active site, but with defects in the hydrophobic domain. The block in triglyceride degradation was mimicked by short interfering RNA directed against ATGL. NLSDM is distinct from Chanarin-Dorfman syndrome, which is characterized by neutral lipid storage disease with ichthyosis, mild myopathy and hepatomegaly due to mutations in ABHD5 (also known as CGI-58).     

Functional mechanisms of the cellular prion protein (PrPC) associated anti-HIV-1 properties

The cellular prion protein PrP(C)/CD230 is a GPI-anchor protein highly expressed in cells from the nervous and immune systems and well conserved among vertebrates. In the last decade, several studies suggested that PrP(C) displays antiviral properties by restricting the replication of different viruses, and in particular retroviruses such as murine leukemia virus (MuLV) and the human immunodeficiency virus type 1 (HIV-1). In this context, we previously showed that PrP(C) displays important similarities with the HIV-1 nucleocapsid protein and found that PrP(C) expression in a human cell line strongly reduced HIV-1 expression and virus production. Using different PrP(C) mutants, we report here that the anti-HIV-1 properties are mostly associated with the amino-terminal 24-KRPKP-28 basic domain. In agreement with its reported RNA chaperone activity, we found that PrP(C) binds to the viral genomic RNA of HIV-1 and negatively affects its translation. Using a combination of biochemical and cell imaging strategies, we found that PrP(C) colocalizes with the virus assembly machinery at the plasma membrane and at the virological synapse in infected T cells. Depletion of PrP(C) in infected T cells and microglial cells favors HIV-1 replication, confirming its negative impact on the HIV-1 life cycle.