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.     

A role for cell-cycle-regulated histone H3 lysine 56 acetylation in the DNA damage response

DNA breaks are extremely harmful lesions that need to be repaired efficiently throughout the genome. However, the packaging of DNA into nucleosomes is a significant barrier to DNA repair, and the mechanisms of repair in the context of chromatin are poorly understood. Here we show that lysine 56 (K56) acetylation is an abundant modification of newly synthesized histone H3 molecules that are incorporated into chromosomes during S phase. Defects in the acetylation of K56 in histone H3 result in sensitivity to genotoxic agents that cause DNA strand breaks during replication. In the absence of DNA damage, the acetylation of histone H3 K56 largely disappears in G2. In contrast, cells with DNA breaks maintain high levels of acetylation, and the persistence of the modification is dependent on DNA damage checkpoint proteins. We suggest that the acetylation of histone H3 K56 creates a favourable chromatin environment for DNA repair and that a key component of the DNA damage response is to preserve this acetylation.     

MODELING COMMERCIAL PROCESSES AND CUSTOMER BEHAVIORS TO ESTIMATE THE DIFFUSION RATE OF NEW PRODUCTS

1. Introduction In his famous seminal book (Rogers 1962), Rogers introduced and popularized a generic framework for analyzing and describing how the mechanism of diffusion of innovations works inside a given population. In this general approach, “innovation” can of course be understood in a large way: it may indeed referto various contexts such as the learning of a new practice, the use of a new tool, the launch of a new product, etc. The strength of Rogers' point of view comes from the fac…     

Direct observation of Anderson localization of matter waves in a controlled disorder

In 1958, Anderson predicted the localization of electronic wavefunctions in disordered crystals and the resulting absence of diffusion. It is now recognized that Anderson localization is ubiquitous in wave physics because it originates from the interference between multiple scattering paths. Experimentally, localization has been reported for light waves, microwaves, sound waves and electron gases. However, there has been no direct observation of exponential spatial localization of matter waves of any type. Here we observe exponential localization of a Bose-Einstein condensate released into a one-dimensional waveguide in the presence of a controlled disorder created by laser speckle. We operate in a regime of pure Anderson localization, that is, with weak disorder-such that localization results from many quantum reflections of low amplitude-and an atomic density low enough to render interactions negligible. We directly image the atomic density profiles as a function of time, and find that weak disorder can stop the expansion and lead to the formation of a stationary, exponentially localized wavefunction-a direct signature of Anderson localization. We extract the localization length by fitting the exponential wings of the profiles, and compare it to theoretical calculations. The power spectrum of the one-dimensional speckle potentials has a high spatial frequency cutoff, causing exponential localization to occur only when the de Broglie wavelengths of the atoms in the expanding condensate are greater than an effective mobility edge corresponding to that cutoff. In the opposite case, we find that the density profiles decay algebraically, as predicted in ref. 13. The method presented here can be extended to localization of atomic quantum gases in higher dimensions, and with controlled interactions.     

COMPARISON OF TWO METHODS OF OPERATING THEATRE PLANNING： APPLICATION IN BELGIAN HOSPITAL

Operating Theatre is the centre of the hospital management＇s efforts. It constitutes the most expensive sector with more than 10% of the intended operating budget of the hospital. To reduce the costs while maintaining a good quality of care, one of the solutions is to improve the existent planning and scheduling methods by improving the services and surgical specialty coordination or finding the best estimation of surgical case durations. The other solution is to construct an effective surgical case plan and schedule. The operating theatre planning and scheduling is the two important steps, which aim to make a surgical case programming with an objective of obtaining a realizable and efficient surgical case schedule. This paper focuses on the first step, the operating theatre planning problem. Two planning methods are introduced and compared. Real data of a Belgian university hospital ＂Tivoli＂ are used for the experiments.     

Centrioles: active players or passengers during mitosis?

Centrioles are cylinders made of nine microtubule (MT) triplets present in many eukaryotes. Early studies, where centrosomes were seen at the poles of the mitotic spindle led to their coining as “the organ for cell division”. However, a variety of subsequent observational and functional studies showed that centrosomes might not always be essential for mitosis. Here we review the arguments in this debate. We describe the centriole structure and its distribution in the eukaryotic tree of life and clarify its role in the organization of the centrosome and cilia, with an historical perspective. An important aspect of the debate addressed in this review is how centrioles are inherited and the role of the spindle in this process. In particular, germline inheritance of centrosomes, such as their de novo formation in parthenogenetic species, poses many interesting questions. We finish by discussing the most likely functions of centrioles and laying out new research avenues.     

Cell biology: nondisjunction, aneuploidy and tetraploidy

One simple, widely accepted mechanism for generating an aberrant chromosome number, or aneuploidy, is through nondisjunction--a chromosome distribution error that occurs during mitosis when both copies of a duplicated chromosome are deposited into one daughter cell and none into the other. Shi and King challenge this view, concluding that nondisjunction does not yield aneuploid cells directly, but instead gives rise to tetraploid cells that may subsequently become aneuploid through further division. Here we show that the direct result of chromosome nondisjunction is gain or loss of a single chromosome, which results in near-diploid aneuploidy, not tetraploidy. We suggest that chromatin trapped in the cytokinetic cleavage furrow is the more likely reason for furrow regression and tetraploidization.     

Global trends of whole-genome duplications revealed by the ciliate Paramecium tetraurelia

The duplication of entire genomes has long been recognized as having great potential for evolutionary novelties, but the mechanisms underlying their resolution through gene loss are poorly understood. Here we show that in the unicellular eukaryote Paramecium tetraurelia, a ciliate, most of the nearly 40,000 genes arose through at least three successive whole-genome duplications. Phylogenetic analysis indicates that the most recent duplication coincides with an explosion of speciation events that gave rise to the P. aurelia complex of 15 sibling species. We observed that gene loss occurs over a long timescale, not as an initial massive event. Genes from the same metabolic pathway or protein complex have common patterns of gene loss, and highly expressed genes are over-retained after all duplications. The conclusion of this analysis is that many genes are maintained after whole-genome duplication not because of functional innovation but because of gene dosage constraints.