Defects in Stratum Corneum Desquamation Are the Predominant Effect of Impaired ABCA12 Function in a Novel Mouse Model of Harlequin Ichthyosis.

Harlequin Ichthyosis is a severe skin disease caused by mutations in the human gene encoding ABCA12. Here, we characterize a novel mutation in intron 29 of the mouse Abca12 gene that leads to the loss of a 5' splice donor site and truncation of the Abca12 RNA transcript. Homozygous mutants of this smooth skin or smsk allele die perinatally with shiny translucent skin, typical of animal models of Harlequin Ichthyosis. Characterization of smsk mutant skin showed that the delivery of glucosylceramides and CORNEODESMOSIN was defective, while ultrastructural analysis revealed abnormal lamellar bodies and the absence of lipid lamellae in smsk epidermis. Unexpectedly, mutant stratum corneum remained intact when subjected to harsh chemical dissociation procedures. Moreover, both KALLIKREIN 5 and -7 were drastically decreased, with retention of desmoplakin in mutant SC. In cultured wild type keratinocytes, both KALLIKREIN 5 and -7 colocalized with ceramide metabolites following calcium-induced differentiation. Reducing the intracellular levels of glucosylceramide with a glucosylceramide synthase inhibitor resulted in decreased secretion of KALLIKREIN proteases by wild type keratinocytes, but not by smsk mutant keratinocytes. Together, these findings suggest an essential role for ABCA12 in transferring not only lipids, which are required for the formation of multilamellar structures in the stratum corneum, but also proteolytic enzymes that are required for normal desquamation. Smsk mutant mice recapitulate many of the pathological features of HI and can be used to explore novel topical therapies against a potentially lethal and debilitating neonatal disease

Antarctic Surface Reflectivity Measurements from the ANITA-3 and HiCal-1 Experiments

The primary science goal of the NASA-sponsored ANITA project is measurement of ultra-high energy neutrinos and cosmic rays, observed via radio-frequency signals resulting from a neutrino- or cosmic ray- interaction with terrestrial matter (atmospheric or ice molecules, e.g.). Accurate inference of the energies of these cosmic rays requires understanding the transmission/reflection of radio wave signals across the ice-air boundary. Satellite-based measurements of Antarctic surface reflectivity, using a co-located transmitter and receiver, have been performed more-or-less continuously for the last few decades. Satellite-based reflectivity surveys, at frequencies ranging from 2--45 GHz and at near-normal incidence, yield generally consistent reflectivity maps across Antarctica. Using the Sun as an RF source, and the ANITA-3 balloon borne radio-frequency antenna array as the RF receiver, we have also measured the surface reflectivity over the interval 200-1000 MHz, at elevation angles of 12-30 degrees, finding agreement with the Fresnel equations within systematic errors. To probe low incidence angles, inaccessible to the Antarctic Solar technique and not probed by previous satellite surveys, a novel experimental approach ("HiCal-1") was devised. Unlike previous measurements, HiCal-ANITA constitute a bi-static transmitter-receiver pair separated by hundreds of kilometers. Data taken with HiCal, between 200--600 MHz shows a significant departure from the Fresnel equations, constant with frequency over that band, with the deficit increasing with obliquity of incidence, which we attribute to the combined effects of possible surface roughness, surface grain effects, radar clutter and/or shadowing of the reflection zone due to Earth curvature effects.Comment: updated to match publication versio

X-ray Structure of Gelatinase A Catalytic Domain Complexed with a Hydroxamate Inhibitor

Gelatinase A is a key enzyme in the family of matrix metalloproteinases (matrixins) that are involved in the degradation of the extracellular matrix. As this process is an integral part of tumour cell metastasis and angiogenesis, gelatinase is an important target for therapeutic intervention. The X-ray crystal structure of the gelatinase A catalytic domain (GaCD) complexed with batimastat (BB94), a hydroxamate inhibitor, shows an active site with a large S1\u27 specificity pocket. The structure is similar to previously solved structures of stromelysin catalytic domain (SCD) but with differences in VR1 and VR2, two surface-exposed loops on either side of the entrance to the active site. Comparison of GaCD with other members of the matrix metalloproteinase (MMP) family highlights the conservation of key secondary structural elements and the significant differences in the specificity pockets, knowledge of which should enhance our ability to design specific inhibitors for this important anticancer target

X-ray Structure of Gelatinase A Catalytic Domain Complexed with a Hydroxamate Inhibitor

Gelatinase A is a key enzyme in the family of matrix metalloproteinases (matrixins) that are involved in the degradation of the extracellular matrix. As this process is an integral part of tumour cell metastasis and angiogenesis, gelatinase is an important target for therapeutic intervention. The X-ray crystal structure of the gelatinase A catalytic domain (GaCD) complexed with batimastat (BB94), a hydroxamate inhibitor, shows an active site with a large S1\u27 specificity pocket. The structure is similar to previously solved structures of stromelysin catalytic domain (SCD) but with differences in VR1 and VR2, two surface-exposed loops on either side of the entrance to the active site. Comparison of GaCD with other members of the matrix metalloproteinase (MMP) family highlights the conservation of key secondary structural elements and the significant differences in the specificity pockets, knowledge of which should enhance our ability to design specific inhibitors for this important anticancer target

A new classification method using array Comparative Genome Hybridization data, based on the concept of Limited Jumping Emerging Patterns

<p>Abstract</p> <p>Background</p> <p>Classification using aCGH data is an important and insufficiently investigated problem in bioinformatics. In this paper we propose a new classification method of DNA copy number data based on the concept of limited Jumping Emerging Patterns. We present the comparison of our limJEPClassifier to SVM which is considered the most successful classifier in the case of high-throughput data.</p> <p>Results</p> <p>Our results revealed that the classification performance using limJEPClassifier is significantly higher than other methods. Furthermore, we show that application of the limited JEP's can significantly improve classification, when strongly unbalanced data are given.</p> <p>Conclusion</p> <p>Nowadays, aCGH has become a very important tool, used in research of cancer or genomic disorders. Therefore, improving classification of aCGH data can have a great impact on many medical issues such as the process of diagnosis and finding disease-related genes. The performed experiment shows that the application of Jumping Emerging Patterns can be effective in the classification of high-dimensional data, including these from aCGH experiments.</p

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13