Natural History of the Porcine Bioprosthetic Heart Valve

The porcine bioprosthesis has been the prosthetic valve of choice at Henry Ford Hospital since October 1971. By 1979, 23 cases of degeneration had been seen, and the rate seven years after implantation was 16%. Now, with a ten-year follow-up, there are 41 degenerated valves. After seven years, the percent free of degeneration is 88%, (SE of 2% [standard error]); at eight years, 82% (SE of 2.9%,); at nine years, 80% (SE of 3.4%); and at ten years, the percent free of degeneration is 69% (SE of 6.5%,). There was no difference in degeneration between men and women, between aortic or mitral position, or between the valves which were or were not rinsed in antibiotics. The incidence of degeneration was significantly greater in patients under 35 years of age. Contrary to our expectations, the number of valves removed for degeneration has not increased linearly, although the number at risk has continued to rise. In 1977, we removed four valves for degeneration; in 1978, eight valves; in 1979, 77 valves; in 1980, five valves; and in 1981, ten valves. The duration of implantation for degenerated valves has increased from 56 months (SD [standard deviation] of 11 months) in 1977-78 to 77 months (SD of 19 months) in 1981. Analysis of cohorts from 1972,1973, 1974, all now followed for seven years, reveals that at seven years the percent free of degeneration for 1972 is 88% (SE of 4.4%,); for 1973, 83% (SE of 4.8%); and for 1974, 95% (SE of 2.6%). Although a difference is suggested, it is not yet statistically significant (p = .48) due to the small number of valves degenerating. The incidence of porcine bioprosthetic degeneration appears to be decreasing, possibly because valves manufactured later in the series are more durable

In-orbit Performance of UVIT on ASTROSAT

We present the in-orbit performance and the first results from the ultra-violet Imaging telescope (UVIT) on ASTROSAT. UVIT consists of two identical 38cm coaligned telescopes, one for the FUV channel (130-180nm) and the other for the NUV (200-300nm) and VIS (320-550nm) channels, with a field of view of 28 $arcmin$. The FUV and the NUV detectors are operated in the high gain photon counting mode whereas the VIS detector is operated in the low gain integration mode. The FUV and NUV channels have filters and gratings, whereas the VIS channel has filters. The ASTROSAT was launched on 28th September 2015. The performance verification of UVIT was carried out after the opening of the UVIT doors on 30th November 2015, till the end of March 2016 within the allotted time of 50 days for calibration. All the on-board systems were found to be working satisfactorily. During the PV phase, the UVIT observed several calibration sources to characterise the instrument and a few objects to demonstrate the capability of the UVIT. The resolution of the UVIT was found to be about 1.4 - 1.7 $arcsec$ in the FUV and NUV. The sensitivity in various filters were calibrated using standard stars (white dwarfs), to estimate the zero-point magnitudes as well as the flux conversion factor. The gratings were also calibrated to estimate their resolution as well as effective area. The sensitivity of the filters were found to be reduced up to 15\% with respect to the ground calibrations. The sensitivity variation is monitored on a monthly basis. UVIT is all set to roll out science results with its imaging capability with good resolution and large field of view, capability to sample the UV spectral region using different filters and capability to perform variability studies in the UV.Comment: 10 pages, To appear in SPIE conference proceedings, SPIE conference paper, 201

Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni.

Submitted by Nuzia Santos ([email protected]) on 2018-11-13T12:09:19Z No. of bitstreams: 1 Structural Basis for the Inhibition of Histone .pdf: 10051721 bytes, checksum: 36ced7239c061ef58937ef2728effa22 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2018-11-13T12:45:56Z (GMT) No. of bitstreams: 1 Structural Basis for the Inhibition of Histone .pdf: 10051721 bytes, checksum: 36ced7239c061ef58937ef2728effa22 (MD5)Made available in DSpace on 2018-11-13T12:45:56Z (GMT). No. of bitstreams: 1 Structural Basis for the Inhibition of Histone .pdf: 10051721 bytes, checksum: 36ced7239c061ef58937ef2728effa22 (MD5) Previous issue date: 2013Département de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire.Université de Strasbourg. Illkirch, FranceInstitut für Pharmazie. Martin-Luther-Universität Halle-Wittenberg. Halle, GermanyInstitut für Pharmazeutische Wissenschaften. Albert-Ludwigs-Universität Freiburg. Freiburg, GermanyFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais. Centro de Excelência em Bioinformática. Grupo de Genômica e Biologia Computacional. Belo Horizonte, MG, BrazilCenter for Infection and Immunity of Lille. Université Lille Nord de France. Institut Pasteur de Lille. Lille, FranceDépartement de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire. Université de Strasbourg. Illkirch, FranceInstitut für Pharmazeutische Wissenschaften. Albert-Ludwigs-Universität Freiburg. Freiburg, GermanyInstitut für Pharmazeutische Wissenschaften. Albert-Ludwigs-Universität Freiburg. Freiburg, GermanyCenter for Infection and Immunity of Lille. Université Lille Nord de France. Institut Pasteur de Lille. Lille, FranceFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais. Centro de Excelência em Bioinformática. Grupo de Genômica e Biologia Computacional. Belo Horizonte, MG, BrazilDépartement de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire. Université de Strasbourg. Illkirch, FranceFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais. Centro de Excelência em Bioinformática. Grupo de Genômica e Biologia Computacional. Belo Horizonte, MG, BrazilInstitut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany, Freiburg Institute of Advanced Studies (FRIAS), Albert-Ludwigs-Universität Freiburg, Freiburg, GermanyInstitut für Pharmazeutische Wissenschaften. Albert-Ludwigs-Universität Freiburg. Freiburg, Germany/Freiburg Institute of Advanced Studies. Albert-Ludwigs-Universität Freiburg. Freiburg, GermanyDépartement de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire. Université de Strasbourg. Illkirch, FranceCenter for Infection and Immunity of Lille. Université Lille Nord de France. Institut Pasteur de Lille. Lille, FranceDépartement de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire. Université de Strasbourg. Illkirch, FranceThe treatment of schistosomiasis, a disease caused by blood flukes parasites of the Schistosoma genus, depends on the intensive use of a single drug, praziquantel, which increases the likelihood of the development of drug-resistant parasite strains and renders the search for new drugs a strategic priority. Currently, inhibitors of human epigenetic enzymes are actively investigated as novel anti-cancer drugs and have the potential to be used as new anti-parasitic agents. Here, we report that Schistosoma mansoni histone deacetylase 8 (smHDAC8), the most expressed class I HDAC isotype in this organism, is a functional acetyl-L-lysine deacetylase that plays an important role in parasite infectivity. The crystal structure of smHDAC8 shows that this enzyme adopts a canonical α/β HDAC fold, with specific solvent exposed loops corresponding to insertions in the schistosome HDAC8 sequence. Importantly, structures of smHDAC8 in complex with generic HDAC inhibitors revealed specific structural changes in the smHDAC8 active site that cannot be accommodated by human HDACs. Using a structure-based approach, we identified several small-molecule inhibitors that build on these specificities. These molecules exhibit an inhibitory effect on smHDAC8 but show reduced affinity for human HDACs. Crucially, we show that a newly identified smHDAC8 inhibitor has the capacity to induce apoptosis and mortality in schistosomes. Taken together, our biological and structural findings define the framework for the rational design of small-molecule inhibitors specifically interfering with schistosome epigenetic mechanisms, and further support an anti-parasitic epigenome targeting strategy to treat neglected diseases caused by eukaryotic pathogen

Ligand-triggered gating of the smHDAC8 active site pocket.

<p>Close-up view of the active sites of the (A) smHDAC8/SAHA, (B) hHDAC8/SAHA (PDB 1T69), (C) smHDAC8/M344, and (D) hHDAC8/M344 (PDB 1T67) complexes shown as ribbon and sticks (upper panels), surface view (middle panels), and side cut-away surface view (lower panels). The conformational changes of smHDAC8 Y99 and F151 compared to hHDAC8 Y100 and F152 strongly influence the binding modes of the SAHA and M344 inhibitors to these enzymes.</p