MEI Kodierung der frühesten Notation in linienlosen Neumen

Das Optical Neume Recognition Project (ONRP) hat die digitale Kodierung von musikalischen Notationszeichen aus dem Jahr um 1000 zum Ziel – ein ambitioniertes Vorhaben, das die Projektmitglieder veranlasste, verschiedenste methodische Ansätze zu evaluieren. Die Optical Music Recognition-Software soll eine linienlose Notation aus einem der ältesten erhaltenen Quellen mit Notationszeichen, dem Antiphonar Hartker aus der Benediktinerabtei St. Gallen (Schweiz), welches heute in zwei Bänden in der Stiftsbibliothek in St. Gallen aufbewahrt wird, erfassen. Aufgrund der handgeschriebenen, linienlosen Notation stellt dieser Gregorianische Gesang den Forscher vor viele Herausforderungen. Das Werk umfasst über 300 verschiedene Neumenzeichen und ihre Notation, die mit Hilfe der Music Encoding Initiative (MEI) erfasst und beschrieben werden sollen. Der folgende Artikel beschreibt den Prozess der Adaptierung, um die MEI auf die Notation von Neumen ohne Notenlinien anzuwenden. Beschrieben werden Eigenschaften der Neumennotation, um zu verdeutlichen, wo die Herausforderungen dieser Arbeit liegen sowie die Funktionsweise des Classifiers, einer Art digitalen Neumenwörterbuchs

Theranostic Pt(IV) Conjugate with Target Selectivity for Androgen Receptor

It is difficult to diagnose and treat castration-resistant prostate cancer (CRPC) which occurs due to the overexpression of androgen receptor (AR). Because there is a high level of AR in CRPC, we designed and prepared three Pt­(IV)-based prodrugs targeting AR. Among them, compound 3, a three-in-one hybrid (an AR binding ligand, a cisplatin unit, and a coumarin moiety), was found to display satisfactory AR binding affinity and antagonist activity against androgen receptor, which could also be effectively internalized and visualized in LNCaP (AR+) cells. Due to its AR affinity, <b>3</b> selectively accumulated in greater quantities in LNCaP (AR+) cells than in PC-3 (AR-) cells. Moreover, compound <b>3</b> exhibited excellent anticancer activity superior to cisplatin.These results highlight the targeting theranostic application of Pt­(IV) prodrugs

Synthesis and biological evaluation of water-soluble <i>trans</i>-[bicyclo[2.2.2]octane-7<i>R</i>,8<i>R</i>-diamine]platinum(II) complexes with linear or branched alkoxyacetates as leaving groups

<p>Four platinum(II) complexes, <i>trans</i>-[bicyclo[2.2.2]octane-7<i>R</i>,8<i>R</i>-diamine]bis(alkoxyacetato-<i>O</i>,<i>O’</i>) platinum(II) (alkoxyacetate = methoxyacetate (<b>2</b>), ethoxyacetate (<b>3</b>), isopropoxyacetate (<b>4</b>), and <i>tert</i>-butoxyacetate (<b>5</b>)) were synthesized and spectrally characterized. The cytotoxicity of these water-soluble complexes was evaluated by CCK-8 assay <i>in vitro</i> against HCT-116, HepG-2, and A549 cancer cell lines. Most of the complexes had cytotoxic activity against the tested cancer cell lines. Among them, <b>3</b> showed more potent antitumor effect than cisplatin or oxaliplatin. Complex <b>3</b> could cause HCT-116 cell line death based on an apoptotic pathway since it has a dicyclic moiety similar to 1<i>R</i>,2<i>R</i>-diaminocyclohexane in oxaliplatin. Agarose gel electrophoresis on the interaction between <b>3</b> and DNA indicated that it has different behavior from that of cisplatin or oxaliplatin, which has a high correlation with the ligand used.</p

Fundamental Reaction Pathway for Peptide Metabolism by Proteasome: Insights from First-Principles Quantum Mechanical/Molecular Mechanical Free Energy Calculations

Proteasome is the major component of the crucial non-lysosomal protein degradation pathway in the cells, but the detailed reaction pathway is unclear. In this study, first-principles quantum mechanical/molecular mechanical free energy calculations have been performed to explore, for the first time, possible reaction pathways for proteasomal proteolysis/hydrolysis of a representative peptide, succinyl-leucyl-leucyl-valyl-tyrosyl-7-amino-4-methylcoumarin (Suc-LLVY-AMC). The computational results reveal that the most favorable reaction pathway consists of six steps. The first is a water-assisted proton transfer within proteasome, activating Thr1-O^γ. The second is a nucleophilic attack on the carbonyl carbon of a Tyr residue of substrate by the negatively charged Thr1-O^γ, followed by the dissociation of the amine AMC (third step). The fourth step is a nucleophilic attack on the carbonyl carbon of the Tyr residue of substrate by a water molecule, accompanied by a proton transfer from the water molecule to Thr1-N^z. Then, Suc-LLVY is dissociated (fifth step), and Thr1 is regenerated <i>via</i> a direct proton transfer from Thr1-N^z to Thr1-O^γ. According to the calculated energetic results, the overall reaction energy barrier of the proteasomal hydrolysis is associated with the transition state (TS3^b) for the third step involving a water-assisted proton transfer. The determined most favorable reaction pathway and the rate-determining step have provided a reasonable interpretation of the reported experimental observations concerning the substituent and isotopic effects on the kinetics. The calculated overall free energy barrier of 18.2 kcal/mol is close to the experimentally derived activation free energy of ∼18.3–19.4 kcal/mol, suggesting that the computational results are reasonable

(A) TL1A is not expressed on resting lymphocytes and up-regulated on activated T cells (top 6 graphs)

Resting splenocyte cell suspensions were gated using the respective labeled antibody as a population marker and the TL1A histogram displayed. Red curve, anti-TL1A; black curve, isotype control (bottom 3 graphs). Splenocytes were activated for 24 h with plate-bound anti-CD3 or with LPS and stained with anti-TL1A and with the population marker, as indicated. After gating on the population marker, TL1A expression on activated cells is shown as blue/shaded histogram. Red curve, resting cells; black curve, isotype control. Representative of more than three experiments. (B) TNFR25 and TL1A expression on cDNA transfected P815 and EL4. Transfected (right curve in each histogram) and untransfected cells were stained with the appropriate antibody and isotype controls and analyzed by flow cytometry. (C) TNFR25 activates NF-κB when triggered by agonistic antibody 4C12, by soluble TL1A or by membrane-bound TL1A. NF-κB activation was measured in EL4 cells transfected with TNFR25 in response to TNFR25 triggering. Cells were treated with the agonistic anti-TNFR25 antibody 4C12 (5 μg/ml) for 50 min; soluble TL1A was given for 25, 50, or 70 min, as indicated in the form of 25% supernatants from TL1A-transfected EL4 cells; membrane-bound TL1A (MTL1A) was given for 50 min by adding TL1A-transfected EL4-cells directly to TNFR25-transfected EL4. Controls received EL4 (untransfected) supernatants for 50 min. Nuclear extracts were prepared and analyzed by EMSA; the arrow indicates activated NF-κB. (D) Anti-TL1A antibody L4G6 blocks TL1A induced cell death of TNFR25-transfected cells. Soluble TL1A harvested from supernatants of P815-TL1A–transfected cells were mixed with Cr-labeled P815-TNFR25 target cells. Different anti-murine TL1A monoclonal antibodies were added into the assay, and Cr release was analyzed 5 h later. L4G6 antibody completely blocked the ability of TL1A to induce apoptosis in TNFR25-transfected P815 cells.<p><b>Copyright information:</b></p><p>Taken from "Essential role of TNF receptor superfamily 25 (TNFRSF25) in the development of allergic lung inflammation"</p><p></p><p>The Journal of Experimental Medicine 2008;205(5):1037-1048.</p><p>Published online 12 May 2008</p><p>PMCID:PMC2373837.</p><p></p

Mice were immunized and subjected to ovalbumin aerosol according to our standard protocol

Administration of 50 μg blocking (L4G6) or nonblocking (L3A10) anti-Tl1A, or control hamster IgG i.p. was started at the time indicated relative to aerosol exposure and continued daily until analysis, which was at 76 h after aerosol. In the 72-h time points, anti-TL1A was administered 4 h before analysis. A, B, and C are separate experiments testing different schedules and controls. Note that nonblocking TL1A (L3A10) does not affect eosinophil exudation, similar to hamster IgG. (A and B) Data from three experiments with two mice. (C) Data from two experiments with five mice. (D and E) Histopathology of lung sections stained with HE and PAS. Five sections from each of three mice in each group were evaluated in a blinded fashion according to the scoring system described in Materials and methods. (F and G) Relative frequency of CD4 and CD8 cells in lung parenchyma after aerosol exposure and blockade of TL1A for different periods of time. Single-cell suspensions were analyzed by flow cytometry gating on the lymphocyte gate. (H–J) RNA was isolated from whole lungs and analyzed by real-time PCR as in . Error bars represent the mean ± the SEM.<p><b>Copyright information:</b></p><p>Taken from "Essential role of TNF receptor superfamily 25 (TNFRSF25) in the development of allergic lung inflammation"</p><p></p><p>The Journal of Experimental Medicine 2008;205(5):1037-1048.</p><p>Published online 12 May 2008</p><p>PMCID:PMC2373837.</p><p></p

(A) Diminished cellular exudation in BALF in anti-TL1A (L4G6)–treated mice

Mice were primed i.p. on day 0 and 5 with 66 μg ovalbumin absorbed to alum. On day 12, mice were aerosol challenged with 0.5% ovalbumin in PBS for 1 h using an ultrasonic nebulizer. Mice received 4 daily doses of 50 μg purified L4G6-IgG i.p. (anti-TL1A), beginning 1 d before aerosol. Controls received the same amount and schedule of purified hamster IgG. All mice were analyzed 3 d after aerosol antigen exposure ( = 4; representative of >10 experiments). *, P < 0.05; **, P < 0.01. (B) TL1A-blocking antibody L4G6 suppresses mucus production and lung inflammation. Lung histology after PAS staining after treatment of mice with control IgG (top) or L4G6-IgG (anti-TL1A; bottom). Notice the lack of mucus production and cell infiltration in L4G6-treated animals (arrows point to mucus in mice treated with control IgG). Experiments were repeated three times. (C) Diminished IL-5 and -13 production by ovalbumin restimulated bronchial lymph node cells after TL1A blockade with L4G6. Bronchial lymph node cells were harvested 3 d after aerosol and restimulated in vitro with 100 μg/ml ovalbumin for 4 d. IL-4 was not detectable (not depicted), even in the absence of anti-TL1A. = 4; **, P < 0.01; ***, P < 0.001. Experiments were repeated more than three times. (D) Cytokine expression in lung parenchyma after ovalbumin aerosol exposure. Lungs were harvested 1, 2, or 3 d after ovalbumin aerosol treatment. RNA was extracted, and after reverse transcription it was analyzed by Taqman PCR. Values are normalized to GAPDH cDNA and expressed as the fold increase of ovalbumin aerosol–treated over untreated mice. (E) Blocking anti-TL1A antibody L4G6 suppresses ovalbumin-induced cytokine expression in lung parenchyma. Mice were immunized twice with ovalbumin/alum, as described. 1 d before ovalbumin aerosol and for the next 3 d, mice received 50 μg blocking TL1A antibody L4G6 or control IgG i.p. Lungs were analyzed for expression of cytokine mRNA on day 1–3 after aerosol administration by Taqman PCR, as above. Data are presented as anti-TL1A–induced suppression of cytokine mRNA over control IgG.<p><b>Copyright information:</b></p><p>Taken from "Essential role of TNF receptor superfamily 25 (TNFRSF25) in the development of allergic lung inflammation"</p><p></p><p>The Journal of Experimental Medicine 2008;205(5):1037-1048.</p><p>Published online 12 May 2008</p><p>PMCID:PMC2373837.</p><p></p

NKT-deficient Jα18 KO mice () were primed with ovalbumin and alum as in our standard protocol in Materials and methods

On day 11, the mice received 3.1 million purified NK/NKT cells containing 1 million WT NKT cells or DN TNFR25-tg NKT cells (DN NKT) or PBS by i.v. adoptive transfer, as indicated. The mice were exposed to ovalbumin aerosol on day 12 and analyzed on day 15. WT mice and Jα18 KO mice receiving WT NKT cells by adoptive transfer served as positive controls for induction of lung inflammation. Jα18 KO mice, immunized and ovalbumin aerosolized without adoptive cell transfer, served as negative controls. The data of three independent experiments and two mice in each group are shown. (A) Eosinophils in BALF. Error bars represent the mean ± the SEM. (B and C) Cytokine and TL1A mRNA expression in bronchial lymph nodes (LN; B) and lung parenchyma (C) determined by real time Taqman PCR. The fold increase or decrease of mRNA in Jα18 KO mice (Jα) adoptively transferred with WT NKT cells over mice adoptively transferred with DN TNFR25-tg NKT (DN NKT) cells is plotted.<p><b>Copyright information:</b></p><p>Taken from "Essential role of TNF receptor superfamily 25 (TNFRSF25) in the development of allergic lung inflammation"</p><p></p><p>The Journal of Experimental Medicine 2008;205(5):1037-1048.</p><p>Published online 12 May 2008</p><p>PMCID:PMC2373837.</p><p></p

Comprehensive scoring system.

<p>Comprehensive scoring system.</p

Patient distribution on breath and feeding difficulties (preoperative).

<p>Patient distribution on breath and feeding difficulties (preoperative).</p