Second messenger analogues highlight unexpected substrate sensitivity of CD38: total synthesis of the hybrid “L-cyclic inosine 5'-diphosphate ribose”

The multifunctional, transmembrane glycoprotein human CD38 catalyses the synthesis of three key Ca2+-mobilising messengers, including cyclic adenosine 5′-diphosphate ribose (cADPR), and CD38 knockout studies have revealed the relevance of the related signalling pathways to disease. To generate inhibitors of CD38 by total synthesis, analogues based on the cyclic inosine 5′-diphosphate ribose (cIDPR) template were synthesised. In the first example of a sugar hybrid cIDPR analogue, “L-cIDPR”, the natural “northern” N1-linked D-ribose of cADPR was replaced by L-ribose. L-cIDPR is surprisingly still hydrolysed by CD38, whereas 8-Br-L-cIDPR is not cleaved, even at high enzyme concentrations. Thus, the inhibitory activity of L-cIDPR analogues appears to depend upon substitution of the base at C-8; 8-Br-L-cIDPR and 8-NH2-L-cIDPR inhibit CD38-mediated cADPR hydrolysis (IC50 7 μM and 21 µM respectively) with 8-Br-L-cIDPR over 20-fold more potent than 8-Br-cIDPR. In contrast, L-cIDPR displays a comparative 75-fold reduction in activity, but is only ca 2-fold less potent than cIDPR itself. Molecular modelling was used to explore the interaction of the CD38 catalytic residue Glu-226 with the “northern” ribose. We propose that Glu226 still acts as the catalytic residue even for an L-sugar substrate. 8-Br-L-cIDPR potentially binds non-productively in an upside-down fashion. Results highlight the key role of the “northern” ribose in the interaction of cADPR with CD38

Die Digitale Bibliothek der Akademie der Wissenschaften zu Göttingen

Die Akademie der Wissenschaften zu Göttingen (AdWG) und die niedersächsische Staats- und Universitätsbibliothek Göttingen (SUB) haben ihre bestehende Kooperation zum Webportal der AdWG intensiviert, das einen Überblick über die Aktivitäten der Göttinger Akademie und umfangreiche Information zu den zahlreichen Langzeitvorhaben bietet und die digitalen Publikationen präsentiert. Zentraler Bestandteil des Webportals ist die Digitale Bibliothek der AdWG, für die im Rahmen der Kooperation neue Präsentationsformen für die Forschungsdaten aus den Akademie-Vorhaben konzipiert und entwickelt wurden. Ein Beispiel für die Umsetzung neuer Präsentationsformen im Portal ist das Edfu-Projekt, dessen Ziel eine Gesamtübersetzung aller Inschriften des Tempels von Edfu in Oberägypten ist. Hinzugezogen werden dazu alle internen, greifbaren, in den Schriften enthaltenen Parallelen, auf die online über das Webportal zugegriffen werden kann. Zerstörte Bereiche lassen sich dadurch oftmals ebenso ergänzen, wie zunächst unverständliche Textpassagen mit Sinn versehen werden können. Nicht nur die bereits vorübersetzten Texte sind auf diese Weise abrufbar, sondern darüber hinaus zahlreiche zusätzliche Materialien, wie z.B. das Fotoarchiv mit seinen mehr als 20.000 Bildern. Die Vernetzung all dieser Daten schafft einen für die Wissenschaft ungewöhnlich tiefen Einblick in die Planung und Konzeption eines altägyptischen Tempels, seiner religiösen Hintergründe und historischen Zusammenhänge.The Göttingen Academy of Sciences and Humanities (AdWG) and the Göttingen State and University Library (SUB) have intensified their existing cooperation on the web portal of the AdWG. The portal provides an overview of the activities of the Göttingen Academy as well as extensive information on its numerous long-term projects. It also presents the academy’s digital publications. A crucial part of the web portal is the Digital Library of the AdWG. Within the framework of the cooperation, new forms of presentation for the research data from the Academy projects have been conceptualized and developed. An example of the implementation of such a new form of presentation is the Edfu project. The goal of this project is an exhaustive translation of all inscriptions from the temple of Edfu in Upper Egypt. For this, all internal text parallels, which are accessible on the internet platform, are taken into account. This helps to reconstruct damaged inscriptions and recover the meaning of texts which seem incomprehensible at first. Not only the pre-translated texts are accessible online, but also the digital photo archive which covers more than 20.000 images. Bringing all this data into one network offers unusually deep insights into the planning and conceptualization of an ancient Egyptian temple, its religious background und historical context

A phosphoinositide hub connects CLE peptide signaling and polar auxin efflux regulation

Auxin efflux through plasma-membrane-integral PIN-FORMED (PIN) carriers is essential for plant tissue organization and tightly regulated. For instance, a molecular rheostat critically controls PIN-mediated auxin transport in developing protophloem sieve elements of Arabidopsis roots. Plasma-membrane-association of the rheostat proteins, BREVIS RADIX (BRX) and PROTEIN KINASE ASSOCIATED WITH BRX (PAX), is reinforced by interaction with PHOSPHATIDYLINOSITOL-4-PHOSPHATE-5-KINASE (PIP5K). Genetic evidence suggests that BRX dampens autocrine signaling of CLAVATA3/EMBRYO SURROUNDING REGION-RELATED 45 (CLE45) peptide via its receptor BARELY ANY MERISTEM 3 (BAM3). How excess CLE45-BAM3 signaling interferes with protophloem development and whether it does so directly or indirectly remains unclear. Here we show that rheostat polarity is independent of PIN polarity, but interdependent with PIP5K. Catalytically inactive PIP5K confers rheostat polarity without reinforcing its localization, revealing a possible PIP5K scaffolding function. Moreover, PIP5K and PAX cooperatively control local PIN abundance. We further find that CLE45-BAM3 signaling branches via RLCK-VII/PBS1-LIKE (PBL) cytoplasmic kinases to destabilize rheostat localization. Our data thus reveal antagonism between CLE45-BAM3-PBL signaling and PIP5K that converges on auxin efflux regulation through dynamic control of PAX polarity. Because second-site bam3 mutation suppresses root as well as shoot phenotypes of pip5k mutants, CLE peptide signaling likely modulates phosphoinositide-dependent processes in various developmental contexts

Second messenger analogues highlight unexpected substrate sensitivity of CD38: total synthesis of the hybrid “L-cyclic inosine 5'-diphosphate ribose”

The multifunctional, transmembrane glycoprotein human CD38 catalyses the synthesis of three key Ca2+ - mobilising messengers, including cyclic adenosine 5-diphosphate ribose (cADPR), and CD38 knockout studies have revealed the relevance of the related signalling pathways to disease. To generate inhibitors of CD38 by total synthesis, analogues based on the cyclic inosine 5-diphosphate ribose (cIDPR) template were synthesised. In the first example of a sugar hybrid cIDPR analogue, “L-cIDPR”, the natural “northern” N1-linked D-ribose of cADPR was replaced by L-ribose. L-cIDPR is surprisingly still hydrolysed by CD38, whereas 8-Br-L-cIDPR is not cleaved, even at high enzyme concentrations. Thus, the inhibitory activity of L-cIDPR analogues appears to depend upon substitution of the base at C-8; 8- Br-L-cIDPR and 8-NH2-L-cIDPR inhibit CD38-mediated cADPR hydrolysis (IC50 7 M and 21 µM respectively) with 8-Br-L-cIDPR over 20-fold more potent than 8-Br-cIDPR. In contrast, L-cIDPR displays a comparative 75-fold reduction in activity, but is only ca 2-fold less potent than cIDPR itself. Molecular modelling was used to explore the interaction of the CD38 catalytic residue Glu-226 with the “northern” ribose. We propose that Glu226 still acts as the catalytic residue even for an L-sugar substrate. 8-Br-L-cIDPR potentially binds non-productively in an upside-down fashion. Results highlight the key role of the “northern” ribose in the interaction of cADPR with CD38

Cyclic adenosine 5′-diphosphate ribose analogs without a southern ribose inhibit ADP-ribosyl cyclase-hydrolase CD38

Cyclic adenosine 5′-diphosphate ribose (cADPR) analogs based on the cyclic inosine 5′-diphosphate ribose (cIDPR) template were synthesized by recently developed stereo- and regioselective <i>N</i>1-ribosylation. Replacing the base <i>N</i>9-ribose with a butyl chain generates inhibitors of cADPR hydrolysis by the human ADP-ribosyl cyclase CD38 catalytic domain (shCD38), illustrating the nonessential nature of the “southern” ribose for binding. Butyl substitution generally improves potency relative to the parent cIDPRs, and 8-amino-<i>N</i>9-butyl-cIDPR is comparable to the best noncovalent CD38 inhibitors to date (IC₅₀ = 3.3 μM). Crystallographic analysis of the shCD38:8-amino-<i>N</i>9-butyl-cIDPR complex to a 2.05 Å resolution unexpectedly reveals an <i>N</i>1-hydrolyzed ligand in the active site, suggesting that it is the <i>N</i>6-imino form of cADPR that is hydrolyzed by CD38. While HPLC studies confirm ligand cleavage at very high protein concentrations, they indicate that hydrolysis does not occur under physiological concentrations. Taken together, these analogs confirm that the “northern” ribose is critical for CD38 activity and inhibition, provide new insight into the mechanism of cADPR hydrolysis by CD38, and may aid future inhibitor design

On the use of cyanine dyes as low-bandgap materials in bulk heterojunction photovoltaic devices

Cyanine dyes with absorption edges of almost 1000 nm were used in combination with MEH-PPV for the fabrication of organic solar cells. For blended thin films, a pronounced phase separation between the two components occurred and resulted in photocurrents with different signs for bilayer and bulk heterojunction devices. Absorption spectra and selective dissolution experiments were used to illustrate the process of vertical phase segregation, with the preferential wetting of the polar anode by the cyanines while maintaining percolating carrier pathways between the electrodes. For a cyanine with long alkyl side chains, the compatibility with the polymer matrix was increased and the development of the effective inverted bilayer configuration was not observed. The generally low oxidative photocurrents were explained with unfavourable shifts of the highest occupied molecular orbital (HOMO) dye energy levels in the solid state

'Click cyclic ADP-ribose':A neutral second messenger mimic

Analogues of the potent Ca(2+) releasing second messenger cyclic ADP-ribose (cADPR) with a 1,2,3-triazole pyrophosphate bioisostere were synthesised by click-mediated macrocyclisation. The ability to activate Ca(2+) release was surprisingly retained, and hydrolysis of cADPR by CD38 could also be inhibited, illustrating the potential of this approach to design drug-like signalling pathway modulators

The Grizzly, September 25, 1981

Greaseband Tonight • Campus Welcome • Fridge Fee Unfrozen • Deutsch und Deutschland Heute: German Professor Co-authors Text • Public Speaking Exemption Exam • Books Sought by Ursinus Friends • Red Cross Bloodmobile at Helfferich Hall • Career Planning and Placement Office • Dessert Held in Union • Fast Food Service Losing Convenience • ProTheatre: Canterbury Tales Presented • Transplanted Texan: Nobody Expects the Moral Majority • School Bands Looking for Musicians • WRUC: Back on the Air? • First Coffeehouse Sparkles With Talent • Late Mail for Off-Campus Houses • [Reprinted Articles About the Greaseband] • Bear\u27s Booters Kick Off Season • Business as Usual for Cross-Country • Bears Drop 10-3 Decision to Western Maryland • Davis Leads Hockey Over Widenerhttps://digitalcommons.ursinus.edu/grizzlynews/1061/thumbnail.jp

Biological Cardiac Tissue Effects of High-Energy Heavy Ions – Investigation for Myocardial Ablation

Noninvasive X-ray stereotactic treatment is considered a promising alternative to catheter ablation in patients affected by severe heart arrhythmia. High-energy heavy ions can deliver high radiation doses in small targets with reduced damage to the normal tissue compared to conventional X-rays. For this reason, charged particle therapy, widely used in oncology, can be a powerful tool for radiosurgery in cardiac diseases. We have recently performed a feasibility study in a swine model using high doses of high-energy C-ions to target specific cardiac structures. Interruption of cardiac conduction was observed in some animals. Here we report the biological effects measured in the pig heart tissue of the same animals six months after the treatment. Immunohistological analysis of the target tissue showed (1.) long-lasting vascular damage, i.e. persistent hemorrhage, loss of microvessels, and occurrence of siderophages, (2.) fibrosis and (3.) loss of polarity of targeted cardiomyocytes and wavy fibers with vacuolization. We conclude that the observed physiological changes in heart function are produced by radiation-induced fibrosis and cardiomyocyte functional inactivation. No effects were observed in the normal tissue traversed by the particle beam, suggesting that charged particles have the potential to produce ablation of specific heart targets with minimal side effects

Crowdfunding Education : Objectives, Content, Pedagogy, and Assessment

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