10,588 research outputs found
Dynamic ligand binding of dualsteric (allosteric/orthosteric) molecular probes controls the graded activation of muscarinic acetylcholine receptors
No full textWe investigated a class of bitopic (dualsteric) ligands of the M2 acetylcholine muscarinic receptor (M2AChR), i.e. compounds whose pharmacophoric groups are able to target the orthosteric as well as the allosteric binding site of the receptor.1,2 These model derivatives are composed of an allosteric fragment, an intermediate linker and an orthosteric moiety. As an example, ligands 1 and 2 incorporate the molecular portion of the allosteric compound Naphmethonium and the potent muscarinic agonist Iperoxo, which are connected by a flexible or a rigidified spacer group, respectively (Figure 1). These bipharmacophoric molecular probes were found to switch between two different binding orientations, resulting in both active and inactive populations of receptors bound by a given ligand, a behavior that has been termed dynamic ligand binding.3
Figure 1
In this study, pharmacological data analysis and computational simulations based on active and inactive M2AChR crystal structures led to identify two distinct binding topographies in a group of dualsteric partial agonists. One binding mode, which resembled that of the co-crystallized orthosteric ligand Iperoxo, engendered an agonist response. Conversely, dualsteric ligands binding to the allosteric site only showed a receptor-complex comparable to that of allosteric modulators. Thus, the observed agonist efficacies depended on the fraction of dualsteric (i.e. active) vs. purely allosteric (i.e. inactive) binding modes.4
References
1. Antony, J.; Kellershon, K.; Mohr-Andrä, M.; Kebig, A.; Prilla, S.; Muth, M.; Heller, E.; Disingrini, T.; Dallanoce, C.; Bertoni, S.; Schrobang, J.; Tränkle, C.; Kostenis, E.; Christopoulos, A.; Höltje, H.-D.; Barocelli, E.; De Amici, M.; Holzgrabe, U.; Mohr, K. FASEB J. 2009, 23, 442-450.
2. Bock, A.; Merten, N.; Schrage, R.; Dallanoce, C.; Bätz, J.; Klöckner, J.; Schmitz, J.; Matera, C.; Simon, K.; Kebig, A.; Peters, L.; Müller, A.; Schrobang-Ley, J.; Tränkle, C.; Hoffmann, C.; De Amici, M.; Holzgrabe, U.; Kostenis, E.; Mohr; K. Nat. Commun. 2012, 3:1044, doi: 10.1038/ncomms2028.
3. Bock, A.; Chirinda, B.; Krebs, F.; Messerer, R.; Bätz, J.; Muth, M.; Dallanoce, C.; Klingenthal, D.; Tränkle, C.; Hoffmann, C.; De Amici, M.; Holzgrabe, U.; Kostenis, E.; Mohr, K. Nat. Chem. Biol. 2014, 10, 18-20.
4. Bock, A.; Bermudez, M.; Krebs, F.; Matera, C.; Chirinda, B.; Sydow, D.; Dallanoce, C.; Holzgrabe, H.; De Amici, M.; Lohse, M.; Wolber, G.; Mohr, K. J. Biol. Chem., in press
A simulation-based approach to business model design and organizational Change
No full textWhile several practice-based approaches of business model design suggest ways to create new business models, there is limited understanding of why and how business models change. This exploratory study employs neural network analysis to simulate business model design and business model change. We conceptualise business model design as a schema of the organisation’s critical resources, transactions, and value proposition. Elements of the schema are connected in a simple neural network. The network evolves based on a constraint satisfaction network until it converges to a stable state of a coherent business model. An in-depth case study of an entrepreneurial venture provides a real-world example to test the analytical framework. Using data from the case study, we run multiple simulations of business model design and business model change. The results suggest that business model change can be understood as a form of constraint satisfaction, linking managerial cognition with business model change. The simulation approach also helps identify possible, but unrealized business models. This novel approach paves the way for new research and practice in business model design and change
Influence of methylphenidate on brain development--an update of recent animal experiments.
No full textGrund T, Lehmann K, Bock N, Rothenberger A, Teuchert-Noodt G. Influence of methylphenidate on brain development--an update of recent animal experiments. Behav Brain Funct. 2006;2(1): 2.Methylphenidate (MPH) is the most commonly used drug to treat attention deficit/hyperactivity disorder (ADHD) in children effectively and safely. In spite of its widespread application throughout one of the most plastic and sensitive phases of brain development, very little is known to date about its long-term effects on brain structure and function. Hence, this short review updates the influence of MPH on brain development, since recent human and animal studies suggest that MPH alters the dopaminergic system with long-term effects beyond the termination of treatment.Animal studies imply that the effects of MPH may depend on the neural responder system: Whereas structural and functional parameters are improved by MPH in animals with psychomotor impairments, they remain unaltered or get worse in healthy controls. While recent behavioural studies do not fully support such a differential effect of MPH in ADHD, the animal studies certainly prompt for further investigation of this issue. Furthermore, the abuse of MPH, when (rarely) intravenously applied, may even impair the maturation of dopaminergic fibres in subcortical brain areas. This argues for careful clinical assessment and diagnostics of ADHD symptomatology not only in conjunction with the prescription of MPH. Hence, one should be assured that MPH is only given to children with clear ADHD symptomatology leading to psychosocial impairment. The animal data suggest that under these conditions MPH is supportive for brain development and the related behaviour in children with ADHD
The Crumbling Wall: Data Archiving and Reproducibility in Published Science
No full textTim Vines, Arianne Y.K. Albert, Rose L. Andrew, Dan G. Bock, Sébastien Renaut, Diana J. Rennison (University of British Columbia
Solvatochromic behavior of intramolecular charge-transfer spectra of inorganic diimine complexes
No full textPT: J; CR: ADAMS DM, 1973, J CHEM SOC DA, P2264 BAKER WA, 1963, INORG CHEM, V2, P1071 BARCELONA MJ, 1975, J CHEM SOC DA, P1906 BECK MT, 1971, J COORD CHEM, V1, P57 BECK MT, 1972, COORDINATION CHEM SO, P241 BEHRENDT S, 1969, J AM CHEM SOC, V91, P2236 BIALKOWSKA E, 1976, MONATSH CHEM, V107, P865 BJERRUM J, 1956, ACTA CHEM SCAND, V10, P329 BLANDAMER MJ, 1976, J CHEM SOC DA, P1293 BOCK H, 1966, ANGEW CHEM INT EDIT, V5, P520 BOCK H, 1967, CHEM BER, V100, P228 BOSNICH B, 1965, INORG CHEM, V4, P1102 BURGESS J, UNPUBLISHED BURGESS J, 1969, J ORGANOMET CHEM, V19, P218 BURGESS J, 1970, SPECTROCHIM ACTA A, V26, P1369 BURGESS J, 1970, SPECTROCHIM ACTA A, V26, P1967 BURGESS J, 1972, J CHEM SOC DA, P1712 BURGESS J, 1974, J CHEM SOC DA, P2032 BURGESS J, 1978, J CHEM SOC DA, P1447 CAMPBELL MJM, 1976, J INORG NUCL CHEM, V38, P173 DANCE IG, 1973, CHEM COMM, P433 DAVIDSON M, 1974, INORG CHIM ACTA, V9, P231 DEMAS JN, 1969, INORG CHEM, V8, P674 DIECK HT, 1970, ANGEW CHEM INT EDIT, V9, P793 DIECK HT, 1971, CHEM BER, V104, P110 DIMROTH K, 1963, J LIEBIGS ANN CHEM, V661, P1 DIXON KR, 1976, CAN J CHEM, V54, P2733 FRYE JS, 1975, J AM CHEM SOC, V97, P3561 GIDNEY PM, 1973, J CHEM SOC DA, P132 GILLARD RD, 1976, TRANSIT METAL CHEM, V1, P226 GOLUB AM, 1972, RUSS J INORG CHEM, V17, P1100 GRAHAM MA, 1971, J CHEM SOC A, P2939 GUTMANN V, 1977, MONATSH CHEM, V108, P429 HAMER NK, 1961, NATURE, V190, P439 HAZRA DK, 1976, Z PHYS CHEM-LEIPZIG, V257, P497 KLASSEN D, COMMUNICATION KLASSEN D, 1966, THESIS NEW MEXICO KNAUER BR, 1976, J AM CHEM SOC, V98, P4395 KOBAYASHI H, 1975, B CHEM SOC JPN, V48, P465 KRUMHOLZ P, 1975, J INORG NUCL CHEM, V37, P1820 LEVER ABP, 1965, ADV INORG CHEM RAD, V7, P27 LIM YY, 1976, J CHEM SOC FARAD T 1, V72, P2876 MADEJA K, 1963, J INORG NUCL CHEM, V25, P377 MAEDA Y, 1976, B CHEM SOC JPN, V49, P2427 MAKI N, 1969, B CHEM SOC JPN, V42, P2275 MAYER U, 1977, MONATSH CHEM, V108, P489 MCKENZIE ED, 1971, COORDIN CHEM REV, V6, P187 MURAKAMI Y, 1976, INORG NUCL CHEM LETT, V12, P809 PALADE DM, 1969, RUSS J INORG CHEM, V14, P227 REICHARDT C, 1965, ANGEW CHEM INT EDIT, V4, P29 REICHARDT C, 1968, LOSUNGSMITTELEFFEKTE RUPP JJ, 1967, INORG CHEM, V6, P755 SAITO H, 1968, B CHEM SOC JPN, V41, P863 SCHILT AA, 1960, J AM CHEM SOC, V82, P3000 SCHILT AA, 1966, J INORG NUCL CHEM, V28, P2677 SHRIVER DF, 1966, J AM CHEM SOC, V88, P1672 SHRIVER DF, 1972, INORG CHEM, V11, P2984 STIDDARD MHB, 1962, J CHEM SOC, P4712 SWINBOURNE ES, 1971, ANAL KINETIC DATA, P7 TAMURA K, 1975, B CHEM SOC JPN, V48, P369 WALTHER D, 1973, Z ANORG ALLG CHEM, V396, P46 WALTHER D, 1976, Z CHEM, V16, P118 WICHOLAS M, 1974, INORG CHEM, V13, P316 WRIGHTON MS, 1975, J ORGANOMET CHEM, V97, P405; NR: 64; TC: 76; J9: TRANSIT METAL CHEM; PG: 7; GA: LY623Source type: Electronic(1
Analyses of gene expression and physiological defence reactions of healthy and damaged beech (Fagus sylvatica L.) trees
No full textThe production and composition of phenolic compounds in beech bark and differences in gene expression have been used as indicator for the defence reaction of beech to pathogenes and biotic stress. Expression analyses at the transcript level showed an up-regulation of the PR1 gene as well as of the ACS2 gene, which is responsible for the production of ethylene. Enzymes of the shikimate pathway showed no significant differences in gene expression. Analyses of phenolic compounds in bark using HPLC showed no differences in their total content but in the composition of individual phenolic metabolites such as an accumulation of catechine in affected trees. Altogether, individual beech showed quite variable responses, probably depending on their individual fitness.Die Bildung und Zusammensetzung phenolischer Inhaltsstoffe und Veränderungen in der Genexpression sind Indikatoren für das Abwehrverhalten der Buche gegenüber Pathogenen und biotischem Stress. Expressionsstudien auf Transkriptebene zeigten in untersuchten Rindenproben von geschädigten Buchen eine Heraufregulierung des pflanzlichen Stressgens PR1, wie auch des ACS2 Gens, das für die Ethylenbildung verantwortlich ist. Enzyme des Shikimatweges wiesen keine deutlichen Veränderungen des Transkriptlevels auf. HPLC-Analysen der phenolischen Inhaltsstoffe in Buchenrinde zeigten keine quantitativen, aber qualitative Veränderungen im Muster einzelner Phenolsäuren. So konnte eine Akkumulation von Catechin in geschädigten Buchen gegenüber den Kontrollen beobachtet werden. Insgesamt reagierten die Buchen individuell sehr unterschiedlich. Dies hing vermutlich von der jeweiligen Fitness ab
Analyses of gene expression and physiological defence reactions of healthy and damaged beech (Fagus sylvatica L.) trees
No full textThe production and composition of phenolic compounds in beech bark and differences in gene expression have been used as indicator for the defence reaction of beech to pathogenes and biotic stress. Expression analyses at the transcript level showed an up-regulation of the PR1 gene as well as of the ACS2 gene, which is responsible for the production of ethylene. Enzymes of the shikimate pathway showed no significant differences in gene expression. Analyses of phenolic compounds in bark using HPLC showed no differences in their total content but in the composition of individual phenolic metabolites such as an accumulation of catechine in affected trees. Altogether, individual beech showed quite variable responses, probably depending on their individual fitness.Die Bildung und Zusammensetzung phenolischer Inhaltsstoffe und Veränderungen in der Genexpression sind Indikatoren für das Abwehrverhalten der Buche gegenüber Pathogenen und biotischem Stress. Expressionsstudien auf Transkriptebene zeigten in untersuchten Rindenproben von geschädigten Buchen eine Heraufregulierung des pflanzlichen Stressgens PR1, wie auch des ACS2 Gens, das für die Ethylenbildung verantwortlich ist. Enzyme des Shikimatweges wiesen keine deutlichen Veränderungen des Transkriptlevels auf. HPLC-Analysen der phenolischen Inhaltsstoffe in Buchenrinde zeigten keine quantitativen, aber qualitative Veränderungen im Muster einzelner Phenolsäuren. So konnte eine Akkumulation von Catechin in geschädigten Buchen gegenüber den Kontrollen beobachtet werden. Insgesamt reagierten die Buchen individuell sehr unterschiedlich. Dies hing vermutlich von der jeweiligen Fitness ab
Long-lived metastable state and hysteresis in the binding of acetylcholine to Torpedo californica acetylcholine receptor
No full textChang HW, Bock E, Neumann E. Long-lived metastable state and hysteresis in the binding of acetylcholine to Torpedo californica acetylcholine receptor. Biochemistry. 1984;23(20):4546-4556
Bone marrow stromal cells and their use in regenerating bone.
No full textTissue engineering approaches have recently been devised to repair large bone losses. Tissue engineering takes advantages of the combined use of cultured living cells and 3D scaffolds to deliver vital cells to the damaged site of the patient. Cultured bone marrow stromal cells (BMSCs) can be regarded as a mesenchymal progenitor/precursor cell population derived from adult stem cells. When implanted in immunodeficient mice, BMSCs combined with mineralized 3D scaffolds to form a primary bone tissue that is highly vascularized. We have used autologous BMSC/bioceramic composites to treat full‐thickness gaps of tibial diaphysis in sheep. The healing process has been investigated. The sequence of events is as follows: (1) bone formation on the outer surface of the implant; (2) bone formation in the inner cylinder canal; (3) formation of fissures and cracks in the implant body; (4) bone formation in the bioceramic pores. Similar composites whose size and shape reflected each bone defect have been implanted at the lesion sites of three patients. External fixation was used. Patients have been followed for more than three years. The results obtained are very promising and we propose the use of culture‐expanded osteoprogenitor cells in conjunction with hydroxyapatite bioceramics as a significant improvement in the repair of critical size long bone defects
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