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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Molecular Characterization of the Inhibin A Heterodimer and its Function as an Activin Antagonist

Kappes, Emily 05 June 2023 (has links)
No description available.
2

Identification of Binding Sites and Determination of Binding Energies of a Ga Adatom on the GaAs(001)–c(4 × 4) –Heterodimer Surface: A First-Principles Study

Aravelli, Sandeep January 1900 (has links)
No description available.
3

Transactivation of Beta 2 Adrenergic Receptor by Bradykinin type 2 Receptor via heterodimerization

Vincent, Karla Kristine 10 November 2009 (has links)
Although a long standing convention maintained that G Protein Coupled Receptors (GPCRs) exist in the plasma membrane solely as monomers, substantial work over the last two decades has demonstrated that these ubiquitous receptors can and in many cases, preferentially, exist as homodimers, heterodimers, or higher order oligomers. Often, two GPCRs of the same class heterodimerize; it is less common for two GPCRs of different signaling pathways to interact. The work presented here studied the physical and functional interaction of two GPCRs from discrete classes, the Beta 2 Adrenergic Receptor (β2AR), a Gαs-coupled receptor, and Bradykinin type 2 Receptor (Bk2R), a Gαq coupled receptor. These data show that Bk2R and β2AR are physically coupled when heterologously expressed in Xenopus oocytes, and in pheochromocytoma (PC12) cells and in freshly isolated murine ventricular myocytes, two systems that endogenously express these receptors. This physical coupling led to functional consequences in heterologous and endogenous expression systems, as Bk2R was able to transactivate β2AR signaling via its direct interaction with the receptor. Furthermore, coexpression of Bk2R shifted the dose response curve of β2AR for its selective agonist rightward in Xenopus oocyte electrophysiology experiments, suggesting the presence of Bk2R negatively affected β2AR native pharmacology. Up to thirty minutes of either bradykinin (BK) or isoproterenol exposure did not change the relative amount of Bk2R/β2AR heterodimer in PC12 cells, a rat adrenal medulla tumor cell line that endogenously expresses these receptors. Despite the obvious signaling consequences, the Bk2R/β2AR heterodimer accounted for only 10% of the total β2AR protein detected and 20% of the total Bk2R protein detected. When other Bk2R-specific ligands were also tested to examine the extent of β2AR transactivation, our data showed that both Lys-des-Arg-Bradykinin, a Bk2R partial agonist and NPC 567, a Bk2R antagonist, transactivated β2AR to the same extent as BK. Taken together, our data provide a novel mode of receptor regulation and signaling via Bk2R/β2AR heterodimerization. Because a large percentage of therapeutics target GPCRs, a greater understanding of how a GPCR heterodimer functions could be beneficial for targeting new drugs and refining existing drugs. Understanding the Bk2R/β2AR heterodimer provides a new perspective on the myriad of fucntional consequences that occur when a GPCR is activated.
4

Kvantinis koherentiškumas molekulių sužadinimo energijos pernašos ir relaksacijos vyksmuose / Quantum coherence in molecular excitation energy transfer and relaxation

Balevičius, Vytautas 25 November 2013 (has links)
Disertacijos santraukoje reziumuojamas sužadinimo energijos pernašos eksitoniniame dimere tyrimas. Nagrinėjamas kvantinio koherentiškumo vaidmuo energijos pernašos procesų hierarchijoje: virpesinėje relaksacijoje, sužadinimo pernašoje vieneksitoninėje juostoje bei relaksacijoje į pagrindinę būseną. Glaustai aprašomas naujas metodas, išplėtotas koherentiniams efektams silpnos rezonansinės sąveikos riboje aprašyti. Pristatomas eksitoninio dimero tyrimas įvariuose sistemos ir termostato sąveikos režimuose, kuomet stebima tiek koherentinė, tiek nekoherentinė sužadinimo evoliucija. Nustatyta, jog esant skirtingoms chromoforų reorganizacijos energijoms ir stipriam eksitoniniam maišymuisi, eksitoninių būsenų potencinės energijos paviršių minimumai gali susikeisti vietomis lygininat su nesąveikaujančių chromoforų minimumais. Pristatomas relaksacijos į pagrindinę būseną eksitoniniame dimere tyrimas, kuris atskleidė, jog rezonansinė sąveika ir būsenų energijų skirtumas daugiausia turi įtakos procesų spartai, bet ne pobūdžiui. Darbe paaiškintas disipacijos mechanizmas sintetinėse karotenoido-ftalocianino diadose; gauti rezultatai naudingi aiškinant apsauginį fotosintezės mechanizmą, vadinamą nefotocheminiu gesimu. / The summary of doctoral dissertation presents the investigation of excitation energy transfer, studied in an excitonic dimer under various conditions of inter-chromophore resonance interaction and in different regimes of the system-bath coupling. The manifestation of quantum coherence in the energy transfer in molecular dimer is considered within the hierarchy of the relaxation processes: vibrational relaxation, energy redistribution within single exciton manifold and relaxation to the ground state. A new method to capture the coherence effects in the limit of weak resonance interaction is presented. The study of an excitonic heterodimer under various system-bath coupling conditions, which revealed both coherent and incoherent excitation evolutions, is summarized. An outline of the study of the relaxation of the excitonic dimer to the ground state is given, which revealed that the resonance coupling strength and the energy gap between the states control the rate of the process but not the character. The dissipation mechanism in the artificial carotenoid-pthalocyanine dyads is explained, and the results may be helpful in determining the mechanism of energy dissipation during photosynthesis, known as the non-photochemical quenching.
5

Quantum coherence in molecular excitation energy transfer and relaxation / Kvantinis koherentiškumas molekulių sužadinimo energijos pernašos ir relaksacijos vyksmuose

Balevičius, Vytautas 25 November 2013 (has links)
In the dissertation, excitation energy transfer was studied in an excitonic dimer under various conditions of inter-chromophore resonance interaction and in different regimes of the system-bath coupling. We examine the manifestation of quantum coherence in the energy transfer in molecular dimer, within the hierarchy of the relaxation processes: vibrational relaxation, energy redistribution within single exciton manifold and relaxation to the ground state. In order to capture the coherence effects in the limit of weak resonance interaction a novel technique has been presented. We are able to reproduce the coherence effects in the simulation of static and dynamic spectroscopic experiments. The study of an excitonic heterodimer under various system-bath coupling conditions revealed both coherent and incoherent excitation evolutions. In the situation of different reorganization energies, in the case of strong excitonic mixing, the vibrationally relaxed excited state energy levels may become swapped with respect to the monomeric counterparts. The study of the relaxation of the excitonic dimer to the ground state revealed that the resonant coupling strength and the energy gap between the states control the rate of the process but not the character. We have explained the dissipation mechanism in the artificial carotenoid-pthalocyanine dyads, and the results may be helpful in determining the mechanism of energy dissipation during photosynthesis, known as the non-photochemical... [to full text] / Šioje disertacijoje nagrinėjama sužadinimo energijos pernaša eksitoniniame dimere, esant įvairaus stiprio rezonansinei sąveikai tarp chromoforų skirtinguose sistemos ir termostato sąveikos režimuose. Nagrinėjamas kvantinio koherentiškumo vaidmuo energijos pernašos procesų hierarchijoje: virpesinėje relaksacijoje, sužadinimo pernašoje vieneksitoninėje juostoje bei relaksacijoje į pagrindinę būseną. Koherentiniams efektams silpnose rezonansinės sąveikos riboje aprašyti buvo išplėtotas naujas metodas. Juo remiantis modeliuojami koherentiškumo nulemti efektai statinės ir dinaminės spektroskopijos eksperimentuose. Tiriant eksitoninį dimerą įvariuose sistemos ir termostato sąveikos režimuose stebima tiek koherentinė, tiek nekoherentinė sužadinimo evoliucija. Nustatyta, jog esant skirtingoms chromoforų reorganizacijos energijoms ir stipriam eksitoniniam maišymuisi, eksitoninių būsenų potencinės energijos paviršių minimumai gali susikeisti vietomis lygininat su nesąveikaujančių chromoforų minimumais. Relaksacijos į pagrindinę būseną eksitoniniame dimere tyrimas atskleidė, jog rezonansinė sąveika ir būsenų energijų skirtumas daugiausia turi įtakos procesų spartai, bet ne pobūdžiui. Darbe paaiškintas disipacijos mechanizmas sintetinėse karotenoido-ftalocianino diadose; gauti rezultatai naudingi aiškinant apsauginį fotosintezės mechanizmą, vadinamą nefotocheminiu gesimu.
6

Identification et caractérisation des complexes transcriptionnels de la protéine TWIST1 essentiels à la progression tumorale / The heterodimeric TWIST1-E12 complex drives the oncogenic potential of TWIST1 in human mammary epithelial cells

Jacqueroud, Laurent 17 April 2015 (has links)
Dans ce manuscrit, nous démontrons par le biais de dimères forcés que toutes les propriétés oncogéniques de la protéine TWIST1, telles qu'évaluées par le biais de nombreux tests in vitro (tests de complémentation, inhibition de la sénescence oncogénique, induction de l'EMT et tests de coopération oncogénique…), sont spécifiquement attribués au complexe TWIST1-E12. L'insertion de mutations ponctuelles, définies d'après l'analyse de modèles de simulation in silico développés au sein du laboratoire (Bouard et al., 2013) et perturbant la dimérisation du complexe ou encore son interaction avec l'ADN conduit à une perte complète de l'activité, validant l'importance des deux partenaires dans l'activité oncogénique de la protéine de fusion. La détection du complexe TWIST1-E12 dans des carcinomes mammaires canalaires in situ humains, récapitulant les phases précoces de l'initiation tumorale, par la technique de Proximity Ligation Assay (PLA) ainsi que la sensibilité accrue de souris transgéniques à développer des carcinomes mammaires lorsque le complexe hétérodimérique est exprimé dans les cellules épithéliales luminales mammaires, renforce la conclusion que le complexe TWIST1-E12 est la (ou l'une des) forme(s) active(s) de la protéine TWIST1 dans le cadre de la carcinogenèse mammaire / Among embryonic transcription factors, TWIST proteins (TWIST1 and TWIST2) display the particularity to behave as master regulators of both RB and p53-oncosuppressive pathways. These embryonic transcription factors annihilate the induction of numerous cyclin-kinase inhibitors, including p16INK4A, p15INK4B and p21CIP1, abrogating thereby cell commitment to a senescence program or their death through apoptosis in response to an oncogenic activation. By doing so, TWIST proteins cooperate with mitogenic oncoproteins such as Ras in promoting cell transformation in vitro and breast and lung carcinogenesis in vivo (Ansieau S. et al. Cancer Cell ; Morel A-P. et al., PLoS ONE ; Tran P.T. et al., PLoS Genetics). Strikingly, TWIST depletion in numerous cancer cell types associates with a reactivation of failsafe programs, suggesting that some tumor cells remain addictive to TWIST for survival and proliferation (Ansieau et al., 2008). In support of this hypothesis, silencing TWIST expression in a TWIST + RAS-driven lung carcinogenesis mouse model displays a cytostatic effect (Tran P.T. et al., PLoS Genetics). Based on these observations, we aim at identifying TWIST specific inhibitors and evaluate the efficiency of such molecules in eradicating tumor cells in vitro as well as in vivo. TWIST proteins either behave as homodimeric (TT) or heterodimeric (TE) complexes (in association with E2A proteins), both complexes displaying distinct and sometimes even antagonistic functions during the embryonic development (Firulli B.A. et al., Nature Genetics ; Connerney F. et al., Dev. Dynamics). Ongoing experiments, comparing activities of tethered TWIST dimers, strongly support the assumption that an oncogenic potential is specifically allotted to the heterodimer. To screen for specific chemical inhibitors, we first established the in silico structure of the bHLH domain of TWIST complexes bound to their cis-responsive elements, by analogy with the NeuroD/E47 crystallographic structure. Relevance of these models has been confirmed through analysis of Twist1 variants associated with a loss of function in Saethre-Chotzen patients (Bouard et al., J. Biomolecular Structure & Dynamics). Strikingly, structural analysis highlights the importance of lateral loops in stabilizing the protein-DNA complex and in specifying the DNA sequence targeted
7

Insertion of an intrinsically disordered domain in VelB supports selective heterodimer formation of fungal velvet domain regulatory proteins in Aspergillus nidulans

Thieme, Sabine 12 April 2018 (has links)
No description available.
8

Atypical Opioid Interactions – Development of Selective Mu-Delta Heterodimer Antagonists, Clinical Opioids at Non-Mu Pain Targets and Endogenous Biased Signaling

Olson, Keith Mathew, Olson, Keith Mathew January 2017 (has links)
Most clinical opioids produce analgesia through the Mu Opioid Receptor (MOR) providing the only effective treatment for chronic pain patients. These studies explore three pre-clinical strategies to improve MOR analgesia and minimize side effects: 1) compounds that target G-protein Coupled Receptors (GPCRs) heterodimers, such as heterodimerization between the Delta Opioid Receptor (DOR) and MOR (MDOR); 2) multi-functional compounds that target multiple receptor systems for synergistic effects, such as a MOR agonist and a the serotonin reuptake transporter (SERT) inhibitor; or 3) biased agonists that preferentially activate one signaling pathway associated with analgesia over another associated with side effects at the same receptor. First, several indirect lines of evidence indicate the MOR-DOR heterodimer (MDOR) can regulate MOR opioid tolerance and withdrawal. However, studying MDOR remains difficult because no selective MDOR antagonists are available. To address this need, we created a novel series of bivalent MDOR antagonists by connecting a low affinity MOR antagonist (H-Tyr-Pro-Phe-D1Nal-NH2) to a moderate affinity DOR (H- Tyr-Tic-OH) antagonist with variable length polyamide spacers (15-41 atoms). In vitro radioligand binding and [35S]-GTPγS coupling assays in MOR, DOR, and MDOR expressing cell lines show bivalent ligands produce a clear length dependence in MDOR but not MOR or DOR cell lines. The lead compound – D24M with a 24-atom spacer – displayed high potency (IC50MDOR = 0.84 nM) with 91-fold selectivity for MDOR:DOR and 1,000-fold MDOR:MOR selectivity. Second, clinicians have long appreciated subtle but distinct differences in analgesia and side effects of MOR opioids. A variety of non-MOR targets including DOR, Kappa Opioid Receptor (KOR), the Cannabinoid Receptor-1 (CB1), the Sigma-1 Receptor (σ1R), the Dopamine- (DAT), Serotonin- (SERT) and Norepinephrine- Reuptake Transporters (NET) induce analgesia and/or modulate MOR mediated side effects. To determine if different opioid profiles arise from non-MOR interactions, we evaluated the binding and function of nine clinical analgesics at the nine aforementioned targets revealing several clinical opioids contain previously unidentified affinity’s or activity’s. Hydrocodone displayed low affinity at the MOR (KI = 1800 nM) and only ~2 fold less affinity at the σ1R (KI = 4000 nM). Second buprenorphine promoted monoamine influx at DAT, SERT and NET with EC50 > 1,000 nM. These novel interactions suggest the nuanced differences of clinical opioids may arise from previously unappreciated off-target effects. Future studies will assess whether these in vitro results predict hydrocodone and buprenorphine activity in vivo. Finally, the unique function of the numerous endogenous opioid peptides at a given receptor remains unclear. How endogenous ligands interact with ORs produces obvious drug design consequences. These studies show two endogenous Dynorphin analogues – Dynorphin A and Dynorphin B – differentially regulate two ubiquitous signaling modules – βarrestin2 and Gαi/o– at the DOR. Dynorphin A and Dynorphin B swap potency rank orders for β-arrestin2 recruitment and [35S]-GTPγS signaling, indicating two distinct signaling platforms are formed. Dynorphin A but not Dynorphin B treatment simulated AC super activation, while Dynoprhin B internalized DOR better than Dynorphin A. These in vitro assays suggest endogenous Dynorphin analogues differentially regulate signals at the DOR in vitro. Future work includes further characterizing signaling differences in vitro and testing these changes in vivo.
9

Organic Synthesis using Bimetallic Catalysis

Ence, Chloe Christine 23 April 2020 (has links)
Bimetallic Catalysis is an emerging field of study that uses two metals to cooperatively perform organic transformations. These metals can serve to activate or bind substrates in order to increase the rate and selectivity of reactions. This work first describes the synthesis and utilization of six new chiral, titanium-containing phosphinoamide ligands. These Lewis acidic ligands withdraw electron density from an active palladium center to induce chirality and increase the rate of allylic amination of hindered, secondary N-alkyl amines. X-ray quality crystals were grown for each ligand and completed the allylic amination of hindered secondary amines in minutes whereas other non-titanium-containing ligands produced trace product. Although enantioselectivity was low initially, through a dynamic kinetic resolution enantioselectivity was increased over time, reaching 53% enantioselectivity. The second type of bimetallic catalysis discussed is dinuclear Pd(II) and Pd(I) catalysis. These dimers were built on a 2-phosphinoamide ligand scaffold and present interesting molecular structure and unique reactivity. These dimers were found to perform tandem arylketone coupling to produce disubstituted naphthalene products under oxidative conditions. It is proposed that the Pd(II) dimer undergoes oxidative addition to produce a Pd(III) dimer which subsequently produces an aryl-ketone intermediate. This process is made possible by the cooperativity of the two palladium centers which enable the formation of a Pd(III) dimer, circumventing the need for the high energy Pd(IV) oxidation state. Oxidative conditions then allows coupling and cyclization of a second ketone to form the naphthalene product.
10

Investigation of the Effect of Dimerization on Human α-Galactosidase Activity

Dooley, Scott R 01 January 2014 (has links) (PDF)
Fabry disease is an X-linked lysosomal storage disease that results from a deficiency in the enzyme α-galactosidase (α-GAL). α-GAL hydrolyzes α-galactosides, and patients with Fabry disease suffer from an accumulation of these undegraded substrates. Human α-GAL naturally occurs as a homodimer, as determined through SEC and crystallographic analysis. This means its quaternary structure consists of two identical α-GAL subunits that are associated together into a single unit. Other species, such as rice, produce a monomeric form of α-GAL, consisting of only a single subunit. If α-GAL is functional as both a homodimer and monomer, then how does homodimerization affect the activity of human α-GAL? This can be answered through two model systems. First, a monomeric form of human α-GAL can be produced, testing the activity of human α-GAL in a monomeric state. A variant of α-GAL was engineered (called α-GALF273G/W277G) that appeared promising. Secondly, another system can be produced capable of stabilizing one active site of the dimer and testing the other active site for activity. Another lysosomal enzyme, α-N-acetylgalactosaminidase (α-NAGAL), shares 46% amino acid sequence identity and share 11 of 13 active site residues. Previously, an α-GAL variant (called α-GALE203S/L206A) was produced, that maintained the antigenicity of α-GAL, but had acquired the enzymatic specificity of α-N-acetylgalactosaminidase (α-NAGAL). A heterodimeric form of α-GAL can be produced combining one subunit of α-GAL with the engineered variant. The engineered site can be stabilized, while the wild-type site can be tested for activity. SEC analysis suggests α-GALF273G/W277G is a monomer, and its kinetic properties are reported. Evidence shows monomeric α-GAL could be useful as an improved enzyme replacement therapy. Western blotting and activity assays suggest the presence of the α-GAL/ α-GALE203S/L206A heterodimer.

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