Les azapeptides sont des mimes peptidiques où le carbone alpha d’un ou de plusieurs acides aminés est remplacé par un atome d’azote. Cette modification tend à stabiliser une conformation en repliement beta en raison de la répulsion électronique entre les paires d’électrons libres des atomes d’azote adjacents et de la géométrie plane de l’urée. De plus, le résidu semicarbazide a une meilleure résistance face aux protéases en plus d’être chimiquement plus stable qu’une liaison amide. Bien que les propriétés des azapeptides en fassent des mimes peptidiques intéressants, leurs méthodes de synthèses font appel à la synthèse laborieuse d’hydrazines substituées en solution. Le peptide sécréteur d’hormone de croissance 6 (GHRP-6, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) est un hexapeptide synthétique qui possède une affinité pour deux récepteurs distincts: les récepteurs GHS-R1a et CD36. Les travaux effectués au cours de mon doctorat qui seront détaillés dans cet ouvrage visent à atteindre deux objectifs: (1) le développement d’analogues du peptide GHRP-6 sélectif à un seul récepteur et (2) la mise au point d’une nouvelle méthodologie pour la synthèse combinatoire d’azapeptides. En réponse au premier objectif, la synthèse parallèle de 49 analogues aza-GHRP-6 a été effectuée et certains candidats sélectifs au récepteur CD36 ont été identifiés. L’étude de leurs propriétés anti-angiogéniques, effectuée par nos collaborateurs, a également permis d’identifier des candidats intéressants pour le traitement potentiel de la dégénérescence maculaire liée à l’âge. Une nouvelle approche pour la synthèse combinatoire d’azapeptides, faisant appel à l’alkylation et la déprotection chimiosélective d’une sous-unité semicarbazone ancrée sur support solide, a ensuite été développée. La portée de cette méthodologie a été augmentée par la découverte de conditions permettant l’arylation régiosélective de cette sous-unité semicarbazone, donnant accès à treize nouveaux dérivés aza-GHRP-6 possédant des résidus aza-arylglycines aux positions D-Trp2 et Trp4. L’élaboration de conditions propices à l’alkylation et la déprotection chimiosélective de la semicarbazone a donné accès à une variété de chaînes latérales sur l’acide aminé « aza » préalablement inaccessibles. Nous avons, entre autres, démontré qu’une chaîne latérale propargyl pouvait être incorporée sur l’acide aminé « aza ». Tenant compte de la réactivité des alcynes, nous avons ensuite élaboré des conditions réactionnelles permettant la formation in situ d’azotures aromatiques, suivie d’une réaction de cycloaddition 1,3-dipolaire sur support solide, dans le but d’obtenir des mimes de tryptophane. Sept analogues du GHRP-6 ont été synthétisés et testés pour affinité au récepteur CD36 par nos collaborateurs. De plus, nous avons effectué une réaction de couplage en solution entre un dipeptide possédant un résidu aza-propargylglycine, du paraformaldehyde et une variété d’amines secondaires (couplage A3) afin d’accéder à des mimes rigides d’aza-lysine. Ces sous-unités ont ensuite été incorporées sur support solide afin de générer sept nouveaux azapeptides avec des dérivés aza-lysine à la position Trp4 du GHRP-6. Enfin, une réaction de cyclisation 5-exo-dig a été développée pour la synthèse de N-amino imidazolin-2-ones en tant que nouveaux mimes peptidiques. Leur fonctionnalisation par une série de groupements benzyliques à la position 4 de l’hétérocycle a été rendue possible grâce à un couplage Sonogashira précédant la réaction de cyclisation. Les propriétés conformationnelles de cette nouvelle famille de composés ont été étudiées par cristallographie aux rayons X et spectroscopie RMN d’un tétrapeptide modèle. L’activité biologique de deux mimes peptidiques, possédant un résidu N-amino-4-méthyl- et 4-benzyl-imidazolin-2-one à la position Trp4 du GHRP-6, a aussi été examinée. L’ensemble de ces travaux devrait contribuer à l’avancement des connaissances au niveau des facteurs structurels et conformationnels requis pour le développement d’azapeptides en tant que ligands du récepteur CD36. De plus, les résultats obtenus devraient encourager davantage l’utilisation d’azapeptides comme peptidomimétiques grâce à leur nouvelle facilité de synthèse et la diversité grandissante au niveau de la chaîne latérale des acides aminés « aza ». / Azapeptides are peptide mimics in which the CH alpha in one or more amino acids has been replaced with a nitirogen atom. Such a modification tends to induce beta turn conformations in peptides, because of the consequences of lone–pair lone–pair repulsion between the two adjacent nitrogens and the planar geometry of the urea in the semicarbazide moiety. Furthermore, the semicarbazide increases protease resistance and is chemically more stable than its amide counterpart. Despite the potential advantages of using azapeptides mimics, their synthesis has been hampered by the solution-phase construction of substituted hydrazines prior to their incorporation into peptide sequences. Growth Hormone Releasing Peptide 6 sequence (GHRP-6, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) is a synthetic hexapeptide that binds to two distinct receptor: the Growth Hormone Secretatgogue Receptor 1a (GHS-R1a) and the Cluster of Differentiation 36 (CD36) receptor. The body of my Ph.D thesis has been generally targeted towards two objectives: (a) the development of azapeptide analogs of GHRP-6 with enhanced receptor selectivity and (b) the elaboration of a new synthetic approach for combinatorial submonomer azapeptide synthesis. In response to the first objective, 49 aza-GHRP-6 derivatives were synthesized and evaluated for receptor binding and biological activity. From this library, certain candidates were identified which exhibited decreased affinity for the GHS-R1a receptor with maintained affinity for the CD36 receptor. Furthermore, in studying their anti-angiogenic properties, our collaborators have identified aza-GHRP-6 analogs, which caused a marked decrease in microvascular sprouting in choroid explants, as well as another displaying potential to increase angiogenesis. A new approach for the combinatorial synthesis of azapeptides was developed to better conduct SAR studies using azapeptides. This method features the chemoselective alkylation and deprotection of a resin-bound semicarbazone building block. The scope of the methodology was further expanded by the development of reaction conditions for the chemoselective N-arylation of this semicarbazone residue, yielding 13 aza-GHRP-6 derivatives with aza-arylglycines residues at the D-Trp2 and Trp4 positions. The elaboration of a methodology based on the chemoselective alkylation and deprotection of a semicarbazone has allowed for greater aza-amino acid side chain diversity, enabling for example, the efficient incorporation of aza-propargylglycine residues into peptide sequences. Considering the reactivity of alkynes, we developed reaction conditions for in situ formation of aromatic azides, followed by a 1,3-dipolar cycloaddition reaction on solid support to yield aza-1-aryl,2,3-triazole-3-alanine residues as tryptophan mimics. Seven aza-GHRP-6 analogs were synthesized and subsequently tested for binding to the CD36 receptor by our collaborators. Moreover, the coupling reaction between an aza-propargylglycine-containing dipeptide building block, paraformaldehyde and a variety of secondary amines (A3 coupling) was accomplished in solution to provide access to rigid aza-lysine mimics. These aza-dipeptides were subsequently incorporated at the Trp4 position of seven new aza-GHRP-6 analogues using a solid-phase protocol, and the resulting azaLys mimics were tested for binding towards the CD36 receptor. Finally, conditions for a 5-exo-dig cyclization of an aza-propargylglycine residue were developed to give N-amino imidazolin-2-ones as turn-inducing peptide mimics. Their modification at the 4 position was achieved using a Sonogashira coupling protocol prior to the cyclization step. The conformational properties of these new heterocyclic motifs were assessed by X-ray crystallography and NMR spectroscopy on a tetrapeptide model system. The incorporation of N-amino-4-methyl- and 4-benzyl-imidazolin-2-ones at the Trp4 position of GHRP-6 was further accomplished and the biological evaluation of the peptidomimetics was examined. Taken together, these results should lead to a better understanding of the structural and conformational factors responsible for binding and biological activity of azapeptide ligands of the CD36 receptor. Furthermore, the submonomer approach for azapeptide synthesis developed should promote the use of azapeptides as peptide mimics, given its accessibility and the increased aza-amino acid side-chain diversity available.

Les azapeptides sont des mimes peptidiques où le carbone alpha d’un ou de plusieurs acides aminés est remplacé par un atome d’azote. Cette modification tend à stabiliser une conformation en repliement beta en raison de la répulsion électronique entre les paires d’électrons libres des atomes d’azote adjacents et de la géométrie plane de l’urée. De plus, le résidu semicarbazide a une meilleure résistance face aux protéases en plus d’être chimiquement plus stable qu’une liaison amide. Bien que les propriétés des azapeptides en fassent des mimes peptidiques intéressants, leurs méthodes de synthèses font appel à la synthèse laborieuse d’hydrazines substituées en solution. Le peptide sécréteur d’hormone de croissance 6 (GHRP-6, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) est un hexapeptide synthétique qui possède une affinité pour deux récepteurs distincts: les récepteurs GHS-R1a et CD36. Les travaux effectués au cours de mon doctorat qui seront détaillés dans cet ouvrage visent à atteindre deux objectifs: (1) le développement d’analogues du peptide GHRP-6 sélectif à un seul récepteur et (2) la mise au point d’une nouvelle méthodologie pour la synthèse combinatoire d’azapeptides. En réponse au premier objectif, la synthèse parallèle de 49 analogues aza-GHRP-6 a été effectuée et certains candidats sélectifs au récepteur CD36 ont été identifiés. L’étude de leurs propriétés anti-angiogéniques, effectuée par nos collaborateurs, a également permis d’identifier des candidats intéressants pour le traitement potentiel de la dégénérescence maculaire liée à l’âge. Une nouvelle approche pour la synthèse combinatoire d’azapeptides, faisant appel à l’alkylation et la déprotection chimiosélective d’une sous-unité semicarbazone ancrée sur support solide, a ensuite été développée. La portée de cette méthodologie a été augmentée par la découverte de conditions permettant l’arylation régiosélective de cette sous-unité semicarbazone, donnant accès à treize nouveaux dérivés aza-GHRP-6 possédant des résidus aza-arylglycines aux positions D-Trp2 et Trp4. L’élaboration de conditions propices à l’alkylation et la déprotection chimiosélective de la semicarbazone a donné accès à une variété de chaînes latérales sur l’acide aminé « aza » préalablement inaccessibles. Nous avons, entre autres, démontré qu’une chaîne latérale propargyl pouvait être incorporée sur l’acide aminé « aza ». Tenant compte de la réactivité des alcynes, nous avons ensuite élaboré des conditions réactionnelles permettant la formation in situ d’azotures aromatiques, suivie d’une réaction de cycloaddition 1,3-dipolaire sur support solide, dans le but d’obtenir des mimes de tryptophane. Sept analogues du GHRP-6 ont été synthétisés et testés pour affinité au récepteur CD36 par nos collaborateurs. De plus, nous avons effectué une réaction de couplage en solution entre un dipeptide possédant un résidu aza-propargylglycine, du paraformaldehyde et une variété d’amines secondaires (couplage A3) afin d’accéder à des mimes rigides d’aza-lysine. Ces sous-unités ont ensuite été incorporées sur support solide afin de générer sept nouveaux azapeptides avec des dérivés aza-lysine à la position Trp4 du GHRP-6. Enfin, une réaction de cyclisation 5-exo-dig a été développée pour la synthèse de N-amino imidazolin-2-ones en tant que nouveaux mimes peptidiques. Leur fonctionnalisation par une série de groupements benzyliques à la position 4 de l’hétérocycle a été rendue possible grâce à un couplage Sonogashira précédant la réaction de cyclisation. Les propriétés conformationnelles de cette nouvelle famille de composés ont été étudiées par cristallographie aux rayons X et spectroscopie RMN d’un tétrapeptide modèle. L’activité biologique de deux mimes peptidiques, possédant un résidu N-amino-4-méthyl- et 4-benzyl-imidazolin-2-one à la position Trp4 du GHRP-6, a aussi été examinée. L’ensemble de ces travaux devrait contribuer à l’avancement des connaissances au niveau des facteurs structurels et conformationnels requis pour le développement d’azapeptides en tant que ligands du récepteur CD36. De plus, les résultats obtenus devraient encourager davantage l’utilisation d’azapeptides comme peptidomimétiques grâce à leur nouvelle facilité de synthèse et la diversité grandissante au niveau de la chaîne latérale des acides aminés « aza ». / Azapeptides are peptide mimics in which the CH alpha in one or more amino acids has been replaced with a nitirogen atom. Such a modification tends to induce beta turn conformations in peptides, because of the consequences of lone–pair lone–pair repulsion between the two adjacent nitrogens and the planar geometry of the urea in the semicarbazide moiety. Furthermore, the semicarbazide increases protease resistance and is chemically more stable than its amide counterpart. Despite the potential advantages of using azapeptides mimics, their synthesis has been hampered by the solution-phase construction of substituted hydrazines prior to their incorporation into peptide sequences. Growth Hormone Releasing Peptide 6 sequence (GHRP-6, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) is a synthetic hexapeptide that binds to two distinct receptor: the Growth Hormone Secretatgogue Receptor 1a (GHS-R1a) and the Cluster of Differentiation 36 (CD36) receptor. The body of my Ph.D thesis has been generally targeted towards two objectives: (a) the development of azapeptide analogs of GHRP-6 with enhanced receptor selectivity and (b) the elaboration of a new synthetic approach for combinatorial submonomer azapeptide synthesis. In response to the first objective, 49 aza-GHRP-6 derivatives were synthesized and evaluated for receptor binding and biological activity. From this library, certain candidates were identified which exhibited decreased affinity for the GHS-R1a receptor with maintained affinity for the CD36 receptor. Furthermore, in studying their anti-angiogenic properties, our collaborators have identified aza-GHRP-6 analogs, which caused a marked decrease in microvascular sprouting in choroid explants, as well as another displaying potential to increase angiogenesis. A new approach for the combinatorial synthesis of azapeptides was developed to better conduct SAR studies using azapeptides. This method features the chemoselective alkylation and deprotection of a resin-bound semicarbazone building block. The scope of the methodology was further expanded by the development of reaction conditions for the chemoselective N-arylation of this semicarbazone residue, yielding 13 aza-GHRP-6 derivatives with aza-arylglycines residues at the D-Trp2 and Trp4 positions. The elaboration of a methodology based on the chemoselective alkylation and deprotection of a semicarbazone has allowed for greater aza-amino acid side chain diversity, enabling for example, the efficient incorporation of aza-propargylglycine residues into peptide sequences. Considering the reactivity of alkynes, we developed reaction conditions for in situ formation of aromatic azides, followed by a 1,3-dipolar cycloaddition reaction on solid support to yield aza-1-aryl,2,3-triazole-3-alanine residues as tryptophan mimics. Seven aza-GHRP-6 analogs were synthesized and subsequently tested for binding to the CD36 receptor by our collaborators. Moreover, the coupling reaction between an aza-propargylglycine-containing dipeptide building block, paraformaldehyde and a variety of secondary amines (A3 coupling) was accomplished in solution to provide access to rigid aza-lysine mimics. These aza-dipeptides were subsequently incorporated at the Trp4 position of seven new aza-GHRP-6 analogues using a solid-phase protocol, and the resulting azaLys mimics were tested for binding towards the CD36 receptor. Finally, conditions for a 5-exo-dig cyclization of an aza-propargylglycine residue were developed to give N-amino imidazolin-2-ones as turn-inducing peptide mimics. Their modification at the 4 position was achieved using a Sonogashira coupling protocol prior to the cyclization step. The conformational properties of these new heterocyclic motifs were assessed by X-ray crystallography and NMR spectroscopy on a tetrapeptide model system. The incorporation of N-amino-4-methyl- and 4-benzyl-imidazolin-2-ones at the Trp4 position of GHRP-6 was further accomplished and the biological evaluation of the peptidomimetics was examined. Taken together, these results should lead to a better understanding of the structural and conformational factors responsible for binding and biological activity of azapeptide ligands of the CD36 receptor. Furthermore, the submonomer approach for azapeptide synthesis developed should promote the use of azapeptides as peptide mimics, given its accessibility and the increased aza-amino acid side-chain diversity available.

This thesis argues that any historiography that would contribute to theological knowledge must take into consideration, at a methodological level, the reality of God. This theological claim, in turn, has significant implications for historical knowledge and thus, historiography. The thesis moves ahead in five chapters. The first is an overview and description of N. T. Wright's historical and theological method as they both are grounded in his critical realist epistemology. The second chapter argues for a particular theological epistemology that goes beyond Wright's and corrects it, drawing primarily on the work of T. F. Torrance and Søren Kierkegaard. In the third and fourth chapters an ‘apocalyptic' theological approach is defined and articulated according to a progression from soteriology to Christology to creation. The final chapter builds upon this constructive theological work by articulating an ‘apocalyptic' theology of history which is then used to articulate some key considerations for a theological approach to historiography in critical dialogue with Wright's historical and theological method.

No description available.

Many previous studies have demonstrated that gold compounds possess successful results in catalysis and in medicinal chemistry. The central aim of this dissertation is the design and synthesis of novel gold (I) acyclic diamino carbene complexes as a chemotherapeutic agent for triple-negative breast cancer (TNBC) and for catalysis. In this study, a series of chiral neutral and cationic gold (I) acyclic diamino carbene (ADC) complexes and neutral gold (I) bis- ADC complexes have been synthesized. As the chiral neutral gold (I) ADCs, four diastereomers of S binaphthyl L proline tertiary butyl ester gold (I) chloride, S binaphthyl D proline tertiary butyl ester gold (I) chloride, R binaphthyl L proline tertiary butyl ester gold (I) chloride, and R binaphthyl D proline tertiary butyl ester gold (I) chloride have been synthesized and characterized. Different chiral gold (I) ADC complexes with bulky chiral binaphthyl group and with different amine groups of morpholine, chiral proline methyl ester, and benzyl ester have been synthesized and characterized. After that four diastereomers of the nitrile adduct of cationic binaphthyl proline tertiary butyl ester nitrile and four diastereomers of the isonitrile versions of it have been synthesized and characterized. A series of gold (I) cationic bis ADC complexes have been synthesized and characterized. All these novel gold ADC complexes were tested for biological activity against TNBC cell line MDA-MB-231 and cationic S binaphthyl D proline ester isonitrile adduct, S binaphthyl D proline ester isonitrile adduct and R binaphthyl D proline ester isonitrile adduct gave promising inhibition rates. According to Lipinski's rule, lipophilicity determines the effectiveness of the drug absorption to the body through the lipid membrane. To determine the drug-likeness of the gold ADC complexes, log P values were calculated for some of the synthesized complexes using a modified shake flask method. Gold (I) ADC complexes have been renowned for their ability in catalysis, but enantioselective catalysis is not that well studied. A3 coupling reaction is a well-known reaction for the synthesis of propargyl amines. Here, A3 coupling reaction with a chiral amine has been performed using the previously synthesized four diastereomers of binaphthyl proline tertial butyl ester gold (I) ADCs (SL, RD, RL, SD) as the catalyst expecting four different diastereomers of the product. The reaction exhibited reasonable yields but with a low enantiomeric excess (ee%). However, it gave proof of the principle that asymmetric induction is possible with the synthesized novel chiral gold (I) ADC complexes.

Networks of interneurons within the spinal cord coordinate the rhythmic activation of muscles during locomotion. These networks are subject to extensive neuromodulation, ensuring appropriate behavioural output. Astrocytes are proposed to detect neuronal activity via Gαq-linked G-protein coupled receptors and to secrete neuromodulators in response. However, there is currently a paucity of evidence that astrocytic information processing of this kind is important in behaviour. Here, it is shown that protease-activated receptor-1 (PAR1), a Gαq-linked receptor, is preferentially expressed by glia in the spinal cords of postnatal mice. During ongoing locomotor-related network activity in isolated spinal cords, PAR1 activation stimulates release of adenosine triphosphate (ATP), which is hydrolysed to adenosine extracellularly. Adenosine then activates A1 receptors to reduce the frequency of locomotor-related bursting recorded from ventral roots. This entails inhibition of D1 dopamine receptors, activation of which enhances burst frequency. The effect of A1 blockade scales with network activity, consistent with activity-dependent production of adenosine by glia. Astrocytes also regulate activity by controlling the availability of D-serine or glycine, both of which act as co-agonists of glutamate at N-methyl-D-aspartate receptors (NMDARs). The importance of NMDAR regulation for locomotor-related activity is demonstrated by blockade of NMDARs, which reduces burst frequency and amplitude. Bath-applied D-serine increases the frequency of locomotor-related bursting but not intense synchronous bursting produced by blockade of inhibitory transmission, implying activity-dependent regulation of co-agonist availability. Depletion of endogenous D-serine increases the frequency of locomotor-related but not synchronous bursting, indicating that D-serine is required at a subset of NMDARs expressed by inhibitory interneurons. Blockade of the astrocytic glycine transporter GlyT1 increases the frequency of locomotor-related activity, but application of glycine has no effect, indicating that GlyT1 regulates glycine at excitatory synapses. These results indicate that glia play an important role in regulating the output of spinal locomotor networks.

Synaptic plasticity describes efficacy changes in synaptic transmission and ranges in duration from tens to hundreds of milliseconds (short-term), to hours and days (long-term). Short-term plasticity plays crucial roles in synaptic computation, information processing, learning, working and short-term memory as well as its dysfunction in psychiatric and neurodegenerative diseases. The main aim of my PhD thesis was to determine the molecular mechanisms of different forms of presynaptic plasticity. Short-term facilitation increases neurotransmitter release in response to a high-frequency pair (paired-pulse facilitation; PPF) or train (train facilitation; TF) of presynaptic stimuli. Synaptotagmin 7 (Syt7) has been shown to act as residual calcium (Ca$_{res}$) sensor for PPF and TF at various synapses. Syt7 also seems to be involved in recovery from depression, whereas its role in neurotransmission remains controversial. My aim was to express Syt7 in a synapse where it is not normally found and determine how it affects short-term synaptic plasticity. Immunohistochemistry indicated that Syt7 is not localized to cerebellar climbing fibers (CFs). Wild-type (WT) and Syt7 knockout (KO) recordings at CF to Purkinje cell (CF-PC) synapses established that at near-physiological external calcium (Ca$_{ext}$) levels both genotypes displayed similar recovery from paired-pulse depression. In low Ca$_{ext}$,WT CF-PC synapses showed robust PPF, which turned out to be independent of Syt7. All my experiments strongly suggested that WT CFs do not express native Syt7, but display low Ca$_{ext}$ CF-PC PPF and TF. Thus, channelrhodopsin-2 and Syt7 were bicistronically expressed via AAV9 virus in CFs. This ectopic Syt7 expression in CFs led to big increases in low-Ca$_{ext}$ CF-PC facilitation, more than doubling PPF and more than tripling TF. While overexpression of Syt7 might turn out to have an effect on the initial release probability (pr), the observed CF-PC facilitation increase still critically depended on presynaptic Syt7 expression. And when comparing only cells in a defined EPSC1 amplitude range, the Syt7-induced increase in low-Ca$_{ext}$ PPF could not be accounted for by changes in initial pr, suggesting a general role for Syt7 as calcium sensor for facilitation. Another form of short-term plasticity, post-tetanic potentiation (PTP), is believed to be mediated presynaptically by calcium-dependent protein kinase C (PKC) isoforms that phosphorylate Munc18-1 proteins. It is unknown how generally applicable this mechanism is throughout the brain and if other proteins might be able to modulate PTP. Combining genetic (PKCαβy triple knockout [TKO] and Munc18-1SA knock-in [Munc18 KI] mice, in which Munc18- 1 cannot get phosphorylated) with pharmacological tools (PKC inhibitor GF109203), helped us show that PTP at the cerebellar parallel fiber to Purkinje cell (PF-PC) synapse seems to depend on PKCs but seems mostly independent of Munc18-1 phosphorylation. In addition, compared to WT animals, genetic elimination of presynaptic active zone protein Liprin-α3 led to similar PF-PC PTP and paired-pulse ratios (PPRs). At the hippocampal CA3-CA1 synapse previous pharmacological studies suggested that PKC mediates PTP. A genetic approach helped to show that calcium dependent PKCs do not seem to be required for CA3-CA1 PTP. Pharmacologically inhibiting protein kinase A as well as genetically eliminating Syt7 also had no effect on CA3-CA1 PTP. In addition, Ca IM-AA mutant mice, in which Ca$_{v}$2.1 channels have a mutated IQ-like motif (IM) so that it cannot get bound by calcium sensor proteins any more, not only displayed regular PTP, but also normal PPF and TF at CA3-CA1 synapses. In conclusion, my PhD thesis helped further characterize different forms of presynaptic plasticity, underlined that short-term synaptic plasticity can be achieved through diverse mechanisms across the Mammalian brain and supported a potentially general role for synaptotagmin 7 acting as residual calcium sensor for facilitation.

The second edition of Shakespeare's sonnets, titled Poems: Written by Wil. Shake-Speare, Gent, and published by stationer John Benson in 1640, was a text typical of its time. In an effort to update the old-fashioned sonnet sequence in which its contents had first reached print, the compiler or editor of the Bensonian version rearranged the poems from the earlier quarto text, adding titles and other texts thought to have been written by or about the sonnets' author. The immediate reception of the 1640 Poems was a quiet one, but the volume's contents and structure served as the foundation for more than half of the editions of Shakespeare's sonnets produced in the eighteenth century. In part due to the textual instability created by the presence of two disparate arrangements of the collection, Shakespeare's sonnets served only as supplements to the preferred Shakespearean canon from 1709 to 1790. When, at the end of the century, the sonnets finally entered the canon in Edmond Malone's groundbreaking edition of the plays and poems together, Benson's version was quickly overshadowed by the earlier text, which was preferred as both more authorial and, due to Malone's careful critical readings, autobiographical. In contrast to the many scholars since Malone who have overlooked or denigrated the Poems of 1640, this thesis studies the second edition of Shakespeare's sonnets within the framework of the early modern culture that produced it, arguing that Benson's edition provides valuable evidence about the editorial habits and literary preferences of the individuals and culture for which it was originally intended.