2018 Fine Art Graduation Exhibition Catalogue

MIXTAPE Fanshawe Fine Art Class of 2018 Graduation Exhibition The Arts ProjectApril 4-14Opening Reception - Saturday April 7th, 20187pm-10pm Guest Speaker: Cora Cluetthttps://first.fanshawec.ca/famd_design_fineart_gradcatalogues/1012/thumbnail.jp

A small molecule ApoE4-targeted therapeutic candidate that normalizes sirtuin 1 levels and improves cognition in an Alzheimer's disease mouse model.

We describe here the results from the testing of a small molecule first-in-class apolipoprotein E4 (ApoE4)-targeted sirtuin1 (SirT1) enhancer, A03, that increases the levels of the neuroprotective enzyme SirT1 while not affecting levels of neurotoxic sirtuin 2 (SirT2) in vitro in ApoE4-transfected cells. A03 was identified by high-throughput screening (HTS) and found to be orally bioavailable and brain penetrant. In vivo, A03 treatment increased SirT1 levels in the hippocampus of 5XFAD-ApoE4 (E4FAD) Alzheimer's disease (AD) model mice and elicited cognitive improvement while inducing no observed toxicity. We were able to resolve the enantiomers of A03 and show using in vitro models that the L-enantiomer was more potent than the corresponding D-enantiomer in increasing SirT1 levels. ApoE4 expression has been shown to decrease the level of the NAD-dependent deacetylase and major longevity determinant SirT1 in brain tissue and serum of AD patients as compared to normal controls. A deficiency in SirT1 level has been recently implicated in increased tau acetylation, a dominant post-translational modification and key pathological event in AD and tauopathies. Therefore, as a novel approach to therapeutic development for AD, we targeted identification of compounds that enhance and normalize brain SirT1 levels

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Elucidating the Structures of Amyloid Oligomers with Chemical Model Systems

While amyloid plaques and fibrils are a visible hallmark of Alzheimer's disease, smaller assemblies of Aβ, termed oligomers, are now widely thought to be the Aβ species that cause neurodegeneration. Since the structures of the oligomers are not known and not well understood, determination of the structure of amyloid oligomers is one of the most important problems in structural biology. The Nowick group uses chemical model systems to study β-sheet structures and interactions, and these systems can also be used to stabilize oligomers for structural studies. This dissertation describes chemical model systems to elucidate different amyloid oligomer assemblies using an amyloidogenic sequence from Aβ and to gain a structure-based understanding of how natural Aβ may form toxic oligomers. Chapter 1 describes the use of chemical model systems in the research group in helping us understand the types of supramolecular interactions in protein quaternary structure and in amyloids. The model systems are macrocyclic β-sheet peptides that contain artificial turn and template units that mimic β-sheet structure and interactions. Studies of the macrocyclic β-sheet peptides by X-ray crystallography illustrate the importance of edge-to-edge hydrogen bonding interactions and the face-to-face hydrophobic interactions between proteins and amyloid peptides. The macrocycles were used in inhibition studies against amyloid aggregation assays. Chapter 2 describes the X-ray crystallographic structures of oligomers of a new chemical model system of a macrocyclic β-sheet peptide that incorporates an amyloidogenic sequence Aβ15-23 from the Aβ peptide. In the solid state structure, the macrocycle folds well as an artificial β-sheet and forms a cruciform tetramer that are made up of antiparallel, hydrogen-bonded dimers. The cruciform tetramers assemble into triangular dodecamers, and the triangular dodecamers further assemble into a lattice. The lattice features a hexagonal cavity, which can be thought of as a porelike assembly, and may disrupt cell membranes by serving as a channel for water or metal cations. The cruciform tetramers also organize into a linear assembly through the lattice. The self-association of the β-sheet macrocycle seen in the crystal structure provides clues into the self-assembly mechanism of amyloid oligomers. Chapter 2 culminates with the use of the crystal structure to model similar oligomer structures using the linear sequence of Aβ (Ac-QKLVFFAED-NHMe, Ac-Aβ15-23-NHMe); the modeling suggests that natural Aβ can form similar structures. Chapter 3 complements the work conducted in Chapter 2 and describes a series of macrocyclic β-sheet peptides that differs in the solution structure vs. the solid-state structure. In the study, the macrocyclic β-sheets dimerize in a shifted, antiparallel fashion as observed by 1H-NMR spectroscopy. Additional studies by 1H-NMR and DOSY spectroscopy suggest that the shifted, β-sheet dimers self-associate into a tetramer through face-to-face interaction. Supramolecular interactions of the peptide were explored with different mutations. The results show the structural importance of incorporating Aβ residues and the polymorphism observed in the solution state structure in comparison to the solid-state structure. Chapter 4 is an extension of the work from Chapter 2 that describes the discovery of a new motif of a macrocyclic β-sheet peptide that forms a fibril-like assembly of oligomers. The results bridge the gap between amyloid oligomers and amyloid fibrils, showing how amyloid oligomers can form fibrillar assemblies in the solid state. In the new macrocycle, the template strand is substituted with an Aβ15-23 hybrid strand. The macrocycle forms a tetramer in aqueous solution, and in X-ray crystallographic studies, the solid-state structure of the macrocycle suggests an alternate mode of assembly for Aβ peptides

Acute management of skin tears with mesh grafting: a prospective study and cost-benefit analysis

**Background**: Skin tears cause a significant burden to the patient and healthcare system. Acute management has traditionally comprised of operative debridement and formal skin grafting, which is costly, invasive and often followed by admission for five to seven days. In a 2014 pilot study by Vandervord and colleagues, a protocol for re-laying the skin tear as a meshed skin graft (mesh protocol) was proposed, which has not been validated to date. Our study aims to compare a prospective cohort to the original pilot study to determine validity in clinical practice and provide an updated cost-benefit analysis. **Method**: All patients who presented with acutely sustained skin tears at Northern Beaches Hospital, NSW, Australia, were prospectively entered into the mesh protocol as described by Vandervord and colleagues. An updated cost-benefit analysis was performed using a national hospital cost data collection report produced by the Independent Hospital Pricing Authority (IHPA). **Results**: We enrolled 53 patients onto the protocol who had sustained a total of 64 discrete skin tears, with 11 patients sustaining more than one skin tear. The average age of patients was 86, and the most common location of the skin tear was pretibial, followed by forearm/hand. Only one patient required a return to theatre for debridement and formal skin grafting, and three patients required long-term dressings for partial mesh graft loss. The cost to the healthcare system is consistent with the pilot study, with a significant difference between discharge from the emergency department post-procedure and formal grafting and admission for five to seven days. **Conclusion**: Use of the mesh protocol creates wound coverage and prevents the need for formal skin grafting, and reduces costs associated with formal operations and hospital admissions

Structures of Oligomers of a Peptide from β‑Amyloid

Amyloid oligomers play a central role in Alzheimer's and other amyloid diseases, and yet the structures of these heterogeneous and unstable species are not well understood. To better understand the structures of oligomers formed by amyloid-β peptide (Aβ), we have incorporated a key amyloidogenic region of Aβ into a macrocyclic peptide that stabilizes oligomers and facilitates structural elucidation by X-ray crystallography. This paper reports the crystallographic structures of oligomers and oligomer assemblies formed by a macrocycle containing the Aβ(15-23) nonapeptide. The macrocycle forms hydrogen-bonded β-sheets that assemble into cruciform tetramers consisting of eight β-strands in a two-layered assembly. Three of the cruciform tetramers assemble into a triangular dodecamer. These oligomers further assemble in the lattice to form hexagonal pores. Molecular modeling studies suggest that the natural Aβ peptide can form similar oligomers and oligomer assemblies. The crystallographic and molecular modeling studies suggest the potential for interaction of the oligomers with cell membranes and provide insights into the role of oligomers in amyloid diseases

Polymorphism of Oligomers of a Peptide from β‑Amyloid

This contribution reports solution-phase structural studies of oligomers of a family of peptides derived from the β-amyloid peptide (Aβ). We had previously reported the X-ray crystallographic structures of the oligomers and oligomer assemblies formed in the solid state by a macrocyclic β-sheet peptide containing the Aβ_15–23 nonapeptide. In the current study, we set out to determine its assembly in aqueous solution. In the solid state, macrocyclic β-sheet peptide <b>1</b> assembles to form hydrogen-bonded dimers that further assemble in a sandwich-like fashion to form tetramers through hydrophobic interactions between the faces bearing V₁₈ and F₂₀. In aqueous solution, macrocyclic β-sheet peptide <b>1</b> and homologue <b>2a</b> form hydrogen-bonded dimers that assemble to form tetramers through hydrophobic interactions between the faces bearing L₁₇, F₁₉, and A₂₁. In the solid state, the hydrogen-bonded dimers are antiparallel, and the β-strands are fully aligned, with residues 17–23 of one of the macrocycles aligned with residues 23–17 of the other. In solution, residues 17–23 of the hydrogen-bonded dimers are shifted out of alignment by two residues toward the C-termini. The two hydrogen-bonded dimers are nearly orthogonal in the solid state, while in solution the dimers are only slightly rotated. The differing morphology of the solution-state and solid-state tetramers is significant, because it may provide a glimpse into some of the structural bases for polymorphism among Aβ oligomers in Alzheimer’s disease

Structures of Oligomers of a Peptide from β‑Amyloid

Amyloid oligomers play a central role in Alzheimer’s and other amyloid diseases, and yet the structures of these heterogeneous and unstable species are not well understood. To better understand the structures of oligomers formed by amyloid-β peptide (Aβ), we have incorporated a key amyloidogenic region of Aβ into a macrocyclic peptide that stabilizes oligomers and facilitates structural elucidation by X-ray crystallography. This paper reports the crystallographic structures of oligomers and oligomer assemblies formed by a macrocycle containing the Aβ_15–23 nonapeptide. The macrocycle forms hydrogen-bonded β-sheets that assemble into cruciform tetramers consisting of eight β-strands in a two-layered assembly. Three of the cruciform tetramers assemble into a triangular dodecamer. These oligomers further assemble in the lattice to form hexagonal pores. Molecular modeling studies suggest that the natural Aβ peptide can form similar oligomers and oligomer assemblies. The crystallographic and molecular modeling studies suggest the potential for interaction of the oligomers with cell membranes and provide insights into the role of oligomers in amyloid diseases

Structures of Oligomers of a Peptide from β‑Amyloid

Amyloid oligomers play a central role in Alzheimer’s and other amyloid diseases, and yet the structures of these heterogeneous and unstable species are not well understood. To better understand the structures of oligomers formed by amyloid-β peptide (Aβ), we have incorporated a key amyloidogenic region of Aβ into a macrocyclic peptide that stabilizes oligomers and facilitates structural elucidation by X-ray crystallography. This paper reports the crystallographic structures of oligomers and oligomer assemblies formed by a macrocycle containing the Aβ_15–23 nonapeptide. The macrocycle forms hydrogen-bonded β-sheets that assemble into cruciform tetramers consisting of eight β-strands in a two-layered assembly. Three of the cruciform tetramers assemble into a triangular dodecamer. These oligomers further assemble in the lattice to form hexagonal pores. Molecular modeling studies suggest that the natural Aβ peptide can form similar oligomers and oligomer assemblies. The crystallographic and molecular modeling studies suggest the potential for interaction of the oligomers with cell membranes and provide insights into the role of oligomers in amyloid diseases