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Molecular Mechanisms Controlling Synaptic Vesicle Fusion
SNARE proteins are the engines that drive membrane fusion throughout the cell. They provide this energy by zippering up into a parallel four helix bundle in a thermodynamically favored process. Because the zippering of SNAREs is spontaneous, fusion events occur immediately upon a vesicle interacting with its target membrane. But, in certain circumstances, such as in synaptic vesicles, spontaneous fusion is not desired, so a clamp protein is necessary to prevent this fusion until signaled to do otherwise.
In synapses, this protein is called Complexin and a second protein, called Synaptotagmin, releases the clamp upon a rapid influx of calcium, the hallmark of an action potential. How Complexin clamps is a subject of great interest in the field, and an area of active research. What is known is that a so-called Accessory helix (residues 28-47) is responsible for clamping, while another, Central Helix (reisudes 48-70) is responsible for physically binding to the helix. A recently solved crystal structure revealed how CPX might behave before the SNAREs fully zipper, namely that the accessory helix extends away from the SNAREs at a 45° angle.
But, because of the packing of the crystal, it is entirely possible that the crystal is an artifact of packing, and/or truncationIn this thesis, my work first validates the crystal structure, using a FRET pair I developed for this purpose. I establish that the angled-out positioning of the accessory helix does, in fact, occur in solution, and is not due to crystal packing or the truncation of the VAMP2 (the neuronal vesicle-associated SNARE), but rather is due to the fact that its C-terminus is not present. I describe a mechanism by which Complexin can clamp.
Further, I demonstrate that the residues in VAMP2 which are responsible for the switch from the "open" to the "closed" conformation are a patch of asparatates in VAMP2 (residues 64, 65, an 68). I also establish that these three aspartates are responsible for the release of the clamp and that without them, Complexin cannot be brought into the angled-in configuration. I propose a model for how the clamp might be released by Synaptotagmin
Web-based collaborative care intervention to manage cancer-related symptoms in the palliative care setting
Background—The aim of the study was to examine the efficacy of a collaborative care intervention to reduce depression, pain and fatigue and improve quality of life. Participants—A total of 261 patients with advanced cancer and 179 family caregivers were randomized to a web-based collaborative care intervention or enhanced usual care. The intervention included (1) a website with written and audiovisual self-management strategies, bulletin board, and other resources; (2) visits with a care coordinator during physician appointment every two months; and (3) telephone follow up every two weeks. Primary patient outcomes included measures of depression, pain, fatigue, and health related quality of life. Secondary outcomes included Interleukin (IL)-1α, IL-1β, IL-6, IL-8, Natural Killer (NK) cell numbers, and caregiver stress and depression.
Results—At baseline, 51% of patients reported one or more symptoms in the clinical range. For patients who presented with clinical levels of symptoms, and were randomized to the intervention, reductions in depression (Cohen’s d=0.71), pain (Cohen’s d=0.62), and fatigue (Cohen’s d=0.26) and improvements in quality of life (Cohen’s d =0.99) were observed when compared to the enhanced usual care arm at 6-months. Reductions in IL-6 (phi=0.18), IL-1β (phi=0.35); IL-1α (phi=0.19); IL-8 (phi=15) and increases in NK cell numbers (phi=0.23) were observed when compared to enhanced usual care arm at 6-months. Reductions in caregiver stress (Cohen’s d=0.75) and depression (Cohen’s d=0.37) were observed at 6-months for caregivers whose loved one was randomized to the intervention arm.
Conclusions—Integration of screening and symptom management into cancer care is recommended
An analysis of the ability of N-allylnormorphine to protect against a lethal dose of meperidine (demerol)
Biology and Biochemistry, Department o
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