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| 2. |
- Heilig, Markus, et al.
(författare)
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Translating the neuroscience of alcoholism into clinical treatments : from blocking the buzz to curing the blues
- 2010
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Ingår i: Neuroscience and Biobehavioral Reviews. - : Elsevier. - 0149-7634 .- 1873-7528. ; 35:2, s. 334-344
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the pathophysiology of addictive disorders is critical for development of new treatments. A major focus of addiction research has for a long time been on systems that mediate acute positively reinforcing effects of addictive drugs, most prominently the mesolimbic dopaminergic (DA) system and its connections. This research line has been successful in shedding light on the physiology of both natural and drug reward, but has not led to therapeutic breakthroughs. The role of classical reward systems is perhaps least clear in alcohol addiction. Here, recent work is summarized that points to some clinically important conclusions. First, important pharmacogenetic differences exist with regard to positively reinforcing effects of alcohol and the ability of this drug to activate classical reward pathways. This offers an opportunity for personalized treatment approaches in alcoholism. Second, brain stress and fear systems become pathologically activated in later stages of alcoholism and their activation is a major influence in escalation of alcohol intake, sensitization of stress responses, and susceptibility to relapse. These findings offer a new category of treatment mechanisms. Corticotropin-releasing hormone (CRH) signaling through CRH1 receptors is a major candidate target in this category, but recent data indicate that antagonists for substance P (SP) neurokinin 1 (NK1) receptors may have a similar potential.
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| 3. |
- Jana, Somnath, et al.
(författare)
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Atomic-scale chemical fluctuation in LaSrVMoO6, a proposed half-metallic antiferromagnet
- 2010
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Ingår i: Physical Review B. Condensed Matter and Materials Physics. - 1098-0121 .- 1550-235X. ; 82:18
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Tidskriftsartikel (refereegranskat)abstract
- Half-metallic antiferromagnets (HMAFMs) have been proposed theoretically long ago but have not been realized experimentally yet. Recently, a double perovskite compound, LaSrVMoO6, has been claimed to be an almost real HMAFM system. Here, we report detailed experimental and theoretical studies on this compound. Our results reveal that the compound is neither a half-metal nor an ordered antiferromagnet. Most importantly, an unusual chemical fluctuation is observed locally, which finally accounts for all the electronic and magnetic properties of this compound.
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| 4. |
- Kasson, Peter M., et al.
(författare)
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Atomic-Resolution Simulations Predict a Transition State for Vesicle Fusion Defined by Contact of a Few Lipid Tails
- 2010
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Ingår i: PloS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 6:6, s. e1000829-
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Tidskriftsartikel (refereegranskat)abstract
- Membrane fusion is essential to both cellular vesicle trafficking and infection by enveloped viruses. While the fusion protein assemblies that catalyze fusion are readily identifiable, the specific activities of the proteins involved and nature of the membrane changes they induce remain unknown. Here, we use many atomic-resolution simulations of vesicle fusion to examine the molecular mechanisms for fusion in detail. We employ committor analysis for these million-atom vesicle fusion simulations to identify a transition state for fusion stalk formation. In our simulations, this transition state occurs when the bulk properties of each lipid bilayer remain in a lamellar state but a few hydrophobic tails bulge into the hydrophilic interface layer and make contact to nucleate a stalk. Additional simulations of influenza fusion peptides in lipid bilayers show that the peptides promote similar local protrusion of lipid tails. Comparing these two sets of simulations, we obtain a common set of structural changes between the transition state for stalk formation and the local environment of peptides known to catalyze fusion. Our results thus suggest that the specific molecular properties of individual lipids are highly important to vesicle fusion and yield an explicit structural model that could help explain the mechanism of catalysis by fusion proteins.
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| 5. |
- Kasson, Peter M., et al.
(författare)
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Water Ordering at Membrane Interfaces Controls Fusion Dynamics
- 2011
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society. - 0002-7863 .- 1520-5126. ; 133:11, s. 3812-3815
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Tidskriftsartikel (refereegranskat)abstract
- Membrane interfaces are critical to many cellular functions, yet the vast array of molecular components involved make the fundamental physics of interaction difficult to define. Water has been shown to play an important role in the dynamics of small biological systems, for example when trapped in hydrophobic regions, but the molecular details of water have generally been thought dispensable when considering large membrane interfaces. Nevertheless, spectroscopic data indicate that water has distinct, ordered behavior near membrane surfaces. While coarse-grained simulations have achieved success recently in aiding understanding the dynamics of membrane assemblies, it is natural to ask, does the missing chemical nature of water play an important role? We have therefore performed atomic-resolution simulations of vesicle fusion to understand the role of chemical detail, particularly the molecular structure of water, in membrane fusion and at membrane interfaces more generally. These membrane interfaces present a form of hydrophilic confinement, yielding surprising, non-bulk-like water behavior.
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