Serotonin 5-HT(2A )and 5-HT(6 )receptors in the prefrontal cortex of Alzheimer and normal aging patients

BACKGROUND: It has been hypothesized that alterations of the serotonergic system contribute to neuropsychiatric symptoms in Alzheimer disease (AD). Cellular expressions of the two serotonergic receptors 5-HT(2A )and 5-HT(6 )have therefore been determined by immunohistochemistry in the prefrontal cortex of patients with AD (n=6) and normal age-matched controls (n = 7). RESULTS: In normal aging patients, 5-HT(2A )label was mainly observed in large pyramidal cells, but to a lesser extent also in small pyramidal cells and in stellate cells of cortical layers II-VI. In AD, a similar distribution was observed, but density of positive cells was significantly reduced by 33%. In aging control patients, the 5-HT(6 )receptor was expressed by pyramidal cells and occasional stellate cells, not only of layers II-V, but also of layer I, where a distinct label was observed in neurons and surrounding fibers. 5-HT(6 )receptor expression in AD patients had the same pattern, but was significantly decreased by 40%. CONCLUSION: Our results indicate that a decline in neurons expressing 5-HT(2A), but also 5-HT(6 )receptors may play a role in the etiopathology of neuropsychiatric symptoms in AD

Protein mechanics probed using simple molecular models

Background: Single-molecule experimental techniques such as optical tweezers or atomic force microscopy are a direct probe of the mechanical unfolding/folding of individual proteins. They are also a means to investigate free energy landscapes. Protein force spectroscopy alone provides limited information; theoretical models relate measurements to thermodynamic and kinetic properties of the protein, but do not reveal atomic level information. By building a molecular model of the protein and probing its properties through numerical simulation, one can gauge the response to an external force for individual interatomic interactions and determine structures along the unfolding pathway. In combination, single-molecule force probes and molecular simulations contribute to uncover the rich behavior of proteins when subjected to mechanical force. Scope of review: We focus on how simplified protein models have been instrumental in showing how general properties of the free energy landscape of a protein relate to its response to mechanical perturbations. We discuss the role of simple protein models to explore the complexity of free energy landscapes and highlight important conceptual issues that more chemically accurate models with all-atom representations of proteins and solvent cannot easily address. Major conclusions: Native-centric, coarse-grained models, despite simplifications in chemical detail compared to all-atom models, can reproduce and interpret experimental results. They also highlight instances where the theoretical framework used to interpret single-molecule data is too simple. However, these simple models are not able to reproduce experimental findings where non-native contacts are involved. General significance: Mechanical forces are ubiquitous in the cell and it is increasingly clear that the way a protein responds to mechanical perturbation is important

Higher-order nonlinear modes and bifurcation phenomena due to degenerate parametric four-wave mixing

We demonstrate that weak parametric interaction of a fundamental beam with its third harmonic field in Kerr media gives rise to a rich variety of families of non-fundamental (multi-humped) solitary waves. Making a comprehensive comparison between bifurcation phenomena for these families in bulk media and planar waveguides, we discover two novel types of soliton bifurcations and other interesting findings. The later includes (i) multi-humped solitary waves without even or odd symmetry and (ii) multi-humped solitary waves with large separation between their humps which, however, may not be viewed as bound states of several distinct one-humped solitons.Comment: 9 pages, 17 figures, submitted to Phys. Rev.

Implementing and evaluating Care and Support Planning : a qualitative study of health professionals’ experiences in public polyclinics in Singapore

Funding. The PACE-D programme is funded by Singapore’s Ministry of Health. This study was funded by the Centre for Chronic Disease Prevention and Management of the National University Health System, Singapore. SM was supported by a Wellcome Trust Institutional Strategic Support Fund flexible returners award (University of Aberdeen, RG13795-18). VAE’s contribution was also supported by a Wellcome Trust Collaborative Award: This research was funded in whole, or in part, by the Wellcome Trust [209811/Z/17/Z]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Acknowledgements We are extremely grateful to the health professionals who took part in interviews for this study and allowed observation of their team huddles. We also thank LIM Mui Eng and ANG Shu Lin for supporting the recruitment of health professionals and arrangement of interviews, Monica ASHWINI for arranging transcription and discussion of patients’ experiences of PACE-D, Matthavi SENGUTTUVAN for contributions to early analytic discussions, Marlie FERENCZI and LOY En Yun for support with grant administration, data sharing agreements and helpful suggestions, and the Year of Care Partnerships team, especially Lindsay OLIVER and Nick LEWIS-BARNED for training health professionals and trainers in Singapore and for ongoing advice and support, including helpful comments on a draft of this manuscript.Peer reviewedPublisher PD

The long-term effects of neurotoxic doses of methamphetamine on the extracellular concentration of dopamine measured with microdialysis in striatum

The extracellular concentrations of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in the striatum were measured by in vivo microdialysis in freely moving rats one week after the animals were treated with neurotoxic doses of methamphetamine. Methamphetamine produced a marked depletion of striatal DA measured in postmortem tissue, and in the extracellular concentrations of DOPAC, HVA and 5-HIAA. In contrast, the resting extracellular concentration of DA in striatum was the same as in saline-pretreated controls. Furthermore, methamphetamine-pretreated rats were able to increase their concentration of extracellular DA to the same extent as controls in response to a (+)-amphetamine challenge. It is suggested that this adaptive response is probably responsible, at least in part, for the absence of obvious behavioral deficits in animals exposed to neurotoxic doses of methamphetamine.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28685/1/0000502.pd

Computer-Aided Fabrication System Structure

Contains report on one research project.Defense Advanced Research Projects Agency Contract MDA 972 88-K-000