Evidence for a model of agonist-induced activation of 5-hydroxytryptamine 2A serotonin receptors that involves the disruption of a strong ionic interaction between helices 3 and 6

5-Hydroxytryptamine 2A (5-HT2A) receptors are essential for the actions of serotonin (5-hydroxytryptamine (5-HT)) on physiological processes as diverse as vascular smooth muscle contraction, platelet aggregation, perception, and emotion. In this study, we investigated the molecular mechanism(s) by which 5-HT activates 5-HT2A receptors using a combination of approaches including site-directed mutagenesis, molecular modeling, and pharmacological analysis using the sensitive, cell-based functional assay R-SAT. Alanine-scanning mutagenesis of residues close to the intracellular end of H6 of the 5-HT2A receptor implicated glutamate Glu-318(6.30) in receptor activation, as also predicted by a newly constructed molecular model of the 5-HT2A receptor, which was based on the x-ray structure of bovine rhodopsin. Close examination of the molecular model suggested that Glu-318(6.30) could form a strong ionic interaction with Arg-173(3.50) of the highly conserved "(D/E)RY motif" located at the interface between the third transmembrane segment and the second intracellular loop (i2). A direct prediction of this hypothesis, that disrupting this ionic interaction by an E318(6.30)R mutation would lead to a highly constitutively active receptor with enhanced affinity for agonist, was confirmed using R-SAT. Taken together, these results predict that the disruption of a strong ionic interaction between transmembrane helices 3 and 6 of 5-HT2A receptors is essential for agonist-induced receptor activation and, as recently predicted by ourselves (B. L. Roth and D. A. Shapiro (2001) Expert Opin. Ther. Targets 5, 685-695) and others, that this may represent a general mechanism of activation for many, but not all, G-protein-coupled receptors

Erratum: Evidence for a model of agonist-induced activation of 5-hydroxytryptamine 2A serotonin receptors that involves the disruption of a strong ionic interaction between helices 3 and 6 (Journal of Biological Chemistry (2002) 277 (11441-11449))

[No abstract available

Instabilities in a Two-Component, Species Conserving Condensate

We consider a system of two species of bosons of equal mass, with interactions $U^{a}(|x|)$ and $U^{x}(|x|)$ for bosons of the same and different species respectively. We present a rigorous proof -- valid when the Hamiltonian does not include a species switching term -- showing that, when $U^{x}(|x|)>U^{a}(|x|)$, the ground state is fully "polarized" (consists of atoms of one kind only). In the unpolarized phase the low energy excitation spectrum corresponds to two linearly dispersing modes that are even a nd odd under species exchange. The polarization instability is signaled by the vani shing of the velocity of the odd modes.Comment: To appear in Phys. Rev.

Interference scheme to measure light-induced nonlinearities in Bose-Einstein condensates

Light-induced nonlinear terms in the Gross-Pitaevskii equation arise from the stimulated coherent exchange of photons between two atoms. For atoms in an optical dipole trap this effect depends on the spatial profile of the trapping laser beam. Two different laser beams can induce the same trapping potential but very different nonlinearities. We propose a scheme to measure light-induced nonlinearities which is based on this observation.Comment: 2 figure

Collective dynamics of internal states in a Bose gas

Theory for the Rabi and internal Josephson effects in an interacting Bose gas in the cold collision regime is presented. By using microscopic transport equation for the density matrix the problem is mapped onto a problem of precession of two coupled classical spins. In the absence of an external excitation field our results agree with the theory for the density induced frequency shifts in atomic clocks. In the presence of the external field, the internal Josephson effect takes place in a condensed Bose gas as well as in a non-condensed gas. The crossover from Rabi oscillations to the Josephson oscillations as a function of interaction strength is studied in detail.Comment: 18 pages, 2 figure

Iron Oxide Nanoparticles Employed as Seeds for the Induction of Microcrystalline Diamond Synthesis

Iron nanoparticles were employed to induce the synthesis of diamond on molybdenum, silicon, and quartz substrates. Diamond films were grown using conventional conditions for diamond synthesis by hot filament chemical vapor deposition, except that dispersed iron oxide nanoparticles replaced the seeding. X-ray diffraction, visible, and ultraviolet Raman Spectroscopy, energy-filtered transmission electron microscopy , electron energy-loss spectroscopy, and X-ray photoelectron spectroscopy (XPS) were employed to study the carbon bonding nature of the films and to analyze the carbon clustering around the seed nanoparticles leading to diamond synthesis. The results indicate that iron oxide nanoparticles lose the O atoms, becoming thus active C traps that induce the formation of a dense region of trigonally and tetrahedrally bonded carbon around them with the ensuing precipitation of diamond-type bonds that develop into microcrystalline diamond films under chemical vapor deposition conditions. This approach to diamond induction can be combined with dip pen nanolithography for the selective deposition of diamond and diamond patterning while avoiding surface damage associated to diamond-seeding methods

A theoretical framework and research agenda for studying team attributions in sport

The attributions made for group outcomes have attracted a great deal of interest in recent years. In this article we bring together much of the current research on attribution theory in sport and outline a new conceptual framework and research agenda for investigating the attributions of team members. The proposed framework draws on multiple conceptual approaches including models of attribution, group dynamics and stress responses to provide a detailed hypothetical description of athletes' physiological, cognitive and affective responses to group competition. In describing this model we outline important antecedents of team attributions before hypothesising how attributions can impact hormonal and cardiovascular responses of athletes, together with cognitive (goals, choices, expectations), affective (self-esteem, emotions), and behavioural (approach-avoidance actions) responses of groups and group members. We conclude by outlining important methodological considerations and implications for structured context specific attribution-based interventions

Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes

[Accepted Manuscript] Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial MRI study.

Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials. Serial T1-weighed magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from normal and the rates of change before and after this point. Atrophy increased after the change-point, which occurred 1-1.5 years (assuming a single step change in atrophy rate) or 3-8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change-point. Atrophy rates are pathologically increased up to seven years before "expected onset". During this period, atrophy rates may be useful for inclusion and tracking of disease progression