Interaction of the S6 Proline Hinge with N-Type and C-Type Inactivation in Kv1.4 Channels

AbstractSeveral voltage-gated channels share a proline-valine-proline (proline hinge) sequence motif at the intracellular side of S6. We studied the proline hinge in Kv1.4 channels, which inactivate via two mechanisms: N- and C-type. We mutated the second proline to glycine or alanine: P558A, P558G. These mutations were studied in the presence/absence of the N-terminal to separate the effects of the interaction between the proline hinge and N- and C-type inactivation. Both S6 mutations slowed or removed N- and C-type inactivation, and altered recovery from inactivation. P558G slowed activation and N- and C-type inactivation by nearly an order of magnitude. Sensitivity to extracellular acidosis and intracellular quinidine binding remained, suggesting that transmembrane communication in N- and C-type inactivation was preserved, consistent with our previous findings of major structural rearrangements involving S6 during C-type inactivation. P558A was very disruptive: activation was slowed by more than an order of magnitude, and no inactivation was observed. These results are consistent with our hypothesis that the proline hinge and intracellular S6 movement play a significant role in inactivation and recovery. Computer modeling suggests that both P558G and P558A mutations modify early voltage-dependent steps and make a final voltage-insensitive step that is rate limiting at positive potentials

Altered functional brain network connectivity and glutamate system function in transgenic mice expressing truncated Disrupted-in-Schizophrenia 1

Considerable evidence implicates DISC1 as a susceptibility gene for multiple psychiatric diseases. DISC1 has been intensively studied at the molecular, cellular and behavioral level, but its role in regulating brain connectivity and brain network function remains unknown. Here, we utilize a set of complementary approaches to assess the functional brain network abnormalities present in mice expressing a truncated Disc1 gene (Disc1tr Hemi mice). Disc1tr Hemi mice exhibited hypometabolism in the prefrontal cortex (PFC) and reticular thalamus along with a reorganization of functional brain network connectivity that included compromised hippocampal–PFC connectivity. Altered hippocampal–PFC connectivity in Disc1tr Hemi mice was confirmed by electrophysiological analysis, with Disc1tr Hemi mice showing a reduced probability of presynaptic neurotransmitter release in the monosynaptic glutamatergic hippocampal CA1–PFC projection. Glutamate system dysfunction in Disc1tr Hemi mice was further supported by the attenuated cerebral metabolic response to the NMDA receptor (NMDAR) antagonist ketamine and decreased hippocampal expression of NMDAR subunits 2A and 2B in these animals. These data show that the Disc1 truncation in Disc1tr Hemi mice induces a range of translationally relevant endophenotypes underpinned by glutamate system dysfunction and altered brain connectivity

Thirty Years of Cometary Spectroscopy from McDonald Observatory

We report on the results of a spectroscopic survey of 130 comets that was conducted at McDonald observatory from 1980 through 2008. Some of the comets were observed on only one night, while others were observed repeatedly. For 20 of these comets, no molecules were detected. For the remaining 110 comets, some emission from CN, OH, NH, C$_{3}$, C$_{2}$, CH, and NH$_{2}$ molecules were observed on at least one occasion. We converted the observed molecular column densities to production rates using a Haser (1957) model. We defined a restricted data set of comets that had at least 3 nights of observations. The restricted data set consists of 59 comets. We used ratios of production rates to study the trends in the data. We find two classes of comets: typical and carbon-chain depleted comets. Using a very strict definition of depleted comets, requiring C$_{2}$ \underline{and} C$_{3}$ to both be depleted, we find 9% of our restricted data set comets to be depleted. Using a more relaxed definition that requires only C$_{2}$ to be below a threshold (similar to other researchers), we find 25% of the comets are depleted. Two-thirds of the depleted comets are Jupiter Family comets, while one-third are Long Period comets. 37% of the Jupiter Family comets are depleted, while 18.5% of the Long Period comets are depleted. We compare our results with other studies and find good agreement.Comment: Accepted for Icarus; 15 figures, 9 tables (some multi-page and in landscape mode

Influence of fear of pain and coping strategies on health-related quality of life and patient-anticipated outcomes in patients with chronic pain: cross-sectional study protocol

Published 08.09.17Background: Fear of pain and coping strategies are emotional-behavioral responses to pain and are known to play an important role in the development and maintenance of pain. It is highly likely that fear of pain and coping strategies influence each other, potentially affecting the course of chronic pain. To our knowledge, the relationship between pain, fear of pain and coping strategies, and how they influence patient-anticipated outcomes and health-related quality of life, have not been investigated. Objective: The aims of this study are to test (1) if both fear of pain and/or coping strategies are sufficient causes for maintaining pain; and (2) whether fear of pain influences coping strategies and pain intensity. The study will also examine the impact of fear of pain and coping strategies on health-related quality of life and patient-anticipated outcomes. Methods: The cross-sectional study will be conducted using an online survey. The Fear of Pain Questionnaire-III (FPQ-III), the Brief Coping Inventory (COPE), and EuroQoL-5d (EQ-5D) validated questionnaires will be used to collect data. Information pertaining to demographic factors, pain-related factors, and patient-anticipated outcomes will also be collected. The study has ethics approval from the Human Research Ethics Committee of the University of Adelaide. Study participants will be individuals aged 18 years and above who are experiencing chronic pain (ie, pain lasting more than 6 months). Effect measure modification technique (EMMM) will be used to examine if fear of pain acts as a moderator or mediator between coping strategies and pain. Simple and multinomial logistic regression analysis will be used to examine the effect of fear of pain and coping strategies on health-related quality of life and patient-anticipated outcomes. Results: Recruitment began July 2017 and it is anticipated that data collection will be completed by October 2017. Findings from this study will help to extend our understanding of fear of pain and coping strategies, their interaction, and their impact on health-related quality of life and patient-anticipated outcomes. Conclusions: Fear of pain and coping strategies have significant influence on the experience of chronic pain and its course. This study will help enhance our understanding of the relationship between fear of pain and coping strategies, which may help in developing patient-centered care practices.Manasi Murthy Mittinty, David S Brennan, Cameron L Randall, Daniel W McNeil, Murthy N Mittinty, Lisa Jamieso

Cosmological constant and gravitational theory on D-brane

In a toy model we derive the gravitational equation on a self-gravitating curved D-brane. The effective theory on the brane is drastically changed from the ordinal Einstein equation. The net cosmological constant on the brane depends on a tuning between the brane tension and the brane charges. Moreover, non-zero matter stress tensor exists if the net cosmological constant is not zero. This fact indicates a direct connection between matters on the brane and the dark energy.Comment: 6 pages, minor corrections, accepted for publication in Physical Review

Second-order corrections to slow-roll inflation in the brane cosmology

We calculate the power spectrum, spectral index, and running spectral index for the RS-II brane inflation in the high-energy regime using the slow-roll expansion. There exist several modifications. As an example, we take the power-law inflation by choosing an inverse power-law potential. When comparing these with those arisen in the standard inflation, we find that the power spectrum is enhanced and the spectral index is suppressed, while the running spectral index becomes zero as in the standard inflation. However, since second-order corrections are rather small, these could not play a role of distinguishing between standard and brane inflations.Comment: 6 page

Equation of State of Oscillating Brans-Dicke Scalar and Extra Dimensions

We consider a Brans-Dicke scalar field stabilized by a general power law potential with power index $n$ at a finite equilibrium value. Redshifting matter induces oscillations of the scalar field around its equilibrium due to the scalar field coupling to the trace of the energy momentum tensor. If the stabilizing potential is sufficiently steep these high frequency oscillations are consistent with observational and experimental constraints for arbitrary value of the Brans-Dicke parameter $\omega$. We study analytically and numerically the equation of state of these high frequency oscillations in terms of the parameters $\omega$ and $n$ and find the corresponding evolution of the universe scale factor. We find that the equation of state parameter can be negative and less than -1 but it is not related to the evolution of the scale factor in the usual way. Nevertheless, accelerating expansion is found for a certain parameter range. Our analysis applies also to oscillations of the size of extra dimensions (the radion field) around an equilibrium value. This duality between self-coupled Brans-Dicke and radion dynamics is applicable for $\omega= -1 + 1/D$ where D is the number of extra dimensions.Comment: 10 two-column pages, RevTex4, 8 figures. Added clarifying discussions, new references. Accepted in Phys. Rev. D (to appear

Looking Beyond Inflationary Cosmology

In spite of the phenomenological successes of the inflationary universe scenario, the current realizations of inflation making use of scalar fields lead to serious conceptual problems which are reviewed in this lecture. String theory may provide an avenue towards addressing these problems. One particular approach to combining string theory and cosmology is String Gas Cosmology. The basic principles of this approach are summarized.Comment: invited talk at "Theory Canada 1" (Univ. of British Columbia, Vancouver, Canada, June 2 - 4, 2005) (references updated

Cosmic coincidence problem and variable constants of physics

The standard model of cosmology is investigated using time dependent cosmological constant $\Lambda$ and Newton's gravitational constant $G$. The total energy content is described by the modified Chaplygin gas equation of state. It is found that the time dependent constants coupled with the modified Chaplygin gas interpolate between the earlier matter to the later dark energy dominated phase of the universe. We also achieve a convergence of parameter $\omega\to-1$, with minute fluctuations, showing an evolving $\omega$. Thus our model fairly alleviates the cosmic coincidence problem which demands $\omega=-1$ at present time.Comment: 27 pages, 15 figure