Hippocampal 2-Arachidonoyl Glycerol signaling regulates Time-of-day- and stress-dependent effects on rat short-term memory

Background: Cannabinoids induce biphasic effects on memory depending on stress levels. We previously demonstrated that different stress intensities, experienced soon after encoding, impaired rat short-term recognition memory in a time-of-day-dependent manner, and that boosting endocannabinoid anandamide (AEA) levels restored memory performance. Here, we examined if two different stress intensities and time-of-day alter hippocampal endocannabinoid tone, and whether these changes modulate short-term memory. Methods: Male Sprague-Dawley rats were subjected to an object recognition task and exposed, at two different times of the day (i.e., morning or afternoon), to low or high stress conditions, immediately after encoding. Memory retention was assessed 1 hr later. Hippocampal AEA and 2-arachidonoyl glycerol (2-AG) content and the activity of their primary degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), were measured soon after testing. Results: Consistent with our previous findings, low stress impaired 1-hr memory performance only in the morning, whereas exposure to high stress impaired memory independently of testing time. Stress exposure decreased AEA levels independently of memory alterations. Interestingly, exposure to high stress decreased 2-AG content and, accordingly, increased MAGL activity, selectively in the afternoon. Thus, to further evaluate 2-AG’s role in the modulation of short-term recognition memory, rats were given bilateral intra-hippocampal injections of the 2-AG hydrolysis inhibitor KML29 immediately after training, then subjected to low or high stress conditions and tested 1 hr later. Conclusions: KML29 abolished the time-of-day-dependent impairing effects of stress on short-term memory, ameliorating short-term recognition memory performance

Constructing Gravitational Dimensions

It would be extremely useful to know whether a particular low energy effective theory might have come from a compactification of a higher dimensional space. Here, this problem is approached from the ground up by considering theories with multiple interacting massive gravitons. It is actually very difficult to construct discrete gravitational dimensions which have a local continuum limit. In fact, any model with only nearest neighbor interactions is doomed. If we could find a non-linear extension for the Fierz-Pauli Lagrangian for a graviton of mass mg which does not break down until the scale Lambda_2=(mg Mpl)^(1/2), this could be used to construct a large class of models whose continuum limit is local in the extra dimension. But this is shown to be impossible: a theory with a single graviton must break down by Lambda_3 = (mg^2 Mpl)^(1/3). Next, we look at how the discretization prescribed by the truncation of the KK tower of an honest extra diemsinon rasies the scale of strong coupling. It dictates an intricate set of interactions among various fields which conspire to soften the strongest scattering amplitudes and allow for a local continuum limit. A number of canditate symmetries associated with locality in the discretized dimension are also discussed.Comment: 21 pages, 6 diagrams, 1 figur

Neural Level Set Topology Optimization Using Unfitted Finite Elements

To facilitate widespread adoption of automated engineering design techniques, existing methods must become more efficient and generalizable. In the field of topology optimization, this requires the coupling of modern optimization methods with solvers capable of handling arbitrary problems. In this work, a topology optimization method for general multiphysics problems is presented. We leverage a convolutional neural parameterization of a level set for a description of the geometry and use this in an unfitted finite element method that is differentiable with respect to the level set everywhere in the domain. We construct the parameter to objective map in such a way that the gradient can be computed entirely by automatic differentiation at roughly the cost of an objective function evaluation. The method produces optimized topologies that are similar in performance yet exhibit greater regularity than baseline approaches on standard benchmarks whilst having the ability to solve a more general class of problems, e.g., interface-coupled multiphysics.Comment: 16 pages + refs, 10 fig

Dual positive and negative regulation of GPCR signaling by GTP hydrolysis

G protein-coupled receptors (GPCRs) regulate a variety of intracellular pathways through their ability to promote the binding of GTP to heterotrimeric G proteins. Regulator of G protein signaling (RGS) proteins increase the intrinsic GTPase activity of G-subunits and are widely regarded as negative regulators of G protein signaling. Using yeast we demonstrate that GTP hydrolysis is not only required for desensitization, but is essential for achieving a high maximal (saturated level) response. Thus RGS-mediated GTP hydrolysis acts as both a negative (low stimulation) and positive (high stimulation) regulator of signaling. To account for this we generated a new kinetic model of the G protein cycle where GGTP enters an inactive GTP-bound state following effector activation. Furthermore, in vivo and in silico experimentation demonstrates that maximum signaling output first increases and then decreases with RGS concentration. This unimodal, non-monotone dependence on RGS concentration is novel. Analysis of the kinetic model has revealed a dynamic network motif that shows precisely how inclusion of the inactive GTP-bound state for the G produces this unimodal relationship

Discrete Gravitational Dimensions

We study the physics of a single discrete gravitational extra dimension using the effective field theory for massive gravitons. We first consider a minimal discretization with 4D gravitons on the sites and nearest neighbor hopping terms. At the linear level, 5D continuum physics is recovered correctly, but at the non-linear level the theory becomes highly non-local in the discrete dimension. There is a peculiar UV/IR connection, where the scale of strong interactions at high energies is related to the radius of the dimension. These new effects formally vanish in the limit of zero lattice spacing, but do not do so quickly enough to reproduce the continuum physics consistently in an effective field theory up to the 5D Planck scale. Nevertheless, this model does make sense as an effective theory up to energies parametrically higher than the compactification scale. In order to have a discrete theory that appears local in the continuum limit, the lattice action must have interactions between distant sites. We speculate on the relevance of these observations to the construction of finite discrete theories of gravity in four dimensions.Comment: 5 pages, 4 diagrams. Important typos in some equations corrected; conclusion s unchange

Localizing ECoG electrodes on the cortical anatomy without post-implantation imaging

AbstractIntroductionElectrocorticographic (ECoG) grids are placed subdurally on the cortex in people undergoing cortical resection to delineate eloquent cortex. ECoG signals have high spatial and temporal resolution and thus can be valuable for neuroscientific research. The value of these data is highest when they can be related to the cortical anatomy. Existing methods that establish this relationship rely either on post-implantation imaging using computed tomography (CT), magnetic resonance imaging (MRI) or X-Rays, or on intra-operative photographs. For research purposes, it is desirable to localize ECoG electrodes on the brain anatomy even when post-operative imaging is not available or when intra-operative photographs do not readily identify anatomical landmarks.MethodsWe developed a method to co-register ECoG electrodes to the underlying cortical anatomy using only a pre-operative MRI, a clinical neuronavigation device (such as BrainLab VectorVision), and fiducial markers. To validate our technique, we compared our results to data collected from six subjects who also had post-grid implantation imaging available. We compared the electrode coordinates obtained by our fiducial-based method to those obtained using existing methods, which are based on co-registering pre- and post-grid implantation images.ResultsOur fiducial-based method agreed with the MRI–CT method to within an average of 8.24mm (mean, median=7.10mm) across 6 subjects in 3 dimensions. It showed an average discrepancy of 2.7mm when compared to the results of the intra-operative photograph method in a 2D coordinate system. As this method does not require post-operative imaging such as CTs, our technique should prove useful for research in intra-operative single-stage surgery scenarios.To demonstrate the use of our method, we applied our method during real-time mapping of eloquent cortex during a single-stage surgery. The results demonstrated that our method can be applied intra-operatively in the absence of post-operative imaging to acquire ECoG signals that can be valuable for neuroscientific investigations

High Depth-of-Discharge Zinc Rechargeability Enabled by a Self-Assembled Polymeric Coating

Zinc has the potential for widespread use as an environmentally friendly and cost-effective anode material pending the resolution of rechargeability issues caused by active material loss and shape change. Here, a self-assembled Nafion-coated Celgard 3501 (NC-Celgard) separator is shown to enable unprecedented cycle life of a Zn anode in alkaline electrolyte at high depth-of-discharge (DODZn). Using commercially relevant energy-dense electrodes with high areal capacities of 60 mAh cm–2, Zn–Ni cells tested at 20% DODZn cells achieve over 200 cycles while 50% DODZn cells achieve over 100 cycles before failure. The 20% and 50% DOD cells deliver an average of 132 and 180 Wh L–1 per cycle over their lifetime respectively. Rechargeability is attributed to the highly selective diffusion properties of the 300 nm thick negatively charged Nafion coating on the separator which prevents shorting by dendrites and inhibits redistribution of the active material. Crossover experiments show that the NC-Celgard separator is practically impermeable to zincate ([Zn(OH)4]2–), outperforming commercial Celgard, cellophane, Nafion 211 and 212 separators while still allowing hydroxide transport. This work demonstrates the efficacy of selective separators for increasing the cycle life of energy-dense Zn electrodes without adding significant volume or complexity to the system

Comorbid anxiety-like behavior in a rat model of colitis is mediated by an upregulation of corticolimbic fatty acid amide hydrolase

Peripheral inflammatory conditions, including those localized to the gastrointestinal tract, are highly comorbid with psychiatric disorders such as anxiety and depression. These behavioral symptoms are poorly managed by conventional treatments for inflammatory diseases and contribute to quality of life impairments. Peripheral inflammation is associated with sustained elevations in circulating glucocorticoid hormones, which can modulate central processes, including those involved in the regulation of emotional behavior. The endocannabinoid (eCB) system is exquisitely sensitive to these hormonal changes and is a significant regulator of emotional behavior. The impact of peripheral inflammation on central eCB function, and whether this is related to the development of these behavioral comorbidities remains to be determined. To examine this, we employed the trinitrobenzene sulfonic acid-induced model of colonic inflammation (colitis) in adult, male, Sprague Dawley rats to produce sustained peripheral inflammation. Colitis produced increases in behavioral measures of anxiety and elevations in circulating corticosterone. These alterations were accompanied by elevated hydrolytic activity of the enzyme fatty acid amide hydrolase (FAAH), which hydrolyzes the eCB anandamide (AEA), throughout multiple corticolimbic brain regions. This elevation of FAAH activity was associated with broad reductions in the content of AEA, whose decline was driven by central corticotropin releasing factor type 1 receptor signaling. Colitis-induced anxiety was reversed following acute central inhibition of FAAH, suggesting that the reductions in AEA produced by colitis contributed to the generation of anxiety. These data provide a novel perspective for the pharmacological management of psychiatric comorbidities of chronic inflammatory conditions through modulation of eCB signaling

Study of LHC Searches for a Lepton and Many Jets

Searches for new physics in high-multiplicity events with little or no missing energy are an important component of the LHC program, complementary to analyses that rely on missing energy. We consider the potential reach of searches for events with a lepton and six or more jets, and show they can provide increased sensitivity to many supersymmetric and exotic models that would not be detected through standard missing-energy analyses. Among these are supersymmetric models with gauge mediation, R-parity violation, and light hidden sectors. Moreover, ATLAS and CMS measurements suggest the primary background in this channel is from t-tbar, rather than W+jets or QCD, which reduces the complexity of background modeling necessary for such a search. We also comment on related searches where the lepton is replaced with another visible object, such as a Z boson.Comment: 23 pages, 12 figures, 1 tabl

GRB Polarimetry with POET

POET (Polarimeters for Energetic Transients) represents a concept for a Small Explorer (SMEX) satellite mission, whose principal scientific goal is to understand the structure of GRB sources through sensitive X‐ray and γ‐ray polarization measurements. The payload consists of two wide field‐of‐view (FoV) instruments: a Low Energy Polarimeter (LEP) capable of polarization measurements in the energy range from 2–15 keV and a high energy polarimeter (Gamma‐Ray Polarimeter Experiment or GRAPE) that would measure polarization in the 60–500 keV energy range. The POET spacecraft provides a zenith‐pointed platform for maximizing the exposure to deep space. Spacecraft rotation provides a means of effectively dealing with any residual systematic effects in the polarization response. POET provides sufficient sensitivity and sky coverage to measure statistically significant polarization (for polarization levels in excess of 20%) for ∼80 GRBs in a two‐year mission. High energy polarization data would also be obtained for SGRs, solar flares, pulsars and other sources of astronomical interest