Cannabinoid Receptor Involvement in Stress-Induced Cocaine Reinstatement: Potential Interaction with Noradrenergic Pathways

This study examined the role of endocannabinoid signaling in stress-induced reinstatement of cocaine seeking and explored the interaction between noradrenergic and endocannabinergic systems in the process. A well-validated preclinical model for human relapse, the rodent conditioned place preference assay, was used. Cocaine-induced place preference was established in C57BL/6 mice using injections of 15 mg/kg cocaine. Following extinction of preference for the cocaine-paired environment, reinstatement of place preference was determined following 6 min of swim stress or cocaine injection (15 mg/kg, i.p.). The role of endocannabinoid signaling was studied using the cannabinoid antagonist AM-251 (3 mg/kg, i.p.). Another cohort of mice was tested for reinstatement following administration of the cannabinoid agonist CP 55,940 (10, 20, or 40 μg/kg, i.p.). The alpha-2 adrenergic antagonist BRL-44408 (5 mg/kg, i.p.) with or without CP 55,940 (20 μg/kg) was administered to a third group of mice. We found that: (1) AM-251 blocked forced swim-induced, but not cocaine-induced, reinstatement of cocaine-seeking behavior; (2) the cannabinoid agonist CP 55,940 did not reinstate cocaine-seeking behavior when administered alone but did synergize with a non-reinstating dose of the alpha-2 adrenergic antagonist BRL-44408 to cause reinstatement. These results are consistent with the hypothesis that stress exposure triggers the endogenous activation of CB1 receptors and that activation of the endocannabinoid system is required for the stress-induced relapse of the mice to cocaine seeking. Further, the data suggest that the endocannabinoid system interacts with noradrenergic mechanisms to influence stress-induced reinstatement of cocaine-seeking behavior

Fundamental Understanding Of Rotordynamics From A Light Rub (Bounce)

LecturePg. 161-166Machinery users, designers, and analysts are both alarmed and fascinated by the occasional occurrences of contact between a rotating shaft and a stationary part. "Rubs," a common description for such contact, are typically categorized into two classes according to the level of interface pressure generated by contact. Very high contact pressure accompanied by high frictional force is classified as a "hard rub" while a "light rub" indicates low contact pressure with a frictional force that may be insignificant. Light rubs that result in half frequency whirl are discussed. The author explains the phenomena using simple spring mass systems and generally understood terms such as critical speed, unbalance response, and contact stiffness. Some design parameters are included that may be used to affect rotor response to light rubs

Rotordynamic Stability - A Simplified Approach.

LecturePg. 3-10Straightforward mechanics are used to give a physical understanding of the important parameters involved in rotor dynamic instability. A concise analysis procedure is proposed for assembling available information into a meaningful design stability analysis of between-bearing rotors. The technique combines the destabilizing effects on the rotor into an equivalent single source at the rotor mid-span, and uses an excitation "threshold value" to rate the system stability. Results of applying this design analysis technique to an unstable compressor and the benefit from bearing redesign are presented

Translation of Anticancer Efficacy From Nonclinical Models to the Clinic

Mouse cancer models have provided critical insights into tumor biology; however, clinical translation of these findings has been challenging. This perspective posits that factors impacting on successful translation start with limitations in capturing human cancer pathophysiology and end with challenges in generating robust translatable preclinical end points. A comprehensive approach that considers clinically relevant mouse models with both an integrated biomarker strategy and a complementary modeling and simulation effort will strengthen the current oncology drug development paradigm

Drag Assessment for Boundary Layer Control Schemes with Mass Injection

The present study considers uniform blowing in turbulent boundary layers as active flow control scheme for drag reduction on airfoils. The focus lies on the important question of how to quantify the drag reduction potential of this control scheme correctly. It is demonstrated that mass injection causes the body drag (the drag resulting from the stresses on the body) to differ from the wake survey drag (the momentum deficit in the wake of an airfoil), which is classically used in experiments as a surrogate for the former. This difference is related to the boundary layer control (BLC) penalty, an unavoidable drag portion which reflects the effort of a mass-injecting boundary layer control scheme. This is independent of how the control is implemented. With an integral momentum budget, we show that for the present control scheme, the wake survey drag contains the BLC penalty and is thus a measure for the inclusive drag of the airfoil, i.e. the one required to determine net drag reduction. The concept of the inclusive drag is extended also to boundary layers using the von Karman equation. This means that with mass injection the friction drag only is not sufficient to assess drag reduction also in canonical flows. Large Eddy Simulations and Reynolds-averaged Navier-Stokes simulations of the flow around airfoils are utilized to demonstrate the significance of this distinction for the scheme of uniform blowing. When the inclusive drag is properly accounted for, control scenarios previously considered to yield drag reduction actually show drag increase

Dislocation core field. I. Modeling in anisotropic linear elasticity theory

Aside from the Volterra field, dislocations create a core field, which can be modeled in linear anisotropic elasticity theory with force and dislocation dipoles. We derive an expression of the elastic energy of a dislocation taking full account of its core field and show that no cross term exists between the Volterra and the core fields. We also obtain the contribution of the core field to the dislocation interaction energy with an external stress, thus showing that dislocation can interact with a pressure. The additional force that derives from this core field contribution is proportional to the gradient of the applied stress. Such a supplementary force on dislocations may be important in high stress gradient regions, such as close to a crack tip or in a dislocation pile-up

The First Survey of X-ray Flares from Gamma Ray Bursts Observed by Swift: Spectral Properties and Energetics

Observations of gamma ray bursts (GRBs) with Swift produced the initially surprising result that many bursts have large X-ray flares superimposed on the underlying afterglow. The flares were sometimes intense, had rapid rise and decay phases, and occurred late relative to the ``prompt'' phase. Some remarkable flares are observed with fluence comparable to the prompt GRB fluence. Many GRBs have several flares, which are sometimes overlapping. Short, intense, repetitive, and late flaring can be most easily understood within the context of the standard fireball model with the internal engine that powers the prompt GRB emission in an active state at late times. However, other models for flares have been proposed. Flare origin can be investigated by comparing the flare spectra to that of the afterglow and the initial prompt emission. In this work, we have analyzed all significant X-ray flares from the first 110 GRBs observed by Swift. From this sample 33 GRBs were found to have significant X-ray flares, with 77 flares that were detected above the 3$\sigma$ level. In addition to temporal analysis presented in a companion paper, a variety of spectral models have been fit to each flare. In some cases, we find that the spectral fits favor a Band function model, which is more akin to the prompt emission than to that of an afterglow. We find that the average fluence of the flares is 2.4e-7 erg/cm^2/s in the 0.2-10 keV energy band, which is approximately a factor of ten below the average prompt GRB fluence. These results, when combined with those presented in the companion paper on temporal properties of flares, supports the hypothesis that most X-ray flares are late-time activity of the internal engine that spawned the initial GRB; not an afterglow related effect.Comment: accepted by ApJ; 39 pages with 14 figures and 7 table

SNPeffect 4.0: on-line prediction of molecular and structural effects of protein-coding variants

Single nucleotide variants (SNVs) are, together with copy number variation, the primary source of variation in the human genome and are associated with phenotypic variation such as altered response to drug treatment and susceptibility to disease. Linking structural effects of non-synonymous SNVs to functional outcomes is a major issue in structural bioinformatics. The SNPeffect database (http://snpeffect.switchlab.org) uses sequence- and structure-based bioinformatics tools to predict the effect of protein-coding SNVs on the structural phenotype of proteins. It integrates aggregation prediction (TANGO), amyloid prediction (WALTZ), chaperone-binding prediction (LIMBO) and protein stability analysis (FoldX) for structural phenotyping. Additionally, SNPeffect holds information on affected catalytic sites and a number of post-translational modifications. The database contains all known human protein variants from UniProt, but users can now also submit custom protein variants for a SNPeffect analysis, including automated structure modeling. The new meta-analysis application allows plotting correlations between phenotypic features for a user-selected set of variants