Interleukin-1 signaling in the basolateral amygdala is necessary for heroin-conditioned immunosuppression

Heroin administration suppresses the production of inducible nitric oxide (NO), as indicated by changes in splenic inducible nitric oxide synthase (iNOS) and plasma nitrate/nitrite. Since NO is a measure of host defense against infection and disease, this provides evidence that heroin can increase susceptibility to pathogens by directly interacting with the immune system. Previous research in our laboratory has demonstrated that these immunosuppressive effects of heroin can also be conditioned to environmental stimuli by repeatedly pairing heroin administration with a unique environmental context. Re-exposure to a previously drug-paired context elicits immunosuppressive effects similar to heroin administration alone. In addition, our laboratory has reported that the basolateral amygdala (BLA) and medial nucleus accumbens shell (mNAcS) are critical neural substrates that mediate this conditioned effect. However, our understanding of the contributing mechanisms within these brain regions is limited. It is known that the cytokine interleukin-1 (IL-1) plays an important role in learning and memory. In fact, our laboratory has demonstrated that inhibition of IL-1β expression in the dorsal hippocampus (DH) prior to reexposure to a heroin-paired context prevents the suppression of measures of NO production. Therefore, the present studies sought to further investigate the role of IL-1 in heroin-conditioned immunosuppression. Blockade of IL-1 signaling in the BLA, but not in the caudate putamen or mNAcS, using IL-1 receptor antagonist (IL-1Ra) attenuated heroin-conditioned immunosuppression of NO production as measured by plasma nitrate/nitrite and iNOS mRNA expression in spleen tissue. Taken together, these findings suggest that IL-1 signaling in the BLA is necessary for the expression of heroin-conditioned immunosuppression of NO production and may be a target for interventions that normalize immune function in heroin users and patient populations exposed to opiate regimens

Acquisition of heroin conditioned immunosuppression requires IL-1 signaling in the dorsal hippocampus

Opioid users experience increased incidence of infection, which may be partially attributable to both direct opiate-immune interactions and conditioned immune responses. Previous studies have investigated the neural circuitry governing opioid conditioned immune responses, but work remains to elucidate the mechanisms mediating this effect. Our laboratory has previously shown that hippocampal IL-1 signaling, specifically, is required for the expression of heroin conditioned immunosuppression following learning. The current studies were designed to further characterize the role of hippocampal IL-1 in this phenomenon by manipulating IL-1 during learning. Experiment 1 tested whether hippocampal IL-1 is also required for the acquisition of heroin conditioned immunosuppression, while Experiment 2 tested whether hippocampal IL-1 is required for the expression of unconditioned heroin immunosuppression. We found that blocking IL-1 signaling in the dorsal hippocampus with IL-1RA during each conditioning session, but not on interspersed non-conditioning days, significantly attenuated the acquisition of heroin conditioned immunosuppression. Strikingly, we found that the same IL-1RA treatment did not alter unconditioned immunosuppression to a single dose of heroin. Thus, IL-1 signaling is not a critical component of the response to heroin but rather may play a role in the formation of the association between heroin and the context. Collectively, these studies suggest that IL-1 signaling, in addition to being involved in the expression of a heroin conditioned immune response, is also involved in the acquisition of this effect. Importantly, this effect is likely not due to blocking the response to the unconditioned stimulus since IL-1RA did not affect heroin’s immunosuppressive effects

Physical Electronics

Contains reports on three research projects

Interactions and dynamics in Li+Li2 ultracold collisions

A potential energy surface for the lowest quartet electronic state (A′4) of lithium trimer is developed and used to study spin-polarized Li+Li2collisions at ultralow kinetic energies. The potential energy surface allows barrierless atom exchange reactions. Elastic and inelastic cross sections are calculated for collisions involving a variety of rovibrational states of Li2. Inelastic collisions are responsible for trap loss in molecule production experiments. Isotope effects and the sensitivity of the results to details of the potential energy surface are investigated. It is found that for vibrationally excited states, the cross sections are only quite weakly dependent on details of the potential energy surface

COMPARZ Post Hoc Analysis: Characterizing Pazopanib Responders With Advanced Renal Cell Carcinoma

Background: The phase III COMPARZ study showed noninferior efficacy of pazopanib versus sunitinib in advanced renal cell carcinoma. In this COMPARZ post hoc analysis we characterized pazopanib responders, patient subgroups with better outcomes, and the effect of dose modification on efficacy and safety. Patients and Methods: Patients were randomized to pazopanib 800 mg/d (n = 557) or sunitinib 50 mg/d, 4 weeks on/2 weeks off (n = 553). Secondary end points included time to complete response (CR)/partial response (PR); the proportion of patients with CR/PR ≥10 months and progression-free survival (PFS) ≥10 months; efficacy in patients with baseline metastasis; and logistic regression analyses of patient characteristics associated with CR/PR ≥10 months. Median PFS, objective response rate (ORR), and safety were evaluated in patients with or without dose reductions or interruptions lasting ≥7 days. Results: Median time to response was numerically shorter for patients treated with pazopanib versus sunitinib (11.9 vs. 17.4 weeks). Similar percentages of pazopanib and sunitinib patients had CR/PR ≥10 months (14% and 13%, respectively), and PFS ≥10 months (31% and 34%, respectively). For patients without versus with adverse event (AE)-related dose reductions, median PFS, median overall survival, and ORR were 7.3 versus 12.5 months, 21.7 versus 36.8 months, and 22% versus 42% (all P <.0001) for pazopanib, and 5.5 versus 13.8 months, 18.1 versus 38.0 months, and 16% versus 34% (all P <.0001) for sunitinib; results were similar for dose interruptions. Conclusion: Dose modifications when required because of AEs were associated with improved efficacy, suggesting that AEs might be used as a surrogate marker of adequate dosing for individual patients

Phonon-Coupled Electron Tunneling in Two and Three-Dimensional Tunneling Configurations

We treat a tunneling electron coupled to acoustical phonons through a realistic electron phonon interaction: deformation potential and piezoelectric, in two or three-dimensional tunneling configurations. Making use of slowness of the phonon system compared to electron tunneling, and using a Green function method for imaginary time, we are able to calculate the change in the transition probability due to the coupling to phonons. It is shown using standard renormalization procedure that, contrary to the one-dimensional case, second order perturbation theory is sufficient in order to treat the deformation potential coupling, which leads to a small correction to the transmission coefficient prefactor. In the case of piezoelectric coupling, which is found to be closely related to the piezoelectric polaron problem, vertex corrections need to be considered. Summing leading logarithmic terms, we show that the piezoelectric coupling leads to a significant change of the transmission coefficient.Comment: 17 pages, 4 figure

Quantum Phase and Quantum Phase Operators: Some Physics and Some History

After reviewing the role of phase in quantum mechanics, I discuss, with the aid of a number of unpublished documents, the development of quantum phase operators in the 1960's. Interwoven in the discussion are the critical physics questions of the field: Are there (unique) quantum phase operators and are there quantum systems which can determine their nature? I conclude with a critique of recent proposals which have shed new light on the problem.Comment: 19 pages, 2 Figs. taken from published articles, LaTeX, to be published in Physica Scripta, Los Alamos preprint LA-UR-92-352

Optical clock intercomparison with 6×10−196\times 10^{-19} precision in one hour

Improvements in atom-light coherence are foundational to progress in quantum information science, quantum optics, and precision metrology. Optical atomic clocks require local oscillators with exceptional optical coherence due to the challenge of performing spectroscopy on their ultra-narrow linewidth clock transitions. Advances in laser stabilization have thus enabled rapid progress in clock precision. A new class of ultrastable lasers based on cryogenic silicon reference cavities has recently demonstrated the longest optical coherence times to date. In this work we utilize such a local oscillator, along with a state-of-the-art frequency comb for coherence transfer, with two Sr optical lattice clocks to achieve an unprecedented level of clock stability. Through an anti-synchronous comparison, the fractional instability of both clocks is assessed to be $4.8\times 10^{-17}/\sqrt{\tau}$ for an averaging time $\tau$ in seconds. Synchronous interrogation reveals a quantum projection noise dominated instability of $3.5(2)\times10^{-17}/\sqrt{\tau}$, resulting in a precision of $5.8(3)\times 10^{-19}$ after a single hour of averaging. The ability to measure sub-$10^{-18}$ level frequency shifts in such short timescales will impact a wide range of applications for clocks in quantum sensing and fundamental physics. For example, this precision allows one to resolve the gravitational red shift from a 1 cm elevation change in only 20 minutes

Finite to infinite steady state solutions, bifurcations of an integro-differential equation

We consider a bistable integral equation which governs the stationary solutions of a convolution model of solid--solid phase transitions on a circle. We study the bifurcations of the set of the stationary solutions as the diffusion coefficient is varied to examine the transition from an infinite number of steady states to three for the continuum limit of the semi--discretised system. We show how the symmetry of the problem is responsible for the generation and stabilisation of equilibria and comment on the puzzling connection between continuity and stability that exists in this problem

Mechanical Stress Inference for Two Dimensional Cell Arrays

Many morphogenetic processes involve mechanical rearrangement of epithelial tissues that is driven by precisely regulated cytoskeletal forces and cell adhesion. The mechanical state of the cell and intercellular adhesion are not only the targets of regulation, but are themselves likely signals that coordinate developmental process. Yet, because it is difficult to directly measure mechanical stress {\it in vivo} on sub-cellular scale, little is understood about the role of mechanics of development. Here we present an alternative approach which takes advantage of the recent progress in live imaging of morphogenetic processes and uses computational analysis of high resolution images of epithelial tissues to infer relative magnitude of forces acting within and between cells. We model intracellular stress in terms of bulk pressure and interfacial tension, allowing these parameters to vary from cell to cell and from interface to interface. Assuming that epithelial cell layers are close to mechanical equilibrium, we use the observed geometry of the two dimensional cell array to infer interfacial tensions and intracellular pressures. Here we present the mathematical formulation of the proposed Mechanical Inverse method and apply it to the analysis of epithelial cell layers observed at the onset of ventral furrow formation in the {\it Drosophila} embryo and in the process of hair-cell determination in the avian cochlea. The analysis reveals mechanical anisotropy in the former process and mechanical heterogeneity, correlated with cell differentiation, in the latter process. The method opens a way for quantitative and detailed experimental tests of models of cell and tissue mechanics