Pharmacological Modulation of the Mitochondrial Electron Transport Chain in Paclitaxel-Induced Painful Peripheral Neuropathy

AbstractPaclitaxel is an effective first-line chemotherapeutic with the major dose-limiting side effect of painful neuropathy. Mitochondrial dysfunction and oxidative stress have been implicated in paclitaxel-induced painful neuropathy. Here we show the effects of pharmacological modulation of mitochondrial sites that produce reactive oxygen species using systemic rotenone (complex I inhibitor) or antimycin A (complex III inhibitor) on the maintenance and development of paclitaxel-induced mechanical hypersensitivity in adult male Sprague Dawley rats. The maximally tolerated dose (5 mg/kg) of rotenone inhibited established paclitaxel-induced mechanical hypersensitivity. However, some of these inhibitory effects coincided with decreased motor coordination; 3 mg/kg rotenone also significantly attenuated established paclitaxel-induced mechanical hypersensitivity without any motor impairment. The maximally tolerated dose (.6 mg/kg) of antimycin A reversed established paclitaxel-induced mechanical hypersensitivity without any motor impairment. Seven daily doses of systemic rotenone or antimycin A were given either after paclitaxel administration or before and during paclitaxel administration. Rotenone had no significant effect on the development of paclitaxel-induced mechanical hypersensitivity. However, antimycin A significantly inhibited the development of paclitaxel-induced mechanical hypersensitivity when given before and during paclitaxel administration but had no effect when given after paclitaxel administration. These studies provide further evidence of paclitaxel-evoked mitochondrial dysfunction in vivo, suggesting that complex III activity is instrumental in paclitaxel-induced pain.PerspectiveThis study provides further in vivo evidence that mitochondrial dysfunction is a key contributor to the development and maintenance of chemotherapy-induced painful neuropathy. This work also indicates that selective modulation of the electron transport chain can induce antinociceptive effects in a preclinical model of paclitaxel-induced pain

Variability monitoring of the hydroxyl maser emission in G12.889+0.489

Through a series of observations with the Australia Telescope Compact Array we have monitored the variability of ground-state hydroxyl maser emission from G12.889+0.489 in all four Stokes polarisation products. These observations were motivated by the known periodicity in the associated 6.7-GHz methanol maser emission. A total of 27 epochs of observations were made over 16 months. No emission was seen from either the 1612 or 1720 MHz satellite line transitions (to a typical five sigma upper limit of 0.2 Jy). The peak flux densities of the 1665 and 1667 MHz emission were observed to vary at a level of ∼20% (with the exception of one epoch which dropped by 640%). There was no distinct flaring activity at any epoch, but there was a weak indication of periodic variability, with a period and phase of minimum emission similar to that of methanol. There is no significant variation in the polarised properties of the hydroxyl, with Stokes Q and U flux densities varying in accord with the Stokes I intensity (linear polarisation, P, varying by 620%) and the right and left circularly polarised components varying by 633% at 1665-MHz and 638% at 1667-MHz. These observations are the first monitoring observations of the hydroxyl maser emission from G12.889+0.489

Correlation inequalities for classical and quantum XY models

We review correlation inequalities of truncated functions for the classical and quantum XY models. A consequence is that the critical temperature of the XY model is necessarily smaller than that of the Ising model, in both the classical and quantum cases. We also discuss an explicit lower bound on the critical temperature of the quantum XY model.Comment: 13 pages. Submitted to the volume "Advances in Quantum Mechanics: contemporary trends and open problems" of the INdAM-Springer series, proceedings of the INdAM meeting "Contemporary Trends in the Mathematics of Quantum Mechanics" (4-8 July 2016) organised by G. Dell'Antonio and A. Michelangel

VIP enhances TRH-stimulated prolactin secretion of pituitary tumours Studies with 31P NMR

AbstractIntravenous thyrotrophin releasing hormone (TRH) caused a 6.5-fold increase in plasma prolactin (PRL) in rats carrying implanted pituitary tumours. Vasoactive intestinal polypeptide (VIP) had no effect, but TRH given after VIP raised TRH stimulated secretion 13-fold above basal. 31P NMR spectroscopy showed that VIP caused a decrease in high energy metabolites (depleted phosphocreatine, elevated inorganic phosphate and lowered intracellular pH). TRH alone caused a similar but smaller effect; given after VIP, it caused no detectable depletion. We suggest that the changes in high energy metabolite cencentrations reflect increased cellular energy consumption consistent with a priming process (stage 1) in PRL secretion, followed by hormone release (stage 2). VIP induces stage 1 whereas RTH induced both stages

Thermodynamic perturbation theory for dipolar superparamagnets

Thermodynamic perturbation theory is employed to derive analytical expressions for the equilibrium linear susceptibility and specific heat of lattices of anisotropic classical spins weakly coupled by the dipole-dipole interaction. The calculation is carried out to the second order in the coupling constant over the temperature, while the single-spin anisotropy is treated exactly. The temperature range of applicability of the results is, for weak anisotropy (A/kT << 1), similar to that of ordinary high-temperature expansions, but for moderately and strongly anisotropic spins (A/kT > 1) it can extend down to the temperatures where the superparamagnetic blocking takes place (A/kT \sim 25), provided only the interaction strength is weak enough. Besides, taking exactly the anisotropy into account, the results describe as particular cases the effects of the interactions on isotropic (A = 0) as well as strongly anisotropic (A \to \infty) systems (discrete orientation model and plane rotators).Comment: 15 pages, 3 figure

Spacetime Information

In usual quantum theory, the information available about a quantum system is defined in terms of the density matrix describing it on a spacelike surface. This definition must be generalized for extensions of quantum theory which do not have a notion of state on a spacelike surface. It must be generalized for the generalized quantum theories appropriate when spacetime geometry fluctuates quantum mechanically or when geometry is fixed but not foliable by spacelike surfaces. This paper introduces a four-dimensional notion of the information available about a quantum system's boundary conditions in the various sets of decohering histories it may display. The idea of spacetime information is applied in several contexts: When spacetime geometry is fixed the information available through alternatives restricted to a spacetime region is defined. The information available through histories of alternatives of general operators is compared to that obtained from the more limited coarse- grainings of sum-over-histories quantum mechanics. The definition of information is considered in generalized quantum theories. We consider as specific examples time-neutral quantum mechanics with initial and final conditions, quantum theories with non-unitary evolution, and the generalized quantum frameworks appropriate for quantum spacetime. In such theories complete information about a quantum system is not necessarily available on any spacelike surface but must be searched for throughout spacetime. The information loss commonly associated with the ``evolution of pure states into mixed states'' in black hole evaporation is thus not in conflict with the principles of generalized quantum mechanics.Comment: 47pages, 2 figures, UCSBTH 94-0

Nuclear Octupole Correlations and the Enhancement of Atomic Time-Reversal Violation

We examine the time-reversal-violating nuclear ``Schiff moment'' that induces electric dipole moments in atoms. After presenting a self-contained derivation of the form of the Schiff operator, we show that the distribution of Schiff strength, an important ingredient in the ground-state Schiff moment, is very different from the electric-dipole-strength distribution, with the Schiff moment receiving no strength from the giant dipole resonance in the Goldhaber-Teller model. We then present shell-model calculations in light nuclei that confirm the negligible role of the dipole resonance and show the Schiff strength to be strongly correlated with low-lying octupole strength. Next, we turn to heavy nuclei, examining recent arguments for the strong enhancement of Schiff moments in octupole-deformed nuclei over that of 199Hg, for example. We concur that there is a significant enhancement while pointing to effects neglected in previous work (both in the octupole-deformed nuclides and 199Hg) that may reduce it somewhat, and emphasizing the need for microscopic calculations to resolve the issue. Finally, we show that static octupole deformation is not essential for the development of collective Schiff moments; nuclei with strong octupole vibrations have them as well, and some could be exploited by experiment.Comment: 25 pages, 4 figures embedded in tex

Specific pathway abundances in the neonatal calf faecal microbiome are associated with susceptibility to Cryptosporidium parvum infection: a metagenomic analysis.

Cryptosporidium parvum is the main cause of calf scour worldwide. With limited therapeutic options and research compared to other Apicomplexa, it is important to understand the parasites' biology and interactions with the host and microbiome in order to develop novel strategies against this infection. The age-dependent nature of symptomatic cryptosporidiosis suggests a link to the undeveloped immune response, the immature intestinal epithelium, and its associated microbiota. This led us to hypothesise that specific features of the early life microbiome could predict calf susceptibility to C. parvum infection. In this study, a single faecal swab sample was collected from each calf within the first week of life in a cohort of 346 animals. All 346 calves were subsequently monitored for clinical signs of cryptosporidiosis, and calves that developed diarrhoea were tested for Rotavirus, Coronavirus, E. coli F5 (K99) and C. parvum by lateral flow test (LFT). A retrospective case–control approach was taken whereby a subset of healthy calves (Control group; n = 33) and calves that went on to develop clinical signs of infectious diarrhoea and test positive for C. parvum infection via LFT (Cryptosporidium-positive group; n = 32) were selected from this cohort, five of which were excluded due to low DNA quality. A metagenomic analysis was conducted on the faecal microbiomes of the control group (n = 30) and the Cryptosporidium-positive group (n = 30) prior to infection, to determine features predictive of cryptosporidiosis. Taxonomic analysis showed no significant differences in alpha diversity, beta diversity, and taxa relative abundance between controls and Cryptosporidium-positive groups. Analysis of functional potential showed pathways related to isoprenoid precursor, haem and purine biosynthesis were significantly higher in abundance in calves that later tested positive for C. parvum (q ≤ 0.25). These pathways are either absent or streamlined in the C. parvum parasites. Though the de novo production of isoprenoid precursors, haem and purines are absent, C. parvum has been shown to encode enzymes that catalyse the downstream reactions of these pathway metabolites, indicating that C. parvum may scavenge those products from an external source. The host has previously been put forward as the source of essential metabolites, but our study suggests that C. parvum may also be able to harness specific metabolic pathways of the microbiota in order to survive and replicate. This finding is important as components of these microbial pathways could be exploited as potential therapeutic targets for the prevention or mitigation of cryptosporidiosis in bovine neonates

Unitarity and Causality in Generalized Quantum Mechanics for Non-Chronal Spacetimes

Spacetime must be foliable by spacelike surfaces for the quantum mechanics of matter fields to be formulated in terms of a unitarily evolving state vector defined on spacelike surfaces. When a spacetime cannot be foliated by spacelike surfaces, as in the case of spacetimes with closed timelike curves, a more general formulation of quantum mechanics is required. In such generalizations the transition matrix between alternatives in regions of spacetime where states {\it can} be defined may be non-unitary. This paper describes a generalized quantum mechanics whose probabilities consistently obey the rules of probability theory even in the presence of such non-unitarity. The usual notion of state on a spacelike surface is lost in this generalization and familiar notions of causality are modified. There is no signaling outside the light cone, no non-conservation of energy, no ``Everett phones'', and probabilities of present events do not depend on particular alternatives of the future. However, the generalization is acausal in the sense that the existence of non-chronal regions of spacetime in the future can affect the probabilities of alternatives today. The detectability of non-unitary evolution and violations of causality in measurement situations are briefly considered. The evolution of information in non-chronal spacetimes is described.Comment: 40pages, UCSBTH92-0

Interleukin-1©¬ (IL-1©¬), IL-1 receptor antagonist, and TNF¥á production in whole blood

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