Construction of Simulation Wavefunctions for Aqueous Species: D3O+

This paper investigates Monte Carlo techniques for construction of compact wavefunctions for the internal atomic motion of the D3O+ ion. The polarization force field models of Stillinger, et al and of Ojamae, et al. were used. Initial pair product wavefunctions were obtained from the asymptotic high temperature many-body density matrix after contraction to atom pairs using Metropolis Monte Carlo. Subsequent characterization shows these pair product wavefunctions to be well optimized for atom pair correlations despite that fact that the predicted zero point energies are too high. The pair product wavefunctions are suitable to use within variational Monte Carlo, including excited states, and density matrix Monte Carlo calculations. Together with the pair product wavefunctions, the traditional variational theorem permits identification of wavefunction features with significant potential for further optimization. The most important explicit correlation variable found for the D3O+ ion was the vector triple product {\bf r}$_{OD1}\cdot$({\bf r}$_{OD2}\times${\bf r}$_{OD3}$). Variational Monte Carlo with 9 of such explicitly correlated functions yielded a ground state wavefunction with an error of 5-6% in the zero point energy.Comment: 17 pages including 6 figures, typos correcte

Mimics of small ribozymes utilizing a supramolecular scaffold

For elucidating the mechanism of the general acid/base catalysis of the hydrolysis of RNA phosphodiester bonds, a number of cleaving agents having two cyclen moieties tethered to a 1,3,5-triazine core have been prepared and their ability to bind and cleave uridylyl-3', 5'-uridine (UpU) studied over a wide pH range. Around neutral pH, the cleaving agents form a highly stable ternary complex with UpU and Zn-II through coordination of the uracil N3 and the cyclen nitrogen atoms to the Zn-II ions. Under conditions where the triazine core exists in the deprotonated neutral form, hydrolysis of UpU, but not of adenylyl-3',5'-adenosine (ApA), is accelerated by approximately two orders of magnitude in the presence of the cleaving agents, suggesting general base rather than metal ion catalysis. The probable mechanism of the observed catalysis and implications to understanding the general acid/base-catalyzed phosphodiester hydrolysis by ribozymes are discussed.</p

Inflammation of peripheral tissues and injury to peripheral nerves induce diferring effects in the expression of the calcium-sensitive anandamide synthesising enzyme and related molecules in rat primary sensory neuron

Elevation of intracellular Ca 2+ concentration induces the synthesis of N0 arachydonoylethanolamine (anandamide) in a sub0popu lation of primary sensory neurons. N0acylphosphatidylethanolamine phospholipa se D (NAPE0PLD) is the only known enzyme, which synthesises anandamide in a Ca 2+ 0dependent manner. NAPE0 PLD mRNA, as well as anandamide's main targets, the excitatory transient receptor potential vanilloid type 1 ion channel (TRPV1) and the inhibitory cannabinoid type 1 (CB1) receptor and the main anandamide0hydrolysing enzyme fatty acid amide hydrolase (FAAH) are all expressed by sub0populatio ns of nociceptive primary sensory neurons. Thus, NAPE0PLD, TRPV1, the CB1 rec eptor and FAAH could form an autocrine signalling system, which could shape t he activity of a major sub0 population of nociceptive primary sensory neurons, hence contribute to the development of pain. While the expression patterns of TRPV1, the CB1 receptor and FAAH have been comprehensively elucidated, little i s known about NAPE0PLD expression in primary sensory neurons under physiol ogical and pathological conditions. We report that NAPE0PLD is expressed by about a third of primary sensory neurons, the overwhelming majority of which also express nociceptive markers as well as the CB1 receptor, TRPV1 and FAAH . Inflammation of peripheral tissues and injury to peripheral nerves induce diff ering but concerted changes in the expression pattern of NAPE0PLD, the CB1 receptor, T RPV1 and FAAH. Together these data indicate the existence of the anatomical basis for an autocrine signalling system, in a major proportion of nociceptive primar y sensory neurons, and that alterations in that autocrine signalling by periphe ral pathologies could contribute to the development of both inflammatory and neuropathi c pain

Caspase-2 is upregulated after sciatic nerve transection and its inhibition protects dorsal root ganglion neurons from Apoptosis after serum withdrawal

Sciatic nerve (SN) transection-induced apoptosis of dorsal root ganglion neurons (DRGN) is one factor determining the efficacy of peripheral axonal regeneration and the return of sensation. Here, we tested the hypothesis that caspase-2(CASP2) orchestrates apoptosis of axotomised DRGN both in vivo and in vitro by disrupting the local neurotrophic supply to DRGN. We observed significantly elevated levels of cleaved CASP2 (C-CASP2), compared to cleaved caspase-3 (C-CASP3), within TUNEL+DRGN and DRG glia (satellite and Schwann cells) after SN transection. A serum withdrawal cell culture model, which induced 40% apoptotic death in DRGN and 60% in glia, was used to model DRGN loss after neurotrophic factor withdrawal. Elevated C-CASP2 and TUNEL were observed in both DRGN and DRG glia, with C-CASP2 localisation shifting from the cytosol to the nucleus, a required step for induction of direct CASP2-mediated apoptosis. Furthermore, siRNAmediated downregulation of CASP2 protected 50% of DRGN from apoptosis after serum withdrawal, while downregulation of CASP3 had no effect on DRGN or DRG glia survival. We conclude that CASP2 orchestrates the death of SN-axotomised DRGN directly and also indirectly through loss of DRG glia and their local neurotrophic factor support. Accordingly, inhibiting CASP2 expression is a potential therapy for improving both the SN regeneration response and peripheral sensory recovery

Lambda and Antilambda polarization from deep inelastic muon scattering

We report results of the first measurements of Lambda and Antilambda polarization produced in deep inelastic polarized muon scattering on the nucleon. The results are consistent with an expected trend towards positive polarization with increasing x_F. The polarizations of Lambda and Antilambda appear to have opposite signs. A large negative polarization for Lambda at low positive x_F is observed and is not explained by existing models.A possible interpretation is presented.Comment: 9 pages, 2 figure

Shadowing in Inelastic Scattering of Muons on Carbon, Calcium and Lead at Low XBj

Nuclear shadowing is observed in the per-nucleon cross-sections of positive muons on carbon, calcium and lead as compared to deuterium. The data were taken by Fermilab experiment E665 using inelastically scattered muons of mean incident momentum 470 GeV/c. Cross-section ratios are presented in the kinematic region 0.0001 < XBj <0.56 and 0.1 < Q**2 < 80 GeVc. The data are consistent with no significant nu or Q**2 dependence at fixed XBj. As XBj decreases, the size of the shadowing effect, as well as its A dependence, are found to approach the corresponding measurements in photoproduction.Comment: 22 pages, incl. 6 figures, to be published in Z. Phys.

Binding of smoothelin-like 1 to tropomyosin and calmodulin is mutually exclusive and regulated by phosphorylation

BACKGROUND: The smoothelin-like 1 protein (SMTNL1) can associate with tropomyosin (Tpm) and calmodulin (CaM), two proteins essential to the smooth muscle contractile process. SMTNL1 is phosphorylated at Ser301 by protein kinase A during calcium desensitization in smooth muscle, yet the effect of SMTNL1 phosphorylation on Tpm- and CaM-binding has yet to be investigated. RESULTS: Using pull down studies with Tpm-Sepharose and CaM-Sepharose, we examined the interplay between Tpm binding, CaM binding, phosphorylation of SMTNL1 and calcium concentration. Phosphorylation greatly enhanced the ability of SMTNL1 to associate with Tpm in vitro; surface plasmon resonance yielded a 10-fold enhancement in K (D) value with phosphorylation. The effect on CaM binding is more complex and varies with the availability of calcium. CONCLUSIONS: Combining both CaM and Tpm with SMTNL1 shows that the binding to both is mutually exclusive. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12858-017-0080-6) contains supplementary material, which is available to authorized users

Extreme events in total ozone over the Northern mid-latitudes: an analysis based on long-term data sets from five European ground-based stations

We apply methods from extreme value theory to identify extreme events in high (termed EHOs) and low (termed ELOs) total ozone and to describe the distribution tails (i.e. very high and very low values) of five long-term European ground-based total ozone time series. The influence of these extreme events on observed mean values, long-term trends and changes is analysed. The results show a decrease in EHOs and an increase in ELOs during the last decades, and establish that the observed downward trend in column ozone during the 1970-1990s is strongly dominated by changes in the frequency of extreme events. Furthermore, it is shown that clear 'fingerprints' of atmospheric dynamics (NAO, ENSO) and chemistry [ozone depleting substances (ODSs), polar vortex ozone loss] can be found in the frequency distribution of ozone extremes, even if no attribution is possible from standard metrics (e.g. annual mean values). The analysis complements earlier analysis for the world's longest total ozone record at Arosa, Switzerland, confirming and revealing the strong influence of atmospheric dynamics on observed ozone changes. The results provide clear evidence that in addition to ODS, volcanic eruptions and strong/moderate ENSO and NAO events had significant influence on column ozone in the European sector

Selective Targeting of TRPV1 Expressing Sensory Nerve Terminals in the Spinal Cord for Long Lasting Analgesia

Chronic pain is a major clinical problem and opiates are often the only treatment, but they cause significant problems ranging from sedation to deadly respiratory depression. Resiniferatoxin (RTX), a potent agonist of Transient Receptor Potential Vanilloid 1 (TRPV1), causes a slow, sustained and irreversible activation of TRPV1 and increases the frequency of spontaneous excitatory postsynaptic currents, but causes significant depression of evoked EPSCs due to nerve terminal depolarization block. Intrathecal administration of RTX to rats in the short-term inhibits nociceptive synaptic transmission, and in the long-term causes a localized, selective ablation of TRPV1-expressing central sensory nerve terminals leading to long lasting analgesia in behavioral models. Since RTX actions are selective for central sensory nerve terminals, other efferent functions of dorsal root ganglion neurons can be preserved. Preventing nociceptive transmission at the level of the spinal cord can be a useful strategy to treat chronic, debilitating and intractable pain

Drug-induced mild therapeutic hypothermia obtained by administration of a transient receptor potential vanilloid type 1 agonist

<p>Abstract</p> <p>Background</p> <p>The use of mechanical/physical devices for applying mild therapeutic hypothermia is the only proven neuroprotective treatment for survivors of out of hospital cardiac arrest. However, this type of therapy is cumbersome and associated with several side-effects. We investigated the feasibility of using a transient receptor potential vanilloid type 1 (TRPV1) agonist for obtaining drug-induced sustainable mild hypothermia.</p> <p>Methods</p> <p>First, we screened a heterogeneous group of TRPV1 agonists and secondly we tested the hypothermic properties of a selected candidate by dose-response studies. Finally we tested the hypothermic properties in a large animal. The screening was in conscious rats, the dose-response experiments in conscious rats and in cynomologus monkeys, and the finally we tested the hypothermic properties in conscious young cattle (calves with a body weight as an adult human). The investigated TRPV1 agonists were administered by continuous intravenous infusion.</p> <p>Results</p> <p>Screening: Dihydrocapsaicin (DHC), a component of chili pepper, displayed a desirable hypothermic profile with regards to the duration, depth and control in conscious rats. Dose-response experiments: In both rats and cynomologus monkeys DHC caused a dose-dependent and immediate decrease in body temperature. Thus in rats, infusion of DHC at doses of 0.125, 0.25, 0.50, and 0.75 mg/kg/h caused a maximal ΔT (°C) as compared to vehicle control of -0.9, -1.5, -2.0, and -4.2 within approximately 1 hour until the 6 hour infusion was stopped. Finally, in calves the intravenous infusion of DHC was able to maintain mild hypothermia with ΔT > -3°C for more than 12 hours.</p> <p>Conclusions</p> <p>Our data support the hypothesis that infusion of dihydrocapsaicin is a candidate for testing as a primary or adjunct method of inducing and maintaining therapeutic hypothermia.</p