Excess electron solvation in ammonia clusters

We performed a combination of quantum chemical calculations and molecular dynamics simulations to assess the stability of various size ("N" "H" _"3" )_n^- ammonia cluster anions up to n = 32 monomers. In the n = 3 – 8 size range, cluster anions are optimized and the vertical detachment energy of the excess electron (VDE) from increasing size clusters are computed using various level methods including density functional theory (DFT), MP2 and CCSD(T) calculations. These clusters bind the electron in non-branched hydrogen bonding chains in dipole bound states. The VDE increases with size from a few meV up to ~200 meV. The electron binding energy is weaker than in water clusters but comparable to small methanol cluster VDEs. We located the first branched hydrogen bonding cluster that binds the excess electron at n = 7. For larger (n = 8 – 32) clusters we generated cold, neutral clusters by semiempirical and ab initio molecular dynamics (AIMD) simulations, and added an extra electron to selected neutral configurations. VDE calculations on the adiabatic and the relaxed anionic structures suggest that the n = 12 - 32 neutral clusters weakly bind the excess electron. Electron binding energies for these clusters (~ 100 meV) appear to be significantly weaker than extrapolated from experimental data. The observed excess electron states are diffuse and localized outside the molecular frame (surface states) with minor (~1%) penetration to the nitrogen frontier orbitals. Stable minima with excess electron states surrounded by solvent molecules (cavity states) were not found in this size regime

Hydrodynamic forces on circular cylinders oscillating with small amplitude in still fluid or transverse to a free stream

In the present study we compare the hydrodynamic forces acting on circular cylinders oscillating in still fluid with corresponding oscillations transverse to a free stream. We find that at small amplitudes of motion the time history of the total force acting in the direction of oscillation in the presence of a free stream is virtually the same as in still fluid and in very good agreement with Stokes–Wang analytical solutions. However, the flow patterns around the cylinders that generate the consistent force history are remarkably disparate

Incorporating prior knowledge improves detection of differences in bacterial growth rate

BACKGROUND: Robust statistical detection of differences in the bacterial growth rate can be challenging, particularly when dealing with small differences or noisy data. The Bayesian approach provides a consistent framework for inferring model parameters and comparing hypotheses. The method captures the full uncertainty of parameter values, whilst making effective use of prior knowledge about a given system to improve estimation. RESULTS: We demonstrated the application of Bayesian analysis to bacterial growth curve comparison. Following extensive testing of the method, the analysis was applied to the large dataset of bacterial responses which are freely available at the web-resource, ComBase. Detection was found to be improved by using prior knowledge from clusters of previously analysed experimental results at similar environmental conditions. A comparison was also made to a more traditional statistical testing method, the F-test, and Bayesian analysis was found to perform more conclusively and to be capable of attributing significance to more subtle differences in growth rate. CONCLUSIONS: We have demonstrated that by making use of existing experimental knowledge, it is possible to significantly improve detection of differences in bacterial growth rate

Purinerg receptorok által közvetített hatások komplex vizsgálata: új neuroprotektív terápiás lehetőségek elméleti alapjai = Complex studies on purinergic receptor-mediated actions: a theoretical basis for neuroprotection

Vizsgálataink fő célja a neurotranszmitter felszabadulást serkentő P2 nukleotid receptorok szerepének tisztázása volt fiziológiás és patológiás állapotokban. Feltérképeztük a P2X7 receptort kódoló mRNS eloszlását a központi idegrendszer számos területén. Elsőként azonosítottunk a GABA és glutamát felszabadulás szabályozásában résztvevő, serkentő P2X7 receptorokat a hippokampuszban. Feltártuk a P2X7 receptorok celluláris és szubcelluláris eloszlását ezen agyterületen, igazoltuk a P2X7 receptor részvételét az ATP GABA és glutamát felszabadító hatásában farmakológiai analízis, valamint transzgenikus technológia igénybevételével. Neurokémiai és elektrofizológiai módszerekkel igazoltuk, hogy a P2X7 receptorok funkcionális válaszkészsége fokozódik energiadepriváció hatására. Kimutattuk, hogy a noradrenalin felszabadulást a hippokampuszban serkentő P2X1 és/vagy P2X3 receptorok szabályozzák. Megállapítottuk, hogy az ATP és egyéb purinok képesek önerősítő módon saját felszabadulásukat fokozni a homo- illetve heteroexchange által. Tisztáztuk a mitokondriális inhibitorok és az oxidatív stressz szupraadditív kölcsönhatását a noradrenalin/dopamin felszabadulás kiváltásában a hippokampuszban, illetve a rotenon indukált Parkinson modellben. Feltártuk az IL-1béta purin felszabadulást előidéző hatását. Eredményeink alátámasztották a pályázatban felállított hipotézist, mely szerint a P2X7 vagy egyéb P2X receptorok befolyásolása ígéretes terápiás célpont lehet neurodegeneratív betegségekben. | The main objective of the studies was to identify the role of the facilitatory P2 nucleotide receptors under physiological and pathological conditions. We explored the mRNA expression of P2X7 receptors in several areas of the CNS. We demonstrated for the first time that the activation of P2X7 receptors facilitate the release of GABA and glutamate in the hippocampus, and the cell-type specific distribution of this receptor was also explored. The involvement of P2X7 receptor in the GABA and glutamate releasing effect of ATP was proved by pharmacological analysis and by the utilization of transgenic technology. We also demonstrated by electrophysiological and neurochemical techniques that the functional responsiveness of P2X7 receptors is increased during energy deprivation. On the other hand, the release of noradrenaline is subject to facilitation by P2X1 and /or P2X3 receptors. We identified the homo-and heteroexchange, as a new mechanism, whereby purines could promote the release of each other and themselves. We revealed the supraadditive impact of mitochondrial inhibitors and oxidative stress on noradrenaline release in the hippocampus and on dopamine release in the rotenon induced Parkinson model. In addition the effect of IL-1beta on the release of purines from the hippocampus was also described. In conclusion our findings support our initial hypothesis that P2X7 or other P2X receptors could be attractive therapeutic targets in neurodegenerative diseases

Changing levels of local crime and mental health: a natural experiment using self-reported and service use data in Scotland

Background: This study contributes robust evidence on the association between mental health and local crime rates by showing how changing exposure to small area-level crime relates to self-reported and administrative data on mental health. Methods: The study sample comprised 112 251 adults aged 16–60 years, drawn from the Scottish Longitudinal Study, a 5.3% representative sample of Scottish population followed across censuses. Outcomes were individual mental health indicators: self-reported mental illness from the 2011 Census and linked administrative data on antidepressants and antipsychotics prescribed through primary care providers in the National Health Service in 2010/2012. Crime rates at data zone level (500–1000 persons) were matched to the participants’ main place of residence, as defined by general practitioner patient registration duration during 2004/2006, 2007/2009 and 2010/12. Average neighbourhood crime exposure and change in area crime were computed. Covariate-adjusted logistic regressions were conducted, stratified by moving status. Results: In addition to average crime exposure during follow-up, recent increases in crime (2007/2009–2010/2012) were associated with a higher risk of self-reported mental illness, among ‘stayers’ aged 16–30 years (OR=1.11; 95% CI 1.00 to 1.22), and among ‘movers’ aged 31–45 years (OR=1.07; 95% CI 1.01 to 1.13). Prescribed medications reinforced these findings; worsening crime rates were linked with antidepressant prescriptions among young stayers (OR=1.09; 95% CI 1.04 to 1.14) and with antipsychotic prescriptions among younger middle-aged movers (OR=1.11; 95% CI 1.01 to 1.23). Conclusion: Changing neighbourhood crime exposure is related to individual mental health, but associations differ by psychiatric conditions, age and moving status. Crime reduction and prevention, especially in communities with rising crime rates, may benefit public mental health

Roles Played by the Na+/Ca2+ Exchanger and Hypothermia in the Prevention of Ischemia-Induced Carrier-Mediated Efflux of Catecholamines into the Extracellular Space: Implications for Stroke Therapy

The release of [3H]dopamine ([3H]DA) and [3H]noradrenaline ([3H]NA) in acutely perfused rat striatal and cortical slice preparations was measured at 37 °C and 17 °C under ischemic conditions. The ischemia was simulated by the removal of oxygen and glucose from the Krebs solution. At 37 °C, resting release rates in response to ischemia were increased; in contrast, at 17 °C, resting release rates were significantly reduced, or resting release was completely prevented. The removal of extracellular Ca2+ further increased the release rates of [3H]DA and [3H]NA induced by ischemic conditions. This finding indicated that the Na+/Ca2+ exchanger (NCX), working in reverse in the absence of extracellular Ca2+, fails to trigger the influx of Ca2+ in exchange for Na+ and fails to counteract ischemia by further increasing the intracellular Na+ concentration ([Na+]i). KB-R7943, an inhibitor of NCX, significantly reduced the cytoplasmic resting release rate of catecholamines under ischemic conditions and under conditions where Ca2+ was removed. Hypothermia inhibited the excessive release of [3H]DA in response to ischemia, even in the absence of Ca2+. These findings further indicate that the NCX plays an important role in maintaining a high [Na+]i, a condition that may lead to the reversal of monoamine transporter functions; this effect consequently leads to the excessive cytoplasmic tonic release of monoamines and the reversal of the NCX. Using HPLC combined with scintillation spectrometry, hypothermia, which enhances the stimulation-evoked release of DA, was found to inhibit the efflux of toxic DA metabolites, such as 3,4-dihydroxyphenylacetaldehyde (DOPAL). In slices prepared from human cortical brain tissue removed during elective neurosurgery, the uptake and release values for [3H]NA did not differ from those measured at 37 °C in slices that were previously maintained under hypoxic conditions at 8 °C for 20 h. This result indicates that hypothermia preserves the functions of the transport and release mechanisms, even under hypoxic conditions. Oxidative stress (H2O2), a mediator of ischemic brain injury enhanced the striatal resting release of [3H]DA and its toxic metabolites (DOPAL, quinone). The study supports our earlier findings that during ischemia transmitters are released from the cytoplasm. In addition, the major findings of this study that hypothermia of brain slice preparations prevents the extracellular calcium concentration ([Ca2+]o)-independent non-vesicular transmitter release induced by ischemic insults, inhibiting Na+/Cl--dependent membrane transport of monoamines and their toxic metabolites into the extracellular space, where they can exert toxic effects

Solar Flare Intermittency and the Earth's Temperature Anomalies

We argue that earth's short-term temperature anomalies and the solar flare intermittency are linked. The analysis is based upon the study of the scaling of both the spreading and the entropy of the diffusion generated by the fluctuations of the temperature time series. The joint use of these two methods evidences the presence of a L\'{e}vy component in the temporal persistence of the temperature data sets that corresponds to the one that would be induced by the solar flare intermittency. The mean monthly temperature datasets cover the period from 1856 to 2002.Comment: 4 pages, 5 figure

Treg-Therapy Allows Mixed Chimerism and Transplantation Tolerance Without Cytoreductive Conditioning

Establishment of mixed chimerism through transplantation of allogeneic donor bone marrow (BM) into sufficiently conditioned recipients is an effective experimental approach for the induction of transplantation tolerance. Clinical translation, however, is impeded by the lack of feasible protocols devoid of cytoreductive conditioning (i.e. irradiation and cytotoxic drugs/mAbs). The therapeutic application of regulatory T cells (Tregs) prolongs allograft survival in experimental models, but appears insufficient to induce robust tolerance on its own. We thus investigated whether mixed chimerism and tolerance could be realized without the need for cytoreductive treatment by combining Treg therapy with BM transplantation (BMT). Polyclonal recipient Tregs were cotransplanted with a moderate dose of fully mismatched allogeneic donor BM into recipients conditioned solely with short-course costimulation blockade and rapamycin. This combination treatment led to long-term multilineage chimerism and donor-specific skin graft tolerance. Chimeras also developed humoral and in vitro tolerance. Both deletional and nondeletional mechanisms contributed to maintenance of tolerance. All tested populations of polyclonal Tregs (FoxP3-transduced Tregs, natural Tregs and TGF-β induced Tregs) were effective in this setting. Thus, Treg therapy achieves mixed chimerism and tolerance without cytoreductive recipient treatment, thereby eliminating a major toxic element impeding clinical translation of this approach