Transient currents and universal timescales for a fully time-dependent quantum dot in the Kondo regime

Using the time-dependent non-crossing approximation, we calculate the transient response of the current through a quantum dot subject to a finite bias when the dot level is moved suddenly into a regime where the Kondo effect is present. After an initial small but rapid response, the time-dependent conductance is a universal function of the temperature, bias, and inverse time, all expressed in units of the Kondo temperature. Two timescales emerge: the first is the time to reach a quasi-metastable point where the Kondo resonance is formed as a broad structure of half-width of the order of the bias; the second is the longer time required for the narrower split peak structure to emerge from the previous structure and to become fully formed. The first time can be measured by the gross rise time of the conductance, which does not substantially change later while the split peaks are forming. The second time characterizes the decay rate of the small split Kondo peak (SKP) oscillations in the conductance, which may provide a method of experimental access to it. This latter timescale is accessible via linear response from the steady stateand appears to be related to the scale identified in that manner [A. Rosch, J. Kroha, and P. Wolfle, Phys. Rev. Lett. 87, 156802 (2001)].Comment: Revtex with 15 eps figures. Compiles to 11 page

Structural modification and biological evaluation of Dmt1-DALDA analogues

The highly charged tetrapeptide Dmt-DALDA (Dmt-D-Arg-Phe-Lys-NH2) has been previously identified as a potent μ-opioid receptor agonist1 and serves as a lead compound for the further development of novel therapeutic (peptidic) opioid analgesics. The present work describes structural modifications of the peptide in order to determine the role of the charges, role of N-methylation, and role of conformation. All prepared compounds have been tested for their in vitro affinity and activity (guinea pig ileum GPI and mouse vas deferens MVD assays), their in vitro permeability (caco-2 test) and in vivo tissue distribution, in- and efflux into and out of mouse brain. These experimental data indicate that : i) side-chain charges are not essential for in vitro activity, ii) the guanidine group of D-Arg2 is important for the blood-brain permeability iii) the conformational constraint of the Phe residue by the benzazepine ring results in highly potent compounds, but is not compatible with the Lys side chain, which can best be removed for high potency. A more detailed discussion of the obtained results will be presented. References: 1. Shimoyama, M.; Szeto, H.H.; Schiller, P.W.; Tagaito, Y.; Tokairin, H.; Eun, C.M., Shimoyama N. Pharmacology 2008, 83, 33-37. 2. Zhao, K.; Luo, G., Zhao, G.-M.; Schiller, P.W.; Szeto, H.H. J. Pharmacol. Exp. Ther. 2003, 304, 425-432

In vivo antinociception of potent mu opioid agonist tetrapeptide analogues and comparison with a compact opioid agonist - neurokinin 1 receptor antagonist chimera

<p>Abstract</p> <p>Background</p> <p>An important limiting factor in the development of centrally acting pharmaceuticals is the blood-brain barrier (BBB). Transport of therapeutic peptides through this highly protective physiological barrier remains a challenge for peptide drug delivery into the central nervous system (CNS). Because the most common strategy to treat moderate to severe pain consists of the activation of opioid receptors in the brain, the development of active opioid peptide analogues as potential analgesics requires compounds with a high resistance to enzymatic degradation and an ability to cross the BBB.</p> <p>Results</p> <p>Herein we report that tetrapeptide analogues of the type H-Dmt¹-Xxx²-Yyy³-Gly⁴-NH₂are transported into the brain after intravenous and subcutaneous administration and are able to activate the μ- and δ opioid receptors more efficiently and over longer periods of time than morphine. Using the hot water tail flick test as the animal model for antinociception, a comparison in potency is presented between a side chain conformationally constrained analogue containing the benzazepine ring (BVD03, Yyy³: Aba), and a "ring opened" analogue (BVD02, Yyy³: Phe). The results show that in addition to the increased lipophilicity through amide bond N-methylation, the conformational constraint introduced at the level of the Phe³side chain causes a prolonged antinociception. Further replacement of NMe-D-Ala²by D-Arg²in the tetrapeptide sequence led to an improved potency as demonstrated by a higher and maintained antinociception for AN81 (Xxx²: D-Arg) vs. BVD03 (Xxx²: NMe-D-Ala). A daily injection of the studied opioid ligands over a time period of 5 days did however result in a substantial decrease in antinociception on the fifth day of the experiment. The compact opioid agonist - NK1 antagonist hybrid SBCHM01 could not circumvent opioid induced tolerance.</p> <p>Conclusions</p> <p>We demonstrated that the introduction of a conformational constraint has an important impact on opioid receptor activation and subsequent antinociception in vivo. Further amino acid substitution allowed to identify AN81 as an opioid ligand able to access the CNS and induce antinociception at very low doses (0.1 mg/kg) over a time period up to 7 hours. However, tolerance became apparent after repetitive i.v. administration of the investigated tetrapeptides. This side effect was also observed with the dual opioid agonist-NK1 receptor antagonist SBCHM01.</p

Kondo effect in coupled quantum dots: a Non-crossing approximation study

The out-of-equilibrium transport properties of a double quantum dot system in the Kondo regime are studied theoretically by means of a two-impurity Anderson Hamiltonian with inter-impurity hopping. The Hamiltonian, formulated in slave-boson language, is solved by means of a generalization of the non-crossing approximation (NCA) to the present problem. We provide benchmark calculations of the predictions of the NCA for the linear and nonlinear transport properties of coupled quantum dots in the Kondo regime. We give a series of predictions that can be observed experimentally in linear and nonlinear transport measurements through coupled quantum dots. Importantly, it is demonstrated that measurements of the differential conductance ${\cal G}=dI/dV$, for the appropriate values of voltages and inter-dot tunneling couplings, can give a direct observation of the coherent superposition between the many-body Kondo states of each dot. This coherence can be also detected in the linear transport through the system: the curve linear conductance vs temperature is non-monotonic, with a maximum at a temperature $T^*$ characterizing quantum coherence between both Kondo states.Comment: 20 pages, 17 figure

Low temperature transport in AC-driven Quantum Dots in the Kondo regime

We present a fully nonequilibrium calculation of the low temperature transport properties of a quantum dot in the Kondo regime when an AC potential is applied to the gate voltage. We solve a time dependent Anderson model with finite on-site Coulomb interaction. The interaction self-energy is calculated up to second order in perturbation theory in the on-site interaction, in the context of the Keldysh non-equilibrium technique, and the effect of the AC voltage is taken into account exactly for all ranges of AC frequencies and AC intensities. The obtained linear conductance and time-averaged density of states of the quantum dot evolve in a non trivial way as a function of the AC frequency and AC intensity of the harmonic modulation.Comment: 30 pages,7 figure

Pairing in nuclear systems: from neutron stars to finite nuclei

We discuss several pairing-related phenomena in nuclear systems, ranging from superfluidity in neutron stars to the gradual breaking of pairs in finite nuclei. We focus on the links between many-body pairing as it evolves from the underlying nucleon-nucleon interaction and the eventual experimental and theoretical manifestations of superfluidity in infinite nuclear matter and of pairing in finite nuclei. We analyse the nature of pair correlations in nuclei and their potential impact on nuclear structure experiments. We also describe recent experimental evidence that points to a relation between pairing and phase transitions (or transformations) in finite nuclear systems. Finally, we discuss recent investigations of ground-state properties of random two-body interactions where pairing plays little role although the interactions yield interesting nuclear properties such as 0+ ground states in even-even nuclei.Comment: 74 pages, 33 figs, uses revtex4. Submitted to Reviews of Modern Physic

Vinculin–actin interaction couples actin retrograde flow to focal adhesions, but is dispensable for focal adhesion growth

In migrating cells, integrin-based focal adhesions (FAs) assemble in protruding lamellipodia in association with rapid filamentous actin (F-actin) assembly and retrograde flow. How dynamic F-actin is coupled to FA is not known. We analyzed the role of vinculin in integrating F-actin and FA dynamics by vinculin gene disruption in primary fibroblasts. Vinculin slowed F-actin flow in maturing FA to establish a lamellipodium–lamellum border and generate high extracellular matrix (ECM) traction forces. In addition, vinculin promoted nascent FA formation and turnover in lamellipodia and inhibited the frequency and rate of FA maturation. Characterization of a vinculin point mutant that specifically disrupts F-actin binding showed that vinculin–F-actin interaction is critical for these functions. However, FA growth rate correlated with F-actin flow speed independently of vinculin. Thus, vinculin functions as a molecular clutch, organizing leading edge F-actin, generating ECM traction, and promoting FA formation and turnover, but vinculin is dispensible for FA growth

Effects of adenosine A2A receptor activation and alanyl-glutamine in Clostridium difficile toxin-induced ileitis in rabbits and cecitis in mice

<p>Abstract</p> <p>Background</p> <p>Severe <it>Clostridium difficile </it>toxin-induced enteritis is characterized by exuberant intestinal tissue inflammation, epithelial disruption and diarrhea. Adenosine, through its action on the adenosine A_2Areceptor, prevents neutrophillic adhesion and oxidative burst and inhibits inflammatory cytokine production. Alanyl-glutamine enhances intestinal mucosal repair and decreases apoptosis of enterocytes. This study investigates the protection from enteritis by combination therapy with ATL 370, an adenosine A_2Areceptor agonist, and alanyl-glutamine in a rabbit and murine intestinal loop models of <it>C. difficile </it>toxin A-induced epithelial injury.</p> <p>Methods</p> <p>Toxin A with or without alanyl-glutamine was administered intraluminally to rabbit ileal or murine cecal loops. Animals were also given either PBS or ATL 370 parenterally. Ileal tissues were examined for secretion, histopathology, apoptosis, Cxcl1/KC and IL-10.</p> <p>Results</p> <p>ATL 370 decreased ileal secretion and histopathologic changes in loops treated with Toxin A. These effects were reversed by the A_2Areceptor antagonist, SCH 58261, in a dose-dependent manner. The combination of ATL 370 and alanyl-glutamine significantly further decreased ileal secretion, mucosal injury and apoptosis more than loops treated with either drug alone. ATL 370 and alanyl-glutamine also decreased intestinal tissue KC and IL-10.</p> <p>Conclusions</p> <p>Combination therapy with an adenosine A_2Areceptor agonist and alanyl-glutamine is effective in reversing <it>C. difficile </it>toxin A-induced epithelial injury, inflammation, secretion and apoptosis in animals and has therapeutic potential for the management of <it>C. difficile </it>infection.</p

Effect of increased convective clearance by on-line hemodiafiltration on all cause and cardiovascular mortality in chronic hemodialysis patients – the Dutch CONvective TRAnsport STudy (CONTRAST): rationale and design of a randomised controlled trial [ISRCTN38365125]

BACKGROUND: The high incidence of cardiovascular disease in patients with end stage renal disease (ESRD) is related to the accumulation of uremic toxins in the middle and large-middle molecular weight range. As online hemodiafiltration (HDF) removes these molecules more effectively than standard hemodialysis (HD), it has been suggested that online HDF improves survival and cardiovascular outcome. Thus far, no conclusive data of HDF on target organ damage and cardiovascular morbidity and mortality are available. Therefore, the CONvective TRAnsport STudy (CONTRAST) has been initiated. METHODS: CONTRAST is a Dutch multi-center randomised controlled trial. In this trial, approximately 800 chronic hemodialysis patients will be randomised between online HDF and low-flux HD, and followed for three years. The primary endpoint is all cause mortality. The main secondary outcome variables are fatal and non-fatal cardiovascular events. CONCLUSION: The study is designed to provide conclusive evidence whether online HDF leads to a lower mortality and less cardiovascular events as compared to standard HD