Photon Subtraction by Many-Body Decoherence

We experimentally and theoretically investigate the scattering of a photonic quantum field from another stored in a strongly interacting atomic Rydberg ensemble. Considering the many-body limit of this problem, we derive an exact solution to the scattering-induced spatial decoherence of multiple stored photons, allowing for a rigorous understanding of the underlying dissipative quantum dynamics. Combined with our experiments, this analysis reveals a correlated coherence-protection process in which the scattering from one excitation can shield all others from spatial decoherence. We discuss how this effect can be used to manipulate light at the quantum level, providing a robust mechanism for single-photon subtraction, and experimentally demonstrate this capability

The Effects of C-terminal Modifications on the Opioid Activity of [N-BenzylTyr1]Dynorphin A-(1-11) Analogs

Structural modifications affecting the efficacy of analogs of the endogenous opioid peptide dynorphin (Dyn) A have focused on the N-terminal “message” sequence, based on the “messageaddress” concept. To test the hypothesis that changes in the C-terminal “address” domain could affect efficacy, modified amino acids and cyclic constraints were incorporated into this region of the partial agonist [N-benzylTyr1]Dyn A-(1-11). Modifications in the C-terminal domain of [NbenzylTyr1] Dyn A-(1-11)NH2 resulted in increased kappa opioid receptor (KOR) affinity for all of the linear analogs, but did not affect the efficacy of these peptides at KOR. Cyclization between positions 5 and 8 yielded [N-benzylTyr1,cyclo(D-Asp5,Dap8)]Dyn A-(1-11)NH2 (13) (Patkar et al. J. Med. Chem. 2005, 48, 4500-4503) with high selectivity for KOR. In contrast to the linear peptides, this peptide exhibits negligible efficacy in the AC assay and is a KOR antagonist. These data are consistent with our hypothesis that appropriate modifications in the “address” domain of Dyn A analogs may affect efficacy

Structure-Activity Relationships of the Peptide Kappa Opioid Receptor Antagonist Zyklophin

The dynorphin (Dyn) A analog zyklophin ([N-benzyl-Tyr1-cyclo(D-Asp5,Dap8)]dynorphin A(1-11)NH2) is a kappa opioid receptor (KOR) selective antagonist in vitro, is active in vivo and antagonizes KOR in the CNS after systemic administration. Hence, we synthesized zyklophin analogs to explore the structure-activity relationships of this peptide. The synthesis of selected analogs required modification to introduce the N-terminal amino acid due to poor solubility and/or to avoid epimerization of this residue. Among the N-terminal modifications the N-phenethyl and the N-cyclopropylmethyl substitutions resulted in the analogs with the highest KOR affinities. Pharmacological results for the alanine-substituted analogs indicated that Phe4 and Arg6, but interestingly not the Tyr1, phenol are important for zyklophin’s KOR affinity, and Arg7 was important for KOR antagonist activity. In the GTPγS assay while all of the cyclic analogs exhibited negligible KOR efficacy, the N-phenethyl-Tyr1, N-CPM-Tyr1 and the N-benzyl-Phe1 analogs were 8- to 24-fold more potent KOR antagonists than zyklophin

Alanine scan of the opioid peptide dynorphin B amide

To date structure-activity relationship (SAR) studies of the dynorphins (Dyn), endogenous peptides for kappa opioid receptors (KOR), have focused almost exclusively on Dyn A with minimal studies on Dyn B. While both Dyn A and Dyn B have identical N-terminal sequences, their C-terminal sequences differ which could result in differences in pharmacological activity. We performed an alanine scan of the non-glycine residues up through residue 11 of Dyn B amide to explore the role of these side chains in the activity of Dyn B. The analogs were synthesized by fluorenylmethyloxycarbonyl (Fmoc)-based solid phase peptide synthesis and evaluated for their opioid receptor affinities and opioid potency and efficacy at KOR. Similar to Dyn A the N-terminal Tyr1 and Phe4 residues of Dyn B amide are critical for opioid receptor affinity and KOR agonist potency. The basic residues Arg6 and Arg7 contribute to the KOR affinity and agonist potency of Dyn B amide, while Lys10 contributes to the opioid receptor affinity, but not KOR agonist potency, of this peptide. Comparison to the Ala analogs of Dyn A(1-13) suggests that the basic residues in the C-terminus of both peptides contribute to KOR binding, but differences in their relative positions may contribute to the different pharmacological profiles of Dyn A and Dyn B. The other unique C-terminal residues in Dyn B amide also appear to influence the relative affinity of this peptide for KOR. This SAR information may be applied in the design of new Dyn B analogs that could be useful pharmacological tool

Discovery of Dermorphin-Based Affinity Labels with Subnanomolar Affinity for Mu Opioid Receptors+

A series of potent electrophilic affinity labels (IC50 = 0.1-5 nM) containing either a bromoacetamide or isothiocyanate based on the mu opioid receptor (MOR) selective peptide dermorphin were prepared. All four analogs exhibited wash resistant inhibition of [3H]DAMGO binding at subnanomolar to nanomolar concentrations, suggesting that these analogs bind covalently to MOR. To our knowledge these peptides are the highest affinity peptide-based affinity labels for MOR reported to date

Design, Synthesis, and Pharmacological Activities of Dynorphin A Analogs Cyclized by Ring-Closing Metathesis

Dynorphin A (Dyn A) is an endogenous ligand for kappa (κ) opioid receptors. To restrict the conformational mobility, we synthesized several cyclic Dyn A-(1-11)NH2 analogs on solid phase utilizing ring-closing metathesis (RCM) between the side chains of allylglycine (AllGly) residues incorporated in positions 2, 5 and/or 8. Cyclizations between the side chains of AllGly gave reasonable yields (56–74%) of all of the desired cyclic peptides. Both the cis and trans isomers were obtained for all of the cyclic peptides, with the ratio of cis to trans isomers depending on the position and stereochemistry of the AllGly. Most of the cyclic Dyn A-(1-11)NH2 analogs examined exhibit low nanomolar binding affinity for κ opioid receptors (Ki = 0.84–11 nM). In two of the three cases the configuration of the double bond has a significant influence on the opioid receptor affinity and agonist potency. All of the peptides inhibited adenylyl cyclase (AC) activity in a concentration-dependent manner with full or close to full agonist activity. These potent Dyn A analogs are the first ones cyclized by RCM

Disruption of PCNA-lamins A/C interactions by prelamin A induces DNA replication fork stalling

The accumulation of prelamin A is linked to disruption of cellular homeostasis, tissue degeneration and aging. Its expression is implicated in compromised genome stability and increased levels of DNA damage, but to date there is no complete explanation for how prelamin A exerts its toxic effects. As the nuclear lamina is important for DNA replication we wanted to investigate the relationship between prelamin A expression and DNA replication fork stability. In this study we report that the expression of prelamin A in U2OS cells induced both mono-ubiquitination of proliferating cell nuclear antigen (PCNA) and subsequent induction of Pol η, two hallmarks of DNA replication fork stalling. Immunofluorescence microscopy revealed that cells expressing prelamin A presented with high levels of colocalisation between PCNA and γH2AX, indicating collapse of stalled DNA replication forks into DNA double-strand breaks. Subsequent protein-protein interaction assays showed prelamin A interacted with PCNA and that its presence mitigated interactions between PCNA and the mature nuclear lamina. Thus, we propose that the cytotoxicity of prelamin A arises in part, from it actively competing against mature lamin A to bind PCNA and that this destabilises DNA replication to induce fork stalling which in turn contributes to genomic instability

Cassini ISS mutual event astrometry of the mid-sized Saturnian satellites 2005-2012

Reproduced with permission from Astronomy & Astrophysics, © ES

Atmospheric Consequences of Cosmic Ray Variability in the Extragalactic Shock Model II: Revised ionization levels and their consequences

It has been suggested that galactic shock asymmetry induced by our galaxy's infall toward the Virgo Cluster may be a source of periodicity in cosmic ray exposure as the solar system oscillates perpendicular to the galactic plane. Here we investigate a mechanism by which cosmic rays might affect terrestrial biodiversity, ionization and dissociation in the atmosphere, resulting in depletion of ozone and a resulting increase in the dangerous solar UVB flux on the ground, with an improved ionization background computation averaged over a massive ensemble (about 7 x 10^5) shower simulations. We study minimal and full exposure to the postulated extragalactic background. The atmospheric effects are greater than with our earlier, simplified ionization model. At the lower end of the range effects are too small to be of serious consequence. At the upper end of the range, ~6 % global average loss of ozone column density exceeds that currently experienced due to effects such as accumulated chlorofluorocarbons. The intensity is less than a nearby supernova or galactic gamma-ray burst, but the duration would be about 10^6 times longer. Present UVB enhancement from current ozone depletion ~3% is a documented stress on the biosphere, but a depletion of the magnitude found at the upper end of our range would double the global average UVB flux. For estimates at the upper end of the range of the cosmic ray variability over geologic time, the mechanism of atmospheric ozone depletion may provide a major biological stress, which could easily bring about major loss of biodiversity. Future high energy astrophysical observations will resolve the question of whether such depletion is likely.Comment: 22 pages, 5 figures, to be published in Journal of Geophysical Research--Planets. This is an update and replacement for our 2008 paper, with a much more extensive simulation of air shower ionization. Ionization effects and ozone depletion are somewhat large

Atmospheric consequences of cosmic ray variability in the extragalactic shock model: 2. Revised ionization levels and their consequences

This is the publisher's version, also available electronically from http://onlinelibrary.wiley.com.It has been suggested that galactic shock asymmetry induced by our galaxy's infall toward the Virgo Cluster may be a source of periodicity in cosmic ray exposure as the solar system oscillates perpendicular to the galactic plane, thereby, inducing an observed terrestrial periodicity in biodiversity. There are a number of plausible mechanisms by which cosmic rays might affect terrestrial biodiversity. Here we investigate one of these mechanisms, the consequent ionization and dissociation in the atmosphere, resulting in changes in atmospheric chemistry that culminate in the depletion of ozone and a resulting increase in the dangerous solar UVB flux on the ground. We use a heuristic model of the cosmic ray intensity enhancement originally suggested by Medvedev and Melott (2007) to compute steady state atmospheric effects. This paper is a reexamination of an issue we have studied before with a simplified approximation for the distribution of incidence angles. The new results are based on an improved ionization background computation averaged over a massive ensemble (about 7 × 10^(5)) shower simulations at various energies and incidence angles. We adopt a range with a minimal model and a fit to full exposure to the postulated extragalactic background. The atmospheric effects are greater than they were with our earlier, simplified ionization model. At the lower end of the intensity range, we find that the effects are too small to be of serious consequence. At the upper end of this range, ∼6% global average loss of ozone column density exceeds that currently experienced due to anthropogenic effects such as accumulated chlorofluorocarbons. We discuss some of the possible effects. The intensity of the atmospheric effects is less than those of a nearby supernova or galactic γ ray burst, but the duration of the effects would be about 106 times longer. Present UVB enhancement from current ozone depletion ∼3% is a documented stress on the biosphere, but a depletion of the magnitude found at the upper end of our range would approximately double the global average UVB flux. We conclude that for estimates at the upper end of the reasonable range of the cosmic ray variability over geologic time, the mechanism of atmospheric ozone depletion may provide a major biological stress, which could easily bring about major loss of biodiversity. It is possible that future high-energy astrophysical observations will resolve the question of whether such depletion is likely