Adenosine-5′-phosphosulfate - a multifaceted modulator of bifunctional 3′-phospho-adenosine-5′-phosphosulfate synthases and related enzymes

All sulfation reactions rely on active sulfate in the form of 3′-phosphoadenosine-5′-phosphosulfate (PAPS). In fungi, bacteria, and plants, the enzymes responsible for PAPS synthesis, ATP sulfurylase and adenosine-5′-phosphosulfate (APS) kinase, reside on separate polypeptide chains. In metazoans, however, bifunctional PAPS synthases catalyze the consecutive steps of sulfate activation by converting sulfate to PAPS via the intermediate APS. This intricate molecule and the related nucleotides PAPS and 3′-phospho-adenosine-5′-phosphate modulate the function of various enzymes from sulfation pathways, and these effects are summarized in this review. On the ATP sulfurylase domain that initially produces APS from sulfate and ATP, APS acts as a potent product inhibitor, being competitive with both ATP and sulfate. For the APS kinase domain that phosphorylates APS to PAPS, APS is an uncompetitive substrate inhibitor that can bind both at the ATP/ADP binding site and the PAPS/APS-binding site. For human PAPS synthase 1, the steady-state concentration of APS has been modelled to be 1.6 lM, but this may increase up to 60 lM under conditions of sulfate excess. It is noteworthy that the APS concentration for maximal APS kinase activity is 15 lM. Finally, we recognized APS as a highly specific stabilizer of bifunctional PAPS synthases. APS most likely stabilizes the APS kinase part of these proteins by forming a dead-end enzyme–ADP–APS complex at APS concentrations between 0.5 and 5 lM; at higher concentrations, APS may bind to the catalytic centers of ATP sulfurylase. Based on the assumption that cellular concentrations of APS fluctuate within this range, APS can therefore be regarded as a key modulator of PAPS synthase functions

Anti-tumor activity mediated by protein and peptide transduction of HIV viral protein R (Vpr)

Peptides that are capable of traversing the cell membrane, via protein transduction domains (PTDs), are attractive either directly as drugs or indirectly as carriers for the delivery of therapeutic molecules. One such PTD, a HIV-1 Tat derived peptide has successfully delivered a variety of "cargoes" including proteins, peptides and nucleic acids into cells. There also exists other naturally occurring membrane permeable peptides which have potential as PTDs. Specifically, one of the accessory proteins of HIV (viral protein R; i.e., Vpr), which is important in controlling viral pathogenesis, possesses cell transduction domain characteristics. Related to these characteristics, Vpr has also been demonstrated to induce cell cycle arrest and host/target cell apoptosis, suggesting a potential anticancer activity for this protein. In this report we assessed the ability of Vpr protein or peptides, with or without conjugation to a PTD, to mediate anti-cancer activity against several tumor cell lines. Specifically, several Vpr peptides spanning carboxy amino acids 65-83 induced significant (i.e., greater than 50%) in vitro growth inhibition/toxicity of murine B16.F10 melanoma cells. Likewise, in in vitro experiments with other tumor cell lines, conjugation of Vpr to the Tat derived PTD and transfection of this construct into cells enhanced the induction of in vitro apoptosis by this protein when compared to the effects of transfection of cells with unconjugated Vpr. These results underscore the potential for Vpr based reagents as well as PTDs to enhance anti-tumor activity, and warrants further examination of Vpr protein and derived peptides as potential therapeutic agents against progressive cell proliferative diseases such as cancer. ©2009 Landes Bioscience

Infrared finite scattering theory in quantum field theory and quantum gravity

It has been known since the earliest days of quantum field theory (QFT) that infrared divergences arise in scattering theory with massless fields. These infrared divergences are manifestations of the memory effect: At order 1/r a massless field generically will not return to the same value at late retarded times $(u→+∞)$ as it had at early retarded times $(u→-∞)$. There is nothing singular about states with memory, but they do not lie in the standard Fock space. Infrared divergences are merely artifacts of trying to represent states with memory in the standard Fock space. If one is interested only in quantities directly relevant to collider physics, infrared divergences can be successfully dealt with by imposing an infrared cutoff, calculating inclusive quantities, and then removing the cutoff. However, this approach does not allow one to treat memory as a quantum observable and is highly unsatisfactory if one wishes to view the $S$-matrix as a fundamental quantity in QFT and quantum gravity, since the S-matrix itself is undefined. In order to have a well-defined $S$-matrix, it is necessary to define "in" and "out" Hilbert spaces that incorporate memory in a satisfactory way. Such a construction was given by Faddeev and Kulish for quantum electrodynamics (QED) with a massive charged field. Their construction can be understood as pairing momentum eigenstates of the charged particles with corresponding memory representations of the electromagnetic field to produce states of vanishing large gauge charges at spatial infinity. (This procedure is usually referred to as "dressing"the charged particles.) We investigate this procedure for QED with massless charged particles and show that, as a consequence of collinear divergences, the required dressing in this case has an infinite total energy flux, so that the states obtained in the Faddeev-Kulish construction are unphysical. An additional difficulty arises in Yang-Mills theory, due to the fact that the "soft Yang-Mills particles"used for the dressing contribute to the Yang-Mills charge-current flux, thereby invalidating the procedure used to construct eigenstates of large gauge charges at spatial infinity. We show that there are insufficiently many charge eigenstates to accommodate scattering theory. In quantum gravity, the analog of the Faddeev-Kulish construction would attempt to produce a Hilbert space of eigenstates of supertranslation charges at spatial infinity. Again, the Faddeev-Kulish dressing procedure does not produce the desired eigenstates because the dressing contributes to the null memory flux. We prove that there are no eigenstates of supertranslation charges at spatial infinity apart from the vacuum. Thus, analogs of the Faddeev-Kulish construction fail catastrophically in quantum gravity. We investigate some alternatives to Faddeev-Kulish constructions but find that these also do not work. We believe that if one wishes to treat scattering at a fundamental level in quantum gravity - as well as in massless QED and Yang-Mills theory - it is necessary to approach it from an algebraic viewpoint on the "in"and "out"states, wherein one does not attempt to "shoehorn"these states into some prechosen "in"and "out"Hilbert spaces. We outline the framework of such a scattering theory, which would be manifestly infrared finite

Killing horizons decohere quantum superpositions

We recently showed that if a massive (or charged) body is put in a quantum spatial superposition, the mere presence of a black hole in its vicinity will eventually decohere the superposition. In this paper we show that, more generally, decoherence of stationary superpositions will occur in any spacetime with a Killing horizon. This occurs because, in effect, the long-range field of the body is registered on the Killing horizon which, we show, necessitates a flux of "soft horizon gravitons/photons"through the horizon. The Killing horizon thereby harvests "which path"information of quantum superpositions and will decohere any quantum superposition in a finite time. It is particularly instructive to analyze the case of a uniformly accelerating body in a quantum superposition in flat spacetime. As we show, from the Rindler perspective the superposition is decohered by "soft gravitons/photons"that propagate through the Rindler horizon with negligible (Rindler) energy. We show that this decoherence effect is distinct from - and larger than - the decoherence resulting from the presence of Unruh radiation. We further show that from the inertial perspective, the decoherence is due to the radiation of high frequency (inertial) gravitons/photons to null infinity. (The notion of gravitons/photons that propagate through the Rindler horizon is the same notion as that of gravitons/photons that propagate to null infinity.) We also analyze the decoherence of a spatial superposition due to the presence of a cosmological horizon in de Sitter spacetime. We provide estimates of the decoherence time for such quantum superpositions in both the Rindler and cosmological cases. Although we explicitly treat the case of spacetime dimension $d=4$, our analysis applies to any dimension $d≥4$

Algebraic Observational Cosmology

What can be measured by an observer in our universe? We address this question by constructing an algebra of gravitationally-dressed observables accessible to a comoving observer in FLRW spacetimes that are asymptotically de Sitter in the past, describing an inflationary epoch. An essential quantized degree of freedom is the zero-mode of the inflaton, which leads to fluctuations in the effective cosmological constant during inflation and prevents the existence of a maximum entropy state in the semiclassical limit. Due to the inaccessibility of measurements beyond our cosmological horizon, we demonstrate that all states are mixed with well-defined von Neumann entropy (up to a state-independent constant). For semiclassical states, the von Neumann entropy corresponds to the generalized entropy of the observer\u27s causal diamond, a fine-grained quantity that is sensitive to the initial conditions of the universe.5 pages, 2 figures. v2: minor clarifications, references adde