Past, Present and Potential Future Prion Disease Treatment Strategies

The prion diseases are rare and invariably fatal neurodegenerative diseases characterized by a unique, protein‐only pathogenesis. Mechanistically, the prion diseases result from the coerced conversion of a protease‐sensitive form of the cellular prion protein (PrPC) into a protease‐resistant infectious form (PrPres). This chapter reviews the past, present, and potentially future prion disease treatment strategies. This chapter begins with an introduction to prion diseases, the misfolding of prion proteins and what is known about this process, and then proceeds to discuss approaches for treatments. Regarding approaches to treat prion diseases, we discuss (1) small molecule inhibitors, (2) antiprion protein antibodies, (3) prion gene disruption, (4) targeting of the unfolded protein response, and (5) heterologous prion proteins. We elaborate on using heterologous prion proteins to treat prion diseases, as this is an area that we are pursuing. The chapter ends with thoughts on the future direction of prion disease treatment strategies and how these strategies might be applicable to other neurodegenerative diseases involving protein misfolding. The increasing awareness of the role of protein misfolding in many neurodegenerative processes makes the development of an effective treatment strategy for prion diseases a high priority

A reassessment of Antarctic plateau reactive nitrogen based on ANTCI 2003 airborne and ground based measurements

The first airborne measurements of nitric oxide (NO) on the Antarctic plateau have demonstrated that the previously reported elevated levels of this species extend well beyond the immediate vicinity of South Pole. Although the current database is still relatively weak and critical laboratory experiments are still needed, the findings here suggest that the chemical uniqueness of the plateau may be substantially greater than first reported. For example, South Pole ground-based findings have provided new evidence showing that the dominant process driving the release of nitrogen from the snowpack during the spring/summer season (post-depositional loss) is photochemical in nature with evaporative processes playing a lesser role. There is also new evidence suggesting that nitrogen, in the form of nitrate, may undergo multiple recycling within a given photochemical season. Speculation here is that this may be a unique property of the plateau and much related to its having persistent cold temperatures even during summer. These conditions promote the efficient adsorption of molecules like HNO3 (and very likely HO2NO2) onto snow-pack surface ice where we have hypothesized enhanced photochemical processing can occur, leading to the efficient release of NOx to the atmosphere. In addition, to these process-oriented tentative conclusions, the findings from the airborne studies, in conjunction with modeling exercises suggest a new paradigm for the plateau atmosphere. The near-surface atmosphere over this massive region can be viewed as serving as much more than a temporary reservoir or holding tank for imported chemical species. It defines an immense atmospheric chemical reactor which is capable of modifying the chemical characteristics of select atmospheric constituents. This reactor has most likely been in place over geological time, and may have led to the chemical modulation of some trace species now found in ice cores. Reactive nitrogen has played a critical role in both establishing and in maintaining this reactor. © 2007 Elsevier Ltd. All rights reserved

Stub model for dephasing in a quantum dot

As an alternative to Buttiker's dephasing lead model, we examine a dephasing stub. Both models are phenomenological ways to introduce decoherence in chaotic scattering by a quantum dot. The difference is that the dephasing lead opens up the quantum dot by connecting it to an electron reservoir, while the dephasing stub is closed at one end. Voltage fluctuations in the stub take over the dephasing role from the reservoir. Because the quantum dot with dephasing lead is an open system, only expectation values of the current can be forced to vanish at low frequencies, while the outcome of an individual measurement is not so constrained. The quantum dot with dephasing stub, in contrast, remains a closed system with a vanishing low-frequency current at each and every measurement. This difference is a crucial one in the context of quantum algorithms, which are based on the outcome of individual measurements rather than on expectation values. We demonstrate that the dephasing stub model has a parameter range in which the voltage fluctuations are sufficiently strong to suppress quantum interference effects, while still being sufficiently weak that classical current fluctuations can be neglected relative to the nonequilibrium shot noise.Comment: 8 pages with 1 figure; contribution for the special issue of J.Phys.A on "Trends in Quantum Chaotic Scattering

1H, 13C, and 15N resonance assignments for the tandem PHD finger motifs of human CHD4

The plant homeodomain (PHD) zinc finger is a structural motif of about 40–60 amino acid residues found in many eukaryotic proteins that are involved in chromatin-mediated gene regulation. The human chromodomain helicase DNA binding protein 4 (CHD4) is a multi-domain protein that harbours, at its N-terminal end, a pair of PHD finger motifs (dPHD) connected by a ~30 amino acid linker. This tandem PHD motif is thought to be involved in targeting CHD4 to chromatin via its interaction with histone tails. Here we report the 1H, 13C and 15N backbone and side-chain resonance assignment of the entire dPHD by heteronuclear multidimensional NMR spectroscopy. These assignments provide the starting point for the determination of the structure, dynamics and histone-binding properties of this tandem domain pair

Detection of CWD Prions in Urine and Saliva of Deer by Transgenic Mouse Bioassay

Chronic wasting disease (CWD) is a prion disease affecting captive and free-ranging cervids (e.g. deer, elk, and moose). The mechanisms of CWD transmission are poorly understood, though bodily fluids are thought to play an important role. Here we report the presence of infectious prions in the urine and saliva of deer with chronic wasting disease (CWD). Prion infectivity was detected by bioassay of concentrated, dialyzed urine and saliva in transgenic mice expressing the cervid PrP gene (Tg[CerPrP] mice). In addition, PrP(CWD) was detected in pooled and concentrated urine by protein misfolding cyclic amplification (PMCA). The concentration of abnormal prion protein in bodily fluids was very low, as indicated by: undetectable PrP(CWD) levels by traditional assays (western blot, ELISA) and prolonged incubation periods and incomplete TSE attack rates in inoculated Tg(CerPrP) mice (373(+/-)3 days in 2 of 9 urine-inoculated mice and 342(+/-)109 days in 8 of 9 saliva-inoculated mice). These findings help extend our understanding of CWD prion shedding and transmission and portend the detection of infectious prions in body fluids in other prion infections

Experimental Biological Protocols with Formal Semantics

Both experimental and computational biology is becoming increasingly automated. Laboratory experiments are now performed automatically on high-throughput machinery, while computational models are synthesized or inferred automatically from data. However, integration between automated tasks in the process of biological discovery is still lacking, largely due to incompatible or missing formal representations. While theories are expressed formally as computational models, existing languages for encoding and automating experimental protocols often lack formal semantics. This makes it challenging to extract novel understanding by identifying when theory and experimental evidence disagree due to errors in the models or the protocols used to validate them. To address this, we formalize the syntax of a core protocol language, which provides a unified description for the models of biochemical systems being experimented on, together with the discrete events representing the liquid-handling steps of biological protocols. We present both a deterministic and a stochastic semantics to this language, both defined in terms of hybrid processes. In particular, the stochastic semantics captures uncertainties in equipment tolerances, making it a suitable tool for both experimental and computational biologists. We illustrate how the proposed protocol language can be used for automated verification and synthesis of laboratory experiments on case studies from the fields of chemistry and molecular programming

Energy-time entanglement of quasi-particles in solid-state devices

We present a proposal for the experimental observation of energy-time entanglement of quasi-particles in mesoscopic physics. This type of entanglement arises whenever correlated particles are produced at the same time and this time is uncertain in the sense of quantum uncertainty, as has been largely used in photonics. We discuss its feasibility for electron-hole pairs. In particular, we argue that the recently fabricated 2DEG-2DHG junctions, irradiated with a continuous laser, behave as "entanglers" for energy-time entanglement.Comment: 4 pages, 3 figure

Laser spectroscopy of hyperfine structure in highly-charged ions: a test of QED at high fields

An overview is presented of laser spectroscopy experiments with cold, trapped, highly-charged ions, which will be performed at the HITRAP facility at GSI in Darmstadt (Germany). These high-resolution measurements of ground state hyperfine splittings will be three orders of magnitude more precise than previous measurements. Moreover, from a comparison of measurements of the hyperfine splittings in hydrogen- and lithium-like ions of the same isotope, QED effects at high electromagnetic fields can be determined within a few percent. Several candidate ions suited for these laser spectroscopy studies are presented.Comment: 5 pages, 1 figure, 1 table. accepted for Canadian Journal of Physics (2006

Electron fractionalization induced dephasing in Luttinger liquids

Using the appropriate fractionalization mechanism, we correctly derive the temperature (T) and interaction dependence of the electron lifetime $\tau_F$ in Luttinger liquids. For strong enough interactions, we report that $(T\tau_F)\propto g$, with $g\ll 1$ being the standard Luttinger exponent; This reinforces that electrons are {\it not} good quasiparticles. We immediately emphasize that this is of importance for the detection of electronic interferences in ballistic 1D rings and carbon nanotubes, inducing ``dephasing'' (strong reduction of Aharonov-Bohm oscillations).Comment: 5 pages, 1 figure (Final version for PRB Brief Report