Immunodomination during peripheral vaccinia virus infection

Immunodominance is a fundamental property of CD8+ T cell responses to viruses and vaccines. It had been observed that route of administration alters immunodominance after vaccinia virus (VACV) infection, but only a few epitopes were examined and no mechanism was provided. We re-visited this issue, examining a panel of 15 VACV epitopes and four routes, namely intradermal (i.d.), subcutaneous (s.c.), intraperitoneal (i.p.) and intravenous (i.v.) injection. We found that immunodominance is sharpened following peripheral routes of infection (i.d. and s.c.) compared with those that allow systemic virus dissemination (i.p. and i.v.). This increased immunodominance was demonstrated with native epitopes of VACV and with herpes simplex virus glycoprotein B when expressed from VACV. Responses to some subdominant epitopes were altered by as much as fourfold. Tracking of virus, examination of priming sites, and experiments restricting virus spread showed that priming of CD8+ T cells in the spleen was necessary, but not sufficient to broaden responses. Further, we directly demonstrated that immunodomination occurs more readily when priming is mainly in lymph nodes. Finally, we were able to reduce immunodominance after i.d., but not i.p. infection, using a VACV expressing the costimulators CD8+ (B7-1) and CD8+ (B7-2), which is notable because VACV-based vaccines incorporating these molecules are in clinical trials. Taken together, our data indicate that resources for CD8+ T cell priming are limiting in local draining lymph nodes, leading to greater immunodomination. Further, we provide evidence that costimulation can be a limiting factor that contributes to immunodomination. These results shed light on a possible mechanism of immunodomination and highlight the need to consider multiple epitopes across the spectrum of immunogenicities in studies aimed at understanding CD8+ T cell immunity to viruses.NHMRC (National Health and Medical Research Council of Australia

Kinetics of antigen expression and epitope presentation during virus infection

Current knowledge about the dynamics of antigen presentation to T cells during viral infection is very poor despite being of fundamental importance to our understanding of anti-viral immunity. Here we use an advanced mass spectrometry method to simultaneously quantify the presentation of eight vaccinia virus peptide-MHC complexes (epitopes) on infected cells and the amounts of their source antigens at multiple times after infection. The results show a startling 1000-fold range in abundance as well as strikingly different kinetics across the epitopes monitored. The tight correlation between onset of protein expression and epitope display for most antigens provides the strongest support to date that antigen presentation is largely linked to translation and not later degradation of antigens. Finally, we show a complete disconnect between the epitope abundance and immunodominance hierarchy of these eight epitopes. This study highlights the complexity of viral antigen presentation by the host and demonstrates the weakness of simple models that assume total protein levels are directly linked to epitope presentation and immunogenicity.NHMRC (National Health and Medical Research Council of Australia

Conformational and Structural Relaxations of Poly(ethylene oxide) and Poly(propylene oxide) Melts: Molecular Dynamics Study of Spatial Heterogeneity, Cooperativity, and Correlated Forward-Backward Motion

Performing molecular dynamics simulations for all-atom models, we characterize the conformational and structural relaxations of poly(ethylene oxide) and poly(propylene oxide) melts. The temperature dependence of these relaxation processes deviates from an Arrhenius law for both polymers. We demonstrate that mode-coupling theory captures some aspects of the glassy slowdown, but it does not enable a complete explanation of the dynamical behavior. When the temperature is decreased, spatially heterogeneous and cooperative translational dynamics are found to become more important for the structural relaxation. Moreover, the transitions between the conformational states cease to obey Poisson statistics. In particular, we show that, at sufficiently low temperatures, correlated forward-backward motion is an important aspect of the conformational relaxation, leading to strongly nonexponential distributions for the waiting times of the dihedrals in the various conformational statesComment: 13 pages, 13 figure

A complete classification of spherically symmetric perfect fluid similarity solutions

We classify all spherically symmetric perfect fluid solutions of Einstein's equations with equation of state p/mu=a which are self-similar in the sense that all dimensionless variables depend only upon z=r/t. For a given value of a, such solutions are described by two parameters and they can be classified in terms of their behaviour at large and small distances from the origin; this usually corresponds to large and small values of z but (due to a coordinate anomaly) it may also correspond to finite z. We base our analysis on the demonstration that all similarity solutions must be asymptotic to solutions which depend on either powers of z or powers of lnz. We show that there are only three similarity solutions which have an exact power-law dependence on z: the flat Friedmann solution, a static solution and a Kantowski-Sachs solution (although the latter is probably only physical for a1/5, there are also two families of solutions which are asymptotically (but not exactly) Minkowski: the first is asymptotically Minkowski as z tends to infinity and is described by one parameter; the second is asymptotically Minkowski at a finite value of z and is described by two parameters. A complete analysis of the dust solutions is given, since these can be written down explicitly and elucidate the link between the z>0 and z<0 solutions. Solutions with pressure are then discussed in detail; these share many of the characteristics of the dust solutions but they also exhibit new features.Comment: 63 pages. To appear in Physical Review

Quantum entanglement and disentanglement of multi-atom systems

We present a review of recent research on quantum entanglement, with special emphasis on entanglement between single atoms, processing of an encoded entanglement and its temporary evolution. Analysis based on the density matrix formalism are described. We give a simple description of the entangling procedure and explore the role of the environment in creation of entanglement and in disentanglement of atomic systems. A particular process we will focus on is spontaneous emission, usually recognized as an irreversible loss of information and entanglement encoded in the internal states of the system. We illustrate some certain circumstances where this irreversible process can in fact induce entanglement between separated systems. We also show how spontaneous emission reveals a competition between the Bell states of a two qubit system that leads to the recently discovered "sudden" features in the temporal evolution of entanglement. An another problem illustrated in details is a deterministic preparation of atoms and atomic ensembles in long-lived stationary squeezed states and entangled cluster states. We then determine how to trigger the evolution of the stable entanglement and also address the issue of a steered evolution of entanglement between desired pairs of qubits that can be achieved simply by varying the parameters of a given system.Comment: Review articl

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Can We Really Prevent Suicide?

Every year, suicide is among the top 20 leading causes of death globally for all ages. Unfortunately, suicide is difficult to prevent, in large part because the prevalence of risk factors is high among the general population. In this review, clinical and psychological risk factors are examined and methods for suicide prevention are discussed. Prevention strategies found to be effective in suicide prevention include means restriction, responsible media coverage, and general public education, as well identification methods such as screening, gatekeeper training, and primary care physician education. Although the treatment for preventing suicide is difficult, follow-up that includes pharmacotherapy, psychotherapy, or both may be useful. However, prevention methods cannot be restricted to the individual. Community, social, and policy interventions will also be essentia

Magnetic resonance imaging (MRI) contrast agents for tumor diagnosis

10.1260/2040-2295.4.1.23Journal of Healthcare Engineering4123-4

A massive hot Jupiter orbiting a metal-rich early-M star discovered in the TESS full frame images

Observations and statistical studies have shown that giant planets are rare around M dwarfs compared with Sun-like stars. The formation mechanism of these extreme systems remains under debate for decades. With the help of the TESS mission and ground based follow-up observations, we report the discovery of TOI-4201b, the most massive and densest hot Jupiter around an M dwarf known so far with a radius of $1.22\pm 0.04\ R_J$ and a mass of $2.48\pm0.09\ M_J$, about 5 times heavier than most other giant planets around M dwarfs. It also has the highest planet-to-star mass ratio ($q\sim 4\times 10^{-3}$) among such systems. The host star is an early-M dwarf with a mass of $0.61\pm0.02\ M_{\odot}$and a radius of$0.63\pm0.02\ R_{\odot}$. It has significant super-solar iron abundance ([Fe/H]=$0.52\pm 0.08$ dex). However, interior structure modeling suggests that its planet TOI-4201b is metal-poor, which challenges the classical core-accretion correlation of stellar-planet metallicity, unless the planet is inflated by additional energy sources. Building on the detection of this planet, we compare the stellar metallicity distribution of four planetary groups: hot/warm Jupiters around G/M dwarfs. We find that hot/warm Jupiters show a similar metallicity dependence around G-type stars. For M dwarf host stars, the occurrence of hot Jupiters shows a much stronger correlation with iron abundance, while warm Jupiters display a weaker preference, indicating possible different formation histories.Comment: 21 pages, 11 figures, 4 tables, submitted to A

Pathway-based expression profiling of benign prostatic hyperplasia and prostate cancer delineates an immunophilin molecule associated with cancer progression

Aberrant restoration of AR activity is linked with prostate tumor growth, therapeutic failures and development of castrate-resistant prostate cancer. Understanding the processes leading to ARreactivation should provide the foundation for novel avenues of drug discovery. A differential gene expression study was conducted using biopsies from CaP and BPH patients to identify the components putatively responsible for reinstating AR activity in CaP. From the set of genes upregulated in CaP, FKBP52, an AR co-chaperone, was selected for further analysis. Expression of FKBP52 was positively correlated with that of c-Myc. The functional cross-talk between c-Myc and FKBP52 was established using c-Myc specific-siRNA to LNCaP cells that resulted in reduction of FKBP52. A non-canonical E-box sequence housing a putative c-Myc binding site was detected on the FKBP4 promoter using in silico search. LNCaP cells transfected with the FKBP52 promoter cloned in pGL3 basic showed increased luciferase activity which declined considerably when the promoter-construct was co-transfected with c-Myc specific-siRNA. ChIP-PCR confirmed the binding of c-Myc with the conserved E-box located in the FKBP52 promoter. c-Myc downregulation concomitantly affected expression of FGF8. Since expression of FGF8 is controlled by AR, our study unveiled a novel functional axis between c-Myc, AR and FGF8 operating through FKBP52