Dendritic cells cross talk with tumor antigen-specific CD8+T cells, Vγ9γδT cells, and Vα24NKT cells in patients with glioblastoma multiforme and in healthy donors

The finding that dendritic cells (DCs) orchestrate innate and adaptive immune responses has stimulated research on harnessing DCs for developing more effective vaccines for DC therapy. The expression of cytomegalovirus (CMV) antigens in glioblastoma multiforme (GBM) presents a unique opportunity to target these viral proteins for tumor immunotherapy. Here, we demonstrate that Vγ9γδT cells, innate immune cells activated by zoledronate (Z), and Vα24NKT cells, innate/adaptive immune cells activated by α-galactosylceramide (G) can link innate and adaptive immunities through cross talk with IFN-DCs from patients with GBM and healthy donors in a way that can amplify the activation and proliferation of CMVpp65-specific CD8+T cells. The IFN-DCs derived from patients with GBM used in this study express lower levels of programmed death ligand (PDL)1 and PDL2 and higher levels of CCR7 than the most commonly used mature IL-4DCs. The expression level of programmed cell death 1 (PD1) on CD8+ T cells, including CMVpp65-specific CD8+T cells, expanded by IFN-DCs pulsed with the CMVpp65-peptide and Z plus G (IFN-DCs/P+Z+G) was lower than that expanded by IFN-DCs pulsed with the peptide alone (IFN-DCs/P). Multifunctional T cells, including HLA-A*0201-restricted CMVpp65-specific CD8+T cells, Vγ9γδT cells, and Vα24NKT cells, efficiently kill HLA-A*0201 positive GBM cell line expressing CMVpp65 protein (T98G). These findings indicate that DC therapy using IFN-DCs/P+Z+G and/or CTL therapy using CMVpp65-specific CD8+T cells expanded by IFN-DCs/P+Z+G may lead to a good clinical outcome for patients with GBM. This article is protected by copyright. All rights reserved

Development of a clinical prediction rule to diagnose Pneumocystis jirovecii pneumonia in the World Health Organization’s algorithm for seriously ill HIV-infected patients

Background: The World Health Organization (WHO) algorithm for the diagnosis of tuberculosis in seriously ill HIV-infected patients recommends that treatment for Pneumocystis jirovecii pneumonia (PJP) should be considered without giving clear guidance on selecting patients for empiric PJP therapy. PJP is a common cause of hospitalisation in HIV-infected patients in resource-poor settings where diagnostic facilities are limited.Methods: We developed clinical prediction rules for PJP in a prospective cohort of HIVinfected inpatients with WHO danger signs and cough of any duration. The reference standard for PJP was > 1000 copies/mL of P. jirovecii DNA on real-time sputum polymerase chain reaction (PCR). Four potentially predictive variables were selected for regression models: dyspnoea, chest X-ray, haemoglobin and oxygen saturation. Respiratory rate was explored as a replacement for oxygen saturation as pulse oximetry is not always available in resource-poor settings.Results: We enrolled 500 participants. After imputation for missing values, there were 56 PJP outcome events. Dyspnoea was not independently associated with PJP. Oxygen saturation and respiratory rate were inversely correlated. Two clinical prediction rules were developed: chest X-ray possible/likely PJP, haemoglobin ≥ 9 g/dL and either oxygen saturation < 94% or respiratory rate. The area under the receiver operating characteristic curve of the clinical prediction rule models was 0.761 (95% CI 0.683–0.840) for the respiratory rate model and 0.797 (95% CI 0.725–0.868) for the oxygen saturation model. Both models had zero probability for PJP for scores of zero, and positive likelihood ratios exceeded 10 for high scores.Conclusion: We developed simple clinical prediction rules for PJP, which, if externally validated, could assist decision-making in the WHO seriously ill algorithm

Picornavirus RNA is protected from cleavage by ribonuclease during virion uncoating and transfer across cellular and model membranes

Picornaviruses are non-enveloped RNA viruses that enter cells via receptor-mediated endocytosis. Because they lack an envelope, picornaviruses face the challenge of delivering their RNA genomes across the membrane of the endocytic vesicle into the cytoplasm to initiate infection. Currently, the mechanism of genome release and translocation across membranes remains poorly understood. Within the enterovirus genus, poliovirus, rhinovirus 2, and rhinovirus 16 have been proposed to release their genomes across intact endosomal membranes through virally induced pores, whereas one study has proposed that rhinovirus 14 releases its RNA following disruption of endosomal membranes. For the more distantly related aphthovirus genus (e.g. foot-and-mouth disease viruses and equine rhinitis A virus) acidification of endosomes results in the disassembly of the virion into pentamers and in the release of the viral RNA into the lumen of the endosome, but no details have been elucidated as how the RNA crosses the vesicle membrane. However, more recent studies suggest aphthovirus RNA is released from intact particles and the dissociation to pentamers may be a late event. In this study we have investigated the RNase A sensitivity of genome translocation of poliovirus using a receptor-decorated-liposome model and the sensitivity of infection of poliovirus and equine-rhinitis A virus to co-internalized RNase A. We show that poliovirus genome translocation is insensitive to RNase A and results in little or no release into the medium in the liposome model. We also show that infectivity is not reduced by co-internalized RNase A for poliovirus and equine rhinitis A virus. Additionally, we show that all poliovirus genomes that are internalized into cells, not just those resulting in infection, are protected from RNase A. These results support a finely coordinated, directional model of viral RNA delivery that involves viral proteins and cellular membranes

London's urban heat island: Impact on current and future energy consumption in office buildings

This article is available open access and shared under a Creative Commons license: (http://creativecommons.org/licenses/by/3.0/). Copyright @ 2011 Elsevier B.V.This paper presents the results of a computational study on the energy consumption and related CO2 emissions for heating and cooling of an office building within the Urban Heat Island of London, currently and in the future. The study developed twenty weather files in an East-West axis through London; the weather files were constructed according to future climate change scenario for 2050 suitable for the UK which have been modified to represent specific locations within the London UHI based on measurements and predictions from a program developed for this purpose (LSSAT). The study simulated an office with typical construction, heat gains and operational patterns with an advanced thermal simulation program (IESVE). The predictions confirm that heating load decreases, cooling load and overheating hours increase as the office location moves from rural to urban sites and from present to future years. It is shown that internal heat gains are an important factor affecting energy performance and that night cooling using natural ventilation will have a beneficial effect at rural and city locations. As overheating will increase in the future, more buildings will use cooling; it is shown that this might lead to a five-fold increase of CO2 emission for city centre offices in London in 2050. The paper presents detailed results of the typical office placed on the East-West axis of the city, arguing the necessity to consider using weather files based on climate projections and urbanheat island for the design of currentbuildings to safeguard their efficiency in the future.EPSR

Variable Step Random Walks and Self-Similar Distributions

We study a scenario under which variable step random walks give anomalous statistics. We begin by analyzing the Martingale Central Limit Theorem to find a sufficient condition for the limit distribution to be non-Gaussian. We note that the theorem implies that the scaling index $\zeta$ is 1/2. For corresponding continuous time processes, it is shown that the probability density function $W(x;t)$ satisfies the Fokker-Planck equation. Possible forms for the diffusion coefficient are given, and related to $W(x,t)$. Finally, we show how a time-series can be used to distinguish between these variable diffusion processes and L\'evy dynamics.Comment: 13pages, 2 figure

Gate-tunable bandgap in bilayer graphene

The tight-binding model of bilayer graphene is used to find the gap between the conduction and valence bands, as a function of both the gate voltage and as the doping by donors or acceptors. The total Hartree energy is minimized and the equation for the gap is obtained. This equation for the ratio of the gap to the chemical potential is determined only by the screening constant. Thus the gap is strictly proportional to the gate voltage or the carrier concentration in the absence of donors or acceptors. In the opposite case, where the donors or acceptors are present, the gap demonstrates the asymmetrical behavior on the electron and hole sides of the gate bias. A comparison with experimental data obtained by Kuzmenko et al demonstrates the good agreement.Comment: 6 pages, 5 figure

Calcium-Dependent Increases in Protein Kinase-A Activity in Mouse Retinal Ganglion Cells Are Mediated by Multiple Adenylate Cyclases

Neurons undergo long term, activity dependent changes that are mediated by activation of second messenger cascades. In particular, calcium-dependent activation of the cyclic-AMP/Protein kinase A signaling cascade has been implicated in several developmental processes including cell survival, axonal outgrowth, and axonal refinement. The biochemical link between calcium influx and the activation of the cAMP/PKA pathway is primarily mediated through adenylate cyclases. Here, dual imaging of intracellular calcium concentration and PKA activity was used to assay the role of different classes of calcium-dependent adenylate cyclases (ACs) in the activation of the cAMP/PKA pathway in retinal ganglion cells (RGCs). Surprisingly, depolarization-induced calcium-dependent PKA transients persist in barrelless mice lacking AC1, the predominant calcium-dependent adenylate cyclase in RGCs, as well as in double knockout mice lacking both AC1 and AC8. Furthermore, in a subset of RGCs, depolarization-induced PKA transients persist during the inhibition of all transmembrane adenylate cyclases. These results are consistent with the existence of a soluble adenylate cyclase that plays a role in calcium-dependent activation of the cAMP/PKA cascade in neurons

Can disordered mobile phone use be considered a behavioral addiction? An update on current evidence and a comprehensive model for future research

Despite the many positive outcomes, excessive mobile phone use is now often associated with potentially harmful and/or disturbing behaviors (e.g., symptoms of deregulated use, negative impact on various aspects of daily life such as relationship problems, and work intrusion). Problematic mobile phone use (PMPU) has generally been considered as a behavioral addiction that shares many features with more established drug addictions. In light of the most recent data, the current paper reviews the validity of the behavioral addiction model when applied to PMPU. On the whole, it is argued that the evidence supporting PMPU as an addictive behavior is scarce. In particular, it lacks studies that definitively show behavioral and neurobiological similarities between mobile phone addiction and other types of legitimate addictive behaviors. Given this context, an integrative pathway model is proposed that aims to provide a theoretical framework to guide future research in the field of PMPU. This model highlights that PMPU is a heterogeneous and multi-faceted condition

Precision scans of the pixel cell response of double sided 3D pixel detectors to pion and x-ray beams

hree-dimensional (3D) silicon sensors offer potential advantages over standard planar sensors for radiation hardness in future high energy physics experiments and reduced charge-sharing for X-ray applications, but may introduce inefficiencies due to the columnar electrodes. These inefficiencies are probed by studying variations in response across a unit pixel cell in a 55μm pitch double-sided 3D pixel sensor bump bonded to TimePix and Medipix2 readout ASICs. Two complementary characterisation techniques are discussed: the first uses a custom built telescope and a 120GeV pion beam from the Super Proton Synchrotron (SPS) at CERN; the second employs a novel technique to illuminate the sensor with a micro-focused synchrotron X-ray beam at the Diamond Light Source, UK. For a pion beam incident perpendicular to the sensor plane an overall pixel efficiency of 93.0±0.5% is measured. After a 10o rotation of the device the effect of the columnar region becomes negligible and the overall efficiency rises to 99.8±0.5%. The double-sided 3D sensor shows significantly reduced charge sharing to neighbouring pixels compared to the planar device. The charge sharing results obtained from the X-ray beam study of the 3D sensor are shown to agree with a simple simulation in which charge diffusion is neglected. The devices tested are found to be compatible with having a region in which no charge is collected centred on the electrode columns and of radius 7.6±0.6μm. Charge collection above and below the columnar electrodes in the double-sided 3D sensor is observed

Hole concentration and phonon renormalization in Ca-doped YBa_2Cu_3O_y (6.76 < y < 7.00)

In order to access the overdoped regime of the YBa_2Cu_3O_y phase diagram, 2% Ca is substituted for Y in YBa_2Cu_3O_y (y = 7.00,6.93,6.88,6.76). Raman scattering studies have been carried out on these four single crystals. Measurements of the superconductivity-induced renormalization in frequency (Delta \omega) and linewidth (\Delta 2\gamma) of the 340 cm^{-1} B_{1g} phonon demonstrate that the magnitude of the renormalization is directly related to the hole concentration (p), and not simply the oxygen content. The changes in \Delta \omega with p imply that the superconducting gap (\Delta_{max}) decreases monotonically with increasing hole concentration in the overdoped regime, and \Delta \omega falls to zero in the underdoped regime. The linewidth renormalization \Delta 2\gamma is negative in the underdoped regime, crossing over at optimal doping to a positive value in the overdoped state.Comment: 18 pages; 5 figures; submitted to Phys. Rev. B Oct. 24, 2002 (BX8292