CD4 T Cell Immunity Is Critical for the Control of Simian Varicella Virus Infection in a Nonhuman Primate Model of VZV Infection

Primary infection with varicella zoster virus (VZV) results in varicella (more commonly known as chickenpox) after which VZV establishes latency in sensory ganglia. VZV can reactivate to cause herpes zoster (shingles), a debilitating disease that affects one million individuals in the US alone annually. Current vaccines against varicella (Varivax) and herpes zoster (Zostavax) are not 100% efficacious. Specifically, studies have shown that 1 dose of varivax can lead to breakthrough varicella, albeit rarely, in children and a 2-dose regimen is now recommended. Similarly, although Zostavax results in a 50% reduction in HZ cases, a significant number of recipients remain at risk. To design more efficacious vaccines, we need a better understanding of the immune response to VZV. Clinical observations suggest that T cell immunity plays a more critical role in the protection against VZV primary infection and reactivation. However, no studies to date have directly tested this hypothesis due to the scarcity of animal models that recapitulate the immune response to VZV. We have recently shown that SVV infection of rhesus macaques models the hallmarks of primary VZV infection in children. In this study, we used this model to experimentally determine the role of CD4, CD8 and B cell responses in the resolution of primary SVV infection in unvaccinated animals. Data presented in this manuscript show that while CD20 depletion leads to a significant delay and decrease in the antibody response to SVV, loss of B cells does not alter the severity of varicella or the kinetics/magnitude of the T cell response. Loss of CD8 T cells resulted in slightly higher viral loads and prolonged viremia. In contrast, CD4 depletion led to higher viral loads, prolonged viremia and disseminated varicella. CD4 depleted animals also had delayed and reduced antibody and CD8 T cell responses. These results are similar to clinical observations that children with agammaglobulinemia have uncomplicated varicella whereas children with T cell deficiencies are at increased risk of progressive varicella with significant complications. Moreover, our studies indicate that CD4 T cell responses to SVV play a more critical role than antibody or CD8 T cell responses in the control of primary SVV infection and suggest that one potential mechanism for enhancing the efficacy of VZV vaccines is by eliciting robust CD4 T cell responses

Observation of a J^PC = 1-+ exotic resonance in diffractive dissociation of 190 GeV/c pi- into pi- pi- pi+

The COMPASS experiment at the CERN SPS has studied the diffractive dissociation of negative pions into the pi- pi- pi+ final state using a 190 GeV/c pion beam hitting a lead target. A partial wave analysis has been performed on a sample of 420000 events taken at values of the squared 4-momentum transfer t' between 0.1 and 1 GeV^2/c^2. The well-known resonances a1(1260), a2(1320), and pi2(1670) are clearly observed. In addition, the data show a significant natural parity exchange production of a resonance with spin-exotic quantum numbers J^PC = 1-+ at 1.66 GeV/c^2 decaying to rho pi. The resonant nature of this wave is evident from the mass-dependent phase differences to the J^PC = 2-+ and 1++ waves. From a mass-dependent fit a resonance mass of 1660 +- 10+0-64 MeV/c^2 and a width of 269+-21+42-64 MeV/c^2 is deduced.Comment: 7 page, 3 figures; version 2 gives some more details, data unchanged; version 3 updated authors, text shortened, data unchange

Is High Resolution Melting Analysis (HRMA) Accurate for Detection of Human Disease-Associated Mutations? A Meta Analysis

BACKGROUND: High Resolution Melting Analysis (HRMA) is becoming the preferred method for mutation detection. However, its accuracy in the individual clinical diagnostic setting is variable. To assess the diagnostic accuracy of HRMA for human mutations in comparison to DNA sequencing in different routine clinical settings, we have conducted a meta-analysis of published reports. METHODOLOGY/PRINCIPAL FINDINGS: Out of 195 publications obtained from the initial search criteria, thirty-four studies assessing the accuracy of HRMA were included in the meta-analysis. We found that HRMA was a highly sensitive test for detecting disease-associated mutations in humans. Overall, the summary sensitivity was 97.5% (95% confidence interval (CI): 96.8-98.5; I(2) = 27.0%). Subgroup analysis showed even higher sensitivity for non-HR-1 instruments (sensitivity 98.7% (95%CI: 97.7-99.3; I(2) = 0.0%)) and an eligible sample size subgroup (sensitivity 99.3% (95%CI: 98.1-99.8; I(2) = 0.0%)). HRMA specificity showed considerable heterogeneity between studies. Sensitivity of the techniques was influenced by sample size and instrument type but by not sample source or dye type. CONCLUSIONS/SIGNIFICANCE: These findings show that HRMA is a highly sensitive, simple and low-cost test to detect human disease-associated mutations, especially for samples with mutations of low incidence. The burden on DNA sequencing could be significantly reduced by the implementation of HRMA, but it should be recognized that its sensitivity varies according to the number of samples with/without mutations, and positive results require DNA sequencing for confirmation

Analysis of In-Vivo LacR-Mediated Gene Repression Based on the Mechanics of DNA Looping

Interactions of E. coli lac repressor (LacR) with a pair of operator sites on the same DNA molecule can lead to the formation of looped nucleoprotein complexes both in vitro and in vivo. As a major paradigm for loop-mediated gene regulation, parameters such as operator affinity and spacing, repressor concentration, and DNA bending induced by specific or non-specific DNA-binding proteins (e.g., HU), have been examined extensively. However, a complete and rigorous model that integrates all of these aspects in a systematic and quantitative treatment of experimental data has not been available. Applying our recent statistical-mechanical theory for DNA looping, we calculated repression as a function of operator spacing (58–156 bp) from first principles and obtained excellent agreement with independent sets of in-vivo data. The results suggest that a linear extended, as opposed to a closed v-shaped, LacR conformation is the dominant form of the tetramer in vivo. Moreover, loop-mediated repression in wild-type E. coli strains is facilitated by decreased DNA rigidity and high levels of flexibility in the LacR tetramer. In contrast, repression data for strains lacking HU gave a near-normal value of the DNA persistence length. These findings underscore the importance of both protein conformation and elasticity in the formation of small DNA loops widely observed in vivo, and demonstrate the utility of quantitatively analyzing gene regulation based on the mechanics of nucleoprotein complexes

Technological diversification within UK’s small serial innovators

This paper investigates the determinants of technological diversification among UK’s small serial innovators (SSIs). Using a longitudinal study of 339 UK-based small businesses accounting for almost 7000 patents between 1990 and 2006, this study constitutes the first empirical examination of technological diversification among SMEs in the literature. Results demonstrate that technological diversification is not solely a large firm activity, challenging the dominant view that innovative SMEs are extremely focused and specialised players with little technological diversification. Our findings suggest a nonlinear (i.e. inverse-U-shaped) relationship between the level of technological opportunities in the environment and the SSIs’ degree of technological diversification. This points to a trade-off between processes of exploration and exploitation across increasingly volatile technology regimes. The paper also demonstrates that small firms with impactful innovations focus their innovative activity around similar technological capabilities while firms that have introduced platform technologies in the past are more likely to engage in technological diversification

Pre-dialytic administration of aminoglycosides - case report and review of literature

Objectives: Aminoglycoside (AG) antimicrobial agents are potent therapeutics against a wide variety of gram positive and negative bacteria including Pseudomonas aeruginosa . Until now AGs are usually administered post-hemodialysis (HD) in patients receiving chronic HD. This regimen has been doubted with increasing knowledge of their PK/PD characteristics. Due to the concentration dependent mechanism of these drugs, high peak and low trough levels seem desirable, leading to the conclusion that a pre-dialytic administration would probably yield increased killing and reduced toxicity. This has already been proposed by O'Shea et al. Unfortunately until now there is little clinical data to support this claim. This report aims to provide an overview of the available literature as well as clinical expertise to the discussion.Methods: We present a case of a 55-year-old double lung transplant patient with chronic renal failure and recurring episodes of sepsis. The patient had received multiple antimicrobial agents without a significant reduction in inflammation parameters (CRP, WBC) or a marked improvement of her general status. Due to the lacking effect of piperacillin/tazobactam as well as carbapenems in this patient, she received 7.1 mg amikacin per kg bodyweight two hours previous to dialysis. To ensure patient safety as well as treatment efficacy amikacin peak as well as trough levels were assessed by the treating physicians.Results: The reported peak concentration was 53.3 µmol/l after the first administration, and 43.6 µmol/l 30 minutes post-infusion. During the subsequent HD the amikacin serum concentration dropped to 13.1 µmol/l. In the following days HD was performed daily with a trough-level adapted dose of amikacin two hours pre-HD, each time resulting in high peak and low trough levels. During this treatment the CRP level dropped from 30 mg/dl to 5.73 mg/dl within six days, and the patient recovered clinically within the first 24 hours. No difference between pre-treatment and post-treatment audiograms was observed.Discussion: Predialytic administration of AGs is a compelling regimen from a pharmacokinetic point of view. In the presented case very high peak and low trough concentrations were reached, showing that the previously proposed regimen is easily employable in daily patient care. The often expressed concern this treatment might lead to treatment failures may be countered with the good clinical result in our patient. We feel that a comparative trial is warranted and might provide better insight into the matter

Visual performance of red luminescent solar concentrating windows in an office environment

The luminescent solar concentrator (LSC) could provide a colorful and adaptable complement to standard silicon solar panels, allowing easier deployment solar energy systems in the urban environment. In order to successfully implement this technological innovation into the built environment, it should also complement the surrounding architecture and be visually acceptable to the user. One prominent feature of the LSC is its bright, fluorescent coloration. Since the devices can be transparent, this opens the possibility of employing the LSC as a power-generating window. Current research on LSCs focused on the energy efficiency and on the theoretical impact on users. So far, the impact of such a colored window on the inhabitants (or users) in spaces using these windows has been largely unexplored. In this work, we study the impact of a red LSC on the visual comfort and impression of volunteer participants. We made the interesting observation that a window covered 25% by an LSC is judged favorably when compared to a normal, clear glass window. Such a window could become a local source of electrical power from sunlight while simultaneously improving the well-being of the room inhabitants

Calculated parenteral initial treatment of bacterial infections: Bone and joint infections

This is the 10th chapter of the guideline "Calculated initial parenteral treatment of bacterial infections in adults - update 2018" in the 2nd updated version. The German guideline by the Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. (PEG) has been translated to address an international audience.This chapter deals with bacterial Infections of bones, joints and prosthetic joints. One of the most pressing points is that after an initial empirical therapy a targeted antimicrobial which penetrates well to the point of infection and is tolerated well over the usually long duration of the therapy is chosen.Dies ist das zehnte Kapitel der von der Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. (PEG) herausgegebenen S2k Leitlinie "Kalkulierte parenterale Initialtherapie bakterieller Erkrankungen bei Erwachsenen - Update 2018" in der 2. aktualisierten Fassung.Diese Kapitel befasst sich mit bakteriellen Knochen- und Gelenks- sowie Implantatinfektionen. Dabei sollte nach einer kalkulierten Initialtherapie nach Möglichkeit immer auf eine keimgerichtete Therapie mit einem gut an den Infektionsort penetrierenden und über die üblicherweise lange Therapiedauer gut verträglichen Antibiotikum umgestellt werden