Immunogenicity and Protective Capacity of a Virosomal Respiratory Syncytial Virus Vaccine Adjuvanted with Monophosphoryl Lipid A in Mice

Respiratory Syncytial Virus (RSV) is a major cause of viral brochiolitis in infants and young children and is also a significant problem in elderly and immuno-compromised adults. To date there is no efficacious and safe RSV vaccine, partially because of the outcome of a clinical trial in the 1960s with a formalin-inactivated RSV vaccine (FI-RSV). This vaccine caused enhanced respiratory disease upon exposure to the live virus, leading to increased morbidity and the death of two children. Subsequent analyses of this incident showed that FI-RSV induces a Th2-skewed immune response together with poorly neutralizing antibodies. As a new approach, we used reconstituted RSV viral envelopes, i.e. virosomes, with incorporated monophosphoryl lipid A (MPLA) adjuvant to enhance immunogenicity and to skew the immune response towards a Th1 phenotype. Incorporation of MPLA stimulated the overall immunogenicity of the virosomes compared to non-adjuvanted virosomes in mice. Intramuscular administration of the vaccine led to the induction of RSV-specific IgG2a levels similar to those induced by inoculation of the animals with live RSV. These antibodies were able to neutralize RSV in vitro. Furthermore, MPLA-adjuvanted RSV virosomes induced high amounts of IFNγ and low amounts of IL5 in both spleens and lungs of immunized and subsequently challenged animals, compared to levels of these cytokines in animals vaccinated with FI-RSV, indicating a Th1-skewed response. Mice vaccinated with RSV-MPLA virosomes were protected from live RSV challenge, clearing the inoculated virus without showing signs of lung pathology. Taken together, these data demonstrate that RSV-MPLA virosomes represent a safe and efficacious vaccine candidate which warrants further evaluation

A dual propagation contours technique for semi-automated assessment of systolic and diastolic cardiac function by CMR

<p>Abstract</p> <p>Background</p> <p>Although cardiovascular magnetic resonance (CMR) is frequently performed to measure accurate LV volumes and ejection fractions, LV volume-time curves (VTC) derived ejection and filling rates are not routinely calculated due to lack of robust LV segmentation techniques. VTC derived peak filling rates can be used to accurately assess LV diastolic function, an important clinical parameter. We developed a novel geometry-independent dual-contour propagation technique, making use of LV endocardial contours manually drawn at end systole and end diastole, to compute VTC and measured LV ejection and filling rates in hypertensive patients and normal volunteers.</p> <p>Methods</p> <p>39 normal volunteers and 49 hypertensive patients underwent CMR. LV contours were manually drawn on all time frames in 18 normal volunteers. The dual-contour propagation algorithm was used to propagate contours throughout the cardiac cycle. The results were compared to those obtained with single-contour propagation (using either end-diastolic or end-systolic contours) and commercially available software. We then used the dual-contour propagation technique to measure peak ejection rate (PER) and peak early diastolic and late diastolic filling rates (ePFR and aPFR) in all normal volunteers and hypertensive patients.</p> <p>Results</p> <p>Compared to single-contour propagation methods and the commercial method, VTC by dual-contour propagation showed significantly better agreement with manually-derived VTC. Ejection and filling rates by dual-contour propagation agreed with manual (dual-contour – manual PER: -0.12 ± 0.08; ePFR: -0.07 ± 0.07; aPFR: 0.06 ± 0.03 EDV/s, all P = NS). However, the time for the manual method was ~4 hours per study versus ~7 minutes for dual-contour propagation. LV systolic function measured by LVEF and PER did not differ between normal volunteers and hypertensive patients. However, ePFR was lower in hypertensive patients vs. normal volunteers, while aPFR was higher, indicative of altered diastolic filling rates in hypertensive patients.</p> <p>Conclusion</p> <p>Dual-propagated contours can accurately measure both systolic and diastolic volumetric indices that can be applied in a routine clinical CMR environment. With dual-contour propagation, the user interaction that is routinely performed to measure LVEF is leveraged to obtain additional clinically relevant parameters.</p

A Novel Inactivated Intranasal Respiratory Syncytial Virus Vaccine Promotes Viral Clearance without Th2 Associated Vaccine-Enhanced Disease

Respiratory syncytial virus (RSV) is a leading cause of bronchiolitis and pneumonia in young children worldwide, and no vaccine is currently available. Inactivated RSV vaccines tested in the 1960's led to vaccine-enhanced disease upon viral challenge, which has undermined RSV vaccine development. RSV infection is increasingly being recognized as an important pathogen in the elderly, as well as other individuals with compromised pulmonary immunity. A safe and effective inactivated RSV vaccine would be of tremendous therapeutic benefit to many of these populations.In these preclinical studies, a mouse model was utilized to assess the efficacy of a novel, nanoemulsion-adjuvanted, inactivated mucosal RSV vaccine. Our results demonstrate that NE-RSV immunization induced durable, RSV-specific humoral responses, both systemically and in the lungs. Vaccinated mice exhibited increased protection against subsequent live viral challenge, which was associated with an enhanced Th1/Th17 response. In these studies, NE-RSV vaccinated mice displayed no evidence of Th2 mediated immunopotentiation, as has been previously described for other inactivated RSV vaccines.These studies indicate that nanoemulsion-based inactivated RSV vaccination can augment viral-specific immunity, decrease mucus production and increase viral clearance, without evidence of Th2 immune mediated pathology

pcaGoPromoter - An R Package for Biological and Regulatory Interpretation of Principal Components in Genome-Wide Gene Expression Data

Analyzing data obtained from genome-wide gene expression experiments is challenging due to the quantity of variables, the need for multivariate analyses, and the demands of managing large amounts of data. Here we present the R package pcaGoPromoter, which facilitates the interpretation of genome-wide expression data and overcomes the aforementioned problems. In the first step, principal component analysis (PCA) is applied to survey any differences between experiments and possible groupings. The next step is the interpretation of the principal components with respect to both biological function and regulation by predicted transcription factor binding sites. The robustness of the results is evaluated using cross-validation, and illustrative plots of PCA scores and gene ontology terms are available. pcaGoPromoter works with any platform that uses gene symbols or Entrez IDs as probe identifiers. In addition, support for several popular Affymetrix GeneChip platforms is provided. To illustrate the features of the pcaGoPromoter package a serum stimulation experiment was performed and the genome-wide gene expression in the resulting samples was profiled using the Affymetrix Human Genome U133 Plus 2.0 chip. Array data were analyzed using pcaGoPromoter package tools, resulting in a clear separation of the experiments into three groups: controls, serum only and serum with inhibitor. Functional annotation of the axes in the PCA score plot showed the expected serum-promoted biological processes, e.g., cell cycle progression and the predicted involvement of expected transcription factors, including E2F. In addition, unexpected results, e.g., cholesterol synthesis in serum-depleted cells and NF-κB activation in inhibitor treated cells, were noted. In summary, the pcaGoPromoter R package provides a collection of tools for analyzing gene expression data. These tools give an overview of the input data via PCA, functional interpretation by gene ontology terms (biological processes), and an indication of the involvement of possible transcription factors

Mapping of HNF4α target genes in intestinal epithelial cells

© 2009 Boyd et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

The Cytosolic Domain of Fis1 Binds and Reversibly Clusters Lipid Vesicles

Every lipid membrane fission event involves the association of two apposing bilayers, mediated by proteins that can promote membrane curvature, fusion and fission. We tested the hypothesis that Fis1, a tail-anchored protein involved in mitochondrial and peroxisomal fission, promotes changes in membrane structure. We found that the cytosolic domain of Fis1 alone binds lipid vesicles, which is enhanced upon protonation and increasing concentrations of anionic phospholipids. Fluorescence and circular dichroism data indicate that the cytosolic domain undergoes a membrane-induced conformational change that buries two tryptophan side chains upon membrane binding. Light scattering and electron microscopy data show that membrane binding promotes lipid vesicle clustering. Remarkably, this vesicle clustering is reversible and vesicles largely retain their original shape and size. This raises the possibility that the Fis1 cytosolic domain might act in membrane fission by promoting a reversible membrane association, a necessary step in membrane fission

Correction: Pervasive gaps in Amazonian ecological research

In the original version of the article, the authors incorrectly stated the value of current and projected deforestation in the results: the values should be 23.50% and 27.29%, respectively. This error does not impact the results or conclusions presented in the paper. The error has now been corrected online. The authors apologize for the error and any confusion that may have resulted

Design concepts for the Cherenkov Telescope Array CTA: an advanced facility for ground-based high-energy gamma-ray astronomy

Ground-based gamma-ray astronomy has had a major breakthrough with the impressive results obtained using systems of imaging atmospheric Cherenkov telescopes. Ground-based gamma-ray astronomy has a huge potential in astrophysics, particle physics and cosmology. CTA is an international initiative to build the next generation instrument, with a factor of 5-10 improvement in sensitivity in the 100 GeV-10 TeV range and the extension to energies well below 100 GeV and above 100 TeV. CTA will consist of two arrays (one in the north, one in the south) for full sky coverage and will be operated as open observatory. The design of CTA is based on currently available technology. This document reports on the status and presents the major design concepts of CTA

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear understanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5,6,7 vast areas of the tropics remain understudied.8,9,10,11 In the American tropics, Amazonia stands out as the world's most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepresented in biodiversity databases.13,14,15 To worsen this situation, human-induced modifications16,17 may eliminate pieces of the Amazon's biodiversity puzzle before we can use them to understand how ecological communities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple organism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region's vulnerability to environmental change. 15%–18% of the most neglected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lost