Deletion of parasite immune modulatory sequences combined with immune activating signals enhances vaccine mediated protection against filarial nematodes

<p>Background: Filarial nematodes are tissue-dwelling parasites that can be killed by Th2-driven immune effectors, but that have evolved to withstand immune attack and establish chronic infections by suppressing host immunity. As a consequence, the efficacy of a vaccine against filariasis may depend on its capacity to counter parasite-driven immunomodulation.</p> <p>Methodology and Principal Findings: We immunised mice with DNA plasmids expressing functionally-inactivated forms of two immunomodulatory molecules expressed by the filarial parasite Litomosoides sigmodontis: the abundant larval transcript-1 (LsALT) and cysteine protease inhibitor-2 (LsCPI). The mutant proteins enhanced antibody and cytokine responses to live parasite challenge, and led to more leukocyte recruitment to the site of infection than their native forms. The immune response was further enhanced when the antigens were targeted to dendritic cells using a single chain Fv-αDEC205 antibody and co-administered with plasmids that enhance T helper 2 immunity (IL-4) and antigen-presenting cell recruitment (Flt3L, MIP-1α). Mice immunised simultaneously against the mutated forms of LsALT and LsCPI eliminated adult parasites faster and consistently reduced peripheral microfilaraemia. A multifactorial analysis of the immune response revealed that protection was strongly correlated with the production of parasite-specific IgG1 and with the numbers of leukocytes present at the site of infection.</p> <p>Conclusions: We have developed a successful strategy for DNA vaccination against a nematode infection that specifically targets parasite-driven immunosuppression while simultaneously enhancing Th2 immune responses and parasite antigen presentation by dendritic cells.</p&gt

HARPS3 for a roboticized Isaac Newton telescope

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.We present a description of a new instrument development, HARPS3, planned to be installed on an upgraded and roboticized Isaac Newton Telescope by end-2018. HARPS3 will be a high resolution (R = 115,000) echelle spectrograph with a wavelength range from 380-690 nm. It is being built as part of the Terra Hunting Experiment - a future 10 year radial velocity measurement programme to discover Earth-like exoplanets. The instrument design is based on the successful HARPS spectrograph on the 3.6m ESO telescope and HARPS-N on the TNG telescope. The main changes to the design in HARPS3 will be: a customised fibre adapter at the Cassegrain focus providing a stabilised beam feed and on-sky fibre diameter ~ 1.4 arcsec, the implementation of a new continuous flow cryostat to keep the CCD temperature very stable, detailed characterisation of the HARPS3 CCD to map the effective pixel positions and thus provide an improved accuracy wavelength solution, an optimised integrated polarimeter and the instrument integrated into a robotic operation. The robotic operation will optimise our programme which requires our target stars to be measured on a nightly basis. We present an overview of the entire project, including a description of our anticipated robotic operation.R.H. acknowledges the Science and Technologies Facilities Council (STFC) for his PhD studentship award (2015).J.I.G.H. acknowledges financial support from the Spanish Ministry of Economy and Competitiveness (MINECO) under the 2013 Ram´on y Cajal program MINECO RYC-2013-14875.J.I.G.H., R.R., and S.S.T. also acknowledge the Spanish ministry project MINECO AYA2014-56359-P.NP and ES are grateful to Knut and Alice Wallenberg Foundation for a generous support of the Swedish contribution to the THE project.AD acknowledges the support from Russian Foundation for Basic Research as part of research grant 15-52-12371

Characterization of a murine model of monocrotaline pyrrole-induced acute lung injury

<p>Abstract</p> <p>Background</p> <p>New animal models of chronic pulmonary hypertension in mice are needed. The injection of monocrotaline is an established model of pulmonary hypertension in rats. The aim of this study was to establish a murine model of pulmonary hypertension by injection of the active metabolite, monocrotaline pyrrole.</p> <p>Methods</p> <p>Survival studies, computed tomographic scanning, histology, bronchoalveolar lavage were performed, and arterial blood gases and hemodynamics were measured in animals which received an intravenous injection of different doses of monocrotaline pyrrole.</p> <p>Results</p> <p>Monocrotaline pyrrole induced pulmonary hypertension in Sprague Dawley rats. When injected into mice, monocrotaline pyrrole induced dose-dependant mortality in C57Bl6/N and BALB/c mice (dose range 6–15 mg/kg bodyweight). At a dose of 10 mg/kg bodyweight, mice developed a typical early-phase acute lung injury, characterized by lung edema, neutrophil influx, hypoxemia and reduced lung compliance. In the late phase, monocrotaline pyrrole injection resulted in limited lung fibrosis and no obvious pulmonary hypertension.</p> <p>Conclusion</p> <p>Monocrotaline and monocrotaline pyrrole pneumotoxicity substantially differs between the animal species.</p

Sildenafil attenuates pulmonary inflammation and fibrin deposition, mortality and right ventricular hypertrophy in neonatal hyperoxic lung injury

<p>Abstract</p> <p>Background</p> <p>Phosphodiesterase-5 inhibition with sildenafil has been used to treat severe pulmonary hypertension and bronchopulmonary dysplasia (BPD), a chronic lung disease in very preterm infants who were mechanically ventilated for respiratory distress syndrome.</p> <p>Methods</p> <p>Sildenafil treatment was investigated in 2 models of experimental BPD: a lethal neonatal model, in which rat pups were continuously exposed to hyperoxia and treated daily with sildenafil (50–150 mg/kg body weight/day; injected subcutaneously) and a neonatal lung injury-recovery model in which rat pups were exposed to hyperoxia for 9 days, followed by 9 days of recovery in room air and started sildenafil treatment on day 6 of hyperoxia exposure. Parameters investigated include survival, histopathology, fibrin deposition, alveolar vascular leakage, right ventricular hypertrophy, and differential mRNA expression in lung and heart tissue.</p> <p>Results</p> <p>Prophylactic treatment with an optimal dose of sildenafil (2 × 50 mg/kg/day) significantly increased lung cGMP levels, prolonged median survival, reduced fibrin deposition, total protein content in bronchoalveolar lavage fluid, inflammation and septum thickness. Treatment with sildenafil partially corrected the differential mRNA expression of amphiregulin, plasminogen activator inhibitor-1, fibroblast growth factor receptor-4 and vascular endothelial growth factor receptor-2 in the lung and of brain and c-type natriuretic peptides and the natriuretic peptide receptors NPR-A, -B, and -C in the right ventricle. In the lethal and injury-recovery model we demonstrated improved alveolarization and angiogenesis by attenuating mean linear intercept and arteriolar wall thickness and increasing pulmonary blood vessel density, and right ventricular hypertrophy (RVH).</p> <p>Conclusion</p> <p>Sildenafil treatment, started simultaneously with exposure to hyperoxia after birth, prolongs survival, increases pulmonary cGMP levels, reduces the pulmonary inflammatory response, fibrin deposition and RVH, and stimulates alveolarization. Initiation of sildenafil treatment after hyperoxic lung injury and continued during room air recovery improves alveolarization and restores pulmonary angiogenesis and RVH in experimental BPD.</p

The Einstein-Vlasov System/Kinetic Theory

The main purpose of this article is to provide a guide to theorems on global properties of solutions to the Einstein--Vlasov system. This system couples Einstein's equations to a kinetic matter model. Kinetic theory has been an important field of research during several decades in which the main focus has been on non-relativistic and special relativistic physics, i.e., to model the dynamics of neutral gases, plasmas, and Newtonian self-gravitating systems. In 1990, Rendall and Rein initiated a mathematical study of the Einstein--Vlasov system. Since then many theorems on global properties of solutions to this system have been established.Comment: Published version http://www.livingreviews.org/lrr-2011-

'BeSAFE', effect-evaluation of internet-based, tailored safety information combined with personal counselling on parents' child safety behaviours: study design of a randomized controlled trial

Background. Injuries in or around the home are the most important cause of death among children aged 0-4 years old. It is also a major source of morbidity and loss of quality of life. In order to reduce the number of injuries, the Consumer Safety Institute introduced the use of Safety Information Leaflets in the Netherlands to provide safety education to parents of children aged 0-4 years. Despite current safety education, necessary safety behaviours are still not taken by a large number of parents, causing unnecessary risk of injury among young children. In an earlier study an E-health module with internet-based, tailored safety information was developed and applied. It concerns an advice for parents on safety behaviours in their homes regarding their child. The aim of this study is to evaluate the effect of this safety information combined with personal counselling on parents' child safety behaviours. Methods/Design. Parents who are eligible for the regular well-child visit with their child at child age 5-8 months are invited to participate in this study. Participating parents are randomized into one of two groups: 1) internet-based, tailored safety information combined with personal counselling (intervention group), or 2) personal counselling using the Safety Information Leaflets of the Consumer Safety Institute in the Netherlands for children aged 12 to 24 months (control group). All parents receive safety information on safety topics regarding the prevention of falling, poisoning, drowning and burning. Parents of the intervention group will access t