Exploring the Potential of Vaccination to Combat Trypanosoma cruzi Infection using Bioluminescent Imaging

Trypanosoma cruzi is the causative agent of Chagas disease. It is responsible for the highest disease burden of any parasitic infection in Latin America. There is no prophylaxis and the only available therapeutic treatments frequently report toxic side-effects. A prophylactic vaccine would provide a valuable tool for reducing the disease burden. Despite this, no vaccine has progressed into clinical testing. A major obstacle has been the lack of available tools to monitor the parasite burden in vivo, particularly during the chronic stage. Here, we have applied highly sensitive bioluminescent imaging technology to develop our understanding of vaccination strategies aimed at combating T. cruzi infection in mice. First, we applied the system to test a viral vectored vaccine, designed to express two leading T. cruzi vaccine targets (ASP2 and TS). Although this reduced the parasite burden during the acute stage (~70%), it had no long term impact on the course of the infection. We then assessed how this outcome compared to protection conferred by drug cured natural infections. We found that the level of protection was considerably greater than that achieved with viral vaccines (>99%, with several instances of sterile protection) and that the degree of protection was associated with the T. cruzi-specific IFN-γ+ T cell response. We also utilised the in vivo bioluminescence model to investigate if induction of gut inflammation could cure chronically infected mice. By administering a chemical inducer of colitis, we assessed the feasibility of eliminating T. cruzi from the colon, a major parasitological niche in the chronic stage. Finally, we sought to develop attenuated parasites to use as tools for studying live attenuated vaccination by generating null mutant strains of T. cruzi using Cas9 genome engineering. This thesis therefore highlights some of the applications of highly sensitive bioluminescent imaging in furthering our understanding of T. cruzi infection and in accelerating the development of vaccines in the pre-clinical stage

The Higgs System in and Beyond the Standard Model

After the discovery of the Higgs boson particle on the 4th of July of 2012 at the Large Hadron Collider, sited at the european CERN laboratory, we are entering in a fascinating period for Particle Physics where both theorists and experimentalists are devoted to fully understand the features of this new particle and the possible consequences for High Energy Physics of the Higgs system both within and beyond the Standard Model of fundamental particle interactions. This paper is a summary of the lectures given at the third IDPASC school (Santiago de Compostela, Feb. 2013, Spain) addressed to PhD students, and contains a short introduction to the main basic aspects of the Higgs boson particle in and beyond the Standard Model.Comment: 62 pages, 31 figures, Lectures of the IDPASC School at Santiago de Compostela, Spain, February 201

Ceria Entrapped Palladium Novel Composites for Hydrogen Oxidation Reaction in Alkaline Medium

A new heterogeneous catalyst for hydrogen oxidation reaction (HOR), metallic palladium within which nanoparticles of ceria are entrapped, CeO2@Pd, is described. Its preparation is based on a new materials methodology of molecular doping of metals. The metallic matrix, which encages the nanoparticles, is prepared in foam architecture, to ensure easy molecular diffusion. Characterization of the structural properties of the CeO2@Pd composite using SEM, STEM, TEM, XRD, EXAFS and nitrogen adsorption reveals its morphological architecture, which leads to improved catalytic activity. In-situ electrochemical and H2 temperature-programmed reduction (H2-TPR) spectra provide direct experimental evidence of the weakening of Pd‒H bond in the CeO2@Pd composites, relative to pure (undoped) Pd catalysts. Gas diffusion electrodes based on the entrapped CeO2@Pd catalysts demonstrated one order of magnitude higher activity than pure Pd analog in the HOR reaction in an alkaline medium

The comparision of glybenclamide and metformin-loaded bacterial cellulose/gelatin nanofibres produced by a portable electrohydrodynamic gun for diabetic wound healing

Wound dressings made from natural polymers are an important aspect of biomaterials. Protein-based materials are less likely to instigate an immunogenic response and have the capacity to degrade in vivo, also without triggering an inflammatory response. Therefore, gelatin (GEL) was chosen and combined with bacterial cellulose (BC) to produce nanofibres and the potential of an all-natural polymer construct was determined. GEL and BC were successfully electrospun with metformin (Met) and glybenclamide (Gb) using a portable, point of need electrospinning set up. The virgin fibre group exhibited a significant effect on the proliferation of L929 (mouse fibroblast) cells but all fibre samples can safely be applied on wound site without risk of cytotoxicity. According to the results obtained by animal tests, the GEL-BC-Gb group showed better recovery than the GEL-BC-Met group. Diabetic wounds treated with GEL-BC-Met were characterized by moderate re-epithelialization and partially organized granulation tissue. Moderate to complete re-epithelialization and well-formed granulation tissue were observed in diabetic wounds treated with GEL-BC-Gb. The histologic scores obtained on day 14 confirmed that the GEL-BC-Gb group played a stronger wound-healing role compared to the GEL-BC-Met group. The highest decrease of TNF-α level was observed in the GEL-BC-Gb group at the end of the experiment but there is no significant difference between drug-loaded fibre groups. Therefore, topical administration of Met and Gb in a sustained release form has a high potential for diabetic wound healing with high bioavailability and fewer systemic side effects but Gb showed better improvement according to the results of the animal tests

New Sum Rules from Low Energy Compton Scattering on Arbitrary Spin Target

We derive two sum rules by studying the low energy Compton scattering on a target of arbitrary (nonzero) spin j. In the first sum rule, we consider the possibility that the intermediate state in the scattering can have spin |j \pm 1| and the same mass as the target. The second sum rule applies if the theory at hand possesses intermediate narrow resonances with masses different from the mass of the scatterer. These sum rules are generalizations of the Gerasimov-Drell-Hearn-Weinberg sum rule. Along with the requirement of tree level unitarity, they relate different low energy couplings in the theory. Using these sum rules, we show that in certain cases the gyromagnetic ratio can differ from the "natural" value g=2, even at tree level, without spoiling perturbative unitarity. These sum rules can be used as constraints applicable to all supergravity and higher-spin theories that contain particles charged under some U(1) gauge field. In particular, applied to four dimensional N=8 supergravity in a spontaneously broken phase, these sum rules suggest that for the theory to have a good ultraviolet behavior, additional massive states need to be present, such as those coming from the embedding of the N=8 supergravity in type II superstring theory. We also discuss the possible implications of the sum rules for QCD in the large-N_c limit.Comment: 18 pages, v2: discussion on black hole contribution is included, references added; v3: extended discussion in introduction, version to appear in JHE

Composite Materials with Combined Electronic and Ionic Properties

In this work, we develop a new type of composite material that combines both electrocatalytic and ionic properties, by doping a silver metal catalyst with an anion-conducting ionomer at the molecular level. We show that ionomer entrapment into the silver metallic structure is possible, imparting unique properties to the catalytic character of the metallic silver. The novel composite material is tested as the cathode electrode of fuel cells, showing significant improvement in cell performance as compared with the undoped counterpart. This new type of material may then replace the current design of electrodes in advanced fuel cells or other electrochemical devices. The possibility to merge different properties into one composite material by molecular entrapment in metals can open the way to new materials, leading to unexplored fields and applications

On the stability of high-speed milling with spindle speed variation

Spindle speed variation is a well-known technique to suppress regenerative machine tool vibrations, but it is usually considered to be effective only for low spindle speeds. In this paper, the effect of spindle speed variation is analyzed in the high-speed domain for spindle speeds corresponding to the first flip (period doubling) and to the first Hopf lobes. The optimal amplitudes and frequencies of the speed modulations are computed using the semidiscre- tization method. It is shown that period doubling chatter can effectively be suppressed by spindle speed variation, although, the technique is not effective for the quasiperiodic chatter above the Hopf lobe. The results are verified by cutting tests. Some special cases are also discussed where the practical behavior of the system differs from the predicted one in some ways. For these cases, it is pointed out that the concept of stability is understood on the scale of the principal period of the system—that is, the speed modulation period for variable spindle speed machining and the tooth passing period for constant spindle speed machining

A high confidence, manually validated human blood plasma protein reference set

<p>Abstract</p> <p>Background</p> <p>The immense diagnostic potential of human plasma has prompted great interest and effort in cataloging its contents, exemplified by the Human Proteome Organization (HUPO) Plasma Proteome Project (PPP) pilot project. Due to challenges in obtaining a reliable blood plasma protein list, HUPO later re-analysed their own original dataset with a more stringent statistical treatment that resulted in a much reduced list of high confidence (at least 95%) proteins compared with their original findings. In order to facilitate the discovery of novel biomarkers in the future and to realize the full diagnostic potential of blood plasma, we feel that there is still a need for an ultra-high confidence reference list (at least 99% confidence) of blood plasma proteins.</p> <p>Methods</p> <p>To address the complexity and dynamic protein concentration range of the plasma proteome, we employed a linear ion-trap-Fourier transform (LTQ-FT) and a linear ion trap-Orbitrap (LTQ-Orbitrap) for mass spectrometry (MS) analysis. Both instruments allow the measurement of peptide masses in the low ppm range. Furthermore, we employed a statistical score that allows database peptide identification searching using the products of two consecutive stages of tandem mass spectrometry (MS3). The combination of MS3 with very high mass accuracy in the parent peptide allows peptide identification with orders of magnitude more confidence than that typically achieved.</p> <p>Results</p> <p>Herein we established a high confidence set of 697 blood plasma proteins and achieved a high 'average sequence coverage' of more than 14 peptides per protein and a median of 6 peptides per protein. All proteins annotated as belonging to the immunoglobulin family as well as all hypothetical proteins whose peptides completely matched immunoglobulin sequences were excluded from this protein list. We also compared the results of using two high-end MS instruments as well as the use of various peptide and protein separation approaches. Furthermore, we characterized the plasma proteins using cellular localization information, as well as comparing our list of proteins to data from other sources, including the HUPO PPP dataset.</p> <p>Conclusion</p> <p>Superior instrumentation combined with rigorous validation criteria gave rise to a set of 697 plasma proteins in which we have very high confidence, demonstrated by an exceptionally low false peptide identification rate of 0.29%.</p

Hip fracture incidence in the elderly in Austria: An epidemiological study covering the years 1994 to 2006

Mann E, Icks A, Haastert B, Meyer G. Hip fracture incidence in the elderly in Austria: an epidemiological study covering the years 1994 to 2006. BMC Geriatrics. 2008;8(1): 35.Background: Hip fractures in the elderly are a major public health burden. Data concerning secular trends of hip fracture incidence show divergent results for age, sex and regions. In Austria, the hip fracture incidence in the elderly population and trends have not been analysed yet. Methods: Hip fractures in the population of 50 years and above were identified from 1994 to 2006 using the national hospital discharge register. Crude incidences (IR) per 100,000 person years and standardised incidences related to the European population 2006 were analysed. Estimate of age-sex-adjusted changes was determined using Poisson regression (incidence rate ratios, IRRs). Results: The number of hospital admissions due to hip fracture increased from a total number of 11,694 in 1994 to 15,987 in 2006. Crude incidences rates (IR) per 100.000 for men increased from 244.3 (95% confidence interval (CI) 234.8 to 253.7) in 1994 to IR 330.8 (95% CI 320.8 to 340.9) in 2006 and for women from 637.3 (95% CI 624.2 to 650.4) in 1994 to IR 758.7 (95% CI 745.0 to 772.4) in 2006. After adjustment for age and sex the annual hip fracture incidence increase was only small but statistically significant (IRR per year 1.01, 95% CI 1.01 to 1.01, p < 0.01). Change of IRR over the 12 years study period was 13%. It was significantly higher for men (IRR over 12 years 1.21, 95% CI 1.16 to 1.27) than for women (IRR over 12 years 1.10, 95% CI 1.06 to 1.14) (interaction: p = 0.03). Conclusion: In contrast to findings in other countries there is no levelling-off or downward trend of hip fracture incidence from 1994 to 2006 in the Austrian elderly population. Further investigations should aim to evaluate the underlying causes in order to plan effective hip fracture reduction programmes

The Minimal Scale Invariant Extension of the Standard Model

We perform a systematic analysis of an extension of the Standard Model that includes a complex singlet scalar field and is scale invariant at the tree level. We call such a model the Minimal Scale Invariant extension of the Standard Model (MSISM). The tree-level scale invariance of the model is explicitly broken by quantum corrections, which can trigger electroweak symmetry breaking and potentially provide a mechanism for solving the gauge hierarchy problem. Even though the scale invariant Standard Model is not a realistic scenario, the addition of a complex singlet scalar field may result in a perturbative and phenomenologically viable theory. We present a complete classification of the flat directions which may occur in the classical scalar potential of the MSISM. After calculating the one-loop effective potential of the MSISM, we investigate a number of representative scenarios and determine their scalar boson mass spectra, as well as their perturbatively allowed parameter space compatible with electroweak precision data. We discuss the phenomenological implications of these scenarios, in particular, whether they realize explicit or spontaneous CP violation, neutrino masses or provide dark matter candidates. In particular, we find a new minimal scale-invariant model of maximal spontaneous CP violation which can stay perturbative up to Planck-mass energy scales, without introducing an unnaturally large hierarchy in the scalar-potential couplings.Comment: 71 pages, 34 eps figures, numerical error corrected, clarifying comments adde