A comparison of earthwork designs for railway transition zones

Railway track transitions are zones where there is an abrupt change in the track-ground structure. They are often the location of rapid track deterioration, which means more frequent track maintenance is needed compared to plain line tracks. With the aim of reducing maintenance, modern transition zone designs use tapered stiffness earthwork profiles to minimise train-track dynamics. However, there has been limited comparison regarding the effect of different tapered profiles on dynamic behaviour. Therefore, this paper's novelty is the investigation of the performance of different earthwork designs in smoothing stiffness transition's considering different types of improvement and also train speed. To do so, first a 3D finite element track model is developed, with support conditions transitioning from an earth embankment onto a concrete bridge. A dynamic moving train load is simulated using a rigid multi-body approach capable of accounting for train-track interaction. The model is used to study the effect of four earthwork solutions with differing stiffness tapers. For each scenario, two different track structure types (ballast and concrete slab) are considered, along with different magnitudes of ground improvement. Lastly, the effects of train speed are explored. It is found tapered earthwork solutions for ballasted tracks show greater dynamic improvement compared to slabs due to their reduced bending stiffness. Further, the more complex improvement geometries such as double trapezoid shapes offer some additional improvement at locations within 3 m of the bridge. However, when considering such tapered stiffness-based earthwork solutions, additional factors such as constructability must also be considered

The Influence of Train Running Direction and Track Supports Position on the Behaviour of Transition Zones

Different types of track infrastructure can be found along railway lines. Separation zones between these different types of structures are the source of a lot of problems. Transition zones on a railway line represent a gradual solution for the problems between conventional railway structure and singular structures located at different points along the line. The different nature, positioning and geometry used with the materials generate changes in thestiffness on both sides of these singular zones leading to an increase in wear and a loss of geometry, with the associated maintenance costs.This article describes the use of mathematical modelling to represent the behaviour of these zones as a function of train running direction and track supports. Available research into transition zones has not studied these separation points where high increases in load aregenerated for very short periods of time.Finite elements are used to model two types of track (conventional ballasted track and slab track), using a vehicle to dynamically simulate the behaviour in these zones as a function of train running direction and the position of track supports. The magnitudes analysed were the vertical stresses and the vertical displacements under the sleepers and the supports in both types of structure.The results show increased stresses at the separation zone between both structures which varied in magnitude and position depending most of track supports’ location than the train running direction

An inactivated Vero cell-grown Japanese encephalitis vaccine formulated with Advax, a novel inulin-based adjuvant, induces protective neutralizing antibody against homologous and heterologous flaviviruses

Advax is a polysaccharide-based adjuvant that potently stimulates vaccine immunogenicity without the increased reactogenicity seen with other adjuvants. This study investigated the immunogenicity of a novel Advax-adjuvanted Vero cell culture candidate vaccine against Japanese encephalitis virus (JEV) in mice and horses. The results showed that, in mice, a two-immunization, low-dose (50 ng JEV antigen) regimen with adjuvanted vaccine produced solid neutralizing immunity comparable to that elicited with live ChimeriVax-JE immunization and superior to that elicited with tenfold higher doses of a traditional non-adjuvanted JEV vaccine (JE-VAX; Biken Institute) or a newly approved alum-adjuvanted vaccine (Jespect; Novartis). Mice vaccinated with the Advax-adjuvanted, but not the unadjuvanted vaccine, were protected against live JEV challenge. Equine immunizations against JEV with Advax-formulated vaccine similarly showed enhanced vaccine immunogenicity, confirming that the adjuvant effects of Advax are not restricted to rodent models. Advax-adjuvanted JEV vaccine elicited a balanced T-helper 1 (Th1)/Th2 immune response against JEV with protective levels of cross-neutralizing antibody against other viruses belonging to the JEV serocomplex, including Murray Valley encephalitis virus (MVEV). The adjuvanted JEV vaccine was well tolerated with minimal reactogenicity and no systemic toxicity in immunized animals. The cessation of manufacture of traditional mouse brain-derived unadjuvanted JEV vaccine in Japan has resulted in a JEV vaccine shortage internationally. There is also an ongoing lack of human vaccines against other JEV serocomplex flaviviruses, such as MVEV, making this adjuvanted, cell culture-grown JEV vaccine a promising candidate to address both needs with one vaccine

Intragenus competition between coccolithoviruses: an insight on how a select few can come to dominate many

Viruses are a major cause of coccolithophore bloom demise in both temperate and sub-temperate oceanic regions. Most infection studies on coccolithoviruses have been conducted with a single virus strain, and the effect of intragenus competition by closely related coccolithoviruses has been ignored. Here we conducted combined infection experiments, infecting Emiliania huxleyi CCMP 2090 with two coccolithoviruses: EhV-86 and EhV-207 both simultaneously and independently. EhV-207 displayed a shorter lytic cycle and increased production potential than EhV-86 and was remarkably superior under competitive conditions. Although the viruses displayed identical adsorption kinetics in the first 2 h post infection, EhV-207 gained a numerical advantage as early as 8 h post infection. Quantitative polymerase chain reaction (PCR) revealed that when infecting in combination, EhV-207 was not affected by the presence of EhV-86, whereas EhV-86 was quickly out-competed, and a significant reduction in free and cell-associated EhV-86 was seen as early as 2 days after the initial infection. The observation of such clear phenotypic differences between genetically distinct, yet similar, coccolithovirus strains, by flow cytometry and quantitative real-time PCR allowed tentative links to the burgeoning genomic, transcriptomic and metabolic data to be made and the factors driving their selection, in particular to the de novo coccolithovirus-encoded sphingolipid biosynthesis pathway. This work illustrates that, even within a family, not all viruses are created equally, and the potential exists for relatively small genetic changes to infer disproportionately large competitive advantages for one coccolithovirus over another, ultimately leading to a few viruses dominating the many

Discrepancies in the Tumor Microenvironment of Spontaneous and Orthotopic Murine Models of Pancreatic Cancer Uncover a New Immunostimulatory Phenotype for B Cells.

B cells are salient features of pancreatic ductal adenocarcinoma (PDAC) tumors, yet their role in this disease remains controversial. Murine studies have indicated a protumoral role for B cells, whereas clinical data show tumor-infiltrating B cells are a positive prognostic factor, both in PDAC and other cancers. This disparity needs to be clarified in order to develop effective immunotherapies. In this study, we provide new evidence that reconcile human and mouse data and highlight the importance of using relevant preclinical tumor models when assessing B cell function. We compared B cell infiltration and activation in both a genetic model of murine PDAC (KPC mouse) and an injectable orthotopic model. A pronounced B cell infiltrate was only observed in KPC tumors and correlated with T cell infiltration, mirroring human disease. In contrast, orthotopic tumors exhibited a relative paucity of B cells. Accordingly, KPC-derived B cells displayed markers of B cell activation (germinal center entry, B cell memory, and plasma cell differentiation) accompanied by significant intratumoral immunoglobulin deposition, a feature markedly weaker in orthotopic tumors. Tumor immunoglobulins, however, did not appear to form immune complexes. Furthermore, in contrast to the current paradigm that tumor B cells are immunosuppressive, when assessed as a bulk population, intratumoral B cells upregulated several proinflammatory and immunostimulatory genes, a distinctly different phenotype to that of splenic-derived B cells; further highlighting the importance of studying tumor-infiltrating B cells over B cells from secondary lymphoid organs. In agreement with the current literature, genetic deletion of B cells (μMT mice) resulted in reduced orthotopic tumor growth, however, this was not recapitulated by treatment with B-cell-depleting anti-CD20 antibody and, more importantly, was not observed in anti-CD20-treated KPC mice. This suggests the result from B cell deficient mice might be caused by their altered immune system, rather than lack of B cells. Therefore, our data indicate B cells do not favor tumor progression. In conclusion, our analysis of relevant preclinical models shows B cells to be active members of the tumor microenvironment, producing immunostimulatory factors that might support the adaptive antitumor immune response, as suggested by human PDAC studies

Analysis of antibody and T helper lymphocyte modulation by lactate dehydrogenase-elevating virus

Notre laboratoire a montré que le lactate dehydrogenase-elevating virus (LDV) induit, en plus de la production d’anticorps antiviraux, une activation polyclonale des lymphocytes B et un effet adjuvant sur les réponses anti-protéine concomitants à l’infection. Après infection, toutes ces réponses sont caractérisées par une forte augmentation de l’isotype IgG2a. De plus, le LDV inhibe fortement les réponses de type Th2. Par le présent travail, nous avosn voulu comprendre les mécanismes par lesquels le LDV induit ces effets sur le système immunitaire. D’abord, en utilisant du virus inactivé aux utlraviolets, nous avons montré que le caractère IgG2a très marqué de la réponse antivirale était lié au processus infectieux et non pas au type d’antigène impliqué. Ensuite, nous avons étudiés le rôle de l’interleukine 6 (IL-6) et de l’interféron-gamme (IFG-γ), connus pour leur activité sur la prolifération et la différenciation des lymphocytes B. L’IL-6 est produite 18 heures après l’infection par le LDV sans doute par les macrophages, et non par les lymphocytes T. Quant à l’IFN-γ, un pic de production est détecté 18 heures après l’injection. Il semble que la population de cellules NK/T (natural killer/T) et probablement les cellules NK soient impliquées dans cette production. En utilisant des souris déficientes en IL_6, nous avons constaté que la prolifération des lymphocytes B, mesurée par incorporation de thymidine tritiée, n’était pas modifiée par l’absence de cette cytokine. Par contre, les souris déficientes pour le récepteur de l’IFN-γ, les IgG2a anti-LDV sont réduites, mais les IgG2a totales sont relativement peu affectées. Ces résultats indiquent que différentes voies pourraient mener au biais isotypique induit par le virus. Il reste à établie si cette différence implique des sous-populations distinctes de lymphocytes B ou différentes stades d’activation de ces cellules. D(un autre côté, chez les souris déficientes pour le récepteur de l’OFN-γ, le LDV n’inhibe pas l’expression et la sécrétion de cytokine Th2, qui surviennent normalement après immunisation contre un antigène protéique soluble, ce qui suggère un rôle critique de l’IFN-γ dans la modulation de la différenciation Th1/Th2 par l’infection virale. Finalement, pour analyser le rôle de l’isotype dans les propriétés fonctionnelles des anticorps antiviraux, nous avons isolé à partir d’un hybridome sécrétant une IgG3 anti-VP-3 LDV, les trois « switch variants », IgG1, IgG2b et IgG2a. L’IgG3, seul, neutralise nettement le virus in vitro. Par contre, c’est l’IgG2a anti-VP-3 LDV qui retarde le plus l’apparition de la polioencéphalomyétrie (PEM) induite par le LDV et réduit le plus les symptômes de la maladie par rapport aux autres sous-classes. Les mécanismes de neutralisation in vitro et de prévention de le PEM semblent dès lors différents et dépendre au moins partiellement de la région Fc des anticorpsIt has been shown previously in the laboratory that lactate dehydrogenase-elevating virus (LDV) triggers, in addition to antiviral antibodies, a B lymphocyte polyclonal activation and an adjuvant effect on concomitant antibody responses against unrelated antigens. All these responses are characterized by a marked increase in the proportion of the IgG2asublass. Moreover, LDV strongly inhibits the Th2 cytokine expression. The purpose of our work was to gain an insight into the mechanisms by which LDV induces these effects on the immune system. First, we observed that the antiviral IG2a preponderance is related to the infections process itself rather than to the type of antigen involved. Then, we studied the role of interleukin-6 (IL-6) and interferon-gamma (IFN-γ), known for their activity on B cell proliferation and differentiation. IL-6 was secreted 18 hours after LDV infection most probably by macrophages and not by T lymphocytes. An increased production of IFN-γ was also detected, with a peak at 18 hours post-infection. The NK/T (natural killer/T) cell population and possibly NK cells were involved in the IFN-γ production. By using IL-6 deficient mice, we showed that the proliferation of B cells, measured by thymine incorporation, was similar in IL-6 deficient mice and normal mice. However, IL-6-deficient mice showed a marked decrease in their total IgG2a production, whereas their antiviral OgG2a production was not changed. In contrast, IgG2a anti-LDV was reduced in mice lacking IFN-γ receptor, but total IgG2a responses were relatively unaffected. These results indicate that different pathways can lead to the virally induced IgG2a restriction. Whether this difference implicates distinct B cell subpopulations or involves different stages of B cell activation remains to be determined. Moreover, the inhibition by LDV of TH2 cytokine expression and production after immunization with keyhole limpet hemicyanin (KLH), a soluble protein antigen, was not observed in mice lacking IFN-γ receptor, suggesting a critical role for this cytokine in the viral modulation of T helper differentiation. Finally, we studied the role of the isotype in the functional properties of antiviral antibodies with IgG1, IgG2b and IgG2a “switch variants” derived from an IgG3 anti-VP-3 LDV hybridoma. IgG3 was the only isotype able to neutralize LDV in vitro. The efficacy of each of the switch variants in the protection from LDV-induced polioencephalomyelitis (PEM) was also compared. Here, IgG2a anti-VP-3 LDV appeared to delay the onset of the paralysis and to reduce the severity of the disease, better than the other subclasses. The mechanisms of in vitro neutralization and of prevention of PEM seem therefore different, but to depend at least partly on the Fc part of these antibodiesThèse de doctorat en sciences pharmaceutiques-- UCL, 200