A protective role of gamma/delta T cells in primary infection with Listeria monocytogenes in mice.

We have previously reported that T cells bearing T cell receptors (TCRs) of gamma/delta type appear at a relatively early stage of primary infection with Listeria monocytogenes in mice. To characterize the early-appearing gamma/delta T cells during listeriosis, we analyzed the specificity and cytokine production of the gamma/delta T cells in the peritoneal cavity in mice inoculated intraperitoneally with a sublethal dose of L. monocytogenes. The early-appearing gamma/delta T cells, most of which were of CD4-CD8- phenotype, proliferated and secreted IFN-gamma and macrophage chemotactic factor in response to purified protein derivative from Mycobacterium tuberculosis, or recombinant 65-kD heat-shock protein derived from M. bovis but not to heat-killed Listeria. To further elucidate the potential role of the gamma/delta T cells in the host-defense mechanism against primary infection with Listeria, we examined the effects of in vivo administration of monoclonal antibodies (mAbs) against TCR-gamma/delta or TCR-alpha/beta on the bacterial eradication in mice infected with Listeria. Most of alpha/beta T cells or gamma/delta T cells were depleted in the peripheral lymphoid organs at least for 12 d after an intraperitoneal injection of 200 micrograms TCR-alpha/beta mAb or 200 micrograms TCR-gamma/delta mAb, respectively. An exaggerated bacterial multiplication was evident at the early stage of listerial infection in the gamma/delta T cells-depleted mice, whereas the alpha/beta T cell-depleted mice exhibited much the same resistance level as the control mice at this stage although the resistance was severely impaired at the late stage after listerial infection.(ABSTRACT TRUNCATED AT 250 WORDS

Fatigue life prediction of bridges considering the effect of Multiaxial stresses

This paper presents a new low cycle fatigue model to predict life of steel bridges. It consists of Coffin-Manson strain-life curve with a new strain based damage index. The damage variable is based on a modified von Mises equivalent strain to account for effects of loading non-proportionality and strain path orientation in low cycle multiaxial stress state. The proposed model was verified by comparing with experimental test results of two materials. Then, it was applied an existing riveted wrought iron railway bridge to estimate fatigue life due to usual traffic and earthquake loadings. The obtained results verify the importance and effectiveness of the proposed model over commonly used Miner’s rule model in fatigue life estimation of steel bridges

Combined high and low cycle fatigue model for prediction of Steel bridge lives

A new fatigue model is presented to predict life of steel bridges for combined high and low cycle fatigue. It consists of a modified strain-life curve and a new strain based damage index. The damage variable is based on a modified von Mises equivalent strain to account for effects of loading non-proportionality and strain path orientation in multiaxial stress state. The proposed model was verified with experimental test results of two materials, available in the literature. Then, the proposed model was applied to a wrought iron railway bridge to estimate the fatigue life due to usual traffic and earthquake loadings. The obtained results confirm the importance and effectiveness of the proposed model over commonly used Miner’s rule based life prediction of steel bridges

Numerical study on remaining strength prediction of corroded Steel bridge plates

Corrosion causes strength deterioration of aged steel infrastructures and hence careful evaluation of their remaining load-carrying capacities are of high importance in maintenance engineering. To develop a more reliable strength estimation technique, only experimental approach is not enough as actual corroded surfaces are different from each other. However in modern practices, numerical simulation is being used to replace the time-consuming and expensive experimental work and to comprehend on the lack of knowledge of mechanical behavior, stress distribution, ultimate behavior and so on. Therefore, using of numerical analysis method will give important knowledge not only for strength estimation but also for subsequent repair and retrofitting plan. The results of non-linear FEM analysis of many actual corroded plates with different corrosion conditions and comparison of them with the respective tensile coupon tests results are presented in this paper. Further, the feasibility of establishing of an analytical methodology to predict the residual strength capacities of a corroded steel member with fewer number of measuring points are also discussed

Maintenance strategy for bridges using reliability concept and analytical hierarchy process

Civil infrastructure in most of countries is getting old and therefore, there is a tremendous need to assess their safety levels. Among civil infrastructure, bridges are one of the main components and there is a need to study more on their safety and durability to minimize the maintenance cost and to avoid sudden failures. This paper presents bridge maintenance strategy which consists of two parts: (1) reliability based condition assessment procedure and; (2) analytical hierarchy process (AHP) based resources prioritization. In reliability based assessment, safety margins are initially proposed depending on the types of bridges. It is assumed that load and strength are random variables. Elementary reliability indices and thereby elementary failure probabilities are estimated for each safety margins. Then, system failure probability of the bridge is calculated for the time of consideration. Finally, this system failure probability is used to get system reliability index of the bridge and it is used as an index to express the condition of the bridge for the considered time. Secondly, AHP is implemented to identify the order of resources prioritization among set of bridges. The selected criteria are safety, cost of maintenance actions and relative importance of the bridge. Relative importance varies depending on historical importance, age and route of bridge location. The proposed methodology is applied to a collection of five bridges in Sri Lanka to estimate their safety levels and resources prioritization in bridge maintenance

Tumor-Derived Microvesicles Induce Proangiogenic Phenotype in Endothelial Cells via Endocytosis

Background: Increasing evidence indicates that tumor endothelial cells (TEC) differ from normal endothelial cells (NEC). Our previous reports also showed that TEC were different from NEC. For example, TEC have chromosomal abnormality and proangiogenic properties such as high motility and proliferative activity. However, the mechanism by which TEC acquire a specific character remains unclear. To investigate this mechanism, we focused on tumor-derived microvesicles (TMV). Recent studies have shown that TMV contain numerous types of bioactive molecules and affect normal stromal cells in the tumor microenvironment. However, most of the functional mechanisms of TMV remain unclear. Methodology/Principal Findings: Here we showed that TMV isolated from tumor cells were taken up by NEC through endocytosis. In addition, we found that TMV promoted random motility and tube formation through the activation of the phosphoinositide 3-kinase/Akt pathway in NEC. Moreover, the effects induced by TMV were inhibited by the endocytosis inhibitor dynasore. Our results indicate that TMV could confer proangiogenic properties to NEC partly via endocytosis. Conclusion: We for the first time showed that endocytosis of TMV contributes to tumor angiogenesis. These findings offer new insights into cancer therapies and the crosstalk between tumor and endothelial cells mediated by TMV in the tumor microenvironment

Multi-cancer computational analysis reveals invasion-associated variant of desmoplastic reaction involving INHBA, THBS2 and COL11A1

<p>Abstract</p> <p>Background</p> <p>Despite extensive research, the details of the biological mechanisms by which cancer cells acquire motility and invasiveness are largely unknown. This study identifies an invasion associated gene signature shedding light on these mechanisms.</p> <p>Methods</p> <p>We analyze data from multiple cancers using a novel computational method identifying sets of genes whose coordinated overexpression indicates the presence of a particular phenotype, in this case high-stage cancer.</p> <p>Results</p> <p>We conclude that there is one shared "core" metastasis-associated gene expression signature corresponding to a specific variant of stromal desmoplastic reaction, present in a large subset of samples that have exceeded a threshold of invasive transition specific to each cancer, indicating that the corresponding biological mechanism is triggered at that point. For example this threshold is reached at stage IIIc in ovarian cancer and at stage II in colorectal cancer. Therefore, its presence indicates that the corresponding stage has been reached. It has several features, such as coordinated overexpression of particular collagens, mainly <it>COL11A1 </it>and other genes, mainly <it>THBS2 </it>and <it>INHBA</it>. The composition of the overexpressed genes indicates invasion-facilitating altered proteolysis in the extracellular matrix. The prominent presence in the signature of INHBA in all cancers strongly suggests a biological mechanism centered on activin A induced TGF-β signaling, because activin A is a member of the TGF-β superfamily consisting of an INHBA homodimer. Furthermore, we establish that the signature is predictive of neoadjuvant therapy response in at least one breast cancer data set.</p> <p>Conclusions</p> <p>Therefore, these results can be used for developing high specificity biomarkers sensing cancer invasion and predicting response to neoadjuvant therapy, as well as potential multi-cancer metastasis inhibiting therapeutics targeting the corresponding biological mechanism.</p

Novel Mouse Xenograft Models Reveal a Critical Role of CD4+ T Cells in the Proliferation of EBV-Infected T and NK Cells

Epstein-Barr virus (EBV), a ubiquitous B-lymphotropic herpesvirus, ectopically infects T or NK cells to cause severe diseases of unknown pathogenesis, including chronic active EBV infection (CAEBV) and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). We developed xenograft models of CAEBV and EBV-HLH by transplanting patients' PBMC to immunodeficient mice of the NOD/Shi-scid/IL-2Rγnull strain. In these models, EBV-infected T, NK, or B cells proliferated systemically and reproduced histological characteristics of the two diseases. Analysis of the TCR repertoire expression revealed that identical predominant EBV-infected T-cell clones proliferated in patients and corresponding mice transplanted with their PBMC. Expression of the EBV nuclear antigen 1 (EBNA1), the latent membrane protein 1 (LMP1), and LMP2, but not EBNA2, in the engrafted cells is consistent with the latency II program of EBV gene expression known in CAEBV. High levels of human cytokines, including IL-8, IFN-γ, and RANTES, were detected in the peripheral blood of the model mice, mirroring hypercytokinemia characteristic to both CAEBV and EBV-HLH. Transplantation of individual immunophenotypic subsets isolated from patients' PBMC as well as that of various combinations of these subsets revealed a critical role of CD4+ T cells in the engraftment of EBV-infected T and NK cells. In accordance with this finding, in vivo depletion of CD4+ T cells by the administration of the OKT4 antibody following transplantation of PBMC prevented the engraftment of EBV-infected T and NK cells. This is the first report of animal models of CAEBV and EBV-HLH that are expected to be useful tools in the development of novel therapeutic strategies for the treatment of the diseases