Evidence that platelet-derived microvesicles may transfer platelet-specific immunoreactive antigens to the surface of endothelial cells and CD34+ hematopoietic stem/ progenitor cells--implication for the pathogenesis of immune thrombocytopenias.

The pathogenesis and tissue damage that accompanies destruction of platelets in immune thrombocytopenias (IT) is still not understood very well and in addition to platelets, other cells (e.g. endothelial cells, CD34+ hematopoietic stem/progenitors) may also become affected. Based on our previous work that platelet antigens (e.g., CD41) may be transferred by platelet-derived microvesicles (PMV) to the surface of other cells, we asked if platelet derived-antigens, especially those that are involved in the formation of anti-platelet antibodies in IT (e.g., against antigen HPA 1 a) could be also transferred by similar mechanism. To address this issue normal human CD34+ cells, human umbilical vein-endothelial cells (HUVEC) and monocytic cell line THP-1 were incubated with PMV derived from HPA1a+ donors. We noticed that the HPA1a antigen is highly expressed on PMV-derived from the HPAla positive platelets and is transferred in PMV-dependent manner to the surface of CD34+ cells, HUVEC and monocytic THP-1 cells. These cells covered with HPA1a positive PMV but not by PMV derived from HPAla negative platelets reacted with anti-HPA1a antibodies derived from the alloimmunized pregnant women. More importantly, human hematopoietic cells that were preincubated with HPA1a+ PMV and subsequently exposed to anti-HPA 1 a serum and human NK cells, become subject to elimination by antibody dependent cell cytotoxicity ADCC. Thus, we postulate that PMV-dependent transfer of antigens may playing an important role in "expanding" the population of target cells that may be affected by anti-platelet antibodies and explain several pathologies that accompany IT (e.g. damage of endothelium, cytopenias)

Evidence that platelet-derived microvesicles may transfer platelet-specific immunoreactive antigens to the surface of endothelial cells and CD34^+ hematopoietic stem/progenitor cells : implication for the pathogenesis of immune thrombocytopenias

The pathogenesis and tissue damage that accompanies destruction of platelets in immune thrombocytopenias (IT) is still not understood very well and in addition to platelets, other cells (e.g. endothelial cells, CD34+ hematopoietic stem/progenitors) may also become affected. Based on our previous work that platelet antigens (e.g., CD41) may be transferred by platelet-derived microvesicles (PMV) to the surface of other cells, we asked if platelet derived-antigens, especially those that are involved in the formation of anti-platelet antibodies in IT (e.g., against antigen HPA 1 a) could be also transferred by similar mechanism. To address this issue normal human CD34+ cells, human umbilical vein-endothelial cells (HUVEC) and monocytic cell line THP-1 were incubated with PMV derived from HPA1a+ donors. We noticed that the HPA1a antigen is highly expressed on PMV-derived from the HPAla positive platelets and is transferred in PMV-dependent manner to the surface of CD34+ cells, HUVEC and monocytic THP-1 cells. These cells covered with HPA1a positive PMV but not by PMV derived from HPAla negative platelets reacted with anti-HPA1a antibodies derived from the alloimmunized pregnant women. More importantly, human hematopoietic cells that were preincubated with HPA1a+ PMV and subsequently exposed to anti-HPA 1 a serum and human NK cells, become subject to elimination by antibody dependent cell cytotoxicity ADCC. Thus, we postulate that PMV-dependent transfer of antigens may playing an important role in "expanding" the population of target cells that may be affected by anti-platelet antibodies and explain several pathologies that accompany IT (e.g. damage of endothelium, cytopenias)

SDF-1 alone and in co-operation with HGF regulates biology of human cervical carcinoma cells

Stromal Derived Factor-1 (SDF-1)-CXCR4 axis plays a pivotal role in biology and metastasis of several tumors. The aim of this study was to see if SDF-1 alone or in combination with Hepatocyte Growth Factor (HGF) affects biology of human cervical carcinoma (HCC) cells. We found that HCC cell lines investigated in our study highly express CXCR4 on their surface. CXCR4 was also expressed on tumor cells in tissue sections derived from cervical cancer patients. At the same time normal cervical epithelium was negative for CXCR4 expression what suggests a strong correlation between CXCR4 and malignant cell phenotype. Subsequently, we studied a potential role of the SDF-1-CXCR4 axis in HCC and noticed that SDF-1 (i) chemoattracted HCC cells, (ii) enhanced their scattering, (iii) stimulated nuclear localization of beta-catenins and upregulated their target gene cyclin D1 and (iv) at the molecular level induced calcium flux and activated RAS-MAPK, PI3-AKT and JAK-STAT pathways. SDF-1-mediated functions were additionally enhanced in the presence of HGF. Thus, our data show that the SDF-1-CXCR4 axis affects biology of HCC cells. Furthermore, we postulate that this axis might become a potential target to prevent progression of cervical cancer

SDF-1 alone and in co-operation with HGF regulates biology of human cervical carcinoma cells.

Stromal Derived Factor-1 (SDF-1)-CXCR4 axis plays a pivotal role in biology and metastasis of several tumors. The aim of this study was to see if SDF-1 alone or in combination with Hepatocyte Growth Factor (HGF) affects biology of human cervical carcinoma (HCC) cells. We found that HCC cell lines investigated in our study highly express CXCR4 on their surface. CXCR4 was also expressed on tumor cells in tissue sections derived from cervical cancer patients. At the same time normal cervical epithelium was negative for CXCR4 expression what suggests a strong correlation between CXCR4 and malignant cell phenotype. Subsequently, we studied a potential role of the SDF-1-CXCR4 axis in HCC and noticed that SDF-1 (i) chemoattracted HCC cells, (ii) enhanced their scattering, (iii) stimulated nuclear localization of beta-catenins and upregulated their target gene cyclin D1 and (iv) at the molecular level induced calcium flux and activated RAS-MAPK, PI3-AKT and JAK-STAT pathways. SDF-1-mediated functions were additionally enhanced in the presence of HGF. Thus, our data show that the SDF-1-CXCR4 axis affects biology of HCC cells. Furthermore, we postulate that this axis might become a potential target to prevent progression of cervical cancer

Sybil tolerance and probabilistic databases to compute web services trust

© Springer International Publishing Switzerland 2015. This paper discusses how Sybil attacks can undermine trust management systems and how to respond to these attacks using advanced techniques such as credibility and probabilistic databases. In such attacks end-users have purposely different identities and hence, can provide inconsistent ratings over the same Web Services. Many existing approaches rely on arbitrary choices to filter out Sybil users and reduce their attack capabilities. However this turns out inefficient. Our approach relies on non-Sybil credible users who provide consistent ratings over Web services and hence, can be trusted. To establish these ratings and debunk Sybil users techniques such as fuzzy-clustering, graph search, and probabilistic databases are adopted. A series of experiments are carried out to demonstrate robustness of our trust approach in presence of Sybil attacks

Quantitative proteomics of patient fibroblasts reveal biomarkers and diagnostic signatures of mitochondrial disease

\ua9 2024, Correia et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.BACKGROUND. Mitochondrial diseases belong to the group of inborn errors of metabolism (IEM), with a prevalence of 1 in 2,000–5,000 individuals. They are the most common form of IEM, but, despite advances in next-generation sequencing technologies, almost half of the patients are left genetically undiagnosed. METHODS. We investigated a cohort of 61 patients with defined mitochondrial disease to improve diagnostics, identify biomarkers, and correlate metabolic pathways to specific disease groups. Clinical presentations were structured using human phenotype ontology terms, and mass spectrometry–based proteomics was performed on primary fibroblasts. Additionally, we integrated 6 patients carrying variants of uncertain significance (VUS) to test proteomics as a diagnostic expansion. RESULTS. Proteomic profiles from patient samples could be classified according to their biochemical and genetic characteristics, with the expression of 5 proteins (GPX4, MORF4L1, MOXD1, MSRA, and TMED9) correlating with the disease cohort, thus acting as putative biomarkers. Pathway analysis showed a deregulation of inflammatory and mitochondrial stress responses. This included the upregulation of glycosphingolipid metabolism and mitochondrial protein import, as well as the downregulation of arachidonic acid metabolism. Furthermore, we could assign pathogenicity to a VUS in MRPS23 by demonstrating the loss of associated mitochondrial ribosome subunits. CONCLUSION. We established mass spectrometry–based proteomics on patient fibroblasts as a viable and versatile tool for diagnosing patients with mitochondrial disease

Highly deformed 40^{40}Ca configurations in 28^{28}Si + 12^{12}C

The possible occurrence of highly deformed configurations in the $^{40}$Ca di-nuclear system formed in the $^{28}$Si + $^{12}$C reaction is investigated by analyzing the spectra of emitted light charged particles. Both inclusive and exclusive measurements of the heavy fragments (A $\geq$ 10) and their associated light charged particles (protons and $\alpha$ particles) have been made at the IReS Strasbourg {\sc VIVITRON} Tandem facility at bombarding energies of $E_{lab} (^{28}$Si) = 112 MeV and 180 MeV by using the {\sc ICARE} charged particle multidetector array. The energy spectra, velocity distributions, and both in-plane and out-of-plane angular correlations of light charged particles are compared to statistical-model calculations using a consistent set of parameters with spin-dependent level densities. The analysis suggests the onset of large nuclear deformation in $^{40}$Ca at high spin.Comment: 33 pages, 11 figure

First Results from KamLAND: Evidence for Reactor Anti-Neutrino Disappearance

KamLAND has been used to measure the flux of $\bar{\nu}_e$'s from distant nuclear reactors. In an exposure of 162 ton$\cdot$yr (145.1 days) the ratio of the number of observed inverse $\beta$-decay events to the expected number of events without disappearance is $0.611\pm 0.085 {\rm (stat)} \pm 0.041 {\rm (syst)}$ for $\bar{\nu}_e$ energies $>$ 3.4 MeV. The deficit of events is inconsistent with the expected rate for standard $\bar{\nu}_e$ propagation at the 99.95% confidence level. In the context of two-flavor neutrino oscillations with CPT invariance, these results exclude all oscillation solutions but the `Large Mixing Angle' solution to the solar neutrino problem using reactor $\bar{\nu}_e$ sources.Comment: 6 pages, 6 figure