TNF-α modulates the migratory response of mesenchymal stem cells to TRAIL

The number of circulating mesenchymal stem cells (MSC), analyzed after acute myocardial infarction (AMI), was lower in AMI patients who developed heart failure (HF) in the follow-up. Conversely, the circulating levels of tumor necrosis factor (TNF)-α, and osteoprotegerin (OPG) were higher in AMI patients who developed HF with respect to the patients who did not develop HF. In vitro exposure to TNF-α enhanced the migration of MSC in response to TNF-related apoptosis-inducing ligand (TRAIL) and significantly increased the release of OPG by endothelial cells. On the contrary, OPG dose-dependently neutralized the in vitro pro-migratory activity of TRAIL. Thus, TNF-α exhibits opposite effects on MSC migration driven by TRAIL: it is capable of potentiating MSC migration as well as of inhibiting MSC migration as an indirect consequence of OPG induction, which might result in a suboptimal recruitment of circulating MSC after AMI in those patients who develop HF in the follow-up.     

Multiple roles for the actin cytoskeleton during regulated exocytosis

Regulated exocytosis is the main mechanism utilized by specialized secretory cells to deliver molecules to the cell surface by virtue of membranous containers (i.e., secretory vesicles). The process involves a series of highly coordinated and sequential steps, which include the biogenesis of the vesicles, their delivery to the cell periphery, their fusion with the plasma membrane, and the release of their content into the extracellular space. Each of these steps is regulated by the actin cytoskeleton. In this review, we summarize the current knowledge regarding the involvement of actin and its associated molecules during each of the exocytic steps in vertebrates, and suggest that the overall role of the actin cytoskeleton during regulated exocytosis is linked to the architecture and the physiology of the secretory cells under examination. Specifically, in neurons, neuroendocrine, endocrine, and hematopoietic cells, which contain small secretory vesicles that undergo rapid exocytosis (on the order of milliseconds), the actin cytoskeleton plays a role in pre-fusion events, where it acts primarily as a functional barrier and facilitates docking. In exocrine and other secretory cells, which contain large secretory vesicles that undergo slow exocytosis (seconds to minutes), the actin cytoskeleton plays a role in post-fusion events, where it regulates the dynamics of the fusion pore, facilitates the integration of the vesicles into the plasma membrane, provides structural support, and promotes the expulsion of large cargo molecules.     

The Reception of Miller's Ether-Drift Experiments in the USA: The History of a Controversy in Relativity Revolution

This paper analyses documents from several US archives in order to examine the controversy that raged within the US scientific community over Dayton C. Miller's ether-drift experiments. In 1925, Miller announced that his repetitions of the famous Michelson-Morley experiment had shown a slight but positive result: an ether-drift of about 10 kilometres per second. Miller's discovery triggered a long debate in the US scientific community about the validity of Einstein's relativity theories. Between 1926 and 1930 some researchers repeated the Michelson-Morley experiment, but no one found the same effect as Miller had. The inability to confirm Miller's result, paired with the fact that no other ether theory existed that could compete with special relativity theory, made his result an enigmatic one. It thus remained of little interest to the scientific community until 1954, when Robert S. Shankland and three colleagues reanalysed the data and proposed that Miller's periodic fringe shift could be attributed to temperature effects. Whereas most of the scientific community readily accepted this explanation as the conclusion of the matter, some contemporary anti-relativists have contested Shankland's methodology up to now. The historical accounts of Miller's experiments provide contradictory reports of the reaction of the US scientific community and do not analyse the mechanisms of the controversy. I will address this shortcoming with an examination of private correspondence of several actors involved in these experiments between 1921 and 1955. A complex interconnection of epistemic elements, sociological factors, and personal interests played a fundamental role in the closure of this experimental controversy in the early 1930s, as well as in the reception of Shankland's reanalysis in the 1950s.     

Emerging topics and new perspectives on HLA-G

Following the Fifth International Conference on non-classical HLA-G antigens (HLA-G), held in Paris in July 2009, we selected some topics which focus on emerging aspects in the setting of HLA-G functions. In particular, HLA-G molecules could play a role in: (1) various inflammatory disorders, such as multiple sclerosis, intracerebral hemorrhage, gastrointestinal, skin and rheumatic diseases, and asthma, where they may act as immunoregulatory factors; (2) the mechanisms to escape immune surveillance utilized by several viruses, such as human cytomegalovirus, herpes simplex virus type 1, rabies virus, hepatitis C virus, influenza virus type A and human immunodeficiency virus 1 (HIV-1); and (3) cytokine/chemokine network and stem cell transplantation, since they seem to modulate cell migration by the downregulation of chemokine receptor expression and mesenchymal stem cell activity blocking of effector cell functions and the generation of regulatory T cells. However, the immunomodulatory circuits mediated by HLA-G proteins still remain to be clarified.     

Kras regulatory elements and exon 4A determine mutation specificity in lung cancer

Kras is the most frequently mutated ras family member in lung carcinomas, whereas Hras mutations are common in tumors from stratified epithelia such as the skin. Using a Hras knock-in mouse model, we demonstrate that specificity for Kras mutations in lung and Hras mutations in skin tumors is determined by local regulatory elements in the target ras genes. Although the Kras 4A isoform is dispensable for mouse development, it is the most important isoform for lung carcinogenesis in vivo and for the inhibitory effect of wild-type (WT) Kras on the mutant allele. Kras 4A expression is detected in a subpopulation of normal lung epithelial cells, but at very low levels in lung tumors, suggesting that it may not be required for tumor progression. The two Kras isoforms undergo different post-translational modifications; therefore, these findings can have implications for the design of therapeutic strategies for inhibiting oncogenic Kras activity in human cancers.     

Simultaneous Component and Clustering Models for Three-way Data: Within and Between Approaches

In this paper two techniques for units clustering and factorial dimensionality reduction of variables and occasions of a three-mode data set are discussed. These techniques can be seen as the simultaneous version of two procedures based on the sequential application of k-means and Tucker2 algorithms and vice versa. The two techniques, T3Clus and 3Fk-means, have been compared theoretically and empirically by a simulation study. In the latter, it has been noted that neither T3Clus nor 3Fk-means outperforms the other in every case. From these results rises the idea to combine the two techniques in a unique general model, named CT3Clus, having T3Clus and 3Fk-means as special cases. A simulation study follows to show the effectiveness of the proposal.     

Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells

Glioblastoma is a highly angiogenetic malignancy, the neoformed vessels of which are thought to arise by sprouting of pre-existing brain capillaries. The recent demonstration that a population of glioblastoma stem-like cells (GSCs) maintains glioblastomas indicates that the progeny of these cells may not be confined to the neural lineage. Normal neural stem cells are able to differentiate into functional endothelial cells. The connection between neural stem cells and the endothelial compartment seems to be critical in glioblastoma, where cancer stem cells closely interact with the vascular niche and promote angiogenesis through the release of vascular endothelial growth factor (VEGF) and stromal-derived factor 1 (refs 5-9). Here we show that a variable number (range 20-90%, mean 60.7%) of endothelial cells in glioblastoma carry the same genomic alteration as tumour cells, indicating that a significant portion of the vascular endothelium has a neoplastic origin. The vascular endothelium contained a subset of tumorigenic cells that produced highly vascularized anaplastic tumours with areas of vasculogenic mimicry in immunocompromised mice. In vitro culture of GSCs in endothelial conditions generated progeny with phenotypic and functional features of endothelial cells. Likewise, orthotopic or subcutaneous injection of GSCs in immunocompromised mice produced tumour xenografts, the vessels of which were primarily composed of human endothelial cells. Selective targeting of endothelial cells generated by GSCs in mouse xenografts resulted in tumour reduction and degeneration, indicating the functional relevance of the GSC-derived endothelial vessels. These findings describe a new mechanism for tumour vasculogenesis and may explain the presence of cancer-derived endothelial-like cells in several malignancies.     

Quality control in the endoplasmic reticulum protein factory

The endoplasmic reticulum (ER) is a factory where secretory proteins are manufactured, and where stringent quality-control systems ensure that only correctly folded proteins are sent to their final destinations. The changing needs of the ER factory are monitored by integrated signalling pathways that constantly adjust the levels of folding assistants. ER chaperones and signalling molecules are emerging as drug targets in amyloidoses and other protein-conformational diseases.     

New finding of micro-diamonds in eclogites from Dabie-Sulu region in central-eastern China

Micro-diamonds were only found ten years ago in eclogite associated with marble at Xindian in the Dabie Mountains. This paper reports our new finding of micro-diamonds not only in eclogites at Maobei in the Sulu region and at Xindian and Laoyoufang in the south part of the Dabie Mountains (South Dabie), but also in eclogites at Baizhangya and Huangweihe in the northern part of the Dabie Mountains (North Dabie) that has usually been considered not to experience ultrahigh pressure metamorphism.Except the micro-diamond at Huangweihe that was found from the artificial heavy sands of zircons used for isotopic dating, the micro-diamonds from other localities were identified in thin sections of the eclogites. Besides a few interstitial grains, most of the micro-diamond grains in thin sections occur as inclusion in garnet. Three crystals of microdiamond at Maobei in the Sulu region are sized in 120, 60 and 30 lira, respectively. Crystal forms look like octahedron and the composite of octahedron and hexahedron. The largest micro-diamond crystal comes from Xindian, which is measured to be 180 lira in diameter with distinct zonal structure and inclusions. The zonal structure occurs as an inclined octahedron inside rounded by an incomplete hexagonal girdle. A smaller micro-diamond inclusion occurs inside the central octahedron, and a larger graphite inclusion is within the outer zone. The Laoyoufang micro-diamond is partially retrograded to graphite. Micro-diamond from the Baizhangya eclogite in the ultramafic rock belt of North Dabie is an aggregate of 70 lira X 90 lira in size. All the micro-diamonds are confirmed by the Raman spectrum analysis. The occurrence of the micro-diamonds from the eclogites in the ultramafic rock belt of North Dabie demonstrates that this region was also subjected to ultrahigh pressure metamorphism as well as the South Dabie did.