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Three perforated reindeer phalanxes, hitherto unknown, found in the Brînzeni and Duruitoarea Veche caves in the Republic of Moldova, are discussed in comparison with the perforated reindeer phalanx from Poiana Cireșului-Piatra Neamț in Romania, which has anthropic working marks to be considered a genuine wind instrument in the Late Gravettian. Furthermore, a mammalian diaphysis from the Duruitoarea Veche Cave, unfortunately split in two, with four perforations aligned along the length of the bone, is presented in this paper., Cârciumaru Marin, Niţu Elena-Cristina, Obadă Theodor, Cîrstina Ovidiu, Ionuț Lupu Florin, Leu Marian. Wind Instruments in the Mid Upper Palaeolithic of the Eastern Carpathians. In: Annales d'Université "Valahia" Târgovişte. Section d'Archéologie et d'Histoire, Tome 21, 2019. pp. 7-19.

In addition to their undeniable aesthetic value, ornaments are the element that may differentiate the various social groups or individuals belonging to certain groups. More specifically, body decoration is closely related to social identity. The ornament, as a form of communication, has a certain advantage over other means of communication because, once displayed, perhaps even more than language itself, the individual wearing it need not make any effort to deliver his/her message, social sta-tus, their belonging to a group etc. The first adornments used during the Paleolithic are beads, while perforated shells are among the earliest examples of this sort. In a few cases, the perforated shells come from species rarely used in the Paleolithic, brought from long distances, in terms of the settlements in which they were found so, apart from individualizing and characterizing a certain group, they may represent important documents regarding migrations over wide areas and even regarding the origin of a culture. This is shown by new discoveries made in an early Gravettian layer at the Poiana Cireului site (Piatra Neam, north-eastern Romania), dated between 30 ka and 31 ka BP (Niu et al., 2019). The ornaments discovered here include a unique association of perforat-ed shells represented by three species of mollusks: Lithoglyphus naticoide, Litho-glyphus apertus and Homalopoma sanguineum (an exclusively Mediterranean spe-cies). This occupation differs from Central and Eastern European Gravettian tradi-tions through the symbolic behavior of the communities, defined by the use of perfo-rated shells of freshwater and marine (Mediterranean origin) mollusk belonging to species very rarely used in the Palaeolithic. Poiana Cireului is one of the very few Gravettian sites where perforated Homalopoma sanguineum shells were found and is the only Gravettian settlement where Lithoglyphus naticoides shells were used. We present the ornaments discovered and the results of analysis performed to identify the perforation methods and the use-wear traces. The presence of a Mediterranean species at the Poiana Cireului settlement located more than 900 km from the nearest source suggests the connection of communities here with the Mediterranean area. In the light of these new findings, the origin and diffusion of the Gravettian from the Mediterranean to the east of the Carpathians are a hypothesis that should be considered. Niu, E.-C., Crciumaru, M., Nicolae, A., Crstina, O., Lupu, F. I., Leu, M. (2019). Mobility and social identity in the Early Upper Palaeolithic: new personal ornaments from Poiana Cireului site (Piatra Neam, Romania). PLOS ONE, 14 (4), e0214932. https://doi.org/10.1371/journal.pone.0214932

In addition to their undeniable aesthetic value, ornaments are the element that may differentiate the various social groups or individuals belonging to certain groups. More specifically, body decoration is closely related to social identity. The ornament, as a form of communication, has a certain advantage over other means of communication because, once displayed, perhaps even more than language itself, the individual wearing it need not make any effort to deliver his/her message, social sta-tus, their belonging to a group etc. The first adornments used during the Paleolithic are beads, while perforated shells are among the earliest examples of this sort. In a few cases, the perforated shells come from species rarely used in the Paleolithic, brought from long distances, in terms of the settlements in which they were found so, apart from individualizing and characterizing a certain group, they may represent important documents regarding migrations over wide areas and even regarding the origin of a culture. This is shown by new discoveries made in an early Gravettian layer at the Poiana Cireului site (Piatra Neam, north-eastern Romania), dated between 30 ka and 31 ka BP (Niu et al., 2019). The ornaments discovered here include a unique association of perforat-ed shells represented by three species of mollusks: Lithoglyphus naticoide, Litho-glyphus apertus and Homalopoma sanguineum (an exclusively Mediterranean spe-cies). This occupation differs from Central and Eastern European Gravettian tradi-tions through the symbolic behavior of the communities, defined by the use of perfo-rated shells of freshwater and marine (Mediterranean origin) mollusk belonging to species very rarely used in the Palaeolithic. Poiana Cireului is one of the very few Gravettian sites where perforated Homalopoma sanguineum shells were found and is the only Gravettian settlement where Lithoglyphus naticoides shells were used. We present the ornaments discovered and the results of analysis performed to identify the perforation methods and the use-wear traces. The presence of a Mediterranean species at the Poiana Cireului settlement located more than 900 km from the nearest source suggests the connection of communities here with the Mediterranean area. In the light of these new findings, the origin and diffusion of the Gravettian from the Mediterranean to the east of the Carpathians are a hypothesis that should be considered. Niu, E.-C., Crciumaru, M., Nicolae, A., Crstina, O., Lupu, F. I., Leu, M. (2019). Mobility and social identity in the Early Upper Palaeolithic: new personal ornaments from Poiana Cireului site (Piatra Neam, Romania). PLOS ONE, 14 (4), e0214932. https://doi.org/10.1371/journal.pone.0214932

Urokinase-type plasminogen activator (uPA) and its cell surface-receptor (uPAR) regulate cellular functions linked to adhesion and migration and contribute to pericellular proteolysis in tissue remodelling processes. Soluble uPAR (suPAR) is present in the circulation, peritoneal and ascitic fluid and in the cystic fluid from ovarian cancer. We have investigated the origin and the vascular distribution of the soluble receptor, which accounts for 10-20% of the total receptor in vascular endothelial and smooth muscle cells. Phase separation analysis of the cell conditioned media with Triton X-114 indicated that suPAR associates with the aqueous phase, indicative of the absence of the glycolipid anchor. There was a polarized release of suPAR from cultured endothelial cells towards the basolateral direction, whereas the membrane-bound receptor was found preferentially on the apical surface. Both, uPAR and suPAR became upregulated 2-4 fold after activation of protein kinase C with phorbol ester, which required de-novo protein biosynthesis. Interleukin-1beta (IL-1beta), basic fibroblast growth factor (bFGF) or vascular endothelial growth factor increased suPAR release from endothelial cells, whereas platelet derived growth factor-BB, bFGF or IL-1beta stimulated suPAR release from vascular smooth muscle cells. Immune electron microscopy indicated that in atherosclerotic vessels (s)uPAR was observed on cell membranes as well as in the extracellular matrix. These findings indicate that (s)uPAR from vascular cells is upregulated by proangiogenic as well as proatherogenic growth factors and cytokines, is preferentially released towards the basolateral side of endothelial cells and accumulates in the vessel wall.

Angiogenesis and activated blood coagulation are involved in tumor growth and metastasis. Although some have suggested that activation of coagulation in tumors is not linked to activation of platelets, no data exist to either support or refute this concept. However, platelet turnover in cancer patients is often increased, and platelets are carriers of angiogenic growth factors. We hypothesized that platelets are involved in tumor-associated angiogenesis. To obtain evidence supporting this hypothesis, we have studied whether the angiogenic and coagulation pathways and platelets are concomitantly activated in cancer patients with soft tissue sarcomas (STSs) using a novel method to detect activated platelets in tumor specimens. Twelve patients with STS were selected on the basis of having intratumoral accumulation of fluid, which was aspirated. These accumulations demonstrated very high concentrations of vascular endothelial growth factor and coagulation factors (including thrombin-antithrombin-complex). Tumor specimens showed dense vascularization with intense vascular endothelial growth factor expression and the presence of activated platelets. Taken together, these results support the concept that angiogenesis, blood coagulation, and platelets are concomitantly activated in STS and support the hypothesis that platelets contribute to tumor-induced angiogenesis.

Cancer patients treated for venous thromboembolism with low molecular weight heparin (LMWH) have a better survival rate than patients treated with unfractionated heparin (UFH). Because fibrin-associated angiogenesis is an important determinant in the progression and metastasis of many solid tumors, the effects of heparins on in vitro angiogenesis were investigated. Both UFH and LMWH inhibited bFGF-induced proliferation of human microvascular endothelial cells (hMVECs) to the same the extent (36-60%). VEGF(165)-induced proliferation was inhibited to a to a lesser extent (19-33%). Turbidity measurements and electron microscopy showed that the presence of LMWH during polymerization of the fibrin matrix led to a more transparent rigid network with thin fibrin bundles, whereas the presence of UFA resulted in a more opaque more porous network with thick fibrin fibers, We used a human in vitro angiogenesis model, which consisted of hMVECs seeded on top of a fibrin matrix, and stimulated the cells with basic fibroblast growth factor plus tumor necrosis factor Lu to induce capillary-like tubular structures, The formation of capillary-like tubular structures was retarded with matrices polymerized in the presence of LMWH (46% inhibition compared with a control matrix for both 1.5 and 10 units/ml LMWH), whereas matrices polymerized in the presence of UFH facilitated tubular structure formation (72 and 36% stimulation compared with a control matrix for 1.5 and 10 units/ml UFH, respectively). Similar results were obtained for cells stimulated with vascular endothelial growth factor plus tumor necrosis factor alpha. These data demonstrate the inhibitory effect of heparins on proliferation of hMTECs and provide a novel mechanism by which LMWH may affect tumor progression, namely reduced ingrowth of microvascular structures in a fibrinous stroma matrix by rendering it less permissive for invasion

Tissue factor pathway inhibitor (TFPI), the main downregulator of the procoagulant activity of tissue factor·factor VIIa complex, locates in human endothelial cells (EC) in culture as well-defined clusters uniformly distributed both on the cell surface and intracellularly. We here demonstrate by immunofluorescence that TFPI colocalizes in EC with caveolin, urokinase- type plasminogen activator receptor, and glycosphingolipids. The localization of TFPI in caveolae in resting endothelium is proved by double immunogold electron microscopy for TFPI and caveolin. After ultracentrifugation of rat lung or EC homogenates through density gradients of Nycodenz, TFPI was highly enriched at densities of 1.05 to 1.08 g/mL, together with caveolin and alkaline phosphatase. By ELISA, more than half of the cellular TFPI was detected in Triton X-100-insoluble extracts of EC. TFPI incorporates [1- 3H]ethanolamine and is cleaved from the cell surface by phosphatidylinositol-phospholipase C, indicating a specific glycosylphosphatidylinositol-anchorage mechanism for TFPI in the plasma membrane. Clustering of TFPI and its localization in caveolae are dependent on the presence of cholesterol in the membrane. Agonist-induced stimulation of EC caused marked changes of distribution for both TFPI and caveolin at subcellular level, with subsequent increase of the cell surface-associated inhibitory activity toward tissue factor·factor VIIa. Our findings suggest that, beside their function in transcytosis, potocytosis, cell surface proteolysis, and regulation of signal transduction, caveolae also play a direct role in the regulation of EC anticoagulant properties.

In this study, we investigated the role of Ca2+ and G proteins in thrombin-induced acute release (regulated secretion) of tissue-type plasminogen activator (TPA) and yon Willebrand factor (vWF), using a previously described system of primary human umbilical vein endothelial cells (HUVECs). The acute release of TPA and vWF, as induced by α-thrombin, was almost zero after chelation of Ca2+(i), showing that an increase in [Ca2+](i) was required. It did not matter whether the increase in [Ca2+](i) came from an intracellular or extracellular Ca2+ source. Thrombin-induced release of TPA and vWF already started at low [Ca2+](i), around 100 nmol/L. Halfmaximal release was found at a [Ca2+](i) of 261 nmol/L for TPA and at 222 nmol/L for vWF. The Ca2+ signal was transduced to calmodulin, as calmodulin inhibitors inhibited TPA and vWF release. The Ca2+ ionophore ionomycin dose dependently released vWF; half-maximal vWF release occurred at a [Ca2+](i) of 311 nmol/L. In contrast, no TPA release was found at all below a [Ca2+](i) of 500 nmol/L. Thus, below 500 nmol/L [Ca2+](i), an increase in [Ca2+](i) alone was sufficient to induce vWF release but not sufficient to induce TPA release. Protein kinase C did not appear to be involved in TPA or vWF release, as neither an activator nor an inhibitor of protein kinase C significantly influenced release. Inhibition of phospholipase A2 also did not reduce thrombin-induced TPA and vWF release. The involvement of G proteins was studied by using both saponin-permeabilized and intact cells. GDP-β-S, which inhibits heterotrimeric and small G proteins, significantly inhibited thrombin-induced vWF and TPA release from permeabilized cells. A1F4-, which activates heterotrimeric G proteins, induced TPA and vWF release in both intact and permeabilized HUVECs. Preincubation of HUVECs with pertussis toxin significantly inhibited thrombin-induced vWF release, due to inhibition of thrombin-induced Ca2+ influx. Pertussis toxin did not affect ionomycin-induced release. The inhibitory effect of pertussis toxin was less obvious in thrombin-induced TPA release, because it was counterbalanced by a positive effect of the toxin on TPA release. Thus, both inhibitory and stimulatory (pertussis toxin- sensitive) G proteins were involved in TPA release. Therefore, thrombin- induced acute release of TPA and vWF differed in two respects. First, below a [Ca2+](i) of 500 nmol/L, an increase in Ca2+ was sufficient for vWF release but not for TPA release. Second, pertussis toxin-sensitive G proteins were differentially involved in acute TPA and vWF release.