A New Rhinoceros From The Lower Miocene Of The Bugti Hills, Baluchistan, Pakistan: The Earliest Elasmotheriine

The stratigraphical position of the Dera Bugti area (Baluchistan, Pakistan), which yielded the remains described herein, is discussed. Dental and postcranial material attributed to Bugtirhinus praecursor gen. et sp. nov., from the lower Miocene (MN 3) of the same area, is described. This species is the oldest and most primitive member of the elasmotheriine group within Rhinocerotidae (Mammalia). A new diagnosis is established for the Elasmotheriini. Comparison with the other lower and middle Miocene elasmotheriine taxa leads to the tree [Bugtirhinus praecursor [Caementodon oettingenae [other elasmotheriine taxa]]]. An upper Oligocene–lowermost Miocene Asiatic differentiation is suggested for the group, strengthened by a first appearance datum in the Dera Bugti area (lower part of the MN 3). The origin and dispersal of the elasmotheriines throughout Eurasia are discussed and correlated with major faunal exchanges. K ey words : Bugti Hills, Pakistan, Rhinocerotidae, Elasmotheriini, Miocene, biostratigraphy, palaeobiogeography.     

Role of the kinin B1 receptor in insulin homeostasis and pancreatic islet function

Kinins are potent vasoactive peptides generated in blood and tissues by the kallikrein serine proteases. Two distinct kinin receptors have been described, one constitutive (subtype B2) and one inducible (subtype B1), and many physiological functions have been attributed to these receptors, including glucose homeostasis and control of vascular permeability. In this study we show that mice lacking the kinin B1 receptor (B1-/- mice) have lower fasting plasma glucose concentrations but exhibit higher glycemia after feeding when compared to wild-type mice. B1-/- mice also present pancreas abnormalities, characterized by fewer pancreatic islets and lower insulin content, which leads to hypoinsulinemia and reduced insulin release after a glucose load. Nevertheless, an insulin tolerance test indicated higher sensitivity in B1-/- mice. In line with this phenotype, pancreatic vascular permeability was shown to be reduced in B1 receptor-ablated mice. The B1 agonist desArg9bradykinin injected intravenously can induce the release of insulin into serum, and this effect was not observed in the B1-/- mice or in isolated islets. Our data demonstrate the importance of the kinin B1 receptor in the control of pancreatic vascular homeostasis and insulin release, highlighting a new role for this receptor in the pathogenesis of diabetes and related diseases.     

Vaccination of melanoma patients using dendritic cells loaded with an allogeneic tumor cell lysate

The aim of the present phase I/II study was to evaluate the safety, immune responses and clinical activity of a vaccine based on autologous dendritic cells (DC) loaded with an allogeneic tumor cell lysate in advanced melanoma patients. DC derived from monocytes were generated in serum-free medium containing GM-CSF and IL-13 according to Good Manufacturing Practices. Fifteen patients with metastatic melanoma (stage III or IV) received four subcutaneous, intradermal, and intranodal vaccinations of both DC loaded with tumor cell lysate and DC loaded with hepatitis B surface protein (HBs) and/or tetanus toxoid (TT). No grade 3 or 4 adverse events related to the vaccination were observed. Enhanced immunity to the allogeneic tumor cell lysate and to TAA-derived peptides were documented, as well as immune responses to HBs/TT antigens. Four out of nine patients who received the full treatment survived for more than 20 months. Two patients showed signs of clinical response and received 3 additional doses of vaccine: one patient showed regression of in-transit metastases leading to complete remission. Eighteen months later, the patient was still free of disease. The second patient experienced stabilization of lung metastases for approximately 10 months. Overall, our results show that vaccination with DC loaded with an allogeneic melanoma cell lysate was feasible in large-scale and well-tolerated in this group of advanced melanoma patients. Immune responses to tumor-related antigens documented in some treated patients support further investigations to optimize the vaccine formulation. Margarita Salcedo and Nadège Bercovici both contributed equally to this work     

Global diversity of gastrotrichs (Gastrotricha) in fresh waters

The global diversity of inland water Gastrotricha is poorly known, and information is extremely heterogeneous. Gastrotricha have been studied most widely in Europe and America, whereas data from the other continents are scattered or not even available. This scanty information is related to several reasons, first of which is the technical difficulty in collecting and studying microscopic and soft-bodied species. In addition, the research has been limited mostly to the epibenthos and periphyton in lentic waters, and the gastrotrich taxonomy is still under discussion mainly because of the great intraspecific variability. Three of the five freshwater families are widespread or cosmopolitan, and most genera have been reported from at least two continents. There is strong evidence of a high diversity in genera and species in tropical areas. Nearly a half of the freshwater species are known from only one country or even only from one site, but the insufficient faunistic knowledge does not allow defining them as endemic. The phylogenetic relationships and possible evolutionary trends of inland water species of Gastrotricha are outlined. Guest editors: E. V. Balian, C. Lévêque, H. Segers & K. Martens Freshwater Animal Diversity Assessment     

Contribution of phytoliths to the suspended load of biogenic silica in the Nyong basin rivers (Cameroon)

Particulate biogenic silica (BSi) carried by rivers to estuaries and marine sediments is generally assumed to be primarily composed of diatoms. Phytoliths – biogenic opal formed in plants – are found in some marine sediments where they are interpreted to be the result of atmospheric and river inputs. In this study, we evaluate the contribution of phytoliths to the suspended load of rivers of the Nyong basin (Cameroon). BSi (2 μm to 2 mm fraction) in the soils and the rivers range respectively, from 0.9 to 3.9 wt% and from 1.3 to 4 wt%. About 90% of the BSi pool in both soils and river suspended load are composed of phytoliths. Thecamoebians and fresh water diatoms are minor components. The concentrations of BSi and the phytolith assemblages show great similarities between the waters and the soil samples. This result implies that the erosion of top soils is the major source of the suspended load, in good agreement with the transport-limited weathering regime of the study basin.     

Stromal cell-derived factor-1/chemokine (C-X-C motif) ligand 12 stimulates human hepatoma cell growth, migration, and invasion

In addition to their physiologic effects in inflammation and angiogenesis, chemokines are involved in cancer pathology. The aim of this study was to determine whether the chemokine stromal cell-derived factor 1 (SDF-1) induces the growth, migration, and invasion of human hepatoma cells. We show that SDF-1 G protein-coupled receptor, chemokine (C-X-C motif) receptor 4 (CXCR4), and SDF-1 mRNA are expressed in human hepatoma Huh7 cells, which secrete and bind SDF-1. This binding depends on CXCR4 and glycosaminoglycans. SDF-1 associates with CXCR4, and syndecan-4 (SDC-4), a heparan sulfate proteoglycan at the plasma membrane of Huh7 cells, induces the growth of Huh7 cells by promoting their entry into the cell cycle, and inhibits the tumor necrosis factor-alpha-mediated apoptosis of the cells. SDF-1 also reorganizes Huh7 cytoskeleton and induces tyrosine phosphorylation of focal adhesion kinase. Finally, SDF-1 activates matrix metalloproteinase-9, resulting in increased migration and invasion of Huh7 cells. These biological effects of SDF-1 were strongly inhibited by the CXCR4 antagonist AMD3100, by a glycosaminoglycan, heparin, as well as by beta-D-xyloside treatment of the cells, or by c-jun NH(2)-terminal kinase/stress-activated protein kinase inhibitor. Therefore, the CXCR4, glycosaminoglycans, and the mitogen-activated protein kinase signaling pathways are involved in these events. The fact that reducing SDC-4 expression by RNA interference decreased SDF-1-induced Huh7 hepatoma cell migration and invasion strongly indicates that SDC-4 may be an auxiliary receptor for SDF-1. Finally, the fact that CXCR4 is expressed in hepatocellular carcinoma cells from liver biopsies indicates that the in vitro results reported here could be extended to in vivo conditions.     

Participation of transmembrane proline 82 in angiotensin II AT1 receptor signal transduction

Most of the classical physiological effects of the octapeptide angiotensin II (AngII) are produced by activating the AT1 receptor which belongs to the G-protein coupled receptor family (GPCR). Peptidic GPCRs may be functionally divided in three regions: (i) extracellular domains involved in ligand binding; (ii) intracellular domains implicated in agonist-induced coupling to G protein and (iii) seven transmembrane domains (TM) involved in signal transduction. The TM regions of such receptors have peculiar characteristics such as the presence of proline residues. In this project we aimed to investigate the participation of two highly conserved proline residues (Pro82 and Pro162), located in TM II and TM IV, respectively, in AT1 receptor signal transduction. Both mutations did not cause major alterations in AngII affinity. Functional assays indicated that the P162A mutant did not influence the signal transduction. On the other hand, a potent deleterious effect of P82A mutation on signal transduction was observed. We believe that the Pro82 residue is crucial to signal transduction, although it is not possible to say yet if this is due to a direct participation or if due to a structural rearrangement of TM II. In this last hypothesis, the removal of proline residue might be correlated to a removal of a kink, which in turn can be involved in the correct positioning of residues involved in signal transduction.