Données sur les transferts du 137Cs et du 60Co dans un écosystème fluvial : le Rhône

L'étude radioécologique du Rhône permet d'évaluer qualitativement et quantitativement les radionucléides présents dans le fleuve. Les études menées in situ posent des questions concernant les modalités de transfert des radionucléides. Dans ce travail des expériences sont mises au point, afin d'analyser les mécanismes de bioconcentration dans les écosystèmes aquatiques. Pour le césium-137 les échanges entre l'eau, le sédiment et divers organismes aquatiques ont permis d'élaborer un modèle mathématique que l'on peut confronter aux valeurs mesurées sur le terrain. En ce qui concerne le Cobalt-60 les auteurs décrivent des expériences permettant l'évaluation de la contribution relative de l'eau et de la nourriture dans l'accumulation du radionucléide par un poisson.The radioecology of the Rhone Basin has been studied for the last 15 years. This has been an opportunity to make a quantitative and qualitative evaluation of radionuclides as a function of their different sources. Special attention is given to 137Cs (present both in fallout and liquid wastes) and 60Co, which characterize the liquid wastes of pressurised water reactors. In order to assess the transfer and bioconcentration of these two radionuclides in freshwater ecosystems, several experimental studies were undertaken.The 137Cs transfer studies were carried out with a 5-component experimental ecosystem and the data were included in a mathematical model. For 60Co, the experimental study concerns the relative contribution of water and food in the accumulation of the radionuclide by Cyprinus carpio.Water, sediment, plants and fishes were taken from 60 sampling stations set up along the river (figure 1). Water was filtrated, then percolated on resin columns. Sediment, plants and fishes were dried and burnt to ashes in an oven at 500° C. Radioactivity was measured by gamma spectrometry and radiochemistry.137Cs experimental transfers were studied between water, sediment, midge larvae, daphnid and carp. These components were taken in pairs in order to estimate the radionuclide transfer from one to the other. Thus ten experiments were carried out (figure 2). In order to study the relative importance of food and water as 60Co sources for the carp, an experiment was carried out simultaneously on three homogeneous groups of ten juvenile fishes. The individuals of the first group were maintained in separate aquaria and offered 45 daily rations of labelled food over a 63-day period. Bach carp of the other two groups was placed in a compartment of a large tank with contaminated water. One group was fed with radioactive food, the other with non-radioactive food (table 1).Natural radioactivity remained steady all along the river. It ranged around 1 Bq.l-1 in water, 2250 Bq.kg-1 DW in sediment, 1700 Bq.kg-1 DW in aquatic plants, 110 Bq.kg-1 WW in fish. The fallout impact was characterized by 137Cs presence. PWR liquid wastes contained mainly, 58Co, 60Co, 134 Cs, 137Cs. The Chernobyl fallout gave an increase of Cs and the presence of 103Ru and 106RU+Rh specially during May and June 1986 which later decreased (tables 2, 3 and 4).137Cs transfer between water and sediment was very fast and important. Less than 2 % of the radionuclide was released from sediment into a non-radioactive water. During the transfer from water to chironomids the larvae radioactivity increased steadily (figure 3). Conversely, the transfer from the sediment to larvae did not seem to depend on the contact time. The transfer from water to carp was regular without any steady state during the 63 days of the experiment (figure 3). Then the fish concentration factor was less than 5. For 42 days, the transfer factor from sediment to carp was 3.6.10-3. The retention factor from food to carp was 0.03 when fishes were fed with daphnids and 0.13 with chironomids. An experiment showed that the various ways of 137Cs transfer could have an added impact. Thus the carp radioactivity was the sum of the separate transfers. Water was responsible for 4 % of the fish 137 Cs concentration, sediment for 45 % and chironomids for 51 %.It is possible to include the different kinetic equations in a mathematical model. If the radioactivity of one of the components is known, the nuclide concentration can be computed in others, as a relation of the contact time, the quantity and quality of ingested food, etc... This model gives a concentration factor for juvenile carp of 1000 in 180 days and 500 for 3-year old fish. Considering the field conditions (e.g. seasonal nutritive cycles) the computed concentration factor in fish was between 200 and 350. For a 1 mBq.l-1 137Cs concentration in water, the model gave a concentration of 0.2 to 0.35 Bq.kg-1 WW in carp, which was the 137Cs radioactivity level measured in the Rhone fish before the Chernobyl accident.During the 60Co accumulation phase, the mean weight of the fish in the three groups increased exponentially and the resultant relative weight gain was 52-59 % after 63 days (table 5).The 60Co accumulation kinetics showed that the steady state should be reached after 165 days for fish exposed to 60Co in food, 92 days for fish exposed to radiocobalt in water and 120 days for fish exposed to 60Co in both sources (figure 4). According to the 60Co concentration in the fish in the three treated groups, the accumulation from water accounted for 75 % of the total radioactivity and the accumulation of the radionuclide from both water and food was in addition.Depuration of 60Co from carp was a relatively intensive process reflecting a high Co turnover. Biological half-lives for loss from the long-lived compartment ranged from 35d in fish previously contaminated by food, to 87d in fish previously contaminated by food, to 87d in fish previously contaminated by water (figure 5).137Cs and 60Co are the most concentrated radionuclides in liquid wastes of the pressurised water reactors, and they are often measured in the aquatic ecosystem components. Though it accounts for the highest fraction of total radioactivity in the liquid wastes, 60Co cobalt is not the most concentrated radionuclide in fish. Experimental studies show that it is primarily transferred from the water so it is logical that its concentration in fish remains at a low level. Conversely the 137Cs has a low concentration in water but as it is transferred simultaneously from water, sediment and food, its concentration in fish is still important. Moreover its 30 years half-life means that the cesium contamination of fish is a long and important process, all the more so as the source terms can add their own effects during time and space

Влияние параметров одномассной системы с упругими ограничителями на характер ее колебаний

У статті розглянуто одномасну систему з пружними обмежувачами. Побудовано області існування різних режимів коливань системи, а також визначено вплив параметрів системи на межі цих областей.A one-mass system with elastic constraints is studied. Areas of existing of different oscillation modes are built. Also an influence of system parameters on limits of these areas is determined

Synthesis and evaluation of new designed multiple ligands directed towards both peroxisome proliferator-activated receptor-γ and angiotensin II type 1 receptor

Because of the complex biological networks, many pathologic disorders fail to be treated with a molecule directed towards a single target. Thus, combination therapies are often necessary, but they have many drawbacks. An alternative consists in building molecules intended to interact with multiple targets, called designed multiple ligands. We followed such a strategy in order to treat metabolic syndrome, by setting up molecules directed towards both type 1 angiotensin II (AT1) receptor and peroxisome proliferator-activated receptor-γ (PPAR-γ). For this purpose, many molecules were prepared by merging both pharmacophores following three different strategies. Their ability to activate PPAR-γ and to block AT1 receptors were evaluated in vitro. This strategy led to the preparation of many new PPAR-γ activating and AT1 blocking molecules. Among them, some exhibited both activities, highlighting the convenience of this approach

Novel Role for the Golgi Membrane Protein TMEM165 in Control of Migration and Invasion for Breast Carcinoma

The TMEM165 gene encodes for a multiple pass membrane protein localized in the Golgi that has been linked to congenital disorders of glycosylation. The TMEM165 protein is a putative ion transporter that regulates H+/Ca++/Mn++ homeostasis and pH in the Golgi. Previously, we identified TMEM165 as a potential biomarker for breast carcinoma in a glycoproteomic study using late stage invasive ductal carcinoma tissues with patient-matched adjacent normal tissues. The TMEM165 protein was not detected in non-malignant matched breast tissues and was detected in invasive ductal breast carcinoma tissues by mass spectrometry. Our hypothesis is that the TMEM165 protein confers a growth advantage to breast cancer. In this preliminary study we have investigated the expression of TMEM165 in earlier stage invasive ductal carcinoma and ductal carcinoma in situ cases. We created a CRISPR/Cas9 knockout of TMEM165 in the human invasive breast cancer cell line MDAMB231. Our results indicate that removal of TMEM165 in these cells results in a significant reduction of cell migration, tumor growth, and tumor vascularization in vivo. Furthermore, we find that TMEM165 expression alters the glycosylation of breast cancer cells and these changes promote the invasion and growth of breast cancer by altering the expression levels of key glycoproteins involved in regulation of the epithelial to mesenchymal transition such as E-cadherin. These studies illustrate new potential functions for this Golgi membrane protein in the control of breast cancer growth and invasion

Mutations in TRAPPC11 are associated with a congenital disorder of glycosylation.

Congenital disorders of glycosylation (CDG) are a heterogeneous and rapidly growing group of diseases caused by abnormal glycosylation of proteins and/or lipids. Mutations in genes involved in the homeostasis of the endoplasmic reticulum (ER), the Golgi apparatus (GA), and the vesicular trafficking from the ER to the ER-Golgi intermediate compartment (ERGIC) have been found to be associated with CDG. Here, we report a patient with defects in both N- and O-glycosylation combined with a delayed vesicular transport in the GA due to mutations in TRAPPC11, a subunit of the TRAPPIII complex. TRAPPIII is implicated in the anterograde transport from the ER to the ERGIC as well as in the vesicle export from the GA. This report expands the spectrum of genetic alterations associated with CDG, providing new insights for the diagnosis and the understanding of the physiopathological mechanisms underlying glycosylation disorders

Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma

Multiple myeloma (MM), an incurable plasma cell malignancy, requires localisation within the bone marrow. This microenvironment facilitates crucial interactions between the cancer cells and stromal cell types that permit the tumour to survival and proliferate. There is increasing evidence that the bone marrow mesenchymal stem cell (BMMSC) is stably altered in patients with MM – a phenotype also postulated to exist in patients with monoclonal gammopathy of undetermined significance (MGUS) a benign condition that precedes MM. In this study, we describe a mechanism by which increased expression of peptidyl arginine deiminase 2 (PADI2) by BMMSCs in patients with MGUS and MM directly alters malignant plasma cell phenotype. We identify PADI2 as one of the most highly upregulated transcripts in BMMSCs from both MGUS and MM patients, and that through its enzymatic deimination of histone H3 arginine 26, PADI2 activity directly induces the upregulation of interleukin-6 (IL-6) expression. This leads to the acquisition of resistance to the chemotherapeutic agent, bortezomib, by malignant plasma cells. We therefore describe a novel mechanism by which BMMSC dysfunction in patients with MGUS and MM directly leads to pro-malignancy signalling through the citrullination of histone H3R26

A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis

Rheumatoid arthritis (RA) is strongly associated with the human leukocyte antigen (HLA)- DRB1 locus that possesses the shared susceptibility epitope (SE) and the citrullination of self-antigens. We show how citrullinated aggrecan and vimentin epitopes bind to HLADRB1* 04:01/04. Citrulline was accommodated within the electropositive P4 pocket of HLA-DRB1*04:01/04, whereas the electronegative P4 pocket of the RA-resistant HLADRB1* 04:02 allomorph interacted with arginine or citrulline-containing epitopes. Peptide elution studies revealed P4 arginine-containing peptides from HLA-DRB1*04:02, but not from HLA-DRB1*04:01/04. Citrullination altered protease susceptibility of vimentin, thereby generating self-epitopes that are presented to T cells in HLA-DRB1*04:01+ individuals. Using HLA-II tetramers, we observed citrullinated vimentin- and aggrecan-specific CD4+ T cells in the peripheral blood of HLA-DRB1*04:01+ RA-affected and healthy individuals. In RA patients, autoreactive T cell numbers correlated with disease activity and were deficient in regulatory T cells relative to healthy individuals. These findings reshape our understanding of the association between citrullination, the HLA-DRB1 locus, and T cell autoreactivity in RA

Domain Organization of Long Signal Peptides of Single-Pass Integral Membrane Proteins Reveals Multiple Functional Capacity

Targeting signals direct proteins to their extra - or intracellular destination such as the plasma membrane or cellular organelles. Here we investigated the structure and function of exceptionally long signal peptides encompassing at least 40 amino acid residues. We discovered a two-domain organization (“NtraC model”) in many long signals from vertebrate precursor proteins. Accordingly, long signal peptides may contain an N-terminal domain (N-domain) and a C-terminal domain (C-domain) with different signal or targeting capabilities, separable by a presumably turn-rich transition area (tra). Individual domain functions were probed by cellular targeting experiments with fusion proteins containing parts of the long signal peptide of human membrane protein shrew-1 and secreted alkaline phosphatase as a reporter protein. As predicted, the N-domain of the fusion protein alone was shown to act as a mitochondrial targeting signal, whereas the C-domain alone functions as an export signal. Selective disruption of the transition area in the signal peptide impairs the export efficiency of the reporter protein. Altogether, the results of cellular targeting studies provide a proof-of-principle for our NtraC model and highlight the particular functional importance of the predicted transition area, which critically affects the rate of protein export. In conclusion, the NtraC approach enables the systematic detection and prediction of cryptic targeting signals present in one coherent sequence, and provides a structurally motivated basis for decoding the functional complexity of long protein targeting signals

Induction of protein citrullination and auto-antibodies production in murine exposed to nickel

Abstract Citrullination, or the post-translational deimination of polypeptide-bound arginine, is involved in several pathological processes in the body, including autoimmunity and tumorigenesis. Recent studies have shown that nanomaterials can trigger protein citrullination, which might constitute a common pathogenic link to disease development. Here we demonstrated auto-antibody production in serum of nanomaterials-treated mice. Citrullination-associated phenomena and PAD levels were found to be elevated in nanomaterials -treated cell lines as well as in the spleen, kidneys and lymph nodes of mice, suggesting a systemic response to nanomaterials injection, and validated in human pleural and pericardial malignant mesothelioma (MM) samples. The observed systemic responses in mice exposed to nanomaterials support the evidence linking exposure to environmental factors with the development of autoimmunity responses and reinforces the need for comprehensive safety screening of nanomaterials. Furthermore, these nanomaterials induce pathological processes that mimic those observed in Pleural MM, and therefore require further investigations into their carcinogenicity