89 research outputs found

    Lymphocyte-Derived Exosomal MicroRNAs Promote Pancreatic β Cell Death and May Contribute to Type 1 Diabetes Development.

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    Type 1 diabetes is an autoimmune disease initiated by the invasion of pancreatic islets by immune cells that selectively kill the β cells. We found that rodent and human T lymphocytes release exosomes containing the microRNAs (miRNAs) miR-142-3p, miR-142-5p, and miR-155, which can be transferred in active form to β cells favoring apoptosis. Inactivation of these miRNAs in recipient β cells prevents exosome-mediated apoptosis and protects non-obese diabetic (NOD) mice from diabetes development. Islets from protected NOD mice display higher insulin levels, lower insulitis scores, and reduced inflammation. Looking at the mechanisms underlying exosome action, we found that T lymphocyte exosomes trigger apoptosis and the expression of genes involved in chemokine signaling, including Ccl2, Ccl7, and Cxcl10, exclusively in β cells. The induction of these genes may promote the recruitment of immune cells and exacerbate β cell death during the autoimmune attack. Our data point to exosomal-miRNA transfer as a communication mode between immune and insulin-secreting cells

    The evolving paleobathymetry of the circum-Antarctic Southern Ocean since 34 Ma – A key to understanding past cryosphere-ocean developments

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    The Southern Ocean is a key player in the climate, ocean and atmospheric system. As the only direct connection between all three major oceans since the opening of the Southern Ocean gateways, the development of the Southern Ocean and its relationship with the Antarctic cryosphere has influenced the climate of the entire planet. Although the depths of the ocean floor have been recognized as an important factor in climate and paleoclimate models, appropriate paleobathymetric models including a detailed analysis of the sediment cover are not available. Here, we utilize more than 40 years of seismic reflection data acquisition along the margins of Antarctica and its conjugate margins, along with multiple drilling campaigns by the International Ocean Discovery Program (IODP) and its predecessor programs. We combine and update the seismic stratigraphy across the regions of the Southern Ocean and calculate ocean-wide paleobathymetry grids via a backstripping method. We present a suite of high-resolution paleobathymetric grids from the Eocene-Oligocene Boundary to modern times. The grids reveal the development of the Southern Ocean from isolated basins to an interconnected ocean affected by the onset and vigor of an Antarctic Circumpolar Current, as well as the glacial sedimentation and erosion of the Antarctic continent. The ocean-wide comparison through time exposes patterns of ice sheet development such as switching of glacial outlets and the change from wet-based to dry-based ice sheets. Ocean currents and bottom-water production interact with the sedimentation along the continental shelf and slope and profit from the opening of the ocean gateways

    Continental slope and rise geomorphology seaward of the Totten Glacier, East Antarctica (112°E-122°E)

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    The continental slope and rise seaward of the Totten Glacier and the Sabrina Coast, East Antarctica features continental margin depositional systems with high sediment input and consistent along-slope current activity. Understanding their genesis is a necessary step in interpreting the paleoenvironmental records they contain. Geomorphic mapping using a systematic multibeam survey shows variations in the roles of downslope and along slope sediment transport influenced by broad-scale topography and oceanography. The study area contains two areas with distinct geomorphology. Canyons in the eastern part of the area have concave thalwegs, are linked to the shelf edge and upper slope and show signs of erosion and deposition along their beds suggesting cycles of activity controlled by climate cycles. Ridges between these canyons are asymmetric with crests close to the west bank of adjacent canyons and are mostly formed by westward advection of fine sediment lofted from turbidity currents and deposition of hemipelagic sediment. They can be thought of as giant levee deposits. The ridges in the western part of the area have more gently sloping eastern flanks and rise to shallower depths than those in the east. The major canyon in the western part of the area is unusual in having a convex thalweg; it is likely fed predominantly by mass movement from the flanks of the adjacent ridges with less sediment input from the shelf edge. The western ridges formed by accretion of suspended sediment moving along the margin as a broad plume in response to local oceanography supplemented with detritus originating from the Totten Glacier. This contrasts with interpretations of similar ridges described from other parts of Antarctica which emphasise sediment input from canyons immediately up-current. The overall geomorphology of the Sabrina Coast slope is part of a continuum of mixed contourite-turbidite systems identified on glaciated margins.Australian Government 4333Australian Research Council DP170100557Italian Programma Nazionale di Richerch in Antartide (PNRA)Spanish Government CTM2014-60451-C2-1-P CTM2017-89711-C2-1-

    Ice loss from the East Antarctic Ice Sheet during late Pleistocene interglacials

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    Understanding ice sheet behaviour in the geological past is essential for evaluating the role of the cryosphere in the climate system and for projecting rates and magnitudes of sea level rise in future warming scenarios1,2,3,4. Although both geological data5,6,7 and ice sheet models3,8 indicate that marine-based sectors of the East Antarctic Ice Sheet were unstable during Pliocene warm intervals, the ice sheet dynamics during late Pleistocene interglacial intervals are highly uncertain3,9,10. Here we provide evidence from marine sedimentological and geochemical records for ice margin retreat or thinning in the vicinity of the Wilkes Subglacial Basin of East Antarctica during warm late Pleistocene interglacial intervals. The most extreme changes in sediment provenance, recording changes in the locus of glacial erosion, occurred during marine isotope stages 5, 9, and 11, when Antarctic air temperatures11 were at least two degrees Celsius warmer than pre-industrial temperatures for 2,500 years or more. Hence, our study indicates a close link between extended Antarctic warmth and ice loss from the Wilkes Subglacial Basin, providing ice-proximal data to support a contribution to sea level from a reduced East Antarctic Ice Sheet during warm interglacial intervals. While the behaviour of other regions of the East Antarctic Ice Sheet remains to be assessed, it appears that modest future warming may be sufficient to cause ice loss from the Wilkes Subglacial Basin

    Ceacam1 separates graft-versus-host-disease from graft-versus-tumor activity after experimental allogeneic bone marrow transplantation.

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    BACKGROUND: Allogeneic bone marrow transplantation (allo-BMT) is a potentially curative therapy for a variety of hematologic diseases, but benefits, including graft-versus-tumor (GVT) activity are limited by graft-versus-host-disease (GVHD). Carcinoembryonic antigen related cell adhesion molecule 1 (Ceacam1) is a transmembrane glycoprotein found on epithelium, T cells, and many tumors. It regulates a variety of physiologic and pathological processes such as tumor biology, leukocyte activation, and energy homeostasis. Previous studies suggest that Ceacam1 negatively regulates inflammation in inflammatory bowel disease models. METHODS: We studied Ceacam1 as a regulator of GVHD and GVT after allogeneic bone marrow transplantation (allo-BMT) in mouse models. In vivo, Ceacam1(-/-) T cells caused increased GVHD mortality and GVHD of the colon, and greater numbers of donor T cells were positive for activation markers (CD25(hi), CD62L(lo)). Additionally, Ceacam1(-/-) CD8 T cells had greater expression of the gut-trafficking integrin α(4)β(7), though both CD4 and CD8 T cells were found increased numbers in the gut post-transplant. Ceacam1(-/-) recipients also experienced increased GVHD mortality and GVHD of the colon, and alloreactive T cells displayed increased activation. Additionally, Ceacam1(-/-) mice had increased mortality and decreased numbers of regenerating small intestinal crypts upon radiation exposure. Conversely, Ceacam1-overexpressing T cells caused attenuated target-organ and systemic GVHD, which correlated with decreased donor T cell numbers in target tissues, and mortality. Finally, graft-versus-tumor survival in a Ceacam1(+) lymphoma model was improved in animals receiving Ceacam1(-/-) vs. control T cells. CONCLUSIONS: We conclude that Ceacam1 regulates T cell activation, GVHD target organ damage, and numbers of donor T cells in lymphoid organs and GVHD target tissues. In recipients of allo-BMT, Ceacam1 may also regulate tissue radiosensitivity. Because of its expression on both the donor graft and host tissues, this suggests that targeting Ceacam1 may represent a potent strategy for the regulation of GVHD and GVT after allogeneic transplantation
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