Description: Laguna Potrok Aike is an exceptional site in the southern hemisphere’s mid-latitudes because it records changes in the hydrological regime through lake-level variations in a continuous, high-resolution sedi- ment record back into the late Pleistocene. In this study, driving forces of lake-level changes at Laguna Potrok Aike are evaluated by means of process studies using data from an extensive multi-year moni- toring in and around the lake. Lake-volume changes were calculated with an energy-budget/bulk- transfer approach and translated into lake-level variations, which were then compared to pressure sensor data. Calculated lake levels are in broad agreement with measured data. We hypothesize that on short time scales, lake-level fluctuations are mainly driven by the precipitation-to-evaporation ratio. Apart from changing catchment conditions, relative humidity, precipitation, temperature, wind strength and wind direction have the most important influence on the hydrological balance of the lake. Lake level decreases during periods of persistently high wind speeds from westerly directions, whereas, during periods with more frequent occurrences of easterly winds, it increases. These situations are linked to a strengthening of the Southern Hemispheric Westerlies in the first and more frequent blocking situa- tions in the latter case. Although lake-level changes at Laguna Potrok Aike show some degree of simi- larity to variations of the El Niño Southern Oscillation (ENSO) and the Southern Hemisphere Annular Mode (SAM), a persistent correspondence remains to be documented. Water chemistry and sediment-trap data suggest that lake-internal carbonate precipitation is highly sensitive to short-term changes in the lake water volume and, thus, to lake-level variations. However, it becomes obvious that the sedimentary carbonate record, representing changes on longer time scales, is not linearly linked to lake-level changes, hence complicating quantitative lake-level reconstructions back in time. We suggest that short-term changes in authigenic carbonate production are mainly driven by changing precipitation/evaporation ratios probably superimposed on longer-term changes in ground- water input that represent a buffered climate signal. Scenario calculations for a period of 60 years show that changes of the controlling meteorological parameters in the range of 15-17% can lead to lake-level changes with a magnitude comparable to the reconstructed Holocene and Lateglacial extreme situations. In addition, modifications in the water- retaining capacity of the lake can also produce large lake-level changes. It is hypothesized that the development or disappearance of permafrost in the catchment of Laguna Potrok Aike during the Last Glacial/Interglacial transition may have changed the water-retaining capacity tremendously. The lake- level reconstructions for Laguna Potrok Aike might express some of the meridional climate variability observed in coupled general circulation model (CGCM) simulations for southern South America for the Last Glacial Maximum (LGM) and the mid Holocene.

Description: Chondroitin sulfate proteoglycan 4 (CSPG4) has been identified as a highly promising target antigen for immunotherapy of triple-negative breast cancer (TNBC). TNBC represents a highly aggressive heterogeneous group of tumors lacking expression of estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2). TNBC is particularly prevalent among young premenopausal women. No suitable targeted therapies are currently available and therefore, novel agents for the targeted elimination of TNBC are urgently needed. Here, we present a novel cytolytic fusion protein (CFP), designated αCSPG4(scFv)-MAP, that consists of a high affinity CSPG4-specific single-chain antibody fragment (scFv) genetically fused to a functionally enhanced form of the human microtubule-associated protein (MAP) tau. Our data indicate that αCSPG4(scFv)-MAP efficiently targets CSPG4 + TNBC-derived cell lines MDA-MB-231 and Hs 578T and potently inhibits their growth with IC 50 values of approximately 200 nM. Treatment with αCSPG(scFv)-MAP resulted in induction of the mitochondrial stress pathway by activation of caspase-9 as well as endonuclease G translocation to the nucleus, while induction of the caspase-3 apoptosis pathway was not detectable. Importantly, in vivo studies in mice bearing human breast cancer xenografts revealed efficient targeting to and accumulation of αCSPG4(scFv)-MAP at tumor sites resulting in prominent tumor regression. Taken together, this preclinical proof of concept study confirms the potential clinical value of αCSPG4(scFv)-MAP as a novel targeted approach for the elimination of CSPG4-positive TNBC. This article is protected by copyright. All rights reserved.