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Ohlendorf C.,University of Bremen | Fey M.,University of Bremen | Massaferro J.,CONICET | Haberzettl T.,Friedrich - Schiller University of Jena | And 10 more authors.
Palaeogeography, Palaeoclimatology, Palaeoecology | Year: 2014

Hydrological changes that occurred during the last 4700years have been reconstructed using multi-proxy analyses of sediment cores from the volcanic crater lake of Laguna Cha´ltel (50°S, 71°W). The chronology is based on AMS 14C age modeling constrained by paleomagnetic secular variations. Chemical and physical properties of the lake water together with results of lake-water surface-temperature monitoring, as well as sediment characteristics reveal conspicuous features archived as different sedimentary carbonate phases and morphologies which are attributed to lake-level changes.Sedimentological, geochemical and biological proxies together suggest the development from an initial playa lake-phase towards a system with progressively rising lake level. In detail, proxies indicate the existence of an ephemeral lake since 4700. cal BP until a glauberite-bearing carbonate crust formed around 4040. cal BP which probably is associated to the globally recognized 4.2. ka event. This crust is interpreted as a desiccation event terminating the ephemeral lake phase. Following this desiccation a shift towards conditions with a positive hydrological balance of Laguna Cha´ltel occurs, which leads to the development of a saline lake with ooid formation between 4040 and 3200. cal BP. Further lake-level increase with initially high minerogenic input until 2700. cal BP resulted in a lake freshening which allowed the preservation of diatoms. Sigmoidal and star shaped carbonate crystals occurred until 1720. cal BP indicating a syn- or post-depositional formation of ikaite. Anoxic conditions and increased deposition of clay and sand through fluvial and eolian input are interpreted as a further lake-level rise and/or a prolonged winter ice cover culminating during the Little Ice Age. The highest lake level was probably reached at that time and since then dropped to its present day height.Previous studies have shown that the southern hemisphere westerly winds (SWW) exert an oppositional control on hydrological regimes at the eastern and the western sides of the Patagonian Andes. At Laguna Cha´ltel SWW forcing is changing evaporation rates by varying wind intensities, air temperatures and lake ice coverages as well as by precipitation rates (easterly vs. westerly sources of moisture). Our data suggests that the lake-level history of Laguna Cha´ltel reflects changes in the SWW during the last 4.7. ka on the eastern side of the Andes. However, the elevated location of Laguna Cha´ltel on an 800. m high plateau at the leeward side of the Andes potentially leads to a local overprint of the SWW influence on the hydrological balance. © 2014 Elsevier B.V. Source

Westhoff J.H.,University of Heidelberg | Schildhorn C.,University of Heidelberg | Schildhorn C.,Hannover Medical School | Jacobi C.,Hannover Medical School | And 9 more authors.
Journal of the American Society of Nephrology | Year: 2010

Telomeres of most somatic cells progressively shorten, compromising the regenerative capacity of human tissues during aging and chronic diseases and after acute injury. Whether telomere shortening reduces renal regeneration after acute injury is unknown. Here, renal ischemia-reperfusion injury led to greater impairment of renal function and increased acute and chronic histopathologic damage in fourth-generation telomerase-deficient mice compared with both wild-type and firstgeneration telomerase-deficient mice. Critically short telomeres, increased expression of the cellcycle inhibitor p21, and more apoptotic renal cells accompanied the pronounced damage in fourthgeneration telomerase-deficient mice. These mice also demonstrated significantly reduced proliferative capacity in tubular, glomerular, and interstitial cells. These data suggest that critical telomere shortening in the kidney leads to increased senescence and apoptosis, thereby limiting regenerative capacity in response to injury. Copyright © 2010 by the American Society of Nephrology. Source

El-Baba C.,Friedrich - Alexander - University, Erlangen - Nuremberg | Mahadevan V.,SASTRA University | Fahlbusch F.B.,University of Erlangen Nu rnberg | S S.M.,SASTRA University | And 3 more authors.
Molecular Cancer | Year: 2014

Background: Thymoquinone (TQ) was shown to reduce tumor growth in several cancer models both in vitro and in vivo. So far only a few targets of TQ, including protein kinases have been identified. Considering that kinases are promising candidates for targeted anticancer therapy, we studied the complex kinase network regulated by TQ.Methods: Novel kinase targets influenced by TQ were revealed by in silico analysis of peptide array data obtained from TQ-treated HCT116wt cells. Western blotting and kinase activity assays were used to determine changes in kinase expression patterns in colorectal cancer cells (HCT116wt, DLD-1, HT29). To study the viability/apoptotic effects of combining the PAK1 inhibitor IPA-3 and TQ, crystal violet assay and AnnexinV/PI staining were employed. Interactions between PAK1 and ERK1/2 were investigated by co-immunoprecipitation and modeled by docking studies. Transfection with different PAK1 mutants unraveled the role of TQ-induced changes in PAK1 phosphorylation and TQ ´s effects on PAK1 scaffold function.Results: Of the 104 proteins identified, 50 were upregulated ≥2 fold by TQ and included molecules in the AKT-MEK-ERK1/2 pathway. Oncogenic PAK1 emerged as an interesting TQ target. Time-dependent changes in two PAK1 phosphorylation sites generated a specific kinase profile with early increase in pPAKThr212 followed by late increase in pPAKThr423. TQ induced an increase of pERK1/2 and triggered the early formation of an ERK1/2-PAK1 complex. Modeling confirmed that TQ binds in the vicinity of Thr212 accompanied by conformational changes in ERK2-PAK1 binding. Transfecting the cells with the non-phosphorylatable mutant T212A revealed an increase of pPAKThr423 and enhanced apoptosis. Likewise, an increase in apoptosis was observed in cells transfected with both the kinase-dead K299R mutant and PAK1 siRNA. Using structural modeling we suggest that TQ interferes also with the kinase domain consequently disturbing its interaction with pPAKThr423, finally inhibiting MEK-ERK1/2 signaling and disrupting its prosurvival function. pERK1/2 loss was also validated in vivo.Conclusions: Our study shows for the first time that the small molecule TQ directly binds to PAK1 changing its conformation and scaffold function. Because TQ affects the central RAF/MEK/ERK1/2 pathway, the combination of TQ with targeted therapies is worth considering for future anticancer treatments. © 2014 El-Baba et al.; licensee BioMed Central Ltd. Source

Kaercher T.,Augenarztpraxis | Dietz J.,University of Erlangen Nu rnberg | Jacobi C.,Friedrich - Alexander - University, Erlangen - Nuremberg | Berz R.,InfraMedic GmbH | Schneider H.,University of Erlangen Nu rnberg
Current Eye Research | Year: 2015

Purpose: X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common form of ectodermal dysplasia. Clinical characteristics include meibomian gland disorder and the resulting hyperevaporative dry eye. In this study, we evaluated meibography and ocular infrared thermography as novel methods to diagnose XLHED.Methods: Eight infants, 12 boys and 14 Male adults with XLHED and 12 healthy control subjects were subjected to a panel of tests including the ocular surface disease index (OSDI), meibography and infrared thermography, non-invasive measurement of tear film break-up time (NIBUT) and osmolarity, Schirmers test, lissamine green staining and fluorescein staining. Sensitivity and specificity were determined for single tests and selected test combinations.Results: Meibography had 100% sensitivity and specificity for identifying XLHED. Infrared thermography, a completely non-invasive procedure, revealed a typical pattern for Male subjects with XLHED. It was, however, less sensitive (86% for adults and 67% for children) than meibography or a combination of established routine tests. In adults, OSDI and NIBUT were the best single routine tests (sensitivity of 86% and 71%, respectively), whereas increased tear osmolarity appeared as a rather unspecific ophthalmic symptom. In children, NIBUT was the most convincing routine test (sensitivity of 91%).Conclusions: Meibography is the most reliable ophthalmic examination to establish a clinical diagnosis in individuals with suspected hypohidrotic ectodermal dysplasia, even before genetic test results are available. Tear film tests and ocular surface staining are less sensitive in children, but very helpful for estimating the severity of ocular surface disease in individuals with known XLHED. © 2014 Informa Healthcare USA, Inc. All rights reserved. Source

Neumann H.,University of Erlangen Nu rnberg | Neumann H.,Friedrich - Alexander - University, Erlangen - Nuremberg | Fry L.C.,University of Alabama at Birmingham | Nagel A.,University of Erlangen Nu rnberg | And 3 more authors.
Current Opinion in Gastroenterology | Year: 2014

PURPOSE OF REVIEW: Here, we review the clinical applications of small bowel capsule endoscopy. Moreover, we provide an outlook on the exceptional future developments of small bowel capsule endoscopy. We discuss clinical algorithms for diagnosis of small bowel diseases. Multiple studies have shown the potential of capsule endoscopy for identification of the bleeding source located in the small bowel and the increased diagnostic yield over radiographic studies. Capsule endoscopy could detect villous atrophy and severe complications in patients with nonresponsive celiac disease. In addition, small bowel capsule endoscopy was proven as a valid tool to diagnose polyps and tumors and Crohn's disease. Summary Major current clinical indications of capsule endoscopy in the small bowel include evaluation of obscure gastrointestinal bleeding, diagnosis and surveillance of small bowel polyps and tumors, celiac disease and Crohn's disease. Recent developments have also passed the way for small bowel capsule endoscopy to become a therapeutic instrument. © 2014 Wolters Kluwer Health. Source

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