Description: Background: KLF6-SV1 ( SV1 ), the major splice variant of KLF6 , antagonizes the KLF6 tumor suppressor by an unknown mechanism. Decreased KLF6 expression in human hepatocellular carcinoma (HCC) correlates with increased mortality, but the contribution of increased SV1 is unknown. We sought to define the impact of SV1 on human outcomes and experimental murine hepatocarcinogenesis, and to elucidate its mechanism of action. Results: In HCV-related HCC, an increased ratio of SV1/KLF6 within the tumor was associated with more features of more advanced disease. Six months after a single injection of diethylnitrosamine (DEN), SV1 hepatocyte transgenic mice developed more histologically advanced tumors, whereas Klf6 -depleted mice developed bigger tumors compared to the Klf6 fl(+/+) control mice. Nine months after DEN, SV1 transgenic-mice with Klf6 -depletion had the greatest tumor burden. Primary mouse hepatocytes from both the SV1 transgenic animals and those with hepatocyte-specific Klf6 depletion displayed increased DNA synthesis, with an additive effect in hepatocytes harboring both SV1 over-expression and Klf6 depletion. Parallel results were obtained by viral SV1-transduction- and depletion of Klf6 through adenovirus-Cre infection of primary Klf6 fl(+/+) hepatocytes. Increased DNA synthesis was due to both enhanced cell proliferation and increased ploidy. Co-IP studies in 293T cells uncovered a direct interaction of transfected SV1 with KLF6 . Accelerated KLF6 degradation in the presence of SV1 was abrogated by the proteasome inhibitor MG132. Conclusion: Increased SV1/KLF6 ratio correlates with more aggressive HCC. In mice, an increased SV1/KLF6 ratio, generated either by increasing SV1, decreasing KLF6, or both, accelerates hepatic carcinogenesis. Moreover, SV1 binds directly to KLF6 and accelerates its degradation. These findings represent a novel mechanism underlying the antagonism of tumor suppressor gene function by a splice variant of the same gene. (H EPATOLOGY 2012.)

Description: ABSTRACT Riffle-pool sequences are a common feature of gravel-bed rivers. However, mechanisms of their generation and maintenance are still not fully understood. In this study a monitoring approach similar to the one of Andrews (1979 and 1982) is employed. It focuses on analysing cross-sectional and longitudinal channel geometry of a large floodplain river (Vereinigte Mulde, Sachsen-Anhalt, Germany) with a high temporal and spatial resolution, in order to conclude from stage-dependant morphometric changes to riffle and pool maintaining processes. In accordance with Richards (1976a), Andrews (1979 and 1982) among others, pool cross sections of the Mulde River are narrow and riffle cross sections are wide suggesting that they should rather be addressed as two general types of channel cross-sections than solely as bedforms. At high flows, riffles and pools in the study reaches changed in length and height but not in position. Pools were scoured and riffles aggraded, a development which was reversed during receding flows below the threshold of 0.4·Q bf (40% bankfull discharge). An index for the longitudinal amplitude of riffle-pool sequences, the bed undulation intensity or bedform amplitude, is introduced and proved to be highly significant as a form parameter, its first derivative as a process parameter. The process of pool scour and riffle fill is addressed as bedform maintenance or bedform accentuation. It is indicated by increasing longitudinal bed amplitudes. According to the observed dynamics of bed amplitudes, maintenance of riffle-pool sequences lags behind discharge peaks. Maximum bed amplitudes may be reached with a delay of several days after peak discharges. Increasing bed undulation intensity is interpreted to indicate bed mobility. Post-flood decrease of the bed undulation intensity indicates a retrograde phase when transport from pools to riffles has ceased and bed mobility is restricted to riffle tails and heads of pools. This type of transport behaviour is referred to as disconnected mobility. The comparison of two river reaches, one with undisturbed sediment supply, the other with sediment deficit, suggests that high bed undulation intensity values at low flows indicate sediment deficit and potentially channel degrading conditions. It is more generally hypothesised that channel bed undulations constitute a major component of form roughness and that increased bed amplitudes are an important feature of channel bed adjustment to sediment deficit be it temporally during late floods or permanently due to a supply limitation of bedload. Copyright © 2011 John Wiley & Sons, Ltd.

Description: Measurements of trace metal ratios in foraminiferal calcite are routinely used to reconstruct paleoceanographic conditions. Analyses using solution-based inductively coupled plasma mass spectrometry (ICP-MS) require dissolution of the entire foraminifer shell. The potential exists for contamination from adherent clays, mineralized coatings, and other diagenetic components that confound the biogenic trace metal signal. We present results from a cleaning experiment on fossil specimens of the planktic foraminifer Orbulina universa that were cracked into several shell fragments and subjected to different cleaning protocols. We use LA-ICP-MS depth profiling to evaluate the effects of reductive, oxidative, and chelating (DTPA) cleaning protocols on shell Mg/Ca and Ba/Ca ratios. Using the natural pattern of intrashell Mg/Ca heterogeneity exhibited by O. universa , we demonstrate that reductive and oxidative cleaning can dissolve shell calcite from available surfaces, although intrashell Mg/Ca minima and maxima are unaffected. High-resolution depth profiles can be used to identify areas of heterogeneous intrashell Ba/Ca, which can be excluded from computations of whole-shell Ba/Ca. The size and density of shell pores plays a major role in the degree of contamination from sedimentary material. We demonstrate an approach for computing whole-shell Me/Ca ratios from LA-ICP-MS depth profiles that accounts for potential contamination and diagenetic overprinting.

Description: Clear cell renal cell carcinoma (ccRCC) is the most common pathological subtype of kidney cancer. Here, we integrated an unbiased genome-wide RNA interference screen for ccRCC survival regulators with an analysis of recurrently over-expressed genes in ccRCC to identify new therapeutic targets in this disease. One of the most potent survival regulators, the monocarboxylate transporter MCT4 (SLC16A3), impaired ccRCC viability in all 8 ccRCC lines tested and was the 7th most over-expressed gene in a meta-analysis of 5 ccRCC expression datasets. MCT4-silencing impaired secretion of lactate generated through glycolysis and induced cell cycle arrest and apoptosis. Silencing MCT4 resulted in intracellular acidosis, and reduction in intracellular ATP production together with partial reversion of the Warburg effect in ccRCC cell lines. Intratumoral heterogeneity in the intensity of MCT4 protein expression was observed in primary ccRCCs. MCT4 protein expression analysis based on the highest intensity of expression in primary ccRCCs was associated with poorer relapse free survival, whereas modal intensity correlated with Fuhrman nuclear grade. Consistent with the potential selection of subclones enriched for MCT4 expression during disease progression, MCT4 expression was greater at sites of metastatic disease. These data suggest that MCT4 may serve as a novel metabolic target to reverse the Warburg effect and limit disease progression in ccRCC. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Description: We report on the calibration of the one-dimensional hydrodynamic lake model DYRESM to simulate the water temperature conditions of the pre-alpine Lake Ammersee (South-east Germany) which is representative of deep and large lakes in this region. Special focus is given to the calibration in order to reproduce the correct thermal distribution and stratification including the time of onset and duration of summer stratification. To ensure the application of the model to investigate the impact of climate change on lakes, an analysis of the model sensitivity under stepwise modification of meteorological input parameters (air temperature, wind speed, precipitation, global radiation, cloud cover, vapor pressure, and tributary water temperature) was conducted. The total mean error of the calibration results is –0.23 °C, the root mean square error amounts to 1.012 °C. All characteristics of the annual stratification cycle were reproduced accurately by the model. Additionally, the simulated deviations for all applied modifications of the input parameters for the sensitivity analysis can be differentiated in the high temporal resolution of monthly values for each specific depth. The smallest applied alteration to each modified input parameter caused a maximum deviation in the simulation results of at least 0.26 °C. The most sensitive reactions of the model can be observed through modifications of the input parameters air temperature and wind speed. Hence the results show that further investigations at Lake Ammersee, such as coupling the hydrodynamic model with chemo-dynamic models to assess the impact of changing climate on biochemical conditions within lakes, can be carried out using DYRESM. Copyright © 2012 John Wiley & Sons, Ltd.