Probabilistic Estimation of Stream Turbidity and Application under Climate Change Scenarios.

Streamflow-based rating curves are widely used to estimate turbidity or suspended sediment concentrations in streams. However, such estimates are often inaccurate at the event scale due to inter- and intra-event variability in sediment-streamflow relationships. In this study, we use a quantile regression approach to derive a probabilistic distribution of turbidity predictions for Esopus Creek, a major stream in one of the watersheds that supply drinking water to New York City, using measured daily mean streamflow-turbidity data pairs for 2003 to 2016. Although a single regression curve can underpredict or overpredict the actual observation, quantile regression can estimate a range of possible turbidity values for a given value of streamflow. Regression relationships for various quantiles were applied to streamflows simulated by a watershed model to predict stream turbidity under: (i) the observed historical climate, and (ii) a future climate derived from 20 global climate model (GCM) scenarios. Future scenarios using quantile regression in combination with these GCMs and a stochastic weather generator indicated an increase in the frequency and magnitude of hydrological events that may generate high stream turbidity and cause potential water quality challenges to the water supply. The methods outlined in this study can be used for probabilistic estimation of stream turbidity for operational decisions and can be part of a vulnerability-based method to explore climate impacts on water resources.

Support of a patient-specific therapeutical acoustic stimulation in tinnitus by numerical modeling.

The pathogenesis of tinnitus involves multiple hierarchical levels of auditory processing and appraisal of sensory saliency. Early tinnitus onset is most likely attributed to homeostatic plasticity in the periphery, while the chronification and decompensation are tightly linked to brain areas for the allocation of attentional resources, such as e.g., the thalamocortical feedback loops and the limbic system. Increased spontaneous firing after sensory deafferentation might be sufficient to generate a phantom perception, yet the question why not every peripheral hearing loss automatically elicits a tinnitus sensation is still to be addressed. Utilizing quantitative modeling of multiple hierarchical levels in the auditory pathway, we demonstrate the effects of lateral inhibition on increased spontaneous firing and the resulting elevation of firing regularity and synchronization of neural activity. The presented therapeutical approach is based on the idea of disrupting the heightened regularity of the neural population response in the tinnitus frequency range. This neural activity regularity depends on lateral dispersion of common noise and thus is susceptible for edge effects and might be influenced by a change in neural activity in bordering frequency ranges by fitted acoustical stimulation. We propose the use of patient specifically adapted tailor-made notched acoustic stimulation, utilizing modeling results for the optimal adjustment of the stimulation frequencies to archive a therapeutical edge-effect.

Epigenetic silencing of HSulf-1 in ovarian cancer:implications in chemoresistance.

To investigate the mechanism by which HSulf-1 expression is downregulated in ovarian cancer, DNA methylation and histone acetylation of HSulf-1 was analysed in ovarian cancer cell lines and primary tumors. Treatment of OV207 and SKOV3 by 5-aza-2'-deoxycytidine resulted in increased transcription of HSulf-1. Sequence analysis of bisulfite-modified genomic DNA from ovarian cell lines and primary tumors without HSulf-1 expression revealed an increase in the frequency of methylation of 12 CpG sites in exon 1A. Chromatin immunoprecipitation assays showed an increase in histone H3 methylation in cell lines without HSulf-1 expression. To assess the significance of HSulf-1 downregulation in ovarian cancer, OV167 and OV202 cells were transfected with HSulf-1 siRNA. Downregulation of HSulf-1 expression in OV167 and OV202 cells lead to an attenuation of cisplatin-induced cytotoxicity. Moreover, patients with ovarian tumors expressing higher levels of HSulf-1 showed a 90% response rate (27/30) to chemotherapy compared to a response rate of 63% (19/30) in those with weak or moderate levels (P=0.0146, chi(2) test). Collectively, these data indicate that HSulf-1 is epigenetically silenced in ovarian cancer and that epigenetic therapy targeting HSulf-1 might sensitize ovarian tumors to conventional first-line therapies.

Combination chemotherapy with adriamycin and streptozotocin. II. Clincopharmacologic correlation of augmented adriamycin toxicity caused by streptozotocin.

Plasma pharmacokinetics were compared in patients with advanced sarcomas receiving adriamycin, 60 mg/m2 intravenously (iv) on day 1 every 3 wk in combination with streptozotocin, 500 mg/m2/day iv on days 1 to 5 every 3 wk, and patients receiving adriamycin alone in the same dose and schedule. The combination-treated group had greater adriamycin drug exposure (concentration X time) when serial plasma levels were analyzed by fluorescence assay and by radioimmunoassay (RIA). The plasma t 1/2 of adriamycin equivalents measured by fluorescence assay was also significantly prolonged in the combination-treated group. These changes correlated well with an increase in adriamycin-related toxicity--mucositis and myelosuppression-seen in the patients who received the combination drug therapy. Plasma streptozotocin kinetics and the incidence of streptozotocin-related side effects--hepatic and renal function abnormalities--were those published for streptozotocin alone. Evidence is presented to support the hypothesis that the increased incidence of adriamycin side effects is due to streptozotocin-related hepatic dysfunction, affecting both the detoxification and excretion of adriamycin. Combination of other drugs with adriamycin should take into account their potential for inducing hepatic dysfunction which may affect the therapeutic index of adriamycin.