Development and application of the modelling system J2000-S for the EU-water framework directive

The scientific sound definition of measures to achieve the goals of the EU water framework directive (WFD) acquires spatially distributed analyses of the water and substance dynamics in meso- to macro-scale catchments. For this purpose, modelling tools or systems are needed which are robust and fast enough to be applied on such scales, but which are also able to simulate the impact of changes on single fields or small areas of a specific land use in the catchment. <br><br> To face these challenges, we combined the fully-distributed hydrological model J2000 with the nitrogen transport routines of the Soil Water Assessment Tool SWAT model, which are normally applied in a semi-distributive approach. With this combination, we could extend the quantitative focus of J2000 with qualitative processes and could overcome the semi-distributed limitation of SWAT. For the implementation and combination of the components, we used the Jena Adaptable Modelling System JAMS (Kralisch and Krause, 2006) which helped tremendously in the relatively rapid and easy development of the new resultant model J2000-S (J2000-Substance). <br><br> The modelling system was applied in the upper Gera watershed, located in Thuringia, Germany. The catchment has an area of 844 km<sup>2</sup> and includes three of the typical landscape forms of Thuringia. The application showed, that the new modelling system was able to reproduce the daily hydrological as well as the nitrogen dynamics with a sufficient quality. The paper will describe the results of the new model and compare them with the results obtained with the original semi-distributed application of SWAT

Multiscale investigations in a mesoscale catchment ? hydrological modelling in the Gera catchment

International audienceThe application of the hydrological process-oriented model J2000 (J2K) is part of a cooperation project between the Thuringian Environmental Agency (Thüringer Landesanstalt für Umwelt und Geologie ? TLUG) and the Department of Geoinformatics of the Friedrich-Schiller-University Jena focussing on the implementation of the EU water framework directive (WFD). In the first project phase J2K was parametrised and calibrated for a mesoscale catchment to quantify if it can be used as hydrological part of a multi-objective tool-box needed for the implementation of the WFD. The main objectives for that pilot study were: The development and application of a suitable distribution concept which provide the spatial data basis for various tasks and which reflects the specific physiogeographical variability and heterogeneity of river basins adequately. This distribution concept should consider the following constraints: The absolute number of spatial entities, which forms the basis for any distributive modelling should be as small as possible, but the spatial distributed factors, which controls quantitative and qualitative hydrological processes should not be generalised to much. The distribution concept of hydrological response units HRUs (Flügel, 1995) was selected and enhanced by a topological routing scheme (Staudenrausch, 2001) for the simulation of lateral flow processes. J2K should be calibrated for one subbasin of the pilot watershed only. Then the parameter set should be used on the other subbasins (referred as transfer basins) to investigate and quantify the transferability of a calibrated model and potential spatial dependencies of its parameter set. In addition, potential structural problems in the process description should be identified by the transfer to basins which show a different process dominance as the one which was used for calibration does. Model calibration and selection of efficiency criteria for the quantification of the model quality should be based on a comprehensive sensitivity and uncertainty analysis (Bäse, 2005) and multi-response validations with independent data sets (Krause and Flügel, 2005) carried out in advance in the headwater part of the calibration basin. To obtain good results in the transfer basins the calibrated parameter set could be adjusted slightly. This step was considered as necessary because of specific constraints which were not of significant importance in the calibration basin. This readjustment should be carried out on parameters which show a sensitive reaction on the identified differences in the environmental setup. Potential scaling problems of the process description, distribution concept or model structure should be identified by the comparison of the modelling results obtained in a small headwater region of the calibration basin with observed streamflow to find out if the selected efficiency measures show a significant change

Anticipation of guilt for everyday moral transgressions : the role of the anterior insula and the influence of interpersonal psychopathic traits

Psychopathy is a personality disorder characterised by atypical moral behaviour likely rooted in atypical affective/motivational processing, as opposed to an inability to judge the wrongness of an action. Guilt is a moral emotion believed to play a crucial role in adherence to moral and social norms, but the mechanisms by which guilt (or lack thereof) may influence behaviour in individuals with high levels of psychopathic traits are unclear. We measured neural responses during the anticipation of guilt about committing potential everyday moral transgressions, and tested the extent to which these varied with psychopathic traits. We found a significant interaction between the degree to which anticipated guilt was modulated in the anterior insula and interpersonal psychopathic traits: anterior insula modulation of anticipated guilt was weaker in individuals with higher levels of these traits. Data from a second sample confirmed that this pattern of findings was specific to the modulation of anticipated guilt and not related to the perceived wrongness of the transgression. These results suggest a central role for the anterior insula in coding the anticipation of guilt regarding potential moral transgressions and advance our understanding of the neurocognitive mechanisms that may underlie propensity to antisocial behaviour

Surgical Techniques to Optimize Early Urinary Continence Recovery Post Robot Assisted Radical Prostatectomy for Prostate Cancer.

PURPOSE OF REVIEW: A variety of different surgical techniques are thought to impact on urinary continence (UC) recovery in patients undergoing robot assisted radical prostatectomy (RARP) for prostate cancer. Herein, we review current evidence and propose a composite evidence-based technique to optimize UC recovery after RARP. RECENT FINDINGS: A literature search on studies reporting on surgical techniques to improve early continence recovery post robotic prostatectomy was conducted on PubMed and EMBASE. The available data from studies ranging from randomized control trials to retrospective cohort studies suggest that minimizing damage to the internal and external urinary sphincters and their neural supply, maximal sparing of urethral length, creating a secure vesicourethral anastomosis, and providing anterior and posterior myo- fascio-ligamentous support to the anastomosis can improve early UC recovery post RARP. A composite evidence-based surgical technique incorporating the above principles could optimize early UC recovery post RARP. Evidence from randomized studies is required to prove benefit

Selective BRAFV600E Inhibitor PLX4720, Requires TRAIL Assistance to Overcome Oncogenic PIK3CA Resistance

Documented sensitivity of melanoma cells to PLX4720, a selective BRAFV600E inhibitor, is based on the presence of mutant BRAFV600E alone, while wt-BRAF or mutated KRAS result in cell proliferation. In colon cancer appearance of oncogenic alterations is complex , since BRAF, like KRAS mutations, tend to co-exist with those in PIK3CA and mutated PI3K has been shown to interfere with the successful application of MEK inhibitors. When PLX4720 was used to treat colon tumours, results were not encouraging and herein we attempt to understand the cause of this recorded resistance and discover rational therapeutic combinations to resensitize oncogene driven tumours to apoptosis. Treatment of two genetically different BRAFV600E mutant colon cancer cell lines with PLX4720 conferred complete resistance to cell death. Even though p-MAPK/ ERK kinase (MEK) suppression was achieved, TRAIL, an apoptosis inducing agent, was used synergistically in order to achieve cell death by apoptosis in RKOBRAFV600E/PIK3CAH1047 cells. In contrast, for the same level of apoptosis in HT29BRAFV600E/PIK3CAP449T cells, TRAIL was combined with 17-AAG, an Hsp90 inhibitor. For cells where PLX4720 was completely ineffective, 17-AAG was alternatively used to target mutant BRAFV600E. TRAIL dependence on the constitutive activation of BRAFV600E is emphasised through the overexpression of BRAFV600E in the permissive genetic background of colon adenocarcinoma Caco-2 cells. Pharmacological suppression of the PI3K pathway further enhances the synergistic effect between TRAIL and PLX4720 in RKO cells, indicating the presence of PIK3CAMT as the inhibitory factor. Another rational combination includes 17-AAG synergism with TRAIL in a BRAFV600E mutant dependent manner to commit cells to apoptosis, through DR5 and the amplification of the apoptotic pathway. We have successfully utilised combinations of two chemically unrelated BRAFV600E inhibitors in combination with TRAIL in a BRAFV600E mutated background and provided insight for new anti-cancer strategies where the activated PI3KCA mutation oncogene should be suppressed

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms.

This is the author accepted manuscript.OBJECTIVE: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. DESIGN: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. RESULTS: We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10-10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). CONCLUSION: In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.German Research CouncilAustrian Science FundFaculty of Medicine, Saarland UniversityResearch Council of LithuaniaSwedish Research CouncilMedical Research Counci

Claudin-containing exosomes in the peripheral circulation of women with ovarian cancer

<p>Abstract</p> <p>Background</p> <p>The absence of highly sensitive and specific serum biomarkers makes mass screening for ovarian cancer impossible. The claudin proteins are frequently overexpressed in ovarian cancers, but their potential as prognostic, diagnostic, or detection markers remains unclear. Here, we have explored the possible use of these proteins as screening biomarkers for ovarian cancer detection.</p> <p>Methods</p> <p>Claudin protein shedding from cells was examined by immunoblotting of conditioned culture media. The presence of claudins in exosomes released from ovarian cancer cells was demonstrated by sucrose gradient separation and immunogold electron microscopy experiments. Claudin-4-containing exosomes in the plasma of ovarian cancer patients were evaluated in a pilot panel of 63 ovarian cancer patients and 50 healthy volunteers. The CA125 marker was also assessed in these samples and compared with claudin-4 positivity.</p> <p>Results</p> <p>We show that full-length claudins can be shed from ovarian cancer cells in culture and found in the media as part of small lipid vesicles known as exosomes. Moreover, 32 of 63 plasma samples from ovarian cancer patients exhibited the presence of claudin-4-containing exosomes. In contrast, only one of 50 samples from individuals without cancer exhibited claudin-4-positive exosomes. In our small panel, at a specificity of 98%, the claudin-4 and CA125 tests had sensitivities of 51% and 71%, respectively. The two tests did not appear to be independent and were strongly correlated.</p> <p>Conclusion</p> <p>Our work shows for the first time that claudin-4 can be released from ovarian cancer cells and can be detected in the peripheral circulation of ovarian cancer patients. The development of sensitive assays for the detection of claudin-4 in blood will be crucial in determining whether this approach can be useful, alone or in combination with other screening methods, for the detection of ovarian cancer.</p

Counseling patients about sexual health when considering post-prostatectomy radiation treatment

Prostate cancer is the second most frequently diagnosed cancer in men in the United States. Many men with clinically localized prostate cancer survive for 15 years or more. Although early detection and successful definitive treatments are increasingly common, a debate regarding how aggressively to treat prostate cancer is ongoing because of the effect of aggressive treatment on the quality of life, including sexual functioning. We examined current research on the effect of post-prostatectomy radiation treatment on sexual functioning, and suggest a way in which patient desired outcomes might be taken into consideration while making decisions with regard to the timing of radiation therapy after prostatectomy

Transient Gastric Irritation in the Neonatal Rats Leads to Changes in Hypothalamic CRF Expression, Depression- and Anxiety-Like Behavior as Adults

A disturbance of the brain-gut axis is a prominent feature in functional bowel disorders (such as irritable bowel syndrome and functional dyspepsia) and psychological abnormalities are often implicated in their pathogenesis. We hypothesized that psychological morbidity in these conditions may result from gastrointestinal problems, rather than causing them.Functional dyspepsia was induced by neonatal gastric irritation in male rats. 10-day old male Sprague-Dawley rats received 0.1% iodoacetamide (IA) or vehicle by oral gavage for 6 days. At 8-10 weeks of age, rats were tested with sucrose preference and forced-swimming tests to examine depression-like behavior. Elevated plus maze, open field and light-dark box tests were used to test anxiety-like behaviors. ACTH and corticosterone responses to a minor stressor, saline injection, and hypothalamic CRF expression were also measured.Behavioral tests revealed changes of anxiety- and depression-like behaviors in IA-treated, but not control rats. As compared with controls, hypothalamic and amygdaloid CRF immunoreactivity, basal levels of plasma corticosterone and stress-induced ACTH were significantly higher in IA-treated rats. Gastric sensory ablation with resiniferatoxin had no effect on behaviors but treatment with CRF type 1 receptor antagonist, antalarmin, reversed the depression-like behavior in IA-treated ratsThe present results suggest that transient gastric irritation in the neonatal period can induce a long lasting increase in depression- and anxiety-like behaviors, increased expression of CRF in the hypothalamus, and an increased sensitivity of HPA axis to stress. The depression-like behavior may be mediated by the CRF1 receptor. These findings have significant implications for the pathogenesis of psychological co-morbidity in patients with functional bowel disorders

Electrons, Photons, and Force: Quantitative Single-Molecule Measurements from Physics to Biology

Single-molecule measurement techniques have illuminated unprecedented details of chemical behavior, including observations of the motion of a single molecule on a surface, and even the vibration of a single bond within a molecule. Such measurements are critical to our understanding of entities ranging from single atoms to the most complex protein assemblies. We provide an overview of the strikingly diverse classes of measurements that can be used to quantify single-molecule properties, including those of single macromolecules and single molecular assemblies, and discuss the quantitative insights they provide. Examples are drawn from across the single-molecule literature, ranging from ultrahigh vacuum scanning tunneling microscopy studies of adsorbate diffusion on surfaces to fluorescence studies of protein conformational changes in solution