Is It Scientific? Viewer Perceptions of Storm Surge Visualizations

Scientists and coastal risk managers use semi-realistic visualizations of storm surge connected to hydrodynamic models to make projected impacts engaging and accessible. Such visualizations do not fit within established frameworks for visualizing risk because they add representational detail and may imply more certainty than exists regarding outcomes. This study explores how audiences regard these visualizations in relation to perceived representational norms for scientific graphics and visualizations. Online survey respondents (735 experts and members of the general public, primarily in Rhode Island and the northeastern United States) were asked about characteristics that make a representation “scientific.” Results demonstrate differences in norms emphasized by experts and the public, and that the persons and institutions creating the visualization may influence perceptions of legitimacy more than the style of the visualization. This may increase the potential of visualizations to be misleading and may foster perceptions that scientists are engaged in advocacy

Cell-type-specific modulation of feedback inhibition by serotonin in the hippocampus

Midbrain raphe nuclei provide strong serotonergic projections to the hippocampus, in which serotonin (5-HT) exerts differential effects mediated by multiple 5-HT receptor subtypes. The functional relevance of this diversity of information processing is poorly understood. Here we show that serotonin via 5-HT(1B) heteroreceptors substantially reduces synaptic excitation of cholecystokinin-expressing interneurons in area CA1 of the rat hippocampus, in contrast to parvalbumin-expressing basket cells. The reduction is input specific, affecting only glutamatergic synaptic transmission originating from CA1 pyramidal cells. As a result, serotonin selectively decreases feedback inhibition via 5-HT(1B) receptor activation and subsequently increases the integration time window for spike generation in CA1 pyramidal cells. Our data imply an important role for serotonergic modulation of GABAergic action in subcortical control of hippocampal output

Clinicopathological correlations of mesenteric fibrosis and evaluation of a novel biomarker for fibrosis detection in small bowel neuroendocrine neoplasms

PURPOSE: Mesenteric fibrosis (MF) in small intestinal neuroendocrine neoplasms (SINENs) is often associated with significant morbidity and mortality. The detection of MF is usually based on radiological criteria, but no previous studies have attempted a prospective, multidimensional assessment of mesenteric desmoplasia to determine the accuracy of radiological measurements. There is also a lack of non-invasive biomarkers for the detection of image-negative MF. METHODS: A multidimensional assessment of MF incorporating radiological, surgical and histological parameters was performed in a prospective cohort of 34 patients with SINENs who underwent primary resection. Pre-operative blood samples were collected in 20 cases to evaluate a set of five profibrotic circulating transcripts-the "fibrosome"-that is included as an "omic" component of the NETest. RESULTS: There was a significant correlation between radiological and surgical assessments of MF (p < 0.05). However, there were several cases of image-negative MF. The NETest-fibrosome demonstrated an accuracy of 100% for the detection of microscopic MF. CONCLUSIONS: The detection of MF by radiological criteria has limitations. The NETest-fibrosome is a promising biomarker for fibrosis detection and further validation of these results would be needed in larger, multicentre studies

Inhibition of Ocular Tumor and Endothelial Cell Growth with a TEAD4216 Peptide Fragment

Purpose: Transcriptional enhancer factor 1-related (RTEF-1) also known as TEAD4 is expressed in ocular vascular endothelial cells and plays a role in the control of VEGF expression. Alternative processing of TEAD4 hnRNA results in different proteins able to stimulate or inhibit VEGF gene transcription. The purpose of this study is to test whether short peptide fragments (STY-RMR), representing functional domains of the inhibitory TEAD4216 isoform, can inhibit tumor as well as endothelial cell proliferation.Experimental Design: Cell proliferation was assessed using a colorimetric assay in cell lines incubated with STY-RMR, the amount of secreted VEGF within media was determined both in treated and control cell lines.Results: Significant dose dependent inhibition of cell proliferation was observed. Maximal inhibition of ocular melanoma (Mel 202 and Mel 207) cell proliferation was observed at a dose of 30 mg/100ml of STY-RMR (87% and 60% inhibition, respectively). At the same dose, more than 50% inhibition was observed in retinoblastoma and breast cancer cells (P &lt;0.001). Significant inhibition of primate ocular endothelial cell proliferation (42% at 30 mg/100 ml (p &lt; 0.001), and retinal pigment epithelial cells showed also a 75% inhibition (p = 0.007). Secreted VEGF was decreased in the media of all tested cell lines that had been exposed to STY-RMR.Conclusion: Functional short peptide domains derived from the TEAD4216 isoform may prove to be useful for treatment of ocular tumors and other VEGF dependent neovascular disease.Inhibition of proliferation and VEGF production within ocular endothelial cells indicate the potential of this agent to treat age-related macular degeneration (ARMD) and diabetic retinopathy (DR)

Serious asthma events with fluticasone plus salmeterol versus fluticasone alone

Background: the safe and appropriate use of long-acting beta-agonists (LABAs) for the treatment of asthma has been widely debated. In two large clinical trials, investigators found a potential risk of serious asthma-related events associated with LABAs. This study was designed to evaluate the risk of administering the LABA salmeterol in combination with an inhaled glucocorticoid, fluticasone propionate. Methods: in this multicenter, randomized, double-blind trial, adolescent and adult patients (age, ≥12 years) with persistent asthma were assigned to receive either fluticasone with salmeterol or fluticasone alone for 26 weeks. All the patients had a history of a severe asthma exacerbation in the year before randomization but not during the previous month. Patients were excluded from the trial if they had a history of life-threatening or unstable asthma. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization). Noninferiority of fluticasone-salmeterol to fluticasone alone was defined as an upper boundary of the 95% confidence interval for the risk of the primary safety end point of less than 2.0. The efficacy end point was the first severe asthma exacerbation. Results: of 11,679 patients who were enrolled, 67 had 74 serious asthma-related events, with 36 events in 34 patients in the fluticasone-salmeterol group and 38 events in 33 patients in the fluticasone-only group. The hazard ratio for a serious asthma-related event in the fluticasone-salmeterol group was 1.03 (95% confidence interval [CI], 0.64 to 1.66), and noninferiority was achieved (P=0.003). There were no asthma-related deaths; 2 patients in the fluticasone-only group underwent asthma-related intubation. The risk of a severe asthma exacerbation was 21% lower in the fluticasone-salmeterol group than in the fluticasone-only group (hazard ratio, 0.79; 95% CI, 0.70 to 0.89), with at least one severe asthma exacerbation occurring in 480 of 5834 patients (8%) in the fluticasone-salmeterol group, as compared with 597 of 5845 patients (10%) in the fluticasone-only group (P<0.001). Conclusions: patients who received salmeterol in a fixed-dose combination with fluticasone did not have a significantly higher risk of serious asthma-related events than did those who received fluticasone alone. Patients receiving fluticasone-salmeterol had fewer severe asthma exacerbations than did those in the fluticasone-only group. (AUSTRI ClinicalTrials.gov number, NCT01475721)

Cannabinoid type 2 receptors mediate a cell type-specific self-inhibition in cortical neurons

Endogenous cannabinoids are diffusible lipid ligands of the main cannabinoid receptors type 1 and 2 (CB1R and CB2R). In the central nervous system endocannabinoids are produced in an activity-dependent manner and have been identified as retrograde modulators of synaptic transmission. Additionally, some neurons display a cell-autonomous slow self-inhibition (SSI) mediated by endocannabinoids. In these neurons, repetitive action potential firing triggers the production of endocannabinoids, which induce a long-lasting hyperpolarization of the membrane potential, rendering the cells less excitable. Different endocannabinoid receptors and effector mechanisms have been described underlying SSI in different cell types and brain areas. Here, we investigate SSI in neurons of layer 2/3 in the somatosensory cortex. High-frequency bursts of action potentials induced SSI in pyramidal cells (PC) and regular spiking non-pyramidal cells (RSNPC), but not in fast-spiking interneurons (FS). In RSNPCs the hyperpolarization was accompanied by a change in input resistance due to the activation of G protein-coupled inward-rectifying K+ (GIRK) channels. A CB2R-specific agonist induced the long-lasting hyperpolarization, whereas preincubation with a CB2R-specific inverse agonist suppressed SSI. Additionally, using cannabinoid receptor knockout mice, we found that SSI was still intact in CB1R-deficient but abolished in CB2R-deficient mice. Taken together, we describe an additional SSI mechanism in which the activity-induced release of endocannabinoids activates GIRK channels via CB2Rs. These findings expand our knowledge about cell type-specific differential neuronal cannabinoid receptor signaling and suggest CB2R-selective compounds as potential therapeutic approaches

Transcriptomic Profiling of In Vitro Tumor-Stromal Cell Paracrine Crosstalk Identifies Involvement of the Integrin Signaling Pathway in the Pathogenesis of Mesenteric Fibrosis in Human Small Intestinal Neuroendocrine Neoplasms.

Aim: Analysis of the pathophysiology of mesenteric fibrosis (MF) in small intestinal neuroendocrine tumors (SI-NETs) in an in vitro paracrine model and in human SI-NET tissue samples. Methods: An indirect co-culture model of SI-NET cells KRJ-I and P-STS with stromal cells HEK293 was designed to evaluate the paracrine effects on cell metabolic activity, gene expression by RT2 PCR Profilers to analyse cancer and fibrosis related genes, and RNA sequencing. The integrin signaling pathway, a specific Ingenuity enriched pathway, was further explored in a cohort of human SI-NET tissues by performing protein analysis and immunohistochemistry. Results: RT Profiler array analysis demonstrated several genes to be significantly up- or down-regulated in a cell specific manner as a result of the paracrine effect. This was further confirmed by employing RNA sequencing revealing multiple signaling pathways involved in carcinogenesis and fibrogenesis that were significantly affected in these cell lines. A significant upregulation in the expression of various integrin pathway - related genes was identified in the mesenteric mass of fibrotic SI-NET as confirmed by RT-qPCR and immunohistochemistry. Protein analysis demonstrated downstream activation of the MAPK and mTOR pathways in some patients with fibrotic SI-NETs. Conclusion: This study has provided the first comprehensive analysis of the crosstalk of SI-NET cells with stromal cells. A novel pathway - the integrin pathway - was identified and further validated and confirmed in a cohort of human SI-NET tissue featured by a dual role in fibrogenesis/carcinogenesis within the neoplastic fibrotic microenvironment

Challenges to climate change adaptation in coastal small towns:Examples from Ghana, Uruguay, Finland, Denmark, and Alaska

The ability of a coastal settlement to adapt to climate change is largely dependent upon access to a range of resources, which many coastal towns and small cities lack. Coastal small towns of less than 10,000 are therefore at a significant disadvantage compared to larger settlements when it comes to adaptation. One way to begin to overcome this disadvantage is to compare coastal small towns in order to identify efficiencies and support knowledge sharing. In this article we present and analyse five case studies of coastal small towns: Fuvemeh, Ghana; Kiyú, Uruguay; Hanko, Finland; Lemvig, Denmark; and Nome, Alaska, USA. A number of key outcomes and lessons were identified which highlights the need for a formal network of international coastal small towns to encourage and develop knowledge sharing practices going forward. A further lesson is the importance of using a range of indicators in order to establish the regional/national importance of a town. Basing this solely on population size can result in an erroneous interpretation of the significance (and therefore adaptive capacity) of a coastal small town. Finally, despite many barriers to adaptation in coastal small towns, being small offers some potential advantages, such as the possibility of being able to form a community consensus more easily, using 3D visualisations for adaptation planning, and having managed realignment as a realistic management option. It is imperative that climate change resilience in coastal small towns is increased by focussing on overcoming barriers and developing appropriate adaptation approaches by governments, non-governmental organisations, business, and researchers