Palmitoylation of Desmoglein 2 Is a Regulator of Assembly Dynamics and Protein Turnover.

Desmosomes are prominent adhesive junctions present between many epithelial cells as well as cardiomyocytes. The mechanisms controlling desmosome assembly and remodeling in epithelial and cardiac tissue are poorly understood. We recently identified protein palmitoylation as a mechanism regulating desmosome dynamics. In this study, we have focused on the palmitoylation of the desmosomal cadherin desmoglein-2 (Dsg2) and characterized the role that palmitoylation of Dsg2 plays in its localization and stability in cultured cells. We identified two cysteine residues in the juxtamembrane (intracellular anchor) domain of Dsg2 that, when mutated, eliminate its palmitoylation. These cysteine residues are conserved in all four desmoglein family members. Although mutant Dsg2 localizes to endogenous desmosomes, there is a significant delay in its incorporation into junctions, and the mutant is also present in a cytoplasmic pool. Triton X-100 solubility assays demonstrate that mutant Dsg2 is more soluble than wild-type protein. Interestingly, trafficking of the mutant Dsg2 to the cell surface was delayed, and a pool of the non-palmitoylated Dsg2 co-localized with lysosomal markers. Taken together, these data suggest that palmitoylation of Dsg2 regulates protein transport to the plasma membrane. Modulation of the palmitoylation status of desmosomal cadherins can affect desmosome dynamics

South Puget Sound dissolved oxygen study: water quality model calibration and scenarios

Portions of South and Central Puget Sound are on the Clean Water Act Section 303(d) list of impaired waters because observed dissolved oxygen measurements do not meet the Washington State water quality standards. Human sources of nutrients can increase algae growth, which can decrease oxygen as the additional organic matter decays. Low oxygen can impair fish and other marine life. Computer modeling tools are needed to isolate the impacts of human contributions. The purpose of this study is to identify how much human contributions are contributing to low dissolved oxygen (DO) in South Puget Sound. Previous reports summarize data collection, nutrient load estimates for marine point sources and watershed inflows that include point and nonpoint sources, and the circulation model. This report summarizes the calibration and application of the water quality model to isolate the impacts from groups of sources. The model predicts the regional and seasonal patterns of chlorophyll, DO, and nitrogen throughout South and Central Puget Sound. The model predicts that internal (inside the model domain) current human nutrient loads from marine point sources and watersheds as well as external (north of model domain) current anthropogenic loads are causing DO to decline by as much as 0.4 mg/L in portions of Totten, Eld, Budd, Carr, and Case inlets, and East Passage, which violates the standards. There are not violations across the entire South or Central Puget Sound. While keeping the external anthropogenic load constant, internal marine point sources exert a greater impact than human sources within watershed inflows. Reducing the internal human nutrient load would decrease the magnitude and extent of DO depletion. Additional scenarios are needed to isolate the effects of individual sources

Varying levels of clonality and ploidy create barriers to gene flow and challenges for conservation of an Australian arid-zone ecosystem engineer, Acacia loderi

Acacia loderi, the ecosystem engineer of the endangered Acacia loderi Shrublands in arid eastern Australia, spans a persistent (\u3e 15 000 year) but poorly studied landscape feature, the Darling River. We investigated the genetic structure of 19 stands of eight to \u3e 1000 plants separated by \u3c 300 km to test for variation in life histories between semi-arid and arid stands to the east and west of the Darling River, respectively. Eight of nine stands east of the Darling were exclusively sexual, whereas most of those to the west were clonal. Three western stands were monoclonal, two were polyploid, and one was a diverse mix of diploid and triploid phenotypes. Bayesian analysis revealed a complex genetic structure within the western stands, whereas the eastern stands formed only two genetic clusters. Conservation of small stands may require augmentation of genotypic diversity. However, most genotypic diversity resides within the eastern stands. Although arid zone stands of A. loderi are not always clonal, clonality and polyploidy are more common in the arid west. Clear demarcation of life histories either side of the Darling River may reflect ancient or contemporary effects of physical disturbance associated with the river channel, or cryptic environmental differences, with sexual and asexual reproduction, respectively, at a selective premium in the semi-arid east and arid west. The restricted distribution of clones and variation in clonality and polyploidy suggests that smaller stands may be vulnerable and warrant individual management

Cellular milieu in clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is globally the most prevalent renal cancer. The cells of origin in ccRCC have been identified as proximal tubular epithelial cells (PTEC); however, the transcriptomic pathways resulting in the transition from normal to malignant PTEC state have remained unclear. Immunotherapy targeting checkpoints have revolutionized the management of ccRCC, but a sustained clinical response is achieved in only a minority of ccRCC patients. This indicates that our understanding of the mechanisms involved in the malignant transition and resistance to immune checkpoint therapy in ccRCC is unclear. This review examines recent single-cell transcriptomics studies of ccRCC to clarify the transition of PTEC in ccRCC development, and the immune cell types, states, and interactions that may limit the response to targeted immune therapy, and finally suggests stromal cells as key drivers in recurrent and locally invasive ccRCC. These and future single-cell transcriptomics studies will continue to clarify the cellular milieu in the ccRCC microenvironment, thus defining actional clinical, therapeutic, and prognostic characteristics of ccRCC

The importance of context and the effect of information and deliberation on opinion change regarding environmental issues in citizens’ juries

Citizens’ juries have become a popular method for engaging citizens in deliberation about complex public policy issues, such as climate action and sustainable development. Empirical evidence routinely indicates that jurors change their minds throughout the process. What is less clear is when and why this occurs and whether the causes are consistent across juries that consider the same topic but are situated within different contexts. We present evidence of opinion change in citizens’ juries through a natural experiment, contrasting three local contexts of onshore windfarm development in Scotland; viz. existing, planned, and absent. Jurors’ individual opinions of climate change, wind energy, and windfarms were measured through questionnaires at four time points: the start, following information-giving, reflection, and deliberation. Statistical examination of jurors’ responses, through paired sample t-tests, Wilcoxon sign-tests, and Generalised Least Squares regression, reveals to what extent substantive changes were associated with different phases and locational contexts. In all three juries, opinion change occurs throughout the process, on different topics, and to different degrees. While the information phase consistently influences jurors’ opinions the most, jury composition affects the magnitude and direction of opinion change, with outcomes contingent on contexts. Our findings are important for informing how mini-publics are designed and used to inform environmental policy-making at different scales

History of the Innovation of Damage Control for Management of Trauma Patients: 1902-2016

Objective: To review the history of the innovation of damage control (DC) for management of trauma patients. Background: DC is an important development in trauma care that provides a valuable case study in surgical innovation. Methods: We searched bibliographic databases (1950-2015), conference abstracts (2009-2013), Web sites, textbooks, and bibliographies for articles relating to trauma DC. The innovation of DC was then classified according to the Innovation, Development, Exploration, Assessment, and Long-term study model of surgical innovation. Results: The innovation\u27\u27 of DC originated from the use of therapeutic liver packing, a practice that had previously been abandoned after World War II because of adverse events. It then developed\u27\u27 into abbreviated laparotomy using rapid conservative operative techniques.\u27\u27 Subsequent exploration\u27\u27 resulted in the application of DC to increasingly complex abdominal injuries and thoracic, peripheral vascular, and orthopedic injuries. Increasing use of DC laparotomy was followed by growing reports of postinjury abdominal compartment syndrome and prophylactic use of the open abdomen to prevent intra-abdominal hypertension after DC laparotomy. By the year 2000, DC surgery had been widely adopted and was recommended for use in surgical journals, textbooks, and teaching courses ( assessment\u27\u27 stage of innovation). Long-term study\u27\u27 of DC is raising questions about whether the procedure should be used more selectively in the context of improving resuscitation practices. Conclusions: The history of the innovation of DC illustrates how a previously abandoned surgical technique was adapted and readopted in response to an increased understanding of trauma patient physiology and changing injury patterns and trauma resuscitation practices

Prospective Phase II trial of drug-eluting bead chemoembolization for liver transplant candidates with hepatocellular carcinoma and marginal hepatic reserve.

Purpose: To determine whether chemoembolization using drug-eluting beads (DEB-TACE) is safe and effective for liver transplantation candidates with liver-limited hepatocellular carcinoma (HCC) without vascular invasion and baseline hepatic dysfunction. Materials and methods: Seventeen adult liver transplantation candidates (median age 66 years, range 58-73 years; 13 men) with HCC were treated with DEB-TACE as a part of Stage 1 of a prospective single-institution Phase II trial. All patients had marginal hepatic reserve based on at least one of the following criteria: ascites (n=14), bilirubin between 3 and 6 mg/dL (n=5), AST 5-10 times upper normal limit (n=1), INR between 1.6 and 2.5 (n=4), portal vein thrombosis (n=2), and/or portosystemic shunt (n=2). Primary study objectives were safety and best observed radiographic response. Results: Thirty-seven DEB-TACE procedures were performed. Objective response rate and disease control rate were 63% and 88%, respectively. HCC progression was observed in 12 patients. Median time to progression was 5.6 months (range 0.9-13.6 months). Within 1 month following DEB-TACE, 13 patients (76%) developed grade 3 or 4 AE attributable to the procedure. Four patients (all within Milan Criteria) were transplanted (2.7-6.9 months after DEB-TACE), and 12 patients died (1.8-32 months after DEB-TACE). All deaths were due to liver failure that was either unrelated to HCC (n=5), in the setting of metastatic HCC (n=5), or in the setting of locally advanced HCC (n=2). Mortality rate at 1 month was 0%. Conclusions: DEB-TACE achieves tumor responses but carries a high risk of hepatotoxicity for liver transplant candidates with HCC and marginal hepatic reserve

Ultraviolet Imaging of the Globular Cluster 47 Tucanae

We have used the Ultraviolet Imaging Telescope to obtain deep far-UV (1620 Angstrom), 40' diameter images of the prototypical metal-rich globular cluster 47 Tucanae. We find a population of about 20 hot (Teff > 9000 K) objects near or above the predicted UV luminosity of the hot horizontal branch (HB) and lying within two half-light radii of the cluster center. We believe these are normal hot HB or post-HB objects rather than interacting binaries or blue stragglers. IUE spectra of two are consistent with post-HB phases. These observations, and recent HST photometry of two other metal-rich clusters, demonstrate that populations with rich, cool HB's can nonetheless produce hot HB and post-HB stars. The cluster center also contains an unusual diffuse far-UV source which is more extended than its V-band light. It is possible that this is associated with an intracluster medium, for which there was earlier infrared and X-ray evidence, and is produced by C IV emission or scattered light from grains.Comment: 13 pages AASLaTeX including one postscript figure and one bitmapped image, JPEG format. Submitted to the Astronomical Jorunal. Full Postscript version available at http://www.astro.virginia.edu/~bd4r

The utility of convection-permitting ensembles for the prediction of stationary convective bands

This study examines convection-permitting numerical simulations of four cases of terrain-locked quasi-stationary convective bands over the UK. For each case, a 2.2-km grid-length 12-member ensemble and 1.5-km grid-length deterministic forecast are analyzed, each with two different initialization times. Object-based verification is applied to determine whether the simulations capture the structure, location, timing, intensity and duration of the observed precipitation. These verification diagnostics reveal that the forecast skill varies greatly between the four cases. Although the deterministic and ensemble simulations captured some aspects of the precipitation correctly in each case, they never simultaneously captured all of them satisfactorily. In general, the models predicted banded precipitation accumulations at approximately the correct time and location, but the precipitating structures were more cellular and less persistent than the coherent quasi-stationary bands that were observed. Ensemble simulations from the two different initialization times were not significantly different, which suggests a potential benefit of time-lagging subsequent ensembles to increase ensemble size. The predictive skill of the upstream larger-scale flow conditions and the simulated precipitation on the convection-permitting grids were strongly correlated, which suggests that more accurate forecasts from the parent ensemble should improve the performance of the convection-permitting ensemble nested within it