Sediment-Water Interactions Affecting Dissolved-Mercury Distributions in Camp Far West Reservoir, California

Field and laboratory studies were conducted in April and November 2002 to provide the first direct measurements of the benthic flux of dissolved (0.2-micrometer filtered) mercury species (total and methylated forms) between the bottom sediment and water column at three sampling locations within Camp Far West Reservoir, California: one near the Bear River inlet to the reservoir, a second at a mid-reservoir site of comparable depth to the inlet site, and the third at the deepest position in the reservoir near the dam (herein referred to as the inlet, midreservoir and near-dam sites, respectively; Background, Fig. 1). Because of interest in the effects of historic hydraulic mining and ore processing in the Sierra Nevada foothills just upstream of the reservoir, dissolved-mercury species and predominant ligands that often control the mercury speciation (represented by dissolved organic carbon, and sulfides) were the solutes of primary interest. Benthic flux, sometimes referred to as internal recycling, represents the transport of dissolved chemical species between the water column and the underlying sediment. Because of the affinity of mercury to adsorb onto particle surfaces and to form insoluble precipitates (particularly with sulfides), the mass transport of mercury in mining-affected watersheds is typically particle dominated. As these enriched particles accumulate at depositional sites such as reservoirs, benthic processes facilitate the repartitioning, transformation, and transport of mercury in dissolved, biologically reactive forms (dissolved methylmercury being the most bioavailable for trophic transfer). These are the forms of mercury examined in this study. In contrast to typical scientific manuscripts, this report is formatted in a pyramid-like structure to serve the needs of diverse groups who may be interested in reviewing or acquiring information at various levels of technical detail (Appendix 1). The report enables quick transitions between the initial summary information (figuratively at the top of the pyramid) and the later details of methods or results (figuratively towards the base of the pyramid) using hyperlinks to supporting figures and tables, and an electronically linked Table of Contents. During two sampling events, two replicate sediment cores (Coring methods; Fig. 2) from each of three reservoir locations (Fig. 1) were used in incubation experiments to provide flux estimates and benthic biological characterizations. Incubation of these cores provided “snapshots” of solute flux across the sediment-water interface in the reservoir, under benthic, environmental conditions representative of the time and place of collection. Ancillary data, including nutrient and ligand fluxes, were gathered to provide a water-quality framework from which to compare the results for mercury

HLA class I-restricted MYD88 L265P-derived peptides as specific targets for lymphoma immunotherapy

Genome sequencing has uncovered an array of recurring somatic mutations in different non-Hodgkin lymphoma (NHL) subtypes. If affecting protein-coding regions, such mutations may yield mutation-derived peptides that may be presented by HLA class I proteins and recognized by cytotoxic T cells. A recurring somatic and oncogenic driver mutation of the Toll-like receptor adaptor protein MYD88, Leu265Pro (L265P) was identified in up to 90% of different NHL subtype patients. We therefore screened the potential of MYD88(L265P)-derived peptides to elicit cytotoxic T cell responses as tumor-specific neoantigens. Based on in silico predictions, we identified potential MYD88(L265P)-containing HLA ligands for several HLA class I restrictions. A set of HLA class I MYD88(L265P)-derived ligands elicited specific cytotoxic T cell responses for HLA-B*07 and -B*15. These data highlight the potential of MYD88(L265P) mutation-specific peptide-based immunotherapy as a novel personalized treatment approach for patients with MYD88(L265P+) NHLs that may complement pharmacological approaches targeting oncogenic MyD88 L265P signaling

MARIS: Method for Analyzing RNA following Intracellular Sorting

Transcriptional profiling is a key technique in the study of cell biology that is limited by the availability of reagents to uniquely identify specific cell types and isolate high quality RNA from them. We report a Method for Analyzing RNA following Intracellular Sorting (MARIS) that generates high quality RNA for transcriptome profiling following cellular fixation, intracellular immunofluorescent staining and FACS. MARIS can therefore be used to isolate high quality RNA from many otherwise inaccessible cell types simply based on immunofluorescent tagging of unique intracellular proteins. As proof of principle, we isolate RNA from sorted human embryonic stem cell-derived insulin-expressing cells as well as adult human β cells. MARIS is a basic molecular biology technique that could be used across several biological disciplines.Howard Hughes Medical InstituteHarvard Stem Cell InstituteNational Institutes of Health (U.S.) (grant 2U01DK07247307)National Institutes of Health (U.S.) (grant RL1DK081184)National Institutes of Health (U.S.) (grant 1U01HL10040804

Slip pulse and resonance of the Kathmandu basin during the 2015 Gorkha earthquake, Nepal.

This is the author accepted manuscript. The final version is available from AAAS via http://dx.doi.org/10.1126/science.aac6383Detailed geodetic imaging of earthquake ruptures enhances our understanding of earthquake physics and associated ground shaking. The 25 April 2015 moment magnitude 7.8 earthquake in Gorkha, Nepal was the first large continental megathrust rupture to have occurred beneath a high-rate (5-hertz) Global Positioning System (GPS) network. We used GPS and interferometric synthetic aperture radar data to model the earthquake rupture as a slip pulse ~20 kilometers in width, ~6 seconds in duration, and with a peak sliding velocity of 1.1 meters per second, which propagated toward the Kathmandu basin at ~3.3 kilometers per second over ~140 kilometers. The smooth slip onset, indicating a large (~5-meter) slip-weakening distance, caused moderate ground shaking at high frequencies (>1 hertz; peak ground acceleration, ~16% of Earth's gravity) and minimized damage to vernacular dwellings. Whole-basin resonance at a period of 4 to 5 seconds caused the collapse of tall structures, including cultural artifacts.The Nepal Geodetic Array was funded by internal funding to JPA from Caltech and DASE and by the Gordon and Betty Moore Foundation, through Grant GBMF 423.01 to the Caltech Tectonics Observatory and was maintained thanks to NSF Grant EAR 13-5136. Andrew Miner and the PAcific Northwest Geodetic Array (PANGA) at Central Washington University are thanked for technical assistance with the construction and operation of the Tribhuvan University-CWU network. Additional funding for the TU-CWU network came from United Nations Development Programme and Nepal Academy for Science and Technology. The high rate data were recovered thanks to a rapid intervention funded by NASA (US) and the Department of Foreign International Development (UK). We thank Trimble Navigation Ltd and the Vaidya family for supporting the rapid response as well. The accelerometer record at KATNP was provided by USGS. Research at UC Berkeley was funded by the Gordon and Betty Moore Foundation through grant GBMF 3024. A portion of this work was carried out at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration. The GPS data were processed by ARIA (JPL) and the Scripps Orbit and Permanent Array Center. The effort at the Scripps Institution of Oceanography was funded by NASA grants NNX14AQ53G and NNX14AT33G. ALOS-2 data were provided under JAXA (Japan) PI Investigations 1148 and 1413. JPA thanks the Royal Society for support. We thank Susan Hough, Doug Given, Irving Flores and Jim Luetgert for contribution to the installation of this station

The protective effect of human renal sinus fat on glomerular cells is reversed by the hepatokine fetuin-A

Renal sinus fat (RSF) is a perivascular fat compartment located around renal arteries. In this in vitro and in vivo study we hypothesized that the hepatokine fetuin-A may impair renal function in non alcoholic fatty liver disease (NAFLD) by altering inflammatory signalling in RSF. To study effects of the crosstalk between fetuin-A, RSF and kidney, human renal sinus fat cells (RSFC) were isolated and cocultured with human endothelial cells (EC) or podocytes (PO). RSFC caused downregulation of proinflammatory and upregulation of regenerative factors in cocultured EC and PO, indicating a protective influence of RFSC. However, fetuin-A inverted these benign effects of RSFC from an anti- to a proinflammatory status. RSF was quantified by magnetic resonance imaging and liver fat content by 1H-MR spectroscopy in 449 individuals at risk for type 2 diabetes. Impaired renal function was determined via urinary albumin/creatinine-ratio (uACR). RSF did not correlate with uACR in subjects without NAFLD (n = 212, p = 0.94), but correlated positively in subjects with NAFLD (n = 105, p = 0.0005). Estimated glomerular filtration rate (eGRF) was inversely correlated with RSF, suggesting lower eGFR for subjects with higher RSF (r = 0.24, p < 0.0001). In conclusion, our data suggest that in the presence of NAFLD elevated fetuin-A levels may impair renal function by RSF-induced proinflammatory signalling in glomerular cells

Expression of the embryonic stem cell marker SOX2 in early-stage breast carcinoma

<p>Abstract</p> <p>Background</p> <p>The SRY-related HMG-box family of transcription factors member <it>SOX2 </it>has been mainly studied in embryonic stem cells as well as early foregut and neural development. More recently, SOX2 was shown to participate in reprogramming of adult somatic cells to a pluripotent stem cell state and implicated in tumorigenesis in various organs. In breast cancer, SOX2 expression was reported as a feature of basal-like tumors. In this study, we assessed SOX2 expression in 95 primary tumors of postmenopausal breast cancer patients.</p> <p>Methods</p> <p>Samples from 95 patients diagnosed and treated at the University of Tuebingen Institute of Pathology and Women's Hospital were analyzed by immunohistochemistry for SOX2 expression in the primary tumor samples and in corresponding lymph node metastasis, where present. Furthermore, SOX2 amplification status was assessed by FISH in representative samples. In addition, eighteen fresh frozen samples were analyzed for <it>SOX2</it>, <it>NANOG </it>and <it>OCT4 </it>gene expression by real-time PCR.</p> <p>Results</p> <p>SOX2 expression was detected in 28% of invasive breast carcinoma as well as in 44% of ductal carcinoma in situ (DCIS) lesions. A score of SOX2 expression (score 0 to 3) was defined in order to distinguish SOX2 negative (score 0) from SOX2 positive samples (score 1-3) and among latter the subgroup of SOX2 high expressors (score 3 > 50% positive cells). Overall, the incidence of SOX2 expression (score 1-3) was higher than previously reported in a cohort of lymph node negative patients (28% versus 16.7%). SOX2 expression was detected across different breast cancer subtypes and did not correlate with tumor grading. However, high SOX2 expression (score 3) was associated with larger tumor size (p = 0.047) and positive lymph node status (0.018). Corresponding metastatic lymph nodes showed higher SOX2 expression and were significantly more often SOX2 positive than primary tumors (p = 0.0432).</p> <p>Conclusions</p> <p>In this report, we show that the embryonic stem cell factor SOX2 is expressed in a variety of early stage postmenopausal breast carcinomas and metastatic lymph nodes. Our data suggest that SOX2 plays an early role in breast carcinogenesis and high expression may promote metastatic potential. Further studies are needed to explore whether SOX2 can predict metastatic potential at an early tumor stage.</p

Cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric cancer: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)

BACKGROUND: Cetuximab enhances the efficacy of chemotherapy in several cancer types. This trial assessed the activity of cetuximab and chemotherapy in advanced gastric cancer. METHODS: Patients with previously untreated, metastatic, gastric cancer received cetuximab 400 mg m(-2) at first infusion followed by weekly infusions of 250 mg m(-2) combined with FUFOX (oxaliplatin 50 mg m(-2), 5-FU 2000 mg m(-2), and DL-folinic acid 200 mg m(-2) d1, 8, 15 and 22 qd36). The primary endpoint was tumour response. RESULTS: Overall, 52 patients were enrolled. The most common grade 3/4 toxicities were diarrhoea (33%), and skin toxicity (24%). Efficacy was evaluable in 46 patients who showed a response rate of 65% (CI 95%: 50-79%) including four complete responses. Time to progression (TTP) was 7.6 months (CI 95%: 5.0-10.1 months) and overall survival (OS) was 9.5 months (CI 95%: 7.9-11.1 months). Epidermal growth factor receptor (EGFR) was detectable in 60% of tumours but showed no correlation with treatment outcome. A KRAS mutation was found in only 1 of 32 (3%) tumour samples analysed. CONCLUSION: Cetuximab plus FUFOX showed an interesting high response rate in metastatic gastric cancer. Cetuximab plus platinum-fluoropyrimidine chemotherapy is at present being investigated in a phase III randomised controlled trial