Increased accumulation of sulfur in lake sediments of the high Arctic

Author Posting. © The Author(s), 2010. This is the author's version of the work. It is posted here by permission of American Chemical Society for personal use, not for redistribution. The definitive version was published in Environmental Science & Technology 44 (2010): 8415-8421, doi:10.1021/es101991p.We report a synchronous increase in accumulation of reduced inorganic sulfur since c. 1980 in sediment cores from eight of nine lakes studied in the Canadian Arctic and Svalbard (Norway). Sediment incubations and detailed analyses of sediment profiles from two of the lakes indicate that increases in sulfur accumulation may be due ultimately to a changing climate. Warming-induced lengthening of the ice-free season is resulting in well-documented increases in algal production and sedimentation of the resulting detrital matter. Algal detritus is a rich source of labile carbon, which in these sediments stimulates dissimilatory sulfate reduction. The sulfide produced is stored in sediment (as acid volatile sulfide), converted to other forms of sulfur, or reoxidized to sulfate and lost to the water column. An acceleration of the sulfur cycle in Arctic lakes could have profound effects on important biogeochemical processes, such as carbon burial and mercury methylation.Funding was provided by the WHOI Ocean and Climate Change Institute, the USGS WHOI Postdoctoral Scholar Program, Environment Canada, the Danmarks Grundforskningsfond, and the Norges forskningsråd (grant number 107745/730)

Pathway profiling of a novel SRC inhibitor, AZD0424, in combination with MEK inhibitors

A more comprehensive understanding of how cells respond to drug intervention, the likely immediate signalling responses and how resistance may develop within different microenvironments will help inform treatment regimes. The nonreceptor tyrosine kinase SRC regulates many cellular signalling processes, and pharmacological inhibition has long been a target of cancer drug discovery projects. Here, we describe the in vitro and in vivo characterisation of the small‐molecule SRC inhibitor AZD0424. We show that AZD0424 potently inhibits the phosphorylation of tyrosine‐419 of SRC (IC50 ~ 100 nm) in many cancer cell lines; however, inhibition of cell viability, via a G1 cell cycle arrest, was observed only in a subset of cancer cell lines in the low (on target) micromolar range. We profiled the changes in intracellular pathway signalling in cancer cells following exposure to AZD0424 and other targeted therapies using reverse‐phase protein array (RPPA) analysis. We demonstrate that SRC is activated in response to treatment of KRAS‐mutant colorectal cell lines with MEK inhibitors (trametinib or AZD6244) and that AZD0424 abrogates this. Cell lines treated with trametinib or AZD6244 in combination with AZD0424 had reduced EGFR, FAK and SRC compensatory activation, and cell viability was synergistically inhibited. In vivo, trametinib treatment of mice‐bearing HCT116 tumours increased phosphorylation of SRC on Tyr419, and, when combined with AZD0424, inhibition of tumour growth was greater than with trametinib alone. We also demonstrate that drug‐induced resistance to trametinib is not re‐sensitised by AZD0424 treatment in vitro, likely as a result of multiple compensatory signalling mechanisms; however, inhibition of SRC remains an effective way to block invasion of trametinib‐resistant tumour cells. These data imply that SRC inhibition may offer a useful addition to MEK inhibitor combination strategies

Kindlin-1 promotes pulmonary breast cancer metastasis

Abstract In breast cancer, increased expression of the cytoskeletal adaptor protein Kindlin-1 has been linked to increased risks of lung metastasis, but the functional basis is unknown. Here, we show that in a mouse model of polyomavirus middle T antigen–induced mammary tumorigenesis, loss of Kindlin-1 reduced early pulmonary arrest and later development of lung metastasis. This phenotype relied on the ability of Kindlin-1 to bind and activate β integrin heterodimers. Kindlin-1 loss reduced α4 integrin–mediated adhesion of mammary tumor cells to the adhesion molecule VCAM-1 on endothelial cells. Treating mice with an anti–VCAM-1 blocking antibody prevented early pulmonary arrest. Kindlin-1 loss also resulted in reduced secretion of several factors linked to metastatic spread, including the lung metastasis regulator tenascin-C, showing that Kindlin-1 regulated metastatic dissemination by an additional mechanism in the tumor microenvironment. Overall, our results show that Kindlin-1 contributes functionally to early pulmonary metastasis of breast cancer. Significance: These findings provide a mechanistic proof in mice that Kindin-1, an integrin-binding adaptor protein, is a critical mediator of early lung metastasis of breast cancer. Cancer Res; 78(6); 1484–96. ©2018 AACR.</jats:p

Growth responses of mixotrophic giant clams on nearshore turbid coral reefs

Increasing evidence suggests that nearshore turbid coral reefs may mitigate bleaching of reef building calcifiers and play a critical role in the future of marine biodiversity in coastal areas. However, biomineralization processes on turbid reefs are relatively understudied compared to clear water counterparts and most published work focuses on corals. Here, we investigate how the mixotrophic giant clam Tridacna squamosa, a bivalve with ecological, cultural and economic significance, grows across a mosaic of less turbid to turbid reefs in the Coral Triangle. We construct growth chronologies from live and dead collected shells by measuring daily growth increments with petrography and scanning electron microscopy (SEM) to gain insight into growth rate on daily, seasonal and annual scales. We find annual growth is not significantly different across a turbidity gradient when scaled to ontogeny, while seasonal growth highly varies. Kd(490) (a measurement positively correlated with turbidity) and chlorophyll-a are likely important factors driving seasonal growth on a turbid reef near a river, compared to sea surface temperature (SST), cloud cover and rainfall on a less turbid reef. On a daily scale, we investigate increment microstructure and spectral characteristics of chronologies, finding a relationship between tidal range and daily increments. Overall, our results indicate that light-enhanced calcification is likely most important in the less turbid reef, compared to heterotrophic feeding in the turbid reef. The trophic plasticity of T. squamosa may allow for its sustained growth in marginal conditions, supporting evidence that these habitats serve as important conservation hotspots for diverse reef building taxa

Phase 1B, randomized, double-blind, dose-escalation trial of CPG 10101 in patients with chronic hepatitis C virus

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Microstructure and crystallographic texture data in modern giant clam shells (Tridacna squamosa and Hippopus hippopus)

This article provides novel data on the microstructure and crystallographic texture of modern giant clam shells (Tridacna squamosa and Hippopus hippopus) from the Coral Triangle region of northeast Borneo. Giant clams have two aragonitic shell layers—the inner and outer shell layer. This dataset focuses on the inner shell layer as this is well preserved and not affected by diagenetic alteration. To prepare samples for analysis, shells were cut longitudinally at the axis of maximum growth and mounted onto thin sections. Data collection involved scanning electron microscopy (SEM) to determine microstructure and SEM based electron backscatter diffraction (EBSD) for quantitative measurement of crystallographic orientation and texture. Post-acquisition reanalysis of saved EBSD patterns to optimize data quality included changing the number of reflectors and band detection mode. We provide EBSD data as band contrast images and colour-coded orientation maps (inverse pole figure maps). Crystallographic co-orientation strength obtained with multiple of uniform density (MUD) values are derived from density distributed pole figures of indexed EBSD points. Raw EBSD data files are also given to ensure repeatability of the steps provided in this article and to allow extraction of further crystallographic properties for future researchers. Overall, this dataset provides 1. a better understanding of shell growth and biomineralization in giant clams and 2. important steps for optimizing data collection with EBSD analyses in biogenic carbonates