Analyzing seasonal variations in benthic foraminifera in Budd Inlet, Puget Sound, Washington, U.S.A.

Coastal and estuarine pollution has been a growing concern within this century. Benthic foraminifera have been commonly used as a bioindicator for waterway pollution because of their abundance, diversity, and relatively short lifespans. Researchers have found test abnormalities among benthic foraminifera in Budd Inlet in Puget Sound. Test abnormalities have typically been found in environments with high levels of heavy metals in the waterways often near anthropogenic sources of pollution. This thesis aims to document winter population diversity, abundances, and percentages of mutation of foraminifera in Budd Inlet, and compare them with past collections from summer months. The results of this study showed that the foraminifera from the summer season was much more abundant than the winter foraminiferal population. There were no test abnormalities in West Bay and East Bay and there were very few in Priest Point. Comparisons of the living and the dead assemblages documented much higher diversities in dead vs living populations, indicating different species must inhabit the region in either the fall or spring seasons as they have not been observed in the living populations collected in the winter or summer. These results suggest a significant gap in our understanding of foraminiferal ecology leading to future projects in the Puget Sound

Integrin (alpha 6 beta 4) regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cells

We define a novel mechanism by which integrins regulate growth factor expression and the survival of carcinoma cells. Specifically, we demonstrate that the alpha 6 beta 4 integrin enhances vascular endothelial growth factor (VEGF) translation in breast carcinoma cells. The mechanism involves the ability of this integrin to stimulate the phosphorylation and inactivation of 4E-binding protein (4E-BP1), a translational repressor that inhibits the function of eukaryotic translation initiation factor 4E (eIF-4E). The regulation of 4E-BP1 phosphorylation by alpha 6 beta 4 derives from the ability of this integrin to activate the PI-3K-Akt pathway and, consequently, the rapamycin-sensitive kinase mTOR that can phosphorylate 4E-BP1. Importantly, we show that this alpha 6 beta 4-dependent regulation of VEGF translation plays an important role in the survival of metastatic breast carcinoma cells by sustaining a VEGF autocrine signaling pathway that involves activation of PI-3K and Akt. These findings reveal that integrin-mediated activation of PI-3K-Akt is amplified by integrin-stimulated VEGF expression and they provide a mechanism that substantiates the reported role of alpha 6 beta 4 in carcinoma progression

Integrin (α6β4) regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cells

We define a novel mechanism by which integrins regulate growth factor expression and the survival of carcinoma cells. Specifically, we demonstrate that the α6β4 integrin enhances vascular endothelial growth factor (VEGF) translation in breast carcinoma cells. The mechanism involves the ability of this integrin to stimulate the phosphorylation and inactivation of 4E-binding protein (4E-BP1), a translational repressor that inhibits the function of eukaryotic translation initiation factor 4E (eIF-4E). The regulation of 4E-BP1 phosphorylation by α6β4 derives from the ability of this integrin to activate the PI-3K–Akt pathway and, consequently, the rapamycin-sensitive kinase mTOR that can phosphorylate 4E-BP1. Importantly, we show that this α6β4-dependent regulation of VEGF translation plays an important role in the survival of metastatic breast carcinoma cells by sustaining a VEGF autocrine signaling pathway that involves activation of PI-3K and Akt. These findings reveal that integrin-mediated activation of PI-3K–Akt is amplified by integrin-stimulated VEGF expression and they provide a mechanism that substantiates the reported role of α6β4 in carcinoma progression

The DOE E3SM Coupled Model Version 1: Overview and Evaluation at Standard Resolution

This work documents the first version of the U.S. Department of Energy (DOE) new Energy Exascale Earth System Model (E3SMv1). We focus on the standard resolution of the fully coupled physical model designed to address DOE mission-relevant water cycle questions. Its components include atmosphere and land (110-km grid spacing), ocean and sea ice (60 km in the midlatitudes and 30 km at the equator and poles), and river transport (55 km) models. This base configuration will also serve as a foundation for additional configurations exploring higher horizontal resolution as well as augmented capabilities in the form of biogeochemistry and cryosphere configurations. The performance of E3SMv1 is evaluated by means of a standard set of Coupled Model Intercomparison Project Phase 6 (CMIP6) Diagnosis, Evaluation, and Characterization of Klima simulations consisting of a long preindustrial control, historical simulations (ensembles of fully coupled and prescribed SSTs) as well as idealized CO2 forcing simulations. The model performs well overall with biases typical of other CMIP-class models, although the simulated Atlantic Meridional Overturning Circulation is weaker than many CMIP-class models. While the E3SMv1 historical ensemble captures the bulk of the observed warming between preindustrial (1850) and present day, the trajectory of the warming diverges from observations in the second half of the twentieth century with a period of delayed warming followed by an excessive warming trend. Using a two-layer energy balance model, we attribute this divergence to the model’s strong aerosol-related effective radiative forcing (ERFari+aci = -1.65 W/m2) and high equilibrium climate sensitivity (ECS = 5.3 K).Plain Language SummaryThe U.S. Department of Energy funded the development of a new state-of-the-art Earth system model for research and applications relevant to its mission. The Energy Exascale Earth System Model version 1 (E3SMv1) consists of five interacting components for the global atmosphere, land surface, ocean, sea ice, and rivers. Three of these components (ocean, sea ice, and river) are new and have not been coupled into an Earth system model previously. The atmosphere and land surface components were created by extending existing components part of the Community Earth System Model, Version 1. E3SMv1’s capabilities are demonstrated by performing a set of standardized simulation experiments described by the Coupled Model Intercomparison Project Phase 6 (CMIP6) Diagnosis, Evaluation, and Characterization of Klima protocol at standard horizontal spatial resolution of approximately 1° latitude and longitude. The model reproduces global and regional climate features well compared to observations. Simulated warming between 1850 and 2015 matches observations, but the model is too cold by about 0.5 °C between 1960 and 1990 and later warms at a rate greater than observed. A thermodynamic analysis of the model’s response to greenhouse gas and aerosol radiative affects may explain the reasons for the discrepancy.Key PointsThis work documents E3SMv1, the first version of the U.S. DOE Energy Exascale Earth System ModelThe performance of E3SMv1 is documented with a set of standard CMIP6 DECK and historical simulations comprising nearly 3,000 yearsE3SMv1 has a high equilibrium climate sensitivity (5.3 K) and strong aerosol-related effective radiative forcing (-1.65 W/m2)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151288/1/jame20860_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151288/2/jame20860.pd

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Mobilization and activation of a signaling competent alpha6beta4integrin underlies its contribution to carcinoma progression

This review examines the hypothesis that the function of the alpha 6beta 4 integrin is altered substantially as normal epithelia undergo malignant transformation and progress to invasive carcinoma and that the functions of this integrin contribute to the behavior of aggressive carcinoma cells. Specifically, alpha 6beta 4 functions primarily as an adhesion receptor in normal epithelia, often as a component of hemidesmosomes and associated with intermediate filaments. Factors in the host-tumor microenvironment have the potential to mobilize alpha 6beta 4 from hemidesmosomes and promote its association with F-actin in lamellae and filopodia, a process that is mediated by PKC-dependent phosphorylation of the beta 4 cytoplasmic domain. Importantly, this altered localization of alpha 6beta 4 appears to be coupled to an activation of its signaling potential, which may occur through its association with growth factor receptors or lipid rafts, possibilities that are not mutually exclusive. The primal signaling event triggered by alpha 6beta 4 appears to be activation of PI3-K and this activation has profound consequences on the migration, invasion and survival of carcinoma cells. Arguably, the ability of alpha 6beta 4 to stimulate the PI3-K-dependent translation of VEGF and possibly other growth factors may be the most significant contribution of this integrin to carcinoma because of the potential autocrine and paracrine effects of these factors

Non-angiogenic functions of VEGF in breast cancer

This review advances the hypothesis that the function of vascular endothelial growth factor (VEGF) in breast cancer is not limited to angiogenesis, and that VEGF signaling in breast carcinoma cells is important for the ability of these cells to evade apoptosis and progress towards invasive and metastatic disease. In other terms, VEGF signaling provides a selective advantage for the survival and dissemination of breast carcinoma cells that may be independent of angiogenesis. The key component of this hypothesis is that breast carcinoma cells express specific VEGF receptors and that these receptors respond to autocrine VEGF, resulting in the activation of signaling pathways that impede apoptosis and promote cell migration. A related hypothesis, which is developed in this review, is that the alpha6beta4 integrin, which has been implicated in the survival and motility of breast cancer cells, can stimulate the translation of VEGF mRNA and, consequently, autocrine VEGF signaling. These findings imply that VEGF and VEGF receptor-based therapeutics, in addition to targeting angiogenesis, may also target tumor cells directly

The Met receptor and alpha 6 beta 4 integrin can function independently to promote carcinoma invasion

It has been proposed that a constitutive, physical association of the Met receptor and the alpha(6)beta(4) integrin exists on the surface of invasive carcinoma cells and that hepatocyte growth factor (HGF)-mediated invasion is dependent on alpha(6)beta(4) (Trusolino, L., Bertotti, A., and Comoglio, P. M. (2001) Cell 107, 643-654). The potential significance of these results prompted us to re-examine this hypothesis. Using three different carcinoma cell lines that express both Met and alpha(6)beta(4), we were unable to detect the constitutive association of these receptors by co-immunoprecipitation. Moreover, carcinoma cells that lacked expression of alpha(6)beta(4) exhibited Met-dependent invasion toward HGF, and increasing Met expression by viral infection of these cells enhanced invasion without inducing alpha(6)beta(4) expression. Although expression of alpha(6)beta(4) in such cells enhanced their invasion to HGF, it also enhanced their ability to invade toward other chemoattractants such as lysophosphatidic acid, and this latter invasion was not inhibited by a function-blocking Met antibody. Finally, depletion of beta(4) by RNA interference in invasive carcinoma cells that express both receptors reduced the ability of these cells to invade toward HGF by approximately 25%, but it did not abrogate their invasion. These data argue that the invasive function of Met can be independent of alpha(6)beta(4) and that alpha(6)beta(4) has a generic influence on the invasion of carcinoma cells that is not specific to Met

Use of RNA interference to inhibit integrin (alpha6beta4)-mediated invasion and migration of breast carcinoma cells

The application of small interfering RNA (siRNA) oligonucleotides to silence gene expression has profound implications for the intervention of human diseases including cancer. Using this technique, we explored the possibility that the alpha6beta4 integrin, a laminin adhesion receptor with a recognized role in the invasive phenotype of many carcinomas, represents a potential therapeutic target to inhibit the migration and invasion of carcinoma cells. We found that siRNA oligonucleotides targeted to either subunit of the alpha6beta4 integrin reduced cell surface expression of this integrin and resulted in decreased invasion of MDA-MB-231 breast carcinoma cells. Interestingly, reduced alpha6beta4 expression also promoted decreased migration on non-laminin substrata indicating that this integrin can function in a ligand-independent manner. In addition, the absence of beta4 expression in these cells augmented the formation of alpha6beta1 heterodimers and increased adhesion to laminin-1. Taken together, these results substantiate the importance of the alpha6beta4 integrin in invasion and migration that has been demonstrated previously by expression of the beta4 subunit in beta4-deficient cell lines and by function blocking antibodies. Furthermore, these data suggest that the utilization of siRNA oligonucleotides to reduce the expression of the alpha6beta4 integrin may be a useful approach to prevent carcinoma cell progression