145 research outputs found

    The Clarks Creek TMDL dispute resolution agreement plan: advancing the use of model based analysis to demonstrate reasonable assurance in WA State

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    Clarks Creek is designated as an important salmon-bearing creek (7 species) in Pierce County, WA. Clarks Creek was identified as a Category 2 waters of concern in 2004 for low dissolved oxygen (DO). In 2014, the Washington State Department of Ecology (Ecology) reassigned Clarks Creek as a Category 5 water body and placed it on the 303d list for being impaired by low dissolved oxygen (DO) and excessive fine sediment. In December 2014, Ecology issued a Total Maximum Daily Load (TMDL) designed to increase DO and reduce sediment loads. The DO waste load allocation (WLA) used stormwater runoff as a “surrogate measure.” It requires the County to remove or treat 50 percent of the stormwater runoff volume from a very large storm event that occurred on October 20-21, 2003. The sediment WLA requires a 66 percent reduction in the average annual sediment load to the creek. In addition, there were two Load Allocations (LAs) issued to address the dense aquatic plant growth (Elodea nuttalii) and lack of riparian shade (high temperatures) that exist in the Creek. Pierce County contested the TMDL, citing concerns regarding data and modeling limitations and the associated uncertainty regarding cause and effect relationships between stormwater, Elodea, sediment, and DO. In addition, the County was very concerned about how expensive programmatic implementation would be and whether its expenditures (investments) would reliably result in the re-attainment of the applicable water quality standards (and result in a delisting). The County entered into a Dispute Resolution process with Ecology, which culminated in a formal agreement to develop a mutually acceptable TMDL implementation plan (Plan). The Dispute Resolution agreement included a 5-Year Reassessment of the TMDL metrics, models, data and progress and an adaptive management approach. The County prepared the Plan using a continuous simulation hydrologic model in combination with a spreadsheet model to estimate (quantify) the stormwater volumes treated and sediment loads reduced by a range of measures including stormwater treatment, channel stabilization and street sweeping. The Plan includes conceptual designs, cost estimates, and a schedule for the measures slated for the next 5 years. The Plan introduces a number of other innovative approaches such as the use of Urban Stormwater Catchments, BMP Rapid Assessments and a crediting program for quantifying and tracking the County’s measures. The Plan also describes the proposed 5-year Reassessment process which includes monitoring, modeling, and other activities to assess progress and identify potential adjustments to the TMDL. The County will begin implementing the Plan in the spring of 2017

    Investigation of the Caveolin-Human Follicle Stimulating Hormone Receptor Interaction through Peptide Treatments

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    The purpose of my research project has been to determine the nature of the binding relationship between caveolin and hFSHR inside sex cells. FSH plays a role in the maturation of these cells, and interfering with the receptor’s interaction with caveolin would prevent cell maturation (down regulating fertility). It is believed the interaction occurs through transmembrane domain IV of the receptor due to its aromatic nature. The treatment of sex cells with synthetic peptides that mimic the hFSHR-caveolin binding sequence should prevent the interaction, shutting down the signaling cascade from hFSHR. This can be tested for by the monitoring of downstream signals given off by hFSHR, including the presence (or absence) of phosphorylated p44, PKA, and CREB. It is hypothesized the wildtype peptide treatment will down regulate all of these signals when compared to the mutant control. Current data points towards this hypothesis holding true, with successful western blots displaying a noted difference in cell signaling between the wildtype and mutant peptide treatments. These results indicate the key interaction between caveolin and hFSHR likely occurs at transmembrane domain IV

    Organizational System for the LEGO WeDo 2.0 Robotics System

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    In this article, we explain an organizational system for the new LEGO Education WeDo 2.0 Core Set used in 4-H robotics; in school enrichment, afterschool, and other youth robotics programs; and by hobbyists. The system presented is for organizing WeDo parts into a translucent parts tray that includes part names and numbers. The article provides step-by-step instructions for obtaining needed materials and constructing the parts inventory card. The system allows for personalization of the parts card to facilitate equipment management

    Characterization of endogenous players in Fibroblast Growth Factor‐regulated functions of hypothalamic tanycytes and energy‐balance nuclei

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    The mammalian hypothalamus regulates key homeostatic and neuroendocrine functions ranging from circadian rhythm and energy‐balance to growth and reproductive cycles via the hypothalamo‐pituitary and hypothalamo‐thyroid axes. In addition to its neurons, tanycytes are taking centre stage in the short and long term augmentation and integration of diverse hypothalamic functions, but the genetic regulators and mediators of their involvement are poorly understood. Exogenous interventions have implicated Fibroblast growth factor (FGF) signalling, but the focal point of FGF action and any role for putative endogenous players also remains elusive. We carried out a comprehensive high‐resolution screen of FGF signalling pathway mediators and modifiers using a combination of in situ hybridization, immunolabelling and transgenic reporter mice, to map their spatial distribution in the adult hypothalamus. Our findings suggest that beta tanycytes are the likely focal point of exogenous and endogenous FGF action in the third ventricular wall, utilising FGF‐receptors (FGFRs) ‐1 and ‐2 IIIc isoforms, but not FGFR3. Key IIIc‐activating endogenous ligands include FGFs 1, 2, 9 and 18, which are expressed by a subset of ependymal and parenchymal cells. In the parenchymal compartment, FGFRs 1‐3 show divergent patterns, with FGFR1 predominant in neuronal nuclei and FGFR3 expression being associated with glial cell function. Intracrine FGFs are also present, suggestive of multiple modes of FGF function. Our findings provide a testable framework for understanding the complex role of FGFs in regulating the metabolic endocrine and neurogenic functions of hypothalamus in vivo

    Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis

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    Signalling pathways that control endothelial cell (EC) permeability, leukocyte adhesion and inflammation are pivotal for atherosclerosis initiation and progression. Here we demonstrate that the Sterile-20-like mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), which has been implicated in inflammation, is abundantly expressed in ECs and in atherosclerotic plaques from mice and humans. On the basis of endothelial-specific MAP4K4 gene silencing and gene ablation experiments in Apoe(-/-) mice, we show that MAP4K4 in ECs markedly promotes Western diet-induced aortic macrophage accumulation and atherosclerotic plaque development. Treatment of Apoe(-/-) and Ldlr(-/-) mice with a selective small-molecule MAP4K4 inhibitor also markedly reduces atherosclerotic lesion area. MAP4K4 silencing in cultured ECs attenuates cell surface adhesion molecule expression while reducing nuclear localization and activity of NFkappaB, which is critical for promoting EC activation and atherosclerosis. Taken together, these results reveal that MAP4K4 is a key signalling node that promotes immune cell recruitment in atherosclerosis

    Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.

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    Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy
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