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Green Roofs (GRs) are becoming more popular as a low-impact building option. They have the potential to minimize peak stormwater runoff while also increasing the quality of runoff from buildings. Improvement of hydrological models for the simulation of GRs will aid design of individual roofs as well as city scale planning that relies on the predicted impacts of widespread GR implementation. Machine learning (ML) has exploded in popularity in recent years, owing to considerable increases in processing power and data availability. However, there are no studies focusing on the use of ML in hydrological simulation of GRs. We focus on two types of ML-based model: long short-term memory (LSTM) and gated recurrent unit (GRU) in modelling hydrological performance of GRs, with sequence input and a single output (SISO), and synced sequence input and output (SSIO) architectures. According to the results of this paper, LSTM and GRU are useful tools for the modelling of GRs. As the time window length (memory length, time step length of input data) increases, SISO appears to have a higher overall forecast accuracy. SSIO delivers the best overall performance, when the SSIO is close to, or even exceeds, the maximum window size.

[Image: see text] Spleen tyrosine kinase (SYK) is a critical regulator of signaling in a variety of immune cell types such as B-cells, monocytes, and macrophages. Accordingly, there have been numerous efforts to identify compounds that selectively inhibit SYK as a means to treat autoimmune and inflammatory diseases. We previously disclosed GS-9973 (entospletinib) as a selective SYK inhibitor that is under clinical evaluation in hematological malignancies. However, a BID dosing regimen and drug interaction with proton pump inhibitors (PPI) prevented development of entospletinib in inflammatory diseases. Herein, we report the discovery of a second-generation SYK inhibitor, GS-9876 (lanraplenib), which has human pharmacokinetic properties suitable for once-daily administration and is devoid of any interactions with PPI. Lanraplenib is currently under clinical evaluation in multiple autoimmune indications.

Background Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterised by immune system hyperactivation leading to the production of autoantibodies and immune attack on multiple organs including the skin and kidneys. High levels of type I interferons (IFNa/b) alter the activation state of immune cell populations and have been identified as a risk factor for SLE. Antibody blockade of the interferon alpha receptor (IFNAR) has demonstrated clinical efficacy in a Phase 2b study in SLE, and validates targeting this pathway in SLE1. Janus kinase 1 (JAK1) is critical for mediating downstream signalling of type I IFNs. Inhibition of JAK1, therefore, is anticipated to reduce IFN signalling, activation of immune cell subsets, and SLE disease activity. The JAK1 selective inhibitor filgotinib (FIL) is currently being evaluated in three proof-of-concept Phase 2 studies in SLE-like diseases. Objectives To characterise the efficacy and mechanism-of-action of FIL in the NZB/W F1 spontaneous mouse model of lupus in a therapeutic setting. Methods FIL was tested in the NZB/W F1 model of lupus at two concentrations (0.05% and 0.1%) formulated in chow and administered ad libitum from weeks 28–40. Cyclophosphamide (CP) was used as a positive control at 5 mg/kg, once daily, i.p. Efficacy was determined by changes in proteinuria, renal histopathology, and survival. Splenic cell populations were analysed by flow cytometry at study termination at week 40 to measure changes in immune cell subsets in diseased versus non-diseased mice and following FIL treatment. An in vitro murine whole blood pSTAT1 assay and PK exposure data were used to assess target coverage in the model. Results In the NZB/W model, FIL showed a dose-dependent decrease in proteinurea with a concomitant reduction in BUN levels, renal inflammation, improved glomerular morphology, and increased survival (table 1). Diseased mouse spleens had decreased frequencies of naive T cells, increased frequencies of CD11+dendritic cells (DCs), and an increased ratio of memory:naive T cells versus non-diseased mice. FIL treatment showed a dose-responsive reversal of these populations toward non-diseased levels. FIL inhibited in vitro IFNa-stimulated pSTAT1 signalling in T cells. Calculated JAK target coverage of pSTAT1 inhibition was similar to that observed in human studies at clinical doses. Conclusions FIL demonstrated efficacy in the NZB/W F1 murine model of lupus with an alteration of splenic immune cell subsets affected by type I IFNs toward non-diseased levels. This data provides the basis for the evaluation of FIL as monotherapy in the currently ongoing Phase 2 studies in lupus-related diseases. Reference [1] Furie R, et al. Arthritis Rheumatol2017;69:376–386. Disclosure of Interest C. Pohlmeyer Shareholder of: Gilead Sciences, Inc, Employee of: Gilead Sciences, Inc, Z.-H. Cui Shareholder of: Gilead Sciences, Inc, Employee of: Gilead Sciences, Inc, P. Han Shareholder of: Gilead Sciences, Inc, Employee of: Gilead Sciences, Inc, A. Clarke Shareholder of: Gilead Sciences, Inc, Employee of: Gilead Sciences, Inc, R. Jones Shareholder of: Gilead Sciences, Inc, Employee of: Gilead Sciences, Inc, N. Mollova Shareholder of: Gilead Sciences, Inc, Employee of: Gilead Sciences, Inc, I. Mikaelian Shareholder of: Gilead Sciences, Inc, Employee of: Gilead Sciences, Inc, S. Zaboli Shareholder of: Gilead Sciences, Inc, Employee of: Gilead Sciences, Inc, A. Shauf Shareholder of: Gilead Sciences, Inc, Employee of: Gilead Sciences, Inc, J. Di Paolo Shareholder of: Gilead Sciences, Inc, Employee of: Gilead Sciences, Inc

Background Compared to single-agent therapy, combination therapy in chronic lymphocytic leukemia (CLL) has the goal to achieve complete responses with greater durability and ultimately to achieve minimal residual disease negativity and cure with finite therapy. The investigational agents entospletinib, ONO/GS-4059, and ABT-199 are selective, oral, small molecule inhibitors of SYK, BTK, and BCL-2, respectively, and currently are each being developed for the treatment of CLL. Idelalisib (Zydelig™), a first-in-class, selective, oral inhibitor of PI3Kδ, is approved for the treatment of relapsed chronic lymphocytic leukemia (CLL) in combination with rituximab. Though significant clinical efficacy has been achieved in CLL with currently approved agents, improvement in outcome could be enhanced with combinations of novel agents. We investigated the activity of combinations of the B cell receptor pathway inhibitors, entospletinib, ONO/GS-4059 and idelalisib, and the BCL-2 inhibitor, ABT-199, in vitro in primary CLL cells to define the potential utility of these combinations for clinical investigation in patients. Methods Peripheral blood mononuclear cells (PBMCs) prepared from CLL patients were stimulated with αIgM/αIgG and αCD40 with or without co-culture with the human bone marrow stromal cell line, HS-5. Entospletinib, ONO/GS-4059, idelalisib, or ABT-199 were combined and incubated with cells for 66-72 hours at clinically achievable concentrations of each. Apoptosis was assessed in CD5+ CD19+ CLL cells by Annexin V/Live-Deadassay (Promega). Combinations of the compounds were assessed using a range of concentrations in an 8 × 3 or 3 × 3 matrix format and assayed for apoptosis using a minimum of 8 individual CLL donors after 66-72 hours. Synergy was evaluated using the Bliss model of independence (Meletiadis, J., et al., Med Mycol, 2005). Results Stimulation of CLL cells by αIgM/αIgG/αCD40 led to a variable, but statistically significant, protection of primary CLL cells in vitro (p=0001), and co-culture with the stromal cell line, HS-5, in conjunction with αIgM/αIgG/αCD40 stimulation further reduced the observed level of apoptosis (p=0.0051). Entospletinib, ONO/GS-4059, idelalisib, and ABT-199, were able to induce apoptosis in primary αIgM/αIgG/αCD40 stimulated CLL cells with an average maximal proportion of apoptotic cells of 50.2%, 26.1%, 23%, and 91.4%, respectively. Addition of ONO/GS-4059 + entospletinib or idelalisib, had an additive effect on induction of apoptosis in primary CLL cells from 5/9 and 6/8 patients, respectively (Figure 1). The addition of ABT-199 to entospletinib, ONO/GS-4059, or idelalisib showed additive to synergistic effects on induction of apoptosis in primary CLL cells from all patients tested, and increased the maximal level of apoptosis (Figure 1). Primary CLL cells were exposed to pairwise combinations of ONO/GS-4059 with entospletinib or idelalisib (A) or ONO/GS-4059 entospletinib, or idelalisib with ABT-199 (B) using a range of concentrations in an 8 x 3 or 3 x 3 matrix format for 66-72 h. Each point represents the mean result for each pairwise combination for each compound at each concentration tested. The percent apoptosis was assessed by AnnexinV/Live-Dead cell staining. The plots show the measured apoptosis versus the calculated, Bliss predicted score for each combination at each concentration tested. Observed apoptosis greater than the bliss predicted score indicates a synergistic relationship. Area within the dashed lines, indicate additive responses. Summary Combination treatment with the B cell receptor pathway inhibitors resulted in additive increases in apoptosis in primary CLL cells compared to treatment with the individual agents. The combination of the BCL2 inhibitor ABT-199 with entospletinib, ONO/GS-4059 or idelalisib resulted in an additive to synergistic increase in apoptosis in these primary CLL cells and achieved the greatest maximal levels of apoptosis. These in vitro data support clinical investigation of these combinations in patients with CLL. Figure 1. Pairwise Combinations of ONO/GS-4059, Entospletinib, Idelalisib, and ABT-199 Induction of Apoptosis in Primary CLL Figure 1. Pairwise Combinations of ONO/GS-4059, Entospletinib, Idelalisib, and ABT-199 Induction of Apoptosis in Primary CLL Figure 2. Figure 2. Disclosures Jones: Gilead Sciences: Employment, Equity Ownership. Axelrod:Gilead Sciences: Employment, Equity Ownership. Tumas:Gilead Sciences: Employment, Equity Ownership. Quéva:Gilead Sciences: Employment, Equity Ownership. Di Paolo:Gilead Sciences: Employment, Equity Ownership.

Bioretention gardens are stormwater management practices that offer numerous water quantity and quality benefits. However, previous studies have reported inconsistent removal of nitrogen and phosphorous in these systems. The first phase of this research involved the construction and monitoring of ten vegetated, mesoscale, bioretention cells in a field setting to provide a comparison of the performance of five alternative designs intended to provide nutrient removal. Results indicated that concentrations of total nitrogen and total phosphorous may be reduced by up to 53 and 79%, respectively, in specially designed bioretention gardens. In the second phase of the research, a GIS-based site selection tool was used to identify areas suitable for bioretention implementation based on physical site requirements. Applying this tool to selected urban catchments demonstrated that bioretention gardens may be integrated into existing urban landscapes on a scale large enough to accommodate runoff and associated nutrient loads from small (

Bruton's tyrosine kinase (Btk) is a therapeutic target for rheumatoid arthritis, but the cellular and molecular mechanisms by which Btk mediates inflammation are poorly understood. Here we describe the discovery of CGI1746, a small-molecule Btk inhibitor chemotype with a new binding mode that stabilizes an inactive nonphosphorylated enzyme conformation. CGI1746 has exquisite selectivity for Btk and inhibits both auto- and transphosphorylation steps necessary for enzyme activation. Using CGI1746, we demonstrate that Btk regulates inflammatory arthritis by two distinct mechanisms. CGI1746 blocks B cell receptor-dependent B cell proliferation and in prophylactic regimens reduces autoantibody levels in collagen-induced arthritis. In macrophages, Btk inhibition abolishes FcγRIII-induced TNFα, IL-1β and IL-6 production. Accordingly, in myeloid- and FcγR-dependent autoantibody-induced arthritis, CGI1746 decreases cytokine levels within joints and ameliorates disease. These results provide new understanding of the function of Btk in both B cell- or myeloid cell-driven disease processes and provide a compelling rationale for targeting Btk in rheumatoid arthritis.

This work focuses on different methods to generate confidence regions for nonlinear parameter identification problems. Three methods for confidence region estimation are considered: a linear approximation method, an F-test method, and a Log-Likelihood method. Each of these methods are applied to three case studies. One case study is a problem with synthetic data, and the other two case studies identify hydraulic parameters in groundwater flow problems based on experimental well-test results. The confidence regions for each case study are analyzed and compared. Although the F-test and Log-Likelihood methods result in similar regions, there are differences between these regions and the regions generated by the linear approximation method for nonlinear problems. The differing results, capabilities, and drawbacks of all three methods are discussed.

Discusses whether if the states surrounding Long Island Sound require permits for using pesticides, specifically permits for malathion or methoprene, which are used for mosquito control.

Discusses whether if any states have adopted new signage, such as a "slow then go" sign, to replace the stop sign.

Discusses whether any states currently use an area-based property tax system and, the advantages and disadvantages of an area-based property tax versus a value-based tax (i.e., ad valorem).

Discusses the Castle Doctrine and stand-your-ground laws, affirmative defenses for individuals charged with criminal homicide.

Summarizes the House rulings for the 2011 regular and special sessions.

Discusses Connecticut regulation of inland wetlands and watercourses, specifically as it pertains to the town of Orange.

Discusses legislative history of PA 89-373 (sSB 915), which increased the quarterly gross earnings tax on the sale of petroleum products from 2% to 3% to finance the newly created Underground Storage Tank Petroleum Cleanup Fund (USTPCF), which the act also created.

Updates OLR research report 2011-R-0355, 2011-2012 energy assistance plan, to reflect greater-than-expected federal funds for the Connecticut Energy Assistance Program (CEAP).

Discusses how often juvenile prosecutors use the serious sexual offender prosecution statute (CGS 46b-133d); whether juvenile sex offenders have to register on the Dept. of Public Safety's sex offender registry; and what impact, if any, the increase in the age for juvenile jurisdiction has had on the law's application and expected foreseeable issues that might result from raising the age again in July 2012.

Discusses statutory "unfunded mandates" on municipalities the legislature repealed between 2007 and 2011.

Discusses other states' restrictions for building homes or other structures in coastline areas and what the ramifications would be for any state implementing a statewide coastal development setback line.

Recent literature has explored both physical and policy linkage between trade and environment. Here we explore linkage through leverage in bargaining, whereby developed countries can use trade policy threats to achieve improved developing country environmental management, while developing countries can use environmental concessions to achieve trade disciplines in developed countries. We use a global numerical simulation model to compute bargaining outcomes from linked trade and environment negotiations, comparing developed-developing country bargaining only on trade policy with joint bargaining on both trade and domestic environmental policies. Results indicate joint gains from expanding the trade bargaining set to include environment, opposite to the current developing country reluctance to negotiate in the World Trade Organization on this issue. However, compared to bargaining with cash side payments, linking trade and environment through negotiation on policy instruments provides significantly inferior developing country outcomes. Thus, a trade and environment policy linked negotiation may be better than a trade-only negotiation for developing countries, but compensation for environmental restraint would be even better for them. We provide sensitivity and further analysis of our results and indicate what other factors could qualify our main finding, including the erosion of the MFN principle involved with environmentally based trade actions.

Electroactive polymer transducers are disclosed. They are biased in a manner that provides for increased force and/or stroke output, thereby offering improved work potential and power output capacity. The biasing may offer additional or alternate functional advantage in terms of matching transducer performance with a given application such as a normally-closed valve. The improved biasing (including increased output biasing) may utilize negative spring rate biasing and/or a combination of negative or zero-rate biasing with positive rate biasing to achieve the desired ends.

This thesis analyzes a variety of aspects concerning arms control with a reformed Soviet Union. Despite the growth of pluralism in the Soviet Union arms control will remain an important policy goal of the United States. Policy-makers will need to be aware of both new problems and opportunities which will be created as the Soviet Union transitions into a democracy. This study postulates four possible outcomes of Soviet governmental reform and then examines one in particular with respect to arms control with the Soviets in the future. Besides postulating the end form of Soviet government it looks at inter-democracy relationships with an eye on illuminating the particular idiosyncrasies involved in them. In addition, it analyzes the possibility of learning lessons from the interaction of previous U.S. democracy to democracy. Specifically, the U.S.-Japanese relationship in trade and security is utilized in this comparison. Arms control will still be necessary even if the Soviets are successful in the restructuring of their government. It may become more difficult rather than easier to reach arms control agreements with the new Soviet Union. A restructured Soviet Union must cause decision-makers to rethink their approach in concluding successful arms control agreements. http://archive.org/details/armscontrolwithd1094527997 Lieutenant, United States Navy Approved for public release; distribution is unlimited.

The thesis is comprised of three essays which analyze trade liberalization on a multilateral basis and in the Canadian context. Essay I concerns multilateral liberalization, Essay II concerns Canadian liberalization, and Essay III presents extensive systematic sensitivity analysis of the results of Essays I and II.;The extension of short-run wage rigidities is found to markedly reduce the welfare gains from multilateral liberalization under some circumstances, while extending sector-specificity of capital has a much smaller impact on welfare and adjustment effects of multilateral liberalization.;In Essay II, Whalley's (1985) model of global trade is revised with the incorporation of economies-of-scale features, in a way similar to Harris and Cox (1984). It is found that both unilateral liberalization or bilateral liberalization with the U.S. cause Canada to suffer small welfare losses. Liberalization may still be in the interest of Canada if compensation by the U.S. is possible. The contrast of these results, with those of Harris and Cox is investigated, but only part of the discrepancy is resolved. The indirect calibration procedure adopted by Harris and Cox is identified as a potential source of the discrepancy.;Extensive conditional and unconditional systematic sensitivity analysis conducted in Essay II yields the following results with regard to systematic sensitivity analysis of NGE model results: (i) Unconditional procedures on selected elasticities yield more diffuse distributions of the results than conditional procedures on all of the elasticities. (ii) Pagan-Shannon approximations of unconditional results are often very accurate, resource saving substitutes for the unconditional analysis.;The results of all three essays suggest a simple relationship between the elasticity configuration of the model, and the resulting welfare effects of multilateral or bilateral trade liberalization.