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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.

In this study, the researchers have modeled an affect detector based on the mouse movements that they have gathered while the respondents, as casual or core gamers, are playing the role-playing game. After being able to gather and prepare the data with the help of several software and tools, features such as the number of mouse clicks and distance moved were extracted and developed a models through the classifiers: Decision Tree, Random Forest, and J48. Given the parameters and features included, the chosen model was used to create a prototype. The prototype developed can be of use to game developers in game testing by giving them the ability to monitor the emotions of their end-users. This will then correspond to valuable data to apply for game design improvement.

The Philippine Conditional Cash Transfer (CCT) of the Philippines has started since 2007. This Philippine government program and human development measure provides conditional cash grants to the poorest of the poor, to improve the health, nutrition, and the education of children aged 0-18. This study provides a framework of state-of-the-art visualization tool in presenting data that provides significant reports that will aid government decision making that involves poor Filipino families. With the vast rising of technology and never-ending growth of government data in the Philippines, it is a big possibility that the data generated by the tool can give solutions and amendments to future management policies and improves administration tasks. This research shows a framework for the development of a web application of a decision support system to support the National Advisory Committee (NAC) and NAC Technical Working Group (NAC-TWG) of the Department of Social Welfare and Development of the Philippines. The data analyses reports produced on this interactive data visualization tool can be used as a basis for program and action recommendation of government offices. The framework includes descriptive and diagnostic analysis after data cleansing and simulation. It also features forecasting and prediction functionalities.

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 Spleen Tyrosine Kinase (SYK) mediates signaling in a range of hematopoietic cells involved in the initiation and progression of RA including B cells, monocytes, macrophages, dendritic cells, and osteoclasts. There is strong preclinical validation for SYK as a therapeutic target for RA based on cellular data and animal models of disease. We have identified GS-9876 as a potent and selective SYK inhibitor with pharmaceutical properties compatible with once daily oral dosing in human. Objectives To characterize the cellular activity of GS-9876 on pathologically relevant pathways in RA, and establish target inhibition requireements for efficacy in rat models of arthritis. Methods The potency and selectivity of GS-9876 were characterized in biochemical and cellular assays. Effects in B cells were measured by inhibition of BCR-mediated protein phosphorylation, CD69 and CD86 expression, and in macrophages by inhibition of immune-complex (IC)-stimulated cytokine release. Cellular selectivity was demonstrated by comparing the inhibition of B cell proliferation versus T cell proliferation. GS-9876 potency in human blood was evaluated by inhibition of phosphorylated SYK (pSYK), CD63 expression on basophils, and CD69 expression on B cells. The in vivo efficacy of GS-9876 was tested in rat models of collagen-induced arthritis (CIA). Results GS-9876 is a potent SYK inhibitor (IC50=9.5±4.3 nM) and is highly selective against a panel of 456 other kinases. GS-9876 inhibited anti-IgM stimulated phosphorylation of AKT, BLNK, BTK, ERK, MEK, and PKCδ in human B cells with EC50 values of 24–51 nM. Functionally, GS-9876 inhibited anti-IgM mediated CD69 and CD86 expression on B-cells (EC50=112±10 nM and 164±15 nM, respectively) and anti-IgM /anti-CD40 co-stimulated B cell proliferation (EC50=108±55 nM). In human macrophages, GS-9876 inhibited IC-stimulated TNFα and IL-1β release (EC50=121±77 nM and 9±17 nM, respectively). Anti-CD3/anti-CD28 stimulated T cell proliferation was weakly inhibited (EC50=1291±398 nM), with selectivity >10-fold versus the inhibition of B cell proliferation. In human blood, GS-9876 blocked SYK phosphorylation, CD69 expression on B cells, and CD63 expression in basophils. GS-9876 demonstrated a dose-dependent improvement in clinical score and histopathology parameters with once-daily dosing in short and long term rat CIA models. Significant efficacy could be achieved with GS-9876 doses that produced trough pSYK inhibition of Conclusions GS-9876 is a novel SYK inhibitor that potently inhibits multiple cellular events implicated in RA pathogenesis and displays excellent in vivo efficacy in rat CIA models after once-daily dosing. GS-9876 has markedly improved selectivity over competitor SYK programs. Our data support the development of GS-9876 in inflammatory diseases, with potential for an improved safety profile. Disclosure of Interest J. Di Paolo Shareholder of: Gilead Sciences, P. Blomgren Shareholder of: Gilead Sciences, M. Dolton Shareholder of: Gilead Sciences, R. Jones Shareholder of: Gilead Sciences, J. Kropf Shareholder of: Gilead Sciences, T. Lee Shareholder of: Gilead Sciences, S. Mitchell Shareholder of: Gilead Sciences, B. Murray Shareholder of: Gilead Sciences, K. Suekawa-Pirrone Shareholder of: Gilead Sciences, S. Wise Shareholder of: Gilead Sciences, J. Xu Shareholder of: Gilead Sciences, Z. Zhao Shareholder of: Gilead Sciences, K. Currie Shareholder of: Gilead Sciences

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.