Discovery of GPR183 Agonists Based on an Antagonist Scaffold

The G protein-coupled receptor GPR183/EBI2, which is activated by oxysterols, is a therapeutic target for inflammatory and metabolic diseases where both antagonists and agonists are of potential interest. Using the piperazine diamide core of the known GPR183 antagonist (E)-3-(4-bromophenyl)-1-(4-(4-methoxybenzoyl)piperazin-1-yl)prop-2-en-1-one (NIBR189) as starting point, we identified and sourced 79 structurally related compounds that were commercially available. In vitro screening of this compound collection using a Ca²⁺ mobilization assay resulted in the identification of 10 compounds with agonist properties. To enable establishment of initial structure-activity relationship trends, these were supplemented with five in-house compounds, two of which were also shown to be GPR183 agonists. Taken together, our findings suggest that the agonist activity of this compound series is dictated by the substitution pattern of one of the two distal phenyl rings, which functions as a molecular efficacy-switch.     

A Dual Inhibitor of DYRK1A and GSK3β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877

Loss of β-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β-cell mass are less developed. Promoting β-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β) was previously reported to induce primary human β-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring β-cell proliferation.     

Modeling aviation baggage screening security systems: a case study

Aviation security protects vital national interests, as well as passengers and aircraft. Key components of an aviation security system include baggage and passenger screening devices and operations. Determining how and where to assign (deploy) such devices can be quite challenging. Moreover, even after such systems are in place, it can be difficult to measure their effectiveness. This paper describes how discrete optimization models can be used to address these questions, based on three performance measures that quantify the effectiveness of airport baggage screening security device systems. These models are used to solve for optimal airport baggage screening security device deployments considering the number of passengers on a set of flights who have not been cleared using a security risk assessment system in use by the Federal Aviation Administration (i.e., passengers whose baggage is subjected to screening), the number of flights in this set, and the size of the aircraft for such flights. Several examples are provided to illustrate these results, including an example that uses data available from the Official Airline Guide.     

The hot blow forming of AZ31 Mg sheet: Formability assessment and application development

The hot blow forming of magnesium sheet offers significant opportunity for forming complex, lightweight parts for automotive applications. This paper characterizes the elevated-temperature formability of AZ31 magnesium sheet materials and the effect of processing conditions on the performance of these materials. In addition, magnesium sheet application development at General Motors Corporation is reviewed.     

Migration of newly generated neurons upon ependymally derived radial guide cells in explant cultures of the adult songbird forebrain

The adult songbird forebrain undergoes neuronal production throughout adulthood, with the production of new neurons in discrete regions of the neostriatal ventricular zone. Upon mitogenesis, these new neurons migrate into the subjacent brain parenchyma along radially directed guide fibers. In long-term ventricular zone explant cultures, derived from the higher vocal center of the adult canary, newly migratory neurons were found to associate preferentially with a characteristic substrate cell type. These small, parvonuclear substrate cells formed tightly packed epithelioid sheets, in which ciliated ependymal cells were common, as recognized by both live observation and electron microscopy. A subpopulation of these cells was immunostained by monoclonal antibody 3A7, which preferentially stains the guide fiber network of the adult avian brain. These 3A7+ cells included ependymal cells and bipolar radial cells, as well as morphologically defined astrocytes. As they matured in vitro, the 3A7+ bipolar radial cells extended long, unbranching fibers, which ultimately traversed the culture substrate. Like ependymal cells, they supported neuronal migration. These cells were likely homologous to radial guide cells in vivo. Thus, neuronal migration in adult avian forebrain culture occurred upon guide cells of ependymal derivation.     

Long-term results after allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic phase: a report from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation

The purpose of this study was to determine the long-term results of allogeneic bone marrow transplantation for chronic myeloid leukemia. A retrospective analysis was carried out of the outcome of 373 consecutive transplants performed at 38 European institutions between 1980 and 1988 and reported to the registry of the European Group for Blood and Marrow Transplantation. All transplants were carried out for first chronic phase of chronic myelogenous leukemia using unmanipulated marow cells from HLA-identical sibling donors. The probability of survival and leukemia-free survival at 8 years were 54% (95% CI: 49-59) and 47% (95% CI: 41-52) respectively. The probabilities of developing acute GVHD (II-IV) at 100 days and chronic GVHD at 4 years after transplant were 47% (95% CI: 41-53) and 52% (95% CI: 46-58) respectively. The probabilities of transplant-related mortality and leukemic relapse 8 years after BMT were 41% (95% CI: 36-48) and 19% (95% CI: 14-25), respectively. Transplant within 12 months of diagnosis was associated with reduced transplant-related mortality (34 vs 45%, P = 0.013) and resulted in improved leukemia-free survival (52 vs 44%, P = 0.03). The probability of relapse was significantly reduced in patients who developed chronic GVHD (RR = 0.33, P = 0.004). The probability of relapse occurring more than 2 years after transplant was increased more than five-fold in patients transplanted from a male donor (RR = 5.5, P = 0.006). Sixty-seven patients in hematologic remission were studied for residual disease by two-step RT/PCR for BCR-ABL mRNA and 61 (91%) tested negative. We conclude that bone marrow transplantation can induce long-term survival in approximately one-half of CML patients; the majority of survivors have no evidence of residual leukemia cells when studied by molecular techniques. The probability of late relapse is increased with use of a male donor.     

Assessing the Assessments: Case Study of an Emergency Action Plan for the Control of Water Hyacinth in Lake Victoria

This study evaluates the impact assessment methodologies used by Uganda's Water Hyacinth Control Programme in Lake Victoria, a domestic project with transboundary implications. The Control Programme sought to reduce infestations of water hyacinth (Eichhornia crassipes), an aquatic weed native to South America, through the use of integrated chemical, mechanical and biological methods. The environmental impact assessment for the project was conducted by Aquatics Unlimited, with support from the United States Agency for International Development. Although the case study involves a domestic impact assessment, it raised transboundary concerns. One of the major outcomes of the assessment was recognition of the need for informed involvement of the other riparian countries, Kenya and Tanzania, in the assessment process to ensure a regional effort among all three East African Community Partner States to control water hyacinth and other invasive weeds in Lake Victoria.     

Giga Security

The flow of information, within organizations, between networks, and from single users to other individuals and networks, is commonly at rates that only a few years ago were dreams. Earlier methods for the detection and prevention of malicious activities are anywhere from inefficient to unworkable with transmissions at the giga speeds that are prevalent today. This writing sets forth the problems and threats associated with these new high speed transmissions, and presents methodologies and systems for treating them.