Differential modulation of microglia superoxide anion and thromboxane B(2 )generation by the marine manzamines

BACKGROUND: Thromboxane B(2 )(TXB(2)) and superoxide anion (O(2)(-)) are neuroinflammatory mediators that appear to be involved in the pathogenesis of several neurodegenerative diseases. Because activated-microglia are the main source of TXB(2 )and O(2)(- )in these disorders, modulation of their synthesis has been hypothesized as a potential therapeutic approach for neuroinflammatory disorders. Marine natural products have become a source of novel agents that modulate eicosanoids and O(2)(- )generation from activated murine and human leukocytes. With the exception of manzamine C, all other manzamines tested are characterized by a complex pentacyclic diamine linked to C-1 of the β-carboline moiety. These marine-derived alkaloids have been reported to possess a diverse range of bioactivities including anticancer, immunostimulatory, insecticidal, antibacterial, antimalarial and antituberculosis activities. The purpose of this investigation was to conduct a structure-activity relationship study with manzamines (MZ) A, B, C, D, E and F on agonist-stimulated release of TXB(2 )and O(2)(- )from E. coli LPS-activated rat neonatal microglia in vitro. RESULTS: The manzamines differentially attenuated PMA (phorbol 12-myristate 13-acetate)-stimulated TXB(2 )generation in the following order of decreasing potency: MZA (IC(50 )<0.016 μM) >MZD (IC(50 )= 0.23 μM) >MZB (IC(50 )= 1.6 μM) >MZC (IC(50 )= 2.98 μM) >MZE and F (IC(50 )>10 μM). In contrast, there was less effect on OPZ (opsonized zymosan)-stimulated TXB(2 )generation: MZB (IC(50 )= 1.44 μM) >MZA (IC(50 )= 3.16 μM) >MZC (IC(50 )= 3.34 μM) >MZD, MZE and MZF (IC(50 )>10 μM). Similarly, PMA-stimulated O(2)(- )generation was affected differentially as follows: MZD (apparent IC(50)<0.1 μM) >MZA (IC(50 )= 0.1 μM) >MZB (IC(50 )= 3.16 μM) >MZC (IC(50 )= 3.43 μM) >MZE and MZF (IC(50 )>10 μM). In contrast, OPZ-stimulated O(2)(- )generation was minimally affected: MZB (IC(50 )= 4.17 μM) >MZC (IC(50 )= 9.3 μM) >MZA, MZD, MZE and MZF (IC(50 )> 10 μM). From the structure-activity relationship perspective, contributing factors to the observed differential bioactivity on TXB(2 )and O(2)(- )generation are the solubility or ionic forms of MZA and D as well as changes such as saturation or oxidation of the β carboline or 8-membered amine ring. In contrast, the fused 13-membered macrocyclic and isoquinoline ring system, and any substitutions in these rings would not appear to be factors contributing to bioactivity. CONCLUSION: To our knowledge, this is the first experimental study that demonstrates that MZA, at in vitro concentrations that are non toxic to E. coli LPS-activated rat neonatal microglia, potently modulates PMA-stimulated TXB(2 )and O(2)(- )generation. MZA may thus be a lead candidate for the development of novel therapeutic agents for the modulation of TXB(2 )and O(2)(- )release in neuroinflammatory diseases. Marine natural products provide a novel and rich source of chemical diversity that can contribute to the design and development of new and potentially useful anti-inflammatory agents to treat neurodegenerative diseases

Support for UNRWA's survival

The United Nations Relief and Works Agency for Palestine Refugees in the Near East (UNRWA) provides life-saving humanitarian aid for 5·4 million Palestine refugees now entering their eighth decade of statelessness and conflict. About a third of Palestine refugees still live in 58 recognised camps. UNRWA operates 702 schools and 144 health centres, some of which are affected by the ongoing humanitarian disasters in Syria and the Gaza Strip. It has dramatically reduced the prevalence of infectious diseases, mortality, and illiteracy. Its social services include rebuilding infrastructure and homes that have been destroyed by conflict and providing cash assistance and micro-finance loans for Palestinians whose rights are curtailed and who are denied the right of return to their homeland

Identification of the bacterial symbiont Entotheonella sp. in the mesohyl of the marine sponge Discodermia sp.

The AC-OPF problem is the key and challenging problem in the power system operation. When solving the AC-OPF problem, the feasibility issue is critical. In this paper, we develop an efficient Deep Neural Network (DNN) approach, DeepOPF, to ensure the feasibility of the generated solution. The idea is to train a DNN model to predict a set of independent operating variables, and then to directly compute the remaining dependable variables by solving the AC power flow equations. While this guarantees the power-flow balances, the principal difficulty lies in ensuring that the obtained solutions satisfy the operation limits of generations, voltages, and branch flow. We tackle this hurdle by employing a penalty approach in training the DNN. As the penalty gradients make the common first-order gradient-based algorithms prohibited due to the hardness of obtaining an explicit-form expression of the penalty gradients, we further apply a zero-order optimization technique to design the training algorithm to address the critical issue. The simulation results of the IEEE test case demonstrate the effectiveness of the penalty approach. Also, they show that DeepOPF can speed up the computing time by one order of magnitude compared to a state-of-the-art solver, at the expense of minor optimality loss

Bacillus thuringiensis toxins: membrane permeabilization and pore formation

NRC publication: Ye