Synthesis and evaluation of N⁶-substituted apioadenosines as potential adenosine A₃ receptor modulators

Adenosine receptors (ARs) trigger signal transduction pathways inside the cell when activated by extracellular adenosine. Selective modulation of the A(3)AR subtype may be beneficial in controlling diseases such as colorectal cancer and rheumatoid arthritis. Here, we report the synthesis and evaluation of beta-D-apio-D-furano- and alpha-D-apio-L-furanoadenosines and derivatives thereof. Introduction of a 2-methoxy-5-chlorobenzyl group at N-6 of beta-D-apio-D-furanoadenosine afforded an A(3)AR antagonist (10c, K = 0.98 mu M), while a similar modification of an alpha-D-apio-L-furanoadenosine gave rise to a partial agonist (11c, K-i = 3.07 mu M). The structural basis for this difference was examined by docking to an A(3)AR model; the antagonist lacked a crucial interaction with Thr94

Formability limits and process window based on fracture analysis of 5A02-O aluminium alloy in splitting spinning

Splitting spinning or rotary flow splitting is an advanced forming process for manufacturing axisymmetric integrated parts with bifurcated features and unique characteristics of high-performance and low-weight. During the process, under the kinematic effects of mandrel rotational movement and roller radial feed, plastic deformation occurs accompanied usually by undesirable fracture, which reduces the formability limit (FL). In this study, the kinematic effects on the FL of a 5A02-O aluminium alloy in the splitting spinning process were systematically investigated by finite element simulation based on a modified Lemaitre criterion and physical experiments. The results show that at a given roller feed speed or mandrel rotational speed (forming speed), the FL has a nonlinear relationship with forming speed, which increases firstly and then decreases. With the increase of forming speed, the maximum FL decreases, which appears at the larger forming speed. These variations of FL show that there exists a combined effect of the roller feed speed and mandrel rotational speed, thus a ratio between them, named as the roller feed ratio, is then used to investigate FL. It is found that there exists a critical roller feed ratio of approximately 2 mm/rev, independent of the speeds of roller and mandrel. Below this critical value, the FL increases with the roller feed ratio. While over the critical value, the FL decreases. In addition, the decrease of FL becomes more remarkable with the increase of mandrel rotational speed. Furthermore, the variations of stress triaxiality and tensile plastic strain were analyzed to see their effects on FL. The analyses show that the decrease of tensile plastic strain with the increasing roller feed ratio is dominant the increase of FL below the critical roller feed ratio value. The increase in the stress triaxiality is dominant in the decrease of FL when the roller feed ratio is over the critical value in combination with not too high forming speed, whereas both increases are dominant in the decrease of FL when it is over the critical roller feed ratio value in combination with high forming speed. Based on the kinematic effects of mandrel and roller, the process windows of the splitting spinning process were obtained to improve the FL. It is found that under the condition of the roller feed ratio within 1–2.5 mm/rev, the mandrel rotational speed within 8–100 rev/min and the roller feed speed within 0.5–4 mm/s are helpful to get high FL values. The experiments were carried out to verify the prediction on the FL and the process window. The research provides an in-depth understanding of FL and its affecting factors, and thus lays a basis for process optimization and process parameter configuration

On Special Relativity with Cosmological Constant

Based on the principle of relativity and the postulate of invariant speed and length, we propose the theory of special relativity with cosmological constant ${\cal SR}_{c,R}$ if the invariant length whose square is the inverse of the one-third cosmological constant of the universe. It is on the Beltrami-de Sitter spacetime ${\cal B}_R$ with de Sitter invariance. We define the observables of free particles and generalize famous Einstein's formula. We also define two kinds of simultaneity. The first is for local experiments and inertial motions. The second is for cosmological observations. Thus there is a relation between the relativity principle and the cosmological principle. We predict that the 3-d cosmic space is then of positive spatial curvature of order cosmological constant. The relation between ${\cal SR}_{c,R}$ and the doubly special relativity is briefly disucssed.Comment: Revtex4 file, no figure

Etanercept Inhibits Pro-inflammatory Cytokines Expression in Titanium Particle-Stimulated Peritoneal Macrophages

Purpose: To investigate the inhibitory role of Etanercept in pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6 production in titanium (Ti) particle stimulated macrophages.Methods: Peritoneal macrophages were stimulated with 1 × 109 Ti particles and treated simultaneously with or without 10, 100, or 1000 ng/mL Etanercept. The levels of TNF-α, IL-1β and IL-6 in the culture supernatants were measured using ELISA.Results: Titanium particles could stimulate TNF-α, IL-1β and IL-6 secretion in peritoneal macrophages. Etanercept inhibited Ti particle-induced TNF-α release by 29.7 % at 10 ng/ml (19.19 ± 4.72 pg/mL, p < 0.01), 49.3 % at 100 ng/mL (13.83 ± 3.72 pg/ml, p < 0.01) and 60.4 % at 1000 ng/mL (10.82 ± 3.87 pg/mL, p < 0.001), IL-1β release by 5.23 % at 10 ng/mL (34.79 ± 7.83 pg/mL, p > 0.05), 21.06 % at 100 ng/mL (28.98 ± 4.81 pg/mL, p < 0.01) and 29.83 % at 1000 ng/mL (25.76 ± 5.23 pg/ml, p < 0.001), and IL-6 release by 38.69 % at 10 ng/mL (256.8 ± 99.56 pg/mL, p < 0.01), by 42.13 % at 100 ng/mL (242.4 ± 33.26 pg/mL, p < 0.01) and 53.4 % at 1000 ng/ml (195.2 ± 48.82 pg/mL, p < 0.001).Conclusion: Etanercept has potent ability to prevent wear debris–induced osteolysis and may be valuable as a therapeutic agent for the treatment of prosthetic loosening in humans.Keywords: Etanercept; titanium particle; proinflammatory cytokines; peritoneal macrophage