Synthesis and biological evaluation of spirocyclic antagonists of CCR2 (chemokine CC receptor subtype 2)

Activation of chemokine CC receptors subtype 2 (CCR2) plays an important role in chronic inflammatory processes such as atherosclerosis, multiple sclerosis and rheumatoid arthritis. A diverse set of spirocyclic butanamides 4 (N-benzyl-4-(3,4-dihydrospiro[[2]benzopyran-1,4'-piperidin]-1'-yl)butanamides) was prepared by different combination of spirocyclic piperidines 8 (3,4-dihydrospiro[[2]benzopyran-1,4'-piperidines]) and γ-halobutanamides 11. A key step in the synthesis of spirocyclic piperidines 8 was an Oxa-Pictet-Spengler reaction of β-phenylethanols 5 with piperidone acetal 6. The substituted γ-hydroxybutanamides 11c-e were prepared by hydroxyethylation of methyl acetates 13 with ethylene sulfate giving the γ-lactones 14c and 14e. Aminolysis of the γ-lactones 14c and 14e with benzylamines provided the γ-hydroxybutanamides 15c-e, which were converted into the bromides 11c-e by an Appel reaction using polymer-bound PPh3. In radioligand binding assays the spirocyclic butanamides 4 did not displace the iodinated radioligand (125)I-CCL2 from the human CCR2. However, in the Ca(2+)-flux assay using human CCR2 strong antagonistic activity of butanamides 4 was detected. Analysis of the IC50-values led to clear relationships between the structure and the inhibition of the Ca(2+)-flux. 4g (4-(3,4-dihydrospiro[[2]benzopyran-1,4'-piperidin]-1'-yl)-N-[3,5-bis(trifluoromethylbenzyl)]-2-(4-fluorophenyl)butanamide) and 4o (N-[3,5-bis(trifluoromethyl)benzyl]-2-cyclopropyl-4-(3,4-dihydrospiro[[2]benzopyran-1,4'-piperidin]-1'-yl)butanamide) represent the most potent CCR2 antagonists with IC50-values of 89 and 17nM, respectively. Micromolar activities were found in the β-arrestin recruitment assay with murine CCR2, but the structure-activity-relationships detected in the Ca(2+)-flux assay were confirmed.Medicinal Chemistr

Qubit Disentanglement and Decoherence via Dephasing

We consider whether quantum coherence in the form of mutual entanglement between a pair of qubits is susceptible to decay that may be more rapid than the decay of the coherence of either qubit individually. An instance of potential importance for solid state quantum computing arises if embedded qubits (spins, quantum dots, Cooper pair boxes, etc.) are exposed to global and local noise at the same time. Here we allow separate phase-noisy channels to affect local and non-local measures of system coherence. We find that the time for decay of the qubit entanglement can be significantly shorter than the time for local dephasing of the individual qubits.Comment: REVTeX, 9 pages, 1 figure, v2 with minor changes, reference adde

Applications of Real-Time Simulation Technologies in Power and Energy Systems

Real-time (RT) simulation is a highly reliable simulation method that is mostly based on electromagnetic transient simulation of complex systems comprising many domains. It is increasingly used in power and energy systems for both academic research and industrial applications. Due to the evolution of the computing power of RT simulators in recent years, new classes of applications and expanded fields of practice could now be addressed with RT simulation. This increase in computation power implies that models can be built more accurately and the whole simulation system gets closer to reality. This Task Force paper summarizes various applications of digital RT simulation technologies in the design, analysis, and testing of power and energy systems

Post-surgical adhesions are triggered by calcium-dependent membrane bridges between mesothelial surfaces.

Surgical adhesions are bands of scar tissues that abnormally conjoin organ surfaces. Adhesions are a major cause of post-operative and dialysis-related complications, yet their patho-mechanism remains elusive, and prevention agents in clinical trials have thus far failed to achieve efficacy. Here, we uncover the adhesion initiation mechanism by coating beads with human mesothelial cells that normally line organ surfaces, and viewing them under adhesion stimuli. We document expansive membrane protrusions from mesothelia that tether beads with massive accompanying adherence forces. Membrane protrusions precede matrix deposition, and can transmit adhesion stimuli to healthy surfaces. We identify cytoskeletal effectors and calcium signaling as molecular triggers that initiate surgical adhesions. A single, localized dose targeting these early germinal events completely prevented adhesions in a preclinical mouse model, and in human assays. Our findings classifies the adhesion pathology as originating from mesothelial membrane bridges and offer a radically new therapeutic approach to treat adhesions

Methods for Analysis and Quantification of Power System Resilience

This paper summarizes the report prepared by an IEEE PES Task Force. Resilience is a fairly new technical concept for power systems, and it is important to precisely delineate this concept for actual applications. As a critical infrastructure, power systems have to be prepared to survive rare but extreme incidents (natural catastrophes, extreme weather events, physical/cyber-attacks, equipment failure cascades, etc.) to guarantee power supply to the electricity-dependent economy and society. Thus, resilience needs to be integrated into planning and operational assessment to design and operate adequately resilient power systems. Quantification of resilience as a key performance indicator is important, together with costs and reliability. Quantification can analyze existing power systems and identify resilience improvements in future power systems. Given that a 100% resilient system is not economic (or even technically achievable), the degree of resilience should be transparent and comprehensible. Several gaps are identified to indicate further needs for research and development.ISSN:0885-8950ISSN:1558-067