Building a three-dimensional model of CYP2C9 inhibition using the Autocorrelator: an autonomous model generator

In modern day drug discovery campaigns, computational chemists have to be concerned not only about improving the potency of molecules but also reducing any off-target ADMET activity. There are a plethora of antitargets that computational chemists may have to consider. Fortunately many antitargets have crystal structures deposited in the PDB. These structures are immediately useful to our Autocorrelator: an automated model generator that optimizes variables for building computational models. This paper describes the use of the Autocorrelator to construct high quality docking models for cytochrome P450 2C9 (CYP2C9) from two publicly available crystal structures. Both models result in strong correlation coefficients (R2 > 0.66) between the predicted and experimental determined log(IC??) values. Results from the two models overlap well with each other, converging on the same scoring function, deprotonated charge state, and predicted the binding orientation for our collection of molecules.     

Search for right-handed currents in muon decay

We report new limits on right-handed currents, based on precise measurements of the endpoint of the e⁺ spectrum from ⁺ decay. Highly polarized ⁺ from the TRIUMF surface beam were stopped in pure metal foils within either an 1.1-T spin-holding logitudinal field, or a 70-gauss spin-precessing transverse field. Decay e⁺ emitted within 200 mrad of the beam direction were momentum-analyzed to ±0.2%. For the spin-held data, decay via (V-A) currents requires the e⁺ rate to approach zero in the beam direction at the endpoint. Measurement of this rate sets the 90%-confidence limits P />0.9959 and M(W_R)>380 GeV, where W_R is the possible right-handed gauge boson. For the spin-precessed data we independently determine a 90% confidence limit P />0.9918.We are indebted to the entire TRIUMF management and staff for their splendid support of this experiment. In its early stages we benefited from discussion with J. Brewer, R. Cahn, K. Crowe, and W. Wenzel. Rapid commissioning of the polarimeter was made possible by the superb efforts of the LBL support staff. This research was supported in part by the U.S. Department of Energy, Division of Basic Energy Sciences, Office of Energy Research under contracts W-7405-ENG-48 and AC02-ER02289.     

Big data analytics: an aid to detection of non-technical losses in power utilities

Computational Management Science - The great amount of data collected by the Advanced Metering Infrastructure can help electric utilities to detect energy theft, a phenomenon that globally costs...     

Comparing Shannon to autocorrelation-based wavelets for solving singularly perturbed elliptic BV problems

A Shannon wavelet algorithm (essentially F. Stenger’s sinc-Galerkin collocation method) is proposed to solve typically singularly perturbed ordinary and elliptic boundary-value problems. The method is shown to be effective and competitive with respect to the autocorrelation-based method in a number of examples, in one and two dimensions, when the smallness parameter becomes smaller and smaller. Advantages can be expected to be even more pronounced when the “fast sinc transform” is used.     

Influence of single-particle shell structure on the energy dissipation in heavy-ion collisions

Shell effects in the mean energy dissipated per transferred nucleon are analysed within a statistical model of random transfers and excitations. Quantitative agreement for all 21 analysed reactions is obtained without fitting any parameter to the data.     

Doping of a dielectric layer as a new alternative for increasing sensitivity of the contactless conductivity detection in microchips

This communication describes a new procedure to increase the sensitivity of C(4)D in PDMS/glass microchips. The method consists in doping the insulating layer (PDMS) over the electrodes with nanoparticles of TiO(2), increasing thus its dielectric constant. The experimental protocol is simple, inexpensive, and fast.     

New Coumarin Derivatives as Cholinergic and Cannabinoid System Modulators

In the last years, the connection between the endocannabinoid system (eCS) and neuroprotection has been discovered, and evidence indicates that eCS signaling is involved in the regulation of cognitive processes and in the pathophysiology of Alzheimer’s disease (AD). Accordingly, pharmacotherapy targeting eCS could represent a valuable contribution in fighting a multifaceted disease such as AD, opening a new perspective for the development of active agents with multitarget potential. In this paper, a series of coumarin-based carbamic and amide derivatives were designed and synthesized as multipotent compounds acting on cholinergic system and eCS-related targets. Indeed, they were tested with appropriate enzymatic assays on acetyl and butyryl-cholinesterases and on fatty acid amide hydrolase (FAAH), and also evaluated as cannabinoid receptor (CB1 and CB2) ligands. Moreover, their ability to reduce the self-aggregation of beta amyloid protein (Aβ₄₂) was assessed. Compounds 2 and 3, bearing a carbamate function, emerged as promising inhibitors of hAChE, hBuChE, FAAH and Aβ₄₂ self-aggregation, albeit with moderate potencies, while the amide 6 also appears a promising CB1/CB2 receptors ligand. These data prove for the new compounds an encouraging multitarget profile, deserving further evaluation.     

Contactless conductivity biosensor in microchip containing folic acid as bioreceptor

We report a glass/PDMS-based microfluidic biosensor that integrates contactless conductivity transduction and folic acid, a target for tumor biomarker, as a bioreceptor. The device presents relevant advantages such as direct determination--dismiss the use of redox mediators as in faradaic electrochemical techniques--and the absence of the known drawbacks related to the electrode-solution interface. Characterizations of the functionalization processes and chemical sensor are described in this communication.