One-pot multicomponent synthesis of two novel thiolactone scaffolds

We designed two novel thiolactone scaffolds. Both scaffolds can be accessed by a convergent Ugi multicomponent reaction (MCR) and are, thus, amenable to library synthesis. Design, stereoselectivity, structures, full experimental details, and virtual libraries will be reported.     

Nonlinear interferometry via Fock-state projection

We use a photon-number-resolving detector to monitor the photon-number distribution of the output of an interferometer, as a function of phase delay. As inputs we use coherent states with mean photon number up to seven. The postselection of a specific Fock (photon-number) state effectively induces high-order optical nonlinearities. Following a scheme by Bentley and Boyd [Opt. Express 12, 5735 (2004).10.1364/OPEX.12.005735], we explore this effect to demonstrate interference patterns a factor of 5 smaller than the Rayleigh limit.     

Observation of bunching of two bell states

The bunching of two single photons on a beam splitter is a fundamental quantum effect, first observed by Hong, Ou, and Mandel. It is a unique interference effect that relies only on the photons' indistinguishability and not on their relative phase. We generalize this effect by demonstrating the bunching of two Bell states, created in two passes of a nonlinear crystal, each composed of two photons. When the two Bell states are indistinguishable, phase-insensitive destructive interference prevents the outcome of fourfold coincidence between the four spatial-polarization modes. For certain combinations of the two Bell states, we demonstrate the opposite effect of antibunching. We relate this result to the number of distinguishable modes in parametric down-conversion.     

Optically driven microelectromechanical-system deformable mirror under high-frequency AC bias

A new, optically addressed deformable mirror device is demonstrated. The device consists of a pixellated metalized polymeric membrane mirror supported above an optically addressed photoconductive substrate. A conductive transparent ZnO layer is deposited on the back side of the substrate. A very high-frequency AC bias is applied between the membrane and the back electrode of the device. The membrane is deformed when the back of the device is illuminated because of impedance and bias redistribution between two cascaded impedances. We fabricated, demonstrated, and modeled the operation of this device.     

Genomics and public health in the United States: signposts on the translation highway

Successful completion of the Human Genome Project has raised public expectations that research findings will translate quickly into health benefits; however, the gap between biomedical research and clinical and public health application seems wider than ever. Public health scientists now have the opportunity to help create a broad concept of research translation that integrates genomic information into policies, programs and services benefiting the whole population. Important 'signposts' along the translation highway include conducting population-based research in genomics, developing evidence on the clinical and public health value of genomic information, and integrating genomics into health practice.     

A combined far-infrared spectroscopic and electrochemical approach for the study of iron-sulfur proteins

Herein, we present the development of a far-infrared spectroscopic approach for studying metalloenzyme active sites in a redox-dependent manner. An electrochemical cell with 5 mm path and based on silicon windows was found to be appropriate for the measurement of aqueous solutions down to 200 cm(-1) . The cell was probed with the infrared redox signature of the metal-ligand vibrations of different iron-sulfur proteins. Each Fe-S cluster type was found to show a specific spectral signature. As a common feature, a downshift of the frequency of the Fe-S vibrations was seen upon reduction, in line with the increase of the Fe-S bond. This downshift was found to be fully reversible. Electrochemically induced FTIR difference spectroscopy in the far infrared is now possible, opening new perspectives on the understanding of metalloproteins in function of the redox state.     

D3R Grand Challenge 4: ligand similarity and MM-GBSA-based pose prediction and affinity ranking for BACE-1 inhibitors

The Drug Design Data Resource (D3R) Grand Challenges present an opportunity to assess, in the context of a blind predictive challenge, the accuracy and the limits of tools and methodologies designed to help guide pharmaceutical drug discovery projects. Here, we report the results of our participation in the D3R Grand Challenge 4 (GC4), which focused on predicting the binding poses and affinity ranking for compounds targeting the $$\beta$$-amyloid precursor protein (BACE-1). Our ligand similarity-based protocol using HYBRID (OpenEye Scientific Software) successfully identified poses close to the native binding mode for most of the ligands with less than 2 Å RMSD accuracy. Furthermore, we compared the performance of our HYBRID-based approach to that of AutoDock Vina and DOCK 6 and found that using a reference ligand to guide the docking process is a better strategy for pose prediction and helped HYBRID to perform better here. We also conducted end-point free energy estimates on molecules dynamics based ensembles of protein-ligand complexes using molecular mechanics combined with generalized Born surface area method (MM-GBSA). We found that the binding affinity ranking based on MM-GBSA scores have poor correlation with the experimental values. Finally, the main lessons from our participation in D3R GC4 are: (i) the generation of the macrocyclic conformers is a key step for successful pose prediction, (ii) the protonation states of the BACE-1 binding site should be treated carefully, (iii) the MM-GBSA method could not discriminate well between different predicted binding poses, and (iv) the MM-GBSA method does not perform well at predicting protein–ligand binding affinities here.     

A strategy for the stepwise ring annulation of all four pyrrolic rings of a porphyrin

The repeated introduction of an a-dione unit and its reaction with an arene-1,2-diamine allows the stepwise annulation of all four pyrrolic rings of a porphyrin, as is demonstrated by the synthesis of a trisquinoxalinoporphyrin, a tetrakisquinoxalinoporphyrin and the more elaborated bisporphyrin.