Novel stereocontrolled addition of allylmetal reagents to alpha-imino esters: efficient synthesis of chiral tetrahydroquinoline derivatives

To prepare in multigram scale new antagonists of the glycine binding site associated to the NMDA receptor, an efficient distereoselective route was set up. The addition of suitable allyltin reagents to chiral N-aryl alpha-imino esters (R-(+)-tert-butyl lactate used as chiral auxiliary), gave the corresponding alpha amino acid-type derivative in high chemical yield and optical purity. This allylation reaction represents a novel example of efficient long-range stereodifferentiation process. In the last part of the synthesis, a regioselective Heck-type cyclization reaction enabled preparation of the target tetrasubstituted exocycle and trisubtituted endocycle double bond derivatives.     

Functionalized heteropolyanions: high-valent metal nitrido fragments incorporated into a Keggin polyoxometalate structure

Three examples of nitrido-functionalized polyoxometalate species are reported, namely (n-Bu4N)4[PW11O39(OsN)] (1), (n-Bu4N)4[PW11O39(ReN)] (2), and (n-Bu4N)3[PW11O39(ReN)] (3), which feature the incorporation of [OsVI identical to N]3+, [ReVI identical to N]3+ and [ReVII identical to N]4+ fragments, respectively, into the framework of a Keggin-type heteropolyanion.     

Diffraction-limited, 300-kW peak-power pulses from a coiled multimode fiber amplifier

We report a multimode, double-clad, Yb-doped fiber amplifier that produces diffraction-limited, 0.8-ns pulses with energies of 255 muJ and peak powers in excess of 300 kW at a repetition rate of ~8 kHz . Single-transverse-mode operation was obtained by bend-loss-induced mode filtering of the gain fiber.     

Towards a new age of virtual ADME/TOX and multidimensional drug discovery

With the continual pressure to ensure follow-up molecules to billion dollar blockbuster drugs, there is a hurdle in profitability and growth for pharmaceutical companies in the next decades. With each success and failure we increasingly appreciate that a key to the success of synthesized molecules through the research and development process is the possession of drug-like properties. These properties include an adequate bioactivity as well as adequate solubility, an ability to cross critical membranes (intestinal and sometimes blood-brain barrier), reasonable metabolic stability and of course safety in humans. Dependent on the therapeutic area being investigated it might also be desirable to avoid certain enzymes or transporters to circumvent potential drug-drug interactions. It may also be important to limit the induction of these same proteins that can result in further toxicities. We have clearly moved the assessment of in vitro absorption, distribution, metabolism, excretion and toxicity (ADME/TOX) parameters much earlier in the discovery organization than a decade ago with the inclusion of higher throughput systems. We are also now faced with huge amounts of ADME/TOX data for each molecule that need interpretation and also provide a valuable resource for generating predictive computational models for future drug discovery. The present review aims to show what tools exist today for visualizing and modeling ADME/TOX data, what tools need to be developed, and how both the present and future tools are valuable for virtual filtering using ADME/TOX and bioactivity properties in parallel as a viable addition to present practices.     

MMP-28 as a regulator of myelination

Background  

Matrix metalloproteinase-28 (MMP-28) is a poorly understood member of the matrix metalloproteinase family. Metalloproteinases are important mediators in the development of the nervous system and can contribute to the maturation of the neural micro-environment.     

Partial fluorination overcomes herringbone crystal packing in small polycyclic aromatics

[structure: see text] We report the synthesis and characterization of partially fluorinated condensed tetracyclic aromatic compounds. Typical edge-to-face/herringbone packing of nonfluorinated analogues is replaced here by columnar stacks with disk planes orthogonal to the columnar axes. Enhanced pi-overlap results with overlaid electron-poor and -rich regions.     

Initial attempts at directly detecting alpha wave activity in the brain using MRI

The “direct detection” of neuronal activity by MRI could offer improved spatial and temporal resolution compared to the blood oxygenation level-dependent (BOLD) effect. Here we describe initial attempts to use MRI to detect directly the neuronal currents resulting from spontaneous alpha wave activity, which have previously been shown to generate the largest extracranial magnetic fields. Experiments were successfully carried out on four subjects at 3 T. A single slice was imaged at a rate of 25 images per second under two conditions. The first (in darkness with eyes-closed) was chosen to promote alpha wave activity, while the second (eyes-open viewing a visual stimulus) was chosen to suppress it. The fluctuations of the phase and magnitude of the resulting MR image data were frequency analysed, and tested for the signature of both alpha wave activity and neuronal activity evoked by the visual stimulus.

Regions were found that consistently showed elevated power in fluctuations of the phase of the MR signal, in the frequency range of alpha waves, during the eyes-closed condition. It was conservatively assumed that if oscillations occurred at the same frequency in the magnitude signal from the same region or at the same frequency in the phase or magnitude signal from other regions overlying large vessels or cerebrospinal fluid (CSF), then the phase changes were not due to neuronal activity related to alpha waves. Using these criteria the data obtained were consistent with direct detection of alpha wave activity in three of the four volunteers. No significant MR signal fluctuations due to evoked activity were identified.     

Resummed photon spectrum in radiative upsilon decays

We present a theoretical prediction for the photon spectrum in radiative upsilon decay including the effects of resumming the end point region, E(gamma)-->M(upsilon)/2. Our approach is based on nonrelativistic QCD (NRQCD) and the soft-collinear effective theory. We find that our results give much better agreement with data than the leading order NRQCD prediction.     

Patterns in the vocalizations of male harbor seals

Comparative analyses of the roar vocalization of male harbor seals from ten sites throughout their distribution showed that vocal variation occurs at the oceanic, regional, population, and subpopulation level. Genetic barriers based on the physical distance between harbor seal populations present a likely explanation for some of the observed vocal variation. However, site-specific vocal variations were present between genetically mixed subpopulations in California. A tree-based classification analysis grouped Scottish populations together with eastern Pacific sites, rather than amongst Atlantic sites as would be expected if variation was based purely on genetics. Lastly, within the classification tree no individual vocal parameter was consistently responsible for consecutive splits between geographic sites. Combined, these factors suggest that site-specific variation influences the development of vocal structure in harbor seals and these factors may provide evidence for the occurrence of vocal dialects.     

The effect of a low-frequency sound source (acoustic thermometry of the ocean climate) on the diving behavior of juvenile northern elephant seals,Mirounga angustirostris

Changes in the diving behavior of individual free-ranging juvenile northern elephant seals, Mirounga angustirostris, exposed to the acoustic thermometry of the ocean climate (ATOC) sound source were examined using data loggers. Data loggers were attached to the animals and measured swim speed, maximum depth of dive, dive duration, surface interval, descent and ascent rate, and descent and ascent angle along with sound pressure level (SPL). The ATOC sound source was at a depth of 939 m and transmitted at 195 dB re: 1 microPa at 1 m centered at 75 Hz with a 37.5-Hz bandwidth. Sound pressure levels (SPL) measured at the seal during transmissions averaged 128 dB and ranged from 118 to 137 dB re: 1 microPa for the 60-90 Hz band, in comparison to ambient levels of 87-107 dB within this band. In no case did an animal end its dive or show any other obvious change in behavior upon exposure to the ATOC sound. Subtle changes in diving behavior were detected, however. During exposure, deviations in descent rate were greater than 1 s.d. of the control mean in 9 of 14 seals. Dive depth increased and descent velocity increased in three animals, ascent velocity decreased in two animals, ascent rate increased in one animal and decreased in another, and dive duration decreased in only one animal. There was a highly significant positive correlation between SPL and descent rate. The biological significance of these subtle changes is likely to be minimal. This is the first study to quantify behavioral responses of an animal underwater with simultaneous measurements of SPL of anthropogenic sounds recorded at the animal.