Humans detect gaps in broadband noise according to effective gap duration without additional cues from abrupt envelope changes

Previous studies of behavior and IC single units in the mouse support theoretical expectations that gaps with ramped trailing markers have reduced detectability compared to equivalent gaps with ramped leading markers. In experiment 1, detection probability and response speeds of humans listening for gaps in broadband noise were investigated by independently varying either leading marker fall-time (FT) or trailing marker rise-time (RT). Gaps with silent duration of 1, 4, or 12 ms were presented 2 s into a 3-s noise burst, with either abrupt marker onsets and offsets or linearly ramped RT/FT of 2, 4, or 8 ms durations. Addition of a nonzero RT or FT to the gap silent period increased detectability and also increased reaction speed on trials with "Yes" response, but there was no difference in detectability or response speeds between RT and FT conditions. Experiment 2 extended this finding to gaps having two, one, or no abrupt marker edges. These findings suggest that human listeners do not make use of abrupt onset or offset information to enhance gap detection, but seem to rely on the effective sound level reduction associated with the gap for detection.     

The attention filter for tones in noise has the same shape and effective bandwidth in the elderly as it has in young listeners

Listeners asked to detect tones masked by noise hear frequent signals but miss infrequent probes, suggesting that they attend to spectral regions where they expect the signals to occur. The narrow detection pattern centered on the frequent target approximates that obtained in notched noise, indicating that attention is focused on the auditory filter. We measured attention bands in young and elderly listeners (n=5, 4; 20-25 and 62-82 years of age) for targets (800 or 1200 Hz) and infrequent probe signals (target +/-25-100 Hz) masked in wideband noise. We anticipated that their width would increase with age, as has been reported for auditory filters. A yes-no single-interval procedure provided detection probabilities and detection response speeds. Both measures showed near-linear declines with decreasing signal level, and graded decay functions as probe frequency deviated from the target frequency. Probes deviating from the target by 25 to 50 Hz were equivalent to a 2-dB reduction in signal level for both measures. The equivalent rectangular bandwidth (ERB) for detection approximated 11% of the signal frequency for each age group. Confidence intervals (95%) showed that the elderly ERB could be at most only about 20% larger than that of younger listeners.     

Oxidizing species in the mechanism of cytochrome P450

This review discusses the mechanisms of oxygen activation by cytochrome P450 enzymes, the possible catalytic roles of the various iron--oxygen species formed in the catalytic cycle, and progress in understanding the mechanisms of hydrocarbon hydroxylation, heteroatom oxidation, and olefin epoxidation. The focus of the review is on recent results, but earlier work is discussed as appropriate. The literature through to February 2002 is surveyed, and 175 referenced are cited.     

Twistophane macrocyles with integrated 6,6'-connected-2,2'-bipyridine units: a new lead class of fluorescence sensors for metal ions

The new twistophane macrocycles 2 and 3 have been synthesised; these compounds are composed of a cyclically conjugated dehydrobenzoannulene framework that incorporates 6,6'-connected-2,2'-bipyridine moieties for the purpose of coordinating metal ions. The cyclophanes were characterised by spectroscopic techniques, and shown by molecular mechanics calculations to be helically twisted and chiral molecules that may exist in several possible ground state conformations. UV/vis spectroscopic studies revealed that 2, 3 and precursor 9 bind with different selectivities to particular members of the following small group of metal analytes: CuII, AgI, HgII, Tl1 and PdII. Significantly, 2, 3 and 9 signal the presence of CuII ions through fluorescence emission quenching output responses. Furthermore, cyclophane 3 exhibited a particularly sensitive protontriggered chromogenic fluorescence response. With respect to their unique structural features, high analyte selectivity coupled with their enhanced and characteristic fluorescence emission responses, these molecules are among the first examples representing a new lead class of chemosensory materials. Compounds 2, 3 and 9 and derivatives thereof may, therefore, be expected to find many future applications in the detection of metal-based environmental pollutants, biologically important trace elements and monitoring proton fluxes.     

1H NMR detection of immobilized water molecules within a strong distal hydrogen-bonding network of substrate-bound human heme oxygenase-1

Solution 1H NMR is used to probe the environments of the donor protons of eight strong hydrogen bonds on the distal side of the heme substrate in the cyanide-inhibited, substrate-bound complex of human heme oxygenase, hHO. It is demonstrated that significant magnetization transfer from the bulk water signal to the eight labile protons does not result from chemical exchange, but from direct nuclear Overhauser effect due to the dipolar interaction of these labile protons with "ordered" water molecules. The enzyme labile proton to water proton distances are estimated at approximately 3 A. It is proposed that the role of the strong hydrogen-bonding network is to immobilize numerous water molecules which both stabilize the activated hydroperoxy species and funnel protons to the active site.     

Oligocarbamate molecular transporters: design,synthesis, and biological evaluation of a new class of transporters for drug delivery

Molecular transporters have the ability to deliver drugs and probe molecules into cells and tissues irrespective of their physical properties. We now report the design, synthesis, and biological evaluation of a new family of molecular transporters, guanidinylated oligocarbamates that enable exceptionally efficient uptake into cells and tissues. The synthesis features a solid-phase stepwise oligomerization to obtain the oligocarbamates and a single step perguanidinylation for the facile introduction of up to nine guanidinium groups. The oligocarbamate 9-mer is found to be among the most efficient transporters known, entering cells faster than even d-Arg9 and HIV-1 Tat49-57. Significantly, this new family of transporters also enables uptake into the formidable skin barrier of a probe molecule that by itself does not penetrate skin.     

Characterisation of the phosgene response of a membrane inlet 63Ni ion mobility spectrometer

A membrane inlet 63Ni ion mobility spectrometer interfaced to a quadrupole mass spectrometer with permeation, exponential dilution approaches and syringe-based systems were used to characterise the ion mobility spectrometry (IMS) response to phosgene in dry air (water concentration less than 16.5 mg m(-3)). Phosgene produced a principle product ion in the negative mode with a reduced mobility of 2.16 cm2 V(-1) s(-1), with an unresolved artefact at higher concentrations having a reduced mobility of 2.32 cm2 V(-1) s(-1). The limit of detection of the system with a membrane inlet fitted was estimated to be less than 1 mg m(-3), with an upper limit to the dynamic range of 32 mg m(-3). Mass spectrometric data indicated the existence of [(H2O)nCl]-, [(H2O)nCl2]-; [(H2O)n(O2)Cl]-; [(H2O)n(O)Cl]-; and, [(H2O)n(CO2)Cl]-. The existence of two possible mechanisms for product ion formation is proposed: dissociative electron capture, as well as hydrolysis followed by electron capture. The effect of water contamination of the drying media within the ion mobility spectrometer was also investigated, and the effects were similar to those observed previously with studies on chlorine. Reduced mobility of the product ions was observed to decrease with increasing water contamination of the drying media used within the instrument, while limits of detection increased slightly to less than 2.4 mg m(-3), with no significant effect on dynamic ranges of response or resolution. Preliminary results also indicated a positive mode response for phosgene, albeit at significantly higher concentrations to those observed in the negative mode.     

Inhibitors of plasmin that extend into both the S and S' binding sites: cooperative interactions between S1 and S2

A new procedure for the synthesis of cyclohexanone-based inhibitors of serine proteases is reported. In this procedure the reactive ketone functionality is carried through the synthesis in masked form as a TBDMS-protected alcohol. Deprotection followed by oxidation of the alcohol generates the final form of the inhibitor. Two new inhibitors, which interact with the S1-S3 and S2' subsites of plasmin, are synthesized using this procedure. Inhibitors 1 and 2 have IC50 values against plasmin of 20 and 24 microM, respectively. The inhibition studies show that cooperative binding of inhibitors in the S1 and S2 subsites of plasmin is important for determining inhibitor selectivity.     

An improved protocol for the preparation of 3-pyridyl- and some arylboronic acids

3-Pyridylboronic acid was prepared in high yield and bulk quantity from 3-bromopyridine via a protocol of lithium-halogen exchange and "in situ quench". This technique was further studied and evaluated on other aryl halides in the preparation of arylboronic acids.     

Conformationally constrained alpha-boc-aminophosphonates via transition metal-catalyzed/curtius rearrangement strategies

A transition metal-catalyzed/Curtius rearrangement sequence toward the development of conformationally constrained alpha-Boc-aminophosphonates 2-6 is described. An approach using the versatile tert-butylphosphonoacetate moieties 1a and 1b to derive an array of mono- and bicyclic alpha-Boc-aminophosphonate systems is presented. Conformational constraint is incorporated using either the ring-closing metathesis reaction catalyzed by the first generation Grubbs catalyst or intramolecular cyclopropanation mediated by Rh2(OAc)4. Using the tert-butyl ester functionality in 1a or 1b as a potential amino group, the Curtius rearrangement provides an efficient route toward the target alpha-Boc-aminophosphonates.