Localization by interaural time difference (ITD): effects of interaural frequency mismatch.

A commonly accepted physiological model for lateralization of low-frequency sounds by interaural time delay (ITD) stipulates that binaural comparison neurons receive input from frequency-matched channels from each ear. Here, the effects of hypothetical interaural frequency mismatches on this model are reported. For this study, the cat's auditory system peripheral to the binaural comparison neurons was represented by a neurophysiologically derived model, and binaural comparison neurons were represented by cross-correlators. The results of the study indicate that, for binaural comparison neurons receiving input from one cochlear channel from each ear, interaural CF mismatches may serve to either augment or diminish the effective difference in ipsilateral and contralateral axonal time delays from the periphery to the binaural comparison neuron. The magnitude of this increase or decrease in the effective time delay difference can be up to 400 microseconds for CF mismatches of 0.2 octaves or less for binaural neurons with CFs between 250 Hz and 2.5 kHz. For binaural comparison neurons with nominal CFs near 500 Hz, the 25-microsecond effective time delay difference caused by a 0.012-octave CF mismatch is equal to the ITD previously shown to be behaviorally sufficient for the cat to lateralize a low-frequency sound source.     

Pseudotetrahedral manganese complexes supported by the anionic tris(phosphino)borate ligand [PhBP(iPr)3

This paper presents aspects of the coordination chemistry of mono- and divalent manganese complexes supported by the anionic tris(phosphino)borate ligand, [PhBP(i)(Pr)3] (where [PhBP(i)(Pr)3] = [PhB(CH(2)P(i)Pr2)3]-). The Mn(II) halide complexes, [PhBP(i)(Pr)3]MnCl (1) and [PhBP(i)(Pr)3]MnI (2), have been characterized by X-ray diffraction, SQUID magnetometry, and EPR spectroscopy. Compound 2 serves as a precursor to a series of Mn azide, alkyl, and amide species: [PhBP(i)(Pr)3]Mn(N3) (3), [PhBP(i)(Pr)3]Mn(CH2Ph) (4), [PhBP(i)(Pr)3]Mn(Me) (5), [PhBP(i)(Pr)3]Mn(NH(2,6-(i)Pr2-C6H3)) (6), [PhBP(i)(Pr)3]Mn(dbabh) (7), and [PhBP(i)(Pr)3]Mn(1-Ph(isoindolate)) (8). The complexes 2-8 feature a divalent-metal center and are pseudotetrahedral. They collectively represent an uncommon structural motif for low-coordinate, polyphosphine-supported Mn complexes. Two Mn(I) species have also been prepared. These include the Tl-Mn adduct [PhBP(i)(Pr)3]Tl-MnBr(CO)4 (9) and the octahedral complex [PhBP(i)(Pr)3]Mn(CN(t)Bu)3 (10). Some of our initial synthetic efforts to generate [PhBP(i)(Pr)3]MnN(x) species are briefly described, as are DFT studies that probe the electronic viability of these types of multiply bonded target structures.     

Encapsulating zinc(II) within a hydrophobic cavity

A new macrobicyclic ligand has been prepared, and it is shown to bind Zn(2+) on the inside. The ligand consists of a triamido(amine) motif to coordinate the metal ion and a narrow, hydrophobic channel above the metal binding site.     

Desulfurization of phosphorothioate oligonucleotides via the sulfur‐by‐oxygen replacement induced by the hydroxyl radical during negative electrospray ionization mass spectrometry

While the occurrence of desulfurization of phosphorothioate oligonucleotides in solution is well established, this study represents the first attempt to investigate the basis of the unexpected desulfurization via the net sulfur‐by‐oxygen (S‐O) replacement during negative electrospray ionization (ESI). The current work, facilitated by quantitative mass deconvolution, demonstrates that considerable desulfurization can take place even under common negative ESI operating conditions. The extent of desulfurization is dependent on the molar phosphorothioate oligonucleotide‐to‐hydroxyl radical ratio, which is consistent with the corona discharge‐induced origin of the hydroxyl radical leading to the S‐O replacement. This hypothesis is supported by the fact that an increase of the high‐performance liquid chromatography (HPLC) flow rate and the on‐column concentration of a phosphorothioate oligonucleotide, as well as a decrease of the electrospray voltage reduce the degree of desulfurization. Comparative LC‐tandem mass spectrometry (MS/MS) sequencing of a phosphorothioate oligonucleotide and its corresponding desulfurization product revealed evidence that the S‐O replacement occurs at multiple phosphorothioate internucleotide linkage sites. In practice, the most convenient and effective strategy for minimizing this P = O artifact is to increase the LC flow rate and the on‐column concentration of phosphorothioate oligonucleotides. Another approach to mitigate possible detrimental effects of the undesired desulfurization is to operate the ESI source at a very low electrospray voltage to diminish the corona discharge; however this will significantly compromise sensitivity when analyzing the low‐level P = O impurities in phosphorothioate oligonucleotides. Copyright © 2012 John Wiley & Sons, Ltd.     

Synthesis and X-ray crystallographic analysis of chiral pyridyl substituted carbocyclic molecular clefts

Ditopic symmetrical bis(pyridyl) ligands incorporating the chiral dibenzobicyclo[b,f][3.3.1]nona-5a,6a-diene-6,12-dione cleft have been synthesised and characterised by NMR spectroscopy, mass spectrometry and X-ray crystallography. The ligands, which incorporate pyridyl groups directly connected to the carbocyclic cleft core or via alkyne or phenyl linkers were accessed from palladium-catalysed coupling reactions of 2,8-dibromodibenzobicyclo[b,f][3.3.1]nona-5a,6a-diene-6,12-dione. X-ray crystal analyses show the interplanar angles between the two cleft aromatic rings in these molecules, which range from 97.80(3) to 109.80(4)°.     

Formal Nickelate(−I) Complexes Supported by Group 13 Ions

Formal nickelate(?I) complexes bearing Group 13 metalloligands (M=Al and Ga) were isolated. These 17 e^? complexes were synthesized by one‐electron reduction of the corresponding Ni⁰→M^III precursors, and were investigated by single‐crystal X‐ray diffraction, EPR spectroscopy, and quantum chemical calculations. Collectively, the experimental and computational data support: 1) the strengthening of the Ni?M bond upon one‐electron reduction, and 2) the delocalization of the unpaired spin across the Ni and M atoms. An intriguing electronic configuration is revealed where three valence electrons occupy two σ‐type bonding interactions: Ni(3d )²→M and σ‐(Ni?M)¹. The latter is an unusual Ni?M σ‐bonding molecular orbital that comprises primarily the Ni 4p_z and M np_z/ns atomic orbitals.     

Strategies for kinome profiling in cancer and potential clinical applications: chemical proteomics and array-based methods

Kinases are key enzymes involved in deregulated signal transduction associated with cancer development and progression. The advent of personalized medicine drives the development of new diagnostic tools for patient stratification and therapy selection Ginsburg and Willard (Transl Res 154:277-287, 2009). Since deregulation of kinase-mediated signal transduction is implied in tumorigenesis, the analysis of all kinases (the kinome) active in a particular tumor may yield tumor-specific information on aberrant cell signalling pathways. Tumor tissue kinase activity profiles may correlate with response to therapy and therefore may be used for future therapy selection. In this Trend paper we describe peptide array and mass spectrometry-based technologies and new developments for kinome profiling, and we present an outlook towards future implementation of therapy selection based on kinome profiling in clinical practice.     

Development and validation of a rapid and sensitive HPLC method for the quantification of 5‐fluorocytosine and its metabolites

To study the intracellular metabolism of the prodrug 5‐fluorocytosine (5FC), we developed a novel reverse‐phase high‐performance liquid chromatography method to simultaneously detect 5FC and its four major anabolic metabolites: 5‐fluorouracil, 5‐fluorouridine, 5‐fluorouridine‐monophosphate and 5‐fluoro‐2′deoxyuridine‐5′‐monophosphate. Separation of each compound was accomplished under isocratic conditions using a C₁₈ column and mobile phase of formic acid–water (1 : 99 v/v). The method was validated for both accuracy and reproducibility in cell culture media. Additionally, metabolites were assessed for stability at ambient temperatures and following freeze–thaw cycles. Calibration curves were linear over a range of 1–200 μg/mL. Limit of quantification for four of the five compounds was 1 μg/mL in cell culture media (RSD < 11%). This method was successfully used to monitor intracellular conversion of 5FC to its metabolic products over a 24h period. Copyright © 2009 John Wiley & Sons, Ltd.     

Hole growth as a microrheological probe to measure the viscosity of polymers confined to thin films

We review recent hole growth measurements performed at elevated temperatures in freely-standing polystyrene (PS) films, using optical microscopy and a differential pressure experiment (DPE). In the hole growth experiments, which were performed at temperatures close to the bulk glass-transition temperature of PS, T = 97 °C, we find evidence for nonlinear viscoelastic effects, which markedly affect the growth of holes in freely-standing PS films. The hole radius R initially grew linearly with time t before undergoing a transition to exponential growth characterized by a growth time τ. The time scale τ₁ for the decay of the initial transient behavior prior to reaching steady state was consistent with the convective constraint release mechanism of the tube theory of entangled polymer dynamics, while the characteristic hole growth times τ of the holes were consistent with significant reductions in viscosity of over eight orders of magnitude with increasing shear strain rate due to shear thinning. DPE measurements of hole growth on very thin freely-standing films revealed that hole formation and growth occurs only at temperatures that are comparable to or greater than T, even for films for which the T_g value was reduced by many tens of degrees Celsius below the bulk value. © 2006 Wiley Periodicals, Inc. J Polym Sci Part B:Polym Phys 44: 3011–3021, 2006