Some kinetic and equilibrium studies of the reactions of nitrobenzofurazan derivatives with nucleophiles

The reactions of 4,6-dinitrobenzofuroxan, (DNBF) with aniline and six of its N- and ring- substituted derivatives have been studied. It is known that aniline usually reacts as a nitrogen nucleophile, forming nitrogen-bonded σ-adducts with trinitrobenzene, (TNB) in the presence of a strong base. However, in acidic solutions, a-adducts are formed with bonding between a ring carbon atom of the anilines and the 7-position of DNBF. A value of 2.0 for k(_H)/k(_D), the kinetic isotope effect, indicates that bond formation is largely rate determining in the substitution pathway. Estimates were made for the pK(_a) values relating to carbon protonation of the anilines. In solutions of aniline buffered with aniline hydrogen chloride it was possible to distinguish an initial, rapid reaction via the nitrogen centre to give anionic a-adducts. The thermodynamically more stable carbon-bonded σ-adducts were observed to form over time. In the presence of excess amine, these zwitterionic σ-adducts were in rapid equilibrium with the deprotonated forms. Equilibrium constants for this acid-base process were measured, and indicate that the negatively charged DNBF moiety is electron withdrawing relative to hydrogen. Kinetic and equilibrium studies are reported for the reactions of several aliphatic amines with a selection of nitrobenzofurazan derivatives in DMSO. Rapid reaction at the 5- position to yield σ-adducts was followed by slower formation of the thermodynamically more stable adducts at the 7-position. Proton transfer from the zwitterionic intermediates to a second molecule of amine was generally rapid, and the attack of the amine rate determining. This is in direct contrast with reactions involving TNB, where the proton transfer step is usually rate limiting. The reactions of four nitrobenzofurazan derivatives with sulfite have been studied in aqueous solutions. The stability of the initially formed 5-adducts was remarkably high in comparison with the corresponding σ-adducts formed from attack of sulfite on TNB. A slow isomerisation was observed to yield the thermodynamically more stable 7-adducts, except in the reaction with 4-nitro-7-chlorobenzofurazan, where attack at the 7-position would lead to nucleophilic substitution of the chloro-group to yield the substitution product. The mechanism of the isomerisation was found to occur via an intermolecular rearrangement, and not according to an intramolecular Boulton-Katritzky rearrangement. Sulfite attack on DNBF was also studied. A value for the equilibrium constant for the formation of a 1:1 adduct, K(_7) 1.1 x 10(^13) dm(^3) mol(^-1) was determined. This high value is a reflection of the high carbon basicity of the sulfite ion, and the highly electrophilic character of DNBF. Evidence was also obtained for the formation of 1:2 di-adducts in the presence of excess sulfite, which are present in the isomeric cis and trans forms

The Supplemental Nutrition Assistance Program and Food Insecurity

This chapter reviews recent theory and empirical evidence regarding the effect of SNAP on food insecurity and replicates the modelling strategies used in the empirical literature. The authors find that recent evidence suggesting an ameliorative effect of SNAP on food insecurity may not be robust to specification choice or data. Most specifications mirror the existing literature in finding a positive association of food insecurity with SNAP participation. Two-stage least squares and control function methods do show that SNAP reduces food insecurity, but effects are not consistent across sub-populations and are not always statistically significant

A Preliminary Study of the Ostracoda of the Big Snowy Group, Mississippian, of Montana.

In the field, samples were taken vertically and horizon­tally along the various outcrops in different sections of central and south-central Montana. At important localities the samples were taken about every half-foot verti­cally; in other sections they were taken every few feet

John Wesley Powell : soldier, explorer, scientist

Gerald W. Williams Collectio

Ensemble of Hankel Matrices for Face Emotion Recognition

In this paper, a face emotion is considered as the result of the composition of multiple concurrent signals, each corresponding to the movements of a specific facial muscle. These concurrent signals are represented by means of a set of multi-scale appearance features that might be correlated with one or more concurrent signals. The extraction of these appearance features from a sequence of face images yields to a set of time series. This paper proposes to use the dynamics regulating each appearance feature time series to recognize among different face emotions. To this purpose, an ensemble of Hankel matrices corresponding to the extracted time series is used for emotion classification within a framework that combines nearest neighbor and a majority vote schema. Experimental results on a public available dataset shows that the adopted representation is promising and yields state-of-the-art accuracy in emotion classification.Comment: Paper to appear in Proc. of ICIAP 2015. arXiv admin note: text overlap with arXiv:1506.0500

Cooperativity of Kv7.4 channels confers ultrafast electromechanical sensitivity and emergent properties in cochlear outer hair cells.

The mammalian cochlea relies on active electromotility of outer hair cells (OHCs) to resolve sound frequencies. OHCs use ionic channels and somatic electromotility to achieve the process. It is unclear, though, how the kinetics of voltage-gated ionic channels operate to overcome extrinsic viscous drag on OHCs at high frequency. Here, we report ultrafast electromechanical gating of clustered Kv7.4 in OHCs. Increases in kinetics and sensitivity resulting from cooperativity among clustered-Kv7.4 were revealed, using optogenetics strategies. Upon clustering, the half-activation voltage shifted negative, and the speed of activation increased relative to solitary channels. Clustering also rendered Kv7.4 channels mechanically sensitive, confirmed in consolidated Kv7.4 channels at the base of OHCs. Kv7.4 clusters provide OHCs with ultrafast electromechanical channel gating, varying in magnitude and speed along the cochlea axis. Ultrafast Kv7.4 gating provides OHCs with a feedback mechanism that enables the cochlea to overcome viscous drag and resolve sounds at auditory frequencies

Dynamic displacement of normal and detached semicircular canal cupula

© 2009 The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution Noncommercial License. The definitive version was published in JARO - Journal of the Association for Research in Otolaryngology 10 (2009): 497-509, doi:10.1007/s10162-009-0174-y.The dynamic displacement of the semicircular canal cupula and modulation of afferent nerve discharge were measured simultaneously in response to physiological stimuli in vivo. The adaptation time constant(s) of normal cupulae in response to step stimuli averaged 36 s, corresponding to a mechanical lower corner frequency for sinusoidal stimuli of 0.0044 Hz. For stimuli equivalent to 40–200 deg/s of angular head velocity, the displacement gain of the central region of the cupula averaged 53 nm per deg/s. Afferents adapted more rapidly than the cupula, demonstrating the presence of a relaxation process that contributes significantly to the neural representation of angular head motions by the discharge patterns of canal afferent neurons. We also investigated changes in time constants of the cupula and afferents following detachment of the cupula at its apex—mechanical detachment that occurs in response to excessive transcupular endolymph pressure. Detached cupulae exhibited sharply reduced adaptation time constants (300 ms–3 s, n = 3) and can be explained by endolymph flowing rapidly over the apex of the cupula. Partially detached cupulae reattached and normal afferent discharge patterns were recovered 5–7 h following detachment. This regeneration process may have relevance to the recovery of semicircular canal function following head trauma.Financial support was provided by the NIDCD R01 DC06685 (Rabbitt) and NASA GSRP 56000135 & NSF IGERT DGE- 9987616 (Breneman)

A mathematical model for top-shelf vertigo: the role of sedimenting otoconia in BPPV

Benign Paroxysmal Positional Vertigo (BPPV) is a mechanical disorder of the vestibular system in which calcite particles called otoconia interfere with the mechanical functioning of the fluid-filled semicircular canals normally used to sense rotation. Using hydrodynamic models, we examine the two mechanisms proposed by the medical community for BPPV: cupulolithiasis, in which otoconia attach directly to the cupula (a sensory membrane), and canalithiasis, in which otoconia settle through the canals and exert a fluid pressure across the cupula. We utilize known hydrodynamic calculations and make reasonable geometric and physical approximations to derive an expression for the transcupular pressure $\Delta P_c$ exerted by a settling solid particle in canalithiasis. By tracking settling otoconia in a two-dimensional model geometry, the cupular volume displacement and associated eye response (nystagmus) can be calculated quantitatively. Several important features emerge: 1) A pressure amplification occurs as otoconia enter a narrowing duct; 2) An average-sized otoconium requires approximately five seconds to settle through the wide ampulla, where $\Delta P_c$ is not amplified, which suggests a mechanism for the observed latency of BPPV; and 3) An average-sized otoconium beginning below the center of the cupula can cause a volumetric cupular displacement on the order of 30 pL, with nystagmus of order $2^\circ$/s, which is approximately the threshold for sensation. Larger cupular volume displacement and nystagmus could result from larger and/or multiple otoconia.Comment: 15 pages, 5 Figures updated, to be published in J. Biomechanic

Optimizing the vertebrate vestibular semicircular canal: could we balance any better?

The fluid-filled semicircular canals (SCCs) of the vestibular system are used by all vertebrates to sense angular rotation. Despite masses spanning seven decades, all mammalian SCCs are nearly the same size. We propose that the SCC represents a sensory organ that evolution has `optimally designed'. Four geometric parameters are used to characterize the SCC, and `building materials' of given physical properties are assumed. Identifying physical and physiological constraints on SCC operation, we find that the most sensitive SCC has dimensions consistent with available data.Comment: 4 pages, 3 figure

Local and systemic glucocorticoid metabolism in inflammatory arthritis

Background: Isolated, primary synovial fibroblasts generate active glucocorticoids through expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). This enzyme produces cortisol from inactive cortisone (and prednisolone from prednisone). Objective: To determine how intact synovial tissue metabolises glucocorticoids and to identify the local and systemic consequences of this activity by examination of glucocorticoid metabolism in patients with rheumatoid arthritis (RA). Methods: Synovial tissue was taken from patients with RA during joint replacement surgery. Glucocorticoid metabolism in explants was assessed by thin-layer chromatography and specific enzyme inhibitors. RT-PCR and immunohistochemistry were used to determine expression and distribution of 11β-HSD enzymes. Systemic glucocorticoid metabolism was examined in patients with RA using gas chromatography/mass spectrometry. Results: Synovial tissue synthesised cortisol from cortisone, confirming functional 11β-HSD1 expression. In patients with RA, enzyme activity correlated with donor erythrocyte sedimentation rate (ESR). Synovial tissues could also convert cortisol back to cortisone. Inhibitor studies and immunohistochemistry suggested this was owing to 11β-HSD2 expression in synovial macrophages, whereas 11β-HSD1 expression occurred primarily in fibroblasts. Synovial fluids exhibited lower cortisone levels than matched serum samples, indicating net local steroid activation. Urinary analyses indicated high 11β-HSD1 activity in untreated patients with RA compared with controls and a significant correlation between total body 11β-HSD1 activity and ESR. Conclusions: Synovial tissue metabolises glucocorticoids, the predominant effect being glucocorticoid activation, and this increases with inflammation. Endogenous glucocorticoid production in the joint is likely to have an impact on local inflammation and bone integrity