Periodicity and frequency coding in human auditory cortex

Understanding the neural coding of pitch and frequency is fundamental to the understanding of speech comprehension, music perception and the segregation of concurrent sound sources. Neuroimaging has made important contributions to defining the pattern of frequency sensitivity in humans. However, the precise way in which pitch sensitivity relates to these frequency-dependent regions remains unclear. Single-frequency tones also cannot be used to test this hypothesis as their pitch always equals their frequency. Here, temporal pitch (periodicity) and frequency coding were dissociated using stimuli that were bandpassed in different frequency spectra (centre frequencies 800 and 4500 Hz), yet were matched in their pitch characteristics. Cortical responses to both pitch-evoking stimuli typically occurred within a region that was also responsive to low frequencies. Its location extended across both primary and nonprimary auditory cortex. An additional control experiment demonstrated that this pitch-related effect was not simply caused by the generation of combination tones. Our findings support recent neurophysiological evidence for a cortical representation of pitch at the lateral border of the primary auditory cortex, while revealing new evidence that additional auditory fields are also likely to play a role in pitch coding

Low-Noise Amplification of a Continuous Variable Quantum State

We present an experimental realization of a low-noise, phase-insensitive optical amplifier using a four-wave mixing interaction in hot Rb vapor. Performance near the quantum limit for a range of amplifier gains, including near unity, can be achieved. Such low-noise amplifiers are essential for so-called quantum cloning machines and are useful in quantum information protocols. We demonstrate that amplification and ``cloning'' of one half of a two-mode squeezed state is possible while preserving entanglement.Comment: To appear in Physical Review Letters July 3rd. 4 pages, 4 figure

Adiposity is associated with blunted cardiovascular, neuroendocrine and cognitive responses to acute mental stress

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited - Copyright @ 2012 Jones et al.Obesity and mental stress are potent risk factors for cardiovascular disease but their relationship with each other is unclear. Resilience to stress may differ according to adiposity. Early studies that addressed this are difficult to interpret due to conflicting findings and limited methods. Recent advances in assessment of cardiovascular stress responses and of fat distribution allow accurate assessment of associations between adiposity and stress responsiveness. We measured responses to the Montreal Imaging Stress Task in healthy men (N=43) and women (N=45) with a wide range of BMIs. Heart rate (HR) and blood pressure (BP) measures were used with novel magnetic resonance measures of stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR) and arterial compliance to assess cardiovascular responses. Salivary cortisol and the number and speed of answers to mathematics problems in the task were used to assess neuroendocrine and cognitive responses, respectively. Visceral and subcutaneous fat was measured using T2*-IDEAL. Greater BMI was associated with generalised blunting of cardiovascular (HR:β=−0.50 bpm.unit−1, P=0.009; SV:β=−0.33 mL.unit−1, P=0.01; CO:β=−61 mL.min−1.unit−1, P=0.002; systolic BP:β=−0.41 mmHg.unit−1, P=0.01; TPR:β=0.11 WU.unit−1, P=0.02), cognitive (correct answers: r=−0.28, P=0.01; time to answer: r=0.26, P=0.02) and endocrine responses (cortisol: r=−0.25, P=0.04) to stress. These associations were largely determined by visceral adiposity except for those related to cognitive performance, which were determined by both visceral and subcutaneous adiposity. Our findings suggest that adiposity is associated with centrally reduced stress responsiveness. Although this may mitigate some long-term health risks of stress responsiveness, reduced performance under stress may be a more immediate negative consequence.This work is funded by the UK National Institute of Health Research (NIHR), Siemens Medical Systems, British Heart Foundation (BHF), NIHR Senior Research Fellowship & The Fondation Leducq, BHF Intermediate Fellowship

Inspiratory muscle training enhances pulmonary O2 uptake kinetics and high-intensity exercise tolerance in humans

Fatigue of the respiratory muscles during intense exercise might compromise leg blood flow, thereby constraining oxygen uptake (VO2) and limiting exercise tolerance. We tested the hypothesis that inspiratory muscle training (IMT) would reduce inspiratory muscle fatigue, speed VO2 kinetics and enhance exercise tolerance. Sixteen recreationally active subjects (mean ± SD, age 22 ± 4 yr) were randomly assigned to receive 4 wk of either pressure threshold IMT [30 breaths twice daily at ~50% of maximum inspiratory pressure (MIP)] or sham treatment (60 breaths once daily at ~15% of MIP). The subjects completed moderate-, severe- and maximal-intensity "step" exercise transitions on a cycle ergometer before (Pre) and after (Post) the 4-wk intervention period for determination of VO2 kinetics and exercise tolerance. There were no significant changes in the physiological variables of interest after Sham. After IMT, baseline MIP was significantly increased (Pre vs. Post: 155 ± 22 vs. 181 ± 21 cmH2O; P < 0.001), and the degree of inspiratory muscle fatigue was reduced after severe- and maximal-intensity exercise. During severe exercise, the VO2 slow component was reduced (Pre vs. Post: 0.60 ± 0.20 vs. 0.53 ± 0.24 l/min; P < 0.05) and exercise tolerance was enhanced (Pre vs. Post: 765 ± 249 vs. 1,061 ± 304 s; P < 0.01). Similarly, during maximal exercise, the VO2 slow component was reduced (Pre vs. Post: 0.28 ± 0.14 vs. 0.18 ± 0.07 l/min; P < 0.05) and exercise tolerance was enhanced (Pre vs. Post: 177 ± 24 vs. 208 ± 37 s; P < 0.01). Four weeks of IMT, which reduced inspiratory muscle fatigue, resulted in a reduced VO2 slow-component amplitude and an improved exercise tolerance during severe- and maximal-intensity exercise. The results indicate that the enhanced exercise tolerance observed after IMT might be related, at least in part, to improved VO2 dynamics, presumably as a consequence of increased blood flow to the exercising limbs

The nucleotide-free state of the multidrug resistance ABC transporter LmrA: Sulfhydryl cross-linking supports a constant contact, head-to-tail configuration of the nucleotide-binding domains

© 2015 Jones, George. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABC transporters are integral membrane pumps that are responsible for the import or export of a diverse range of molecules across cell membranes. ABC transporters have been implicated in many phenomena of medical importance, including cystic fibrosis and multidrug resistance in humans. The molecular architecture of ABC transporters comprises two transmembrane domains and two ATP-binding cassettes, or nucleotide-binding domains (NBDs), which are highly conserved and contain motifs that are crucial to ATP binding and hydrolysis. Despite the improved clarity of recent structural, biophysical, and biochemical data, the seemingly simple process of ATP binding and hydrolysis remains controversial, with a major unresolved issue being whether the NBD protomers separate during the catalytic cycle. Here chemical cross-linking data is presented for the bacterial ABC multidrug resistance (MDR) transporter LmrA. These indicate that in the absence of nucleotide or substrate, the NBDs come into contact to a significant extent, even at 4°C, where ATPase activity is abrogated. The data are clearly not in accord with an inward-closed conformation akin to that observed in a crystal structure of V. cholerae MsbA. Rather, they suggest a head-to-tail configuration 'sandwich' dimer similar to that observed in crystal structures of nucleotide-bound ABC NBDs. We argue the data are more readily reconciled with the notion that the NBDs are in proximity while undergoing intra-domain motions, than with an NBD 'Switch' mechanism in which the NBD monomers separate in between ATP hydrolysis cycles

An Asymmetric Post-Hydrolysis State of the ABC Transporter ATPase Dimer

ABC transporters are a superfamily of enzyme pumps that hydrolyse ATP in exchange for translocation of substrates across cellular membranes. Architecturally, ABC transporters are a dimer of transmembrane domains coupled to a dimer of nucleotide binding domains (NBDs): the NBD dimer contains two ATP-binding sites at the intersubunit interface. A current controversy is whether the protomers of the NBD dimer separate during ATP hydrolysis cycling, or remain in constant contact. In order to investigate the ABC ATPase catalytic mechanism, MD simulations using the recent structure of the ADP+Pi-bound MJ0796 isolated NBD dimer were performed. In three independent simulations of the ADP+Pi/apo state, comprising a total of >0.5 μs, significant opening of the apo (empty) active site was observed; occurring by way of intrasubunit rotations between the core and helical subdomains within both NBD monomers. In contrast, in three equivalent simulations of the ATP/apo state, the NBD dimer remained close to the crystal structure, and no opening of either active site occurred. The results thus showed allosteric coupling between the active sites, mediated by intrasubunit conformational changes. Opening of the apo site is exquisitely tuned to the nature of the ligand, and thus to the stage of the reaction cycle, in the opposite site. In addition to this, in also showing how one active site can open, sufficient to bind nucleotide, while the opposite site remains occluded and bound to the hydrolysis products ADP+Pi, the results are consistent with a Constant Contact Model. Conversely, they show how there may be no requirement for the NBD protomers to separate to complete the catalytic cycle. © 2013 Jones, George

Computational analysis of the MCoTI-II plant defence knottin reveals a novel intermediate conformation that facilitates trypsin binding

MCoTI-I and II are plant defence proteins, potent trypsin inhibitors from the bitter gourd Momordica cochinchinensis. They are members of the Knottin Family, which display exceptional stability due to unique topology comprising three interlocked disulfide bridges. Knottins show promise as scaffolds for new drug development. A crystal structure of trypsin-bound MCoTI-II suggested that loop 1, which engages the trypsin active site, would show decreased dynamics in the bound state, an inference at odds with an NMR analysis of MCoTI-I, which revealed increased dynamics of loop 1 in the presence of trypsin. To investigate this question, we performed unrestrained MD simulations of trypsin-bound and free MCoTI-II. This analysis found that loop 1 of MCoTI-II is not more dynamic in the trypsin-bound state than in the free state. However, it revealed an intermediate conformation, transitional between the free and bound MCoTI-II states. The data suggest that MCoTI-II binding involves a process in which initial interaction with trypsin induces transitions between the free and intermediate conformations, and fluctuations between these states account for the increase in dynamics of loop 1 observed for trypsin-bound MCoTI-I. The MD analysis thus revealed new aspects of the inhibitors dynamics that may be of utility in drug design

Vacuum Stability of the wrong sign (−ϕ6)(-\phi^{6}) Scalar Field Theory

We apply the effective potential method to study the vacuum stability of the bounded from above $(-\phi^{6})$ (unstable) quantum field potential. The stability ($\partial E/\partial b=0)$ and the mass renormalization ($\partial^{2} E/\partial b^{2}=M^{2})$ conditions force the effective potential of this theory to be bounded from below (stable). Since bounded from below potentials are always associated with localized wave functions, the algorithm we use replaces the boundary condition applied to the wave functions in the complex contour method by two stability conditions on the effective potential obtained. To test the validity of our calculations, we show that our variational predictions can reproduce exactly the results in the literature for the $\mathcal{PT}$-symmetric $\phi^{4}$ theory. We then extend the applications of the algorithm to the unstudied stability problem of the bounded from above $(-\phi^{6})$ scalar field theory where classical analysis prohibits the existence of a stable spectrum. Concerning this, we calculated the effective potential up to first order in the couplings in $d$ space-time dimensions. We find that a Hermitian effective theory is instable while a non-Hermitian but $\mathcal{PT}$-symmetric effective theory characterized by a pure imaginary vacuum condensate is stable (bounded from below) which is against the classical predictions of the instability of the theory. We assert that the work presented here represents the first calculations that advocates the stability of the $(-\phi^{6})$ scalar potential.Comment: 21pages, 12 figures. In this version, we updated the text and added some figure

Safety of blood transfusion: prevalence of hepatitis B surface antigen in blood donors in Zaria, Northern Nigeria

Background: Hepatitis B infection has long been known to be common in the general population and due to its mode of transmission through blood transfusion; it had made provision of safe blood difficult especially in developing countries. Method: A retrospective study aimed at reassessing the current of sero-prevalence of hepatitis B infection in blood donors in a typical developing country was conducted. Results: Six thousand and twenty five regular blood were screened our of which 254 (4.2%) were HBsAg positive with lowest rates being in 2001 (3.5%) and the highest rates occurred in 2002(5.1%).Age of donors ranged from 19-42years with a mean 33 years, 98% were males while only 2% were females. Prevalence of HBsAg was 47.2% in patients' replacement donors, 44.5% in relations of antenatal clinic attendees and 8.3% in voluntary donors. Conclusions: This study has revealed a high prevalence rate of hepatitis B infections in all age groups and categories of blood donors in our setting which makes transfusion of unscreened hazardous. Nigerian Journal of Surgical Research Vol. 7(3&4) 2005: 290-29