Myosin VIIA is required for aminoglycoside accumulation in cochlear hair cells.

Myosin VIIA is expressed by sensory hair cells and has a primary structure predicting a role in membrane trafficking and turnover, processes that may underlie the susceptibility of hair cells to aminoglycoside antibiotics. [3H]Gentamicin accumulation and the effects of aminoglycosides were therefore examined in cochlear cultures of mice with different missense mutations in the myosin VIIA gene, Myo7a, to see whether myosin VIIA plays a role in aminoglycoside ototoxicity. Hair cells from homozygous mutant Myo7a(sh1) mice, with a mutation in a non-conserved region of the myosin VIIA head, respond rapidly to aminoglycoside treatment and accumulate high levels of gentamicin. Hair cells from homozygous mutant Myo7a(6J) mice, with a mutation at a highly conserved residue close to the ATP binding site of the myosin VIIA head, do not accumulate [3H]gentamicin and are protected from aminoglycoside ototoxicity. Hair cells from heterozygotes of both alleles accumulate [3H]gentamicin and respond to aminoglycosides. Although aminoglycoside uptake is thought to be via apical surface-associated endocytosis, coated pit numbers on the apical membrane of heterozygous and homozygous Myo7a(6J) hair cells are similar. Pulse-chase experiments with cationic ferritin confirm that the apical endocytotic pathway is functional in homozygous Myo7a(6J) hair cells. Transduction currents can be recorded from both heterozygous and homozygous Myo7a(6J) hair cells, suggesting it is unlikely that the drug enters via diffusion through the mechanotransducer channel. The results show that myosin VIIA is required for aminoglycoside accumulation in hair cells. Myosin VIIA may transport a putative aminoglycoside receptor to the hair cell surface, indirectly translocate it to sites of membrane retrieval, or retain it in the endocytotic pathway

Stimulated Raman spin coherence and spin-flip induced hole burning in charged GaAs quantum dots

High-resolution spectral hole burning (SHB) in coherent nondegenerate differential transmission spectroscopy discloses spin-trion dynamics in an ensemble of negatively charged quantum dots. In the Voigt geometry, stimulated Raman spin coherence gives rise to Stokes and anti-Stokes sidebands on top of the trion spectral hole. The prominent feature of an extremely narrow spike at zero detuning arises from spin population pulsation dynamics. These SHB features confirm coherent electron spin dynamics in charged dots, and the linewidths reveal spin spectral diffusion processes.Comment: 5 pages, 5 figure

A tradeoff in simultaneous quantum-limited phase and loss estimation in interferometry

Interferometry with quantum light is known to provide enhanced precision for estimating a single phase. However, depending on the parameters involved, the quantum limit for the simultaneous estimation of multiple parameters may not attainable, leading to trade-offs in the attainable precisions. Here we study the simultaneous estimation of two parameters related to optical interferometry: phase and loss, using a fixed number of photons. We derive a trade-off in the estimation of these two parameters which shows that, in contrast to single-parameter estimation, it is impossible to design a strategy saturating the quantum Cramer-Rao bound for loss and phase estimation in a single setup simultaneously. We design optimal quantum states with a fixed number of photons achieving the best possible simultaneous precisions. Our results reveal general features about concurrently estimating Hamiltonian and dissipative parameters, and has implications for sophisticated sensing scenarios such as quantum imaging.Comment: 9 pages, 6 figure

Peripheral Dendritic Cells Are Essential for Both the Innate and Adaptive Antiviral Immune Responses in the Central Nervous System

Intranasal application of vesicular stomatitis virus (VSV) causes acute infection of the central nervous system (CNS). However, VSV encephalitis is not invariably fatal, suggesting that the CNS may contain a professional antigen-presenting cell (APC) capable of inducing or propagating a protective antiviral immune response. To examine this possibility, we first characterized the cellular elements that infiltrate the brain as well as the activation status of resident microglia in the brains of normal and transgenic mice acutely ablated of peripheral dendritic cells (DCs) in vivo. VSV encephalitis was characterized by a pronounced infiltrate of myeloid cells (CD45highCD11b+)and CD8+ T cells containing a subset that was specific for the immunodominant VSV nuclear protein epitope. This T cell response correlated temporally with a rapid and sustained upregulation of MHC class I expression on microglia, whereas class II expression was markedly delayed. Ablation of peripheral DCs profoundly inhibited the inflammatory response as well as infiltration of virus-specific CD8+ T cells. Unexpectedly, the VSV-induced interferon-gamma (IFN-γ) response in the CNS remained intact in DC-deficient mice. Thus, both the inflammatory and certain components of the adaptive primary antiviral immune response in the CNS are dependent on peripheral DCs in vivo

Effective elements of cognitive behaviour therapy for psychosis: results of a novel type of subgroup analysis based on principal stratification

Background. Meta-analyses show that cognitive behaviour therapy for psychosis (CBT-P) improves distressing positive symptoms. However, it is a complex intervention involving a range of techniques. No previous study has assessed the delivery of the different elements of treatment and their effect on outcome. Our aim was to assess the differential effect of type of treatment delivered on the effectiveness of CBT-P, using novel statistical methodology. Method. The Psychological Prevention of Relapse in Psychosis (PRP) trial was a multi-centre randomized controlled trial (RCT) that compared CBT-P with treatment as usual (TAU). Therapy was manualized, and detailed evaluations of therapy delivery and client engagement were made. Follow-up assessments were made at 12 and 24 months. In a planned analysis, we applied principal stratification (involving structural equation modelling with finite mixtures) to estimate intention-to-treat (ITT) effects for subgroups of participants, defined by qualitative and quantitative differences in receipt of therapy, while maintaining the constraints of randomization. Results. Consistent delivery of full therapy, including specific cognitive and behavioural techniques, was associated with clinically and statistically significant increases in months in remission, and decreases in psychotic and affective symptoms. Delivery of partial therapy involving engagement and assessment was not effective. Conclusions. Our analyses suggest that CBT-P is of significant benefit on multiple outcomes to patients able to engage in the full range of therapy procedures. The novel statistical methods illustrated in this report have general application to the evaluation of heterogeneity in the effects of treatment

The internal-external respiratory motion correlation is unaffected by audiovisual biofeedback.

This study evaluated if an audiovisual (AV) biofeedback causes variation in the level of external and internal correlation due to its interactive intervention in natural breathing. The internal (diaphragm) and external (abdominal wall) respiratory motion signals of 15 healthy human subjects under AV biofeedback and free breathing (FB) were analyzed and measures of correlation and regularity taken. Regularity metrics (root mean square error and spectral power dispersion metric) were obtained and the correlation between these metrics and the internal and external correlation was investigated. For FB and AV biofeedback assisted breathing the mean correlations found between internal and external respiratory motion were 0.96±0.02 and 0.96±0.03, respectively. This means there is no evidence to suggest (p-value=0.88) any difference in the correlation between internal and external respiratory motion with the use of AV biofeedback. Our results confirmed the hypothesis that the internal-external correlation with AV biofeedback is the same as for free breathing. Should this correlation be maintained for patients, AV biofeedback can be implemented in the clinic with confidence as regularity improvements using AV biofeedback with an external signal will be reflected in increased internal motion regularity

Systematic effects and a new determination of the primordial abundance of 4He and dY/dZ from observations of blue compact galaxies

We use spectroscopic observations of a sample of 82 HII regions in 76 blue compact galaxies to determine the primordial helium abundance Yp and the slope dY/dZ from the Y-O/H linear regression. To improve the accuracy of the dY/dZ measurement, we have included new spectrophotometric observations of 33 HII regions which span a large metallicity range, with oxygen abundance 12+log(O/H) varying between 7.43 and 8.30 (Zsun/30<Z<Zsun/4). For a subsample of 7 HII regions, we derive the He mass fraction taking into account known systematic effects, including collisional and fluorescent enhancements of HeI emission lines, collisional excitation of hydrogen emission, underlying stellar HeI absorption and the difference between the temperatures Te(HeII) in the He^+ zone and Te(OIII) derived from the collisionally excited [OIII] lines. We find that the net result of all the systematic effects combined is small, changing the He mass fraction by less than 0.6%. By extrapolating the Y vs. O/H linear regression to O/H=0 for 7 HII regions of this subsample, we obtain Yp=0.2421+/-0.0021 and dY/dO=5.7+/-1.8, which corresponds to dY/dZ=3.7+/-1.2, assuming the oxygen mass fraction to be O=0.66Z. In the framework of the standard Big Bang nucleosynthesis theory, this Yp corresponds to Omega_b h^2 = 0.012^+0.003_-0.002, where h is the Hubble constant in units of 100 km/s/Mpc. This is smaller at the 2sigma level than the value obtained from recent deuterium abundance and microwave background radiation measurements. The linear regression slope dY/dO=4.3+/-0.7 (corresponding to dY/dZ=2.8+/-0.5) for the whole sample of 82 HII regions is similar to that derived for the subsample of 7 HII regions, although it has a considerably smaller uncertainty.Comment: 53 pages, 3 Postscript figures, accepted for publication in the Astrophysical Journa

Stimulated and spontaneous optical generation of electron spin coherence in charged GaAs quantum dots

We report on the coherent optical excitation of electron spin polarization in the ground state of charged GaAs quantum dots via an intermediate charged exciton (trion) state. Coherent optical fields are used for the creation and detection of the Raman spin coherence between the spin ground states of the charged quantum dot. The measured spin decoherence time, which is likely limited by the nature of the spin ensemble, approaches 10 ns at zero field. We also show that the Raman spin coherence in the quantum beats is caused not only by the usual stimulated Raman interaction but also by simultaneous spontaneous radiative decay of either excited trion state to a coherent combination of the two spin states.Comment: 4 pages, 3 figures. Minor modification