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

Chromosome 9p deletion in clear cell renal cell carcinoma predicts recurrence and survival following surgery

BACKGROUND: Wider clinical applications of 9p status in clear cell renal cell carcinoma (ccRCC) are limited owing to the lack of validation and consensus for interphase fluorescent in situ hybridisation (I-FISH) scoring technique. The aim of this study was to analytically validate the applicability of I-FISH in assessing 9p deletion in ccRCC and to clinically assess its long-term prognostic impact following surgical excision of ccRCC. METHODS: Tissue microarrays were constructed from 108 renal cell carcinoma (RCC) tumour paraffin blocks. Interphase fluorescent in situ hybridisation analysis was undertaken based on preset criteria by two independent observers to assess interobserver variability. 9p status in ccRCC tumours was determined and correlated to clinicopathological variables, recurrence-free survival and disease-specific survival. RESULTS: There were 80 ccRCCs with valid 9p scoring and a median follow-up of 95 months. Kappa statistic for interobserver variability was 0.71 (good agreement). 9p deletion was detected in 44% of ccRCCs. 9p loss was associated with higher stage, larger tumours, necrosis, microvascular and renal vein invasion, and higher SSIGN (stage, size, grade and necrosis) score. Patients with 9p-deleted ccRCC were at a higher risk of recurrence (P=0.008) and RCC-specific mortality (P=0.001). On multivariate analysis, 9p deletion was an independent predictor of recurrence (hazard ratio 4.323; P=0.021) and RCC-specific mortality (hazard ratio 4.603; P=0.007). The predictive accuracy of SSIGN score improved from 87.7% to 93.1% by integrating 9p status to the model (P=0.001). CONCLUSIONS: Loss of 9p is associated with aggressive ccRCC and worse prognosis in patients following surgery. Our findings independently confirm the findings of previous reports relying on I-FISH to detect 9p (CDKN2A) deletion

Leptoproduction of J/psi

We study leptoproduction of $J/\psi$ at large $Q^2$ within the nonrelativistic QCD (NRQCD) factorization formalism. The cross section is dominated by color-octet terms that are of order $\alpha_s$. The color-singlet term, which is of order $\alpha^2_s$, is shown to be a small contribution to the total cross section. We also calculate the tree diagrams for color-octet production at order $\alpha^2_s$ in a region of phase space where there is no leading color-octet contribution. We find that in this regime the color-singlet contribution dominates. We argue that non-perturbative corrections arising from diffractive leptoproduction, higher twist effects, and higher order terms in the NRQCD velocity expansion should be suppressed as $Q^2$ is increased. Therefore, the color-octet matrix elements $$and$$ can be reliably extracted from this process. Finally, we point out that an experimental measurement of the polarization of leptoproduced $J/\psi$ will provide an excellent test of the NRQCD factorization formalism.Comment: 33 pages latex. 10 figures. Uses revtex, epsf, and rotate macros. This paper is also available via the UW phenomenology archives at http://phenom.physics.wisc.edu/pub/preprints

The Accuracy of Perturbative Master Equations

We consider open quantum systems with dynamics described by master equations that have perturbative expansions in the system-environment interaction. We show that, contrary to intuition, full-time solutions of order-2n accuracy require an order-(2n+2) master equation. We give two examples of such inaccuracies in the solutions to an order-2n master equation: order-2n inaccuracies in the steady state of the system and order-2n positivity violations, and we show how these arise in a specific example for which exact solutions are available. This result has a wide-ranging impact on the validity of coupling (or friction) sensitive results derived from second-order convolutionless, Nakajima-Zwanzig, Redfield, and Born-Markov master equations.Comment: 6 pages, 0 figures; v2 updated references; v3 updated references, extension to full-time and nonlocal regime

Quantitative proteomics in resected renal cancer tissue for biomarker discovery and profiling

<b>Background:</b>  Proteomics-based approaches for biomarker discovery are promising strategies used in cancer research. We present state-of-art label-free quantitative proteomics method to assess proteome of renal cell carcinoma (RCC) compared with noncancer renal tissues.<p></p> <b>Methods:</b>  Fresh frozen tissue samples from eight primary RCC lesions and autologous adjacent normal renal tissues were obtained from surgically resected tumour-bearing kidneys. Proteins were extracted by complete solubilisation of tissues using filter-aided sample preparation (FASP) method. Trypsin digested proteins were analysed using quantitative label-free proteomics approach followed by data interpretation and pathways analysis.<p></p> <b>Results:</b>  A total of 1761 proteins were identified and quantified with high confidence (MASCOT ion score threshold of 35 and P-value <0.05). Of these, 596 proteins were identified as differentially expressed between cancer and noncancer tissues. Two upregulated proteins in tumour samples (adipose differentiation-related protein and Coronin 1A) were further validated by immunohistochemistry. Pathway analysis using IPA, KOBAS 2.0, DAVID functional annotation and FLink tools showed enrichment of many cancer-related biological processes and pathways such as oxidative phosphorylation, glycolysis and amino acid synthetic pathways.<p></p> <b>Conclusions:<b>  Our study identified a number of differentially expressed proteins and pathways using label-free proteomics approach in RCC compared with normal tissue samples. Two proteins validated in this study are the focus of on-going research in a large cohort of patients.<p></p&gt

Quantum Time and Spatial Localization: An Analysis of the Hegerfeldt Paradox

Two related problems in relativistic quantum mechanics, the apparent superluminal propagation of initially localized particles and dependence of spatial localization on the motion of the observer, are analyzed in the context of Dirac's theory of constraints. A parametrization invariant formulation is obtained by introducing time and energy operators for the relativistic particle and then treating the Klein-Gordon equation as a constraint. The standard, physical Hilbert space is recovered, via integration over proper time, from an augmented Hilbert space wherein time and energy are dynamical variables. It is shown that the Newton-Wigner position operator, being in this description a constant of motion, acts on states in the augmented space. States with strictly positive energy are non-local in time; consequently, position measurements receive contributions from states representing the particle's position at many times. Apparent superluminal propagation is explained by noting that, as the particle is potentially in the past (or future) of the assumed initial place and time of localization, it has time to propagate to distant regions without exceeding the speed of light. An inequality is proven showing the Hegerfeldt paradox to be completely accounted for by the hypotheses of subluminal propagation from a set of initial space-time points determined by the quantum time distribution arising from the positivity of the system's energy. Spatial localization can nevertheless occur through quantum interference between states representing the particle at different times. The non-locality of the same system to a moving observer is due to Lorentz rotation of spatial axes out of the interference minimum.Comment: This paper is identical to the version appearing in J. Math. Phys. 41; 6093 (Sept. 2000). The published version will be found at http://ojps.aip.org/jmp/. The paper (40 page PDF file) has been completely revised since the last posting to this archiv

Controllability analysis of multi objective control systems

The performance requirements stated in project specifications often comprise conflicting objectives. These objectives may further be a complex mix of steady state and dynamic performance. Control devices such as solenoid actuators are often chosen purely on steady state force characteristics, due to the difficulty of appraising the conflicting and generally non-linear nature of the performance objectives. This can have ramifications in terms not only of the actuator performance, but also in the overall controllability of the system when closed-loop control is implemented. An example automotive application examining the multi objective controllability of electronically actuated valves is presented. Multi objective evolutionary techniques are utilised to derive the optimal force-displacement characteristics and also dynamic characteristics of the desired actuator under the constraint of design performance criteria. The selected actuator is then assessed for its controllability and dynamic performance

Improving the economic value of photographic screening for optical coherence tomography-detectable macular oedema : a prospective, multicentre, UK study

Peer reviewedPublisher PD

Charmonium production at neutrino factories

At existing and planned neutrino factories (high energy and high intensity neutrino beam facilities) precision studies of QCD in neutrino-nucleon interactions are a realistic opportunity. We investigate charmonium production in fixed target neutrino experiments. We find that $J/\psi$ production in neutrino-nucleon collision is dominated by the color octet $^3S_1$ NRQCD matrix element in a neutral current process, which is not accessible in photo or leptoproduction. Neutrino experiments at a future Muon Collider will acquire sufficient event rate to accurately measure color octet matrix element contributions. The currently running high energy neutrino experiments, NOMAD and NuTeV could also observe several such events.Comment: 13 pages Latex, with five embedded eps figures. Cosmetic fixups in the figures, otherwise unchange