Lessons from LIMK1 enzymology and their impact on inhibitor design

LIM domain kinase 1 (LIMK1) is a key regulator of actin dynamics. It is thereby a potential therapeutic target for the prevention of fragile X syndrome and amyotrophic lateral sclerosis. Herein, we use X-ray crystallography and activity assays to describe how LIMK1 accomplishes substrate specificity, to suggest a unique ‘rock-and-poke’ mechanism of catalysis and to explore the regulation of the kinase by activation loop phosphorylation. Based on these findings, a differential scanning fluorimetry assay and a RapidFire mass spectrometry activity assay were established, leading to the discovery and confirmation of a set of small-molecule LIMK1 inhibitors. Interestingly, several of the inhibitors were inactive towards the closely related isoform LIMK2. Finally, crystal structures of the LIMK1 kinase domain in complex with inhibitors (PF-477736 and staurosporine, respectively) are presented, providing insights into LIMK1 plasticity upon inhibitor binding

Thermodynamic properties of extremely diluted symmetric Q-Ising neural networks

Using the replica-symmetric mean-field theory approach the thermodynamic and retrieval properties of extremely diluted {\it symmetric} $Q$-Ising neural networks are studied. In particular, capacity-gain parameter and capacity-temperature phase diagrams are derived for $Q=3, 4$ and $Q=\infty$. The zero-temperature results are compared with those obtained from a study of the dynamics of the model. Furthermore, the de Almeida-Thouless line is determined. Where appropriate, the difference with other $Q$-Ising architectures is outlined.Comment: 16 pages Latex including 6 eps-figures. Corrections, also in most of the figures have been mad

Ultrafast femtosecond-laser-induced fiber Bragg gratings in air-hole microstructured fibers for high-temperature pressure sensing

We present fiber Bragg grating pressure sensors in air-hole microstructured fibers for high-temperature operation above 800°C. An ultrafast laser was used to inscribe Type II grating in two-hole optical fibers. The fiber Bragg grating resonance wavelength shift and peak splits were studied as a function of external hydrostatic pressure from 15 psi to 2000 psi. The grating pressure sensor shows stable and reproducible operation above 800°C. We demonstrate a multiplexible pressure sensor technology for a high-temperature environment using a single fiber and a single-fiber feedthrough. © 2010 Optical Society of America

Room temperature sol-gel fabrication and functionalization for sensor applications

The structure and physical properties of a thin titania sol-gel layer prepared on silicon and silica surfaces were examined. Spectroscopic (FTIR, UV-VIS spectroscopy), refractive index (ellipsometry) and microscopic (light microscopy and SEM/EDS) tools were used to examine both chemical uniformity and physical uniformity of the sol-gel glass layers. The conditions for the fabrication of uniform layers were established, and room temperature dopant incorporation was examined. The absorption bands of porphyrin-containing titania sol-gel layers were characterized. By addition of a metal salt to the titania layer, it was possible to metallate the free-base porphyrin within and change the UV-VIS absorbance of the porphyrin, the basis of metal detection using porphyrins. The metalloporphyrins were detected by localized laser ablation inductive coupled mass spectroscopy (LA-ICP-MS), indicating fairly uniform distribution of metals across the titania surface. © 2012 The Author(s)

External validation of a simple clinical tool used to predict falls in people with Parkinson disease

Published in final edited form as: Parkinsonism Relat Disord. 2015 August ; 21(8): 960–963. doi:10.1016/j.parkreldis.2015.05.008.BACKGROUND: Assessment of fall risk in an individual with Parkinson disease (PD) is a critical yet often time consuming component of patient care. Recently a simple clinical prediction tool based only on fall history in the previous year, freezing of gait in the past month, and gait velocity <1.1 m/s was developed and accurately predicted future falls in a sample of individuals with PD. METHODS: We sought to externally validate the utility of the tool by administering it to a different cohort of 171 individuals with PD. Falls were monitored prospectively for 6 months following predictor assessment. RESULTS: The tool accurately discriminated future fallers from non-fallers (area under the curve [AUC] = 0.83; 95% CI 0.76–0.89), comparable to the developmental study. CONCLUSION: The results validated the utility of the tool for allowing clinicians to quickly and accurately identify an individual's risk of an impending fall.Davis Phinney Foundation, Parkinson Disease Foundation, NIH, APDA. (Davis Phinney Foundation; Parkinson Disease Foundation; NIH; APDA

Retrieval behavior and thermodynamic properties of symmetrically diluted Q-Ising neural networks

The retrieval behavior and thermodynamic properties of symmetrically diluted Q-Ising neural networks are derived and studied in replica-symmetric mean-field theory generalizing earlier works on either the fully connected or the symmetrical extremely diluted network. Capacity-gain parameter phase diagrams are obtained for the Q=3, Q=4 and $Q=\infty$ state networks with uniformly distributed patterns of low activity in order to search for the effects of a gradual dilution of the synapses. It is shown that enlarged regions of continuous changeover into a region of optimal performance are obtained for finite stochastic noise and small but finite connectivity. The de Almeida-Thouless lines of stability are obtained for arbitrary connectivity, and the resulting phase diagrams are used to draw conclusions on the behavior of symmetrically diluted networks with other pattern distributions of either high or low activity.Comment: 21 pages, revte

The distribution of dark and luminous matter in the unique galaxy cluster merger Abell 2146

Abell 2146 ($z$ = 0.232) consists of two galaxy clusters undergoing a major merger. The system was discovered in previous work, where two large shock fronts were detected using the $\textit{Chandra X-ray Observatory}$, consistent with a merger close to the plane of the sky, caught soon after first core passage. A weak gravitational lensing analysis of the total gravitating mass in the system, using the distorted shapes of distant galaxies seen with Advanced Camera for Surveys - Wide Field Channel on $\textit{Hubble Space Telescope}$, is presented. The highest peak in the reconstruction of the projected mass is centred on the brightest cluster galaxy (BCG) in Abell 2146-A. The mass associated with Abell 2146-B is more extended. Bootstrapped noise mass reconstructions show the mass peak in Abell 2146-A to be consistently centred on the BCG. Previous work showed that BCG-A appears to lag behind an X-ray cool core; although the peak of the mass reconstruction is centred on the BCG, it is also consistent with the X-ray peak given the resolution of the weak lensing mass map. The best-fitting mass model with two components centred on the BCGs yields $M_{200}$ = 1.1$^{+0.3}_{-0.4}$ × 10$^{15}$ and 3$^{+1}_{-2}$ × 10$^{14}$ M$_\odot$ for Abell 2146-A and Abell 2146-B, respectively, assuming a mass concentration parameter of $c$ = 3.5 for each cluster. From the weak lensing analysis, Abell 2146-A is the primary halo component, and the origin of the apparent discrepancy with the X-ray analysis where Abell 2146-B is the primary halo is being assessed using simulations of the merger