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

Multi-segmented Adaptive Feet for Versatile Legged Locomotion in Natural Terrain

Most legged robots are built with leg structures from serially mounted links and actuators and are controlled through complex controllers and sensor feedback. In comparison, animals developed multi-segment legs, mechanical coupling between joints, and multi-segmented feet. They run agile over all terrains, arguably with simpler locomotion control. Here we focus on developing foot mechanisms that resist slipping and sinking also in natural terrain. We present first results of multi-segment feet mounted to a bird-inspired robot leg with multi-joint mechanical tendon coupling. Our one- and two-segment, mechanically adaptive feet show increased viable horizontal forces on multiple soft and hard substrates before starting to slip. We also observe that segmented feet reduce sinking on soft substrates compared to ball-feet and cylinder-feet. We report how multi-segmented feet provide a large range of viable centre of pressure points well suited for bipedal robots, but also for quadruped robots on slopes and natural terrain. Our results also offer a functional understanding of segmented feet in animals like ratite birds

Short-duration lensing events: I. wide-orbit planets? free-floating low-mass objects? or high-velocity stars?

Short duration lensing events tend to be generated by low-mass lenses or by lenses with high transverse velocities. Furthermore, for any given lens mass and speed, events of short duration are preferentially caused by nearby lenses (mesolenses) that can be studied in detail, or else by lenses so close to the source star that finite-source-size effects may be detected, yielding information about both the Einstein ring radius and the surface of the lensed star. Planets causing short-duration events may be in orbits with any orientation, and may have semimajor axes smaller than an AU, or they may reach the outer limits of their planetary systems, in the region corresponding to the Solar System's Oort Cloud. They can have masses larger than Jupiter's or smaller than Pluto's. Lensing therefore has a unique potential to expand our understanding of planetary systems. A particular advantage of lensing is that it can provide precision measurements of system parameters, including the masses of and projected separation between star and planet. We demonstrate how the parameters can be extracted and show that a great deal can be learned. For example, it is remarkable that the gravitational mass of nearby free-floating planet-mass lenses can be measured by complementing observations of a photometric event with deep images that detect the planet itself. A fraction of short events may be caused by high-velocity stars located within a kpc. Many high-velocity lenses are likely to be neutron stars that received large natal kicks. Other high-speed stars may be members of the halo population. Still others may be hypervelocity stars that have been ejected from the Galactic Center, or runaway stars escaped from close binaries, possibly including the progenitor binaries of Type Ia supernovae.Comment: 17 pages; 2 figures; submitted to ApJ 3 July 200

The incidence of liver injury in Uyghur patients treated for TB in Xinjiang Uyghur autonomous region, China, and its association with hepatic enzyme polymorphisms nat2, cyp2e1, gstm1 and gstt1.

BACKGROUND AND OBJECTIVE: Of three first-line anti-tuberculosis (anti-TB) drugs, isoniazid is most commonly associated with hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, NAT2, CYP2E1, GSTM1and GSTT1, that code for drug-metabolizing enzymes. This study evaluated whether the polymorphisms in these enzymes were associated with an increased risk of anti-TB drug-induced hepatitis in patients and could potentially be used to identify patients at risk of liver injury. METHODS AND DESIGN: In a cross-sectional study, 2244 tuberculosis patients were assessed two months after the start of treatment. Anti-TB drug-induced liver injury (ATLI) was defined as an ALT, AST or bilirubin value more than twice the upper limit of normal. NAT2, CYP2E1, GSTM1 and GSTT1 genotypes were determined using the PCR/ligase detection reaction assays. RESULTS: 2244 patients were evaluated, there were 89 cases of ATLI, a prevalence of 4% 9 patients (0.4%) had ALT levels more than 5 times the upper limit of normal. The prevalence of ATLI was greater among men than women, and there was a weak association with NAT2*5 genotypes, with ATLI more common among patients with the NAT2*5*CT genotype. The sensitivity of the CT genotype for identifying patients with ATLI was 42% and the positive predictive value 5.9%. CT ATLI was more common among slow acetylators (prevalence ratio 2.0 (95% CI 0.95,4.20) )compared to rapid acetylators. There was no evidence that ATLI was associated with CYP2E1 RsaIc1/c1genotype, CYP2E1 RsaIc1/c2 or c2/c2 genotypes, or GSTM1/GSTT1 null genotypes. CONCLUSIONS: In Xinjiang Uyghur TB patients, liver injury was associated with the genetic variant NAT2*5, however the genetic markers studied are unlikely to be useful for screening patients due to the low sensitivity and low positive predictive values for identifying persons at risk of liver injury

Where were the monsoon regions and arid zones in Asia prior to the Tibetan Plateau uplift?

The impact of the Tibetan Plateau uplift on the Asian monsoons and inland arid climates is an important but also controversial question in studies of paleoenvironmental change during the Cenozoic. In order to achieve a good understanding of the background for the formation of the Asian monsoons and arid environments, it is necessary to know the characteristics of the distribution of monsoon regions and arid zones in Asia before the plateau uplift. In this study, we discuss in detail the patterns of distribution of the Asian monsoon and arid regions before the plateau uplift on the basis of modeling results without topography from a global coupled atmosphere–ocean general circulation model, compare our results with previous simulation studies and available biogeological data, and review the uncertainties in the current knowledge. Based on what we know at the moment, tropical monsoon climates existed south of 20°N in South and Southeast Asia before the plateau uplift, while the East Asian monsoon was entirely absent in the extratropics. These tropical monsoons mainly resulted from the seasonal shifts of the Inter-Tropical Convergence Zone. There may have been a quasi-monsoon region in central-southern Siberia. Most of the arid regions in the Asian continent were limited to the latitudes of 20–40°N, corresponding to the range of the subtropical high pressure year-around. In the meantime, the present-day arid regions located in the relatively high latitudes in Central Asia were most likely absent before the plateau uplift. The main results from the above modeling analyses are qualitatively consistent with the available biogeological data. These results highlight the importance of the uplift of the Tibetan Plateau in the Cenozoic evolution of the Asian climate pattern of dry–wet conditions. Future studies should be focused on effects of the changes in land–sea distribution and atmospheric CO2 concentrations before and after the plateau uplift, and also on cross-comparisons between numerical simulations and geological evidence, so that a comprehensive understanding of the evolution of the Cenozoic paleoenvironments in Asia can be achieved

Polypyrrole-Fe2O3 nanohybrid materials for electrochemical storage

We report on the synthesis and electrochemical characterization of nanohybrid polypyrrole (PPy) (PPy/Fe2O3) materials for electrochemical storage applications. We have shown that the incorporation of nanoparticles inside the PPy notably increases the charge storage capability in comparison to the “pure” conducting polymer. Incorporation of large anions, i.e., paratoluenesulfonate, allows a further improvement in the capacity. These charge storage modifications have been attributed to the morphology of the composite in which the particle sizes and the specific surface area are modified with the incorporation of nanoparticles. High capacity and stability have been obtained in PC/NEt4BF4 (at 20 mV/s), i.e., 47 mAh/g, with only a 3% charge loss after one thousand cyles. The kinetics of charge–discharge is also improved by the hybrid nanocomposite morphology modifications, which increase the rate of insertion–expulsion of counter anions in the bulk of the film. A room temperature ionic liquid such as imidazolium trifluoromethanesulfonimide seems to be a promising electrolyte because it further increases the capacity up to 53 mAh/g with a high stability during charge–discharge processes

A Heuristic Solution of the Identifiability Problem of the Age-Period-Cohort Analysis of Cancer Occurrence: Lung Cancer Example

Background: The Age–Period–Cohort (APC) analysis is aimed at estimating the following effects on disease incidence: (i) the age of the subject at the time of disease diagnosis; (ii) the time period, when the disease occurred; and (iii) the date of birth of the subject. These effects can help in evaluating the biological events leading to the disease, in estimating the influence of distinct risk factors on disease occurrence, and in the development of new strategies for disease prevention and treatment. Methodology/Principal Findings: We developed a novel approach for estimating the APC effects on disease incidence rates in the frame of the Log-Linear Age-Period-Cohort (LLAPC) model. Since the APC effects are linearly interdependent and cannot be uniquely estimated, solving this identifiability problem requires setting four redundant parameters within a set of unknown parameters. By setting three parameters (one of the time-period and the birth-cohort effects and the corresponding age effect) to zero, we reduced this problem to the problem of determining one redundant parameter and, used as such, the effect of the time-period adjacent to the anchored time period. By varying this identification parameter, a family of estimates of the APC effects can be obtained. Using a heuristic assumption that the differences between the adjacent birth-cohort effects are small, we developed a numerical method for determining the optimal value of the identification parameter, by which a unique set of all APC effects is determined and the identifiability problem is solved

g-Functions and gluon scattering amplitudes at strong coupling

We study gluon scattering amplitudes/Wilson loops in N=4 super Yang-Mills theory at strong coupling by calculating the area of the minimal surfaces in AdS_3 based on the associated thermodynamic Bethe ansatz system. The remainder function of the amplitudes is computed by evaluating the free energy, the T- and Y-functions of the homogeneous sine-Gordon model. Using conformal field theory (CFT) perturbation, we examine the mass corrections to the free energy around the CFT point corresponding to the regular polygonal Wilson loop. Based on the equivalence between the T-functions and the g-functions, which measure the boundary entropy, we calculate corrections to the T- and Y-functions as well as express them at the CFT point by the modular S-matrix. We evaluate the remainder function around the CFT point for 8 and 10-point amplitudes explicitly and compare these analytic expressions with the 2-loop formulas. The two rescaled remainder functions show very similar power series structures.Comment: 51 pages, 4 figures, v2: some comments and references added, based on the published version, v3: minor change

Optical coherence tomography-based freeze-drying microscopy

A new type of freeze-drying microscope based upon time-domain optical coherence tomography is presented here (OCT-FDM). The microscope allows for real-time, in situ 3D imaging of pharmaceutical formulations in vials relevant for manufacturing processes with a lateral resolution of <7 μm and an axial resolution of <5 μm. Correlation of volumetric structural imaging with product temperature measured during the freeze-drying cycle allowed investigation of structural changes in the product and determination of the temperature at which the freeze-dried cake collapses. This critical temperature is the most important parameter in designing freeze-drying processes of pharmaceutical products