The actin-myosin regulatory MRCK kinases: regulation, biological functions and associations with human cancer

The contractile actin-myosin cytoskeleton provides much of the force required for numerous cellular activities such as motility, adhesion, cytokinesis and changes in morphology. Key elements that respond to various signal pathways are the myosin II regulatory light chains (MLC), which participate in actin-myosin contraction by modulating the ATPase activity and consequent contractile force generation mediated by myosin heavy chain heads. Considerable effort has focussed on the role of MLC kinases, and yet the contributions of the myotonic dystrophy-related Cdc42-binding kinases (MRCK) proteins in MLC phosphorylation and cytoskeleton regulation have not been well characterized. In contrast to the closely related ROCK1 and ROCK2 kinases that are regulated by the RhoA and RhoC GTPases, there is relatively little information about the CDC42-regulated MRCKα, MRCKβ and MRCKγ members of the AGC (PKA, PKG and PKC) kinase family. As well as differences in upstream activation pathways, MRCK and ROCK kinases apparently differ in the way that they spatially regulate MLC phosphorylation, which ultimately affects their influence on the organization and dynamics of the actin-myosin cytoskeleton. In this review, we will summarize the MRCK protein structures, expression patterns, small molecule inhibitors, biological functions and associations with human diseases such as cancer

Artificial tektites: an experimental technique for capturing the shapes of spinning drops

Determining the shapes of a rotating liquid droplet bound by surface tension is an archetypal problem in the study of the equilibrium shapes of a spinning and charged droplet, a problem that unites models of the stability of the atomic nucleus with the shapes of astronomical-scale, gravitationally-bound masses. The shapes of highly deformed droplets and their stability must be calculated numerically. Although the accuracy of such models has increased with the use of progressively more sophisticated computational techniques and increases in computing power, direct experimental verification is still lacking. Here we present an experimental technique for making wax models of these shapes using diamagnetic levitation. The wax models resemble splash-form tektites, glassy stones formed from molten rock ejected from asteroid impacts. Many tektites have elongated or ‘dumb-bell’ shapes due to their rotation mid-flight before solidification, just as we observe here. Measurements of the dimensions of our wax ‘artificial tektites’ show good agreement with equilibrium shapes calculated by our numerical model, and with previous models. These wax models provide the first direct experimental validation for numerical models of the equilibrium shapes of spinning droplets, of importance to fundamental physics and also to studies of tektite formation

Long-lived magnetism from solidification-driven convection on the pallasite parent body.

Palaeomagnetic measurements of meteorites suggest that, shortly after the birth of the Solar System, the molten metallic cores of many small planetary bodies convected vigorously and were capable of generating magnetic fields. Convection on these bodies is currently thought to have been thermally driven, implying that magnetic activity would have been short-lived. Here we report a time-series palaeomagnetic record derived from nanomagnetic imaging of the Imilac and Esquel pallasite meteorites, a group of meteorites consisting of centimetre-sized metallic and silicate phases. We find a history of long-lived magnetic activity on the pallasite parent body, capturing the decay and eventual shutdown of the magnetic field as core solidification completed. We demonstrate that magnetic activity driven by progressive solidification of an inner core is consistent with our measured magnetic field characteristics and cooling rates. Solidification-driven convection was probably common among small body cores, and, in contrast to thermally driven convection, will have led to a relatively late (hundreds of millions of years after accretion), long-lasting, intense and widespread epoch of magnetic activity among these bodies in the early Solar System.The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement No. 320750, the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 312284, the Natural Environment Research Council, Fundación ARAID and the Spanish MINECO MAT2011-23791.This is the accepted manuscript. The final version is available from Nature at http://www.nature.com/nature/journal/v517/n7535/full/nature14114.html

A chemical survey of exoplanets with ARIEL

Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.Peer reviewedFinal Published versio

Co-Crystal Structures of Inhibitors with MRCKβ, a Key Regulator of Tumor Cell Invasion

MRCKα and MRCKβ (myotonic dystrophy kinase-related Cdc42-binding kinases) belong to a subfamily of Rho GTPase activated serine/threonine kinases within the AGC-family that regulate the actomyosin cytoskeleton. Reflecting their roles in myosin light chain (MLC) phosphorylation, MRCKα and MRCKβ influence cell shape and motility. We report further evidence for MRCKα and MRCKβ contributions to the invasion of cancer cells in 3-dimensional matrix invasion assays. In particular, our results indicate that the combined inhibition of MRCKα and MRCKβ together with inhibition of ROCK kinases results in significantly greater effects on reducing cancer cell invasion than blocking either MRCK or ROCK kinases alone. To probe the kinase ligand pocket, we screened 159 kinase inhibitors in an in vitro MRCKβ kinase assay and found 11 compounds that inhibited enzyme activity >80% at 3 µM. Further analysis of three hits, Y-27632, Fasudil and TPCA-1, revealed low micromolar IC50 values for MRCKα and MRCKβ. We also describe the crystal structure of MRCKβ in complex with inhibitors Fasudil and TPCA-1 bound to the active site of the kinase. These high-resolution structures reveal a highly conserved AGC kinase fold in a typical dimeric arrangement. The kinase domain is in an active conformation with a fully-ordered and correctly positioned αC helix and catalytic residues in a conformation competent for catalysis. Together, these results provide further validation for MRCK involvement in regulation of cancer cell invasion and present a valuable starting point for future structure-based drug discovery efforts

Automation of a problem list using natural language processing

BACKGROUND: The medical problem list is an important part of the electronic medical record in development in our institution. To serve the functions it is designed for, the problem list has to be as accurate and timely as possible. However, the current problem list is usually incomplete and inaccurate, and is often totally unused. To alleviate this issue, we are building an environment where the problem list can be easily and effectively maintained. METHODS: For this project, 80 medical problems were selected for their frequency of use in our future clinical field of evaluation (cardiovascular). We have developed an Automated Problem List system composed of two main components: a background and a foreground application. The background application uses Natural Language Processing (NLP) to harvest potential problem list entries from the list of 80 targeted problems detected in the multiple free-text electronic documents available in our electronic medical record. These proposed medical problems drive the foreground application designed for management of the problem list. Within this application, the extracted problems are proposed to the physicians for addition to the official problem list. RESULTS: The set of 80 targeted medical problems selected for this project covered about 5% of all possible diagnoses coded in ICD-9-CM in our study population (cardiovascular adult inpatients), but about 64% of all instances of these coded diagnoses. The system contains algorithms to detect first document sections, then sentences within these sections, and finally potential problems within the sentences. The initial evaluation of the section and sentence detection algorithms demonstrated a sensitivity and positive predictive value of 100% when detecting sections, and a sensitivity of 89% and a positive predictive value of 94% when detecting sentences. CONCLUSION: The global aim of our project is to automate the process of creating and maintaining a problem list for hospitalized patients and thereby help to guarantee the timeliness, accuracy and completeness of this information

Influence of eruptive style on volcanic gas emission chemistry and temperature

Gas bubbles form as magmas ascend in the crust and exsolve volatiles. These bubbles evolve chemically and physically as magma decompression and crystallization proceed. It is generally assumed that the gas remains in thermal equilibrium with the melt but the relationship between gas and melt redox state is debated. Here, using absorption spectroscopy, we report the composition of gases emitted from the lava lake of Kīlauea Volcano, Hawaii, and calculate equilibrium conditions for the gas emissions. Our observations span a transition between more and less vigorous-degassing regimes. They reveal a temperature range of up to 250 °C, and progressive oxidation of the gas, relative to solid rock buffers, with decreasing gas temperature. We suggest that these phenomena are the result of changing gas bubble size. We find that even for more viscous magmas, fast-rising bubbles can cool adiabatically, and lose the redox signature of their associated melts. This process can result in rapid changes in the abundances of redox-sensitive gas species. Gas composition is monitored at many volcanoes in support of hazard assessment but time averaging of observations can mask such variability arising from the dynamics of degassing. In addition, the observed redox decoupling between gas and melt calls for caution in using lava chemistry to infer the composition of associated volcanic gases