MID1 and MID2 homo- and heterodimerise to tether the rapamycin-sensitive PP2A regulatory subunit, Alpha 4, to microtubules: implications for the clinical variability of X-linked Opitz GBBB syndrome and other developmental disorders

BACKGROUND: Patients with Opitz GBBB syndrome present with a variable array of developmental defects including craniofacial, cardiac, and genital anomalies. Mutations in the X-linked MID1 gene, which encodes a microtubule-binding protein, have been found in ~50% of Opitz GBBB syndrome patients consistent with the genetically heterogeneous nature of the disorder. A protein highly related to MID1, called MID2, has also been described that similarly associates with microtubules. RESULTS: To identify protein partners of MID1 and MID2 we undertook two separate yeast two-hybrid screens. Using this system we identified Alpha 4, a regulatory subunit of PP2-type phosphatases and a key component of the rapamycin-sensitive signaling pathway, as a strong interactor of both proteins. Analysis of domain-specific deletions has shown that the B-boxes of both MID1 and MID2 mediate the interaction with Alpha 4, the first demonstration in an RBCC protein of a specific role for the B-box region. In addition, we show that the MID1/2 coiled-coil motifs mediate both homo- and hetero-dimerisation, and that dimerisation is a prerequisite for association of the MID-Alpha 4 complex with microtubules. CONCLUSIONS: Our findings not only implicate Alpha 4 in the pathogenesis of Opitz GBBB syndrome but also support our earlier hypothesis that MID2 is a modifier of the X-linked phenotype. Of further note is the observation that Alpha 4 maps to Xq13 within the region showing linkage to FG (Opitz-Kaveggia) syndrome. Overlap in the clinical features of FG and Opitz GBBB syndromes warrants investigation of Alpha 4 as a candidate for causing FG syndrome

BigraphTalk: verified design of IoT applications

Graphical IoT device management platforms, such as IoTtalk, make it easy to describe interactions between IoT devices. Applications are defined by dragging-and-dropping devices and specifying how they are connected, e.g. a door sensor controlling a light. While this allows simple and rapid development, it remains possible to specify unwanted device configurations – such as using the same device to drive a motor up and down simultaneously, risking damaging the motor. We propose , a verification framework for IoTtalk that utilizes formal techniques, based on bigraphs, to statically guarantee that unwanted configurations do not arise. In particular, we check for invalid connections between devices, as well as type errors, e.g. passing a float to a boolean switch. To the best of our knowledge, is the first platform to support the graphical specification of correct-by-design IoT applications. provides fully automated verification and feedback without end-users ever needing to specify a bigraph. This means any application, specifiable in IoTtalk, is guaranteed, so long as verification succeeds, not to violate the given configuration constraints when deployed; with no extra cost to the user

Specification and Verification of Media Constraints using UPPAAL

We present the formal specification and verification of a multimedia stream. The stream is described in a timed automata notation. We verify that the stream satisfies certain quality of service properties, in particular, throughput and end-to-end latency. The verification tool used is the real-time model checker UPPAAL

On the kinematics of the neutron star low mass X-ray binary Cen X-4

We present the first determination of the proper motion of the neutron star low mass X-ray binary {Cen X-4} measured from relative astrometry of the secondary star using optical images at different epochs. We determine the Galactic space velocity components of the system and find them to be significantly different from the mean values that characterize the kinematics of stars belonging to the halo, and the thin and the thick disc of the Galaxy. The high metallicity of the secondary star of the system rules out a halo origin and indicates that the system probably originated in the Galactic disc. A statistical analysis of the galactocentric motion revealed that this binary moves in a highly eccentric ($e\simeq 0.85\pm0.1$) orbit with an inclination of $\simeq 110^\circ$ to the Galactic plane. The large Galactic space velocity components strongly support that a high natal kick as a result of a supernova explosion could have propelled the system into such an orbit from a birth place in the Galactic disc. The high Li abundance in the secondary, comparable to that of stars in star forming regions and young stellar clusters like the Pleiades, may suggest a relatively recent formation of the system. Following the orbit backwards in time, we found that the system could have been in the inner regions of the Galactic disc $\sim$100--200 Myr ago. The neutron star might have formed at that moment. However, we cannot rule out the possibility that the system formed at a much earlier time if a Li production mechanism exists in this LMXB.Comment: 6 pages, 4 figures, accepted for publication in A&

Higher-order optical resonance node detection of integrated disk microresonator

We have demonstrated higher-order optical resonance node detection by using an integrated disk microresonator from through port of the coupling bus waveguide. In addition to the fundamental mode, the disk resonator has higher-order whispering gallery modes. The excited second-order higher-order mode has a node at the position where the electromagnetic energy of the fundamental mode is close to a maximum. This high resolution measurement of optical resonance mode profile has a variety of applications for optical sensing and detection. The self-referencing characteristics of the two optical resonance modes have potential to achieve optical detection independent of external perturbation, such as temperature change

The Chandra Local Volume Survey: The X-ray Point Source Catalog of NGC 300

We present the source catalog of a new Chandra ACIS-I observation of NGC 300 obtained as part of the Chandra Local Volume Survey. Our 63 ks exposure covers ~88% of the D25 isophote (R~6.3 kpc) and yields a catalog of 95 X-ray point sources detected at high significance to a limiting unabsorbed 0.35-8 keV luminosity of ~10^36 erg s^-1. Sources were cross-correlated with a previous XMM-Newton catalog, and we find 75 "X-ray transient candidate" sources that were detected by one observatory, but not the other. We derive an X-ray scale length of 1.7+/-0.2 kpc and a recent star formation rate of 0.12 Msun yr^-1, in excellent agreement with optical observations. Deep, multi-color imaging from the Hubble Space Telescope, covering ~32% of our Chandra field, was used to search for optical counterparts to the X-ray sources, and we have developed a new source classification scheme to determine which sources are likely X-ray binaries, supernova remnants, and background AGN candidates. Finally, we present the X-ray luminosity functions (XLFs) at different X-ray energies, and we find the total NGC 300 X-ray point source population to be consistent with other late-type galaxies hosting young stellar populations (<50 Myr). We find XLF of sources associated with older stellar populations has a steeper slope than the XLF of X-ray sources coinciding with young stellar populations, consistent with theoretical predictions.Comment: 23 pages, 13 figures. Accepted to Ap

Anti-epileptic effect of Ganoderma lucidum polysaccharides by inhibition of intracellular calcium accumulation and stimulation of expression of CaMKII a in epileptic hippocampal neurons

Purpose: To investigate the mechanism of the anti-epileptic effect of Ganoderma lucidum polysaccharides (GLP), the changes of intracellular calcium and CaMK II a expression in a model of epileptic neurons were investigated. Method: Primary hippocampal neurons were divided into: 1) Control group, neurons were cultured with Neurobasal medium, for 3 hours; 2) Model group I: neurons were incubated with Mg2+ free medium for 3 hours; 3) Model group II: neurons were incubated with Mg2+ free medium for 3 hours then cultured with the normal medium for a further 3 hours; 4) GLP group I: neurons were incubated with Mg2+ free medium containing GLP (0.375 mg/ml) for 3 hours; 5) GLP group II: neurons were incubated with Mg2+ free medium for 3 hours then cultured with a normal culture medium containing GLP for a further 3 hours. The CaMK II a protein expression was assessed by Western-blot. Ca2+ turnover in neurons was assessed using Fluo-3/AM which was added into the replacement medium and Ca2+ turnover was observed under a laser scanning confocal microscope. Results: The CaMK II a expression in the model groups was less than in the control groups, however, in the GLP groups, it was higher than that observed in the model group. Ca2+ fluorescence intensity in GLP group I was significantly lower than that in model group I after 30 seconds, while in GLP group II, it was reduced significantly compared to model group II after 5 minutes. Conclusion: GLP may inhibit calcium overload and promote CaMK II a expression to protect epileptic neuron

Human Computation and Convergence

Humans are the most effective integrators and producers of information, directly and through the use of information-processing inventions. As these inventions become increasingly sophisticated, the substantive role of humans in processing information will tend toward capabilities that derive from our most complex cognitive processes, e.g., abstraction, creativity, and applied world knowledge. Through the advancement of human computation - methods that leverage the respective strengths of humans and machines in distributed information-processing systems - formerly discrete processes will combine synergistically into increasingly integrated and complex information processing systems. These new, collective systems will exhibit an unprecedented degree of predictive accuracy in modeling physical and techno-social processes, and may ultimately coalesce into a single unified predictive organism, with the capacity to address societies most wicked problems and achieve planetary homeostasis.Comment: Pre-publication draft of chapter. 24 pages, 3 figures; added references to page 1 and 3, and corrected typ

Contact Manifolds, Contact Instantons, and Twistor Geometry

Recently, Kallen and Zabzine computed the partition function of a twisted supersymmetric Yang-Mills theory on the five-dimensional sphere using localisation techniques. Key to their construction is a five-dimensional generalisation of the instanton equation to which they refer as the contact instanton equation. Subject of this article is the twistor construction of this equation when formulated on K-contact manifolds and the discussion of its integrability properties. We also present certain extensions to higher dimensions and supersymmetric generalisations.Comment: v3: 28 pages, clarifications and references added, version to appear in JHE