Localization of the Functional Domains of Human Tissue Inhibitor of Metalloproteinases-3 and the Effects of a Sorsby's Fundus Dystrophy Mutation

A transient COS-7 cell expression system was used to investigate the functional domain arrangement of tissue inhibitor of metalloproteinases-3 (TIMP-3), specifically to assess the contribution of the amino- and carboxylterminal domains of the molecule to its matrix metalloproteinase (MMP) inhibitory and extracellular matrix (ECM) binding properties. Wild type TIMP-3 was entirely localized to the ECM in both its glycosylated (27 kDa) and unglycosylated (24 kDa) forms. A COOH-terminally truncated TIMP-3 molecule was found to be a non- ECM bound MMP inhibitor, whereas a chimeric TIMP molecule, consisting of the NH2-terminal domain of TIMP-2 fused to the COOH-terminal domain of TIMP-3, displayed ECM binding, albeit with a lower affinity than the wild type TIMP-3 molecule. Thus the functional domain arrangement of TIMP-3 is analogous to that seen in TIMP-1 and -2, namely that the NH2-terminal domain is responsible for MMP inhibition whereas the COOH-terminal domain is most important in mediating the specific functions of the molecule. A mutant TIMP-3 in which serine 181 was changed to a cysteine, found in Sorsby’s fundus dystrophy, a hereditary macular degenerative disease, was also expressed in COS-7 cells. This gave rise to an additional 48-kDa species (possibly a TIMP-3 dimer) that retained its ability to inhibit MMPs and localize to the ECM. These data favor the hypothesis that the TIMP-3 mutations seen in Sorsby’s fundus dystrophy contribute to disease progression by accumulation of mutant protein rather than by the loss of functional TIMP-3

A novel tissue inhibitor of metalloproteinases-3 mutation reveals a common molecular phenotype in sorsby's fundus dystrophy

Sorsby’s fundus dystrophy (SFD) is a dominantly inherited degenerative disease of the retina that leads to loss of vision in middle age. It has been shown to be caused by mutations in the gene for tissue inhibitor of metalloproteinases-3 (TIMP-3). Five different mutations have previously been identified, all introducing an extra cysteine residue into exon 5 (which forms part of the C-terminal domain) of the TIMP-3 molecule; however, the significance of these mutations to the disease phenotype was unknown. In this report, we describe the expression of several of these mutated genes, together with a previously unreported novel TIMP-3 mutation from a family with SFD that results in truncation of most of the C-terminal domain of the molecule. Despite these differences, all of these molecules are expressed and exhibit characteristics of the normal protein, including inhibition of metalloproteinases and binding to the extracellular matrix. However, unlike wild-type TIMP-3, they all form dimers. These observations, together with the recent finding that expression of TIMP-3 is increased, rather than decreased, in eyes from patients with SFD, provides compelling evidence that dimerized TIMP-3 plays an active role in the disease process by accumulating in the eye. Increased expression of TIMP-3 is also observed in other degenerative retinal diseases, including the more severe forms of agerelated macular degeneration, the most common cause of blindness in the elderly in developed countries. We hypothesize that overexpression of TIMP-3 may prove to be a critical step in the progression of a variety of degenerative retinopathies

Universal Cellular Automata and Class 4

Wolfram has provided a qualitative classification of cellular automata(CA) rules according to which, there exits a class of CA rules (called Class 4) which exhibit complex pattern formation and long-lived dynamical activity (long transients). These properties of Class 4 CA's has led to the conjecture that Class 4 rules are Universal Turing machines i.e. they are bases for computational universality. We describe an embedding of a ``small'' universal Turing machine due to Minsky, into a cellular automaton rule-table. This produces a collection of $(k=18,r=1)$ cellular automata, all of which are computationally universal. However, we observe that these rules are distributed amongst the various Wolfram classes. More precisely, we show that the identification of the Wolfram class depends crucially on the set of initial conditions used to simulate the given CA. This work, among others, indicates that a description of complex systems and information dynamics may need a new framework for non-equilibrium statistical mechanics.Comment: Latex, 10 pages, 5 figures uuencode

Parametric ordering of complex systems

Cellular automata (CA) dynamics are ordered in terms of two global parameters, computable {\sl a priori} from the description of rules. While one of them (activity) has been used before, the second one is new; it estimates the average sensitivity of rules to small configurational changes. For two well-known families of rules, the Wolfram complexity Classes cluster satisfactorily. The observed simultaneous occurrence of sharp and smooth transitions from ordered to disordered dynamics in CA can be explained with the two-parameter diagram

Cognitive demands of face monitoring: Evidence for visuospatial overload

Young children perform difficult communication tasks better face to face than when they cannot see one another (e.g., Doherty-Sneddon & Kent, 1996). However, in recent studies, it was found that children aged 6 and 10 years, describing abstract shapes, showed evidence of face-to-face interference rather than facilitation. For some communication tasks, access to visual signals (such as facial expression and eye gaze) may hinder rather than help children’s communication. In new research we have pursued this interference effect. Five studies are described with adults and 10- and 6-year-old participants. It was found that looking at a face interfered with children’s abilities to listen to descriptions of abstract shapes. Children also performed visuospatial memory tasks worse when they looked at someone’s face prior to responding than when they looked at a visuospatial pattern or at the floor. It was concluded that performance on certain tasks was hindered by monitoring another person’s face. It is suggested that processing of visual communication signals shares certain processing resources with the processing of other visuospatial information

Three-dimensional atmospheric circulation of hot Jupiters on highly eccentric orbits

Of the over 800 exoplanets detected to date, over half are on non-circular orbits, with eccentricities as high as 0.93. Such orbits lead to time-variable stellar heating, which has implications for the planet's atmospheric dynamical regime. However, little is known about this dynamical regime, and how it may influence observations. Therefore, we present a systematic study of hot Jupiters on highly eccentric orbits using the SPARC/MITgcm, a model which couples a three-dimensional general circulation model with a plane-parallel, two-stream, non-grey radiative transfer model. In our study, we vary the eccentricity and orbit-average stellar flux over a wide range. We demonstrate that the eccentric hot Jupiter regime is qualitatively similar to that of planets on circular orbits; the planets possess a superrotating equatorial jet and exhibit large day-night temperature variations. We show that these day-night heating variations induce momentum fluxes equatorward to maintain the superrotating jet throughout its orbit. As the eccentricity and/or stellar flux is increased, the superrotating jet strengthens and narrows, due to a smaller Rossby deformation radius. For a select number of model integrations, we generate full-orbit lightcurves and find that the timing of transit and secondary eclipse viewed from Earth with respect to periapse and apoapse can greatly affect what we see in infrared (IR) lightcurves; the peak in IR flux can lead or lag secondary eclipse depending on the geometry. For those planets that have large day-night temperature variations and rapid rotation rates, we find that the lightcurves exhibit "ringing" as the planet's hottest region rotates in and out of view from Earth. These results can be used to explain future observations of eccentric transiting exoplanets.Comment: 20 pages, 18 figures, 2 tables; Accepted to Ap

Brief report: how adolescents with ASD process social information in complex scenes. Combining evidence from eye movements and verbal descriptions

We investigated attention, encoding and processing of social aspects of complex photographic scenes. Twenty-four high-functioning adolescents (aged 11–16) with ASD and 24 typically developing matched control participants viewed and then described a series of scenes, each containing a person. Analyses of eye movements and verbal descriptions provided converging evidence that both groups displayed general interest in the person in each scene but the salience of the person was reduced for the ASD participants. Nevertheless, the verbal descriptions revealed that participants with ASD frequently processed the observed person’s emotion or mental state without prompting. They also often mentioned eye-gaze direction, and there was evidence from eye movements and verbal descriptions that gaze was followed accurately. The combination of evidence from eye movements and verbal descriptions provides a rich insight into the way stimuli are processed overall. The merits of using these methods within the same paradigm are discussed

The Transit Light Curve Project. X. A Christmas Transit of HD 17156b

Photometry is presented of the Dec. 25, 2007 transit of HD 17156b, which has the longest orbital period and highest orbital eccentricity of all the known transiting exoplanets. New measurements of the stellar radial velocity are also presented. All the data are combined and integrated with stellar-evolutionary modeling to derive refined system parameters. The planet's mass and radius are found to be 3.212_{-0.082}^{+0.069} Jupiter masses and 1.023_{-0.055}^{+0.070} Jupiter radii. The corresponding stellar properties are 1.263_{-0.047}^{+0.035} solar masses and 1.446_{-0.067}^{+0.099} solar radii. The planet is smaller by 1 sigma than a theoretical solar-composition gas giant with the same mass and equilibrium temperature, a possible indication of heavy-element enrichment. The midtransit time is measured to within 1 min, and shows no deviation from a linear ephemeris (and therefore no evidence for orbital perturbations from other planets). We provide ephemerides for future transits and superior conjunctions. There is an 18% chance that the orbital plane is oriented close enough to edge-on for secondary eclipses to occur at superior conjunction. Observations of secondary eclipses would reveal the thermal emission spectrum of a planet that experiences unusually large tidal heating and insolation variations.Comment: To appear in ApJ [26 pages

A framework for the local information dynamics of distributed computation in complex systems

The nature of distributed computation has often been described in terms of the component operations of universal computation: information storage, transfer and modification. We review the first complete framework that quantifies each of these individual information dynamics on a local scale within a system, and describes the manner in which they interact to create non-trivial computation where "the whole is greater than the sum of the parts". We describe the application of the framework to cellular automata, a simple yet powerful model of distributed computation. This is an important application, because the framework is the first to provide quantitative evidence for several important conjectures about distributed computation in cellular automata: that blinkers embody information storage, particles are information transfer agents, and particle collisions are information modification events. The framework is also shown to contrast the computations conducted by several well-known cellular automata, highlighting the importance of information coherence in complex computation. The results reviewed here provide important quantitative insights into the fundamental nature of distributed computation and the dynamics of complex systems, as well as impetus for the framework to be applied to the analysis and design of other systems.Comment: 44 pages, 8 figure