NOTCH3 cysteine correction : developing a rational therapeutic approach for CADASIL

The aim of this thesis was to work towards pre-clinical proof-of-concept for NOTCH3 cysteine corrective exon skipping as a rational therapeutic approach for CADASIL. To address all aspects required for therapeutic development, the work performed for this thesis included not only in vitro testing of NOTCH3 exon skipping in CADASIL patient derived vascular smooth muscle cells and studies into the function of the cysteine corrected proteins, but also the generation of a relevant humanized in vivo model, pre-clinical biomarker development, and studies defining prevalence, spectrum and characteristics of NOTCH3 mutations worldwide

Ultraviolet jets and bright points in the solar chromosphere : II : statistical correlations

We use HRTS{VI rocket observations of the solar chromosphere to search for relationships between high-Dopplershift \jets" observed in the CI lines near = 156 nm and internetwork \bright points" observed in the = 160 nm continuum, in sequel to the analysis by Cook et al. (1996) which failed to find a direct connection between these phenomena. We now use the same data to establish statistical correlations between CI Dopplershift and 160 nm brightness modulation in internetwork areas. These mean relations emerge only after extensive spatial averaging and have small amplitude, but are definitely significant. They show that both CI Dopplershift and 160 nm brightness participate in oscillatory behavior with three-minute periodicity and mesoscale (8 Mm wavelength) as well as small-scale (1.4 Mm wavelength) spatial patterning. We find spatial and temporal phase relations between Dopplershift and brightness that confirm that jets and bright points should not be interpreted as isolated entities. Rather, they are chromospheric manifestations, with much pattern interference, of the oscillatory acoustic shock dynamics in the internetwork which also cause Ca II K2V grains. Additional small-scale modulation is present which we attribute to waves with f-mode character

Ultraviolet jets and bright points in the solar chromosphere: I : search for one-to-one relationships

Ultraviolet spectrograms and spectroheliograms of the solar chromosphere are used to test the suggestion (Dere et al. 1986, Rutten & Uitenbroek 1991a) that bright points observed at h = 1600 Å, chromospheric jets observed in CI lines near h = 1560 Å, and Ca II K2V bright points are associated with each other and that they are all manifestations of the same wave interaction in the non-magnetic chromosphere. We search for spatio-temporal connections between 1600 Å bright points and CI blue jets using data from the HRTS VI rocket mission, comparing 1600 Å spectroheliograms and a co-spatial CI Dopplershift map on a pixel-by-pixel basis. We find no direct evidence for spatial co-location of bright points and jets, not for instantaneous correspondence and also not when allowing for phase delays as long as three minutes. Also, the average brightness evolution and its rms uctuation are not obviously different between sites of large CI blueshift and the remaining surface

Fully abstract denotational models for nonuniform concurrent languages

AbstractThis paper investigates full abstraction of denotational model w.r.t. operational ones for two concurrent languages. The languages are nonuniform in the sense that the meaning of atomic statements generally depends on the current state. The first language, L1, has parallel composition but no communication, whereas the second one, L2, has CSP-like communications in addition. For each of Li (i = 1, 2), an operational model Oi is introduced in terms of a Plotkin-style transition system, while a denotational model Di for Li is defined compositionally using interpreted operations of the language, with meanings of recursive programs as fixed points in appropriate complete metric spaces. The full abstraction is shown by means of a context with parallel composition: Given two statements s1 and s2 with different denotational meanings, a suitable statement T is constructed such that the operational meanings of s1 ∥ T and s2 ∥ T are distinct. A combinatorial method for constructing such T is proposed. Thereby the full abstraction of D1 and D2 w.r.t. O1 and O2, respectively, is established. That is, Di is most abstract of those models C which are compositional and satisfy Oi = α ∘ C for some abstraction function α (i = 1, 2)