Whole-exome re-sequencing in a family quartet identifies POP1 mutations as the cause of a novel skeletal dysplasia

Recent advances in DNA sequencing have enabled mapping of genes for monogenic traits in families with small pedigrees and even in unrelated cases. We report the identification of disease-causing mutations in a rare, severe, skeletal dysplasia, studying a family of two healthy unrelated parents and two affected children using whole-exome sequencing. The two affected daughters have clinical and radiographic features suggestive of anauxetic dysplasia (OMIM 607095), a rare form of dwarfism caused by mutations of RMRP. However, mutations of RMRP were excluded in this family by direct sequencing. Our studies identified two novel compound heterozygous loss-of-function mutations in POP1, which encodes a core component of the RNase mitochondrial RNA processing (RNase MRP) complex that directly interacts with the RMRP RNA domains that are affected in anauxetic dysplasia. We demonstrate that these mutations impair the integrity and activity of this complex and that they impair cell proliferation, providing likely molecular and cellular mechanisms by which POP1 mutations cause this severe skeletal dysplasia. © 2011 Glazov et al.

Intraloop and Interloop Interactions in the Folded-G Quartet Structure of Oxytricha Telomeric Sesquence

The antiparallel intramolecular G quartet structure for the 3.5 copy Oxytricha telomeric sequence d(G(4)T(4))(3)G4 has been established using a combination of spectroscopic and chemical probing methods. In the presence of Naf ions, this sequence exhibits a circular dichroism spectrum with a positive band at 295 nm and a negative band around 265 nm, characteristic of an antiparallel G quartet structure. Further, we show that d(G(4)T(4))(3)G(4) adopts an antiparallel intramolecular G quartet structure even in K+ unlike d(G(4)T(4)G(4)). KMnO4 probing experiments indicated the existence of intra and interloop interactions in the Na+ induced structure. We have found that K+ not only increases the thermal stability of,G quartet structure but also binds to the loop region and disrupts stacking and interloop interactions. Biological consequences of such cation-dependent conformational micro-heterogeneity in the loop region of G quartet structures is also discussed.

Totality of experience: sound, music and mythology in Gus Van Sant’s “Death Quartet”

Reflecting on Gus Van Sant’s films Gerry (2003) Elephant (2004) and Last Days (2005), the director’s long-term sound-designer Leslie Shatz observed that “You have to get into the totality of the experience and not just the dialogue”. Shatz’s comment expresses something fundamental about the experimental approach to cinema and to soundscapes undertaken by Van Sant in these three films, unofficially known as the “Death Trilogy”. This thesis contends that Van Sant makes deliberate aesthetic choices which do indicate a distinctly “auteurist” leaning. However, I also argue that intertextual elements, prior knowledge, and audience participation in meaningmaking enhance the experience of, and reveal the nuances in, the soundtracks themselves. This thesis aims to contribute to a growing body of work within filmmusic scholarship concerned with resisting a traditional bias in the field: that film music should be understood as a means of characterisation and as emotional signifier. The films of the “Death Quartet”, which includes Paranoid Park (2007), I believe, offer fertile ground on which to explore these new approaches. It is my contention that these films deconstruct the traditional approach to soundtracking and the relationship between soundtrack and character, and that only an approach sensitive to the aesthetic and philosophical functions of music and sound can adequately acknowledge their unique cinematic qualities.

Lament for String Quartet

This piece explores the changing nature of emotion focusing especially on the feeling of sorrow. The opening and ending parts of the first movement represent the overall motive of sorrow. The first movement opens with an augmented chord G-C#-F-B and from this chord the first violin expands upwards while the cello moves downwards towards the C chord (p.2). As the melody alternates between each part, there is a subtle change in harmony which creates tension and release and changes the sound color. In addition, ornamentation in each part reinforces the movement towards the C chord. This progression represents the inner emotion of lament. Sostenuto e largamente section (p.2) uses heterophony in order to express a feeling of chaos. Section Scherzando (p.4) uses the interval relationship M7 and m2, and is a respite from the overwhelming feeling of sorrow. The ending of the first movement (p.12) returns to create a second tension by every instrument ascending slowly, and the viola produces a distinctive melody derived from the previous chaotic section that ends on an Ab. The second movement contrasts with the first movement in order to express a concealed, not explicit, sorrow, and differs in both tempo and texture. The tempo is a waltz that is faster than the first movement. This produces a light, playful figure and a simple melody without much ornamentation. Imitation and canonic structure emphasize the individuality of the strings. The third movement merges material from the first movement rhythmic figure and the second movement pizzicato (p.17). It shows timbral change through con sordino, pizzicato arpeggio, and sul ponticello to display string techniques. An Allegro section (p.19) especially contrasts with Misterioso in rhythm and dynamics. In the Grazioso (p.22), random beats are accentuated by pizzicato arpeggio to de-emphasize the meter. Finally, there is a return to the ending figure of the first movement with con sordino (p.23) and sul ponticello in viola that articulates the internal tension and the timbral change to return to a voice of sorrow.