Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

THz Spectra and Dynamics of Aqueous Solutions Studied by the Ultrafast Optical Kerr Effect

The nature and extent of the effects that hydrophilic and hydrophobic solutes have on the dynamics of water molecules continues to be an area of intense experimental and theoretical investigation. In this work, we use the ultrafast optical Kerr effect to measure the picosecond dynamics and THz Raman spectral densities of a series of aqueous solutions. The solutes studied are the hydrophilic urea and formamide and the hydrophobic trimethylamine N-oxide and tetramethylurea. Measurements are made as a function of concentration betwee

Hydroxide Hydrogen Bonding: Probing the Solvation Structure through Ultrafast Time Domain Raman Spectroscopy

The mechanism of charge transport in aqueous media is critical in molecular, materials, and life sciences. The structure of the solvated hydroxide ion has been an area of some controversy. Polarization-resolved ultrafast time domain polarizability relaxation is used here to resolve the terahertz frequency Raman spectrum of hydroxide solutions. The measurements reveal the totally symmetric hydrogen-bond stretching (HO–···HOH) mode of the solvated hydroxide, permitting an experimental measurement of the bond force constant. The observed polarized Raman spectra are compared with those obtained from DFT calculations performed on HO–(H2O)n clusters. Good agreement between the observed frequency and the polarization dependence is found for the n = 3 or 4 clusters, particularly for those in which the solvating water molecules adopt a planar structure. The frequency of the symmetric stretch increases with concentration, consistent with an effect of ionic strength on either the H-bond or the structure of the cluster

Time-resolved structural dynamics of extended π-electron porphyrin nanoring

The design of molecular structures inspired by naturally occuring light harvesting systems has been intensely pursued over the last couple of decades. Interesting new structures include the Ï-conjugated porphyrin nanorings, which show promising features such as ultrafast excited-state delocalization, leading to suppressed radiative rates, superradiance with increasing temperature, and energy transfer times comparable to their natural counterparts. An important question to be addressed in such systems is the role and time scale of structural motions and how they affect excited-state delocalization. Here it is shown that porphyrin nanorings which are not rigidified by a template are structurally heterogeneous in the ground state and evolve dynamically on a tens of picoseconds time scale. In the excited state a structural relaxation of the porphyrin nanorings is observed on a picosecond time scale. Furthermore, ultrafast excitation delocalization is observed by anisotropy measurements, being insensitive to structural motions of the nanorings

Resolving vibrational from electronic coherences in two-dimensional electronic spectroscopy: The role of the laser spectrum

The observation of coherent quantum effects in photosynthetic light-harvesting complexes prompted the question whether quantum coherence could be exploited to improve the efficiency in new energy materials. The detailed characterization of coherent effects relies on sensitive methods such as two-dimensional electronic spectroscopy (2D-ES). However, the interpretation of the results produced by 2D-ES is challenging due to the many possible couplings present in complex molecular structures. In this work, we demonstrate how the laser spectral profile can induce electronic coherence-like signals in monomeric chromophores, potentially leading to data misinterpretation. We argue that the laser spectrum acts as a filter for certain coherence pathways and thus propose a general method to differentiate vibrational from electronic coherences