Chromosome structural changes with nonrecurrent endpoints associated with genomic disorders offer windows into the mechanism of origin of copy number variation (CNV). A recent report of nonrecurrent ...duplications associated with Pelizaeus-Merzbacher disease identified three distinctive characteristics. First, the majority of events can be seen to be complex, showing discontinuous duplications mixed with deletions, inverted duplications, and triplications. Second, junctions at endpoints show microhomology of 2-5 base pairs (bp). Third, endpoints occur near pre-existing low copy repeats (LCRs). Using these observations and evidence from DNA repair in other organisms, we derive a model of microhomology-mediated break-induced replication (MMBIR) for the origin of CNV and, ultimately, of LCRs. We propose that breakage of replication forks in stressed cells that are deficient in homologous recombination induces an aberrant repair process with features of break-induced replication (BIR). Under these circumstances, single-strand 3' tails from broken replication forks will anneal with microhomology on any single-stranded DNA nearby, priming low-processivity polymerization with multiple template switches generating complex rearrangements, and eventual re-establishment of processive replication.
Mechanisms of change in gene copy number Hastings, P. J; Lupski, James R; Rosenberg, Susan M ...
Nature reviews. Genetics,
08/2009, Letnik:
10, Številka:
8
Journal Article
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Deletions and duplications of chromosomal segments (copy number variants, CNVs) are a major source of variation between individual humans and are an underlying factor in human evolution and in many ...diseases, including mental illness, developmental disorders and cancer. CNVs form at a faster rate than other types of mutation, and seem to do so by similar mechanisms in bacteria, yeast and humans. Here we review current models of the mechanisms that cause copy number variation. Non-homologous end-joining mechanisms are well known, but recent models focus on perturbation of DNA replication and replication of non-contiguous DNA segments. For example, cellular stress might induce repair of broken replication forks to switch from high-fidelity homologous recombination to non-homologous repair, thus promoting copy number change.
Structural rearrangements within single molecules occur on ultrafast time scales. Many aspects of molecular dynamics, such as the energy flow through excited states, have been studied using ...spectroscopic techniques, yet the goal to watch molecules evolve their geometrical structure in real time remains challenging. By mapping nuclear motions using femtosecond x-ray pulses, we have created real-space representations of the evolving dynamics during a well-known chemical reaction and show a series of time-sorted structural snapshots produced by ultrafast time-resolved hard x-ray scattering. A computational analysis optimally matches the series of scattering patterns produced by the x rays to a multitude of potential reaction paths. In so doing, we have made a critical step toward the goal of viewing chemical reactions on femtosecond time scales, opening a new direction in studies of ultrafast chemical reactions in the gas phase.
A hybrid achromatic metalens Balli, F.; Sultan, M.; Lami, Sarah K. ...
Nature communications,
08/2020, Letnik:
11, Številka:
1
Journal Article
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Abstract
Metalenses, ultra-thin optical elements that focus light using subwavelength structures, have been the subject of a number of recent investigations. Compared to their refractive ...counterparts, metalenses offer reduced size and weight, and new functionality such as polarization control. However, metalenses that correct chromatic aberration also suffer from markedly reduced focusing efficiency. Here we introduce a Hybrid Achromatic Metalens (HAML) that overcomes this trade-off and offers improved focusing efficiency over a broad wavelength range from 1000–1800 nm. HAMLs can be designed by combining recursive ray-tracing and simulated phase libraries rather than computationally intensive global search algorithms. Moreover, HAMLs can be fabricated in low-refractive index materials using multi-photon lithography for customization or using molding for mass production. HAMLs demonstrated diffraction limited performance for numerical apertures of 0.27, 0.11, and 0.06, with average focusing efficiencies greater than 60% and maximum efficiencies up to 80%. A more complex design, the air-spaced HAML, introduces a gap between elements to enable even larger diameters and numerical apertures.
During the last two decades, the importance of human genome copy number variation (CNV) in disease has become widely recognized. However, much is not understood about underlying mechanisms. We show ...how, although model organism research guides molecular understanding, important insights are gained from study of the wealth of information available in the clinic. We describe progress in explaining nonallelic homologous recombination (NAHR), a major cause of copy number change occurring when control of allelic recombination fails, highlight the growing importance of replicative mechanisms to explain complex events, and describe progress in understanding extreme chromosome reorganization (chromothripsis). Both nonhomologous end-joining and aberrant replication have significant roles in chromothripsis. As we study CNV, the processes underlying human genome evolution are revealed.
The recently commissioned Linac Coherent Light Source is an X-ray free-electron laser at the SLAC National Accelerator Laboratory. It produces coherent soft and hard X-rays with peak brightness ...nearly ten orders of magnitude beyond conventional synchrotron sources and a range of pulse durations from 500 to <10 fs (10-15 s). With these beam characteristics this light source is capable of imaging the structure and dynamics of matter at atomic size and timescales. The facility is now operating at X-ray wavelengths from 22 to 1.2 A and is presently delivering this high-brilliance beam to a growing array of scientific researchers. We describe the operation and performance of this new 'fourth-generation light source'.
Molecular-scale dynamics in sub- to supercritical water is studied with inelastic x-ray scattering and molecular dynamics simulations. The obtained longitudinal current correlation spectra can be ...decomposed into two main components: a low-frequency (LF), gaslike component and a high-frequency (HF) component arising from the O-O stretching mode between hydrogen-bonded molecules, reminiscent of the longitudinal acoustic mode in ambient water. With increasing temperature, the hydrogen-bond network diminishes and the spectral weight shifts from HF to LF, leading to a transition from liquid- to gaslike dynamics with rapid changes around the Widom line.
We present the first highly resolved measurements of the plasmon spectrum in an ultrafast heated solid. Multi-keV x-ray photons from the Linac Coherent Light Source have been focused to one ...micrometer diameter focal spots producing solid density aluminum plasmas with a known electron density of n_{e}=1.8×10^{23} cm^{-3}. Detailed balance is observed through the intensity ratio of up- and down-shifted plasmons in x-ray forward scattering spectra measuring the electron temperature. The plasmon damping is treated by electron-ion collision models beyond the Born approximation to determine the electrical conductivity of warm dense aluminum.
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