Global Mapping of DNA Conformational Flexibility on Saccharomyces cerevisiae

In this study we provide the first comprehensive map of DNA conformational flexibility in Saccharomyces cerevisiae complete genome. Flexibility plays a key role in DNA supercoiling and DNA/protein binding, regulating DNA transcription, replication or repair. Specific interest in flexibility analysis concerns its relationship with human genome instability. Enrichment in flexible sequences has been detected in unstable regions of human genome defined fragile sites, where genes map and carry frequent deletions and rearrangements in cancer. Flexible sequences have been suggested to be the determinants of fragile gene proneness to breakage; however, their actual role and properties remain elusive. Our in silico analysis carried out genome-wide via the StabFlex algorithm, shows the conserved presence of highly flexible regions in budding yeast genome as well as in genomes of other Saccharomyces sensu stricto species. Flexibile peaks in S. cerevisiae identify 175 ORFs mapping on their 3’UTR, a region affecting mRNA translation, localization and stability. (TA)n repeats of different extension shape the central structure of peaks and co-localize with polyadenylation efficiency element (EE) signals. ORFs with flexible peaks share common features. Transcripts are characterized by decreased half-life: this is considered peculiar of genes involved in regulatory systems with high turnover; consistently, their function affects biological processes such as cell cycle regulation or stress response. Our findings support the functional importance of flexibility peaks, suggesting that the flexible sequence may be derived by an expansion of canonical TAYRTA polyadenylation efficiency element. The flexible (TA)n repeat amplification could be the outcome of an evolutionary neofunctionalization leading to a differential 3’-end processing and expression regulation in genes with peculiar function. Our study provides a new support to the functional role of flexibility in genomes and a strategy for its characterization inside human fragile sites

Crystallization of strongly interacting photons in a nonlinear optical fiber

Understanding strongly correlated quantum systems is a central problem in many areas of physics. The collective behavior of interacting particles gives rise to diverse fundamental phenomena such as confinement in quantum chromodynamics, phase transitions, and electron fractionalization in the quantum Hall regime. While such systems typically involve massive particles, optical photons can also interact with each other in a nonlinear medium. In practice, however, such interactions are often very weak. Here we describe a novel technique that allows the creation of a strongly correlated quantum gas of photons using one-dimensional optical systems with tight field confinement and coherent photon trapping techniques. The confinement enables the generation of large, tunable optical nonlinearities via the interaction of photons with a nearby cold atomic gas. In its extreme, we show that a quantum light field can undergo fermionization in such one-dimensional media, which can be probed via standard photon correlation measurements

Targeted Sister Chromatid Cohesion by Sir2

The protein complex known as cohesin binds pericentric regions and other sites of eukaryotic genomes to mediate cohesion of sister chromatids. In budding yeast Saccharomyces cerevisiae, cohesin also binds silent chromatin, a repressive chromatin structure that functionally resembles heterochromatin of higher eukaryotes. We developed a protein-targeting assay to investigate the mechanistic basis for cohesion of silent chromatin domains. Individual silencing factors were tethered to sites where pairing of sister chromatids could be evaluated by fluorescence microscopy. We report that the evolutionarily conserved Sir2 histone deacetylase, an essential silent chromatin component, was both necessary and sufficient for cohesion. The cohesin genes were required, but the Sir2 deacetylase activity and other silencing factors were not. Binding of cohesin to silent chromatin was achieved with a small carboxyl terminal fragment of Sir2. Taken together, these data define a unique role for Sir2 in cohesion of silent chromatin that is distinct from the enzyme's role as a histone deacetylase

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons

A guide to the Choquard equation

We survey old and recent results dealing with the existence and properties of solutions to the Choquard type equations $$-\Delta u + V(x)u = \bigl(|x|^{-(N-\alpha)} * |u|^p\bigr)|u|^{p - 2} u \qquad \text{in $\mathbb{R}^N$},$$ and some of its variants and extensions.Comment: 39 page

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons

A user's guide to the Encyclopedia of DNA elements (ENCODE)

The mission of the Encyclopedia of DNA Elements (ENCODE) Project is to enable the scientific and medical communities to interpret the human genome sequence and apply it to understand human biology and improve health. The ENCODE Consortium is integrating multiple technologies and approaches in a collective effort to discover and define the functional elements encoded in the human genome, including genes, transcripts, and transcriptional regulatory regions, together with their attendant chromatin states and DNA methylation patterns. In the process, standards to ensure high-quality data have been implemented, and novel algorithms have been developed to facilitate analysis. Data and derived results are made available through a freely accessible database. Here we provide an overview of the project and the resources it is generating and illustrate the application of ENCODE data to interpret the human genome

Atomic mixing and interface reactions in Ta/Si bilayers during noble-gas ion irradiation

This article focuses on the influence of chemical driving forces on the mixing and phase formation taking place at the interface of highly reactive metal/semiconductor systems under ion-beam irradiation. Ta/Si bilayers were irradiated with Ar, Kr, and Xe ions to fluences of (0.5-2.5) X 10(16) ions/cm(2) and at temperatures between liquid nitrogen and 400degreesC. The interface mixing and silicide formation were monitored as function of the ion mass and fluence by means of Rutherford backscattering spectrometry and x-ray diffraction. The interface broadening variance was found to depend linearly on the ion fluence and was explained with the help of a compound formation model involving local or global thermal spikes. The results are compared with those found in other silicide and germanide systems. The transition from local to global spikes was found to occur at the critical deposited damage energy of about 2.5 keV/nm

Mixing and silicide formation during Xe-ion beam irradiations of Ta/Si bilayers

Thin Ta layers deposited on Si (100) substrates were irradiated with 475 keV Xe+ ions to fluences of (0.5-2) x 10(16) ions/cm(2) at temperatures between room temperature and 400 degreesC. By means of Rutherford Backscattering Spectrometry, the interface mixing and tantalum silicide formation were monitored as function of the ion fluence. TaSi2 phase formation was verified using X-ray diffraction. The interface broadening variance was found to depend linearly on the ion fluence and was explained with the help of a compound formation model involving global thermal spikes