University of California, Santa Cruz

About: University of California, Santa Cruz is a education organization based out in Santa Cruz, California, United States. It is known for research contribution in the topics: Galaxy & Population. The organization has 15541 authors who have published 44120 publications receiving 2759983 citations. The organization is also known as: UCSC & UC, Santa Cruz.

The chromatin accessibility landscape of primary human cancers

Abstract: INTRODUCTION Cancer is one of the leading causes of death worldwide. Although the 2% of the human genome that encodes proteins has been extensively studied, much remains to be learned about the noncoding genome and gene regulation in cancer. Genes are turned on and off in the proper cell types and cell states by transcription factor (TF) proteins acting on DNA regulatory elements that are scattered over the vast noncoding genome and exert long-range influences. The Cancer Genome Atlas (TCGA) is a global consortium that aims to accelerate the understanding of the molecular basis of cancer. TCGA has systematically collected DNA mutation, methylation, RNA expression, and other comprehensive datasets from primary human cancer tissue. TCGA has served as an invaluable resource for the identification of genomic aberrations, altered transcriptional networks, and cancer subtypes. Nonetheless, the gene regulatory landscapes of these tumors have largely been inferred through indirect means. RATIONALE A hallmark of active DNA regulatory elements is chromatin accessibility. Eukaryotic genomes are compacted in chromatin, a complex of DNA and proteins, and only the active regulatory elements are accessible by the cell’s machinery such as TFs. The assay for transposase-accessible chromatin using sequencing (ATAC-seq) quantifies DNA accessibility through the use of transposase enzymes that insert sequencing adapters at these accessible chromatin sites. ATAC-seq enables the genome-wide profiling of TF binding events that orchestrate gene expression programs and give a cell its identity. RESULTS We generated high-quality ATAC-seq data in 410 tumor samples from TCGA, identifying diverse regulatory landscapes across 23 cancer types. These chromatin accessibility profiles identify cancer- and tissue-specific DNA regulatory elements that enable classification of tumor subtypes with newly recognized prognostic importance. We identify distinct TF activities in cancer based on differences in the inferred patterns of TF-DNA interaction and gene expression. Genome-wide correlation of gene expression and chromatin accessibility predicts tens of thousands of putative interactions between distal regulatory elements and gene promoters, including key oncogenes and targets in cancer immunotherapy, such as MYC , SRC , BCL2 , and PDL1 . Moreover, these regulatory interactions inform known genetic risk loci linked to cancer predisposition, nominating biochemical mechanisms and target genes for many cancer-linked genetic variants. Lastly, integration with mutation profiling by whole-genome sequencing identifies cancer-relevant noncoding mutations that are associated with altered gene expression. A single-base mutation located 12 kilobases upstream of the FGD4 gene, a regulator of the actin cytoskeleton, generates a putative de novo binding site for an NKX TF and is associated with an increase in chromatin accessibility and a concomitant increase in FGD4 gene expression. CONCLUSION The accessible genome of primary human cancers provides a wealth of information on the susceptibility, mechanisms, prognosis, and potential therapeutic strategies of diverse cancer types. Prediction of interactions between DNA regulatory elements and gene promoters sets the stage for future integrative gene regulatory network analyses. The discovery of hundreds of noncoding somatic mutations that exhibit allele-specific regulatory effects suggests a pervasive mechanism for cancer cells to manipulate gene expression and increase cellular fitness. These data may serve as a foundational resource for the cancer research community.

The waning of the WIMP? A review of models, searches, and constraints

Abstract: Weakly Interacting Massive Particles (WIMPs) are among the best-motivated dark matter candidates. No conclusive signal, despite an extensive search program that combines, often in a complementary way, direct, indirect, and collider probes, has been detected so far. This situation might change in near future due to the advent of one/multi-TON Direct Detection experiments. We thus, find it timely to provide a review of the WIMP paradigm with focus on a few models which can be probed at best by these facilities. Collider and Indirect Detection, nevertheless, will not be neglected when they represent a complementary probe.

Concentration, spin and shape of dark matter haloes as a function of the cosmological model: WMAP1, WMAP3 and WMAP5 results

Abstract: We investigate the effects of changes in the cosmological parameters between the Wilkinson Microwave Anisotropy Probe (WMAP) 1st, 3rd and 5th year results on the structure of dark matter haloes. We use a set of simulations that cover five decades in halo mass ranging from the scales of dwarf galaxies (V c ≈ 30 km s -1 ) to clusters of galaxies (V c ≈ 1000 km s -1 ). We find that the concentration mass relation is a power law in all three cosmologies. However, the slope is shallower and the zero-point is lower moving from WMAP1 to WMAP5 to WMAP3. For haloes of mass log M 200 /[h -1 M ⊙ ] = 10, 12 and 14 the differences in the concentration parameter between WMAP1 and WMAP3 are a factor of 1.55,1.41 and 1.29, respectively. As we show, this brings the central densities of dark matter haloes in good agreement with the central densities of dwarf and low surface brightness galaxies inferred from their rotation curves, for both the WMAP3 and WMAP5 cosmologies. We also show that none of the existing toy models for the concentration-mass relation can reproduce our simulation results over the entire range of masses probed. In particular, the model of Bullock et al. fails at the higher mass end (M ≥ 10 13 h-1 M ⊙ ), while the NFW model of Navarro, Frenk and White fails dramatically at the low-mass end (M ≤ 10 12 h -1 M ⊙ ). We present a new model, based on a simple modification of that of Bullock et al., which reproduces the concentration-mass relations in our simulations over the entire range of masses probed (10 10 ≤ M ≤ 10 15 h -1 M ⊙ ). Haloes in the WMAP3 cosmology (at a fixed mass) are more flatted compared to the WMAP1 cosmology, with a medium to long axis ration reduced by ≈ 0 per cent. Finally, we show that the distribution of halo spin parameters is the same for all three cosmologies.

Hyperaccreting black holes and gamma-ray bursts

Abstract: A variety of current models of gamma-ray bursts (GRBs) suggest a common engine: a black hole of several solar masses accreting matter from a disk at a rate of 0.01 to 10 M☉ s-1. Using a numerical model for relativistic disk accretion, we have studied steady state accretion at these high rates. Outside about 108 cm, the disk is advection dominated; energy released by dissipation is carried in by the optically thick gas, and the disk does not cool. Inside this radius, for accretion rates greater than about 0.01 M☉ s-1 a global state of balanced power comes to exist between neutrino losses, chiefly pair capture on nucleons, and dissipation. As a result of these losses, the temperature is reduced, the density is raised, and the disk scale height is reduced compared to the advective solution. The sudden onset of neutrino losses (due to the high temperature dependence) and photodisintegration leads to an abrupt thinning of the disk that may provide a favorable geometry for jet production. The inner disk remains optically thin to neutrinos for accretion rates of up to about 1 M☉ s-1. The energy emitted in neutrinos is less, and in the case of low accretion rates, very much less, than the maximum efficiency factor for black hole accretion (0.057 for no rotation; 0.42 for extreme Kerr rotation) times the accretion rate, c2. Neutrino temperatures at the last stable orbit range from 2 MeV (no rotation, slow accretion) to 13 MeV (Kerr geometry, rapid accretion), and the density ranges from 109 to 1012 g cm-3. The efficiency for producing a pair fireball along the rotational axis by neutrino annihilation is calculated and found to be highly variable and very sensitive to the accretion rate. For some of the higher accretion rates studied, it can be several percent or more; for accretion rates less than 0.05 M☉ s-1, it is essentially zero. The efficiency of the Blandford-Znajek mechanism in extracting rotational energy from the black hole is also estimated. In light of these results, the viability of various gamma-ray burst models is discussed, and the sensitivity of the results to disk viscosity, black hole rotation rate, and black hole mass is explored. A diverse range of GRB energies seems unavoidable, and neutrino annihilation in hyperaccreting black hole systems can explain bursts of up to 1052 ergs. Larger energies can be inferred for beaming systems.