Large-Scale Simulations of Reionization

We use cosmological simulations to explore the large-scale effects of reionization. Since reionization is a process that involves a large dynamic range - from galaxies to rare bright quasars - we need to be able to cover a significant volume of the universe in our simulation without losing hte important small scale effects from galaxies. Here we have taken an approach that uses clumping factors derived from small scale simulations to approximate the radiative transfer on the sub-cell scales. Using this technique, we can cover a simulation size up to $1280 h^{-1} Mpc$ with $10 h^{-1} Mpc$ cells. This allows us to construct synthetic spectra of quasars similar to observed spectra of SDSS quasars at high reshifts and compare them to the observational data. These spectra can then be analyzed for HII region sizes, the presence of the Gunn-Peterson trough and the Lyman-$\alpha$ forest.Comment: 25 page

Entropy creation inside black holes points to observer complementarity

Heating processes inside large black holes can produce tremendous amounts of entropy. Locality requires that this entropy adds on space-like surfaces, but the resulting entropy (10^10 times the Bekenstein-Hawking entropy in an example presented in the companion paper) exceeds the maximum entropy that can be accommodated by the black hole's degrees of freedom. Observer complementarity, which proposes a proliferation of non-local identifications inside the black hole, allows the entropy to be accommodated as long as individual observers inside the black hole see less than the Bekenstein-Hawking entropy. In the specific model considered with huge entropy production, we show that individual observers do see less than the Bekenstein-Hawking entropy, offering strong support for observer complementarity.Comment: 13 pages. This is a companion paper to arXiv:0801.4415; Added reference

Large entropy production inside black holes: a simple model

Particles dropped into a rotating black hole can collide near the inner horizon with enormous energies. The entropy produced by these collisions can be several times larger than the increase in the horizon entropy due to the addition of the particles. In this paper entropy is produced by releasing large numbers of neutrons near the outer horizon of a rotating black hole such that they collide near the inner horizon at energies similar to those achieved at the Relativistic Heavy Ion Collider. The increase in horizon entropy is approximately 80 per dropped neutron pair, while the entropy produced in the collisions is 160 per neutron pair. The collision entropy is produced inside the horizon, so this excess entropy production does not violate Bousso's bound limiting the entropy that can go through the black hole's horizon. The generalized laws of black hole thermodynamics are obeyed. No individual observer inside the black hole sees a violation of the second law of thermodynamicsComment: 10 page

The physics of the relativistic counter-streaming instability that drives mass inflation inside black holes

If you fall into a real astronomical black hole (choosing a supermassive black hole, to make sure that the tidal forces don't get you first), then you will probably meet your fate not at a central singularity, but rather in the exponentially growing, relativistic counter-streaming instability at the inner horizon first pointed out by Poisson & Israel (1990), who called it mass inflation. The chief purpose of this paper is to present a clear exposition of the physical cause and consequence of inflation in spherical, charged black holes. Inflation acts like a particle accelerator in that it accelerates cold ingoing and outgoing streams through each other to prodigiously high energies. Inflation feeds on itself: the acceleration is powered by the gravity produced by the streaming energy. The paper: (1) uses physical arguments to develop simple approximations that follow the evolution of inflation from ignition, through inflation itself, to collapse; (2) confirms that the simple approximations capture accurately the results of fully nonlinear one- and two-fluid self-similar models; (3) demonstrates that, counter-intuitively, the smaller the accretion rate, the more rapidly inflation exponentiates; (4) shows that in single perfect-fluid models, inflation occurs only if the sound speed equals the speed of light, supporting the physical idea that inflation in single fluids is driven by relativistic counter-streaming of waves; (5) shows that what happens during inflation up to the Planck curvature depends not on the distant past or future, but rather on events happening only a few hundred black hole crossing times into the past or future; (6) shows that, if quantum gravity does not intervene, then the generic end result of inflation is not a general relativistic null singularity, but rather a spacelike singularity at zero radius.Comment: 11 eps figures. 2nd version has minor revisions. 3rd version is reformatted, has expanded abstract, and some additional minor revisions. 4th version as accepted for publication in Physics Report

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches

DNA Methylation and Somatic Mutations Converge on the Cell Cycle and Define Similar Evolutionary Histories in Brain Tumors

The evolutionary history of tumor cell populations can be reconstructed from patterns of genetic alterations. In contrast to stable genetic events, epigenetic states are reversible and sensitive to the microenvironment, prompting the question whether epigenetic information can similarly be used to discover tumor phylogeny. We examined the spatial and temporal dynamics of DNA methylation in a cohort of low-grade gliomas and their patient-matched recurrences. Genes transcriptionally upregulated through promoter hypomethylation during malignant progression to high-grade glioblastoma were enriched in cell cycle function, evolving in parallel with genetic alterations that deregulate the G1/S cell cycle checkpoint. Moreover, phyloepigenetic relationships robustly recapitulated phylogenetic patterns inferred from somatic mutations. These findings highlight widespread co-dependency of genetic and epigenetic events throughout brain tumor evolution

A genomewide analysis provides evidence for novel linkages in inflammatory bowel disease in a large European cohort.

Inflammatory bowel disease (IBD) is characterized by a chronic relapsing intestinal inflammation, typically starting in early adulthood. IBD is subdivided into two subtypes, on the basis of clinical and histologic features: Crohn disease and ulcerative colitis (UC). Previous genomewide searches identified regions harboring susceptibility loci on chromosomes 1, 3, 4, 7, 12, and 16. To expand our understanding of the genetic risk profile, we performed a 9-cM genomewide search for susceptibility loci in 268 families containing 353 affected sibling pairs. Previous linkages on chromosomes 12 and 16 were replicated, and the chromosome 4 linkage was extended in this sample. New suggestive evidence for autosomal linkages was observed on chromosomes 1, 6, 10, and 22, with LOD scores of 2.08, 2.07, 2.30, and 1.52, respectively. A maximum LOD score of 1.76 was observed on the X chromosome, for UC, which is consistent with the clinical association of IBD with Ullrich-Turner syndrome. The linkage finding on chromosome 6p is of interest, given the possible contribution of human leukocyte antigen and tumor necrosis-factor genes in IBD. This genomewide linkage scan, done with a large family cohort, has confirmed three previous IBD linkages and has provided evidence for five additional regions that may harbor IBD predisposition genes