Galaxies in box: A simulated view of the interstellar medium

We review progress in the development of physically realistic three dimensional simulated models of the galaxy.We consider the scales from star forming molecular clouds to the full spiral disc. Models are computed using hydrodynamic (HD) or magnetohydrodynamic (MHD) equations and may include cosmic ray or tracer particles. The range of dynamical scales between the full galaxy structure and the turbulent scales of supernova (SN) explosions and even cloud collapse to form stars, make it impossible with current computing tools and resources to resolve all of these in one model. We therefore consider a hierarchy of models and how they can be related to enhance our understanding of the complete galaxy.Comment: Chapter in Large Scale Magnetic Fields in the Univers

Holography, Unfolding and Higher-Spin Theory

Holographic duality is argued to relate classes of models that have equivalent unfolded formulation, hence exhibiting different space-time visualizations for the same theory. This general phenomenon is illustrated by the $AdS_4$ higher-spin gauge theory shown to be dual to the theory of 3d conformal currents of all spins interacting with 3d conformal higher-spin fields of Chern-Simons type. Generally, the resulting 3d boundary conformal theory is nonlinear, providing an interacting version of the 3d boundary sigma model conjectured by Klebanov and Polyakov to be dual to the $AdS_4$ HS theory in the large $N$ limit. Being a gauge theory it escapes the conditions of the theorem of Maldacena and Zhiboedov, which force a 3d boundary conformal theory to be free. Two reductions of particular higher-spin gauge theories where boundary higher-spin gauge fields decouple from the currents and which have free boundary duals are identified. Higher-spin holographic duality is also discussed for the cases of $AdS_3/CFT_2$ and duality between higher-spin theories and nonrelativistic quantum mechanics. In the latter case it is shown in particular that ($dS$) $AdS$ geometry in the higher-spin setup is dual to the (inverted) harmonic potential in the quantum-mechanical setup.Comment: 57 pages, V2: Acknowledgements, references, comments, clarifications and new section on reductions of particular HS theories associated with free boundary theories are added. Typos corrected, V3. Minor corrections: clarification in section 9 is added and typos correcte

A Note on Vectorial AdS5_5/CFT4_4 Duality for Spin-jj Boundary Theory

The vectorial holographic correspondences between higher-spin theories in AdS$_5$ and free vector models on the boundary are extended to the cases where the latter is described by free massless spin-$j$ field. The dual higher-spin theory in the bulk does not include gravity and can only be defined on rigid AdS$_5$ background with $S^4$ boundary. We discuss various properties of these rather special higher-spin theories and calculate their one-loop free energies. We show that the result is proportional to the same quantity for spin-$j$ doubleton treated as if it is a AdS$_5$ field. Finally, we consider even more special case where the boundary theory itself is given by an infinite tower of massless higher-spin fields.Comment: 27 pages, version to appear in JHE

On the cubic interactions of massive and partially-massless higher spins in (A)dS

Cubic interactions of massive and partially-massless totally-symmetric higher-spin fields in any constant-curvature background of dimension greater than three are investigated. Making use of the ambient-space formalism, the consistency condition for the traceless and transverse parts of the parity-invariant interactions is recast into a system of partial differential equations. The latter can be explicitly solved for given s_1-s_2-s_3 couplings and the 2-2-2 and 3-3-2 examples are provided in detail for general choices of the masses. On the other hand, the general solutions for the interactions involving massive and massless fields are expressed in a compact form as generating functions of all the consistent couplings. The St\"uckelberg formulation of the cubic interactions as well as their massless limits are also analyzed.Comment: 42 pages, 2 tables, LaTex. Comments on two-derivative couplings involving partially-massless spin-2 fields added, typos corrected, references added. v2: final version to appear in JHEP. v3: formulae (3.4) and (3.9) correcte

Methylsulfonylmethane Suppresses Breast Cancer Growth by Down-Regulating STAT3 and STAT5b Pathways

Breast cancer is the most aggressive form of all cancers, with high incidence and mortality rates. The purpose of the present study was to investigate the molecular mechanism by which methylsulfonylmethane (MSM) inhibits breast cancer growth in mice xenografts. MSM is an organic sulfur-containing natural compound without any toxicity. In this study, we demonstrated that MSM substantially decreased the viability of human breast cancer cells in a dose-dependent manner. MSM also suppressed the phosphorylation of STAT3, STAT5b, expression of IGF-1R, HIF-1α, VEGF, BrK, and p-IGF-1R and inhibited triple-negative receptor expression in receptor-positive cell lines. Moreover, MSM decreased the DNA-binding activities of STAT5b and STAT3, to the target gene promoters in MDA-MB 231 or co-transfected COS-7 cells. We confirmed that MSM significantly decreased the relative luciferase activities indicating crosstalk between STAT5b/IGF-1R, STAT5b/HSP90α, and STAT3/VEGF. To confirm these findings in vivo, xenografts were established in Balb/c athymic nude mice with MDA-MB 231 cells and MSM was administered for 30 days. Concurring to our in vitro analysis, these xenografts showed decreased expression of STAT3, STAT5b, IGF-1R and VEGF. Through in vitro and in vivo analysis, we confirmed that MSM can effectively regulate multiple targets including STAT3/VEGF and STAT5b/IGF-1R. These are the major molecules involved in tumor development, progression, and metastasis. Thus, we strongly recommend the use of MSM as a trial drug for treating all types of breast cancers including triple-negative cancers

Disruption of asxl1 results in myeloproliferative neoplasms in zebrafish

Somatic loss-of-function mutations of the additional sex combs-like transcriptional regulator 1 (ASXL1) gene are common genetic abnormalities in human myeloid malignancies and induce clonal expansion of mutated hematopoietic stem cells (HSCs). To understand how ASXL1 disruption leads to myeloid cell transformation, we generated asxl1 haploinsufficient and null zebrafish lines using genome-editing technology. Here, we show that homozygous loss of asxl1 leads to apoptosis of newly formed HSCs. Apoptosis occurred via the mitochondrial apoptotic pathway mediated by upregulation of bim and bid Half of the asxl1+/ - zebrafish had myeloproliferative neoplasms (MPNs) by 5 months of age. Heterozygous loss of asxl1 combined with heterozygous loss of tet2 led to a more penetrant MPN phenotype, while heterozygous loss of asxl1 combined with complete loss of tet2 led to acute myeloid leukemia (AML). These findings support the use of asxl1+/ - zebrafish as a strategy to identify small-molecule drugs to suppress the growth of asxl1 mutant but not wild-type HSCs in individuals with somatically acquired inactivating mutations of ASXL1

CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity.

Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA-processing pathways, and chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of human induced motor neurons from patients with C9ORF72 ALS. Together, our results demonstrate the promise of CRISPR-Cas9 screens in defining mechanisms of neurodegenerative diseases

Effect of promoter architecture on the cell-to-cell variability in gene expression

According to recent experimental evidence, the architecture of a promoter, defined as the number, strength and regulatory role of the operators that control the promoter, plays a major role in determining the level of cell-to-cell variability in gene expression. These quantitative experiments call for a corresponding modeling effort that addresses the question of how changes in promoter architecture affect noise in gene expression in a systematic rather than case-by-case fashion. In this article, we make such a systematic investigation, based on a simple microscopic model of gene regulation that incorporates stochastic effects. In particular, we show how operator strength and operator multiplicity affect this variability. We examine different modes of transcription factor binding to complex promoters (cooperative, independent, simultaneous) and how each of these affects the level of variability in transcription product from cell-to-cell. We propose that direct comparison between in vivo single-cell experiments and theoretical predictions for the moments of the probability distribution of mRNA number per cell can discriminate between different kinetic models of gene regulation.Comment: 35 pages, 6 figures, Submitte

Changes over time in the effect of marital status on cancer survival

<p>Abstract</p> <p>Background</p> <p>Rates of all-cause and cause-specific mortality are higher among unmarried than married individuals. Cancer survival is also poorer in the unmarried population. Recently, some studies have found that the excess all-cause mortality of the unmarried has increased over time, and the same pattern has been shown for some specific causes of death. The objective of this study was to investigate whether there has been a similar change over time in marital status differences in cancer survival.</p> <p>Methods</p> <p>Discrete-time hazard regression models for cancer deaths among more than 440 000 women and men diagnosed with cancer 1970-2007 at age 30-89 were estimated, using register data encompassing the entire Norwegian population. More than 200 000 cancer deaths during over 2 million person-years of exposure were analyzed.</p> <p>Results</p> <p>The excess mortality of the never-married compared to the married has increased steadily for men, in particular the elderly. Among elderly women, the excess mortality of the never-married compared to the married has increased, and there are indications of an increasing excess mortality of the widowed. The excess mortality of divorced men and women, however, has been stable.</p> <p>Conclusions</p> <p>There is no obvious explanation for the increasing disadvantage among the never-married. It could be due to a relatively poorer general health at time of diagnosis, either because of a more protective effect of partnership in a society that may have become less cohesive or because of more positive selection into marriage. Alternatively, it could be related to increasing differentials with respect to treatment. Today's complex cancer therapy regimens may be more difficult for never-married to follow, and health care interventions directed and adapted more specifically to the broad subgroup of never-married patients might be warranted.</p

Black holes in three dimensional higher spin gravity: A review

We review recent progress in the construction of black holes in three dimensional higher spin gravity theories. Starting from spin-3 gravity and working our way toward the theory of an infinite tower of higher spins coupled to matter, we show how to harness higher spin gauge invariance to consistently generalize familiar notions of black holes. We review the construction of black holes with conserved higher spin charges and the computation of their partition functions to leading asymptotic order. In view of the AdS/CFT correspondence as applied to certain vector-like conformal field theories with extended conformal symmetry, we successfully compare to CFT calculations in a generalized Cardy regime. A brief recollection of pertinent aspects of ordinary gravity is also given.Comment: 49 pages, harvmac, invited contribution to J. Phys. A special volume on "Higher Spin Theories and AdS/CFT" edited by M. R. Gaberdiel and M. Vasilie