The evolution of galaxy intrinsic alignments in the MassiveBlackII universe

We investigate the redshift evolution of the intrinsic alignments (IAs) of galaxies in the MassiveBlackII (MBII) simulation. We select galaxy samples above fixed subhalo mass cuts (⁠Mh>1011,12,13M⊙h−1⁠) at z = 0.6 and trace their progenitors to z = 3 along their merger trees. Dark matter components of z = 0.6 galaxies are more spherical than their progenitors while stellar matter components tend to be less spherical than their progenitors. The distribution of the galaxy–subhalo misalignment angle peaks at ∼10 deg with a mild increase with time. The evolution of the ellipticity–direction (ED) correlation amplitude ω(r) of galaxies (which quantifies the tendency of galaxies to preferentially point towards surrounding matter overdensities) is governed by the evolution in the alignment of underlying dark matter (DM) subhaloes to the matter density of field, as well as the alignment between galaxies and their DM subhaloes. At scales ∼1 Mpch−1⁠, the alignment between DM subhaloes and matter overdensity gets suppressed with time, whereas the alignment between galaxies and DM subhaloes is enhanced. These competing tendencies lead to a complex redshift evolution of ω(r) for galaxies at ∼1 Mpch−1⁠. At scales >1 Mpch−1⁠, alignment between DM subhaloes and matter overdensity does not evolve significantly; the evolution of the galaxy–subhalo misalignment therefore leads to an increase in ω(r) for galaxies by a factor of ∼4 from z = 3 to 0.6 at scales >1 Mpch−1⁠. The balance between competing physical effects is scale dependent, leading to different conclusions at much smaller scales (⁠∼0.1 Mpch−1⁠)

Durability prediction of an ultra-large mining truck tire using an enhanced finite element method

Ultra-class mining trucks used for material haulage in rugged surface mining terrains experience premature tire fatigue failure in operation. Typical failures include belt edge separation, ply turn-up separation, and tread base and sidewall cracking. The use of reinforcing fillers and processing aids in tire compounds result in the formation of microstructural in-homogeneities in the compounds. This article presents an application of the critical plane analysis technique for predicting the fatigue life of the belt package of an ultra-large mining truck (CAT 795F) tire of size 56/80R63 in a surface coal mine. Experimental data obtained from extracted specimens (sidewall, tread, and belt edge region) of the tire are used to characterize the stress—strain and fatigue behavior of the modeled tire. The tire\u27s duty cycle stresses and strains were obtained from finite element analysis of the rolling tire in Abaqus. Fatigue life calculations were performed in the rubber fatigue solver Endurica CL. Effects of inflation pressure, tire speed, and axle load on the fatigue life of the belt package under strain-crystallizing and non-crystallizing conditions of the belt compound are discussed. Specifically, the results show the belt edges to be critical regarding crack nucleation

Cosmic variance of z > 7 galaxies: prediction from BLUETIDES

In the coming decade, a new generation of telescopes, including JWST and WFIRST, will probe the period of the formation of first galaxies and quasars, and open up the last frontier for structure formation. Recent simulations and observations have suggested that these galaxies are strongly clustered (with large-scale bias 6), and therefore have significant cosmic variance. In this work, we use BLUETIDES, the largest volume cosmological simulation of galaxy formation, to directly estimate the cosmic variance for current and upcoming surveys. Given its resolution and volume, BLUETIDES can probe the bias and cosmic variance of z > 7 galaxies between magnitude MUV ∼ −16 and MUV ∼ −22 over survey areas ∼0.1 arcmin2 to ∼10 deg2. Within this regime, the cosmic variance decreases with survey area/ volume as a power law with exponents between ∼−0.25 and ∼−0.45. For the planned 10 deg2 field of WFIRST, the\ud cosmic variance is between 3 per cent and 10 per cent. Upcoming JWST medium/ deep surveys with areas up to A ∼ 100 arcmin2 will have cosmic variance ranging from ∼20 to 50 per cent. Lensed surveys have the highest cosmic variance 40 per cent; the cosmic variance of MUV −16 galaxies is 100 per cent up to z ∼ 11. At higher redshifts such as z ∼ 12 (14), effective volumes of (8 Mpc h−1) 3 ((12 Mpc h−1) 3) are required to limit the cosmic variance to within 100 per cent. Finally, we find that cosmic variance is larger than Poisson variance and forms the dominant component of the overall uncertainty in all current and upcoming surveys. We present our calculations in the form of simple fitting functions and an online cosmic variance calculator (CV AT COSMIC DAWN) that we publicly release

Systems-Level Modeling of Cancer-Fibroblast Interaction

Cancer cells interact with surrounding stromal fibroblasts during tumorigenesis, but the complex molecular rules that govern these interactions remain poorly understood thus hindering the development of therapeutic strategies to target cancer stroma. We have taken a mathematical approach to begin defining these rules by performing the first large-scale quantitative analysis of fibroblast effects on cancer cell proliferation across more than four hundred heterotypic cell line pairings. Systems-level modeling of this complex dataset using singular value decomposition revealed that normal tissue fibroblasts variably express at least two functionally distinct activities, one which reflects transcriptional programs associated with activated mesenchymal cells, that act either coordinately or at cross-purposes to modulate cancer cell proliferation. These findings suggest that quantitative approaches may prove useful for identifying organizational principles that govern complex heterotypic cell-cell interactions in cancer and other contexts

STAT3 can be activated through paracrine signaling in breast epithelial cells

<p>Abstract</p> <p>Background</p> <p>Many cancers, including breast cancer, have been identified with increased levels of phosphorylated or the active form of Signal Transducers and Activators of Transcription 3 (STAT3) protein. However, whether the tumor microenvironment plays a role in this activation is still poorly understood.</p> <p>Methods</p> <p>Conditioned media, which contains soluble factors from MDA-MB-231 and MDA-MB-468 breast cancer cells and breast cancer associated fibroblasts, was added to MCF-10A breast epithelial and MDA-MB-453 breast cancer cells. The stimulation of phosphorylated STAT3 (p-STAT3) levels by conditioned media was assayed by Western blot in the presence or absence of neutralized IL-6 antibody, or a JAK/STAT3 inhibitor, JSI-124. The stimulation of cell proliferation in MCF-10A cells by conditioned media in the presence or absence of JSI-124 was subjected to MTT analysis. IL-6, IL-10, and VEGF levels were determined by ELISA analysis.</p> <p>Results</p> <p>Our results demonstrated that conditioned media from cell lines with constitutively active STAT3 are sufficient to induce p-STAT3 levels in various recipients that do not possess elevated p-STAT3 levels. This signaling occurs through the JAK/STAT3 pathway, leading to STAT3 phosphorylation as early as 30 minutes and is persistent for at least 24 hours. ELISA analysis confirmed a correlation between elevated levels of IL-6 production and p-STAT3. Neutralization of the IL-6 ligand or gp130 was sufficient to block increased levels of p-STAT3 (Y705) in treated cells. Furthermore, soluble factors within the MDA-MB-231 conditioned media were also sufficient to stimulate an increase in IL-6 production from MCF-10A cells.</p> <p>Conclusion</p> <p>These results demonstrate STAT3 phosphorylation in breast epithelial cells can be stimulated by paracrine signaling through soluble factors from both breast cancer cells and breast cancer associated fibroblasts with elevated STAT3 phosphorylation. The induction of STAT3 phosphorylation is through the IL-6/JAK pathway and appears to be associated with cell proliferation. Understanding how IL-6 and other soluble factors may lead to STAT3 activation via the tumor microenvironment will provide new therapeutic regimens for breast carcinomas and other cancers with elevated p-STAT3 levels.</p

A Bacterial Cytotoxin Identifies the RhoA Exchange Factor Net1 as a Key Effector in the Response to DNA Damage

Background: Exposure of adherent cells to DNA damaging agents, such as the bacterial cytolethal distending toxin (CDT) or ionizing radiations (IR), activates the small GTPase RhoA, which promotes the formation of actin stress fibers and delays cell death. The signalling intermediates that regulate RhoA activation and promote cell survival are unknown. Principal Findings: We demonstrate that the nuclear RhoA-specific Guanine nucleotide Exchange Factor (GEF) Net1 becomes dephosphorylated at a critical inhibitory site in cells exposed to CDT or IR. Expression of a dominant negative Net1 or Net1 knock down by iRNA prevented RhoA activation, inhibited the formation of stress fibers, and enhanced cell death, indicating that Net1 activation is required for this RhoA-mediated responses to genotoxic stress. The Net1 and RhoAdependent signals involved activation of the Mitogen-Activated Protein Kinase p38 and its downstream target MAPKactivated protein kinase 2. Significance: Our data highlight the importance of Net1 in controlling RhoA and p38 MAPK mediated cell survival in cells exposed to DNA damaging agents and illustrate a molecular pathway whereby chronic exposure to a bacterial toxin ma

New highlights on stroma–epithelial interactions in breast cancer

Although the stroma in which carcinomas arise has been previously regarded as a bystander to the clonal expansion and acquisition of malignant characteristics of tumor cells, it is now generally acknowledged that stromal changes are required for the establishment of cancer. In the present article, we discuss three recent publications that highlight the complex role the stroma has during the development of cancer and the potential for targeting the stroma by therapeutic approaches

Identification of stromally expressed molecules in the prostate by tag-profiling of cancer-associated fibroblasts, normal fibroblasts and fetal prostate.

The stromal microenvironment has key roles in prostate development and cancer, and cancer-associated fibroblasts (CAFs) stimulate tumourigenesis via several mechanisms including the expression of pro-tumourigenic factors. Mesenchyme (embryonic stroma) controls prostate organogenesis, and in some circumstances can re-differentiate prostate tumours. We have applied next-generation Tag profiling to fetal human prostate, normal human prostate fibroblasts (NPFs) and CAFs to identify molecules expressed in prostatic stroma. Comparison of gene expression profiles of a patient-matched pair of NPFs vs CAFs identified 671 transcripts that were enriched in CAFs and 356 transcripts whose levels were decreased, relative to NPFs. Gene ontology analysis revealed that CAF-enriched transcripts were associated with prostate morphogenesis and CAF-depleted transcripts were associated with cell cycle. We selected mRNAs to follow-up by comparison of our data sets with published prostate cancer fibroblast microarray profiles as well as by focusing on transcripts encoding secreted and peripheral membrane proteins, as well as mesenchymal transcripts identified in a previous study from our group. We confirmed differential transcript expression between CAFs and NPFs using QrtPCR, and defined protein localization using immunohistochemistry in fetal prostate, adult prostate and prostate cancer. We demonstrated that ASPN, CAV1, CFH, CTSK, DCN, FBLN1, FHL1, FN, NKTR, OGN, PARVA, S100A6, SPARC, STC1 and ZEB1 proteins showed specific and varied expression patterns in fetal human prostate and in prostate cancer. Colocalization studies suggested that some stromally expressed molecules were also expressed in subsets of tumour epithelia, indicating that they may be novel markers of EMT. Additionally, two molecules (ASPN and STC1) marked overlapping and distinct subregions of stroma associated with tumour epithelia and may represent new CAF markers