Cosmic Ray Processes in Galactic Ecosystems

Galaxy evolution is an important topic, and our physical understanding must be complete to establish a correct picture. This includes a thorough treatment of feedback. The effects of thermal–mechanical and radiative feedback have been widely considered; however, cosmic rays (CRs) are also powerful energy carriers in galactic ecosystems. Resolving the capability of CRs to operate as a feedback agent is therefore essential to advance our understanding of the processes regulating galaxies. The effects of CRs are yet to be fully understood, and their complex multi-channel feedback mechanisms operating across the hierarchy of galaxy structures pose a significant technical challenge. This review examines the role of CRs in galaxies, from the scale of molecular clouds to the circumgalactic medium. An overview of their interaction processes, their implications for galaxy evolution, and their observable signatures is provided and their capability to modify the thermal and hydrodynamic configuration of galactic ecosystems is discussed. We present recent advancements in our understanding of CR processes and interpretation of their signatures, and highlight where technical challenges and unresolved questions persist. We discuss how these may be addressed with upcoming opportunities

The Impact of Cluster Structure and Dynamical State on Scatter in the Sunyaev-Zel'dovich Flux-Mass Relation

Cosmological constraints from cluster surveys rely on accurate mass estimates from the mass-observable relations. In order to avoid systematic biases and reduce uncertainties, we study the form and physical origin of the intrinsic scatter about the mean Sunyaev-Zel'dovich (SZ) flux-mass relation using a hydrodynamical simulation of galaxy cluster formation. We examine the assumption of lognormal scatter and detect non-negligible positive skewness and kurtosis (> 0.5) for a wide range of limiting masses and redshifts. These higher-order moments should be included in the parametrization of scatter in order not to bias cosmological constraints. We investigate the sources of the scatter by correlating it with measures of cluster morphology, halo concentration, and dynamical state, and we quantify the individual contribution from each source. We find that statistically the impact of dynamical state is weak, so the selection bias due to mergers is negligible. On the other hand, there is a strong correlation between the scatter and halo concentration, which can be used to reduce the scatter significantly (from 12.07% to 7.34% or by ~40% for clusters at z = 0). We also show that a cross-calibration by combining information from X-ray followups can be used to reduce the scatter in the flux-mass relation and also identify outliers in both X-ray and SZ cluster surveys.Comment: 14 pages, 12 figures; accepted for publication in Ap

Application of pharmacogenomics and bioinformatics to exemplify the utility of human <i>ex vivo</i> organoculture models in the field of precision medicine

Here we describe a collaboration between industry, the National Health Service (NHS) and academia that sought to demonstrate how early understanding of both pharmacology and genomics can improve strategies for the development of precision medicines. Diseased tissue ethically acquired from patients suffering from chronic obstructive pulmonary disease (COPD), was used to investigate inter-patient variability in drug efficacy using ex vivo organocultures of fresh lung tissue as the test system. The reduction in inflammatory cytokines in the presence of various test drugs was used as the measure of drug efficacy and the individual patient responses were then matched against genotype and microRNA profiles in an attempt to identify unique predictors of drug responsiveness. Our findings suggest that genetic variation in CYP2E1 and SMAD3 genes may partly explain the observed variation in drug response

Tumour Suppressive Function and Modulation of Programmed Cell Death 4 (PDCD4) in Ovarian Cancer

Background: Programmed cell death 4 (PDCD4), originally identified as the neoplastic transformation inhibitor, was attenuated in various cancer types. Our previous study demonstrated a continuous down-regulation of PDCD4 expression in the sequence of normal-borderline-malignant ovarian tissue samples and a significant correlation of PDCD4 expression with disease-free survival. The objective of the current study was to further investigate the function and modulation of PDCD4 in ovarian cancer cells. Principal Findings: We demonstrated that ectopic PDCD4 expression significantly inhibited cell proliferation by inducing cell cycle arrest at G1 stage and up-regulation of cell cycle inhibitors of p27 and p21. Cell migration and invasion were also inhibited by PDCD4. PDCD4 over-expressing cells exhibited elevated phosphatase and tensin homolog (PTEN) and inhibited protein kinase B (p-Akt). In addition, the expression of PDCD4 was up-regulated and it was exported to the cytoplasm upon serum withdrawal treatment, but it was rapidly depleted via proteasomal degradation upon serum re-administration. Treatment of a phosphoinositide 3-kinase (PI3K) inhibitor prevented the degradation of PDCD4, indicating the involvement of PI3K-Akt pathway in the modulation of PDCD4. Conclusion: PDCD4 may play a critical function in arresting cell cycle progression at key checkpoint, thus inhibiting cell proliferation, as well as suppressing tumour metastasis. The PI3K-Akt pathway was implied to be involved in the regulatio

Acetyltransferases and tumour suppression

The acetyltransferase p300 was first identified associated with the adenoviral transforming protein E1A, suggesting a potential role for p300 in the regulation of cell proliferation. Direct evidence demonstrating a role for p300 in human tumours was lacking until the recentl publication by Gayther et al, which strongly supports a role for p300 as a tumour suppressor. The authors identify truncating mutations associated with the loss or mutation of the second allele in both tumour samples and cell lines, suggesting that loss of p300 may play a role in the development of a subset of human cancers

Regulation of Adipocyte 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) by CCAAT/Enhancer-Binding Protein (C/EBP) β Isoforms, LIP and LAP

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyses intracellular regeneration of active glucocorticoids, notably in liver and adipose tissue. 11β-HSD1 is increased selectively in adipose tissue in human obesity, a change implicated in the pathogenesis of metabolic syndrome. With high fat (HF)-feeding, adipose tissue 11β-HSD1 is down-regulated in mice, plausibly to counteract metabolic disease. Transcription of 11β-HSD1 is directly regulated by members of the CCAAT/enhancer binding protein (C/EBP) family. Here we show that while total C/EBPβ in adipose tissue is unaltered by HF diet, the ratio of the C/EBPβ isoforms liver-enriched inhibitor protein (LIP) and liver-enriched activator protein (LAP) (C/EBPβ-LIP:LAP) is increased in subcutaneous adipose. This may cause changes in 11β-HSD1 expression since genetically modified C/EBPβ(+/L) mice, with increased C/EBPβ-LIP:LAP ratio, have decreased subcutaneous adipose 11β-HSD1 mRNA levels, whereas C/EBPβΔuORF mice, with decreased C/EBPβ-LIP:LAP ratio, show increased subcutaneous adipose 11β-HSD1. C/EBPβ-LIP:LAP ratio is regulated by endoplasmic reticulum (ER) stress and mTOR signalling, both of which are altered in obesity. In 3T3-L1 adipocytes, 11β-HSD1 mRNA levels were down-regulated following induction of ER stress by tunicamycin but were up-regulated following inhibition of mTOR by rapamycin. These data point to a central role for C/EBPβ and its processing to LIP and LAP in transcriptional regulation of 11β-HSD1 in adipose tissue. Down-regulation of 11β-HSD1 by increased C/EBPβ-LIP:LAP in adipocytes may be part of a nutrient-sensing mechanism counteracting nutritional stress generated by HF diet

Theoretical Uncertainties due to AGN Subgrid Models in Predictions of Galaxy Cluster Observable Properties

Cosmological constraints derived from galaxy clusters rely on accurate predictions of cluster observable properties, in which feedback from active galactic nuclei (AGN) is a critical component. In order to model the physical effects due to supermassive black holes (SMBH) on cosmological scales, subgrid modeling is required, and a variety of implementations have been developed in the literature. However, theoretical uncertainties due to model and parameter variations are not yet well understood, limiting the predictive power of simulations including AGN feedback. By performing a detailed parameter sensitivity study in a single cluster using several commonly-adopted AGN accretion and feedback models with FLASH, we quantify the model uncertainties in predictions of cluster integrated properties. We find that quantities that are more sensitive to gas density have larger uncertainties (~20% for Mgas and a factor of ~2 for Lx at R500), whereas Tx, Ysz, and Yx are more robust (~10-20% at R500). To make predictions beyond this level of accuracy would require more constraints on the most relevant parameters: the accretion model, mechanical heating efficiency, and size of feedback region. By studying the impact of AGN feedback on the scaling relations, we find that an anti-correlation exists between Mgas and Tx, which is another reason why Ysz and Yx are excellent mass proxies. This anti-correlation also implies that AGN feedback is likely to be an important source of intrinsic scatter in the Mgas-Tx and Lx-Tx relations.Comment: Accepted for publication in MNRA