Accelerated expansion from ghost-free bigravity: a statistical analysis with improved generality

We study the background cosmology of the ghost-free, bimetric theory of gravity. We perform an extensive statistical analysis of the model using both frequentist and Bayesian frameworks and employ the constraints on the expansion history of the Universe from the observations of supernovae, the cosmic microwave background and the large scale structure to estimate the model's parameters and test the goodness of the fits. We explore the parameter space of the model with nested sampling to find the best-fit chi-square, obtain the Bayesian evidence, and compute the marginalized posteriors and mean likelihoods. We mainly focus on a class of sub-models with no explicit cosmological constant (or vacuum energy) term to assess the ability of the theory to dynamically cause a late-time accelerated expansion. The model behaves as standard gravity without a cosmological constant at early times, with an emergent extra contribution to the energy density that converges to a cosmological constant in the far future. The model can in most cases yield very good fits and is in perfect agreement with the data. This is because many points in the parameter space of the model exist that give rise to time-evolution equations that are effectively very similar to those of the $\Lambda$CDM. This similarity makes the model compatible with observations as in the $\Lambda$CDM case, at least at the background level. Even though our results indicate a slightly better fit for the $\Lambda$CDM concordance model in terms of the $p$-value and evidence, none of the models is statistically preferred to the other. However, the parameters of the bigravity model are in general degenerate. A similar but perturbative analysis of the model as well as more data will be required to break the degeneracies and constrain the parameters, in case the model will still be viable compared to the $\Lambda$CDM.Comment: 42 pages, 9 figures; typos corrected in equations (2.12), (2.13), (3.7), (3.8) and (3.9); more discussions added (footnotes 5, 8, 10 and 13) and abstract, sections 4.2, 4.3 and 5 (conclusions) modified in response to referee's comments; references added; acknowledgements modified; all results completely unchanged; matches version accepted for publication in JHE

WNT signalling in prostate cancer

Genome sequencing and gene expression analyses of prostate tumours have highlighted the potential importance of genetic and epigenetic changes observed in WNT signalling pathway components in prostate tumours-particularly in the development of castration-resistant prostate cancer. WNT signalling is also important in the prostate tumour microenvironment, in which WNT proteins secreted by the tumour stroma promote resistance to therapy, and in prostate cancer stem or progenitor cells, in which WNT-β-catenin signals promote self-renewal or expansion. Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression. Some WNT signalling inhibitors are in phase I trials, but they have yet to be tested in patients with prostate cancer

Identifying patient preferences for communicating risk estimates: A descriptive pilot study

BACKGROUND: Patients increasingly seek more active involvement in health care decisions, but little is known about how to communicate complex risk information to patients. The objective of this study was to elicit patient preferences for the presentation and framing of complex risk information. METHOD: To accomplish this, eight focus group discussions and 15 one-on-one interviews were conducted, where women were presented with risk data in a variety of different graphical formats, metrics, and time horizons. Risk data were based on a hypothetical woman's risk for coronary heart disease, hip fracture, and breast cancer, with and without hormone replacement therapy. Participants' preferences were assessed using likert scales, ranking, and abstractions of focus group discussions. RESULTS: Forty peri- and postmenopausal women were recruited through hospital fliers (n = 25) and a community health fair (n = 15). Mean age was 51 years, 50% were non-Caucasian, and all had completed high school. Bar graphs were preferred by 83% of participants over line graphs, thermometer graphs, 100 representative faces, and survival curves. Lifetime risk estimates were preferred over 10 or 20-year horizons, and absolute risks were preferred over relative risks and number needed to treat. CONCLUSION: Although there are many different formats for presenting and framing risk information, simple bar charts depicting absolute lifetime risk were rated and ranked highest overall for patient preferences for format

A High Red Blood Cell Distribution Width Predicts Failure of Arteriovenous Fistula

In hemodialysis patients, a native arteriovenous fistula (AVF) is the preferred form of permanent vascular access. Despite recent improvements, vascular access dysfunction remains an important cause of morbidity in these patients. In this prospective observational cohort study, we evaluated potential risk factors for native AVF dysfunction. We included 68 patients with chronic renal disease stage 5 eligible for AVF construction at the Department of General and Vascular Surgery, Central Clinical Hospital Ministry of Internal Affairs, Warsaw, Poland. Patient characteristics and biochemical parameters associated with increased risk for AVF failure were identified using Cox proportional hazards models. Vessel biopsies were analyzed for inflammatory cells and potential associations with biochemical parameters. In multivariable analysis, independent predictors of AVF dysfunction were the number of white blood cells (hazard ratio [HR] 1.67; 95% confidence interval [CI] 1.24 to 2.25; p<0.001), monocyte number (HR 0.02; 95% CI 0.00 to 0.21; p = 0.001), and red blood cell distribution width (RDW) (HR 1.44; 95% CI 1.17 to 1.78; p<0.001). RDW was the only significant factor in receiver operating characteristic curve analysis (area under the curve 0.644; CI 0.51 to 0.76; p = 0.046). RDW>16.2% was associated with a significantly reduced AVF patency frequency 24 months after surgery. Immunohistochemical analysis revealed CD45-positive cells in the artery/vein of 39% of patients and CD68-positive cells in 37%. Patients with CD68-positive cells in the vessels had significantly higher white blood cell count. We conclude that RDW, a readily available laboratory value, is a novel prognostic marker for AVF failure. Further studies are warranted to establish the mechanistic link between high RDW and AVF failure

Flagellin-Induced Corneal Antimicrobial Peptide Production and Wound Repair Involve a Novel NF-κB–Independent and EGFR-Dependent Pathway

The bacterial protein flagellin plays a major role in stimulating mucosal surface innate immune response to bacterial infection and uniquely induces profound cytoprotection against pathogens, chemicals, and radiation. This study sought to determine signaling pathways responsible for the flagellin-induced inflammatory and cytoprotective effects on human corneal epithelial cells (HCECs).Flagellin purified from Pseudomonas aeruginosa (strain PAK) or live bacteria were used to challenge cultured HCECs. The activation of signaling pathways was assessed with Western blot, and the secretion of cytokine/chemokine and production of antimicrobial peptides (AMPs) were measured with ELISA and dot blot, respectively. Effects of flagellin on wound healing were assessed in cultured porcine corneas. L94A (a site mutation in TLR5 binding region) flagellin and PAK expressing L94A flagellin were unable to stimulate NF-kappaB activation, but were potent in eliciting EGFR signaling in a TGF-alpha-related pathway in HCECs. Concomitant with the lack of NF-kappaB activation, L94A flagellin was ineffective in inducing IL-6 and IL-8 production in HCECs. Surprisingly, the secretion of two inducible AMPs, LL-37 and hBD2, was not affected by L94A mutation. Similar to wild-type flagellin, L94A induced epithelial wound closure in cultured porcine cornea through maintaining EGFR-mediated signaling.Our data suggest that inflammatory response mediated by NF-kappaB can be uncoupled from epithelial innate defense machinery (i.e., AMP expression) and major epithelial proliferation/repair pathways mediated by EGFR, and that flagellin and its derivatives may have broad therapeutic applications in cytoprotection and in controlling infection in the cornea and other mucosal tissues

The clinical potential of antiangiogenic fragments of extracellular matrix proteins

Neovasculature development is a crucial step in the natural history of a cancer. While much emphasis has been placed on proangiogenic growth factors such as VEGF, it is clear that endogenous angiogenesis inhibitors also have critical roles in the regulation of this process. Recent research has identified several cryptic fragments of extracellular matrix/vascular basement membrane proteins that have potent antiangiogenic properties in vivo. It has become apparent that many of these fragments signal via interactions with endothelial integrins, although multiple downstream effector pathways have been implicated and endostatin, the first non-collagenous domain of collagen XVIII, influences an intricate signalling network. The activity of these molecules in animal models suggests that they may have significant clinical activity; however, results of phase I/II trials with endostatin were disappointing. Many possible reasons can be found for the failure of these studies. Weaknesses in trial design, endostatin administration regimen and patient selection are identifiable, and importantly the lack of a clearly defined antiangiogenic mechanism for endostatin hindered assessment of biologically effective dose. Additionally, in vivo immunological and proteolytic function-neutralising mechanisms may have negated endostatin's actions. Lessons learned from these studies will aid the future clinical development of other antiangiogenic extracellular matrix protein fragments

Genomic Prevalence of Heterochromatic H3K9me2 and Transcription Do Not Discriminate Pluripotent from Terminally Differentiated Cells

Cellular differentiation entails reprogramming of the transcriptome from a pluripotent to a unipotent fate. This process was suggested to coincide with a global increase of repressive heterochromatin, which results in a reduction of transcriptional plasticity and potential. Here we report the dynamics of the transcriptome and an abundant heterochromatic histone modification, dimethylation of histone H3 at lysine 9 (H3K9me2), during neuronal differentiation of embryonic stem cells. In contrast to the prevailing model, we find H3K9me2 to occupy over 50% of chromosomal regions already in stem cells. Marked are most genomic regions that are devoid of transcription and a subgroup of histone modifications. Importantly, no global increase occurs during differentiation, but discrete local changes of H3K9me2 particularly at genic regions can be detected. Mirroring the cell fate change, many genes show altered expression upon differentiation. Quantitative sequencing of transcripts demonstrates however that the total number of active genes is equal between stem cells and several tested differentiated cell types. Together, these findings reveal high prevalence of a heterochromatic mark in stem cells and challenge the model of low abundance of epigenetic repression and resulting global basal level transcription in stem cells. This suggests that cellular differentiation entails local rather than global changes in epigenetic repression and transcriptional activity

Light Variability Illuminates Niche-Partitioning among Marine Picocyanobacteria

Prochlorococcus and Synechococcus picocyanobacteria are dominant contributors to marine primary production over large areas of the ocean. Phytoplankton cells are entrained in the water column and are thus often exposed to rapid changes in irradiance within the upper mixed layer of the ocean. An upward fluctuation in irradiance can result in photosystem II photoinactivation exceeding counteracting repair rates through protein turnover, thereby leading to net photoinhibition of primary productivity, and potentially cell death. Here we show that the effective cross-section for photosystem II photoinactivation is conserved across the picocyanobacteria, but that their photosystem II repair capacity and protein-specific photosystem II light capture are negatively correlated and vary widely across the strains. The differences in repair rate correspond to the light and nutrient conditions that characterize the site of origin of the Prochlorococcus and Synechococcus isolates, and determine the upward fluctuation in irradiance they can tolerate, indicating that photoinhibition due to transient high-light exposure influences their distribution in the ocean

Qualia: The Geometry of Integrated Information

According to the integrated information theory, the quantity of consciousness is the amount of integrated information generated by a complex of elements, and the quality of experience is specified by the informational relationships it generates. This paper outlines a framework for characterizing the informational relationships generated by such systems. Qualia space (Q) is a space having an axis for each possible state (activity pattern) of a complex. Within Q, each submechanism specifies a point corresponding to a repertoire of system states. Arrows between repertoires in Q define informational relationships. Together, these arrows specify a quale—a shape that completely and univocally characterizes the quality of a conscious experience. Φ— the height of this shape—is the quantity of consciousness associated with the experience. Entanglement measures how irreducible informational relationships are to their component relationships, specifying concepts and modes. Several corollaries follow from these premises. The quale is determined by both the mechanism and state of the system. Thus, two different systems having identical activity patterns may generate different qualia. Conversely, the same quale may be generated by two systems that differ in both activity and connectivity. Both active and inactive elements specify a quale, but elements that are inactivated do not. Also, the activation of an element affects experience by changing the shape of the quale. The subdivision of experience into modalities and submodalities corresponds to subshapes in Q. In principle, different aspects of experience may be classified as different shapes in Q, and the similarity between experiences reduces to similarities between shapes. Finally, specific qualities, such as the “redness” of red, while generated by a local mechanism, cannot be reduced to it, but require considering the entire quale. Ultimately, the present framework may offer a principled way for translating qualitative properties of experience into mathematics