Nature and Nurture in Dark Matter Halos

Cosmological simulations consistently predict specific properties of dark matter halos, but these have not yet led to a physical understanding that is generally accepted. This is especially true for the central regions of these structures. Recently two major themes have emerged. In one, the dark matter halo is primarily a result of the sequential accretion of primordial structure (ie `Nature'); while in the other, dynamical relaxation (ie `Nurture') dominates at least in the central regions. Some relaxation is however required in either mechanism. In this paper we accept the recently established scale-free sub-structure of halos as an essential part of both mechanisms. Consequently; a simple model for the central relaxation based on a self-similar cascade of tidal interactions, is contrasted with a model based on the accretion of adiabatically self-similar, primordial structure. We conclude that a weak form of this relaxation is present in the simulations, but that is normally described as the radial orbit instability.Comment: 25 pages, 3 figures, fig with parts 1 to d, fig 3 with parts a to

Implications of Halo Inside-out Growth on the X-Ray Properties of Nearby Galaxy Systems within the Preheating Scenario

We present an entirely analytic model for a preheated, polytropic intergalactic medium in hydrostatic equilibrium within a NFW dark halo potential in which the evolution of the halo structure between major merger events proceeds inside-out by accretion. This model is used to explain, within a standard $\Lambda$CDM cosmogony, the observed X-ray properties of nearby relaxed, non-cooling flow groups and clusters of galaxies. We find that our preferred solution to the equilibrium equations produces scaling relations in excellent agreement with observations, while simultaneously accounting for the typical structural characteristics of the distribution of the diffuse baryons. In the class of preheating models, ours stands out because it offers a unified description of the intrahalo medium for galaxy systems with total masses above \sm 2\times 10^{13}\msun, does not produce baryonic configurations with large isentropic cores, and reproduces faithfully the observed behavior of the gas entropy at large radii. All this is achieved with a moderate level of energy injection of about half a keV, which can be easily accommodated within the limits of the total energy released by the most commonly invoked feedback mechanisms, as well as with a polytropic index of 1.2, consistent with both many observational determinations and predictions from high-resolution gas-dynamical simulations of non-cooling flow clusters. More interestingly, our scheme offers a physical motivation for the adoption of this specific value of the polytropic index, as it is the one that best ensures the conservation after halo virialization of the balance between the total specific energies of the gas and dark matter components for the full range of masses investigated.Comment: 18 pages, 11 figures, accepted for publication in the Astrophysical Journa

Redox-dependent and redox-independent functions of Caenorhabditis elegans thioredoxin 1

Thioredoxins (TRX) are traditionally considered as enzymes catalyzing redox reactions. However, redox-independent functions of thioredoxins have been described in different organisms, although the underlying molecular mechanisms are yet unknown. We report here the characterization of the first generated endogenous redox-inactive thioredoxin in an animal model, the TRX-1 in the nematode Caenorhabditis elegans. We find that TRX-1 dually regulates the formation of an endurance larval stage (dauer) by interacting with the insulin pathway in a redox-independent manner and the cGMP pathway in a redox-dependent manner. Moreover, the requirement of TRX-1 for the extended longevity of worms with compromised insulin signalling or under calorie restriction relies on TRX-1 redox activity. In contrast, the nuclear translocation of the SKN-1 transcription factor and increased LIPS-6 protein levels in the intestine upon trx-1 deficiency are strictly redox-independent. Finally, we identify a novel function of C. elegans TRX-1 in male food-leaving behaviour that is redox-dependent. Taken together, our results position C. elegans as an ideal model to gain mechanistic insight into the redox-independent functions of metazoan thioredoxins, overcoming the limitations imposed by the embryonic lethal phenotypes of thioredoxin mutants in higher organisms

Dynamic soluble changes in sVEGFR1, HGF, and VEGF promote chemotherapy and bevacizumab resistance: A prospective translational study in the BECOX (GEMCAD 09-01) trial

Despite initial responsiveness, acquired resistance to both bevacizumab and chemotherapy in metastatic colorectal cancer is universal. We have recently published that in vitro, chronically oxaliplatin resistance upregulates soluble vascular endothelial growth factor receptor 1, downregulates vascular endothelial growth factor, and also promotes c-MET, b-ca catenin/transcription factor 4, and AKT activation. We tested whether variation in three serum biomarkers such as the natural c-MET ligand (hepatocyte growth factor), soluble vascular endothelial growth factor receptor 1, and vascular endothelial growth factor-A was associated with efficacy in metastatic colorectal cancer patients treated in the prospective BECOX study. Serum levels of vascular endothelial growth factor-A165, soluble vascular endothelial growth factor receptor 1, and hepatocyte growth factor were assessed by enzyme-linked immunosorbent assay method basally and every 3 cycles (at the time of computed tomography evaluation) in a preplanned translational study in the first-line BECOX trial in metastatic colorectal cancer patients treated with CAPOX plus bevacizumab. Response was evaluated by routine contrast-enhanced computed tomography by RECIST 1.1 by investigator assessment and by three blinded independent radiologists. Ratios between soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A and hepatocyte growth factor/vascular endothelial growth factor-A were established and variations through time were related to RECIST 1.1 by investigator assessment and independent radiologist. The BECOX trial included 68 patients, and 27 patients were analyzed in the translational trial. A total of 80 RECIST 1.1 evaluations were done by investigator assessment and 56 by independent radiologist. We found that a 3.22-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by investigator assessment and a 3.06-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by independent radiologist from previous determination were associated with responses compared with 1.38-fold increase by investigator assessment and 1.59 by independent radiologist in non-responders (p= 0.0009 and p = 0.03, respectively). Responders had a 3.36-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A from previous determination by investigator assessment and 3.66-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A by independent radiologist compared with 1.43-fold increase by investigator assessment and 1.53 by independent radiologist for non-responders (p = 0.002 and 0.003, respectively). In conclusion, a decrease in vascular endothelial growth factor-A and an increase in soluble vascular endothelial growth factor receptor 1 during chemotherapy and bevacizumab exposure can contribute to both chemotherapy (due to c- MET/b-catenin activation) and bevacizumab (due to low vascular endothelial growth factor requirements) resistance. Because hepatocyte growth factor levels decrease also during acquired resistance, alternative strategies to hepatocyte growth factor–ligand inhibition should be investigatedThis work was supported by “beca SEOM a Jóvenes Investigadores 2009” and by the Emili Letang fellowship to Estela Pineda

Internal dynamics of the radio-halo cluster A2744

We present a detailed dynamical analysis of the rich galaxy cluster A2744, containing a powerful diffuse radio halo.Our analysis is based on redshift data for 102 galaxies, part of them recovered from unexplored spectra in the ESO archive. We combine galaxy velocity and position information to select the cluster members and determine global dynamical properties of the cluster. We use a variety of statistical tests to detect possible substructures. We find that A2744 appears as a well isolated peak in the redshift space at =0.306, which includes 85 galaxies recognized as cluster members. We compute the line-of-sight (LOS) velocity dispersion of galaxies (~1750 km/sec), which is significantly larger than what is expected in the case of a relaxed cluster with an observed X-ray temperature of 8 keV. We find evidence that this cluster is far from dynamical equilibrium, as shown by the non-Gaussian nature of the velocity distribution, the presence of a velocity gradient and a significant substructure. In particular, our results suggest a merging scenario of two clumps with a mass ratio of 3:1 and a LOS impact velocity (rest frame) of ~3000 km/sec, likely observed just after the core passage. The merging is occuring roughly in the NS direction with the axis close to the LOS. This scenario agrees with that proposed on the basis of recent Chandra results in its general lines, although suggesting a somewhat more advanced merging phase.Comment: 14 pages. Paper in press on Astronomy & Astrophysic

Upregulation of NKG2D ligands impairs hematopoietic stem cell function in Fanconi anemia

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER); Next Generation EU; EUROFANCOLEN); Comunidad de Madrid (AvanCell, B2017/BMD-3692); ICREA-Academia program.Fanconi anemia (FA) is the most prevalent inherited bone marrow failure (BMF) syndrome. Nevertheless, the pathophysiological mechanisms of BMF in FA have not been fully elucidated. Since FA cells are defective in DNA repair, we hypothesized that FA hematopoietic stem and progenitor cells (HSPCs) might express DNA damage-associated stress molecules such as natural killer group 2 member D ligands (NKG2D-Ls). These ligands could then interact with the activating NKG2D receptor expressed in cytotoxic NK or CD8+ T cells, which may result in progressive HSPC depletion. Our results indeed demonstrated upregulated levels of NKG2D-Ls in cultured FA fibroblasts and T cells, and these levels were further exacerbated by mitomycin C or formaldehyde. Notably, a high proportion of BM CD34+ HSPCs from patients with FA also expressed increased levels of NKG2D-Ls, which correlated inversely with the percentage of CD34+ cells in BM. Remarkably, the reduced clonogenic potential characteristic of FA HSPCs was improved by blocking NKG2D-NKG2D-L interactions. Moreover, the in vivo blockage of these interactions in a BMF FA mouse model ameliorated the anemia in these animals. Our study demonstrates the involvement of NKG2D-NKG2D-L interactions in FA HSPC functionality, suggesting an unexpected role of the immune system in the progressive BMF that is characteristic of FA

Internal dynamics of the z sim 0.8 cluster RX J0152.7-1357

We present the results from the dynamical analysis of the cluster of galaxies RX J0152-1357, which shows a complex structure in its X-ray emission, with two major clumps in the central region, and a third clump in the Eastern region. Our analysis is based on redshift data for 187 galaxies. We compute the line-of-sight velocity dispersion of galaxies, sigma_V=1322^+74_-68 kms^-1, which is significantly larger than what is expected in the case of a relaxed cluster with an observed X-ray temperature of 5-6 keV. We find evidence that this cluster is far from dynamical equilibrium, as shown by the non Gaussianity of the velocity distribution, the presence of a velocity gradient and significant substructure. Our analysis shows that the high value of sigma_V is due to the complex structure of RX J0152-1357, i.e. to the presence of three galaxy clumps of different mean velocity. Using optical data we detect a low-velocity clump (with sigma_V=300-500 kms^-1) in the central SW region and a high--velocity clump (with sigma_V sim 700 kms^-1) in the E region, well corresponding to the SW and E peaks detected in the X-ray emission. The central NE X-ray peak is associated to the main galaxy structure with a velocity which is intermediate between those of the other two clumps and sigma_V sim 900 kms^-1. The mass of the whole system within 2 Mpc is estimated to lie in the range (1.2-2.2)X10^{15} M_sun. Analytic calculations based on the two-body model indicate that the system is most likely bound, currently undergoing merging. In particular, we suggest that the SW clump is not a small group, but rather the dense cluster-core of a massive cluster.Comment: 14 pages, 15 eps figures, A&A accepte

A chronic fatigue syndrome – related proteome in human cerebrospinal fluid

BACKGROUND: Chronic Fatigue Syndrome (CFS), Persian Gulf War Illness (PGI), and fibromyalgia are overlapping symptom complexes without objective markers or known pathophysiology. Neurological dysfunction is common. We assessed cerebrospinal fluid to find proteins that were differentially expressed in this CFS-spectrum of illnesses compared to control subjects. METHODS: Cerebrospinal fluid specimens from 10 CFS, 10 PGI, and 10 control subjects (50 μl/subject) were pooled into one sample per group (cohort 1). Cohort 2 of 12 control and 9 CFS subjects had their fluids (200 μl/subject) assessed individually. After trypsin digestion, peptides were analyzed by capillary chromatography, quadrupole-time-of-flight mass spectrometry, peptide sequencing, bioinformatic protein identification, and statistical analysis. RESULTS: Pooled CFS and PGI samples shared 20 proteins that were not detectable in the pooled control sample (cohort 1 CFS-related proteome). Multilogistic regression analysis (GLM) of cohort 2 detected 10 proteins that were shared by CFS individuals and the cohort 1 CFS-related proteome, but were not detected in control samples. Detection of ≥1 of a select set of 5 CFS-related proteins predicted CFS status with 80% concordance (logistic model). The proteins were α-1-macroglobulin, amyloid precursor-like protein 1, keratin 16, orosomucoid 2 and pigment epithelium-derived factor. Overall, 62 of 115 proteins were newly described. CONCLUSION: This pilot study detected an identical set of central nervous system, innate immune and amyloidogenic proteins in cerebrospinal fluids from two independent cohorts of subjects with overlapping CFS, PGI and fibromyalgia. Although syndrome names and definitions were different, the proteome and presumed pathological mechanism(s) may be shared

Potassium Starvation in Yeast: Mechanisms of Homeostasis Revealed by Mathematical Modeling

The intrinsic ability of cells to adapt to a wide range of environmental conditions is a fundamental process required for survival. Potassium is the most abundant cation in living cells and is required for essential cellular processes, including the regulation of cell volume, pH and protein synthesis. Yeast cells can grow from low micromolar to molar potassium concentrations and utilize sophisticated control mechanisms to keep the internal potassium concentration in a viable range. We developed a mathematical model for Saccharomyces cerevisiae to explore the complex interplay between biophysical forces and molecular regulation facilitating potassium homeostasis. By using a novel inference method (“the reverse tracking algorithm”) we predicted and then verified experimentally that the main regulators under conditions of potassium starvation are proton fluxes responding to changes of potassium concentrations. In contrast to the prevailing view, we show that regulation of the main potassium transport systems (Trk1,2 and Nha1) in the plasma membrane is not sufficient to achieve homeostasis