51 research outputs found
Distinguishing between Neutrinos and time-varying Dark Energy through Cosmic Time
We study the correlations between parameters characterizing neutrino physics
and the evolution of dark energy. Using a fluid approach, we show that
time-varying dark energy models exhibit degeneracies with the cosmic neutrino
background over extended periods of the cosmic history, leading to a degraded
estimation of the total mass and number of species of neutrinos. We investigate
how to break degeneracies and combine multiple probes across cosmic time to
anchor the behaviour of the two components. We use Planck CMB data and BAO
measurements from the BOSS, SDSS and 6dF surveys to present current limits on
the model parameters, and then forecast the future reach from the CMB Stage-4
and DESI experiments. We show that a multi-probe analysis of current data
provides only marginal improvement on the determination of the individual
parameters and no reduction of the correlations. Future observations will
better distinguish the neutrino mass and preserve the current sensitivity to
the number of species even in case of a time-varying dark energy component.Comment: 10 pages, 7 figures, minor updates to match the version accepted by
Phys. Rev.
Time-varying neutrino mass from a supercooled phase transition: current cosmological constraints and impact on the - plane
In this paper we investigate a time-varying neutrino mass model, motivated by
the mild tension between cosmic microwave background (CMB) measurements of the
matter fluctuations and those obtained from low-redshift data. We modify the
minimal case of the model proposed by Dvali and Funcke (2016) that predicts
late neutrino mass generation in a post-recombination cosmic phase transition,
by assuming that neutrino asymmetries allow for the presence of relic neutrinos
in the late-time Universe. We show that, if the transition is supercooled,
current cosmological data (including CMB temperature, polarization and lensing,
baryon acoustic oscillations, and Type Ia supernovae) prefer the scale factor
of the phase transition to be very large, peaking at , and
therefore supporting a cosmological scenario in which neutrinos are almost
massless until very recent times. We find that in this scenario the
cosmological bound on the total sum of the neutrino masses today is
significantly weakened compared to the standard case of constant-mass
neutrinos, with ~eV at 95\% confidence, and in agreement with
the model predictions. The main reason for this weaker bound is a large
correlation arising between the dark energy and neutrino components in the
presence of false vacuum energy that converts into the non-zero neutrino masses
after the transition. This result provides new targets for the coming KATRIN
and PTOLEMY experiments. We also show that the time-varying neutrino mass model
considered here does not provide a clear explanation to the existing
cosmological - discrepancies.Comment: 13 pages, 13 figures, matches updated version accepted by Physical
Review
Symbolic Implementation of Extensions of the Boltzmann Solver
is a Python-based framework for the fast computation of
cosmological model predictions. One of its core features is the symbolic
representation of the Einstein-Boltzmann system of equations. Efficient
code is generated from the symbolic
expressions making use of the package. This enables easy
extensions of the equation system for the implementation of new cosmological
models. We illustrate this with three extensions of the
Boltzmann solver to include a dark energy component with a constant equation of
state, massive neutrinos and a radiation streaming approximation. We describe
the framework, highlighting new features, and the symbolic
implementation of the new models. We compare the predictions
for the CDM model extensions with , both in terms of
accuracy and computational speed. We find a good agreement, to better than 0.1%
when using high-precision settings and a comparable computational speed. Links
to the Python Package Index (PyPI) page of the code release and to the PyCosmo
Hub, an online platform where the package is installed, are available at:
https://cosmology.ethz.ch/research/software-lab/PyCosmo.html.Comment: 35 pages including 5 figures and 3 tables. Link to
package: https://cosmology.ethz.ch/research/software-lab/PyCosmo.htm
Development and internal validation of prognostic models to predict negative health outcomes in older patients with multimorbidity and polypharmacy in general practice
Background Polypharmacy interventions are resource-intensive and should be targeted to those at risk of negative health outcomes. Our aim was to develop and internally validate prognostic models to predict health-related quality of life (HRQoL) and the combined outcome of falls, hospitalisation, institutionalisation and nursing care needs, in older patients with multimorbidity and polypharmacy in general practices. Methods Design: two independent data sets, one comprising health insurance claims data (n=592 456), the other data from the PRIoritising MUltimedication in Multimorbidity (PRIMUM) cluster randomised controlled trial (n=502). Population: >= 60 years, >= 5 drugs, >= 3 chronic diseases, excluding dementia. Outcomes: combined outcome of falls, hospitalisation, institutionalisation and nursing care needs (after 6, 9 and 24 months) (claims data); and HRQoL (after 6 and 9 months) (trial data). Predictor variables in both data sets: age, sex, morbidity-related variables (disease count), medication-related variables (European Union-Potentially Inappropriate Medication list (EU-PIM list)) and health service utilisation. Predictor variables exclusively in trial data: additional socio-demographics, morbidity-related variables (Cumulative Illness Rating Scale, depression), Medication Appropriateness Index (MAI), lifestyle, functional status and HRQoL (EuroQol EQ-5D-3L). Analysis: mixed regression models, combined with stepwise variable selection, 10-fold cross validation and sensitivity analyses. Results Most important predictors of EQ-5D-3L at 6 months in best model (Nagelkerke's R-2 0.507) were depressive symptoms (-2.73 (95% CI: -3.56 to -1.91)), MAI (-0.39 (95% CI: -0.7 to -0.08)), baseline EQ-5D-3L (0.55 (95% CI: 0.47 to 0.64)). Models based on claims data and those predicting long-term outcomes based on both data sets produced low R-2 values. In claims data-based model with highest explanatory power (R-2=0.16), previous falls/fall-related injuries, previous hospitalisations, age, number of involved physicians and disease count were most important predictor variables. Conclusions Best trial data-based model predicted HRQoL after 6 months well and included parameters of well-being not found in claims. Performance of claims data-based models and models predicting long-term outcomes was relatively weak. For generalisability, future studies should refit models by considering parameters representing well-being and functional status
A comprehensive microarray-based DNA methylation study of 367 hematological neoplasms
Background: Alterations in the DNA methylation pattern are a hallmark of leukemias and lymphomas. However, most epigenetic studies in hematologic neoplasms (HNs) have focused either on the analysis of few candidate genes or many genes and few HN entities, and comprehensive studies are required. Methodology/Principal Findings: Here, we report for the first time a microarray-based DNA methylation study of 767 genes in 367 HNs diagnosed with 16 of the most representative B-cell (n = 203), T-cell (n = 30), and myeloid (n = 134) neoplasias, as well as 37 samples from different cell types of the hematopoietic system. Using appropriate controls of B-, T-, or myeloid cellular origin, we identified a total of 220 genes hypermethylated in at least one HN entity. In general, promoter hypermethylation was more frequent in lymphoid malignancies than in myeloid malignancies, being germinal center mature B-cell lymphomas as well as B and T precursor lymphoid neoplasias those entities with highest frequency of gene-associated DNA hypermethylation. We also observed a significant correlation between the number of hypermethylated and hypomethylated genes in several mature B-cell neoplasias, but not in precursor B- and T-cell leukemias. Most of the genes becoming hypermethylated contained promoters with high CpG content, and a significant fraction of them are targets of the polycomb repressor complex. Interestingly, T-cell prolymphocytic leukemias show low levels of DNA hypermethylation and a comparatively large number of hypomethylated genes, many of them showing an increased gene expression. Conclusions/Significance: We have characterized the DNA methylation profile of a wide range of different HNs entities. As well as identifying genes showing aberrant DNA methylation in certain HN subtypes, we also detected six genes—DBC1, DIO3, FZD9, HS3ST2, MOS, and MYOD1—that were significantly hypermethylated in B-cell, T-cell, and myeloid malignancies. These might therefore play an important role in the development of different HNs
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CNP Promotes Antiarrhythmic Effects via Phosphodiesterase 2
Background: Ventricular arrhythmia and sudden cardiac death are the most common lethal complications after myocardial infarction. Antiarrhythmic pharmacotherapy remains a clinical challenge and novel concepts are highly desired. Here, we focus on the cardioprotective CNP (C-type natriuretic peptide) as a novel antiarrhythmic principle. We hypothesize that antiarrhythmic effects of CNP are mediated by PDE2 (phosphodiesterase 2), which has the unique property to be stimulated by cGMP to primarily hydrolyze cAMP. Thus, CNP might promote beneficial effects of PDE2-mediated negative crosstalk between cAMP and cGMP signaling pathways. Methods: To determine antiarrhythmic effects of cGMP-mediated PDE2 stimulation by CNP, we analyzed arrhythmic events and intracellular trigger mechanisms in mice in vivo, at organ level and in isolated cardiomyocytes as well as in human-induced pluripotent stem cell-derived cardiomyocytes. Results: In ex vivo perfused mouse hearts, CNP abrogated arrhythmia after ischemia/reperfusion injury. Upon high-dose catecholamine injections in mice, PDE2 inhibition prevented the antiarrhythmic effect of CNP. In mouse ventricular cardiomyocytes, CNP blunted the catecholamine-mediated increase in arrhythmogenic events as well as in ICaL, INaL, and Ca2+spark frequency. Mechanistically, this was driven by reduced cellular cAMP levels and decreased phosphorylation of Ca2+handling proteins. Key experiments were confirmed in human iPSC-derived cardiomyocytes. Accordingly, the protective CNP effects were reversed by either specific pharmacological PDE2 inhibition or cardiomyocyte-specific PDE2 deletion. Conclusions: CNP shows strong PDE2-dependent antiarrhythmic effects. Consequently, the CNP-PDE2 axis represents a novel and attractive target for future antiarrhythmic strategies
Genetic Evidence of Serum Phosphate-Independent Functions of FGF-23 on Bone
Maintenance of physiologic phosphate balance is of crucial biological importance, as it is fundamental to cellular function, energy metabolism, and skeletal mineralization. Fibroblast growth factor-23 (FGF-23) is a master regulator of phosphate homeostasis, but the molecular mechanism of such regulation is not yet completely understood. Targeted disruption of the Fgf-23 gene in mice (Fgf-23−/−) elicits hyperphosphatemia, and an increase in renal sodium/phosphate co-transporter 2a (NaPi2a) protein abundance. To elucidate the pathophysiological role of augmented renal proximal tubular expression of NaPi2a in Fgf-23−/− mice and to examine serum phosphate–independent functions of Fgf23 in bone, we generated a new mouse line deficient in both Fgf-23 and NaPi2a genes, and determined the effect of genomic ablation of NaPi2a from Fgf-23−/− mice on phosphate homeostasis and skeletal mineralization. Fgf-23−/−/NaPi2a−/− double mutant mice are viable and exhibit normal physical activities when compared to Fgf-23−/− animals. Biochemical analyses show that ablation of NaPi2a from Fgf-23−/− mice reversed hyperphosphatemia to hypophosphatemia by 6 weeks of age. Surprisingly, despite the complete reversal of serum phosphate levels in Fgf-23−/−/NaPi2a−/−, their skeletal phenotype still resembles the one of Fgf23−/− animals. The results of this study provide the first genetic evidence of an in vivo pathologic role of NaPi2a in regulating abnormal phosphate homeostasis in Fgf-23−/− mice by deletion of both NaPi2a and Fgf-23 genes in the same animal. The persistence of the skeletal anomalies in double mutants suggests that Fgf-23 affects bone mineralization independently of systemic phosphate homeostasis. Finally, our data support (1) that regulation of phosphate homeostasis is a systemic effect of Fgf-23, while (2) skeletal mineralization and chondrocyte differentiation appear to be effects of Fgf-23 that are independent of phosphate homeostasis
Long-Lived Plasma Cells and Memory B Cells Produce Pathogenic Anti-GAD65 Autoantibodies in Stiff Person Syndrome
Stiff person syndrome (SPS) is a rare, neurological disorder characterized by sudden cramps and spasms. High titers of enzyme-inhibiting IgG autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GAD65) are a hallmark of SPS, implicating an autoimmune component in the pathology of the syndrome. Studying the B cell compartment and the anti-GAD65 B cell response in two monozygotic twins suffering from SPS, who were treated with the B cell-depleting monoclonal anti-CD20 antibody rituximab, we found that the humoral autoimmune response in SPS is composed of a rituximab-sensitive part that is rapidly cleared after treatment, and a rituximab-resistant component, which persists and acts as a reservoir for autoantibodies inhibiting GAD65 enzyme activity. Our data show that these potentially pathogenic anti-GAD65 autoantibodies are secreted by long-lived plasma cells, which may either be persistent or develop from rituximab-resistant memory B lymphocytes. Both subsets represent only a fraction of anti-GAD65 autoantibody secreting cells. Therefore, the identification and targeting of this compartment is a key factor for successful treatment planning of SPS and of similar autoimmune diseases
Simulating rewetting events in intermittent rivers and ephemeral streams: A global analysis of leached nutrients and organic matter
Climate change and human pressures are changing the global distribution and the ex‐
tent of intermittent rivers and ephemeral streams (IRES), which comprise half of the
global river network area. IRES are characterized by periods of flow cessation, during
which channel substrates accumulate and undergo physico‐chemical changes (precon‐
ditioning), and periods of flow resumption, when these substrates are rewetted and
release pulses of dissolved nutrients and organic matter (OM). However, there are no
estimates of the amounts and quality of leached substances, nor is there information
on the underlying environmental constraints operating at the global scale. We experi‐
mentally simulated, under standard laboratory conditions, rewetting of leaves, river‐
bed sediments, and epilithic biofilms collected during the dry phase across 205 IRES
from five major climate zones. We determined the amounts and qualitative character‐
istics of the leached nutrients and OM, and estimated their areal fluxes from riverbeds.
In addition, we evaluated the variance in leachate characteristics in relation to selected
environmental variables and substrate characteristics. We found that sediments, due
to their large quantities within riverbeds, contribute most to the overall flux of dis‐
solved substances during rewetting events (56%–98%), and that flux rates distinctly
differ among climate zones. Dissolved organic carbon, phenolics, and nitrate contrib‐
uted most to the areal fluxes. The largest amounts of leached substances were found
in the continental climate zone, coinciding with the lowest potential bioavailability of
the leached OM. The opposite pattern was found in the arid zone. Environmental vari‐
ables expected to be modified under climate change (i.e. potential evapotranspiration,
aridity, dry period duration, land use) were correlated with the amount of leached sub‐
stances, with the strongest relationship found for sediments. These results show that
the role of IRES should be accounted for in global biogeochemical cycles, especially
because prevalence of IRES will increase due to increasing severity of drying event
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