Genetic robustness, or the ability of an organism to maintain fitness in the presence of harmful mutations, can be achieved via protein feedback loops. Previous work has suggested that organisms may ...also respond to mutations by transcriptional adaptation, a process by which related gene(s) are upregulated independently of protein feedback loops. However, the prevalence of transcriptional adaptation and its underlying molecular mechanisms are unknown. Here, by analysing several models of transcriptional adaptation in zebrafish and mouse, we uncover a requirement for mutant mRNA degradation. Alleles that fail to transcribe the mutated gene do not exhibit transcriptional adaptation, and these alleles give rise to more severe phenotypes than alleles displaying mutant mRNA decay. Transcriptome analysis in alleles displaying mutant mRNA decay reveals the upregulation of a substantial proportion of the genes that exhibit sequence similarity with the mutated gene's mRNA, suggesting a sequence-dependent mechanism. These findings have implications for our understanding of disease-causing mutations, and will help in the design of mutant alleles with minimal transcriptional adaptation-derived compensation.
Heliospheric modulation conditions were unusually quiet during the last solar minimum activity between solar cycles 23 and 24. Fortunately, the PAMELA space experiment measured 6 month-averaged ...Galactic positron spectra for the period 2006 July to 2009 December over an energy range of 80 MeV to 30 GeV, which is important for solar modulation. The highest level of Galactic positrons was observed at Earth during the 2009 July-December period. A well-established, comprehensive three-dimensional (3D) numerical model is applied to study the modulation of the observed positron spectra. This model had been used previously to understand the modulation of Galactic protons and electrons also measured by PAMELA for the same period. First, a new, very local interstellar spectrum for positrons is constructed using the well-known GALPROP code, together with the mentioned PAMELA observations. The 3D model is used to distinguish between the dominant mechanisms responsible for the heliospheric modulation of Galactic positrons and understand the effect of particle drift during this unusual minimum in particular, which is considered diffusion-dominant, even though particle drift still had a significant role in modulating positrons. Lastly, the expected intensity of Galactic positrons during an A > 0 polarity minimum, with similar heliospheric conditions than for 2006-2009, is predicted to be higher than what was observed by PAMELA for the 2006-2009 unusual minimum.
Abstract
Simultaneous and continuous observations of galactic cosmic-ray electrons (
e
−
) and positrons (
e
+
) from the PAMELA and AMS02 space experiments are most suitable for numerical modeling ...studies of the heliospheric modulation of these particles below 50 GeV. A well-established comprehensive three-dimensional modulation model is applied to compute full spectra for
e
−
and
e
+
with the purpose of reproducing the observed ratio
e
+
/
e
−
for a period that covers the previous long and unusual deep solar minimum activity and the recent maximum activity phase, including the polarity reversal of the solar magnetic field. For this purpose, the very local interstellar spectra for these particles were established first. Our study is focused on how the main modulation processes, including particle drifts, and other parameters, such as the three major diffusion coefficients, evolved and how the corresponding charge-sign dependent modulation subsequently occurred. The end result of our effort is the detailed reproduction of
e
+
/
e
−
from 2006 to 2015, displaying both qualitative and quantitative agreement with the main observed features. Particularly, we determine how much particle drift is needed to explain the time dependence exhibited by the observed
e
+
/
e
−
during each solar activity phase, especially during the polarity reversal phase, when no well-defined magnetic polarity was found.
Precision measurements of the positron component in the cosmic radiation provide important information about the propagation of cosmic rays and the nature of particle sources in our Galaxy. The ...satellite-borne experiment PAMELA has been used to make a new measurement of the cosmic-ray positron flux and fraction that extends previously published measurements up to 300 GeV in kinetic energy. The combined measurements of the cosmic-ray positron energy spectrum and fraction provide a unique tool to constrain interpretation models. During the recent solar minimum activity period from July 2006 to December 2009, approximately 24,500 positrons were observed. The results cannot be easily reconciled with purely secondary production, and additional sources of either astrophysical or exotic origin may be required.
The epicardium, the outermost layer of the heart, is an important regulator of cardiac regeneration. However, a detailed understanding of the crosstalk between the epicardium and myocardium during ...development requires further investigation. Here, we generated three models of epicardial impairment in zebrafish by mutating the transcription factor genes tcf21 and wt1a, and ablating tcf21+ epicardial cells. Notably, all three epicardial impairment models exhibited smaller ventricles. We identified the initial cause of this phenotype as defective cardiomyocyte growth, resulting in reduced cell surface and volume. This failure of cardiomyocyte growth was followed by decreased proliferation and increased abluminal extrusion. By temporally manipulating its ablation, we show that the epicardium is required to support cardiomyocyte growth mainly during early cardiac morphogenesis. By transcriptomic profiling of sorted epicardial cells, we identified reduced expression of FGF and VEGF ligand genes in tcf21-/- hearts, and pharmacological inhibition of these signaling pathways in wild type partially recapitulated the ventricular growth defects. Taken together, these data reveal distinct roles of the epicardium during cardiac morphogenesis and signaling pathways underlying epicardial-myocardial crosstalk.
The last solar minimum activity period, and the consequent minimum modulation conditions for cosmic rays, was unusual. The highest levels of galactic protons were recorded at Earth in late 2009 in ...contrast to expectations. Proton spectra observed for 2006 to 2009 from the PAMELA cosmic ray detector on-board the
Resurs-DK1
satellite are presented together with the solutions of a comprehensive numerical model for the solar modulation of cosmic rays. The model is used to determine what mechanisms were mainly responsible for the modulation of protons during this period, and why the observed spectrum for 2009 was the highest ever recorded. From mid-2006 until December 2009 we find that the spectra became significantly softer because increasingly more low energy protons had reached Earth. To simulate this effect, the rigidity dependence of the diffusion coefficients had to decrease significantly below ∼ 3 GeV. The modulation minimum period of 2009 can thus be described as relatively more ‘diffusion dominated’ than previous solar minima. However, we illustrate that drifts still had played a significant role but that the observable modulation effects were not as well correlated with the waviness of the heliospheric current sheet as before. Protons still experienced global gradient and curvature drifts as the heliospheric magnetic field had decreased significantly until the end of 2009, in contrast to the moderate decreases observed during previous minimum periods. We conclude that all modulation processes contributed to the observed increases in the proton spectra for this period, exhibiting an intriguing interplay of these major mechanisms.
The energy spectra of galactic cosmic rays carry fundamental information regarding their origin and propagation. These spectra, when measured near Earth, are significantly affected by the solar ...magnetic field. A comprehensive description of the cosmic radiation must therefore include the transport and modulation of cosmic rays inside the heliosphere. During the end of the last decade, the Sun underwent a peculiarly long quiet phase well suited to study modulation processes. In this paper we present proton spectra measured from 2006 July to 2009 December by PAMEFA. The large collected statistics of protons allowed the time variation to be followed on a nearly monthly basis down to 400 MV. Data are compared with a state-of-the-art three-dimensional model of solar modulation.
The propagation of cosmic rays inside our galaxy plays a fundamental role in shaping their injection spectra into those observed at Earth. One of the best tools to investigate this issue is the ratio ...of fluxes for secondary and primary species. The boron-to-carbon (B/C) ratio, in particular, is a sensitive probe to investigate propagation mechanisms. This paper presents new measurements of the absolute fluxes of boron and carbon nuclei as well as the B/C ratio from the PAMELA space experiment. The results span the range 0.44-129 GeV/n in kinetic energy for data taken in the period 2006 July to 2008 March.
The satellite-borne experiment PAMELA has been used to make a new measurement of the cosmic-ray antiproton flux and the antiproton-to-proton flux ratio which extends previously published measurements ...down to 60 MeV and up to 180 GeV in kinetic energy. During 850 days of data acquisition approximately 1500 antiprotons were observed. The measurements are consistent with purely secondary production of antiprotons in the Galaxy. More precise secondary production models are required for a complete interpretation of the results.
The global features of the modulation of galactic cosmic ray protons and helium nuclei in a very quiet heliosphere are studied with a comprehensive, three-dimensional, drift model and compared to ...proton and helium observations measured by PAMELA from 2006 to 2009. Combined with accurate very local interstellar spectra (VLIS) for protons and helium nuclei, this provides the opportunity to study in detail how differently cosmic ray species with dissimilar mass-to-charge ratio (
A
/
Z
) are modulated down to a few GV. The effects at Earth of the difference in their VLIS’s and those caused by the main modulation mechanisms are illustrated. We find that both the PAMELA proton and helium spectra are reproduced well with the numerical model, assuming the same set of modulation parameters and diffusion coefficients. A comparative study of
3
He
2
(He-3) and
4
He
2
(He-4) modulated spectra reveals that they do not undergo identical spectral changes below 3 GV mainly due to differences in their VLIS’s. This result is important to uncover and investigate the effects on the proton to total helium ratio (
p
/He) caused by the difference in their VLIS’s and those by
A
/
Z
. The computed
p
/He displays three modulation regimes, reflecting the complex interplay of modulation processes in the heliosphere. At rigidities above ∼3 GV, the
p
/He ratio at the Earth is found to deviate modestly from a value of ∼5.5, largely independent of the assumed modulation conditions. This result indicates that the PAMELA measurement of
p
/He reveals at these rigidities the shapes of their VLIS’s. Below ∼0.6 GV,
p
/He increases with decreasing rigidity from 2006 to 2009 and significant variations are predicted depending on the assumed solar modulation conditions. This result indicates that as modulation levels decreased from 2006 to 2009, the contribution of adiabatic energy changes dissipated faster for protons than for helium nuclei at the same rigidity mainly due to different slopes of their VLIS’s. The differences between modulation effects for protons and helium are found to be the consequence of how the combined interplaying modulation mechanisms in the heliosphere affect the modulated spectra based on their
A
/
Z
and particularly on their VLIS’s.
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