Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of ...the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic human liver. We identify a scar-associated TREM2
CD9
subpopulation of macrophages, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define ACKR1
and PLVAP
endothelial cells that expand in cirrhosis, are topographically restricted to the fibrotic niche and enhance the transmigration of leucocytes. Multi-lineage modelling of ligand and receptor interactions between the scar-associated macrophages, endothelial cells and PDGFRα
collagen-producing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis.
Vegetation affects precipitation patterns by mediating moisture, energy and trace-gas fluxes between the surface and atmosphere. When forests are replaced by pasture or crops, evapotranspiration of ...moisture from soil and vegetation is often diminished, leading to reduced atmospheric humidity and potentially suppressing precipitation. Climate models predict that large-scale tropical deforestation causes reduced regional precipitation, although the magnitude of the effect is model and resolution dependent. In contrast, observational studies have linked deforestation to increased precipitation locally but have been unable to explore the impact of large-scale deforestation. Here we use satellite remote-sensing data of tropical precipitation and vegetation, combined with simulated atmospheric transport patterns, to assess the pan-tropical effect of forests on tropical rainfall. We find that for more than 60 per cent of the tropical land surface (latitudes 30 degrees south to 30 degrees north), air that has passed over extensive vegetation in the preceding few days produces at least twice as much rain as air that has passed over little vegetation. We demonstrate that this empirical correlation is consistent with evapotranspiration maintaining atmospheric moisture in air that passes over extensive vegetation. We combine these empirical relationships with current trends of Amazonian deforestation to estimate reductions of 12 and 21 per cent in wet-season and dry-season precipitation respectively across the Amazon basin by 2050, due to less-efficient moisture recycling. Our observation-based results complement similar estimates from climate models, in which the physical mechanisms and feedbacks at work could be explored in more detail.
Observations indicate that nearly all galaxies contain supermassive black holes at their centers. When galaxies merge, their component black holes form SMBH binaries (SMBHBs), which emit ...low-frequency gravitational waves (GWs) that can be detected by pulsar timing arrays. We have searched the North American Nanohertz Observatory for Gravitational Waves 11 yr data set for GWs from individual SMBHBs in circular orbits. As we did not find strong evidence for GWs in our data, we placed 95% upper limits on the strength of GWs from such sources. At = 8 nHz, we placed a sky-averaged upper limit of h0 < 7.3(3) × 10−15. We also developed a technique to determine the significance of a particular signal in each pulsar using "dropout" parameters as a way of identifying spurious signals. From these upper limits, we ruled out SMBHBs emitting GWs with = 8 nHz within 120 Mpc for , and within 5.5 Gpc for at our most sensitive sky location. We also determined that there are no SMBHBs with emitting GWs with = 2.8-317.8 nHz in the Virgo Cluster. Finally, we compared our strain upper limits to simulated populations of SMBHBs, based on galaxies in the Two Micron All-Sky Survey and merger rates from the Illustris cosmological simulation project, and found that only 34 out of 75,000 realizations of the local universe contained a detectable source.
The regularity of pulsar emissions becomes apparent once we reference the pulses' times of arrivals to the inertial rest frame of the solar system. It follows that errors in the determination of ...Earth's position with respect to the solar system barycenter can appear as a time-correlated bias in pulsar-timing residual time series, affecting the searches for low-frequency gravitational waves performed with pulsar-timing arrays. Indeed, recent array data sets yield different gravitational-wave background upper limits and detection statistics when analyzed with different solar system ephemerides. Crucially, the ephemerides do not generally provide usable error representations. In this article, we describe the motivation, construction, and application of a physical model of solar system ephemeris uncertainties, which focuses on the degrees of freedom (Jupiter's orbital elements) most relevant to gravitational-wave searches with pulsar-timing arrays. This model, BayesEphem, was used to derive ephemeris-robust results in NANOGrav's 11 yr stochastic-background search, and it provides a foundation for future searches by NANOGrav and other consortia. The analysis and simulations reported here suggest that ephemeris modeling reduces the gravitational-wave sensitivity of the 11 yr data set and that this degeneracy will vanish with improved ephemerides and with pulsar-timing data sets that extend well beyond a single Jovian orbital period.
The development of widely accessible, effective psychological interventions for depression is a priority. This randomized trial provides the first controlled data on an innovative cognitive bias ...modification (CBM) training guided self-help intervention for depression.
One hundred and twenty-one consecutively recruited participants meeting criteria for current major depression were randomly allocated to treatment as usual (TAU) or to TAU plus concreteness training (CNT) guided self-help or to TAU plus relaxation training (RT) guided self-help. CNT involved repeated practice at mental exercises designed to switch patients from an unhelpful abstract thinking habit to a helpful concrete thinking habit, thereby targeting depressogenic cognitive processes (rumination, overgeneralization).
The addition of CNT to TAU significantly improved depressive symptoms at post-treatment mean difference on the Hamilton Rating Scale for Depression (HAMD) 4.28, 95% confidence interval (CI) 1.29-7.26, 3- and 6-month follow-ups, and for rumination and overgeneralization post-treatment. There was no difference in the reduction of symptoms between CNT and RT (mean difference on the HAMD 1.98, 95% CI -1.14 to 5.11), although CNT significantly reduced rumination and overgeneralization relative to RT post-treatment, suggesting a specific benefit on these cognitive processes.
This study provides preliminary evidence that CNT guided self-help may be a useful addition to TAU in treating major depression in primary care, although the effect was not significantly different from an existing active treatment (RT) matched for structural and common factors. Because of its relative brevity and distinct format, it may have value as an additional innovative approach to increase the accessibility of treatment choices for depression.
We report on the high-precision timing of 42 radio millisecond pulsars (MSPs) observed by the European Pulsar Timing Array (EPTA). This EPTA Data Release 1.0 extends up to mid-2014 and baselines ...range from 7–18 yr. It forms the basis for the stochastic gravitational-wave background, anisotropic background, and continuous-wave limits recently presented by the EPTA elsewhere. The Bayesian timing analysis performed with temponest
yields the detection of several new parameters: seven parallaxes, nine proper motions and, in the case of six binary pulsars, an apparent change of the semimajor axis. We find the NE2001 Galactic electron density model to be a better match to our parallax distances (after correction from the Lutz–Kelker bias) than the M2 and M3 models by Schnitzeler. However, we measure an average uncertainty of 80 per cent (fractional) for NE2001, three times larger than what is typically assumed in the literature. We revisit the transverse velocity distribution for a set of 19 isolated and 57 binary MSPs and find no statistical difference between these two populations. We detect Shapiro delay in the timing residuals of PSRs J1600−3053 and J1918−0642, implying pulsar and companion masses
$m_{\rm p}=1.22_{-0.35}^{+0.5}\ {\rm M}_{{\odot }}$
,
$m_{\rm c} = 0.21_{-0.04}^{+0.06}\ {\rm M}_{{\odot } }$
and
$m_{\rm p}=1.25_{-0.4}^{+0.6}\ {\rm M}_{{\odot }}$
,
$m_{\rm c} = 0.23_{-0.05}^{+0.07}\ {\rm M}_{{\odot } }$
, respectively. Finally, we use the measurement of the orbital period derivative to set a stringent constraint on the distance to PSRs J1012+5307 and J1909−3744, and set limits on the longitude of ascending node through the search of the annual-orbital parallax for PSRs J1600−3053 and J1909−3744.
ABSTRACT
We searched for an isotropic stochastic gravitational wave background in the second data release of the International Pulsar Timing Array, a global collaboration synthesizing decadal-length ...pulsar-timing campaigns in North America, Europe, and Australia. In our reference search for a power-law strain spectrum of the form $h_c = A(f/1\, \mathrm{yr}^{-1})^{\alpha }$, we found strong evidence for a spectrally similar low-frequency stochastic process of amplitude $A = 3.8^{+6.3}_{-2.5}\times 10^{-15}$ and spectral index α = −0.5 ± 0.5, where the uncertainties represent 95 per cent credible regions, using information from the auto- and cross-correlation terms between the pulsars in the array. For a spectral index of α = −2/3, as expected from a population of inspiralling supermassive black hole binaries, the recovered amplitude is $A = 2.8^{+1.2}_{-0.8}\times 10^{-15}$. None the less, no significant evidence of the Hellings–Downs correlations that would indicate a gravitational-wave origin was found. We also analysed the constituent data from the individual pulsar timing arrays in a consistent way, and clearly demonstrate that the combined international data set is more sensitive. Furthermore, we demonstrate that this combined data set produces comparable constraints to recent single-array data sets which have more data than the constituent parts of the combination. Future international data releases will deliver increased sensitivity to gravitational wave radiation, and significantly increase the detection probability.
During biological invasions, multiple introductions can provide opportunities for admixture among genetically distinct lineages. Admixture is predicted to contribute to invasion success by directly ...increasing fitness through hybrid vigour or by enhancing evolutionary potential within populations. Here, we demonstrate genome-wide admixture during an invasion that substantially boosted fitness in the cosmopolitan weed, Silene vulgaris. We identified three divergent demes in the native European range that expanded from glacial refugia and experienced historical admixture in a well-known suture zone. During recent invasion of North America, multiple introductions created additional opportunities for admixture. In common garden experiments, recombinant genotypes from North America experienced a two-fold increase in fitness relative to nonrecombinants, whereas recombinant genotypes from Europe showed no lasting fitness benefits. This contrast implicates hybrid vigour behind the boost in fitness and supports the hypothesis that admixture can lead to fitness increases that may catapult invasion into a new range.
We present two methods for determining the significance of a stochastic gravitational-wave (GW) background affecting a pulsar-timing array, where detection is based on evidence for quadrupolar ...spatial correlations between pulsars. Rather than constructing noise simulations, we eliminate the GWB spatial correlations in the true data sets to assess detection significance with all real data features intact. In our first method, we perform random phase shifts in the signal-model basis functions. This phase shifting eliminates signal phase coherence between pulsars, while keeping the statistical properties of the pulsar timing residuals intact. We then explore a method to null correlations between pulsars by using a “scrambled” overlap-reduction function in the signal model for the array. This scrambled function is orthogonal to what we expect of a real GW background signal. We demonstrate the efficacy of these methods using Bayesian model selection on a set of simulated data sets that contain a stochastic GW signal, timing noise, undiagnosed glitches, and uncertainties in the Solar system ephemeris. Finally, we introduce an overarching formalism under which these two techniques are naturally linked. These methods are immediately applicable to all current pulsar-timing array data sets, and should become standard tools for future analyses.
We search for an isotropic stochastic gravitational-wave background (GWB) in the newly released 11 year data set from the North American Nanohertz Observatory for Gravitational Waves (NANOGrav). ...While we find no evidence for a GWB, we place constraints on a population of inspiraling supermassive black hole (SMBH) binaries, a network of decaying cosmic strings, and a primordial GWB. For the first time, we find that the GWB constraints are sensitive to the solar system ephemeris (SSE) model used and that SSE errors can mimic a GWB signal. We developed an approach that bridges systematic SSE differences, producing the first pulsar-timing array (PTA) constraints that are robust against SSE errors. We thus place a 95% upper limit on the GW-strain amplitude of AGWB < 1.45 × 10−15 at a frequency of f = 1 yr−1 for a fiducial f−2/3 power-law spectrum and with interpulsar correlations modeled. This is a factor of ∼2 improvement over the NANOGrav nine-year limit calculated using the same procedure. Previous PTA upper limits on the GWB (as well as their astrophysical and cosmological interpretations) will need revision in light of SSE systematic errors. We use our constraints to characterize the combined influence on the GWB of the stellar mass density in galactic cores, the eccentricity of SMBH binaries, and SMBH-galactic-bulge scaling relationships. We constrain the cosmic-string tension using recent simulations, yielding an SSE-marginalized 95% upper limit of G < 5.3 × 10−11-a factor of ∼2 better than the published NANOGrav nine-year constraints. Our SSE-marginalized 95% upper limit on the energy density of a primordial GWB (for a radiation-dominated post-inflation universe) is GWB(f) h2 < 3.4 × 10−10.
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