Giardia Colonizes and Encysts in High-Density Foci in the Murine Small Intestine.

Giardia lamblia is a highly prevalent yet understudied protistan parasite causing significant diarrheal disease worldwide. Hosts ingest Giardia cysts from contaminated sources. In the gastrointestinal tract, cysts excyst to become motile trophozoites, colonizing and attaching to the gut epithelium. Trophozoites later differentiate into infectious cysts that are excreted and contaminate the environment. Due to the limited accessibility of the gut, the temporospatial dynamics of giardiasis in the host are largely inferred from laboratory culture and thus may not mirror Giardia physiology in the host. Here, we have developed bioluminescent imaging (BLI) to directly interrogate and quantify the in vivo temporospatial dynamics of Giardia infection, thereby providing an improved murine model to evaluate anti-Giardia drugs. Using BLI, we determined that parasites primarily colonize the proximal small intestine nonuniformly in high-density foci. By imaging encystation-specific bioreporters, we show that encystation initiates shortly after inoculation and continues throughout the duration of infection. Encystation also initiates in high-density foci in the proximal small intestine, and high density contributes to the initiation of encystation in laboratory culture. We suggest that these high-density in vivo foci of colonizing and encysting Giardia likely result in localized disruption to the epithelium. This more accurate visualization of giardiasis redefines the dynamics of the in vivo Giardia life cycle, paving the way for future mechanistic studies of density-dependent parasitic processes in the host. IMPORTANCEGiardia is a single-celled parasite causing significant diarrheal disease in several hundred million people worldwide. Due to limited access to the site of infection in the gastrointestinal tract, our understanding of the dynamics of Giardia infections in the host has remained limited and largely inferred from laboratory culture. To better understand Giardia physiology and colonization in the host, we developed imaging methods to quantify Giardia expressing bioluminescent physiological reporters in two relevant animal models. We discovered that parasites primarily colonize and encyst in the proximal small intestine in discrete, high-density foci. We also show that high parasite density contributes to encystation initiation

The BAHAMAS project: Effects of a running scalar spectral index on large-scale structure

Recent analyses of the cosmic microwave background (CMB) and the Lyman-alpha forest indicate a mild preference for a deviation from a power law primordial matter power spectrum (a so-called negative `running'). We use an extension to the BAHAMAS suite of cosmological hydrodynamic simulations to explore the effects that a running scalar spectral index has on large-scale structure (LSS), using Planck CMB constraints to initialize the simulations. We focus on 5 key statistics: i) the non-linear matter power spectrum ii) the halo mass function; iii) the halo two-point auto correlation function; iv) total mass halo density profiles; and v) the halo concentration-mass relation. In terms of the matter power spectrum, we find that a running scalar spectral index affects all k-scales examined in this study, with a negative (positive) running leading to an amplification (suppression) of power. These effects should be easily detectable with upcoming surveys such as LSST and Euclid. In the mass range sampled, a positive running leads to an increase in the mass of galaxy groups and clusters, with the favoured negative running leading to a decrease in mass of lower-mass (M ~ 10^13 M_solar) halos. Changes in the mass are generally confined to 5-10% which, while not insignificant, cannot by itself reconcile the claimed tension between the primary CMB and cluster number counts. We find that running does not significantly affect the shapes of density profiles of matched halos, changing only their amplitude. Finally, we demonstrate that the observed effects on LSS due to a running scalar spectral index are separable from those of baryonic effects to typically a few percent precision

The BAHAMAS project: Effects of dynamical dark energy on large-scale structure

In this work we consider the impact of spatially-uniform but time-varying dark energy (or `dynamical dark energy', DDE) on large-scale structure in a spatially flat universe, using large cosmological hydrodynamical simulations that form part of the BAHAMAS project. As DDE changes the expansion history of the universe, it impacts the growth of structure. We explore variations in DDE that are constrained to be consistent with the cosmic microwave background. We find that DDE can affect the clustering of matter and haloes at the ~10% level (suppressing it for so-called `freezing' models, while enhancing it for `thawing' models), which should be distinguishable with upcoming large-scale structure surveys. DDE cosmologies can also enhance or suppress the halo mass function (with respect to LCDM) over a wide range of halo masses. The internal properties of haloes are minimally affected by changes in DDE, however. Finally, we show that the impact of baryons and associated feedback processes is largely independent of the change in cosmology and that these processes can be modelled separately to typically better than a few percent accurac

Quenching of satellite galaxies of Milky Way analogues: reconciling theory and observations

The vast majority of low-mass satellite galaxies around the Milky Way and M31 appear virtually devoid of cool gas and show no signs of recent or ongoing star formation. Cosmological simulations demonstrate that such quenching is expected and is due to the harsh environmental conditions that satellites face when joining the Local Group (LG). However, recent observations of Milky Way analogues in the SAGA survey present a very different picture, showing the majority of observed satellites to be actively forming stars, calling into question the realism of current simulations and the typicality of the LG. Here we use the ARTEMIS suite of high-resolution cosmological hydrodynamical simulations to carry out a careful comparison with observations of dwarf satellites in the LG, SAGA, and the Local Volume (LV) survey. We show that differences between SAGA and the LG and LV surveys, as well as between SAGA and the ARTEMIS simulations, can be strongly reduced by considering differences in the host mass distributions and (more importantly) observational selection effects, specifically that low-mass satellites which have only recently been accreted are more likely to be star-forming, have a higher optical surface brightness, and are therefore more likely to be included in the SAGA survey. This picture is confirmed using data from the deeper LV survey, which shows pronounced quenching at low masses, in accordance with the predictions of LCDM-based simulations

The halo bispectrum as a sensitive probe of massive neutrinos an baryon physics

The power spectrum has been a workhorse for cosmological studies of large-scale structure. However, the present-day matter distribution is highly non-Gaussian and significant cosmological information is also contained in higher order correlation functions. Meanwhile, baryon physics (particularly active galactic nucleus feedback) has previously been shown to strongly affect the two-point statistics but there has been limited exploration of its effects on higher order functions to date. Here, we use the BAHAMAS suite of cosmological hydrodynamical simulations to explore the effects of baryon physics and massive neutrinos on the halo bispectrum. In contrast to matter clustering which is suppressed by baryon physics, we find that the halo clustering is typically enhanced. The strength of the effect and the scale over which it extends depends on how haloes are selected. On small scales (⁠k≳1 h Mpc−1, dominated by satellites of groups/clusters), we find that the bispectrum is highly sensitive to the efficiency of star formation and feedback, making it an excellent testing ground for galaxy formation models. We show that the effects of feedback and the effects of massive neutrinos are largely separable (independent of each other) and that massive neutrinos strongly suppress the halo bispectrum on virtually all scales up to the free-streaming length (apart from the smallest scales, where baryon physics dominates). The strong sensitivity of the bispectrum to neutrinos on the largest scales and galaxy formation physics on the smallest scales bodes well for upcoming precision measurements from the next generation of wide-field surveys

A companion to a quasar at redshift 4.7

There is a growing consensus that the emergence of quasars at high redshifts is related to the onset of galaxy formation, suggesting that the detection of concentrations of gas accompanying such quasars should provide clues about the early history of galaxies. Quasar companions have been recently identified at redshifts up to $z \approx 3$. Here we report observations of Lyman-$\alpha$ emission (a tracer of ionised hydrogen) from the companion to a quasar at $z$=4.702, corresponding to a time when the Universe was less than ten per cent of its present age. We argue that most of the emission arises in a gaseous nebula that has been photoionised by the quasar, but an additional component of continuum light -perhaps quasar light scattered from dust in the companion body, or emission from young stars within the nebula- appears necessary to explain the observations. These observations may be indicative of the first stages in the assembly of galaxy-sized structures.Comment: 8 pages, 4 figures, plain LaTeX. Accepted for publication in Natur

Testing extensions to LCDM on small scales with forthcoming cosmic shear surveys

We investigate the constraining power of forthcoming Stage-IV weak lensing surveys (Euclid, LSST, and NGRST) for extensions to the LCDM model on small scales, via their impact on the cosmic shear power spectrum. We use high-resolution cosmological simulations to calculate how warm dark matter (WDM), self-interacting dark matter (SIDM) and a running of the spectral index affect the non-linear matter power spectrum, P(k), as a function of scale and redshift. We evaluate the cosmological constraining power using synthetic weak lensing observations derived from these power spectra and that take into account the anticipated source densities, shape noise and cosmic variance errors of upcoming surveys. We show that upcoming Stage-IV surveys will be able to place useful, independent constraints on both WDM models (ruling out models with a particle mass of 10 cm^2 g^-1) through their effects on the small-scale cosmic shear power spectrum. Similarly, they will be able to strongly constrain cosmologies with a running spectral index. Finally, we explore the error associated with the cosmic shear cross-spectrum between tomographic bins, finding that it can be significantly affected by Poisson noise (the standard assumption is that the Poisson noise cancels between tomographic bins). We provide a new analytic form for the error on the cross-spectrum which accurately captures this effect

The BAHAMAS project: Evaluating the accuracy of the halo model in predicting the non-linear matter power spectrum

The halo model formalism is widely adopted in cosmological studies for predicting the growth of large-scale structure in the Universe. However, to date there have been relatively few direct comparisons of the halo model with more accurate (but much more computationally expensive) cosmological simulations. We test the accuracy of the halo model in reproducing the non-linear matter power spectrum, P(k), when the main inputs of the halo model (specifically the matter density profiles, halo mass function, and linear bias) are taken directly from the BAHAMAS simulations and we assess how well the halo model reproduces P(k) from the same simulations. We show that the halo model generally reproduces P(k) in the deep non-linear regime (1-halo) to typically a few percent accuracy, but struggles to reproduce (approx. 15% error) P(k) at intermediate scales of 0.1 < k [h/ Mpc] < 3 at z=0, marking the transition between the 1-halo and 2-halo terms. We show that the magnitude of this error is a strong function of the halo mass definition (through its effects on radial extent of haloes) and of redshift. Furthermore, we test the accuracy of the halo model in recovering the relative impact of baryons on P(k). We show that the systematic errors in recovering the absolute P(k) largely cancel when considering the relative impact of baryons. This suggests that the halo model can make precise predictions for the baryonic suppression, offering a fast and accurate way to adjust collisionless matter power spectra for the presence of baryons and associated processes

Informing dark matter direct detection limits with the ARTEMIS simulations

Dark matter (DM) direct detection experiments aim to place constraints on the DM--nucleon scattering cross-section and the DM particle mass. These constraints depend sensitively on the assumed local DM density and velocity distribution function. While astrophysical observations can inform the former (in a model-dependent way), the latter is not directly accessible with observations. Here we use the high-resolution ARTEMIS cosmological hydrodynamical simulation suite of 42 Milky Way-mass halos to explore the spatial and kinematical distributions of the DM in the solar neighbourhood, and we examine how these quantities are influenced by substructures, baryons, the presence of dark discs, as well as general halo-to-halo scatter (cosmic variance). We also explore the accuracy of the standard Maxwellian approach for modelling the velocity distribution function. We find significant halo-to-halo scatter in the density and velocity functions which, if propagated through the standard halo model for predicting the DM detection limits, implies a significant scatter about the typically quoted limit. We also show that, in general, the Maxwellian approximation works relatively well for simulations that include the important gravitational effects of baryons, but is less accurate for collisionless (DM-only) simulations. Given the significant halo-to-halo scatter in quantities relevant for DM direct detection, we advocate propagating this source of uncertainty through in order to derive conservative DM detection limits

Exon Exchange Approach to Repair Duchenne Dystrophin Transcripts

Background: Trans-splicing strategies for mRNA repair involve engineered transcripts designed to anneal target mRNAs in order to interfere with their natural splicing, giving rise to mRNA chimeras where endogenous mutated exons have been replaced by exogenous replacement sequences. A number of trans-splicing molecules have already been proposed for replacing either the 59 or the 39 part of transcripts to be repaired. Here, we show the feasibility of RNA surgery by using a double trans-splicing approach allowing the specific substitution of a given mutated exon. Methodology/Principal Findings: As a target we used a minigene encoding a fragment of the mdx dystrophin gene enclosing the mutated exon (exon 23). This minigene was cotransfected with a variety of exon exchange constructions, differing in their annealing domains. We obtained accurate and efficient replacement of exon 23 in the mRNA target. Adding up a downstream intronic splice enhancer DISE in the exon exchange molecule enhanced drastically its efficiency up to 25–45 % of repair depending on the construction in use. Conclusions/Significance: These results demonstrate the possibility to fix up mutated exons, refurbish deleted exons and introduce protein motifs, while keeping natural untranslated sequences, which are essential for mRNA stability and translation regulation. Conversely to the well-known exon skipping, exon exchange has the advantage to be compatible with almost any type of mutations and more generally to a wide range of genetic conditions. In particular, it allows addressing disorders caused by dominant mutations