Decomposition of Gene Expression State Space Trajectories

Representing and analyzing complex networks remains a roadblock to creating dynamic network models of biological processes and pathways. The study of cell fate transitions can reveal much about the transcriptional regulatory programs that underlie these phenotypic changes and give rise to the coordinated patterns in expression changes that we observe. The application of gene expression state space trajectories to capture cell fate transitions at the genome-wide level is one approach currently used in the literature. In this paper, we analyze the gene expression dataset of Huang et al. (2005) which follows the differentiation of promyelocytes into neutrophil-like cells in the presence of inducers dimethyl sulfoxide and all-trans retinoic acid. Huang et al. (2005) build on the work of Kauffman (2004) who raised the attractor hypothesis, stating that cells exist in an expression landscape and their expression trajectories converge towards attractive sites in this landscape. We propose an alternative interpretation that explains this convergent behavior by recognizing that there are two types of processes participating in these cell fate transitions—core processes that include the specific differentiation pathways of promyelocytes to neutrophils, and transient processes that capture those pathways and responses specific to the inducer. Using functional enrichment analyses, specific biological examples and an analysis of the trajectories and their core and transient components we provide a validation of our hypothesis using the Huang et al. (2005) dataset

A CHIME/FRB Study of Burst Rate and Morphological Evolution of the Periodically Repeating FRB 20180916B

FRB 20180916B is a repeating fast radio burst (FRB) with a 16.3 day periodicity in its activity. In this study, we present morphological properties of 60 FRB 20180916B bursts detected by CHIME/FRB between 2018 August and 2021 December. We recorded raw voltage data for 45 of these bursts, enabling microseconds time resolution in some cases. We studied variation of spectro-temporal properties with time and activity phase. We find that the variation in dispersion measure (DM) is ≲1 pc cm−3 and that there is burst-to-burst variation in scattering time estimates ranging from ∼0.16 to over 2 ms, with no discernible trend with activity phase for either property. Furthermore, we find no DM and scattering variability corresponding to the recent change in rotation measure from the source, which has implications for the immediate environment of the source. We find that FRB 20180916B has thus far shown no epochs of heightened activity as have been seen in other active repeaters by CHIME/FRB, with its burst count consistent with originating from a Poissonian process. We also observe no change in the value of the activity period over the duration of our observations and set a 1σ upper limit of 1.5 × 10−4 day day−1 on the absolute period derivative. Finally, we discuss constraints on progenitor models yielded by our results, noting that our upper limits on changes in scattering and DM as a function of phase do not support models invoking a massive binary companion star as the origin of the 16.3 day periodicity.</p

Protocol Dependence of Sequencing-Based Gene Expression Measurements

RNA Seq provides unparalleled levels of information about the transcriptome including precise expression levels over a wide dynamic range. It is essential to understand how technical variation impacts the quality and interpretability of results, how potential errors could be introduced by the protocol, how the source of RNA affects transcript detection, and how all of these variations can impact the conclusions drawn. Multiple human RNA samples were used to assess RNA fragmentation, RNA fractionation, cDNA synthesis, and single versus multiple tag counting. Though protocols employing polyA RNA selection generate the highest number of non-ribosomal reads and the most precise measurements for coding transcripts, such protocols were found to detect only a fraction of the non-ribosomal RNA in human cells. PolyA RNA excludes thousands of annotated and even more unannotated transcripts, resulting in an incomplete view of the transcriptome. Ribosomal-depleted RNA provides a more cost-effective method for generating complete transcriptome coverage. Expression measurements using single tag counting provided advantages for assessing gene expression and for detecting short RNAs relative to multi-read protocols. Detection of short RNAs was also hampered by RNA fragmentation. Thus, this work will help researchers choose from among a range of options when analyzing gene expression, each with its own advantages and disadvantages

Improved Constraints on the 21 cm EoR Power Spectrum and the X-Ray Heating of the IGM with HERA Phase I Observations

We report the most sensitive upper limits to date on the 21 cm epoch of reionization power spectrum using 94 nights of observing with Phase I of the Hydrogen Epoch of Reionization Array (HERA). Using similar analysis techniques as in previously reported limits, we find at 95% confidence that Δ2(k = 0.34 h Mpc−1) ≤ 457 mK2 at z = 7.9 and that Δ2(k = 0.36 h Mpc−1) ≤ 3496 mK2 at z = 10.4, an improvement by a factor of 2.1 and 2.6, respectively. These limits are mostly consistent with thermal noise over a wide range of k after our data quality cuts, despite performing a relatively conservative analysis designed to minimize signal loss. Our results are validated with both statistical tests on the data and end-to-end pipeline simulations. We also report updated constraints on the astrophysics of reionization and the cosmic dawn. Using multiple independent modeling and inference techniques previously employed by HERA Collaboration, we find that the intergalactic medium must have been heated above the adiabatic cooling limit at least as early as z = 10.4, ruling out a broad set of so-called “cold reionization” scenarios. If this heating is due to high-mass X-ray binaries during the cosmic dawn, as is generally believed, our result’s 99% credible interval excludes the local relationship between soft X-ray luminosity and star formation and thus requires heating driven by evolved low-metallicity stars

A fast radio burst localized at detection to a galactic disk using very long baseline interferometry

Fast radio bursts (FRBs) are millisecond-duration, luminous radio transients of extragalactic origin. These events have been used to trace the baryonic structure of the Universe using their dispersion measure (DM) assuming that the contribution from host galaxies can be reliably estimated. However, contributions from the immediate environment of an FRB may dominate the observed DM, thus making redshift estimates challenging without a robust host galaxy association. Furthermore, while at least one Galactic burst has been associated with a magnetar, other localized FRBs argue against magnetars as the sole progenitor model. Precise localization within the host galaxy can discriminate between progenitor models, a major goal of the field. Until now, localizations on this spatial scale have only been carried out in follow-up observations of repeating sources. Here we demonstrate the localization of FRB 20210603A with very long baseline interferometry (VLBI) on two baselines, using data collected only at the time of detection. We localize the burst to SDSS J004105.82+211331.9, an edge-on galaxy at $z\approx 0.177$, and detect recent star formation in the kiloparsec-scale vicinity of the burst. The edge-on inclination of the host galaxy allows for a unique comparison between the line of sight towards the FRB and lines of sight towards known Galactic pulsars. The DM, Faraday rotation measure (RM), and scattering suggest a progenitor coincident with the host galactic plane, strengthening the link between the environment of FRB 20210603A and the disk of its host galaxy. Single-pulse VLBI localizations of FRBs to within their host galaxies, following the one presented here, will further constrain the origins and host environments of one-off FRBs.Comment: 40 pages, 13 figures, submitted. Fixed typo in abstrac

Antagonizing retinoic acid receptors increases myeloid cell production by cultured human hematopoietic stem cells

Activities of the retinoic acid receptor (RAR)α and RARγ are important to hematopoiesis. Here, we have investigated the effects of receptor selective agonists and antagonists on the primitive human hematopoietic cell lines KG1 and NB-4 and purified normal human hematopoietic stem cells (HSCs). Agonizing RARα (by AGN195183) was effective in driving neutrophil differentiation of NB-4 cells and this agonist synergized with a low amount (10 nM) of 1α,25-dihydroxyvitamin D(3) to drive monocyte differentiation of NB-4 and KG1 cells. Treatment of cultures of human HSCs (supplemented with stem cell factor ± interleukin 3) with an antagonist of all RARs (AGN194310) or of RARα (AGN196996) prolonged the lifespan of cultures, up to 55 days, and increased the production of neutrophils and monocytes. Slowing down of cell differentiation was not observed, and instead, hematopoietic stem and progenitor cells had expanded in number. Antagonism of RARγ (by AGN205728) did not affect cultures of HSCs. Studies of CV-1 and LNCaP cells transfected with RAR expression vectors and a reporter vector revealed that RARγ and RARβ are activated by sub-nM all-trans retinoic acid (EC(50)–0.3 nM): ~50-fold more is required for activation of RARα (EC(50)–16 nM). These findings further support the notion that the balance of expression and activity of RARα and RARγ are important to hematopoietic stem and progenitor cell expansion and differentiation