A Systems Biology Approach Reveals the Role of a Novel Methyltransferase in Response to Chemical Stress and Lipid Homeostasis

Using small molecule probes to understand gene function is an attractive approach that allows functional characterization of genes that are dispensable in standard laboratory conditions and provides insight into the mode of action of these compounds. Using chemogenomic assays we previously identified yeast Crg1, an uncharacterized SAM-dependent methyltransferase, as a novel interactor of the protein phosphatase inhibitor cantharidin. In this study we used a combinatorial approach that exploits contemporary high-throughput techniques available in Saccharomyces cerevisiae combined with rigorous biological follow-up to characterize the interaction of Crg1 with cantharidin. Biochemical analysis of this enzyme followed by a systematic analysis of the interactome and lipidome of CRG1 mutants revealed that Crg1, a stress-responsive SAM-dependent methyltransferase, methylates cantharidin in vitro. Chemogenomic assays uncovered that lipid-related processes are essential for cantharidin resistance in cells sensitized by deletion of the CRG1 gene. Lipidome-wide analysis of mutants further showed that cantharidin induces alterations in glycerophospholipid and sphingolipid abundance in a Crg1-dependent manner. We propose that Crg1 is a small molecule methyltransferase important for maintaining lipid homeostasis in response to drug perturbation. This approach demonstrates the value of combining chemical genomics with other systems-based methods for characterizing proteins and elucidating previously unknown mechanisms of action of small molecule inhibitors

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 (HERA Collaboration 2022a), we find at 95% confidence that $\Delta^2(k = 0.34$ $h$ Mpc$^{-1}$) $\leq 457$ mK$^2$ at $z = 7.9$ and that $\Delta^2 (k = 0.36$ $h$ Mpc$^{-1}) \leq 3,496$ mK$^2$ 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 (2022b), 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.Comment: 57 pages, 37 figures. Updated to match the accepted ApJ version. Corresponding author: Joshua S. Dillo

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

HERA Phase I Limits on the Cosmic 21 cm Signal: Constraints on Astrophysics and Cosmology during the Epoch of Reionization

Recently, the Hydrogen Epoch of Reionization Array (HERA) has produced the experiment's first upper limits on the power spectrum of 21 cm fluctuations at z ~ 8 and 10. Here, we use several independent theoretical models to infer constraints on the intergalactic medium (IGM) and galaxies during the epoch of reionization from these limits. We find that the IGM must have been heated above the adiabatic-cooling threshold by z ~ 8, independent of uncertainties about IGM ionization and the radio background. Combining HERA limits with complementary observations constrains the spin temperature of the z ~ 8 neutral IGM to 27 K $\langle {\overline{T}}_{S}\rangle$ 630 K (2.3 K $\langle {\overline{T}}_{S}\rangle$ 640 K) at 68% (95%) confidence. They therefore also place a lower bound on X-ray heating, a previously unconstrained aspects of early galaxies. For example, if the cosmic microwave background dominates the z ~ 8 radio background, the new HERA limits imply that the first galaxies produced X-rays more efficiently than local ones. The z ~ 10 limits require even earlier heating if dark-matter interactions cool the hydrogen gas. If an extra radio background is produced by galaxies, we rule out (at 95% confidence) the combination of high radio and low X-ray luminosities of L r,ν /SFR > 4 × 1024 W Hz-1 ${M}_{\odot }^{-1}$ yr and L X /SFR 39 erg s-1 ${M}_{\odot }^{-1}$ yr. The new HERA upper limits neither support nor disfavor a cosmological interpretation of the recent Experiment to Detect the Global EOR Signature (EDGES) measurement. The framework described here provides a foundation for the interpretation of future HERA results

A blood atlas of COVID-19 defines hallmarks of disease severity and specificity.

Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete description of specific immune biomarkers. We present here a comprehensive multi-omic blood atlas for patients with varying COVID-19 severity in an integrated comparison with influenza and sepsis patients versus healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity involved cells, their inflammatory mediators and networks, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism, and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Systems-based integrative analyses including tensor and matrix decomposition of all modalities revealed feature groupings linked with severity and specificity compared to influenza and sepsis. Our approach and blood atlas will support future drug development, clinical trial design, and personalized medicine approaches for COVID-19

Marginal Bayesian Statistics Using Masked Autoregressive Flows and Kernel Density Estimators with Examples in Cosmology †

Peer reviewed: TrueFunder: Fitzwilliam College, CambridgeFunder: Royal Society University Research FellowshipsFunder: McGill Space Institute FellowshipFunder: Canada 150 Research Chairs ProgramFunder: STFC through the Ernest Rutherford FellowshipCosmological experiments often employ Bayesian workflows to derive constraints on cosmological and astrophysical parameters from their data. It has been shown that these constraints can be combined across different probes, such as Planck and the Dark Energy Survey, and that this can be a valuable exercise to improve our understanding of the universe and quantify tension between multiple experiments. However, these experiments are typically plagued by differing systematics, instrumental effects, and contaminating signals, which we collectively refer to as ‘nuisance’ components, which have to be modelled alongside target signals of interest. This leads to high dimensional parameter spaces, especially when combining data sets, with ≳20 dimensions of which only ∼5 correspond to key physical quantities. We present a means by which to combine constraints from different data sets in a computationally efficient manner by generating rapid, reusable, and reliable marginal probability density estimators, giving us access to nuisance-free likelihoods. This is possible through the unique combination of nested sampling, which gives us access to Bayesian evidence, and the marginal Bayesian statistics code margarine. Our method is lossless in the signal parameters, resulting in the same posterior distributions as would be found from a full nested sampling run over all nuisance parameters, and typically quicker than evaluating full likelihoods. We demonstrate our approach by applying it to the combination of posteriors from the Dark Energy Survey and Planck

Removing the fat from your posterior samples with margarine

Bayesian workflows often require the introduction of nuisance parameters, yet for core science modelling one needs access to a marginal posterior density. In this work we use masked autoregressive flows and kernel density estimators to encapsulate the marginal posterior, allowing us to compute marginal Kullback-Leibler divergences and marginal Bayesian model dimensionalities in addition to generating samples and computing marginal log probabilities. We demonstrate this in application to topical cosmological examples of the Dark Energy Survey, and global 21cm signal experiments. In addition to the computation of marginal Bayesian statistics, this work is important for further applications in Bayesian experimental design, complex prior modelling and likelihood emulation. This technique is made publicly available in the pip-installable code margarine.Comment: Submitted to NeurIP

In Transition: The Visionary Art Environment of Pasaquan

This exhibit captures the transition of the visionary art environment of Pasaquan as it shifts from the Pasaquan Preservation Society to the Kohler Foundation. It includes a collection of resources to inform and contextualize Pasaquan, the life of Eddie Owens Martin, and the preservation and conservation processes