The clinical and largely unpredictable heterogeneity of phenotypes in patients with mitochondrial disorders demonstrates the ongoing challenges in the understanding of this semi-autonomous organelle in biology and disease. Previously, we used the gene-breaking transposon to create 1200 transgenic zebrafish strains tagging protein-coding genes (Ichino et al., 2020), including the lrpprc locus. Here, we present and characterize a new genetic revertible animal model that recapitulates components of Leigh Syndrome French Canadian Type (LSFC), a mitochondrial disorder that includes diagnostic liver dysfunction. LSFC is caused by allelic variations in the LRPPRC gene, involved in mitochondrial mRNA polyadenylation and translation. lrpprc zebrafish homozygous mutants displayed biochemical and mitochondrial phenotypes similar to clinical manifestations observed in patients, including dysfunction in lipid homeostasis. We were able to rescue these phenotypes in the disease model using a liver-specific genetic model therapy, functionally demonstrating a previously under-recognized critical role for the liver in the pathophysiology of this disease.

Stomata, cellular valves found on the surfaces of aerial plant tissues, present a paradigm for studying cell fate and patterning in plants. A highly conserved core set of related basic helix-loop-helix (bHLH) transcription factors regulate stomatal development across diverse species. We characterized BdFAMA in the temperate grass Brachypodium distachyon and found this late-acting transcription factor was necessary and sufficient for specifying stomatal guard cell fate, and unexpectedly could also induce the recruitment of subsidiary cells in the absence of its paralogue, BdMUTE. The overlap in function is paralleled by an overlap in expression pattern and by unique regulatory relationships between BdMUTE and BdFAMA. To better appreciate the relationships among the Brachypodium stomatal bHLHs, we used in vivo proteomics in developing leaves and found evidence for multiple shared interaction partners. We reexamined the roles of these genes in Arabidopsis thaliana by testing genetic sufficiency within and across species, and found that while BdFAMA and AtFAMA can rescue stomatal production in Arabidopsis fama and mute mutants, only AtFAMA can specify Brassica -specific myrosin idioblasts. Taken together, our findings refine the current models of stomatal bHLH function and regulatory feedbacks amongst paralogues within grasses as well as across the monocot/dicot divide.

We report the Sr and Ba isotopic compositions of 18 presolar SiC grains of types Y (11) and Z (7), rare types commonly argued to have formed in lower-than-solar metallicity asymptotic giant branch (AGB) stars. We find that the Y and Z grains show higher Sr-88/Sr-87 and more variable Ba-138/Ba-136 ratios than mainstream (MS) grains. According to FRANEC Torino AGB models, the Si, Sr, and Ba isotopic compositions of our Y and Z grains can be consistently explained if the grains came from low-mass AGB stars with 0.15 Z(circle dot) <= Z < 1.00 Z(circle dot), in which the C-13 neutron exposure for the slow neutron-capture process is greatly reduced with respect to that required by MS grains for a 1.0 Z(circle dot) AGB star. This scenario is in line with the previous finding based on Ti isotopes, but it fails to explain the indistinguishable Mo isotopic compositions of MS, Y, and Z grains.

Cells respond to physical stimuli, such as stiffness(1), fluid shear stress(2) and hydraulic pressure(3,4). Extracellular fluid viscosity is a key physical cue that varies under physiological and pathological conditions, such as cancer(5). However, its influence on cancer biology and the mechanism by which cells sense and respond to changes in viscosity are unknown. Here we demonstrate that elevated viscosity counterintuitively increases the motility of various cell types on two-dimensional surfaces and in confinement, and increases cell dissemination from three-dimensional tumour spheroids. Increased mechanical loading imposed by elevated viscosity induces an actin-related protein 2/3 (ARP2/3)-complex-dependent dense actin network, which enhances Na+/H+ exchanger 1 (NHE1) polarization through its actin-binding partner ezrin. NHE1 promotes cell swelling and increased membrane tension, which, in turn, activates transient receptor potential cation vanilloid 4 (TRPV4) and mediates calcium influx, leading to increased RHOA-dependent cell contractility. The coordinated action of actin remodelling/dynamics, NHE1-mediated swelling and RHOA-based contractility facilitates enhanced motility at elevated viscosities. Breast cancer cells pre-exposed to elevated viscosity acquire TRPV4-dependent mechanical memory through transcriptional control of the Hippo pathway, leading to increased migration in zebrafish, extravasation in chick embryos and lung colonization in mice. Cumulatively, extracellular viscosity is a physical cue that regulates both short- and long-term cellular processes with pathophysiological relevance to cancer biology.

Collocated crystal sizes and mineral identities are critical for interpreting textural relationships in rocks and testing geological hypotheses, but it has been previously impossible to unambiguously constrain these properties using in situ instruments on Mars rovers. Here, we demonstrate that diffracted and fluoresced x-rays detected by the PIXL instrument (an x-ray fluorescence microscope on the Perseverance rover) provide information about the presence or absence of coherent crystalline domains in various minerals. X-ray analysis and multispectral imaging of rocks from the Seitah formation on the floor of Jezero crater shows that they were emplaced as coarsely crystalline igneous phases. Olivine grains were then partially dissolved and filled by finely crystalline or amorphous secondary silicate, carbonate, sulfate, and chloride/oxychlorine minerals. These results support the hypothesis that Seitah formation rocks represent olivine cumulates altered by fluids far from chemical equilibrium at low water-rock ratios.

High-throughput RNA sequencing offers broad opportunities to explore the Earth RNA virome. Mining 5,150 diverse metatranscriptomes uncovered >2.5 million RNA virus contigs. Analysis of >330,000 RNA-dependent RNA polymerases (RdRPs) shows that this expansion corresponds to a 5-fold increase of the known RNA vi-rus diversity. Gene content analysis revealed multiple protein domains previously not found in RNA viruses and implicated in virus-host interactions. Extended RdRP phylogeny supports the monophyly of the five es-tablished phyla and reveals two putative additional bacteriophage phyla and numerous putative additional classes and orders. The dramatically expanded phylum Lenarviricota, consisting of bacterial and related eu-karyotic viruses, now accounts for a third of the RNA virome. Identification of CRISPR spacer matches and bacteriolytic proteins suggests that subsets of picobirnaviruses and partitiviruses, previously associated with eukaryotes, infect prokaryotic hosts.

The Perseverance rover landed in Jezero crater, Mars, in February 2021. We used the Scanning Habitable Environments with Raman and Luminescence for Organics and Chemicals (SHERLOC) instrument to perform deep-ultraviolet Raman and fluorescence spectroscopy of three rocks within the crater. We identify evidence for two distinct ancient aqueous environments at different times. Reactions with liquid water formed carbonates in an olivine-rich igneous rock. A sulfate-perchlorate mixture is present in the rocks, which probably formed by later modifications of the rocks by brine. Fluorescence signatures consistent with aromatic organic compounds occur throughout these rocks and are preserved in minerals related to both aqueous environments.

The nature of dark matter is one of the most important unsolved questions in science. Some darkf matter candidates do not have sufficient nongravitational interactions to be probed in laboratory or accelerator experiments. It is thus important to develop astrophysical probes which can constrain or lead to a discovery of such candidates. We illustrate this using state-of-the-art measurements of strong gravitationally lensed quasars to constrain four of the most popular sterile neutrino models, and also report the constraints for other independent methods that are comparable in procedure. First, we derive effective relations to describe the correspondence between the mass of a thermal relic warm dark matter particle and the mass of sterile neutrinos produced via Higgs decay and grand unified theory (GUT)-scale scenarios, in terms of large-scale structure and galaxy formation astrophysical effects. Second, we show that sterile neutrinos produced through the Higgs decay mechanism are allowed only for mass >26keV, and GUT-scale scenario >5.3keV. Third, we show that the single sterile neutrino model produced through active neutrino oscillations is allowed for mass >92keV, and the three sterile neutrino minimal standard model (nuMSM) for mass >16keV. These are the most stringent experimental limits on these models.

Modern Galactic surveys have revealed an ancient merger that dominates the stellar halo of our galaxy (Gaia-Sausage-Enceladus, GSE). Using chemical abundances and kinematics from the H3 Survey, we identify 5559 halo stars from this merger in the radial range r (Gal) = 6-60kpc. We forward model the full selection function of H3 to infer the density profile of this accreted component of the stellar halo. We consider a general ellipsoid with principal axes allowed to rotate with respect to the galactocentric axes, coupled with a multiply broken power law. The best-fit model is a triaxial ellipsoid (axes ratios 10:8:7) tilted 25 degrees above the Galactic plane toward the Sun and a doubly broken power law with breaking radii at 12 kpc and 28 kpc. The doubly broken power law resolves a long-standing dichotomy in literature values of the halo breaking radius, being at either similar to 15 kpc or similar to 30 kpc assuming a singly broken power law. N-body simulations suggest that the breaking radii are connected to apocenter pile-ups of stellar orbits, and so the observed double-break provides new insight into the initial conditions and evolution of the GSE merger. Furthermore, the tilt and triaxiality of the stellar halo could imply that a fraction of the underlying dark matter halo is also tilted and triaxial. This has important implications for dynamical mass modeling of the galaxy as well as direct dark matter detection experiments.