161 research outputs found
De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder
DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder
Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer
Immune checkpoint blockade (ICB) has improved outcomes in some cancers. A major limitation of ICB is that most patients fail to respond, which is partly attributable to immunosuppression. Obesity appears to improve immune checkpoint therapies in some cancers, but impacts on breast cancer (BC) remain unknown. In lean and obese mice, tumor progression and immune reprogramming were quantified in BC tumors treated with anti-programmed death-1 (PD-1) or control. Obesity augments tumor incidence and progression. Anti-PD-1 induces regression in lean mice and potently abrogates progression in obese mice. BC primes systemic immunity to be highly responsive to obesity, leading to greater immunosuppression, which may explain greater anti-PD-1 efficacy. Anti-PD-1 significantly reinvigorates antitumor immunity despite persistent obesity. Laminin subunit beta-2 (Lamb2), downregulated by anti-PD-1, significantly predicts patient survival. Lastly, a microbial signature associated with anti-PD-1 efficacy is identified. Thus, anti-PD-1 is highly efficacious in obese mice by reinvigorating durable antitumor immunity
SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness
A vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is needed to control the coronavirus disease 2019 (COVID-19) global pandemic. Structural studies have led to the development of mutations that stabilize Betacoronavirus spike proteins in the prefusion state, improving their expression and increasing immunogenicity1. This principle has been applied to design mRNA-1273, an mRNA vaccine that encodes a SARS-CoV-2 spike protein that is stabilized in the prefusion conformation. Here we show that mRNA-1273 induces potent neutralizing antibody responses to both wild-type (D614) and D614G mutant2 SARS-CoV-2 as well as CD8+ T cell responses, and protects against SARS-CoV-2 infection in the lungs and noses of mice without evidence of immunopathology. mRNA-1273 is currently in a phase III trial to evaluate its efficacy
Tides in colliding galaxies
Long tails and streams of stars are the most noticeable upshots of galaxy
collisions. Their origin as gravitational, tidal, disturbances has however been
recognized only less than fifty years ago and more than ten years after their
first observations. This Review describes how the idea of galactic tides
emerged, in particular thanks to the advances in numerical simulations, from
the first ones that included tens of particles to the most sophisticated ones
with tens of millions of them and state-of-the-art hydrodynamical
prescriptions. Theoretical aspects pertaining to the formation of tidal tails
are then presented. The third part of the review turns to observations and
underlines the need for collecting deep multi-wavelength data to tackle the
variety of physical processes exhibited by collisional debris. Tidal tails are
not just stellar structures, but turn out to contain all the components usually
found in galactic disks, in particular atomic / molecular gas and dust. They
host star-forming complexes and are able to form star-clusters or even
second-generation dwarf galaxies. The final part of the review discusses what
tidal tails can tell us (or not) about the structure and content of present-day
galaxies, including their dark components, and explains how tidal tails may be
used to probe the past evolution of galaxies and their mass assembly history.
On-going deep wide-field surveys disclose many new low-surface brightness
structures in the nearby Universe, offering great opportunities for attempting
galactic archeology with tidal tails.Comment: 46 pages, 13 figures, Review to be published in "Tidal effects in
Astronomy and Astrophysics", Lecture Notes in Physics. Comments are most
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Performance of ternary PtRuRh/C electrocatalyst with varying Pt:Ru:Rh ratio for methanol electro-oxidation
The polarized image of a synchrotron-emitting ring of gas orbiting a black hole
High Energy Astrophysic
Constraints on black-hole charges with the 2017 EHT observations of M87*
InstrumentationHigh Energy Astrophysic
The variability of the black hole image in M87 at the dynamical timescale
The black hole images obtained with the Event Horizon Telescope (EHT) are expected to be variable at the dynamical timescale near their horizons. For the black hole at the center of the M87 galaxy, this timescale (5–61 days) is comparable to the 6 day extent of the 2017 EHT observations. Closure phases along baseline triangles are robust interferometric observables that are sensitive to the expected structural changes of the images but are free of station-based atmospheric and instrumental errors. We explored the day-to-day variability in closure-phase measurements on all six linearly independent nontrivial baseline triangles that can be formed from the 2017 observations. We showed that three triangles exhibit very low day-to-day variability, with a dispersion of ∼3°–5°. The only triangles that exhibit substantially higher variability (∼90°–180°) are the ones with baselines that cross the visibility amplitude minima on the u–v plane, as expected from theoretical modeling. We used two sets of general relativistic magnetohydrodynamic simulations to explore the dependence of the predicted variability on various black hole and accretion-flow parameters. We found that changing the magnetic field configuration, electron temperature model, or black hole spin has a marginal effect on the model consistency with the observed level of variability. On the other hand, the most discriminating image characteristic of models is the fractional width of the bright ring of emission. Models that best reproduce the observed small level of variability are characterized by thin ring-like images with structures dominated by gravitational lensing effects and thus least affected by turbulence in the accreting plasmas.https://iopscience.iop.org/article/10.3847/1538-4357/ac332e/pdfPublished versio
Event Horizon Telescope observations of the jet launching and collimation in Centaurus A
InstrumentationLarge scale structure and cosmolog
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