792 research outputs found
A Formalization of Forcing and the Unprovability of the Continuum Hypothesis
We describe a formalization of forcing using Boolean-valued models in the Lean 3 theorem prover, including the fundamental theorem of forcing and a deep embedding of first-order logic with a Boolean-valued soundness theorem. As an application of our framework, we specialize our construction to the Boolean algebra of regular opens of the Cantor space 2^{omega_2 x omega} and formally verify the failure of the continuum hypothesis in the resulting model
The Mechanism of β-N-methylamino-l-alanine Inhibition of tRNA Aminoacylation and Its Impact on Misincorporation
β-N-methylamino-l-alanine (BMAA) is a nonproteinogenic amino acid that has been associated with neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Alzheimer\u27s disease (AD). BMAA has been found in human protein extracts; however, the mechanism by which it enters the proteome is still unclear. It has been suggested that BMAA is misincorporated at serine codons during protein synthesis, but direct evidence of its cotranslational incorporation is currently lacking. Here, using LC-MS–purified BMAA and several biochemical assays, we sought to determine whether any aminoacyl-tRNA synthetase (aaRS) utilizes BMAA as a substrate for aminoacylation. Despite BMAA\u27s previously predicted misincorporation at serine codons, following a screen for amino acid activation in ATP/PPi exchange assays, we observed that BMAA is not a substrate for human seryl-tRNA synthetase (SerRS). Instead, we observed that BMAA is a substrate for human alanyl-tRNA synthetase (AlaRS) and can form BMAA-tRNAAla by escaping from the intrinsic AlaRS proofreading activity. Furthermore, we found that BMAA inhibits both the cognate amino acid activation and the editing functions of AlaRS. Our results reveal that, in addition to being misincorporated during translation, BMAA may be able to disrupt the integrity of protein synthesis through multiple different mechanisms
Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus
Current HIV-1 vaccines elicit strain-specific neutralizing antibodies. However, cross-reactive neutralizing antibodies arise in ~20% of HIV-1-infected individuals, and details of their generation could provide a roadmap for effective vaccination. Here we report the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from time of infection. The mature antibody, CH103, neutralized ~55% of HIV-1 isolates, and its co-crystal structure with gp120 revealed a novel loop-based mechanism of CD4-binding site recognition. Virus and antibody gene sequencing revealed concomitant virus evolution and antibody maturation. Notably, the CH103-lineage unmutated common ancestor avidly bound the transmitted/founder HIV-1 envelope glycoprotein, and evolution of antibody neutralization breadth was preceded by extensive viral diversification in and near the CH103 epitope. These data elucidate the viral and antibody evolution leading to induction of a lineage of HIV-1 broadly neutralizing antibodies and provide insights into strategies to elicit similar antibodies via vaccination
The Atacama Cosmology Telescope: A Measurement of the DR6 CMB Lensing Power Spectrum and its Implications for Structure Growth
We present new measurements of cosmic microwave background (CMB) lensing over
sq. deg. of the sky. These lensing measurements are derived from the
Atacama Cosmology Telescope (ACT) Data Release 6 (DR6) CMB dataset, which
consists of five seasons of ACT CMB temperature and polarization observations.
We determine the amplitude of the CMB lensing power spectrum at
precision ( significance) using a novel pipeline that minimizes
sensitivity to foregrounds and to noise properties. To ensure our results are
robust, we analyze an extensive set of null tests, consistency tests, and
systematic error estimates and employ a blinded analysis framework. The
baseline spectrum is well fit by a lensing amplitude of
relative to the Planck 2018 CMB power spectra
best-fit CDM model and relative to
the best-fit model. From our lensing power
spectrum measurement, we derive constraints on the parameter combination
of
from ACT DR6 CMB lensing alone and
when combining ACT DR6 and Planck NPIPE
CMB lensing power spectra. These results are in excellent agreement with
CDM model constraints from Planck or
CMB power spectrum measurements. Our lensing measurements from redshifts
-- are thus fully consistent with CDM structure growth
predictions based on CMB anisotropies probing primarily . We find no
evidence for a suppression of the amplitude of cosmic structure at low
redshiftsComment: 45+21 pages, 50 figures. Prepared for submission to ApJ. Also see
companion papers Madhavacheril et al and MacCrann et a
The Atacama Cosmology Telescope: High-resolution component-separated maps across one-third of the sky
Observations of the millimeter sky contain valuable information on a number
of signals, including the blackbody cosmic microwave background (CMB), Galactic
emissions, and the Compton- distortion due to the thermal Sunyaev-Zel'dovich
(tSZ) effect. Extracting new insight into cosmological and astrophysical
questions often requires combining multi-wavelength observations to spectrally
isolate one component. In this work, we present a new arcminute-resolution
Compton- map, which traces out the line-of-sight-integrated electron
pressure, as well as maps of the CMB in intensity and E-mode polarization,
across a third of the sky (around 13,000 sq.~deg.). We produce these through a
joint analysis of data from the Atacama Cosmology Telescope (ACT) Data Release
4 and 6 at frequencies of roughly 93, 148, and 225 GHz, together with data from
the \textit{Planck} satellite at frequencies between 30 GHz and 545 GHz. We
present detailed verification of an internal linear combination pipeline
implemented in a needlet frame that allows us to efficiently suppress Galactic
contamination and account for spatial variations in the ACT instrument noise.
These maps provide a significant advance, in noise levels and resolution, over
the existing \textit{Planck} component-separated maps and will enable a host of
science goals including studies of cluster and galaxy astrophysics, inferences
of the cosmic velocity field, primordial non-Gaussianity searches, and
gravitational lensing reconstruction of the CMB.Comment: The Compton-y map and associated products will be made publicly
available upon publication of the paper. The CMB T and E mode maps will be
made available when the DR6 maps are made publi
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