Abstract Due to their short timescale, stellar flares are a challenging target for the most modern synoptic sky surveys. The upcoming Vera C. Rubin Legacy Survey of Space and Time (LSST), a project ...designed to collect more data than any precursor survey, is unlikely to detect flares with more than one data point in its main survey. We developed a methodology to enable LSST studies of stellar flares, with a focus on flare temperature and temperature evolution, which remain poorly constrained compared to flare morphology. By leveraging the sensitivity expected from the Rubin system, differential chromatic refraction (DCR) can be used to constrain flare temperature from a single-epoch detection, which will enable statistical studies of flare temperatures and constrain models of the physical processes behind flare emission using the unprecedentedly high volume of data produced by Rubin over the 10 yr LSST. We model the refraction effect as a function of the atmospheric column density, photometric filter, and temperature of the flare, and show that flare temperatures at or above ∼4000 K can be constrained by a single g -band observation at air mass X ≳ 1.2, given the minimum specified requirement on the single-visit relative astrometric accuracy of LSST, and that a surprisingly large number of LSST observations are in fact likely be conducted at X ≳ 1.2, in spite of image quality requirements pushing the survey to preferentially low X . Having failed to measure flare DCR in LSST precursor surveys, we make recommendations on survey design and data products that enable these studies in LSST and other future surveys.
Most eukaryotic proteins are N-terminally acetylated. This modification can be recognized as a signal for selective protein degradation (degron) by the N-end rule pathways. However, the prevalence ...and specificity of such degrons in the proteome are unclear. Here, by systematically examining how protein turnover is affected by N-terminal sequences, we perform a comprehensive survey of degrons in the yeast N-terminome. We find that approximately 26% of nascent protein N termini encode cryptic degrons. These degrons exhibit high hydrophobicity and are frequently recognized by the E3 ubiquitin ligase Doa10, suggesting a role in protein quality control. In contrast, N-terminal acetylation rarely functions as a degron. Surprisingly, we identify two pathways where N-terminal acetylation has the opposite function and blocks protein degradation through the E3 ubiquitin ligase Ubr1. Our analysis highlights the complexity of N-terminal degrons and argues that hydrophobicity, not N-terminal acetylation, is the predominant feature of N-terminal degrons in nascent proteins.
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•A method to map and dissect degradation signals (degrons) in high throughput•A comprehensive survey of degrons in N termini of yeast proteins•Hydrophobicity, not N-terminal acetylation, is a key feature of N-terminal degrons•Two pathways where N-terminal acetylation blocks protein degradation
Kats et al. develop a method for high-throughput measurements of protein turnover and perform a large-scale study of degradation signals in protein N termini. They observe that hydrophobicity, not N-terminal acetylation, is a key feature of N-terminal degradation signals, and they describe two new pathways where N-terminal acetylation prevents protein degradation.
Recombinant adeno-associated virus (rAAV) vectors have shown promise for the treatment of several diseases; however, immune-mediated elimination of transduced cells has been suggested to limit and ...account for a loss of efficacy. To determine whether rAAV vector expression can persist long term, we administered rAAV vectors expressing normal, M-type α-1 antitrypsin (M-AAT) to AAT-deficient subjects at various doses by multiple i.m. injections. M-specific AAT expression was observed in all subjects in a dose-dependent manner and was sustained for more than 1 year in the absence of immune suppression. Muscle biopsies at 1 year had sustained AAT expression and a reduction of inflammatory cells compared with 3 month biopsies. Deep sequencing of the TCR Vβ region from muscle biopsies demonstrated a limited number of T cell clones that emerged at 3 months after vector administration and persisted for 1 year. In situ immunophenotyping revealed a substantial Treg population in muscle biopsy samples containing AAT-expressing myofibers. Approximately 10% of all T cells in muscle were natural Tregs, which were activated in response to AAV capsid. These results suggest that i.m. delivery of rAAV type 1-AAT (rAAV1-AAT) induces a T regulatory response that allows ongoing transgene expression and indicates that immunomodulatory treatments may not be necessary for rAAV-mediated gene therapy.
ABSTRACT
This paper presents a new optical imaging survey of four deep drilling fields (DDFs), two Galactic and two extragalactic, with the Dark Energy Camera (DECam) on the 4-m Blanco telescope at ...the Cerro Tololo Inter-American Observatory (CTIO). During the first year of observations in 2021, >4000 images covering 21 deg2 (seven DECam pointings), with ∼40 epochs (nights) per field and 5 to 6 images per night per filter in g, r, i, and/or z have become publicly available (the proprietary period for this program is waived). We describe the real-time difference-image pipeline and how alerts are distributed to brokers via the same distribution system as the Zwicky Transient Facility (ZTF). In this paper, we focus on the two extragalactic deep fields (COSMOS and ELAIS-S1) characterizing the detected sources, and demonstrating that the survey design is effective for probing the discovery space of faint and fast variable and transient sources. We describe and make publicly available 4413 calibrated light curves based on difference-image detection photometry of transients and variables in the extragalactic fields. We also present preliminary scientific analysis regarding the Solar system small bodies, stellar flares and variables, Galactic anomaly detection, fast-rising transients and variables, supernovae, and active Galactic nuclei.
We present ultraviolet (UV) spectroscopy and photometry of four Type Ia supernovae (SNe 2004dt, 2004ef, 2005M, and 2005cf) obtained with the UV prism of the Advanced Camera for Surveys on the Hubble ...Space Telescope. This data set provides unique spectral time series down to 2000 Angstrom. Significant diversity is seen in the near-maximum-light spectra (~2000-3500 Angstrom) for this small sample. The corresponding photometric data, together with archival data from Swift Ultraviolet/Optical Telescope observations, provide further evidence of increased dispersion in the UV emission with respect to the optical. The peak luminosities measured in the uvw1/F250W filter are found to correlate with the B-band light-curve shape parameter Delta m sub(15)(B), but with much larger scatter relative to the correlation in the broadband B band (e.g., ~0.4 mag versus ~0.2 mag for those with 0.8 mag < Delta m sub(15)(B) < 1.7 mag). SN 2004dt is found as an outlier of this correlation (at > 3sigma), being brighter than normal SNe Ia such as SN 2005cf by ~0.9 mag and ~2.0 mag in the uvw1/F250W and uvm2/F220W filters, respectively. We show that different progenitor metallicity or line-expansion velocities alone cannot explain such a large discrepancy. Viewing-angle effects, such as due to an asymmetric explosion, may have a significant influence on the flux emitted in the UV region. Detailed modeling is needed to disentangle and quantify the above effects.
Recombinant adeno-associated virus (rAAV) vectors offer promise for the gene therapy of α(1)-antitrypsin (AAT) deficiency. In our prior trial, an rAAV vector expressing human AAT (rAAV1-CB-hAAT) ...provided sustained, vector-derived AAT expression for >1 year. In the current phase 2 clinical trial, this same vector, produced by a herpes simplex virus complementation method, was administered to nine AAT-deficient individuals by intramuscular injection at doses of 6.0×10(11), 1.9×10(12), and 6.0×10(12) vector genomes/kg (n=3 subjects/dose). Vector-derived expression of normal (M-type) AAT in serum was dose dependent, peaked on day 30, and persisted for at least 90 days. Vector administration was well tolerated, with only mild injection site reactions and no serious adverse events. Serum creatine kinase was transiently elevated on day 30 in five of six subjects in the two higher dose groups and normalized by day 45. As expected, all subjects developed anti-AAV antibodies and interferon-γ enzyme-linked immunospot responses to AAV peptides, and no subjects developed antibodies to AAT. One subject in the mid-dose group developed T cell responses to a single AAT peptide unassociated with any clinical effects. Muscle biopsies obtained on day 90 showed strong immunostaining for AAT and moderate to marked inflammatory cell infiltrates composed primarily of CD3-reactive T lymphocytes that were primarily of the CD8(+) subtype. These results support the feasibility and safety of AAV gene therapy for AAT deficiency, and indicate that serum levels of vector-derived normal human AAT >20 μg/ml can be achieved. However, further improvements in the design or delivery of rAAV-AAT vectors will be required to achieve therapeutic target serum AAT concentrations.
ABSTRACT
This paper presents a new optical imaging survey of four deep drilling fields (DDFs), two Galactic and two extragalactic, with the Dark Energy Camera (DECam) on the 4-m Blanco telescope at ...the Cerro Tololo Inter-American Observatory (CTIO). During the first year of observations in 2021, >4000 images covering 21 deg2 (seven DECam pointings), with ∼40 epochs (nights) per field and 5 to 6 images per night per filter in g, r, i, and/or z have become publicly available (the proprietary period for this program is waived). We describe the real-time difference-image pipeline and how alerts are distributed to brokers via the same distribution system as the Zwicky Transient Facility (ZTF). In this paper, we focus on the two extragalactic deep fields (COSMOS and ELAIS-S1) characterizing the detected sources, and demonstrating that the survey design is effective for probing the discovery space of faint and fast variable and transient sources. We describe and make publicly available 4413 calibrated light curves based on difference-image detection photometry of transients and variables in the extragalactic fields. We also present preliminary scientific analysis regarding the Solar system small bodies, stellar flares and variables, Galactic anomaly detection, fast-rising transients and variables, supernovae, and active Galactic nuclei.
A numerical model of a wheel consists of a series of particles evenly spaced around the rim of the wheel, each connected with both neighboring particles by a damped spring. In the simulation, the ...wheel rolls along the ground, allowing determination of position, velocity, deformation, and angular velocity of the wheel as the system evolves. The results of the simulation are consistent with what is observed experimentally with rolling friction: the rolling resistance goes up as pressure goes down, and it goes up as speed goes up. The simulation indicates that the majority of the kinetic energy lost from the wheel is dissipated in deformations of the wheel, i.e., in the dampers between the particles. Kinetic friction is negligible. Both static friction and the contact normal force vary over the region of contact between wheel and ground, with the effective position of the normal force acting forward of the center of the wheel. Static friction is the force responsible for the change in linear momentum of the wheel.
The purpose of this study was to determine the sensitivity and positive predictive value of magnetic resonance imaging (MRI) in the identification of full-thickness articular cartilage defects in the ...porcine knee. Seventy-two full-thickness chondral defects (small or large; circular, oval, or triangular) were created in 12 porcine knees. The authors used 3.0-T MRI with 3-dimensional gradient echo water-selective/fluid (WATSf) sequences acquired in axial, coronal, and sagittal planes. Sensitivity and positive predictive value parameters were calculated for 2 readers. Magnetic resonance imaging was highly sensitive for detection of full-thickness defects in the knee (85%). The highest sensitivity was observed at the medial femoral condyle (93%), while the lowest was observed at the medial patella (71%). The sensitivities for detecting different shapes were unique to each shape, with oval lesions identified with greatest sensitivity (93%). Small lesions (86%) were detected at a similar sensitivity as large lesions (83%). The positive predictive values for accurate true-positive reads were low for all lesion shapes (18%-57%) and moderate for small (69%) and large (59%) sizes, with significant differences observed between the 2 readers. Magnetic resonance imaging has a high sensitivity in the detection of full-thickness articular cartilage defects in the porcine knee. Variability in defect shape and intra-articular location affects MRI sensitivity, while size does not. Magnetic resonance imaging was not effective in describing lesion shape or size. Further, there was subjectivity in reading defect shape and size between 2 radiologists.
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