The hallmark of serpins is the ability to undergo the so-called “stressed-to-relaxed” switch during which the surface-exposed reactive center loop (RCL) becomes incorporated as strand 4 in central ...β-sheet A. RCL insertion drives not only the inhibitory reaction of serpins with their target serine proteases but also the conversion to the inactive latent state. RCL insertion is coupled to conformational changes in the flexible joint region flanking β-sheet A. One interesting serpin is plasminogen activator inhibitor-1 (PAI-1), a fast and specific inhibitor of the serine proteases tissue-type and urokinase-type plasminogen activator. Via its flexible joints' region, native PAI-1 binds vitronectin and relaxed, protease-complexed PAI-1 certain endocytosis receptors. From a library of 35-nucleotides long 2′-fluoropyrimidine-containing RNA oligonucleotides, we have isolated two aptamers binding PAI-1 by the flexible joint region with low nanomolar K D values. One of the aptamers exhibited measurable binding to native PAI-1 only, while the other also bound relaxed PAI-1. While none of the aptamers inhibited the antiproteolytic effect of PAI-1, both aptamers inhibited vitronectin binding and the relaxed PAI-1-binding aptamer also endocytosis receptor binding. The aptamer binding exclusively to native PAI-1 increased the half-life for the latency transition to more than 6 h, manyfold more than vitronectin. Contact with Lys124 in the flexible joint region was critical for strong inhibition of the latency transition and the lack of binding to relaxed PAI-1. We conclude that aptamers yield important information about the serpin conformational switch and, because they can compete with high-affinity protein−protein interactions, may provide leads for pharmacological intervention.
ABSTRACT We present a catalog of 840 X-ray sources and first results from a 100 ks Chandra X-ray Observatory imaging study of the filamentary infrared (IR) dark cloud G014.225-00.506, which forms the ...central regions of a larger cloud complex known as the M17 southwest extension (M17 SWex). In addition to the rich population of protostars and young stellar objects with dusty circumstellar disks revealed by archival data from the Spitzer Space Telescope, we discover a population of X-ray-emitting, intermediate-mass pre-main-sequence stars that lack IR excess emission from circumstellar disks. We model the IR spectral energy distributions of this source population to measure its mass function and place new constraints on the destruction timescales for the inner dust disk for 2-8 M☉ stars. We also place a lower limit on the star formation rate (SFR) and find that it is quite high ( M☉ yr−1), equivalent to several Orion Nebula Clusters in G14.225-0.506 alone, and likely accelerating. The cloud complex has not produced a population of massive, O-type stars commensurate with its SFR. This absence of very massive ( 20 M☉) stars suggests that either (1) M17 SWex is an example of a distributed mode of star formation that will produce a large OB association dominated by intermediate-mass stars but relatively few massive clusters, or (2) the massive cores are still in the process of accreting sufficient mass to form massive clusters hosting O stars.
We present a catalog of 1439 young stellar objects (YSOs) spanning the 1.42 deg2 field surveyed by the Chandra Carina Complex Project (CCCP), which includes the major ionizing clusters and the most ...active sites of ongoing star formation within the Great Nebula in Carina. Candidate YSOs were identified via infrared (IR) excess emission from dusty circumstellar disks and envelopes, using data from the Spitzer Space Telescope (the Vela-Carina survey) and the Two-Micron All Sky Survey. We model the 1-24 Delta *mm IR spectral energy distributions of the YSOs to constrain physical properties. Our Pan-Carina YSO Catalog (PCYC) is dominated by intermediate-mass (2 M < m 10 M ) objects with disks, including Herbig Ae/Be stars and their less evolved progenitors. The PCYC provides a valuable complementary data set to the CCCP X-ray source catalogs, identifying 1029 YSOs in Carina with no X-ray detection. We also catalog 410 YSOs with X-ray counterparts, including 62 candidate protostars. Candidate protostars with X-ray detections tend to be more evolved than those without. In most cases, X-ray emission apparently originating from intermediate-mass, disk-dominated YSOs is consistent with the presence of low-mass companions, but we also find that X-ray emission correlates with cooler stellar photospheres and higher disk masses. We suggest that intermediate-mass YSOs produce X-rays during their early pre-main-sequence evolution, perhaps driven by magnetic dynamo activity during the convective atmosphere phase, but this emission dies off as the stars approach the main sequence. Extrapolating over the stellar initial mass function scaled to the PCYC population, we predict a total population of >2 X 104 YSOs and a present-day star formation rate (SFR) of >0.008 M yr--1. The global SFR in the Carina Nebula, averaged over the past ~5 Myr, has been approximately constant.
Measuring the evolution of X-ray emission from pre-main-sequence (PMS) stars gives insight into two issues: the response of magnetic dynamo processes to changes in the interior structure, and the ...effects of high-energy radiation on protoplanetary disks and primordial planetary atmospheres. We present a sample of 6003 stars with ages 7–25 Myr in 10 nearby open clusters from Chandra X-ray and Gaia-EDR3 surveys. Combined with previous results in large samples of younger (≲5 Myr) stars in MYStIX and SFiNCs star-forming regions, mass-stratified activity-age relations are derived for the early phases of stellar evolution. X-ray luminosity (LX) is constant during the first few Myr, possibly due to the presence of extended X-ray coronas insensitive to temporal changes in stellar size. LX then decays during the 7–25 Myr period, more rapidly as stellar mass increases. This decay is interpreted as decreasing efficiency of the α2 dynamo as radiative cores grow and a solar-type αΩ dynamo emerges. For more massive 3.5–7 M⊙ fully radiative stars, the X-ray emission plummets—indicating the lack of an effective magnetic dynamo. The findings provide improved measurements of high-energy radiation effects on circumstellar material, first for the protoplanetary disk and then for the atmospheres of young planets. The observed X-ray luminosities can be so high that an inner Earth-mass rocky, unmagnetized planet around a solar-mass PMS star might lose its primary and secondary atmospheres within a few (several) million years. PMS X-ray emission may thus have a significant impact on the evolution of early-planetary atmospheres and the conditions promoting the rise of habitability.
The swift ultra-violet/optical telescope ROMING, Peter W. A; KENNEDY, Thomas E; HUNSBERGER, S. D ...
Space science reviews,
10/2005, Letnik:
120, Številka:
3-4
Journal Article
Recenzirano
Odprti dostop
The Ultra-Violet/Optical Telescope (UVOT) is one of three instruments flying aboard the Swift Gamma-ray Observatory. It is designed to capture the early (1 min) UV and optical photons from the ...afterglow of gamma-ray bursts in the 170-600 nm band as well as long term observations of these afterglows. This is accomplished through the use of UV and optical broadband filters and grisms. The UVOT has a modified Ritchey-Chrétien design with micro-channel plate intensified charged-coupled device detectors that record the arrival time of individual photons and provide sub-arcsecond positioning of sources. We discuss some of the science to be pursued by the UVOT and the overall design of the instrument.PUBLICATION ABSTRACT
Local administration of immune-activating antibodies may increase the efficacy and reduce the immune-related adverse events associated with systemic immunotherapy of cancer. Here, we report the ...development and affinity maturation of a fully human agonistic CD40 antibody (IgG1), ADC-1013.
We have used molecular engineering to generate an agonistic antibody with high affinity for CD40. The functional activity of ADC-1013 was investigated in human and murine in vitro models. The in vivo effect was investigated in two separate bladder cancer models, both using human xenograft tumors in immune deficient NSG mice and using a syngeneic bladder cancer model in a novel human CD40 transgenic mouse.
Activation of dendritic cells (DC) by ADC-1013 results in upregulation of the costimulatory molecules CD80 and CD86, and secretion of IL12. ADC-1013 also activates DCs from human CD40 transgenic mice, and peptide-pulsed and ADC-1013-stimulated DCs induce antigen-specific T-cell proliferation in vitro. In vivo, treatment with ADC-1013 in a syngeneic bladder cancer model, negative for hCD40, induces significant antitumor effects and long-term tumor-specific immunity. Furthermore, ADC-1013 demonstrates significant antitumor effects in a human bladder cancer transplanted into immunodeficient NSG mice.
Our data demonstrate that ADC-1013 induces long-lasting antitumor responses and immunologic memory mediated by CD40 stimulation. To the best of our knowledge, ADC-1013 represents the first immunomodulatory antibody developed for local immunotherapy of cancer.
Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the ...hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant.
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•Increasing frequency of SARS-CoV-2 D614G is consistent with a selective advantage•Phylodynamic analyses do not show significantly different growth of D614G clusters•There is no association of D614G replacement with greater severity of infection•The D614G replacement is associated with higher viral loads and younger patient age
Analysis of the spread and frequency of SARS-CoV-2 D614G in the United Kingdom suggests a selective advantage for this strain that is associated with higher viral loads in younger patients but not higher COVID-19 clinical severity or mortality.
We present a description of the data reduction methods and the derived catalog of more than 1600 X-ray point sources from the exceptionally deep 2003 January Chandra X-Ray Observatory (Chandra) ...observation of the Orion Nebula Cluster and embedded populations around OMC-1. The observation was obtained with Chandra's Advanced CCD Imaging Spectrometer (ACIS) and has been nicknamed the Chandra Orion Ultradeep Project (COUP). With an 838 ks exposure made over a continuous period of 13.2 days, the COUP observation provides the most uniform and comprehensive data set on the X-ray emission of normal stars ever obtained in the history of X-ray astronomy.
Maladaptive impulsivity is a core symptom in various psychiatric disorders. However, there is only limited evidence available on whether different measures of impulsivity represent largely unrelated ...aspects or a unitary construct. In a cross-species translational study, thirty rats were trained in impulsive choice (delayed reward task) and impulsive action (five-choice serial reaction time task) paradigms. The correlation between those measures was assessed during baseline performance and after pharmacological manipulations with the psychostimulant amphetamine and the norepinephrine reuptake inhibitor atomoxetine. In parallel, to validate the animal data, 101 human subjects performed analogous measures of impulsive choice (delay discounting task, DDT) and impulsive action (immediate and delayed memory task, IMT/DMT). Moreover, all subjects completed the Stop Signal Task (SST, as an additional measure of impulsive action) and filled out the Barratt impulsiveness scale (BIS-11). Correlations between DDT and IMT/DMT were determined and a principal component analysis was performed on all human measures of impulsivity. In both rats and humans measures of impulsive choice and impulsive action did not correlate. In rats the within-subject pharmacological effects of amphetamine and atomoxetine did not correlate between tasks, suggesting distinct underlying neural correlates. Furthermore, in humans, principal component analysis identified three independent factors: (1) self-reported impulsivity (BIS-11); (2) impulsive action (IMT/DMT and SST); (3) impulsive choice (DDT). This is the first study directly comparing aspects of impulsivity using a cross-species translational approach. The present data reveal the non-unitary nature of impulsivity on a behavioral and pharmacological level. Collectively, this warrants a stronger focus on the relative contribution of distinct forms of impulsivity in psychopathology.
X-ray Star Clusters in the Carina Complex Feigelson, Eric D; Getman, Konstantin V; Townsley, Leisa K ...
The Astrophysical journal. Supplement series,
05/2011, Letnik:
194, Številka:
1
Journal Article
Recenzirano
Odprti dostop
ABSTRACT
The distribution of young stars found in the
Chandra
Carina
Complex Project (CCCP) is examined for clustering structure. X-ray surveys are
advantageous for identifying young stellar ...populations compared to optical and
infrared surveys in suffering less contamination from nebular emission and
Galactic field stars. The analysis is based on smoothed maps of a spatially
complete subsample of ∼3000 brighter X-ray sources classified as Carina members
and ∼10,000 stars from the full CCCP sample. The principal known clusters are
recovered, and some additional smaller groups are identified. No rich embedded
clusters are present, although a number of sparse groups are found. The CCCP
reveals considerable complexity in clustering properties. The Trumpler 14 and 15
clusters have rich stellar populations in unimodal, centrally concentrated
structures several parsecs across. Non-spherical internal structure is seen, and
large-scale low surface density distributions surround these rich clusters.
Trumpler 16, in contrast, is comprised of several smaller clusters within a
circular boundary. Collinder 228 is a third type of cluster which extends over
tens of parsecs with many sparse compact groups likely arising from triggered
star formation processes. A widely dispersed, but highly populous, distribution
of X-ray stars across the ∼50 pc CCCP mosaic supports a model of past
generations of star formation in the region. Collinder 234, a group of massive
stars without an associated cluster of pre-main-sequence stars, may be part of
this dispersed population.
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