Almost 30% of all acute myeloid leukemias (AML) are associated with an internal tandem duplication (ITD) in the juxtamembrane domain of FMS-like tyrosine kinase 3 receptor (FLT3). Patients with ...FLT3-ITD mutations tend to have a poor prognosis. MicroRNAs (miRNAs) have a pivotal role in myeloid differentiation and leukemia. MiRNA-155 (MiR-155) was found to be upregulated in FLT3-ITD-associated AMLs. In this study, we discovered that FLT3-ITD signaling induces the oncogenic miR-155. We show in vitro and in vivo that miR-155 expression is regulated by FLT3-ITD downstream targets nuclear factor-κB (p65) and signal transducer and activator of transcription 5 (STAT5). Further, we demonstrate that miR-155 targets the myeloid transcription factor PU.1. Knockdown of miR-155 or overexpression of PU.1 blocks proliferation and induces apoptosis of FLT3-ITD-associated leukemic cells. Our data demonstrate a novel network in which FLT3-ITD signaling induces oncogenic miR-155 by p65 and STAT5 in AML, thereby targeting transcription factor PU.1.
High‐accuracy protein structure prediction in CASP14 Pereira, Joana; Simpkin, Adam J.; Hartmann, Marcus D. ...
Proteins, structure, function, and bioinformatics,
December 2021, Letnik:
89, Številka:
12
Journal Article
Recenzirano
Odprti dostop
The application of state‐of‐the‐art deep‐learning approaches to the protein modeling problem has expanded the “high‐accuracy” category in CASP14 to encompass all targets. Building on the metrics used ...for high‐accuracy assessment in previous CASPs, we evaluated the performance of all groups that submitted models for at least 10 targets across all difficulty classes, and judged the usefulness of those produced by AlphaFold2 (AF2) as molecular replacement search models with AMPLE. Driven by the qualitative diversity of the targets submitted to CASP, we also introduce DipDiff as a new measure for the improvement in backbone geometry provided by a model versus available templates. Although a large leap in high‐accuracy is seen due to AF2, the second‐best method in CASP14 out‐performed the best in CASP13, illustrating the role of community‐based benchmarking in the development and evolution of the protein structure prediction field.
Reanalysis data are used to study the El Niño–Southern Oscillation (ENSO) signal in the troposphere and stratosphere during the late fall to midwinter period. Warm ENSO events have extratropical ...tropospheric teleconnections that increase the wave 1 eddies and reduce the wave 2 eddies, as compared to cold ENSO. The increase in wave 1 overwhelms the decrease in wave 2, so the net effect is a weakened vortex. This modification in tropospheric wave forcing is induced by a deepening of the wintertime Aleutian low via the Pacific–North America pattern (PNA). Model results are also used to verify that the PNA is the primary mechanism through which ENSO modulates the vortex. During easterly Quasi‐Biennial Oscillation (EQBO), warm ENSO does not show a PNA response in the observational record. Consequently, the polar vortex does not show a strong response to the different phases of ENSO under EQBO, nor to the different phases of QBO under WENSO. It is not clear whether the lack of a PNA response to warm ENSO during EQBO is a real physical phenomenon or a feature of the limited data record we have.
The Central Engines of Fermi Blazars Paliya, Vaidehi S.; Domínguez, A.; Ajello, M. ...
The Astrophysical journal. Supplement series,
04/2021, Letnik:
253, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Abstract
We present a catalog of central engine properties, i.e., black hole mass (
M
BH
) and accretion luminosity (
L
disk
), for a sample of 1077 blazars detected with the Fermi Large Area ...Telescope. This includes broad emission-line systems and blazars whose optical spectra lack emission lines but are dominated by the absorption features arising from the host galaxy. The average
M
BH
for the sample is
, and there is evidence suggesting the association of more massive black holes with absorption-line systems. Our results indicate a bimodality of
L
disk
in Eddington units (
L
disk
/
L
Edd
) with broad-line objects tend to have a higher accretion rate (
L
disk
/
L
Edd
> 0.01). We have found that
L
disk
/
L
Edd
and Compton dominance (CD; the ratio of the inverse Compton to synchrotron peak luminosities) are positively correlated at the >5
σ
confidence level, suggesting that the latter can be used to reveal the state of accretion in blazars. Based on this result, we propose a CD-based classification scheme. Sources with CD > 1 can be classified as high-Compton-dominated or HCD blazars, whereas those with CD ≲ 1 are low-Compton-dominated (LCD) objects. This scheme is analogous to that based on the mass accretion rate proposed in the literature; however, it overcomes the limitation imposed by the difficulty in measuring
L
disk
and
M
BH
for objects with quasi-featureless spectra. We conclude that the overall physical properties of Fermi blazars are likely to be controlled by the accretion rate in Eddington units. The catalog is made public at
http://www.ucm.es/blazars/engines
and Zenodo.
Cereblon (CRBN) is the substrate receptor of the CRL4CRBN E3 ubiquitin ligase and is a central player in targeted protein degradation. It is the target of the thalidomide‐derived immunomodulatory ...drugs (IMiDs) and is one of the most widely employed receptors for proteolysis‐targeting chimeras (PROTACs), both of which induce the ubiquitination and subsequent proteasomal degradation of target proteins. Structural studies of ligand binding to CRBN are crucial to elucidate the mechanisms of action and for mediation of side effects, ultimately aiding the development of next‐generation IMiDs and PROTACs. With this aim, a crystal‐soaking system based on the single‐domain bacterial homologue MsCI4 has previously been established and used to delineate the binding modes of several classes of small molecules, including FDA‐approved drugs, at the molecular level. Here, this system was used to characterize the binding of the next‐generation IMiDs avadomide (CC‐122) and iberdomide (CC‐220) at high resolution, highlighting the advantages and limitations of the MsCI4 system and its implications for the development of future cereblon effectors.
Using the MsCI4 soaking system, the binding of the next‐generation thalidomide‐derived immunomodulatory drugs avadomide (CC‐122) and iberdomide (CC‐220) to cereblon was characterized at high resolution, highlighting the utility of the MsCI4 system for studies of the structure–activity relationship of cereblon effectors.
We present the results of a multi-frequency, time-averaged analysis of blazars included in the Candidate Gamma-ray Blazar Survey catalog. Our sample consists of 324 γ-ray detected (γ-ray loud) and ...191 γ-ray undetected (γ-ray quiet) blazars; we consider all the data up to 2016 April 1. We find that both the γ-ray loud and γ-ray quiet blazar populations occupy similar regions in the WISE color-color diagram, and γ-ray loud sources are brighter in the radio and X-ray bands. A simple one-zone synchrotron inverse-Compton emission model is applied to derive the physical properties of both populations. We find that the central black hole mass and accretion disk luminosity ( L disk ) computed from the modeling of the optical-UV emission with a Shakura-Sunyaev disk reasonably matches that estimated from the optical spectroscopic emission-line information. A significantly larger Doppler boosting in the γ-ray loud blazars is noted, and their jets are more radiatively efficient. On the other hand, the γ-ray quiet objects are more MeV-peaked and thus could be potential targets for next-generation MeV missions. Our results confirm earlier findings about the accretion-jet connection in blazars; however, many of the γ-ray quiet blazars tend to deviate from the recent claim that the jet power exceeds L disk in blazars. A broadband study, considering a larger set of γ-ray quiet objects and also including BL Lacs, will be needed to confirm/reject this hypothesis as well as to verify the evolution of the powerful high-redshift blazars into their low-power nearby counterparts.
How Massive Single Stars End Their Life Heger, A; Fryer, C. L; Woosley, S. E ...
The Astrophysical journal,
07/2003, Letnik:
591, Številka:
1
Journal Article
The extragalactic background light (EBL) can be probed via the absorption imprint it leaves in the spectra of gamma-ray sources ( ). We recently developed a dedicated technique to reconstruct the ...EBL, and its evolution with redshift, from γ-ray optical depth data using a large sample of blazars detected by the Fermi Large Area Telescope. Here, we extend this data set to the TeV regime using ground-based Cherenkov observations of 38 blazars and report the first homogeneous measurement of the EBL spectral intensity covering the ultraviolet to infrared wavelengths (∼0.1-100 m). A minimal EBL throughout the wavelength range with respect to integrated galaxy light is found, allowing little additional unresolved emission from faint or truly diffuse populations setting an upper limit of 4 nW m−2 sr−1 at 1.4 m. In particular, the cosmic optical background at z = 0 is found to be . This work lays the foundation for accurate gamma-ray measurements of the EBL across its whole spectral range using a combination of GeV and TeV data.
The detection of significant γ-ray emission from radio-loud narrow-line Seyfert 1 (NLSy1s) galaxies enables us to study jets in environments different than those in blazars. However, due to the small ...number of known γ-ray-emitting NLSy1 (γ-NLSy1) galaxies, a comprehensive study could not be performed. Here, we report the first detection of significant γ-ray emission from four active galactic nuclei (AGNs), recently classified as NLSy1 from their Sloan Digital Sky Survey (SDSS) optical spectrum. Three flat-spectrum radio quasars (FSRQs) present in the third Large Area Telescope AGN catalog (3LAC) are also found as γ-NLSy1 galaxies. Comparing the γ-ray properties of these objects with 3LAC blazars reveals their spectral shapes to be similar to FSRQs, however, with low γ-ray luminosity ( 1046-47 erg s−1). In the Wide-field Infrared Survey Explorer color-color diagram, these objects occupy a region mainly populated by FSRQs. Using the Hβ emission line parameters, we find that on average γ-NLSy1 have smaller black hole masses than FSRQs at similar redshifts. In the low-resolution SDSS image of one of the γ-NLSy1 source, we find the evidence of an extended structure. We conclude by noting that overall many observational properties of γ-NLSy1 sources are similar to FSRQs, and therefore these objects could be their low black hole mass counterparts, as predicted in the literature.
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