Acute promyelocytic leukemia (APL) is characterized by t(15;17)(q22;q21), resulting in a PML-RARA fusion that is the master driver of APL. A few cases that cannot be identified with PML-RARA by using ...conventional methods (karyotype analysis, FISH, and RT-PCR) involve abnormal promyelocytes that are fully in accordance with APL in morphology, cytochemistry, and immunophenotype. To explore the mechanisms involved in pathogenesis and recurrence of morphologically diagnosed APL, we performed comprehensive variant analysis by next-generation sequencing in 111 pediatric patients morphologically diagnosed as APL. Structural variant (SV) analysis in 120 DNA samples from both diagnosis and relapse stage identified 95 samples with RARA rearrangement (including 94 with PML-RARA and one with NPM-RARA) and two samples with KMT2A rearrangement. In the eligible 13 RNA samples without any RARA rearrangement at diagnosis, one case each with CPSF6-RARG, NPM1-CCDC28A, and TBC1D15-RAB21 and two cases with a TBL1XR1-RARB fusion were discovered. These uncovered fusion genes strongly suggested their contributions to leukemogenesis as driver alternations and APL phenotype may arise by abnormalities of other members of the nuclear receptor superfamily involved in retinoid signaling (RARB or RARG) or even by mechanisms distinct from the formation of aberrant retinoid receptors. Single-nucleotide variant (SNV) analysis in 77 children (80 samples) with RARA rearrangement showed recurrent alternations of primary APL in FLT3, WT1, USP9X, NRAS, and ARID1A, with a strong potential for involvement in pathogenesis, and WT1 as the only recurrently mutated gene in relapsed APL. WT1, NPM1, NRAS, FLT3, and NSD1 were identified as recurrently mutated in 17 primary samples without RARA rearrangement and WT1, NPM1, TP53, and RARA as recurrently mutated in 9 relapsed samples. The survival of APL with RARA rearrangement is much better than without RARA rearrangement. Thus, patients morphologically diagnosed as APL that cannot be identified as having a RARA rearrangement are more reasonably classified as a subclass of AML other than APL, and individualized treatment should be considered according to the genetic abnormalities.
Enantiomerically enriched indole-containing heterocycles play a vital role in bioscience, medicine, and chemistry. As one of the most attractive subtypes of indole alkaloids, highly substituted ...tetrahydro-γ-carbolines are the basic structural unit in many natural products and pharmaceuticals. However, the syntheses of tetrahydro-γ-carbolines with high functionalities from readily available reagents are significant challenging. In particular, the stereodivergent syntheses of tetrahydro-γ-carbolines containing multi-stereogenic centers remain quite difficult. Herein, we report an expedient and stereodivergent assembly of tetrahydro-γ-carbolines with remarkably high levels of stereoselective control in an efficient cascade process from aldimine esters and indolyl allylic carbonates via a synergistic Cu/Ir catalyst system. Control experiments-guided optimization of synergistic catalysts and mechanistic investigations reveal that a stereodivergent allylation reaction and a subsequent highly stereoselective iso-Pictet-Spengler cyclization are the key elements to success.
Abstract
Clinical trials showed pangenotypic direct-acting antivirals’ (DAAs) excellent efficacy and safety when treating hepatitis C virus (HCV). Two pangenotypic regimens were examined, ...glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir (SOF/VEL), in a real-world Taiwanese setting, including all HCV patients treated with GLE/PIB or SOF/VEL from August 2018 to April 2020. The primary endpoint was sustained virologic response 12 weeks after treatment cessation (SVR12), including adverse events (AEs). A total of 1,356 HCV patients received pangenotypic DAA treatment during the study: 742 and 614 received GLE/PIB and SOF/VEL, respectively. The rates of SVR12 for GLE/PIB and SOF/VEL were 710/718 (98.9%) and 581/584 (99.5%), respectively, by per-protocol analysis, and 710/742 (95.7%) and 581/614 (94.6%), respectively, by evaluable population analysis. Eleven (GLE/PIB: 8, SOF/VEL: 3) did not achieve SVR12. The most common AEs for GLE/PIB and SOF/VEL were pruritus (17.4% vs. 2.9%), abdominal discomfort (5.8% vs. 4.4%), dizziness (4.2% vs. 2%), and malaise (3.1% vs. 2.9%). Laboratory abnormalities were uncommon; only < 1% exhibited elevated total bilirubin or aminotransferase levels with both regimens. Five drug discontinuations occurred due to AEs (bilirubin elevation: 3; dermatological issues: 2). Pangenotypic DAAs GLE/PIB and SOF/VEL are effective and well tolerated, achieving high SVR12 rates for patients with all HCV genotypes.
The favored progenitor model for Gamma-ray Bursts (GRBs) with Supernova (SN) association is the core collapse of massive stars. One possible outcome of such a collapse is a rapidly spinning, strongly ...magnetized neutron star ("magnetar"). We systematically analyze the multi-wavelength data of GRB/SN associations detected by several instruments before 2017 June. Twenty GRB/SN systems have been confirmed via direct spectroscopic evidence or a clear light curve bump, as well as some spectroscopic evidence resembling a GRB-SN. We derive/collect the basic physical parameters of the GRBs and the SNe, and look for correlations among these parameters. We find that the peak brightness, 56Ni mass, and explosion energy of SNe associated with GRBs are statistically higher than other Type Ib/c SNe. A statistically significant relation between the peak energy of GRBs and the peak brightness of their associated SNe is confirmed. No significant correlations are found between the GRB energies (either isotropic or beaming-corrected) and the supernova energy. We investigate the energy partition within these systems and find that the beaming-corrected GRB energy of most systems is smaller than the SN energy, with less than 30% of the total energy distributed in the relativistic jet. The total energy of the systems is typically smaller than the maximum available energy of a millisecond magnetar (2 × 1052 erg), especially if aspherical SN explosions are considered. The data are consistent with-although not proof of-the hypothesis that most, but not all, GRB/SN systems are powered by millisecond magnetars.
•Estimating head pose with a Coarse-to-Fine neural network.•The network is achieved by joint learning, and thus are computationally efficient.•Design a rendering pipeline to synthesize realistic head ...images with annotations.•The generated head pose dataset contains 310k images.
Various applications of human-computer interaction are based on the estimation of head pose, which is challenging due to different facial appearance, inhomogeneous illumination, partial occlusion, etc. In this paper, we propose a deep neural network following the Coarse-to-Fine strategy to estimate head poses. The scheme includes two branches: Coarse classification phase classifying the input image into four categories, and Fine Regression phase estimating the accurate pose parameters. The two sub-networks are trained jointly. To tackle the problem of insufficient annotated data in training process, we design a rendering pipeline to synthesize realistic head images and generate an annotated dataset with a collection of 310k head poses. The results on benchmark datasets and synthetic dataset validate the effectiveness of our approach, as well as the results on images with diverse illumination, occlusion, and motion blur. Moreover, our method can be easily extended to estimate head poses on depth images.
Summary
WRKY transcription factors play important roles in response to various abiotic stresses. Previous study have proved that soybean GmWRKY54 can improve stress tolerance in transgenic ...Arabidopsis. Here, we generated soybean transgenic plants and further investigated roles and biological mechanisms of GmWRKY54 in response to drought stress. We demonstrated that expression of GmWRKY54, driven by either a constitutive promoter (pCm) or a drought‐induced promoter (RD29a), confers drought tolerance. GmWRKY54 is a transcriptional activator and affects a large number of stress‐related genes as revealed by RNA sequencing. Gene ontology (GO) enrichment and co‐expression network analysis, together with measurement of physiological parameters, supported the idea that GmWRKY54 enhances stomatal closure to reduce water loss, and therefore confers drought tolerance in soybean. GmWRKY54 directly binds to the promoter regions of genes including PYL8, SRK2A, CIPK11 and CPK3 and activates them. Therefore GmWRKY54 achieves its function through abscisic acid (ABA) and Ca2+ signaling pathways. It is valuable that GmWRKY54 activates an ABA receptor and an SnRK2 kinase in the upstream position, unlike other WRKY proteins that regulate downstream genes in the ABA pathway. Our study revealed the role of GmWRKY54 in drought tolerance and further manipulation of this gene should improve growth and production in soybean and other legumes/crops under unfavorable conditions.
Significance Statement
This paper reveals that GmWRKY54 is a transcription factor that effectively modulates drought signaling, GmWRKY54 affects expression of large numbers of downstream genes that possess positive roles in drought tolerance. Using a precise analysis strategy of gene enrichment and co‐expression, it was discovered that GmWRKY54 confers drought tolerance through participating in the ABA and Ca2+ signaling pathways.
We compile the radio-optical-X-ray spectral energy distributions (SEDs) of 65 knots and 29 hotspots in 41 active galactic nucleus jets to examine their high-energy radiation mechanisms. Their SEDs ...can be fitted with the single-zone leptonic models, except for the hotspot of Pictor A and six knots of 3C 273. The X-ray emission of 1 hotspot and 22 knots is well explained as synchrotron radiation under the equipartition condition; they usually have lower X-ray and radio luminosities than the others, which may be due to a lower beaming factor. An inverse Compton (IC) process is involved for explaining the X-ray emission of the other SEDs. Without considering the equipartition condition, their X-ray emission can be attributed to the synchrotron-self-Compton process, but the derived jet powers (Pjet) are not correlated with Lk and most of them are larger than Lk, with more than three orders of magnitude, where Lk is the jet kinetic power estimated with their radio emission. Under the equipartition condition, the X-ray emission is well interpreted with the IC process for the cosmic microwave background photons (IC/CMB). In this scenario, the derived Pjet of knots and hotspots are correlated with and comparable to Lk. These results suggest that the IC/CMB model may be a promising interpretation of the X-ray emission. In addition, a tentative knot-hotspot sequence in the synchrotron peak-energy-peak-luminosity plane is observed, similar to the blazar sequence, which may be attributed to the different cooling mechanisms of electrons.
Abstract
Knowledge about the Lorentz factor and its evolution of relativistic jets in gamma-ray bursts (GRBs) is crucial to understand their physics. An exact value of the bulk Lorentz factor can be ...estimated based on a high-energy spectral cutoff, which may appear in the GRBs’ prompt emission owing to the absorption of photon–photon pair production. In this work, we focus on an investigation of the bulk Lorentz factor evolution of jets in an individual burst. Based on Fermi observations, we search for bursts with multiple GRB pulses characterized by a high-energy spectral cutoff, and nine GRBs are obtained. Together with the estimation of the pulse duration and radiation spectrum, the Lorentz factor of jets corresponding to different pulses in an individual GRB is estimated. It is shown that the Lorentz factor of jets in an individual GRB fluctuates within a certain range and without a general trend in these nine GRBs. In addition, the Lorentz factors of the jets in GRBs 130821A, 160509A, and 160625B seem to increase with time. We also study the relations among
L
iso
,
E
p,z
, and Γ for the pulses in our sample, which are found to be consistent with those found in previous works.
In wireless location-aware networks, mobile nodes (agents) typically obtain their positions using the range measurements to the nodes with known positions. Transmit power allocation not only affects ...network lifetime and throughput, but also determines localization accuracy. In this paper, we present an optimization framework for robust power allocation in network localization with imperfect knowledge of network parameters. In particular, we formulate power allocation problems to minimize localization errors for a given power budget and show that such formulations can be solved via conic programming. Moreover, we design a distributed power allocation algorithm that allows parallel computation among agents. The simulation results show that the proposed schemes significantly outperform uniform power allocation, and the robust schemes outperform their non-robust counterparts when the network parameters are subject to uncertainty .
The spectral lags of gamma-ray bursts (GRBs) have been viewed as the most promising probes of the possible violations of Lorentz invariance (LIV). However, these constraints usually depend on the ...assumption of the unknown intrinsic time lag in different energy bands and the use of a single highest-energy photon. A new approach to test the LIV effects has been proposed by directly fitting the spectral-lag behavior of a GRB with a well-defined transition from positive lags to negative lags. This method simultaneously provides a reasonable formulation of the intrinsic time lag and robust lower limits on the quantum-gravity energy scales (EQG). In this work, we perform a global fitting to the spectral-lag data of GRB 190114C by considering the possible LIV effects based on a Bayesian approach. We then derive limits on EQG and the coefficients of the standard model extension. The Bayes factor output in our analysis shows very strong evidence for the spectral-lag transition in GRB 190114C. Our constraints on a variety of isotropic and anisotropic coefficients for LIV are somewhat weaker than existing bounds, but they can be viewed as comparatively robust and have the promise to complement existing LIV constraints. The observations of GRBs with higher-energy emissions and higher temporal resolutions will contribute to a better formulation of the intrinsic time lag and more rigorous LIV constraints in the dispersive photon sector.
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