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  • 1
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    Transcriptome-wide subtyping of pediatric and adult T cell acute lymphoblastic leukemia in an international study of 707 cases
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 15 ( 2022-04-12)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 15 ( 2022-04-12)
    Abstract: T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of T cell progenitors, known to be a heterogeneous disease in pediatric and adult patients. Here we attempted to better understand the disease at the molecular level based on the transcriptomic landscape of 707 T-ALL patients (510 pediatric, 190 adult patients, and 7 with unknown age; 599 from published cohorts and 108 newly investigated). Leveraging the information of gene expression enabled us to identify 10 subtypes (G1–G10), including the previously undescribed one characterized by GATA3 mutations, with GATA3 R276Q capable of affecting lymphocyte development in zebrafish. Through associating with T cell differentiation stages, we found that high expression of LYL1/LMO2/SPI1/HOXA (G1–G6) might represent the early T cell progenitor, pro/precortical/cortical stage with a relatively high age of disease onset, and lymphoblasts with TLX3/TLX1 high expression (G7–G8) could be blocked at the cortical/postcortical stage, while those with high expression of NKX2-1/TAL1/LMO1 (G9–G10) might correspond to cortical/postcortical/mature stages of T cell development. Notably, adult patients harbored more cooperative mutations among epigenetic regulators, and genes involved in JAK-STAT and RAS signaling pathways, with 44% of patients aged 40 y or above in G1 bearing DNMT3A/IDH2 mutations usually seen in acute myeloid leukemia, suggesting the nature of mixed phenotype acute leukemia.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2120787119
    RVK:
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    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2022
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  • 2
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    Transcriptome-based molecular subtypes and differentiation hierarchies improve the classification framework of acute myeloid leukemia
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 49 ( 2022-12-06)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 49 ( 2022-12-06)
    Abstract: The current classification of acute myeloid leukemia (AML) relies largely on genomic alterations. Robust identification of clinically and biologically relevant molecular subtypes from nongenomic high-throughput sequencing data remains challenging. We established the largest multicenter AML cohort (n = 655) in China, with all patients subjected to RNA sequencing (RNA-Seq) and 619 (94.5%) to targeted or whole-exome sequencing (TES/WES). Based on an enhanced consensus clustering, eight stable gene expression subgroups (G1–G8) with unique clinical and biological significance were identified, including two unreported (G5 and G8) and three redefined ones (G4, G6, and G7). Apart from four well-known low-risk subgroups including PML::RARA (G1), CBFB::MYH11 (G2), RUNX1::RUNX1T1 (G3), biallelic CEBPA mutations or -like (G4), four meta-subgroups with poor outcomes were recognized. The G5 (myelodysplasia-related/-like) subgroup enriched clinical, cytogenetic and genetic features mimicking secondary AML, and hotspot mutations of IKZF1 (p.N159S) (n = 7). In contrast, most NPM1 mutations and KMT2A and NUP98 fusions clustered into G6–G8, showing high expression of HOXA / B genes and diverse differentiation stages, from hematopoietic stem/progenitor cell down to monocyte, namely HOX -primitive (G7) , HOX -mixed (G8), and HOX -committed (G6). Through constructing prediction models, the eight gene expression subgroups could be reproduced in the Cancer Genome Atlas (TCGA) and Beat AML cohorts. Each subgroup was associated with distinct prognosis and drug sensitivities, supporting the clinical applicability of this transcriptome-based classification of AML. These molecular subgroups illuminate the complex molecular network of AML, which may promote systematic studies of disease pathogenesis and foster the screening of targeted agents based on omics.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2211429119
    RVK:
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    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2022
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 3
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    Depletion of Perineuronal Nets in the Amygdala to Enhance the Erasure of Drug Memories
    Society for Neuroscience ; 2014
    In:  The Journal of Neuroscience Vol. 34, No. 19 ( 2014-05-07), p. 6647-6658
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 34, No. 19 ( 2014-05-07), p. 6647-6658
    Abstract: Extinction therapy has been suggested to suppress the conditioned motivational effect of drug cues to prevent relapse. However, extinction forms a new inhibiting memory rather than erasing the original memory trace and drug memories invariably return. Perineuronal nets (PNNs) are a specialized extracellular matrix around interneurons in the brain that have been suggested to be a permissive factor that allows synaptic plasticity in the adolescent brain. The degradation of PNNs caused by chondroitinase ABC (ChABC) may generate induced juvenile-like plasticity (iPlasticity) and promote experience-dependent plasticity in the adult brain. In the present study, we investigated the effect of removing PNNs in the amygdala of rat on the extinction of drug memories. We found that extinction combined with intra-amygdala injections of ChABC (0.01 U/side) prevented the subsequent priming-induced reinstatement of morphine-induced and cocaine-induced, but not food -induced, conditioned place preference (CPP). Intra-amygdala injections of ChABC alone had no effect on the retention, retrieval, or relearning of morphine-induced CPP and storage of acquired food-induced CPP. Moreover, we found that the procedure facilitated the extinction of heroin- and cocaine-seeking behavior and prevented the spontaneous recovery and drug-induced reinstatement of heroin- and cocaine-seeking behavior. We also found that the effect of PNNs degradation combined with extinction may be mediated by the potentiation of several plasticity-related proteins in the amygdala. Altogether, our findings demonstrate that a combination of extinction training with PNNs degradation in the amygdala erases drug memories and suggest that ChABC may be an attractive candidate for the prevention of relapse.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.5390-13.2014
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2014
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  • 4
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    Role of Hippocampal β-Adrenergic and Glucocorticoid Receptors in the Novelty-Induced Enhancement of Fear Extinction
    Society for Neuroscience ; 2015
    In:  The Journal of Neuroscience Vol. 35, No. 21 ( 2015-05-27), p. 8308-8321
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 35, No. 21 ( 2015-05-27), p. 8308-8321
    Abstract: Fear extinction forms a new memory but does not erase the original fear memory. Exposure to novelty facilitates transfer of short-term extinction memory to long-lasting memory. However, the underlying cellular and molecular mechanisms are still unclear. Using a classical contextual fear-conditioning model, we investigated the effect of novelty on long-lasting extinction memory in rats. We found that exposure to a novel environment but not familiar environment 1 h before or after extinction enhanced extinction long-term memory (LTM) and reduced fear reinstatement. However, exploring novelty 6 h before or after extinction had no such effect. Infusion of the β-adrenergic receptor (βAR) inhibitor propranolol and glucocorticoid receptor (GR) inhibitor RU486 into the CA1 area of the dorsal hippocampus before novelty exposure blocked the effect of novelty on extinction memory. Propranolol prevented activation of the hippocampal PKA-CREB pathway, and RU486 prevented activation of the hippocampal extracellular signal-regulated kinase 1/2 (Erk1/2)-CREB pathway induced by novelty exposure. These results indicate that the hippocampal βAR-PKA-CREB and GR-Erk1/2-CREB pathways mediate the extinction-enhancing effect of novelty exposure. Infusion of RU486 or the Erk1/2 inhibitor U0126, but not propranolol or the PKA inhibitor Rp-cAMPS, into the CA1 before extinction disrupted the formation of extinction LTM, suggesting that hippocampal GR and Erk1/2 but not βAR or PKA play critical roles in this process. These results indicate that novelty promotes extinction memory via hippocampal βAR- and GR-dependent pathways, and Erk1/2 may serve as a behavioral tag of extinction.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.0005-15.2015
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2015
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  • 5
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    Chronic Morphine Treatment Impaired Hippocampal Long-Term Potentiation and Spatial Memory via Accumulation of Extracellular Adenosine Acting on Adenosine A 1 Receptors
    Society for Neuroscience ; 2010
    In:  The Journal of Neuroscience Vol. 30, No. 14 ( 2010-04-07), p. 5058-5070
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 30, No. 14 ( 2010-04-07), p. 5058-5070
    Abstract: Chronic exposure to opiates impairs hippocampal long-term potentiation (LTP) and spatial memory, but the underlying mechanisms remain to be elucidated. Given the well known effects of adenosine, an important neuromodulator, on hippocampal neuronal excitability and synaptic plasticity, we investigated the potential effect of changes in adenosine concentrations on chronic morphine treatment-induced impairment of hippocampal CA1 LTP and spatial memory. We found that chronic treatment in mice with either increasing doses (20–100 mg/kg) of morphine for 7 d or equal daily dose (20 mg/kg) of morphine for 12 d led to a significant increase of hippocampal extracellular adenosine concentrations. Importantly, we found that accumulated adenosine contributed to the inhibition of the hippocampal CA1 LTP and impairment of spatial memory retrieval measured in the Morris water maze. Adenosine A 1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine significantly reversed chronic morphine-induced impairment of hippocampal CA1 LTP and spatial memory. Likewise, adenosine deaminase, which converts adenosine into the inactive metabolite inosine, restored impaired hippocampal CA1 LTP. We further found that adenosine accumulation was attributable to the alteration of adenosine uptake but not adenosine metabolisms. Bidirectional nucleoside transporters (ENT2) appeared to play a key role in the reduction of adenosine uptake. Changes in PKC-α/β activity were correlated with the attenuation of the ENT2 function in the short-term (2 h) but not in the long-term (7 d) period after the termination of morphine treatment. This study reveals a potential mechanism by which chronic exposure to morphine leads to impairment of both hippocampal LTP and spatial memory.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.0148-10.2010
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2010
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  • 6
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    A tera–electron volt afterglow from a narrow jet in an extremely bright gamma-ray burst
    American Association for the Advancement of Science (AAAS) ; 2023
    In:  Science Vol. 380, No. 6652 ( 2023-06-30), p. 1390-1396
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 380, No. 6652 ( 2023-06-30), p. 1390-1396
    Abstract: Observations of the bright gamma-ray burst GRB 221009A at tera–electron volt energies show that it contained a very narrow jet.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.adg9328
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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  • 7
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    Peta–electron volt gamma-ray emission from the Crab Nebula
    American Association for the Advancement of Science (AAAS) ; 2021
    In:  Science Vol. 373, No. 6553 ( 2021-07-23), p. 425-430
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 373, No. 6553 ( 2021-07-23), p. 425-430
    Abstract: The Crab Nebula is a bright source of gamma rays powered by the Crab Pulsar’s rotational energy through the formation and termination of a relativistic electron-positron wind. We report the detection of gamma rays from this source with energies from 5 × 10 −4 to 1.1 peta–electron volts with a spectrum showing gradual steepening over three energy decades. The ultrahigh-energy photons imply the presence of a peta–electron volt electron accelerator (a pevatron) in the nebula, with an acceleration rate exceeding 15% of the theoretical limit. We constrain the pevatron’s size between 0.025 and 0.1 parsecs and the magnetic field to ≈110 microgauss. The production rate of peta–electron volt electrons, 2.5 × 10 36 ergs per second, constitutes 0.5% of the pulsar spin-down luminosity, although we cannot exclude a contribution of peta–electron volt protons to the production of the highest-energy gamma rays.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abg5137
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2021
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  • 8
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    De novo mutations across 1,465 diverse genomes reveal mutational insights and reductions in the Amish founder population
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 5 ( 2020-02-04), p. 2560-2569
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 5 ( 2020-02-04), p. 2560-2569
    Abstract: De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.98 to 34.92%, depending on the model) of the genome-wide variation in population-level genetic variation from 41K unrelated TOPMed samples. Genome-wide heterozygosity does correlate with DNM rate, but only explains 〈 1% of variation. While we are underpowered to see small differences, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, we did find significantly fewer DNMs in Amish individuals, even when compared with other Europeans, and even after accounting for parental age and sequencing center. Specifically, we found significant reductions in the number of C→A and T→C mutations in the Amish, which seem to underpin their overall reduction in DNMs. Finally, we calculated near-zero estimates of narrow sense heritability ( h 2 ), which suggest that variation in DNM rate is significantly shaped by nonadditive genetic effects and the environment.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1902766117
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
    detail.hit.zdb_id: 209104-5
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    SSG: 11
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  • 9
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    A Draft Sequence of the Rice Genome ( Oryza sativa L. ssp. indica )
    American Association for the Advancement of Science (AAAS) ; 2002
    In:  Science Vol. 296, No. 5565 ( 2002-04-05), p. 79-92
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 296, No. 5565 ( 2002-04-05), p. 79-92
    Abstract: We have produced a draft sequence of the rice genome for the most widely cultivated subspecies in China, Oryza sativa L. ssp. indica , by whole-genome shotgun sequencing. The genome was 466 megabases in size, with an estimated 46,022 to 55,615 genes. Functional coverage in the assembled sequences was 92.0%. About 42.2% of the genome was in exact 20-nucleotide oligomer repeats, and most of the transposons were in the intergenic regions between genes. Although 80.6% of predicted Arabidopsis thaliana genes had a homolog in rice, only 49.4% of predicted rice genes had a homolog in A. thaliana . The large proportion of rice genes with no recognizable homologs is due to a gradient in the GC content of rice coding sequences.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.1068037
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2002
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
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  • 10
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    Propagated α-synucleinopathy recapitulates REM sleep behaviour disorder followed by parkinsonian phenotypes in mice
    Oxford University Press (OUP) ; 2020
    In:  Brain Vol. 143, No. 11 ( 2020-11-01), p. 3374-3392
    Details
    In: Brain, Oxford University Press (OUP), Vol. 143, No. 11 ( 2020-11-01), p. 3374-3392
    Abstract: Idiopathic rapid eye movement sleep behaviour disorder (RBD) is now recognized as an early manifestation of α-synucleinopathies. Increasing experimental studies demonstrate that manipulative lesion or inactivation of the neurons within the sublaterodorsal tegmental nucleus (also known as the subcoeruleus nucleus in humans) can induce RBD-like behaviours in animals. As current RBD animal models are not established on the basis of α-synucleinopathy, they do not represent the pathological substrate of idiopathic RBD and thus cannot model the phenoconversion to Parkinson’s disease. The purpose of this study was therefore to establish an α-synucleinopathy-based RBD animal model with the potential to convert to parkinsonian disorder. To this end, we first determined the functional neuroanatomical location of the sublaterodorsal tegmental nucleus in wild-type C57BL/6J mice and then validated its function by recapitulating RBD-like behaviours based on this determined nucleus. Next, we injected preformed α-synuclein fibrils into the sublaterodorsal tegmental nucleus and performed regular polysomnographic recordings and parkinsonian behavioural and histopathological studies in these mice. As a result, we recapitulated RBD-like behaviours in the mice and further showed that the α-synucleinopathy and neuron degeneration identified within the sublaterodorsal tegmental nucleus acted as the neuropathological substrates. Subsequent parkinsonian behavioural studies indicated that the α-synucleinopathy-based RBD mouse model were not stationary, but could further progress to display parkinsonian locomotor dysfunction, depression-like disorder, olfactory dysfunction and gastrointestinal dysmotility. Corresponding to that, we determined α-synuclein pathology in the substantia nigra pars compacta, olfactory bulb, enteral neuroplexus and dorsal motor nucleus of vagus nerve, which could underlie the parkinsonian manifestations in mice. In conclusion, we established a novel α-synucleinopathy-based RBD mouse model and further demonstrated the phenoconversion of RBD to Parkinson’s disease in this animal model.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awaa283
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    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 1474117-9
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