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  • Linguistics  (274)
  • Biology  (274)
  • 1
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    Online Resource
    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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  • 2
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    Online Resource
    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
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    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2021
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  • 3
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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:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
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  • 4
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    A Particle Consistent with the Higgs Boson Observed with the ATLAS Detector at the Large Hadron Collider
    American Association for the Advancement of Science (AAAS) ; 2012
    In:  Science Vol. 338, No. 6114 ( 2012-12-21), p. 1576-1582
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 338, No. 6114 ( 2012-12-21), p. 1576-1582
    Abstract: The ATLAS detector measured several characteristic decay products of the standard model Higgs boson, allowing its mass to be determined.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.1232005
    RVK:
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2012
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  • 5
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    Modulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors
    American Association for the Advancement of Science (AAAS) ; 2023
    In:  Science Vol. 381, No. 6662 ( 2023-09-08)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 381, No. 6662 ( 2023-09-08)
    Abstract: KRAS is one of the most frequently mutated genes in human cancer. Despite advances in the development of inhibitors that directly target mutant KRAS and the approval of KRAS G12C inhibitors sotorasib and adagrasib for the treatment of KRAS G12C -mutant non–small cell lung cancer (NSCLC) patients, multiple lines of clinical and preclinical evidence demonstrate that adaptive resistance to KRAS inhibitors (KRASi) is rapid and almost inevitable. The heterogeneous resistance mechanisms in patients and dose-limiting toxicity associated with targeting multiple KRASi resistance pathways—such as receptor tyrosine kinases (RTKs), extracellular signal–regulated kinase (ERK), and AKT–remain a major barrier to progress. RATIONALE Most cancers require a balanced protein homeostasis (proteostasis) network to maintain oncogenic growth. Therapeutic insults often disrupt proteostasis and induce proteotoxic stresses. Residual drug-tolerant cells must overcome imbalances in the proteostasis network to maintain survival. How a proteostasis network is orchestrated by driver oncogenes and the proteostasis reprogramming mechanisms that bypass oncogene addiction and allow for acquired resistance to targeted therapies remain largely unknown. In this study, we investigated the regulation of proteostasis by oncogenic KRAS and the rewiring of proteostasis network underlying the acquired resistance to KRAS inhibition. RESULTS We show that oncogenic KRAS is critical for protein quality control in cancer cells. Genetic or pharmacological inhibition of oncogenic KRAS rapidly inactivated both cytosolic and endoplasmic reticulum (ER) protein quality control machinery, two essential components of the proteostasis network, through inhibition of the master regulators heat shock factor 1 (HSF1) and inositol-requiring enzyme 1α (IRE1α). However, residue cancer cells that survive KRASi directly reactivated IRE1α through an ER stress–independent phosphorylation mechanism that reestablished proteostasis and sustained acquired resistance to KRAS inhibition. We identified four oncogenic signaling–regulated phosphorylation sites in IRE1α (Ser 525 , Ser 529 , Ser 549 , and Thr 973 ) that are distinct from IRE1α autophosphorylation sites but are required for enhanced protein stability. The phosphorylation of IRE1α at these sites prevents IRE1α binding with the SEL1L/HRD1 E3 ligase complex, thus impairing the ubiquitination-dependent degradation of IRE1α and stabilizing the protein. These sites are the convergence points of multiple resistance mechanisms in KRASi-resistant tumors. RTK-mediated reactivation of ERK and hyperactivation of AKT sustained the unconventional phosphorylation of IRE1α in the KRASi-resistant tumors, which consequently restored its protein stability and reestablished proteostasis. Genetic or pharmacological suppression of IRE1α collapsed the rewired proteostasis network and overcame resistance to KRAS–MAPK (mitogen-activated protein kinase) inhibitors. CONCLUSION This study reveals the direct cross-talk between oncogenic signaling and the protein quality control machinery and uncovers the mechanisms that account for the proteostasis rewiring in response to KRAS inhibition. Multiple resistance mechanisms converge on IRE1α through ER stress–independent phosphorylation to restore proteostasis and promote KRASi-resistant tumor growth. Targeting this key convergence point represents an effective therapeutic strategy to overcome KRASi resistance. Proteostasis reprogramming upon KRAS inhibition. Inhibition of oncogenic KRAS inactivates both cytosolic and ER protein quality control machinery by inhibiting HSF1 and IRE1α. Residual cells that survive KRASi directly restore IRE1α phosphorylation through receptor tyrosine kinase–mediated reactivation of ERK and hyperactivation of AKT, preventing IRE1α from SEL1L/HRD1–mediated ubiquitination and degradation. Multiple heterogeneous resistance pathways converge on IRE1α to reestablish proteostasis and promote resistance to KRASi.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abn4180
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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  • 6
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    Reduced default mode network functional connectivity in patients with recurrent major depressive disorder
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 18 ( 2019-04-30), p. 9078-9083
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 18 ( 2019-04-30), p. 9078-9083
    Abstract: Major depressive disorder (MDD) is common and disabling, but its neuropathophysiology remains unclear. Most studies of functional brain networks in MDD have had limited statistical power and data analysis approaches have varied widely. The REST-meta-MDD Project of resting-state fMRI (R-fMRI) addresses these issues. Twenty-five research groups in China established the REST-meta-MDD Consortium by contributing R-fMRI data from 1,300 patients with MDD and 1,128 normal controls (NCs). Data were preprocessed locally with a standardized protocol before aggregated group analyses. We focused on functional connectivity (FC) within the default mode network (DMN), frequently reported to be increased in MDD. Instead, we found decreased DMN FC when we compared 848 patients with MDD to 794 NCs from 17 sites after data exclusion. We found FC reduction only in recurrent MDD, not in first-episode drug-naïve MDD. Decreased DMN FC was associated with medication usage but not with MDD duration. DMN FC was also positively related to symptom severity but only in recurrent MDD. Exploratory analyses also revealed alterations in FC of visual, sensory-motor, and dorsal attention networks in MDD. We confirmed the key role of DMN in MDD but found reduced rather than increased FC within the DMN. Future studies should test whether decreased DMN FC mediates response to treatment. All R-fMRI indices of data contributed by the REST-meta-MDD consortium are being shared publicly via the R-fMRI Maps Project.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1900390116
    RVK:
    TA 1000
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    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
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  • 7
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    Synaptotagmin-7 deficiency induces mania-like behavioral abnormalities through attenuating GluN2B activity
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 49 ( 2020-12-08), p. 31438-31447
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 49 ( 2020-12-08), p. 31438-31447
    Abstract: Synaptotagmin-7 (Syt7) probably plays an important role in bipolar-like behavioral abnormalities in mice; however, the underlying mechanisms for this have remained elusive. Unlike antidepressants that cause mood overcorrection in bipolar depression, N -methyl- d -aspartate receptor (NMDAR)-targeted drugs show moderate clinical efficacy, for unexplained reasons. Here we identified Syt7 single nucleotide polymorphisms (SNPs) in patients with bipolar disorder and demonstrated that mice lacking Syt7 or expressing the SNPs showed GluN2B-NMDAR dysfunction, leading to antidepressant behavioral consequences and avoidance of overcorrection by NMDAR antagonists. In human induced pluripotent stem cell (iPSC)-derived and mouse hippocampal neurons, Syt7 and GluN2B-NMDARs were localized to the peripheral synaptic region, and Syt7 triggered multiple forms of glutamate release to efficiently activate the juxtaposed GluN2B-NMDARs. Thus, while Syt7 deficiency and SNPs induced GluN2B-NMDAR dysfunction in mice, patient iPSC-derived neurons showed Syt7 deficit-induced GluN2B-NMDAR hypoactivity that was rescued by Syt7 overexpression. Therefore, Syt7 deficits induced mania-like behaviors in mice by attenuating GluN2B activity, which enabled NMDAR antagonists to avoid mood overcorrection.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2016416117
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
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  • 8
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    High-performance and low-power source-gated transistors enabled by a solution-processed metal oxide homojunction
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 3 ( 2023-01-17)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 3 ( 2023-01-17)
    Abstract: Cost-effective fabrication of mechanically flexible low-power electronics is important for emerging applications including wearable electronics, artificial intelligence, and the Internet of Things. Here, solution-processed source-gated transistors (SGTs) with an unprecedented intrinsic gain of ~2,000, low saturation voltage of +0.8 ± 0.1 V, and a ~25.6 μW power consumption are realized using an indium oxide In 2 O 3 /In 2 O 3 :polyethylenimine (PEI) blend homojunction with Au contacts on Si/SiO 2 . Kelvin probe force microscopy confirms source-controlled operation of the SGT and reveals that PEI doping leads to more effective depletion of the reverse-biased Schottky contact source region. Furthermore, using a fluoride-doped AlO x gate dielectric, rigid (on a Si substrate) and flexible (on a polyimide substrate) SGTs were fabricated. These devices exhibit a low driving voltage of +2 V and power consumption of ~11.5 μW, yielding inverters with an outstanding voltage gain of 〉 5,000. Furthermore, electrooculographic (EOG) signal monitoring can now be demonstrated using an SGT inverter, where a ~1.0 mV EOG signal is amplified to over 300 mV, indicating significant potential for applications in wearable medical sensing and human–computer interfacing.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2216672120
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
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  • 9
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    Synaptotagmin-7 is a key factor for bipolar-like behavioral abnormalities in mice
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 8 ( 2020-02-25), p. 4392-4399
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 8 ( 2020-02-25), p. 4392-4399
    Abstract: The pathogenesis of bipolar disorder (BD) has remained enigmatic, largely because genetic animal models based on identified susceptible genes have often failed to show core symptoms of spontaneous mood cycling. However, pedigree and induced pluripotent stem cell (iPSC)-based analyses have implicated that dysfunction in some key signaling cascades might be crucial for the disease pathogenesis in a subpopulation of BD patients. We hypothesized that the behavioral abnormalities of patients and the comorbid metabolic abnormalities might share some identical molecular mechanism. Hence, we investigated the expression of insulin/synapse dually functioning genes in neurons derived from the iPSCs of BD patients and the behavioral phenotype of mice with these genes silenced in the hippocampus. By these means, we identified synaptotagmin-7 (Syt7) as a candidate risk factor for behavioral abnormalities. We then investigated Syt7 knockout (KO) mice and observed nocturnal manic-like and diurnal depressive-like behavioral fluctuations in a majority of these animals, analogous to the mood cycling symptoms of BD. We treated the Syt7 KO mice with clinical BD drugs including olanzapine and lithium, and found that the drug treatments could efficiently regulate the behavioral abnormalities of the Syt7 KO mice. To further verify whether Syt7 deficits existed in BD patients, we investigated the plasma samples of 20 BD patients and found that the Syt7 mRNA level was significantly attenuated in the patient plasma compared to the healthy controls. We therefore concluded that Syt7 is likely a key factor for the bipolar-like behavioral abnormalities.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1918165117
    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
    detail.hit.zdb_id: 1461794-8
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  • 10
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    High fried food consumption impacts anxiety and depression due to lipid metabolism disturbance and neuroinflammation
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 18 ( 2023-05-02)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 18 ( 2023-05-02)
    Abstract: Western dietary patterns have been unfavorably linked with mental health. However, the long-term effects of habitual fried food consumption on anxiety and depression and underlying mechanisms remain unclear. Our population-based study with 140,728 people revealed that frequent fried food consumption, especially fried potato consumption, is strongly associated with 12% and 7% higher risk of anxiety and depression, respectively. The associations were more pronounced among male and younger consumers. Consistently, long-term exposure to acrylamide, a representative food processing contaminant in fried products, exacerbates scototaxis and thigmotaxis, and further impairs exploration ability and sociality of adult zebrafish, showing anxiety- and depressive-like behaviors. Moreover, treatment with acrylamide significantly down-regulates the gene expression of tjp2a related to the permeability of blood–brain barrier. Multiomics analysis showed that chronic exposure to acrylamide induces cerebral lipid metabolism disturbance and neuroinflammation. PPAR signaling pathway mediates acrylamide-induced lipid metabolism disorder in the brain of zebrafish. Especially, chronic exposure to acrylamide dysregulates sphingolipid and phospholipid metabolism, which plays important roles in the development of anxiety and depression symptoms. In addition, acrylamide promotes lipid peroxidation and oxidation stress, which participate in cerebral neuroinflammation. Acrylamide dramatically increases the markers of lipid peroxidation, including (±)5-HETE, 11(S)-HETE, 5-oxoETE, and up-regulates the expression of proinflammatory lipid mediators such as (±)12-HETE and 14(S)-HDHA, indicating elevated cerebral inflammatory status after chronic exposure to acrylamide. Together, these results both epidemiologically and mechanistically provide strong evidence to unravel the mechanism of acrylamide-triggered anxiety and depression, and highlight the significance of reducing fried food consumption for mental health.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2221097120
    RVK:
    TA 1000
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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