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  • 1
    Online Resource
    Online Resource
    2D materials–based homogeneous transistor-memory architecture for neuromorphic hardware
    American Association for the Advancement of Science (AAAS) ; 2021
    In:  Science Vol. 373, No. 6561 ( 2021-09-17), p. 1353-1358
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 373, No. 6561 ( 2021-09-17), p. 1353-1358
    Abstract: In neuromorphic hardware, peripheral circuits and memories based on heterogeneous devices are generally physically separated. Thus, exploration of homogeneous devices for these components is key for improving module integration and resistance matching. Inspired by the ferroelectric proximity effect on two-dimensional (2D) materials, we present a tungsten diselenide–on–lithium niobate cascaded architecture as a basic device that functions as a nonlinear transistor, assisting the design of operational amplifiers for analog signal processing (ASP). This device also functions as a nonvolatile memory cell, achieving memory operating (MO) functionality. On the basis of this homogeneous architecture, we also investigated an ASP-MO integrated system for binary classification and the design of ternary content-addressable memory for potential use in neuromorphic hardware.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abg3161
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2021
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  • 2
    Online Resource
    Online Resource
    SARS-CoV-2 M pro inhibitors with antiviral activity in a transgenic mouse model
    American Association for the Advancement of Science (AAAS) ; 2021
    In:  Science Vol. 371, No. 6536 ( 2021-03-26), p. 1374-1378
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 371, No. 6536 ( 2021-03-26), p. 1374-1378
    Abstract: The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continually poses serious threats to global public health. The main protease (M pro ) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing M pro inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 M pro activity in vitro, with 50% inhibitory concentration values ranging from 7.6 to 748.5 nM. The cocrystal structure of M pro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a transgenic mouse model of SARS-CoV-2 infection, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abf1611
    RVK:
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2021
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  • 3
    Online Resource
    Online Resource
    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:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
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  • 4
    Online Resource
    Online Resource
    A Semi-Floating Gate Transistor for Low-Voltage Ultrafast Memory and Sensing Operation
    American Association for the Advancement of Science (AAAS) ; 2013
    In:  Science Vol. 341, No. 6146 ( 2013-08-09), p. 640-643
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 341, No. 6146 ( 2013-08-09), p. 640-643
    Abstract: As the semiconductor devices of integrated circuits approach the physical limitations of scaling, alternative transistor and memory designs are needed to achieve improvements in speed, density, and power consumption. We report on a transistor that uses an embedded tunneling field-effect transistor for charging and discharging the semi-floating gate. This transistor operates at low voltages (≤2.0 volts), with a large threshold voltage window of 3.1 volts, and can achieve ultra–high-speed writing operations (on time scales of ~1 nanosecond). A linear dependence of drain current on light intensity was observed when the transistor was exposed to light, so possible applications include image sensing with high density and performance.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.1240961
    RVK:
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2013
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  • 5
    Online Resource
    Online Resource
    An allosteric PGAM1 inhibitor effectively suppresses pancreatic ductal adenocarcinoma
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 46 ( 2019-11-12), p. 23264-23273
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 46 ( 2019-11-12), p. 23264-23273
    Abstract: Glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) plays a critical role in cancer metabolism by coordinating glycolysis and biosynthesis. A well-validated PGAM1 inhibitor, however, has not been reported for treating pancreatic ductal adenocarcinoma (PDAC), which is one of the deadliest malignancies worldwide. By uncovering the elevated PGAM1 expressions were statistically related to worse prognosis of PDAC in a cohort of 50 patients, we developed a series of allosteric PGAM1 inhibitors by structure-guided optimization. The compound KH3 significantly suppressed proliferation of various PDAC cells by down-regulating the levels of glycolysis and mitochondrial respiration in correlation with PGAM1 expression. Similar to PGAM1 depletion, KH3 dramatically hampered the canonic pathways highly involved in cancer metabolism and development. Additionally, we observed the shared expression profiles of several signature pathways at 12 h after treatment in multiple PDAC primary cells of which the matched patient-derived xenograft (PDX) models responded similarly to KH3 in the 2 wk treatment. The better responses to KH3 in PDXs were associated with higher expression of PGAM1 and longer/stronger suppressions of cancer metabolic pathways. Taken together, our findings demonstrate a strategy of targeting cancer metabolism by PGAM1 inhibition in PDAC. Also, this work provided “proof of concept” for the potential application of metabolic treatment in clinical practice.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1914557116
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
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  • 6
    Online Resource
    Online Resource
    Single hormone or synthetic agonist induces G s /G i coupling selectivity of EP receptors via distinct binding modes and propagating paths
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 30 ( 2023-07-25)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 30 ( 2023-07-25)
    Abstract: To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize the same hormone, and 2) different cellular effectors couple to the same hormone–receptor pair [R.P. Xiao, Sci STKE 2001 , re15 (2001); L. Hein, J. D. Altman, B.K. Kobilka, Nature 402 , 181–184 (1999); Y. Daaka, L. M. Luttrell, R. J. Lefkowitz, Nature 390 , 88–91 (1997)]. Not only these questions lie in the heart of hormone actions and receptor signaling but also dissecting mechanisms underlying these questions could offer therapeutic routes for refractory diseases, such as kidney injury (KI) or X-linked nephrogenic diabetes insipidus (NDI). Here, we identified that G s -biased signaling, but not G i activation downstream of EP4, showed beneficial effects for both KI and NDI treatments. Notably, by solving Cryo-electron microscope (cryo-EM) structures of EP3-G i , EP4-G s , and EP4-G i in complex with endogenous prostaglandin E 2 (PGE 2 )or two synthetic agonists and comparing with PGE 2 -EP2-G s structures, we found that unique primary sequences of prostaglandin E2 receptor (EP) receptors and distinct conformational states of the EP4 ligand pocket govern the G s /G i transducer coupling selectivity through different structural propagation paths, especially via TM6 and TM7, to generate selective cytoplasmic structural features. In particular, the orientation of the PGE 2 ω-chain and two distinct pockets encompassing agonist L902688 of EP4 were differentiated by their G s /G i coupling ability. Further, we identified common and distinct features of cytoplasmic side of EP receptors for G s /G i coupling and provide a structural basis for selective and biased agonist design of EP4 with therapeutic potential.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2216329120
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
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  • 7
    Online Resource
    Online Resource
    Modality- and Task-specific Brain Regions Involved in Chinese Lexical Processing
    MIT Press ; 2009
    In:  Journal of Cognitive Neuroscience Vol. 21, No. 8 ( 2009-08-01), p. 1473-1487
    Details
    In: Journal of Cognitive Neuroscience, MIT Press, Vol. 21, No. 8 ( 2009-08-01), p. 1473-1487
    Abstract: fMRI was used to examine lexical processing in native adult Chinese speakers. A 2 task (semantics and phonology) × 2 modality (visual and auditory) within-subject design was adopted. The semantic task involved a meaning association judgment and the phonological task involved a rhyming judgment to two sequentially presented words. The overall effect across tasks and modalities was used to identify seven ROIs, including the left fusiform gyrus (FG), the left superior temporal gyrus (STG), the left ventral inferior frontal gyrus (VIFG), the left middle temporal gyrus (MTG), the left dorsal inferior frontal gyrus (DIFG), the left inferior parietal lobule (IPL), and the left middle frontal gyrus (MFG). ROI analyses revealed two modality-specific areas, FG for visual and STG for auditory, and three task-specific areas, IPL and DIFG for phonology and VIFG for semantics. Greater DIFG activation was associated with conflicting tonal information between words for the auditory rhyming task, suggesting this region's role in strategic phonological processing, and greater VIFG activation was correlated with lower association between words for both the auditory and the visual meaning task, suggesting this region's role in retrieval and selection of semantic representations. The modality- and task-specific effects in Chinese revealed by this study are similar to those found in alphabetical languages. Unlike English, we found that MFG was both modality- and task-specific, suggesting that MFG may be responsible for the visuospatial analysis of Chinese characters and orthography-to-phonology integration at a syllabic level.
    Type of Medium: Online Resource
    ISSN: 0898-929X , 1530-8898
    URL: Article
    DOI: 10.1162/jocn.2009.21141
    Language: English
    Publisher: MIT Press
    Publication Date: 2009
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  • 8
    Online Resource
    Online Resource
    Structural insight into precursor tRNA processing by yeast ribonuclease P
    American Association for the Advancement of Science (AAAS) ; 2018
    In:  Science Vol. 362, No. 6415 ( 2018-11-09)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 362, No. 6415 ( 2018-11-09)
    Abstract: Ribonuclease P (RNase P) is a universal ribozyme responsible for processing the 5′-leader of pre–transfer RNA (pre-tRNA). Here, we report the 3.5-angstrom cryo–electron microscopy structures of Saccharomyces cerevisiae RNase P alone and in complex with pre-tRNA Phe . The protein components form a hook-shaped architecture that wraps around the RNA and stabilizes RNase P into a “measuring device” with two fixed anchors that recognize the L-shaped pre-tRNA. A universally conserved uridine nucleobase and phosphate backbone in the catalytic center together with the scissile phosphate and the O3′ leaving group of pre-tRNA jointly coordinate two catalytic magnesium ions. Binding of pre-tRNA induces a conformational change in the catalytic center that is required for catalysis. Moreover, simulation analysis suggests a two-metal-ion S N 2 reaction pathway of pre-tRNA cleavage. These results not only reveal the architecture of yeast RNase P but also provide a molecular basis of how the 5′-leader of pre-tRNA is processed by eukaryotic RNase P.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aat6678
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2018
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  • 9
    Online Resource
    Online Resource
    Double-negative-index ceramic aerogels for thermal superinsulation
    American Association for the Advancement of Science (AAAS) ; 2019
    In:  Science Vol. 363, No. 6428 ( 2019-02-15), p. 723-727
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 363, No. 6428 ( 2019-02-15), p. 723-727
    Abstract: Ceramic aerogels are attractive for thermal insulation but plagued by poor mechanical stability and degradation under thermal shock. In this study, we designed and synthesized hyperbolic architectured ceramic aerogels with nanolayered double-pane walls with a negative Poisson’s ratio (−0.25) and a negative linear thermal expansion coefficient (−1.8 × 10 −6 per °C). Our aerogels display robust mechanical and thermal stability and feature ultralow densities down to ~0.1 milligram per cubic centimeter, superelasticity up to 95%, and near-zero strength loss after sharp thermal shocks (275°C per second) or intense thermal stress at 1400°C, as well as ultralow thermal conductivity in vacuum [~2.4 milliwatts per meter-kelvin (mW/m·K)] and in air (~20 mW/m·K). This robust material system is ideal for thermal superinsulation under extreme conditions, such as those encountered by spacecraft.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aav7304
    RVK:
    TA 1000
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2019
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    SSG: 11
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  • 10
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    Online Resource
    A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2
    American Association for the Advancement of Science (AAAS) ; 2020
    In:  Science Vol. 368, No. 6496 ( 2020-06-12), p. 1274-1278
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 368, No. 6496 ( 2020-06-12), p. 1274-1278
    Abstract: Neutralizing antibodies could potentially be used as antivirals against the coronavirus disease 2019 (COVID-19) pandemic. Here, we report isolation of four human-origin monoclonal antibodies from a convalescent patient, all of which display neutralization abilities. The antibodies B38 and H4 block binding between the spike glycoprotein receptor binding domain (RBD) of the virus and the cellular receptor angiotensin-converting enzyme 2 (ACE2). A competition assay indicated different epitopes on the RBD for these two antibodies, making them a potentially promising virus-targeting monoclonal antibody pair for avoiding immune escape in future clinical applications. Moreover, a therapeutic study in a mouse model validated that these antibodies can reduce virus titers in infected lungs. The RBD-B38 complex structure revealed that most residues on the epitope overlap with the RBD-ACE2 binding interface, explaining the blocking effect and neutralizing capacity. Our results highlight the promise of antibody-based therapeutics and provide a structural basis for rational vaccine design.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abc2241
    RVK:
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2020
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    detail.hit.zdb_id: 2060783-0
    SSG: 11
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