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  • 1
    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:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
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  • 2
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    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:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
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  • 3
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    Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 36 ( 2023-09-05)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 36 ( 2023-09-05)
    Abstract: Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2302720120
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
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  • 4
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    A pair of dopamine neurons mediate chronic stress signals to induce learning deficit in Drosophila melanogaster
    Proceedings of the National Academy of Sciences ; 2021
    In:  Proceedings of the National Academy of Sciences Vol. 118, No. 42 ( 2021-10-19)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 42 ( 2021-10-19)
    Abstract: Chronic stress could induce severe cognitive impairments. Despite extensive investigations in mammalian models, the underlying mechanisms remain obscure. Here, we show that chronic stress could induce dramatic learning and memory deficits in Drosophila melanogaster . The chronic stress–induced learning deficit (CSLD) is long lasting and associated with other depression-like behaviors. We demonstrated that excessive dopaminergic activity provokes susceptibility to CSLD. Remarkably, a pair of PPL1-γ1pedc dopaminergic neurons that project to the mushroom body (MB) γ1pedc compartment play a key role in regulating susceptibility to CSLD so that stress-induced PPL1-γ1pedc hyperactivity facilitates the development of CSLD. Consistently, the mushroom body output neurons (MBON) of the γ1pedc compartment, MBON-γ1pedc 〉 α/β neurons, are important for modulating susceptibility to CSLD. Imaging studies showed that dopaminergic activity is necessary to provoke the development of chronic stress–induced maladaptations in the MB network. Together, our data support that PPL1-γ1pedc mediates chronic stress signals to drive allostatic maladaptations in the MB network that lead to CSLD.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2023674118
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2021
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  • 5
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    S-Nitrosylation of Divalent Metal Transporter 1 Enhances Iron Uptake to Mediate Loss of Dopaminergic Neurons and Motoric Deficit
    Society for Neuroscience ; 2018
    In:  The Journal of Neuroscience Vol. 38, No. 39 ( 2018-09-26), p. 8364-8377
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 38, No. 39 ( 2018-09-26), p. 8364-8377
    Abstract: Elevated iron deposition has been reported in Parkinson's disease (PD). However, the route of iron uptake leading to high deposition in the substantia nigra is unresolved. Here, we show a mechanism in enhanced Fe 2+ uptake via S-nitrosylation of divalent metal transporter 1 (DMT1). While DMT1 could be S-nitrosylated by exogenous nitric oxide donors, in human PD brains, endogenously S-nitrosylated DMT1 was detected in postmortem substantia nigra. Patch-clamp electrophysiological recordings and iron uptake assays confirmed increased Mn 2+ or Fe 2+ uptake through S-nitrosylated DMT1. We identified two major S-nitrosylation sites, C23 and C540, by mass spectrometry, and DMT1 C23A or C540A substitutions abolished nitric oxide (NO)-mediated DMT1 current increase. To evaluate in vivo significance, lipopolysaccharide (LPS) was stereotaxically injected into the substantia nigra of female and male mice to induce inflammation and production of NO. The intranigral LPS injection resulted in corresponding increase in Fe 2+ deposition, JNK activation, dopaminergic neuronal loss and deficit in motoric activity, and these were rescued by the NO synthase inhibitor l -NAME or by the DMT1-selective blocker ebselen. Lentiviral knockdown of DMT1 abolished LPS-induced dopaminergic neuron loss. SIGNIFICANCE STATEMENT Neuroinflammation and high cytoplasmic Fe 2+ levels have been implicated in the initiation and progression of neurodegenerative diseases. Here, we report the unexpected enhancement of the functional activity of transmembrane divalent metal transporter 1 (DMT1) by S-nitrosylation. We demonstrated that S-nitrosylation increased DMT1-mediated Fe 2+ uptake, and two cysteines were identified by mass spectrometry to be the sites for S-nitrosylation and for enhanced iron uptake. One conceptual advance is that while DMT1 activity could be increased by external acidification because the gating of the DMT1 transporter is proton motive, we discovered that DMT1 activity could also be enhanced by S-nitrosylation. Significantly, lipopolysaccharide-induced nitric oxide (NO)-mediated neuronal death in the substantia nigra could be ameliorated by using l -NAME, a NO synthase inhibitor, or by ebselen, a DMT1-selective blocker.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.3262-17.2018
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2018
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  • 6
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    Prediction of Alzheimer's disease using multi-variants from a Chinese genome-wide association study
    Oxford University Press (OUP) ; 2021
    In:  Brain Vol. 144, No. 3 ( 2021-04-12), p. 924-937
    Details
    In: Brain, Oxford University Press (OUP), Vol. 144, No. 3 ( 2021-04-12), p. 924-937
    Abstract: Previous genome-wide association studies have identified dozens of susceptibility loci for sporadic Alzheimer’s disease, but few of these loci have been validated in longitudinal cohorts. Establishing predictive models of Alzheimer’s disease based on these novel variants is clinically important for verifying whether they have pathological functions and provide a useful tool for screening of disease risk. In the current study, we performed a two-stage genome-wide association study of 3913 patients with Alzheimer’s disease and 7593 controls and identified four novel variants (rs3777215, rs6859823, rs234434, and rs2255835; Pcombined = 3.07 × 10−19, 2.49 × 10−23, 1.35 × 10−67, and 4.81 × 10−9, respectively) as well as nine variants in the apolipoprotein E region with genome-wide significance (P  & lt; 5.0 × 10−8). Literature mining suggested that these novel single nucleotide polymorphisms are related to amyloid precursor protein transport and metabolism, antioxidation, and neurogenesis. Based on their possible roles in the development of Alzheimer’s disease, we used different combinations of these variants and the apolipoprotein E status and successively built 11 predictive models. The predictive models include relatively few single nucleotide polymorphisms useful for clinical practice, in which the maximum number was 13 and the minimum was only four. These predictive models were all significant and their peak of area under the curve reached 0.73 both in the first and second stages. Finally, these models were validated using a separate longitudinal cohort of 5474 individuals. The results showed that individuals carrying risk variants included in the models had a shorter latency and higher incidence of Alzheimer’s disease, suggesting that our models can predict Alzheimer’s disease onset in a population with genetic susceptibility. The effectiveness of the models for predicting Alzheimer’s disease onset confirmed the contributions of these identified variants to disease pathogenesis. In conclusion, this is the first study to validate genome-wide association study-based predictive models for evaluating the risk of Alzheimer’s disease onset in a large Chinese population. The clinical application of these models will be beneficial for individuals harbouring these risk variants, and particularly for young individuals seeking genetic consultation.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awaa364
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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  • 7
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    Dirac-source field-effect transistors as energy-efficient, high-performance electronic switches
    American Association for the Advancement of Science (AAAS) ; 2018
    In:  Science Vol. 361, No. 6400 ( 2018-07-27), p. 387-392
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 361, No. 6400 ( 2018-07-27), p. 387-392
    Abstract: An efficient way to reduce the power consumption of electronic devices is to lower the supply voltage, but this voltage is restricted by the thermionic limit of subthreshold swing (SS), 60 millivolts per decade, in field-effect transistors (FETs). We show that a graphene Dirac source (DS) with a much narrower electron density distribution around the Fermi level than that of conventional FETs can lower SS. A DS-FET with a carbon nanotube channel provided an average SS of 40 millivolts per decade over four decades of current at room temperature and high device current I 60 of up to 40 microamperes per micrometer at 60 millivolts per decade. When compared with state-of-the-art silicon 14-nanometer node FETs, a similar on-state current I on is realized but at a much lower supply voltage of 0.5 volts (versus 0.7 volts for silicon) and a much steeper SS below 35 millivolts per decade in the off-state.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aap9195
    RVK:
    TA 1000
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2018
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  • 8
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    Advancing Our Understanding of Culture Mixing
    SAGE Publications ; 2016
    In:  Journal of Cross-Cultural Psychology Vol. 47, No. 10 ( 2016-11), p. 1257-1267
    Details
    In: Journal of Cross-Cultural Psychology, SAGE Publications, Vol. 47, No. 10 ( 2016-11), p. 1257-1267
    Abstract: Globalization has rendered culture mixing a pervading and overwhelming phenomenon. Culture mixing refers to the coexistence of representative symbols of different cultures in the same space at the same time. It reflects the new paradigm of polyculturalism in the culture and psychology research. The articles in this issue offer nuanced understandings to features of the culture mixing stimuli, personal and situational factors that affect responses to culture mixing, and the sociocultural and psychological consequences of culture mixing. We discuss how these articles provide a new context that extends existing psychological theories and set the stage for the burgeoning psychological inquiry of culture mixing. Future research is needed to uncover how different cultural elements are mixed and how ecological factors affect responses to culture mixing, to investigate the underlying psychological mechanisms of culture mixing, and use multiple methods at various levels of analysis to uncover the dynamic, interactive culturally mixed processes.
    Type of Medium: Online Resource
    ISSN: 0022-0221 , 1552-5422
    URL: Article
    DOI: 10.1177/0022022116670514
    RVK:
    CL 1000
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2016
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  • 9
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    Examining the generalizability of research findings from archival data
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 30 ( 2022-07-26)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 30 ( 2022-07-26)
    Abstract: This initiative examined systematically the extent to which a large set of archival research findings generalizes across contexts. We repeated the key analyses for 29 original strategic management effects in the same context (direct reproduction) as well as in 52 novel time periods and geographies; 45% of the reproductions returned results matching the original reports together with 55% of tests in different spans of years and 40% of tests in novel geographies. Some original findings were associated with multiple new tests. Reproducibility was the best predictor of generalizability—for the findings that proved directly reproducible, 84% emerged in other available time periods and 57% emerged in other geographies. Overall, only limited empirical evidence emerged for context sensitivity. In a forecasting survey, independent scientists were able to anticipate which effects would find support in tests in new samples.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2120377119
    RVK:
    TA 1000
    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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  • 10
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    Dissecting yield-associated loci in super hybrid rice by resequencing recombinant inbred lines and improving parental genome sequences
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 35 ( 2013-08-27), p. 14492-14497
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 35 ( 2013-08-27), p. 14492-14497
    Abstract: The growing world population and shrinkage of arable land demand yield improvement of rice, one of the most important staple crops. To elucidate the genetic basis of yield and uncover its associated loci in rice, we resequenced the core recombinant inbred lines of Liang–You–Pei–Jiu , the widely cultivated super hybrid rice, and constructed a high-resolution linkage map. We detected 43 yield-associated quantitative trait loci, of which 20 are unique. Based on the high-density physical map, the genome sequences of paternal variety 93–11 and maternal cultivar PA64s of Liang–You–Pei–Jiu were significantly improved. The large recombinant inbred line population combined with plentiful high-quality single nucleotide polymorphisms and insertions/deletions between parental genomes allowed us to fine-map two quantitative trait loci, qSN8 and qSPB1 , and to identify days to heading8 and lax panicle1 as candidate genes, respectively. The quantitative trait locus qSN8 was further confirmed to be days to heading8 by a complementation test. Our study provided an ideal platform for molecular breeding by targeting and dissecting yield-associated loci in rice.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1306579110
    RVK:
    TA 1000
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
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    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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